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Nikparast A, Razavi M, Sohouli MH, Hekmatdoost A, Dehghan P, Tohidi M, Rouhani P, Asghari G. The association between dietary intake of branched-chain amino acids and the odds of nonalcoholic fatty liver disease among overweight and obese children and adolescents. J Diabetes Metab Disord 2025; 24:19. [PMID: 39712343 PMCID: PMC11659539 DOI: 10.1007/s40200-024-01516-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 11/08/2024] [Indexed: 12/24/2024]
Abstract
Objectives Dietary supplementation with branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, has shown potential benefits for the metabolic profile. However, emerging population-based studies suggest that BCAAs may mediate pathways related to cardiometabolic risk factors, possibly due to their involvement in the dysregulation of insulin metabolic pathways. This study aimed to investigate the association between BCAAs intake and the odds of nonalcoholic fatty liver disease (NAFLD) in children and adolescents with overweight and obesity. Methods This cross-sectional study encompassed individuals aged 6 to 18 years with WHO body mass index (BMI)-for-age z-score ≥ 1. NAFLD diagnosis was done using an ultrasonography scan of the liver and gastroenterologist confirmation. Dietary BCAAs intake was assessed using a validated 147-item food frequency questionnaire. Logistic regression models, adjusted for potential confounders, were used to estimate the odds ratios (OR) and 95% confidence interval (CI) of NAFLD across quartiles of BCAAs intake. Results A total of 505 (52.9% boys) with mean ± SD age and BMI-for-age-Z-score of 10.0 ± 2.3 and 2.70 ± 1.01, respectively, were enrolled. After adjusting for potential confounders, participants in the highest quartile of total dietary BCAAs (OR: 1.87;95%CI:1.06-3.28) and leucine (OR: 1.84;95%CI:1.03-3.29) intake had greater odds of developing NAFLD compared with those in the lowest quartile. There was no significant association between dietary valine and isoleucine intake and the odds of NAFLD. Conclusions The study findings suggest that increased dietary intake of BCAAs, particularly leucine, may have detrimental effects on the development of NAFLD.
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Affiliation(s)
- Ali Nikparast
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Pediatric Gastroenterology and Hepatology Research Center Pediatrics Centre of Excellence Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Razavi
- Growth and development research center, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hassan Sohouli
- Pediatric Gastroenterology and Hepatology Research Center Pediatrics Centre of Excellence Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Azita Hekmatdoost
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pooneh Dehghan
- Department of Imaging, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Tohidi
- Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pejman Rouhani
- Pediatric Gastroenterology and Hepatology Research Center Pediatrics Centre of Excellence Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Golaleh Asghari
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Zhu Y, Geng SY, Chen Y, Ru QJ, Zheng Y, Jiang N, Zhu FY, Zhang YS. Machine learning algorithms reveal gut microbiota signatures associated with chronic hepatitis B-related hepatic fibrosis. World J Gastroenterol 2025; 31:105985. [DOI: 10.3748/wjg.v31.i16.105985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 03/17/2025] [Accepted: 04/09/2025] [Indexed: 04/27/2025] Open
Abstract
BACKGROUND Hepatic fibrosis (HF) represents a pivotal stage in the progression and potential reversal of cirrhosis, underscoring the importance of early identification and therapeutic intervention to modulate disease trajectory.
AIM To explore the complex relationship between chronic hepatitis B (CHB)-related HF and gut microbiota to identify microbiota signatures significantly associated with HF progression in CHB patients using advanced machine learning algorithms.
METHODS This study included patients diagnosed with CHB and classified them into HF and non-HF groups based on liver stiffness measurements. The HF group was further subdivided into four subgroups: F1, F2, F3, and F4. Data on clinical indicators were collected. Stool samples were collected for 16S rRNA sequencing to assess the gut microbiome. Microbiota diversity, relative abundance, and linear discriminant analysis effect size (LEfSe) were analyzed in different groups. Correlation analysis between clinical indicators and the relative abundance of gut microbiota was performed. The random forest and eXtreme gradient boosting algorithms were used to identify key differential gut microbiota. The Shapley additive explanations were used to evaluate microbiota importance.
RESULTS Integrating the results from univariate analysis, LEfSe, and machine learning, we identified that the presence of Dorea in gut microbiota may be a key feature associated with CHB-related HF. Dorea possibly serves as a core differential feature of the gut microbiota that distinguishes HF from non-HF patients, and the presence of Dorea shows significant variations across different stages of HF (P < 0.05). The relative abundance of Dorea significantly decreases with increasing HF severity (P = 0.041). Moreover, the gut microbiota composition in patients with different stages of HF was found to correlate with several liver function indicators, such as γ-glutamyl transferase, alkaline phosphatase, total bilirubin, and the aspartate aminotransferase/alanine transaminase ratio (P < 0.05). The associated pathways were predominantly enriched in biosynthesis, degradation/utilization/assimilation, generation of precursors, metabolites, and energy, among other categories.
CONCLUSION HF affects the composition of the gut microbiota, indicating that the gut microbiota plays a crucial role in its pathophysiological processes. The abundance of Dorea varies significantly across various stages of HF, making it a potential microbial marker for identifying HF onset and progression.
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Affiliation(s)
- Ying Zhu
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Shi-Yu Geng
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Yao Chen
- National Key Laboratory of Immunity and Inflammation Suzhou Institute of Systems Medicine Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou 215123, Jiangsu Province, China
| | - Qing-Jing Ru
- Department of Infectious Disease, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310005, Zhejiang Province, China
| | - Yi Zheng
- Department of Infectious Disease, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310005, Zhejiang Province, China
| | - Na Jiang
- Department of Infectious Disease, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310005, Zhejiang Province, China
| | - Fei-Ye Zhu
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Yong-Sheng Zhang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
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Yang SJ, Yu XK, Zuo Q. Branched- Chain Fatty Acids and Obesity: A Narrative Review. Nutr Rev 2025:nuaf022. [PMID: 40207993 DOI: 10.1093/nutrit/nuaf022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2025] Open
Abstract
Branched- chain fatty acids (BCFAs) are a category of saturated fatty acids that are commonly present in various organisms and play a crucial role in a variety of metabolic reactions, including anticancer, lipid-lowering, anti-inflammatory, and neuroprotective actions. Currently, there is growing interest in the relationship between BCFAs and obesity. Branched- chain fatty acids regulate the gene expression of related enzymes by activating PPARα and sterol regulatory element-binding protein-1c, thereby reducing triglyceride synthesis in the body. Additionally, BCFAs reduce inflammation by decreasing the expression of pro-inflammatory factors in obesity such as cyclooxygenase-2, interleukin-6, and lipoxygenase-15 genes. Branched- chain fatty acids can also expedite the conversion of branched chain amino acids to BCFAs to regulate obesity-induced insulin resistance. In this article we provide a comprehensive review of research progress on how BCFAs affect obesity from the perspectives of lipid metabolism, inflammation, and insulin resistance.
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Affiliation(s)
- Shi-Jiao Yang
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China
| | - Xin-Kai Yu
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China
| | - Qun Zuo
- School of Sports Performance, Shanghai University of Sport, Shanghai 200438, China
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Xu J, Wang Y, Zhang J, Tang J, Zhou Z. The role of branched-chain amino acids in cardio-oncology: A review. Life Sci 2025; 372:123614. [PMID: 40189196 DOI: 10.1016/j.lfs.2025.123614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/18/2025] [Accepted: 04/01/2025] [Indexed: 04/26/2025]
Abstract
Cancer and cardiovascular diseases (CVDs) are global health challenges. In cancer patients, CVD is the second leading cause of death following disease progression. There are few specialized services for cardio-oncology patients worldwide currently. Branched-chain amino acids (BCAAs) are essential amino acids that promote protein synthesis and energy homeostasis. The disruption of BCAAs metabolism facilitates the development of cancer and CVDs while the benefit of BCAA supplement is full of controversy. In this review, we summarized BCAA-related studies in cardiometabolism, cancer and chemotherapy-induced cardiotoxicity, and provided our perspectives on the roles of BCAAs in cardio-oncology. We find that supplementation of BCAAs presents protective effects in cardiometabolic diseases, while the influence on cancer is intricate and varies across different types of cancers. Large-scale clinical studies are needed to understand the long-term effects of BCAA intake and its impact on different stages of the disease. BCAAs have potential to mitigate chemotherapy-induced cardiotoxicity. Continued research is still essential to understand the precise mechanisms, determine optimal dosage and timing, and assess the effectiveness of BCAA supplement in cardio-oncology, in particular clinical research.
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Affiliation(s)
- Jiaqi Xu
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu Wang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Cardiology, The First Hospital of Hebei Medical University, Hebei, China
| | - Jing Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong; Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Jingyi Tang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Zhongyan Zhou
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong; Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong.
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Fu J, Ni Y, Hu Y, Tang W, Fu J, Wang Y, Yu S, Xu W. Glutamine, Serine and Glycine at Increasing Concentrations Regulate Cisplatin Sensitivity in Gastric Cancer by Posttranslational Modifications of KDM4A. Mol Carcinog 2025; 64:703-715. [PMID: 39835657 DOI: 10.1002/mc.23881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 12/19/2024] [Accepted: 01/02/2025] [Indexed: 01/22/2025]
Abstract
Gastric cancer is a common digestive system tumor with a high resistance rate that reduces the sensitivity to chemotherapy. Nutrition therapy is an important adjuvant approach to favor the prognosis of gastric cancer. Dietary amino acids contribute greatly to gastric cancer progression by mediating tumor gene expressions, epigenetics, signal transduction, and metabolic remodeling. In the present study, 20 types of amino acids were screened and glutamine, glycine and serine were identified as the critical regulators of cisplatin (DDP) sensitivity in gastric cancer cells. Moreover, KDM4A acetylation drove the reduced chemotherapy sensitivity in gastric cancer cells by maintaining protein stability and activating DNA repair ability when the concentrations of glutamine (Gln), serine (Ser), and glycine (Gly) decreased. Conversely, Gln/Ser/Gly at increasing concentrations stimulated ubiquitination degradation of KDM4A, which in turn elevated the sensitivity of gastric cancer cells to chemotherapy. Our findings unveiled the role of amino acid nutrition in regulating chemotherapy sensitivity of gastric cancer and the underlying mechanism, thus providing a scientific basis for expanding the clinical significance of nutrition therapy for gastric cancer patients.
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Affiliation(s)
- Junhao Fu
- Department of Gastrointestinal Oncology, Central Laboratory and Precision Medicine Center, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China
- Department of Gastrointestinal Oncology, Jinhua Key Laboratory of Cancer Nutrition and Metabolism Research, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China
| | - Yuqi Ni
- Department of Gastrointestinal Oncology, Central Laboratory and Precision Medicine Center, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China
- Department of Gastrointestinal Oncology, Jinhua Key Laboratory of Cancer Nutrition and Metabolism Research, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China
| | - Yuqing Hu
- Department of Gastrointestinal Oncology, Central Laboratory and Precision Medicine Center, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China
- Department of Gastrointestinal Oncology, Jinhua Key Laboratory of Cancer Nutrition and Metabolism Research, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China
| | - Wanfen Tang
- Department of Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China
| | - Jianfei Fu
- Department of Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China
| | - Yue Wang
- Department of Experimental Technology, Dian Diagnostics Group Co. Ltd., Hangzhou, Zhejiang Province, China
| | - Shian Yu
- Department of General Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China
| | - Wenxia Xu
- Department of Gastrointestinal Oncology, Central Laboratory and Precision Medicine Center, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China
- Department of Gastrointestinal Oncology, Jinhua Key Laboratory of Cancer Nutrition and Metabolism Research, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China
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Yun MKD, Subramanian C, Miller K, Jackson P, Radka CD, Rock CO. Isoleucine binding and regulation of Escherichia coli and Staphylococcus aureus threonine dehydratase (IlvA). BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.06.641827. [PMID: 40093177 PMCID: PMC11908243 DOI: 10.1101/2025.03.06.641827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
In Staphylococcus aureus, the branched-chain amino acid biosynthetic pathway provides essential intermediates for membrane biosynthesis. Threonine deaminase (IlvA) is the first enzyme in the pathway, and isoleucine feedback-regulates the enzyme in Escherichia coli. These studies on E. coli IlvA (EcIlvA) introduced the concept of allosteric regulation. To investigate the regulation of S. aureus IlvA (SaIlvA), we first conducted additional studies on EcIlvA. The previously determined crystal structure of EcIlvA revealed a tetrameric assembly of protomers, each with catalytic and regulatory domains, but the structural basis of isoleucine regulation was not characterized. Here, we present the crystal structure of the EcIlvA regulatory domain bound to isoleucine, which reveals the isoleucine binding site and conformational changes that initiate at Phe352 and propagate 23 Angstrom across the domain. This suggests an allosteric pathway that extends to the active site of the adjacent protomer, mediating regulation across the protomer-protomer interface. The EcIlvA(F352A) mutant binds isoleucine but is feedback-resistant due to the absence of the initiating Phe352. In contrast, SaIlvA is not feedback-regulated by isoleucine and does not bind it. The structure of the SaIlvA regulatory domain reveals a different organization that lacks the isoleucine binding site. Other potential allosteric inhibitors of SaIlvA, including phospholipid intermediates, do not affect enzyme activity. We propose that the absence of feedback inhibition in SaIlvA is due to its role in membrane biosynthesis. These findings enhance our understanding of IlvA's allosteric regulation and offer opportunities for engineering feedback-resistant IlvA variants for biotechnological use.
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Tesoriere G, Pilesi E, De Rosa M, Giampaoli O, Patriarca A, Spagnoli M, Chiocciolini F, Tramonti A, Contestabile R, Sciubba F, Vernì F. Vitamin B6 deficiency produces metabolic alterations in Drosophila. Metabolomics 2025; 21:42. [PMID: 40123014 PMCID: PMC11930875 DOI: 10.1007/s11306-025-02236-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 02/11/2025] [Indexed: 03/25/2025]
Abstract
INTRODUCTION Pyridoxal 5'-phosphate (PLP), the biologically active form of vitamin B6 is involved in 4% of cellular enzymatic activities and its deficiency is responsible for or contributes to several human diseases. The study of underlying mechanisms is still in its infancy and requires suitable model organisms. In Drosophila the deficiency of vitamin B6 produces chromosome aberrations and hallmarks of human diseases including diabetes and cancer. However, the effects of vitamin B6 deficiency have never been examined at a metabolic level. OBJECTIVES This study evaluates the metabolic changes in vitamin B6 deficient Drosophila larvae with the aim of validating flies as a suitable model for diseases associated to vitamin B6 deficiency. METHODS To induce vitamin B6 deficiency we fed Drosophila wild type larvae with 4-deoxypyridoxine (4DP), a PLP antagonist. By HPLC analysis we verified that the 4DP treatment was effective in inducing vitamin B6 deficiency. Using an NMR-based metabolomic approach we compared the metabolites in larval extracts from untreated and 4DP-fed larvae. RESULTS The NMR spectra analysis identified quantitative differences for sixteen metabolites out of forty, including branched chain and aromatic amino acids, glucose, and lipids, thus revealing interesting possible associations with the phenotypes showed by vitamin B6 deficient flies. CONCLUSIONS Our results validate Drosophila as a suitable model to study in depth the molecular mechanisms underlying human diseases associated with vitamin B6 deficiency and confirmed that 4DP treatment is effective in inducing vitamin B6 deficiency.
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Affiliation(s)
- Giulia Tesoriere
- Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, 00185, Rome, Italy
| | - Eleonora Pilesi
- Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, 00185, Rome, Italy
| | - Michele De Rosa
- Department of Chemistry, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, Rome, Italy
| | - Ottavia Giampaoli
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, Rome, Italy
- Department of Environmental Biology, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy
| | - Adriano Patriarca
- Department of Chemistry, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, Rome, Italy
- Department of Environmental Biology, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy
| | - Mariangela Spagnoli
- Department of Occupational and Environmental Medicine, Epidemiology and Hygiene, INAIL, Via Fontana Candida 1, 00078, Monte Porzio Catone, Italy
| | - Federica Chiocciolini
- Institute of Molecular Biology and Pathology, Consiglio Nazionale delle Ricerche, 00185, Rome, Italy
| | - Angela Tramonti
- Institute of Molecular Biology and Pathology, Consiglio Nazionale delle Ricerche, 00185, Rome, Italy
| | - Roberto Contestabile
- Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza, University of Rome, 00185, Rome, Italy
| | - Fabio Sciubba
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, Rome, Italy
- Department of Environmental Biology, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy
| | - Fiammetta Vernì
- Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, 00185, Rome, Italy.
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Tan J, Zhang H, Liu Y, Hou Z, Wang D, Zhou J, Cao Y, Qian S, Zheng B, Nie J, Cui Y, Du Y, Huang K, Yang S, Chen D, Liu X. Interfering with proton and electron transfer enables antibacterial starvation therapy. SCIENCE ADVANCES 2025; 11:eadt3159. [PMID: 40106542 PMCID: PMC11922021 DOI: 10.1126/sciadv.adt3159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 02/19/2025] [Indexed: 03/22/2025]
Abstract
Implant-associated infections are urgently addressed; however, existing materials are difficult to kill bacteria without damaging cells. Here, we propose an innovative concept of selective antibacterial starvation therapy based on interfering with proton and electron transfer on the bacterial membrane. As a proof-of-principle demonstration, a special Schottky heterojunction film composed of gold and alkaline magnesium-iron mixed metal oxides (Au/MgFe-MMO) was constructed on the titanium implant. Once bacteria contacted this implant, the Au/MgFe-MMO film continuously captured the proton and electron participated in respiratory chain of bacteria to impede their energy metabolism, leading to the deficit of adenosine 5'-triphosphate. Prolonged exposure to this starvation state inhibited numerous biosynthesis processes and triggered severe oxidative stress in bacteria, ultimately leading to their death due to DNA and membrane damage. In addition, this heterojunction film was comfortable for mammalian cells, without inhibiting mitochondrial function. This proposed starvation antibacterial therapy gives a notable perspective in designing biosafe smart antibacterial biomaterials.
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Affiliation(s)
- Ji Tan
- State Key Laboratory of Advanced Ceramics, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China
| | - Haifeng Zhang
- State Key Laboratory of Advanced Ceramics, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China
| | - Yisi Liu
- State Key Laboratory of Advanced Ceramics, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China
| | - Zhenhao Hou
- State Key Laboratory of Advanced Ceramics, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China
| | - Donghui Wang
- School of Health Science and Biomedical Engineering, Hebei University of Technology, Tianjin 300130, China
| | - Junjie Zhou
- State Key Laboratory of Advanced Ceramics, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China
| | - Yuanming Cao
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
| | - Shi Qian
- State Key Laboratory of Advanced Ceramics, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China
| | - Bowen Zheng
- State Key Laboratory of Advanced Ceramics, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China
| | - JingJun Nie
- Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing 100035, China
| | | | - Yun Du
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China
| | - Kai Huang
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China
| | - Shengbing Yang
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China
| | - Dafu Chen
- Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing 100035, China
| | - Xuanyong Liu
- State Key Laboratory of Advanced Ceramics, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
- School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
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Hao QY, Weng J, Zeng TT, Zeng YH, Guo JB, Li SC, Chen YR, Yang PZ, Gao JW, Li ZH. Dietary branched-chain amino acids intake and coronary artery calcium progression: insights from the coronary artery risk development in young adults (CARDIA) study. Eur J Nutr 2025; 64:131. [PMID: 40106011 DOI: 10.1007/s00394-025-03649-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 03/05/2025] [Indexed: 03/22/2025]
Abstract
OBJECTIVE Branched-chain amino acids (BCAA) have been implicated in the risk of cardiovascular disease. However, it is unclear whether dietary BCAA intake, specifically isoleucine, leucine, and valine are associated with coronary artery calcium (CAC) progression. METHODS We included the participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study cohort for the analysis. Dietary intake of BCAA was assessed at year 7 of the study. CAC was measured using standardized computed tomography scans at years 15, 20, and 25. CAC progression was defined as follows: for participants with a baseline CAC of 0, progression was defined as CAC > 0 at follow-up; for those with 0 < baseline CAC < 100, progression was defined as an annualized change of ≥ 10; and for those with baseline CAC ≥ 100, progression was defined as an annualized percent change of ≥ 10%. Multivariate adjusted Cox regression models were utilized to examine the associations between BCAA intake and CAC progression. RESULTS Among 2381 included participants (average age 40.4 ± 3.5 years, 44.9% men), 629 participants (26.4%) exhibited CAC progression during a follow-up period of 8.90 ± 2.03 years. In the fully adjusted model, high intake of total BCAA, and its individual components, isoleucine, leucine, and valine were associated with an increased risk of CAC progression by 35.6% (HR, 1.356 [95% CI, 1.040-1.769]), 30.5% (HR, 1.305 [95% CI, 1.001-1.701]), 30.9% (HR, 1.309 [95% CI, 1.003-1.706]), and 33.9% (HR, 1.339 [95% CI, 1.026-1.747]), respectively, compared to their corresponding low intake groups. The associations were consistent across various subgroups, including age, sex, race, and body mass index, but were stronger in participants without baseline CAC (interaction P < 0.001). These results remained robust in a series of sensitivity analyses. CONCLUSIONS High dietary intake of BCAA, including isoleucine, leucine, and valine, were independently associated with an increased risk of CAC progression. The findings may implication for dietary modifications in primary prevention of subclinical atherosclerosis. REGISTRATION URL: https://www. CLINICALTRIALS gov ; Unique identifier: NCT00005130.
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Affiliation(s)
- Qing-Yun Hao
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jun Weng
- Department of Endoscopy, SunYat-sen University Cancer Center, Guangzhou, China
| | - Ting-Ting Zeng
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yu-Hong Zeng
- Medical Apparatus and Equipment Deployment, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jing-Bin Guo
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Shi-Chao Li
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yi-Ran Chen
- Institute of Public Health, Guangzhou Medical University & Guangzhou Center for Disease Control and Prevention, Guangzhou, Guangdong, China
| | - Ping-Zhen Yang
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
| | - Jing-Wei Gao
- Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Ze-Hua Li
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
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Mbilinyi RH, Deutz NEP, Cruthirds CL, Ruebush LE, Sontam T, Ten Have GAM, Thaden JJ, Engelen MPKJ. Prolonged increase in glutamate whole body and intracellular production in older adults with COPD and healthy controls post-resistance exercise. Metabolism 2025; 168:156185. [PMID: 40113079 DOI: 10.1016/j.metabol.2025.156185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 03/06/2025] [Accepted: 03/06/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND Exercise training is essential for pulmonary rehabilitation in chronic obstructive pulmonary disease (COPD), yet patient responsiveness varies widely. We previously observed metabolic disturbances in amino acids critical for muscle health-such as glutamate, glutamine, branched-chain amino acids (BCAAs), and taurine-in COPD patients after an endurance exercise session, possibly related to increased energy demands and oxidative stress. However, the impact of resistance exercise on these metabolic pathways remains unclear. METHODS We measured plasma concentration, whole-body production (WBP), and intracellular production of glutamate, glutamine, BCAAs, and taurine using stable isotope pulse techniques in 24 COPD and 25 healthy older participants. Measurements were obtained before, and at 1 and 24 h after, a resistance exercise session. RESULTS At baseline, COPD participants exhibited lower WBP of glutamine, taurine, and BCAAs compared to healthy participants (p < 0.05). Resistance exercise increased WBP of glutamate by 37-42 %, glutamine by 9-10 %, and intracellular glutamate production by 37-40 %, while decreasing WBP of taurine by 7 % (all p < 0.0001). These effects persisted at 24 h post-exercise (p < 0.05). Although WBP of BCAAs remained unchanged, plasma leucine and isoleucine levels decreased by 16 % and 13 %, respectively, in COPD participants post-exercise (p < 0.05). CONCLUSIONS A single resistance exercise session alters glutamate-related metabolism for at least 24 h in healthy and COPD participants. A high BCAA clearance is likely required to rapidly upregulate glutamate production in COPD to meet increased energy demands, but this occurs at the cost of lowering plasma levels of BCAA necessary for muscle anabolism. CLINICAL TRIAL REGISTRY Trial registration ClinicalTrials.gov: NCT02780219.
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Affiliation(s)
- Robert H Mbilinyi
- Center for Translational Research in Aging & Longevity, Dept. of Kinesiology and Sport Management, Texas A&M University, College Station, TX, United States; Dept. of Medical Education, Texas A&M College of Medicine, College Station, TX, United States
| | - Nicolaas E P Deutz
- Center for Translational Research in Aging & Longevity, Dept. of Kinesiology and Sport Management, Texas A&M University, College Station, TX, United States; Dept. of Primary Care & Rural Medicine, Texas A&M College of Medicine, College Station, TX, United States
| | - Clayton L Cruthirds
- Center for Translational Research in Aging & Longevity, Dept. of Kinesiology and Sport Management, Texas A&M University, College Station, TX, United States
| | - Laura E Ruebush
- Center for Translational Research in Aging & Longevity, Dept. of Kinesiology and Sport Management, Texas A&M University, College Station, TX, United States
| | - Tarun Sontam
- Center for Translational Research in Aging & Longevity, Dept. of Kinesiology and Sport Management, Texas A&M University, College Station, TX, United States; Dept. of Medical Education, Texas A&M College of Medicine, College Station, TX, United States
| | - Gabriella A M Ten Have
- Center for Translational Research in Aging & Longevity, Dept. of Kinesiology and Sport Management, Texas A&M University, College Station, TX, United States
| | - John J Thaden
- Center for Translational Research in Aging & Longevity, Dept. of Kinesiology and Sport Management, Texas A&M University, College Station, TX, United States
| | - Mariëlle P K J Engelen
- Center for Translational Research in Aging & Longevity, Dept. of Kinesiology and Sport Management, Texas A&M University, College Station, TX, United States; Dept. of Primary Care & Rural Medicine, Texas A&M College of Medicine, College Station, TX, United States.
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11
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Guo Z, Xiang Z, Su W, Lv B, Zhao Q, Zhang W, Ren R, Peng W, Su C, Wu Y, Pan J. Metabolic regulation of amino acids provides an important basis for individualized nutritional therapy for patients with gastric cancer during the perioperative period. World J Surg Oncol 2025; 23:89. [PMID: 40087750 PMCID: PMC11907831 DOI: 10.1186/s12957-025-03729-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 02/26/2025] [Indexed: 03/17/2025] Open
Abstract
BACKGROUND Gastric cancer is a prevalent malignancy worldwide, with early detection and treatment being vital to improving patient outcomes. Amino acids (AAs), as essential regulators in cancer cell metabolism, are implicated in the progression and response to treatment. METHODS This study aimed to investigate the dynamics of plasma AA levels in gastric cancer patients preoperatively, postoperatively, and following nutritional intervention, comparing them to healthy controls. We analyzed 22 AAs in plasma samples from 66 gastric cancer patients and 55 healthy individuals. RESULTS The results show that significant preoperative elevation of AAs, such as threonine (Thr), serine (Ser), proline (Pro), lysine (Lys), arginine (Arg), citrulline (Cit), glutamine (Gln), glycine(Gly), and alanine (Ala), with reductions in taurine (Tau), phenylalanine (Phe) and hydroxylysine (Hylys). Post-surgery, levels of many AAs decreased markedly, but were partially restored following nutritional intervention, with some exceeding preoperative values. Nevertheless, specific AAs, including methionine (Met) and Gln, remained lower than in healthy controls, suggesting potential benefit from targeted supplementation. Correlations between AA changes and postoperative recovery indicators were observed; notably, increased postoperative Thr, Ser, Tau, tyrosine (Tyr), glutamic acid (Glu), and Hylys levels were associated with quicker gastrointestinal recovery. Additionally, several AAs, such as Pro, Lys, Tyr, Met, Cit, and Glu, were linked to reduced inflammation, as reflected by C-reactive protein (CRP) and white blood cell (WBC) levels, suggesting roles in the postoperative immune response. Pathway enrichment analysis highlighted metabolic pathways involving Gly, Ser, Phe, Tyr, Lys, and Met as critical in the recovery process. CONCLUSIONS These findings underscore the potential of AA profiles as biomarkers for postoperative recovery and suggest nutritional interventions targeting specific AAs may improve outcomes.
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Affiliation(s)
- Zhening Guo
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, China
| | - Zheng Xiang
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, China
| | - Wenzhao Su
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, China
| | - Bo Lv
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, China
| | - Qinhong Zhao
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, China
| | - Wen Zhang
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, China
| | - Rui Ren
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, China
| | - Wei Peng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, China
| | - Cunjin Su
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, China
| | - Yongyou Wu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, China.
| | - Jie Pan
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, China.
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12
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Wang Y, Wang X, Zhang H, Zhu B. Global research dynamics in urea cycle disorders: a bibliometric study highlighting key players and future directions. Orphanet J Rare Dis 2025; 20:101. [PMID: 40038740 DOI: 10.1186/s13023-025-03625-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 02/18/2025] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND This study aims to explore the research hotspots and trends of urea cycle disorders through bibliometric analysis. METHODS Using the Web of Science Core Collection as the database, we retrieved literature published from 2007 to 2024. We utilized CiteSpace, VOSviewer, and Bibliometrix R package to conduct a bibliometric visualization analysis, including the number of publications, citation frequency, publishing countries, institutions, journals, authors, references, and keywords. RESULTS A total of 926 publications on UCDs were published in 318 journals by 4807 authors at 1494 institutions from 49 countries/regions. The USA had the highest number of publications and citation frequency. The Children's National Health System in the USA published the most literature. The most frequent collaboration was between the USA and Germany. The journal with the most publications was Molecular Genetics and Metabolism. The author with the most publications was Johannes Häberle. The most frequently cited reference was the 2019 publication of the revised guidelines for the diagnosis and management of UCDs. The identified future research hotspots are expected to focus on "gene therapy", "mutations" and "efficacy". CONCLUSION This study is the first bibliometric analysis of publications in the field of UCDs. These findings suggest that European and American countries dominate UCD research, it is necessary to further strengthen global cooperation in the field of UCDs. Early detection of the disease and emerging therapies, including gene therapy, are likely to be future research hotspots.
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Affiliation(s)
- Yan Wang
- Department of Pediatrics, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China
| | - Xueer Wang
- Department of Pediatrics, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China
| | - Huiqin Zhang
- Department of Pediatrics, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China
| | - Binhui Zhu
- Department of Pediatrics, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
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13
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De Rosa M, Giampaoli O, Patriarca A, Marini F, Pietroiusti A, Ippoliti L, Paolino A, Militello A, Fetoni AR, Sisto R, Tranfo G, Spagnoli M, Sciubba F. Urinary Metabolomics of Plastic Manufacturing Workers: A Pilot Study. J Xenobiot 2025; 15:39. [PMID: 40126257 PMCID: PMC11932285 DOI: 10.3390/jox15020039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 02/19/2025] [Accepted: 02/28/2025] [Indexed: 03/25/2025] Open
Abstract
The plastic manufacturing industry has a crucial role in the global economy with a significant impact in a wide range of fields. The chemical risk to which workers are potentially exposed is difficult to characterize and strictly related to both the products and processes adopted. Among the chemicals used, we can cite styrene, phenol, butadiene and phthalates, but nano- and microplastic particles can also be released in the work environment. In this pilot study, we present for the first time an NMR-based metabolomic approach for assessing urinary profiles of workers employed in a plastic manufacturing company. Urine samples from twelve workers and thirteen healthy volunteers were collected and analyzed by NMR spectroscopy. Forty-six urinary metabolites belonging to different chemical classes were univocally identified and quantified. The dataset so obtained was then subjected to multivariate statistical analysis to characterize each profile and highlight any differences. An alteration in some metabolites involved in several pathways, such as amino acid metabolism and NAD metabolism, was found, and a strong impact on gut microflora was also speculated. Ultimately, our work has the objective of adding a tile to the knowledge of biological effects possibly related to occupational exposure even if it is below the threshold limit values.
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Affiliation(s)
- Michele De Rosa
- Department of Chemistry, Sapienza University of Rome, 00185 Rome, Italy; (M.D.R.); (A.P.); (F.M.)
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, 00185 Rome, Italy; (O.G.); (F.S.)
| | - Ottavia Giampaoli
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, 00185 Rome, Italy; (O.G.); (F.S.)
- Department of Environmental Biology, Sapienza University of Rome, 00185 Rome, Italy
| | - Adriano Patriarca
- Department of Chemistry, Sapienza University of Rome, 00185 Rome, Italy; (M.D.R.); (A.P.); (F.M.)
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, 00185 Rome, Italy; (O.G.); (F.S.)
| | - Federico Marini
- Department of Chemistry, Sapienza University of Rome, 00185 Rome, Italy; (M.D.R.); (A.P.); (F.M.)
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, 00185 Rome, Italy; (O.G.); (F.S.)
| | - Antonio Pietroiusti
- Faculty of Medicine, Saint Camillus International University of Health Science, 00131 Rome, Italy; (A.P.); (L.I.)
| | - Lorenzo Ippoliti
- Faculty of Medicine, Saint Camillus International University of Health Science, 00131 Rome, Italy; (A.P.); (L.I.)
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy;
| | - Agostino Paolino
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy;
| | - Andrea Militello
- Department of Medicine, Epidemiology, Environmental and Occupational Hygiene, Istituto Nazionale Assicurazione contro gli Infortuni sul Lavoro (INAIL), 00078 Monte Porzio Catone, Italy; (A.M.); (R.S.); (G.T.)
| | - Anna Rita Fetoni
- Department of Neuroscience, Reproductive and Odontostomatological Sciences-Audiology Section, University of Naples Federico II, 80131 Naples, Italy;
| | - Renata Sisto
- Department of Medicine, Epidemiology, Environmental and Occupational Hygiene, Istituto Nazionale Assicurazione contro gli Infortuni sul Lavoro (INAIL), 00078 Monte Porzio Catone, Italy; (A.M.); (R.S.); (G.T.)
| | - Giovanna Tranfo
- Department of Medicine, Epidemiology, Environmental and Occupational Hygiene, Istituto Nazionale Assicurazione contro gli Infortuni sul Lavoro (INAIL), 00078 Monte Porzio Catone, Italy; (A.M.); (R.S.); (G.T.)
| | - Mariangela Spagnoli
- Department of Medicine, Epidemiology, Environmental and Occupational Hygiene, Istituto Nazionale Assicurazione contro gli Infortuni sul Lavoro (INAIL), 00078 Monte Porzio Catone, Italy; (A.M.); (R.S.); (G.T.)
| | - Fabio Sciubba
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, 00185 Rome, Italy; (O.G.); (F.S.)
- Department of Environmental Biology, Sapienza University of Rome, 00185 Rome, Italy
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14
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Van Slambrouck J, Loopmans S, Prisciandaro E, Barbarossa A, Kortleven P, Feys S, Vandervelde CM, Jin X, Cenik I, Moermans K, Fieuws S, Provoost AL, Willems A, De Leyn P, Van Veer H, Depypere L, Jansen Y, Pirenne J, Neyrinck A, Weynand B, Vanaudenaerde B, Carmeliet G, Vos R, Van Raemdonck D, Ghesquière B, Van Weyenbergh J, Ceulemans LJ. The effect of rewarming ischemia on tissue transcriptome and metabolome signatures: A clinical observational study in lung transplantation. J Heart Lung Transplant 2025; 44:437-447. [PMID: 39486771 DOI: 10.1016/j.healun.2024.10.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 09/17/2024] [Accepted: 10/21/2024] [Indexed: 11/04/2024] Open
Abstract
BACKGROUND In lung transplantation (LuTx), various ischemic phases exist, yet the rewarming ischemia time (RIT) during implantation has often been overlooked. During RIT, lungs are deflated and exposed to the body temperature in the recipient's chest cavity. Our prior clinical findings demonstrated that prolonged RIT increases the risk of primary graft dysfunction. However, the molecular mechanisms of rewarming ischemic injury in this context remain unexplored. We aimed to characterize the rewarming ischemia phase during LuTx by measuring organ temperature and comparing transcriptome and metabolome profiles in tissue obtained at the end versus the start of implantation. METHODS In a clinical observational study, 34 double-LuTx with ice preservation were analyzed. Lung core and surface temperature (n = 65 and 55 lungs) were measured during implantation. Biopsies (n = 59 lungs) were wedged from right middle lobe and left lingula at start and end of implantation. Tissue transcriptomic and metabolomic profiling were performed. RESULTS Temperature increased rapidly during implantation, reaching core/surface temperatures of 21.5°C/25.4°C within 30 minutes. Transcriptomics showed increased proinflammatory signaling and oxidative stress at the end of implantation. Upregulation of NLRP3 and NFKB1 correlated with RIT. Metabolomics indicated elevated levels of amino acids, hypoxanthine, uric acid, and cysteineglutathione disulfide alongside decreased levels of glucose and carnitines. Arginine, tyrosine, and 1-carboxyethylleucine showed a correlation with incremental RIT. CONCLUSIONS The final rewarming ischemia phase in LuTx involves rapid organ rewarming, accompanied by transcriptomic and metabolomic changes indicating proinflammatory signaling and disturbed cell metabolism. Limiting implantation time and cooling of the lung represent potential interventions to alleviate rewarming ischemic injury.
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Affiliation(s)
- Jan Van Slambrouck
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Shauni Loopmans
- Department of Cellular and Molecular Medicine, Laboratory of Applied Mass Spectrometry, KU Leuven, Leuven, Belgium; Center for Cancer Biology, Metabolomics Core Facility Leuven, VIB, Leuven, Belgium
| | - Elena Prisciandaro
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Annalisa Barbarossa
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Phéline Kortleven
- Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium; Department of Pharmaceutical and Pharmacological Sciences, Molecular Virology and Gene Therapy, KU Leuven, Leuven, Belgium
| | - Simon Feys
- Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical Infectious and Inflammatory Disorders, KU Leuven, Leuven, Belgium; Department of Medical Intensive Care, University Hospitals Leuven, Leuven, Belgium
| | - Christelle M Vandervelde
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Xin Jin
- Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Ismail Cenik
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Karen Moermans
- Department of Chronic Diseases and Metabolism, Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium
| | - Steffen Fieuws
- Department of Public Health, Interuniversity Center for Biostatistics and Statistical Bioinformatics, KU Leuven, Leuven, Belgium
| | - An-Lies Provoost
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Anton Willems
- Department of Cellular and Molecular Medicine, Laboratory of Applied Mass Spectrometry, KU Leuven, Leuven, Belgium; Center for Cancer Biology, Metabolomics Core Facility Leuven, VIB, Leuven, Belgium
| | - Paul De Leyn
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Hans Van Veer
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Lieven Depypere
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Yanina Jansen
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Jacques Pirenne
- Department of Microbiology, Immunology and Transplantation, Laboratory of Abdominal Transplantation, KU Leuven, Leuven, Belgium; Department of Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Arne Neyrinck
- Department of Cardiovascular Sciences, Anesthesiology and Algology, KU Leuven, Leuven, Belgium; Department of Anesthesiology, University Hospitals Leuven, Leuven, Belgium
| | - Birgit Weynand
- Department of Pathology, University Hospitals Leuven, Leuven, Belgium; Department of Imaging and Pathology, Laboratory of Translational Cell & Tissue Research, KU Leuven, Leuven, Belgium
| | - Bart Vanaudenaerde
- Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Geert Carmeliet
- Department of Chronic Diseases and Metabolism, Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium
| | - Robin Vos
- Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium; Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Dirk Van Raemdonck
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Bart Ghesquière
- Department of Cellular and Molecular Medicine, Laboratory of Applied Mass Spectrometry, KU Leuven, Leuven, Belgium; Center for Cancer Biology, Metabolomics Core Facility Leuven, VIB, Leuven, Belgium
| | - Johan Van Weyenbergh
- Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Rega Institute, KU Leuven, Leuven, Belgium
| | - Laurens J Ceulemans
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium.
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15
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Yeo M, Rehsi P, Yeo JM, Dixon M, Chakrapani A. Single centre retrospective review of plasma branched-chain amino acid levels in children with urea cycle disorders: Impact of treatment modalities and disease severity. Mol Genet Metab Rep 2025; 42:101190. [PMID: 39897473 PMCID: PMC11786853 DOI: 10.1016/j.ymgmr.2025.101190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 01/09/2025] [Accepted: 01/09/2025] [Indexed: 02/04/2025] Open
Abstract
Branched-chain amino acids (BCAAs) are important for normal growth, development, and function. In urea cycle disorders (UCDs), plasma BCAA levels can be relatively low; this has been attributed variously to low protein intake, hyperammonaemia, and nitrogen scavenger treatment. We undertook a retrospective review of plasma BCAA levels in individuals with UCDs comprising ornithine carbamoyltransferase deficiency (OTCD n = 22), arginosuccinate lyase deficiency (ASLD n = 12), and argininosuccinate synthase deficiency (ASSD n = 6). Scavenger treatment groups comprised sodium benzoate (NaBz, n = 20), sodium phenylbutyrate (NaPBA, n = 5), NaBz+NaPBA (n = 14), and a control group receiving neither NaBz nor NaPBA (n = 14). In these treatment groups, respectively, median (IQR) plasma levels of leucine were 54 (32), 55 (25), 58 (19), and 91 (70) μmol/L (leucine was lower in the NaBz group than the control, p = 0.0282) and numbers of individuals (%) with leucine below normal were 10/20 (50 %), 1/4 (25 %), 10/14 (71 %), and 2/9 (20 %). The pattern was similar for isoleucine and valine. In the NaBz group, plasma BCAA levels were inversely correlated with protein intake (p ≤ 0.01 to p ≤ 0.001), plasma ammonia level (p ≤ 0.01 to p ≤ 0.0001), and scavenger dose (p ≤ 0.0001). We speculate that individuals with greater disease severity may be prone to BCAA deficiency, caused by BCAA consumption when alternative urea disposal pathways are used. Practical reflections on our audit were that to increase the proportion of plasma BCAA levels in the normal range, we needed to alter the biological value of protein intake, prescribe higher doses of scavenger to facilitate safe levels of protein intake, and give EAA supplements if indicated.
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Affiliation(s)
- Mildrid Yeo
- Department of Paediatric Inherited Metabolic Disease, Great Ormond Street Hospital for Children, NHS Foundation Trust and Institute for Child Health, London, UK
| | - Preeya Rehsi
- Department of Paediatric Inherited Metabolic Disease, Great Ormond Street Hospital for Children, NHS Foundation Trust and Institute for Child Health, London, UK
| | - Jie Ming Yeo
- Department of Paediatric Inherited Metabolic Disease, Great Ormond Street Hospital for Children, NHS Foundation Trust and Institute for Child Health, London, UK
| | - Marjorie Dixon
- Dietetics, Great Ormond Street Hospital for Children, NHS Foundation Trust and Institute for Child Health, London, UK
| | - Anupam Chakrapani
- Department of Paediatric Inherited Metabolic Disease, Great Ormond Street Hospital for Children, NHS Foundation Trust and Institute for Child Health, London, UK
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16
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Perakakis N, Funk AM, Kolb T, Jonas S, Hellerhoff I, Tam FI, Bornstein SR, Chavakis T, Mirtschink P, Ehrlich S. Perturbations in plasma amino acid and lipoprotein subfraction profiles in anorexia nervosa before and after refeeding: A metabolomic cross-sectional and longitudinal analysis. Clin Nutr 2025; 46:107-116. [PMID: 39892164 DOI: 10.1016/j.clnu.2025.01.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 12/07/2024] [Accepted: 01/08/2025] [Indexed: 02/03/2025]
Abstract
BACKGROUND Anorexia nervosa (AN) is a life-threatening eating disorder, which is increasingly being considered a metabo-psychiatric condition. We aimed to assess how the lipoprotein subfraction and plasma metabolome are altered in acutely underweight patients with AN (AcAN), if they change with short-term weight-restoration, and whether these changes point towards altered cardiometabolic risk. METHODS Using nuclear magnetic resonance spectroscopy, we measured and compared the plasma concentrations of 132 metabolites, aminoacids and lipoprotein subfractions in young female patients with AcAN before (n = 72) versus after (n = 46) a short-term inpatient refeeding program resulting in weight-restoration (longitudinal analysis), as well as versus female healthy control (HC) participants of similar age (n = 74) (cross-sectional analysis). FINDINGS Patients with AcAN showed elevated plasma cholesterol levels due to higher concentrations of small and dense Low Density Lipoprotein (LDL-6) and of large and less dense High Density Lipoprotein (HDL-1) subfractions compared to HC. Additionally, they had lower plasma concentrations of branched chain amino acids and glucose and higher concentrations of the gluconeogenic amino acids glutamine, alanine and methionine. Refeeding elevated the plasma cholesterol levels further, but with a different pattern compared to AcAN, by increasing the concentrations of the larger and less dense LDL (LDL-1, LDL-2, LDL-3) particles and of smaller and more dense HDL (HDL-2, HDL-3) subfractions. However, refeeding only partially restored the amino acid concentrations. CONCLUSION Lipoprotein profiles in AcAN point towards a potentially elevated risk for atherosclerosis; an altered lipoprotein profile was also detected after refeeding. Metabolite profiles in AcAN indicate an advanced catabolic state with only partial restoration after refeeding.
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Affiliation(s)
- Nikolaos Perakakis
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
| | - Alexander M Funk
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany
| | - Theresa Kolb
- Translational Developmental Neuroscience Section, Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Sophie Jonas
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Inger Hellerhoff
- Translational Developmental Neuroscience Section, Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; Eating Disorder Treatment and Research Center, Department of Child and Adolescent Psychiatry, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Friederike I Tam
- Translational Developmental Neuroscience Section, Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; Eating Disorder Treatment and Research Center, Department of Child and Adolescent Psychiatry, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Stefan R Bornstein
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Triantafyllos Chavakis
- Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany; Institute of Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany
| | - Peter Mirtschink
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany
| | - Stefan Ehrlich
- Translational Developmental Neuroscience Section, Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; Eating Disorder Treatment and Research Center, Department of Child and Adolescent Psychiatry, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
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Tarik M, Ramakrishnan L, Bhatia N, Roy A, Kandasamy D, Chandran DS, Singh A, Kalaivani M, Neelamraju J, Madempudi RS. Supplementation With Bacillus clausii UBBC-07 Enhances Circulating Essential Amino Acids in Young Adults: A Double-Blind, Randomized, Controlled Trial. Cureus 2025; 17:e81119. [PMID: 40276429 PMCID: PMC12020262 DOI: 10.7759/cureus.81119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2025] [Indexed: 04/26/2025] Open
Abstract
Background and aim Probiotics have been linked to improved gastrointestinal health and essential nutrient absorption. This study aimed to assess the impact of Bacillus clausii(Shouchella clausii) UBBC-07 plus whey protein supplementation on the bioavailability of circulating essential amino acids (EAAs) in physically active young adults. Methods In this double-blind, randomized, controlled trial, 70 physically active male participants (21.46±3.19 years) were instructed to ingest either a probiotic supplement containing two billion colony-forming unit (CFU) Bacillus clausii UBBC-07 + 20 g of whey protein or a control supplement containing placebo + 20 g of whey protein once daily for 60 days. All the participants followed a supervised exercise protocol. The circulating amino acid levels were determined using a high-performance liquid chromatography with fluorescence detection (HPLC-FLD) assay and compared using the student's t-test and a repeated measures analysis of variance (ANOVA). Results After 60 days, a significant improvement in the probiotic group was observed compared to the control group in terms of total levels of circulating EAAs (mean change: 258 pmol/μl, 95% CI: 161.5-354.4 vs. 76.4 pmol/μl, 95% CI: 16.5-136.4; p=0.002) and branched-chain amino acids or BCAAs (mean change: 144.2 pmol/μl, 95% CI: 89-199.3 vs. 37.5 pmol/μl, 95% CI: 7.3-67.8; p=0.001) as well as levels of isoleucine (p=0.003), leucine (p>0.001), and valine (p=0.001). Total plasma free amino acids (PFAAs) were also increased in the probiotic group (p<0.001). The improvement in the one-repetition maximum (RM) leg press was higher in the probiotic group as compared to the control group (mean change: 20.46 kg, 95% CI: 14.73-26.19 vs. 14.09 kg, 95% CI: 8.44, 19.73; p=0.045). A trend towards improvement in deadlift and vertical jump was also observed in the former group. No probiotic-mediated gastrointestinal upsets and respiratory symptoms or any other adverse events were observed. Conclusion A significant improvement in circulating EAA levels in the probiotic group suggests an enhancement of protein absorption with Bacillus clausii UBBC-07 supplementation. The effect of BCAAs, which enhance muscle strength, is evident in the significant improvement in leg press and a trend towards improvement in deadlift and vertical jump in the probiotic group. This has positive implications for individuals involved in sports activities.
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Affiliation(s)
- Mohamad Tarik
- Department of Cardiac Biochemistry, All India Institute of Medical Sciences, New Delhi, New Delhi, IND
| | - Lakshmy Ramakrishnan
- Department of Cardiac Biochemistry, All India Institute of Medical Sciences, New Delhi, New Delhi, IND
| | - Nidhi Bhatia
- Department of Orthopaedics, All India Institute of Medical Sciences, New Delhi, New Delhi, IND
| | - Atanu Roy
- Department of Physiology, All India Institute of Medical Sciences, New Delhi, New Delhi, IND
| | | | - Dinu S Chandran
- Department of Physiology, All India Institute of Medical Sciences, New Delhi, New Delhi, IND
| | - Archna Singh
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, New Delhi, IND
| | - Mani Kalaivani
- Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, New Delhi, IND
| | | | - Ratna S Madempudi
- Centre for Research and Development, Unique Biotech Limited, Hyderabad, IND
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18
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Naigaonkar A, Dadachanji R, Kumari M, Mukherjee S. Insight into metabolic dysregulation of polycystic ovary syndrome utilizing metabolomic signatures: a narrative review. Crit Rev Clin Lab Sci 2025; 62:85-112. [PMID: 39697160 DOI: 10.1080/10408363.2024.2430775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 07/15/2024] [Accepted: 11/12/2024] [Indexed: 12/20/2024]
Abstract
Polycystic ovary syndrome (PCOS) is a complex multifactorial endocrinopathy affecting reproductive aged women globally, whose presentation is strongly influenced by genetic makeup, ethnic, and geographic diversity leaving these affected women substantially predisposed to reproductive and metabolic perturbations. Sophisticated techniques spanning genomics, proteomics, epigenomics, and transcriptomics have been harnessed to comprehensively understand the enigmatic pathophysiology of PCOS, however, conclusive markers for PCOS are still lacking today. Metabolomics represents a paradigm shift in biotechnological advances enabling the simultaneous identification and quantification of metabolites and the use of this approach has added yet another dimension to help unravel the strong metabolic component of PCOS. Reports dissecting the metabolic signature of PCOS have revealed disparate levels of metabolites such as pyruvate, lactate, triglycerides, free fatty acids, carnitines, branched chain and essential amino acids, and steroid intermediates in major biological compartments. These metabolites have been shown to be altered in women with PCOS overall, after phenotypic subgrouping, in animal models of PCOS, and also following therapeutic intervention. This review seeks to supplement previous reviews by highlighting the aforementioned aspects and to provide easy, coherent and elementary access to significant findings and emerging trends. This will in turn help to delineate the metabolic plot in women with PCOS in various biological compartments including plasma, urine, follicular microenvironment, and gut. This may pave the way to design additional studies on the quest of unraveling the etiology of PCOS and delving into novel biomarkers for its diagnosis, prognosis and management.
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Affiliation(s)
- Aalaap Naigaonkar
- Department of Molecular Endocrinology, National Institute for Research in Reproductive and Child Health, Indian Council of Medical Research, Mumbai, India
| | - Roshan Dadachanji
- Department of Molecular Endocrinology, National Institute for Research in Reproductive and Child Health, Indian Council of Medical Research, Mumbai, India
| | - Manisha Kumari
- Department of Molecular Endocrinology, National Institute for Research in Reproductive and Child Health, Indian Council of Medical Research, Mumbai, India
| | - Srabani Mukherjee
- Department of Molecular Endocrinology, National Institute for Research in Reproductive and Child Health, Indian Council of Medical Research, Mumbai, India
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Wang Y, Zhu Z, Deng L, Cheng KK, Guo F, Lin G, Raftery D, Dong J. Multiscale Synergy Networks Offer Insights into Disease and Comorbidity Mechanisms. Anal Chem 2025; 97:3633-3642. [PMID: 39908457 DOI: 10.1021/acs.analchem.4c06133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2025]
Abstract
Complex diseases involve extensive metabolic interactions within intricate biological networks. Consequently, it is advantageous to analyze metabolic phenotype data through metabolite interactions rather than focus on individual metabolites in isolation. In this article, we propose a novel analysis strategy called SynNet, which constructs multiscale synergy networks associated with specific metabolic phenotypes, offering new perspectives on the metabolic response mechanisms of diseases, including the mechanisms underlying disease comorbidity. The SynNet strategy begins with the construction of a metabolite-level synergy network (m-SynNet). This network is based on the definition and identification of significant metabolite pair interactions that distinguish disease phenotypes. Subsequently, a pathway synergy effect is defined by mapping these synergistic metabolite pairs onto the predefined metabolic pathways and performing a hypergeometric test to assess the probability of these pairs affecting a given pathway pair. The resulting significant pathway pairs identified form a pathway-level synergy network (p-SynNet). Both m-SynNet and p-SynNet offer complementary insights into disease mechanisms that go beyond conventional metabolomics analysis. For example, nodes with high connectivity in m-/p-SynNet suggest a strong correlation with the phenotype, while shared pathways across different phenotypes offer clues about the mechanisms of disease comorbidity. We applied the SynNet strategy to two real-world metabolomic data sets of disease comorbidity and identified key pathways associated with disease comorbidity from the p-SynNet. The candidate pathways are supported by the existing literature. Thus, the SynNet strategy may represent an alternative approach for metabolomic data analysis, providing novel insights into disease mechanisms and comorbidity.
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Affiliation(s)
- Yongpei Wang
- Department of Electronic Science, National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen 361005, China
| | - Zeyu Zhu
- Department of Electronic Science, National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen 361005, China
| | - Lingli Deng
- Department of Information Engineering, East China University of Technology, Nanchang 330013, China
| | - Kian-Kai Cheng
- Faculty of Chemical and Energy Engineering, Universiti Teknologi Malaysia, Johor Bahru, Johor 81310, Malaysia
| | - Fanjing Guo
- Department of Electronic Science, National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen 361005, China
| | - Genjin Lin
- Department of Electronic Science, National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen 361005, China
| | - Daniel Raftery
- Northwest Metabolomics Research Center, University of Washington, Seattle, Washington 98109, United States
| | - Jiyang Dong
- Department of Electronic Science, National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen 361005, China
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20
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Zhou X, Zhang Y, Wei L, Yang Y, Wang B, Liu C, Bai J, Wang C. In vitro fermentation characteristics of fucoidan and its regulatory effects on human gut microbiota and metabolites. Food Chem 2025; 465:141998. [PMID: 39549519 DOI: 10.1016/j.foodchem.2024.141998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 10/29/2024] [Accepted: 11/08/2024] [Indexed: 11/18/2024]
Abstract
Dietary polysaccharides affect the intestinal microorganisms and their metabolites in the host. Clarifying the relationship among polysaccharides, intestinal microflora, and their metabolites is helpful to formulate dietary nutrition intervention strategies. Thus, we explored the regulatory effects of fucoidan on the human gut microbiota and its metabolites. After 48 h of fermentation, fucoidan significantly reduced the pH value in the broth, accompanied by an increase in total short-chain fatty acids, acetic acid, and propanoic acid contents. Fucoidan significantly reduced the relative abundance of Escherichia_shigella and Blebsiella and increased the relative abundance of Bifidobacterium and Lactobacillus. Concurrently, fucoidan altered the composition of intestinal microbial metabolites. These results indicate that fucoidan can regulate the metabolism of the intestinal flora and host, which may contribute to the intestinal health of the host.
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Affiliation(s)
- Xu Zhou
- College of Food Science, Southwest University, Chongqing 400715, China
| | - Yuyan Zhang
- College of Food Science, Southwest University, Chongqing 400715, China
| | - Li Wei
- College of Food Science, Southwest University, Chongqing 400715, China
| | - Yuhan Yang
- College of Food Science, Southwest University, Chongqing 400715, China
| | - Botao Wang
- Bloomage Biotechnology CO, LTD, Jinan, Shandong 250000, China
| | - Cuiping Liu
- Department of Radiology, Yuxi Children's Hospital, Yuxi, Yunnan 653100, China
| | - Junying Bai
- Citrus Research Institute, Southwest University, Chongqing 400700, China.
| | - Chen Wang
- College of Food Science, Southwest University, Chongqing 400715, China.
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21
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Ji W, Dang D, Zhou G, Tao L, Sun T, Li D, Cheng C, Feng H, Long J, Chen S, Yang H, Duan G, Jin Y. Metabolomic analysis reveals an important role of sphingosine 1-phosphate in the development of HFMD due to EV-A71 infection. Antimicrob Agents Chemother 2025; 69:e0127224. [PMID: 39692504 PMCID: PMC11823611 DOI: 10.1128/aac.01272-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 12/03/2024] [Indexed: 12/19/2024] Open
Abstract
Hand, foot, and mouth disease (HFMD) is a serious pediatric infectious disease that causes immeasurable physical and mental health burdens. Currently, there is a lack of information on the mechanisms of HFMD severity and early diagnosis. We performed metabolomic profiling of sera from 84 Enterovirus A71 (EV-A71) infections and 45 control individuals. Targeted metabolomics assays were employed to further validate some of the differential metabolic molecules. We identified significant molecular changes in the sera of HFMD patients compared to healthy controls (HCs). A total of 54, 60, 35, and 62 differential metabolites were screened between mild cases and HCs, severe cases and HCs, severe cases and mild cases, and among the three groups, respectively. These differential metabolites implicated dysregulation of the tricarboxylic acid cycle, alanine, aspartate, and glutamate metabolism, and valine, leucine, and isoleucine biosynthesis. The diagnostic panel based on some overlapped differential metabolites could effectively discriminate severe cases from mild cases with an AUC of 0.912 (95% CI: 0.85-0.97) using the logistic regression model. Next, we found the elevation of serum sphingosine 1-phosphate (S1P) level in EV-A71 infection mice, which was similar to clinical observation. Importantly, after blocking the release of S1P by MK571, the clinical symptoms and survival of mice were significantly improved, involving the reduction of leukocyte infiltration in infected brain tissues. Collectively, our data provided a landscape view of metabolic alterations in EV-A71 infected children and revealed regulating S1P metabolism was an exploitable therapeutic target against EV-A71 infection.
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Affiliation(s)
- Wangquan Ji
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Dejian Dang
- Department of Infection Control, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Guangyuan Zhou
- School of Public Health, Xinxiang Medical University, Xinxiang, Henan, China
| | - Ling Tao
- School of Public Health, Xinxiang Medical University, Xinxiang, Henan, China
| | - Tiantian Sun
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Dong Li
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Cheng Cheng
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Huifen Feng
- Department of Infection Control, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jinzhao Long
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Shuaiyin Chen
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Haiyan Yang
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Guangcai Duan
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Yuefei Jin
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
- Pingyuan Laboratory, Xinxiang, China
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22
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Zhou L, Song C, Zhao L, Guo Z, Lei Y, Han Y, Gao K, Xu Y, Xiang Z, Li B, Guo J. Impact of variations in airborne microbiota on pneumonia infection: An exploratory study. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 291:117795. [PMID: 39875253 DOI: 10.1016/j.ecoenv.2025.117795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 01/21/2025] [Accepted: 01/22/2025] [Indexed: 01/30/2025]
Abstract
BACKGROUND Previous studies showed airborne bacteria affect pneumonia incidence, but specific impacts of bacterial communities on Klebsiella pneumoniae infection were unknown. METHODS Five different ratios of bacterial community structures were randomly generated. Mice were divided into control, artificial bacterial community exposure, and corresponding Klebsiella pneumoniae challenge groups. Changes in body weight, blood parameters, pulmonary pathology, inflammatory factors, metabolomics, and fecal microbiota were analyzed. RESULTS Different bacterial community exposures had varying degrees of influence on body weight, complete blood count, inflammatory factors, alveolar lavage fluid and plasma metabolome, as well as intestinal microbiota at baseline and after infection. Metabolomic analysis showed that microbial exposure affected both bronchoalveolar lavage fluid and plasma metabolomes, suggesting systemic effects of microbial exposure on the organism. Differences in the structure of artificial microbiota had inconsistent effects on both the baseline state and the post-infection state, hinting at crosstalk between microbial exposure and Klebsiella pneumoniae infection. KEGG pathway analysis unveiled possible molecular mechanisms underlying the overall impact of microbial exposure on the lungs and the body as a whole. In the intestinal microbiota, differences were found in composition at the phylum and genus levels. Spearman correlation analysis established potential correlations between intestinal microbiota and differential metabolites, suggesting a potential link within the lung-gut axis. CONCLUSION This study demonstrated the significant and systemic impact of air microbiota structure differences on health. Future research should explore the underlying mechanisms to enhance our understanding of the air-environment-health relationship and identify interventions for improving public health strategies.
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Affiliation(s)
- Li Zhou
- National Human Diseases Animal Model Resource Center, National Center of Technology Innovation for animal model, State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious Diseases, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, CAMS & PUMC, Beijing, China
| | - Chenchen Song
- National Human Diseases Animal Model Resource Center, National Center of Technology Innovation for animal model, State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious Diseases, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, CAMS & PUMC, Beijing, China
| | - Lianlian Zhao
- National Human Diseases Animal Model Resource Center, National Center of Technology Innovation for animal model, State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious Diseases, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, CAMS & PUMC, Beijing, China
| | - Zhi Guo
- National Human Diseases Animal Model Resource Center, National Center of Technology Innovation for animal model, State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious Diseases, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, CAMS & PUMC, Beijing, China
| | - Yuhan Lei
- National Human Diseases Animal Model Resource Center, National Center of Technology Innovation for animal model, State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious Diseases, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, CAMS & PUMC, Beijing, China
| | - Yunlin Han
- National Human Diseases Animal Model Resource Center, National Center of Technology Innovation for animal model, State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious Diseases, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, CAMS & PUMC, Beijing, China
| | - Kai Gao
- National Human Diseases Animal Model Resource Center, National Center of Technology Innovation for animal model, State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious Diseases, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, CAMS & PUMC, Beijing, China
| | - Yanfeng Xu
- National Human Diseases Animal Model Resource Center, National Center of Technology Innovation for animal model, State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious Diseases, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, CAMS & PUMC, Beijing, China
| | - Zhiguang Xiang
- National Human Diseases Animal Model Resource Center, National Center of Technology Innovation for animal model, State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious Diseases, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, CAMS & PUMC, Beijing, China.
| | - Baicun Li
- National Clinical Research Center for Respiratory Diseases, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, ,China.
| | - Jianguo Guo
- National Human Diseases Animal Model Resource Center, National Center of Technology Innovation for animal model, State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious Diseases, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, CAMS & PUMC, Beijing, China.
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Lian N, Li F, Luo K, Kang Y, Yin Y, Lui S, Li T, Zhou C, Lu P. Reducing Dietary Branched-Chain Amino Acids Intake Alleviates High-Fat Diet-Induced Pain Sensitization and Postoperative Pain in Male Mice. J Nutr 2025; 155:413-421. [PMID: 39694143 DOI: 10.1016/j.tjnut.2024.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 12/02/2024] [Accepted: 12/06/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Poor dietary intake is associated with peripheral pain sensitization and postoperative pain. Given the limited research on diet and pain, it is essential to examine the possible analgesic effects of dietary interventions in preclinical studies. OBJECTIVES This study aimed to elucidate the role of high-fat diet (HFD) on pain sensitivity and postoperative pain, and determine the potential effects of modulating branched-chain amino acids (BCAA) intake on pain phenotypes. METHODS Four-week-old male mice were fed a purified control diet (CD) or HFD for 10 wk, followed by a hind paw incision. Four-week-old male mice were initially fed a CD or HFD for 8 wk, then switched to the high or low BCAA diet, and underwent a hind paw incision at 10 wk of these diets. Pain behaviors were assessed. Several proinflammatory genes in the lumbar dorsal root ganglion (DRG) were detected by quantitative polymerase chain reaction. Immunohistochemistry was used to estimate nerve fiber density at the incision site. Two-tailed unpaired Student's t-test, 2-way repeated-measures analysis of variance (ANOVA) with Bonferroni posttests, and 1-way ANOVA with Tukey's multiple comparisons test were used for data analysis. RESULTS HFD consumption induced pain sensitization and worsened postoperative pain in male mice (P < 0.0001). In CD group, mice switching to high or low BCAA diet displayed minor impacts on pain phenotypes. In HFD mice, switching to high BCAA diet exacerbated hyperalgesia and postsurgical pain (P < 0.05), leading to proinflammatory responses in the DRG and the reduction of nerve fiber density near the incision site on day 3 postsurgery (P < 0.05); whereas low BCAA diet intake alleviated these effects (P < 0.05). CONCLUSIONS High BCAA intake has negative impacts on pain sensitivity and postoperative pain in HFD-fed mice. Reducing dietary BCAA may be a novel nonpharmacological therapeutic to relieve pain in individuals on a conventional HFD.
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Affiliation(s)
- Nan Lian
- Department of Anesthesiology, Laboratory of Mitochondrial Metabolism and Perioperative Medicine, West China Hospital of Sichuan University, Chengdu, China; Department of Radiology, Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan University, Chengdu, China
| | - Fangzhou Li
- Department of Anesthesiology, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China; Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China
| | - Kaiteng Luo
- Department of Anesthesiology, Laboratory of Mitochondrial Metabolism and Perioperative Medicine, West China Hospital of Sichuan University, Chengdu, China; Department of Anesthesiology, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China; Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China
| | - Yi Kang
- Department of Anesthesiology, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China
| | - Yan Yin
- Department of Pain Management, West China Hospital of Sichuan University, Chengdu, China
| | - Su Lui
- Department of Radiology, Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan University, Chengdu, China
| | - Tao Li
- Department of Anesthesiology, Laboratory of Mitochondrial Metabolism and Perioperative Medicine, West China Hospital of Sichuan University, Chengdu, China; Department of Anesthesiology, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China
| | - Cheng Zhou
- Department of Anesthesiology, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China.
| | - Peilin Lu
- Department of Anesthesiology, Laboratory of Mitochondrial Metabolism and Perioperative Medicine, West China Hospital of Sichuan University, Chengdu, China; Department of Anesthesiology, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China; Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China.
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24
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Rocchetti G, Vezzulli F, Senizza B, Betti A, Dordoni R, Lambri M, Lucini L. The contribution of sturgeon species and processing conditions on caviar texture, metabolomic profile and sensory traits. Food Chem 2025; 463:141516. [PMID: 39369608 DOI: 10.1016/j.foodchem.2024.141516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 09/17/2024] [Accepted: 09/30/2024] [Indexed: 10/08/2024]
Abstract
A comprehensive evaluation of the attributes that determine caviar quality, including sturgeon species and processing methods, is still lacking in the scientific literature. In this study, eight types of caviar, obtained from six different sturgeon species and produced using either salt or a combination of salt and sodium tetraborate (E285) with pasteurization, were characterized through untargeted metabolomics, sensory analysis, and texture evaluation. The results showed that Huso huso caviar was rich in gamma-glutamyl peptides (contributing to a kokumi taste), while the other sturgeon species were primarily distinguished by lipids (mainly glycerophospholipids) and nucleotides (such as AMP, inosinic acid, and other metabolites driving umami taste). Moreover, untargeted metabolomics revealed the technological effects of salting and pasteurization. Sensory analysis identified crunchiness, color homogeneity, and darkness as the main traits differentiating the products. Butter, hazelnut, and briny flavours were also key characteristics of the caviar.
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Affiliation(s)
- Gabriele Rocchetti
- Department of Animal Science, Food and Nutrition, Università Cattolica del Sacro Cuore, Via Emilia Parmense 84, 29122 Piacenza, Italy.
| | - Fosca Vezzulli
- Department for Sustainable Food Process, Università Cattolica del Sacro Cuore, Via Emilia Parmense 84, 29122 Piacenza, Italy
| | - Biancamaria Senizza
- Department for Sustainable Food Process, Università Cattolica del Sacro Cuore, Via Emilia Parmense 84, 29122 Piacenza, Italy
| | - Andrea Betti
- Department for Sustainable Food Process, Università Cattolica del Sacro Cuore, Via Emilia Parmense 84, 29122 Piacenza, Italy
| | - Roberta Dordoni
- Department for Sustainable Food Process, Università Cattolica del Sacro Cuore, Via Emilia Parmense 84, 29122 Piacenza, Italy
| | - Milena Lambri
- Department for Sustainable Food Process, Università Cattolica del Sacro Cuore, Via Emilia Parmense 84, 29122 Piacenza, Italy
| | - Luigi Lucini
- Department for Sustainable Food Process, Università Cattolica del Sacro Cuore, Via Emilia Parmense 84, 29122 Piacenza, Italy
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25
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Yamamoto N, Tojo K, Mihara T, Maeda R, Sugiura Y, Goto T. Creatinine production rate is an integrative indicator to monitor muscle status in critically ill patients. Crit Care 2025; 29:23. [PMID: 39810218 PMCID: PMC11731194 DOI: 10.1186/s13054-024-05222-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 12/18/2024] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND Both quantitative and qualitative aspects of muscle status significantly impact clinical outcomes in critically ill patients. Comprehensive monitoring of baseline muscle status and its changes is crucial for risk stratification and management optimization. However, repeatable and accessible indicators are lacking. We hypothesized that creatinine production rate (CPR) could serve as an integrative indicator of skeletal muscle status. METHODS We conducted a series of animal and clinical studies. First, animal experiments were performed to determine whether CPR reflects not only muscle volume, but also qualitative muscle properties. We also evaluated the effects of acute systemic inflammation, a common feature of critical illness, on CPR, as well as its impact on muscle volume and metabolism. In clinical studies, we analyzed CPR, calculated based on urinary creatinine excretion and changes in serum creatinine, of critically ill patients. We assessed the factors affecting CPR on ICU admission and its temporal changes. Finally, we evaluated the clinical utility of CPR by examining the associations of the CPR index (CPR divided by height squared) on ICU admission and its changes with one-year survival. RESULTS Animal studies revealed that CPR is determined by muscle volume, creatine content, and metabolic status. Systemic inflammation accompanied by muscle loss led to reduced CPR. Moreover, even without muscle loss, systemic inflammation decreased CPR, likely due to metabolic derangements. In ICU patients, CPR on admission strongly correlated with muscle cross-sectional area (CSA), with age and sex as additional significant factors. In contrast, the percent change in CPR showed a weak correlation with muscle CSA changes. Additionally, the acute-phase CPR trajectories did not show a consistent decline, suggesting multifactorial influences. In a cohort of 629 ICU patients, lower baseline CPR index (hazard ratio [HR] 1.125 per 0.1 g/day/m2 less, P < .001) and a decrease in CPR over the first three days (HR 1.028 per 5%, P = 0.032) were independently associated with higher one-year mortality. CONCLUSIONS CPR represents an integrative indicator of skeletal muscle status in critically ill patients, reflecting both quantitative and qualitative aspects. Monitoring CPR in the ICU may facilitate risk stratification and optimization of patient care.
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Affiliation(s)
- Natsuhiro Yamamoto
- Department of Anesthesiology and Critical Care Medicine, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
| | - Kentaro Tojo
- Department of Anesthesiology and Critical Care Medicine, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan.
| | - Takahiro Mihara
- Department of Health Data Science, Yokohama City University Graduate School of Data Science, Yokohama, Kanagawa, Japan
| | - Rae Maeda
- Center for Cancer Immunotherapy and Immunobiology (CCII), Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuki Sugiura
- Center for Cancer Immunotherapy and Immunobiology (CCII), Kyoto University Graduate School of Medicine, Kyoto, Japan
- Human Biology Microbiome Quantum Research Center (WPI-Bio2Q), Keio University School of Medicine, Tokyo, Japan
| | - Takahisa Goto
- Department of Anesthesiology and Critical Care Medicine, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
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da Silva FMO, Pimenta AM, Juvanhol LL, Hermsdorff HHM, Bressan J. Obesity Incidence According to Branched-Chain Amino Acid Intake and Plant-Based Diet Index Among Brazilian Adults: A Six-Year Follow-Up of the CUME Study. Nutrients 2025; 17:227. [PMID: 39861357 PMCID: PMC11767458 DOI: 10.3390/nu17020227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 01/03/2025] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND Few studies have evaluated the impact of branched-chain amino acid (BCAA) intake on the risk of obesity in adults. The results are contradictory, and the causality has not been explored. This study assessed the association between BCAA intake and obesity incidence among Brazilian adults and investigated the potential moderating role of the plant-based index (PDI) in this relationship. METHODS A longitudinal study was conducted between 2016 and 2022, with 3090 participants (2043 women, 1047 men; mean age 34 years) from the Cohort of Universities of Minas Gerais (CUME) Study. Data were collected through an online questionnaire. The relationship between BCAA intake and obesity incidence was assessed using crude and adjusted Cox regression models. Restricted cubic spline analysis (RCS) was used to estimate the nonlinearity. The multiplicative interaction with PDI was tested. RESULTS The overall incidence of obesity was 192 cases (6.21%). The incidence was 16.4/1000 person-years in females; 21.8/1000 person-years in males; and 18.3/1000 person-years total, with a mean follow-up period of 3.4 years. Compared to the first tertile, the highest intake tertiles for BCAA (HR = 1.50, 95% CI = 1.03-2.18), isoleucine (HR = 1.52, 95% CI = 1.04-2.22), and leucine (HR = 1.51, 95% CI = 1.03-2.20) were independently associated with obesity risk. BCAA intake above 16 g/day increases the risk of obesity. CONCLUSIONS There was a positive association between the intake of BCAA, isoleucine, and leucine with the risk of obesity. The PDI accentuated the association between BCAA intake and obesity in both the lowest and highest quintiles.
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Affiliation(s)
- Fernanda Maria Oliveira da Silva
- Laboratory of Energy Metabolism and Body Composition, Department of Nutrition and Health, Federal University of Viçosa, Viçosa 36570-900, Brazil; (F.M.O.d.S.); (H.H.M.H.)
- Laboratory of Clinical Analysis and Genomics, Department of Nutrition and Health, Federal University of Viçosa, Viçosa 36570-900, Brazil
| | | | | | - Helen Hermana Miranda Hermsdorff
- Laboratory of Energy Metabolism and Body Composition, Department of Nutrition and Health, Federal University of Viçosa, Viçosa 36570-900, Brazil; (F.M.O.d.S.); (H.H.M.H.)
- Laboratory of Clinical Analysis and Genomics, Department of Nutrition and Health, Federal University of Viçosa, Viçosa 36570-900, Brazil
| | - Josefina Bressan
- Laboratory of Energy Metabolism and Body Composition, Department of Nutrition and Health, Federal University of Viçosa, Viçosa 36570-900, Brazil; (F.M.O.d.S.); (H.H.M.H.)
- Laboratory of Clinical Analysis and Genomics, Department of Nutrition and Health, Federal University of Viçosa, Viçosa 36570-900, Brazil
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Li Y, Zhou J, Guo T, Zhang H, Cao C, Cai Y, Zhang J, Li T, Zhang J. Effects of adding a kind of compound bio-enzyme to the diet on the production performance, serum immunity, and intestinal health of Pekin ducks. Poult Sci 2025; 104:104506. [PMID: 39700598 PMCID: PMC11720614 DOI: 10.1016/j.psj.2024.104506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 10/25/2024] [Accepted: 11/02/2024] [Indexed: 12/21/2024] Open
Abstract
The use of bio-enzyme as feed additives holds significant potential. This study aimed to evaluate the impact of a kind of compound bio-enzyme supplementation (the main functional components are probiotics and astragalus polysaccharides) on the production performance, serum immunity, and intestinal health of Pekin ducks. A total of 126 male Pekin ducks were randomly assigned to three groups: a control group (CG, no additive), a low-dose group (LG, 0.1 % bio-enzyme), and a high-dose group (HG, 0.2 % bio-enzyme), with 6 replicates per group. Ducks were raised until 35 days of age, with weekly measurements of growth performance. At day 35, serum immunoglobulins were measured, carcass traits were recorded, and cecal contents were analyzed using 16S rRNA sequencing and metabolomics. Results indicated a significant increase in ADG (P = 0.049) and a decrease in feed-to-gain ratio (F:G) (P = 0.020) in LG and HG compared to CG during rearing. The HG showed a notable improvement in half eviscerated yield (HEY) (P = 0.023) and full eviscerated yield (FEY) (P = 0.008). No substantial changes were observed in immunological parameters (P > 0.05). The jejunal villus height to crypt depth ratio (VH/CD) significantly increased (P < 0.001) in LG, with notable improvements in duodenal (P = 0.001) and jejunal (P < 0.001) VH/CD in HG. The Shannon index (P = 0.042) and Pielou index (P = 0.038) of cecal microbiota were markedly lower in HG. Notable changes in the relative abundance of Firmicutes and Bacteroidota were observed in LG and HG. Differential bacteria and metabolites among the treatments were identified, and their correlations were analyzed. KEGG enrichment pathways of the metabolites were also identified. In conclusion, this bio-enzyme can improve production performance, intestinal wall structure, and microbiota in Pekin ducks. A 0.1 % concentration of this bio-enzyme is optimal for Pekin duck production.
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Affiliation(s)
- Yuxiao Li
- College of Animal Science and Technology, Northwest A&F University, Xianyang 712100, China
| | - Jie Zhou
- College of Animal Science and Technology, Northwest A&F University, Xianyang 712100, China
| | - Tong Guo
- College of Animal Science and Technology, Northwest A&F University, Xianyang 712100, China
| | - Huiya Zhang
- College of Animal Science and Technology, Northwest A&F University, Xianyang 712100, China
| | - Chang Cao
- College of Animal Science and Technology, Northwest A&F University, Xianyang 712100, China
| | - Yingjie Cai
- College of Animal Science and Technology, Northwest A&F University, Xianyang 712100, China
| | - Jiqiao Zhang
- College of Animal Science and Technology, Northwest A&F University, Xianyang 712100, China
| | - Tao Li
- College of Animal Science and Technology, Northwest A&F University, Xianyang 712100, China
| | - Jianqin Zhang
- College of Animal Science and Technology, Northwest A&F University, Xianyang 712100, China.
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Wunderle C, Ciobanu C, Ritz J, Tribolet P, Neyer P, Bernasconi L, Stanga Z, Mueller B, Schuetz P. Association of leucine and other branched chain amino acids with clinical outcomes in malnourished inpatients: a secondary analysis of the randomized clinical trial EFFORT. Eur J Clin Nutr 2025; 79:42-49. [PMID: 39245679 DOI: 10.1038/s41430-024-01507-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 08/30/2024] [Accepted: 09/02/2024] [Indexed: 09/10/2024]
Abstract
BACKGROUND The essential branched-chain amino acids leucine, isoleucine and valine are considered anabolic and stimulate protein synthesis in the muscles as well in the liver. They also promote muscle recovery and contribute to glucose homeostasis. Recent studies in critically ill patients have demonstrated that depletion of plasma leucine is associated with increased mortality, but data in the non-critical care setting is lacking. METHODS This secondary analysis of the randomized controlled Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT), investigated the impact of leucine, isoleucine, and valine metabolism on clinical outcomes. The primary endpoint was 180-day all-cause mortality. RESULTS Among 238 polymorbid patients with available metabolite measurements, low serum leucin levels were associated with a doubled risk of 180-day all-cause mortality in a fully adjusted regression model (adjusted HR 2.20 [95% CI 1.46-3.30], p < 0.001). There was also an association with mortality for isoleucine (1.56 [95% CI 1.03-2.35], p = 0.035) and valine (1.69 [95% CI 1.13-2.53], p = 0.011). When comparing effects of nutritional support on mortality in patients with high and low levels of leucine, there was no evidence of significant differences in effectiveness of the intervention. The same was true for isoleucine and valine. CONCLUSION Our data suggest that depletion of leucine, isoleucine, and valine among malnourished polymorbid patients is associated with increases in long-term mortality. However, patients with low metabolite levels did not show a pronounced benefit from nutritional support. Further research should focus on the clinical effects of nutritional support in patients with depleted stores of essential branched-chain amino acids. CLINICAL TRIAL REGISTRATION clinicaltrials.gov as NCT02517476 (registered 7 August 2015).
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Affiliation(s)
- Carla Wunderle
- Medical University Department, Division of General Internal and Emergency Medicine, Division of Endocrinology, Diabetes and Metabolism, Kantonsspital Aarau, Aarau, Switzerland
| | - Claudia Ciobanu
- Medical University Department, Division of General Internal and Emergency Medicine, Division of Endocrinology, Diabetes and Metabolism, Kantonsspital Aarau, Aarau, Switzerland
- Medical Faculty of the University of Basel, Basel, Switzerland
| | - Jacqueline Ritz
- Medical University Department, Division of General Internal and Emergency Medicine, Division of Endocrinology, Diabetes and Metabolism, Kantonsspital Aarau, Aarau, Switzerland
- Medical Faculty of the University of Basel, Basel, Switzerland
| | - Pascal Tribolet
- Medical University Department, Division of General Internal and Emergency Medicine, Division of Endocrinology, Diabetes and Metabolism, Kantonsspital Aarau, Aarau, Switzerland
- Department of Health Professions, Bern University of Applied Sciences, Bern, Switzerland
- Department of Nutritional Sciences and Research Platform Active Ageing, University of Vienna, Vienna, Austria
| | - Peter Neyer
- Institute of Laboratory Medicine, Kantonsspital Aarau, Aarau, Switzerland
| | - Luca Bernasconi
- Institute of Laboratory Medicine, Kantonsspital Aarau, Aarau, Switzerland
| | - Zeno Stanga
- Division of Diabetes, Endocrinology, Nutritional Medicine, and Metabolism, Bern University Hospital and University of Bern, Bern, Switzerland
| | - Beat Mueller
- Medical University Department, Division of General Internal and Emergency Medicine, Division of Endocrinology, Diabetes and Metabolism, Kantonsspital Aarau, Aarau, Switzerland
- Medical Faculty of the University of Basel, Basel, Switzerland
| | - Philipp Schuetz
- Medical University Department, Division of General Internal and Emergency Medicine, Division of Endocrinology, Diabetes and Metabolism, Kantonsspital Aarau, Aarau, Switzerland.
- Medical Faculty of the University of Basel, Basel, Switzerland.
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Bo T, Osaki T, Fujii J. Dephosphorylation of branched-chain α-keto acid dehydrogenase E1α (BCKDHA) promotes branched-chain amino acid catabolism and renders cancer cells resistant to X-rays by mitigating DNA damage. Biochem Biophys Res Commun 2025; 742:151154. [PMID: 39672007 DOI: 10.1016/j.bbrc.2024.151154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 11/29/2024] [Accepted: 12/05/2024] [Indexed: 12/15/2024]
Abstract
Branched-chain amino acids (BCAAs) facilitate cancer cell proliferation and survival. Stresses, including X-irradiation, increase BCAA uptake. However, the role of BCAA metabolism in cancer cell survival remains unclear. Therefore, this study aimed to elucidate the role of the BCAA catabolic pathway in cancer cell survival following X-irradiation. X-irradiation dose-dependently dephosphorylated branched-chain α-keto acid dehydrogenaseE1α (BCKDHA) suggesting the activation of the BCKDH complex, which catalyzes the rate-determining step of BCAA catabolism. We considered that activation of BCKDH promoted the BCAA catabolism, which resulted in cancer cell resistance to X-irradiation. Consistent with this notion, cells with BCKDHA knockdown exhibited increased radiosensitivity, which was associated with the increase in mitotic catastrophe and residual double-strand breaks by decreasing cellular ATP levels after X-irradiation. Our results suggest that BCKDHA dephosphorylation promotes BCAA catabolism, leading to cell survival by mitigating DNA damage after X-irradiation. Thus, BCAA catabolic pathway may be a target for radiation therapy.
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Affiliation(s)
- Tomoki Bo
- Laboratory Animal Center, Institute for Promotion of Medical Science Research, Yamagata University Faculty of Medicine, Japan.
| | - Tsukasa Osaki
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Japan
| | - Junichi Fujii
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Japan
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Deng X, Tang C, Fang T, Li T, Li X, Liu Y, Zhang X, Sun B, Sun H, Chen L. Disruption of branched-chain amino acid homeostasis promotes the progression of DKD via enhancing inflammation and fibrosis-associated epithelial-mesenchymal transition. Metabolism 2025; 162:156037. [PMID: 39317264 DOI: 10.1016/j.metabol.2024.156037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 09/12/2024] [Accepted: 09/18/2024] [Indexed: 09/26/2024]
Abstract
BACKGROUND AND AIMS The disrupted homeostasis of branched-chain amino acids (BCAAs, including leucine, isoleucine, and valine) has been strongly correlated with diabetes with a potential causal role. However, the relationship between BCAAs and diabetic kidney disease (DKD) remains to be established. Here, we show that the elevated BCAAs from BCAAs homeostatic disruption promote DKD progression unexpectedly as an independent risk factor. METHODS AND RESULTS Similar to other tissues, the suppressed BCAAs catabolic gene expression and elevated BCAAs abundance were detected in the kidneys of type 2 diabetic mice and individuals with DKD. Genetic and nutritional studies demonstrated that the elevated BCAAs from systemic disruption of BCAAs homeostasis promoted the progression of DKD. Of note, the elevated BCAAs promoted DKD progression without exacerbating diabetes in the animal models of type 2 DKD. Mechanistic studies demonstrated that the elevated BCAAs promoted fibrosis-associated epithelial-mesenchymal transition (EMT) by enhancing the activation of proinflammatory macrophages through mTOR signaling. Furthermore, pharmacological enhancement of systemic BCAAs catabolism using small molecule inhibitor attenuated type 2 DKD. Finally, the elevated BCAAs also promoted DKD progression in type 1 diabetic mice without exacerbating diabetes. CONCLUSION BCAA homeostatic disruption serves as an independent risk factor for DKD and restoring BCAA homeostasis pharmacologically or dietarily represents a promising therapeutic strategy to ameliorate the progression of DKD.
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Affiliation(s)
- Xiaoqing Deng
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Chao Tang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China; Affiliated Huzhou Hospital, Zhejiang University School of Medicine, China
| | - Ting Fang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Ting Li
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Xiaoyu Li
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Yajin Liu
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Xuejiao Zhang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Bei Sun
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Haipeng Sun
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China; Center for Cardiovascular Diseases, The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin, China.
| | - Liming Chen
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China.
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Fritz R, Kiricsi Á, Csanády M, Fritz P. Effects of branched-chain amino acids on changes in body composition during the recovery period following tonsillectomy. Eur Arch Otorhinolaryngol 2025; 282:387-394. [PMID: 39242416 PMCID: PMC11735486 DOI: 10.1007/s00405-024-08902-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 08/08/2024] [Indexed: 09/09/2024]
Abstract
PURPOSE In recent decades studies have examined body weight changes following tonsillectomy. In nutrition science, the focus has shifted from body mass index to body composition analysis. However, no studies have explored body composition changes post-tonsillectomy. In oncology and digestive surgeries, the potential benefits of branched-chain amino acids (BCAAs) have been investigated; however, their effects on pharyngeal surgery remain unknown. Therefore, the aim of the present study was to investigate the body composition changes after tonsillectomy and to explore the potential benefits of branched-chain amino acids. METHODS This prospective interventional controlled study enrolled 48 patients who were randomly assigned to a control group (CG) and an experimental group (EG). These groups were further divided into active and inactive subgroups on the basis of their activity levels. The EG consumed 2 × 4 mg of BCAA daily. Body composition was measured using bioimpedance (InBody 270) on the day of surgery and again on days 7 and 21 postoperatively. RESULTS Both groups experienced similar weight loss; however, significant differences in body composition emerged. The CG showed significant muscle mass loss (from 30,29 to 28,51 kg), whereas active EG members maintained muscle mass (from 35,33 to 35,40 kg); inactive EG members increased muscle mass (from 26,70 to 27,56 kg) and reduced body fat percentage (from 31.94% to 29.87%). The general health status (InBody score) remained stable or improved in the EG (from 75,13 to 75,96); however, it decreased in the CG (from 75,42 to 72,67). CONCLUSION The negative effects of tonsillectomy on body composition are mitigated by BCAA supplementation.
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Affiliation(s)
- Réka Fritz
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary.
- Department of Oto-Rhino-Laryngology and Head-and Neck Surgery, University of Szeged, Tisza Lajos Krt. 111, Szeged, 6725, Hungary.
| | - Ágnes Kiricsi
- Department of Oto-Rhino-Laryngology and Head-and Neck Surgery, University of Szeged, Tisza Lajos Krt. 111, Szeged, 6725, Hungary
| | - Miklós Csanády
- Department of Oto-Rhino-Laryngology and Head-and Neck Surgery, University of Szeged, Tisza Lajos Krt. 111, Szeged, 6725, Hungary
| | - Péter Fritz
- Károli Gáspár University of the Reformed Church in Hungary, Faculty of Humanities and Social Sciences, Budapest, Hungary
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Wu Y, Jiang W, Wang J, Xie G, Sun Y, Yang J. Disruption of BCAA degradation is a critical characteristic of diabetic cardiomyopathy revealed by integrated transcriptome and metabolome analysis. Open Life Sci 2024; 19:20220974. [PMID: 39822378 PMCID: PMC11736389 DOI: 10.1515/biol-2022-0974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 08/27/2024] [Accepted: 08/29/2024] [Indexed: 01/19/2025] Open
Abstract
In this study, we integrated transcriptomic and metabolomic analyses to achieve a comprehensive understanding of the underlying mechanisms of diabetic cardiomyopathy (DCM) in a diabetic rat model. Functional and molecular characterizations revealed significant cardiac injury, dysfunction, and ventricular remodeling in DCM. A thorough analysis of global changes in genes and metabolites showed that amino acid metabolism, especially the breakdown of branched-chain amino acids (BCAAs) such as valine, leucine, and isoleucine, is highly dysregulated. Furthermore, the study identified the transcription factor Gata3 as a predicted negative regulator of the gene encoding the key enzyme for BCAA degradation. These findings suggest that the disruption of BCAA degradation is a critical characteristic of diabetic myocardial damage and indicate a potential role for Gata3 in the dysregulation of BCAA metabolism in the context of DCM.
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Affiliation(s)
- Yanxia Wu
- State/National Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, 610000, P. R. China
- Sichuan Greentech Bioscience Co., Ltd., Meishan, Sichuan, 620010, P. R. China
| | - Wanxiang Jiang
- Sichuan Greentech Bioscience Co., Ltd., Meishan, Sichuan, 620010, P. R. China
| | - Junlong Wang
- Sichuan Greentech Bioscience Co., Ltd., Meishan, Sichuan, 620010, P. R. China
| | - Guoqing Xie
- Sichuan Greentech Bioscience Co., Ltd., Meishan, Sichuan, 620010, P. R. China
| | - Yan Sun
- Sichuan Greentech Bioscience Co., Ltd., Meishan, Sichuan, 620010, P. R. China
| | - Jinliang Yang
- State/National Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, 610000, P. R. China
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Huang H, Qin J, Wen Z, Wang C, Chen C, Liu Y, Li H, Cao S, Yang X. Association of branched-chain amino acids and risk of three urologic cancers: a Mendelian randomization study. Transl Cancer Res 2024; 13:6709-6720. [PMID: 39816560 PMCID: PMC11729756 DOI: 10.21037/tcr-24-1142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 10/31/2024] [Indexed: 01/18/2025]
Abstract
Background Multiple studies suggest a plausible connection between urologic cancers and branched-chain amino acids (BCAAs) breakdown metabolic enzymes. Nevertheless, there is scarce exploration into the variations in circulating BCAAs. In our research, we utilize bidirectional, two-sample Mendelian randomization (MR) analysis to predict the link between BCAAs levels and three distinct types of urological tumors. Methods The study examined data from the UK Biobank, including a comprehensive genome-wide association study (GWAS) of total BCAAs, leucine, isoleucine, and valine, alongside three urological system tumors [prostate cancer (PCa), kidney cancer, and bladder cancer] sourced from the Medical Research Council Integrative Epidemiology Unit (MRC-IEU) and FinnGen Consortium databases. The primary analytical approach involved the use of the inverse variance weighted (IVW) method, complemented by MR-PRESSO global testing and MR-Egger regression to identify potential horizontal pleiotropy. Heterogeneity was evaluated using the Cochran Q test. Results The levels of circulating total BCAAs [odds ratio (OR) =1.002688, 95% confidence interval (CI): 1.000, 1.005, P=0.03], leucine (OR =1.0038, 95% CI: 1.001, 1.007, P=0.008), isoleucine (OR =1.003352, 95% CI: 1.000, 1.007, P=0.04), and valine (OR =1.00279, 95% CI: 1.001, 1.005, P=0.009) showed positive associations with PCa risk. However, there was inadequate evidence to establish a link between BCAAs and bladder or kidney cancer. Conclusions In summary, an association existed between elevated levels of circulating total BCAAs, leucine, isoleucine, and valine, and an increased risk of PCa. However, no correlation was detected between BCAAs and kidney or bladder cancer.
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Affiliation(s)
- Haotian Huang
- Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Jiao Qin
- Department of Anesthesiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Zhi Wen
- Department of Urology, Langzhong People’s Hospital, Langzhong, China
| | - Chongjian Wang
- Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Caixia Chen
- Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Yang Liu
- Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Hongyuan Li
- Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Song Cao
- Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Xuesong Yang
- Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Health Management Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
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Bo T, Fujii J. Primary Roles of Branched Chain Amino Acids (BCAAs) and Their Metabolism in Physiology and Metabolic Disorders. Molecules 2024; 30:56. [PMID: 39795113 PMCID: PMC11721030 DOI: 10.3390/molecules30010056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 12/25/2024] [Accepted: 12/25/2024] [Indexed: 01/13/2025] Open
Abstract
Leucine, isoleucine, and valine are collectively known as branched chain amino acids (BCAAs) and are often discussed in the same physiological and pathological situations. The two consecutive initial reactions of BCAA catabolism are catalyzed by the common enzymes referred to as branched chain aminotransferase (BCAT) and branched chain α-keto acid dehydrogenase (BCKDH). BCAT transfers the amino group of BCAAs to 2-ketoglutarate, which results in corresponding branched chain 2-keto acids (BCKAs) and glutamate. BCKDH performs an oxidative decarboxylation of BCKAs, which produces their coenzyme A-conjugates and NADH. BCAT2 in skeletal muscle dominantly catalyzes the transamination of BCAAs. Low BCAT activity in the liver reduces the metabolization of BCAAs, but the abundant presence of BCKDH promotes the metabolism of muscle-derived BCKAs, which leads to the production of glucose and ketone bodies. While mutations in the genes responsible for BCAA catabolism are involved in rare inherited disorders, an aberrant regulation of their enzymatic activities is associated with major metabolic disorders such as diabetes, cardiovascular disease, and cancer. Therefore, an understanding of the regulatory process of metabolic enzymes, as well as the functions of the BCAAs and their metabolites, make a significant contribution to our health.
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Affiliation(s)
- Tomoki Bo
- Laboratory Animal Center, Institute for Promotion of Medical Science Research, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan
| | - Junichi Fujii
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata 990-9585, Japan
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Dawangpa A, Chitta P, Rodrigues GDS, Iadsee N, Noronha NY, Nonino CB, Bueno Júnior CR, Sae-Lee C. Impact of combined exercise on blood DNA methylation and physical health in older women with obesity. PLoS One 2024; 19:e0315250. [PMID: 39680552 DOI: 10.1371/journal.pone.0315250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 11/21/2024] [Indexed: 12/18/2024] Open
Abstract
This study examined the effects of a 14-week combined exercise program on blood DNA methylation (DNAm) and its potential biological pathways in normal-weight, overweight, and obese older women. A total of 41 participants were assessed at baseline, 7 weeks, and 14 weeks into the training. Their whole-blood DNAm profiles were measured using the Infinitum MethylationEPIC BeadChip, alongside physical and biochemical health evaluations. The results showed notable health improvements, with decreases in blood pressure and cholesterol levels in the overweight and obese groups. Blood triglycerides were reduced only in the overweight group. Physical performance also improved across all groups. At 14 weeks, 1,043 differentially methylated positions (DMPs) were identified, affecting 744 genes. The genes were linked to biological processes, such as cellular metabolism, with significant pathway enrichment related to oxidative phosphorylation and chemical carcinogenesis. Additionally, the overweight group experienced significant reductions in methylation levels at eight lipogenesis-related genes. Protein EpiScore analysis revealed decreased levels of CCL11, VEGFA, and NTRK3 proteins at 14 weeks compared to baseline. Despite these significant molecular changes, there was no observable difference in DNAm age after the intervention. This study highlights how combined exercise can modify DNAm patterns in older women, particularly in lipogenesis-related genes, but suggests that further research is needed to understand the full implications for biological ageing.
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Affiliation(s)
- Atchara Dawangpa
- Research Division, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Pitaksin Chitta
- Research Division, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | | | - Nutta Iadsee
- Research Division, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Natália Y Noronha
- Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Carla B Nonino
- Health Sciences Department, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Carlos R Bueno Júnior
- School of Physical Education and Sport of Ribeirão Preto, University of Sao Paulo, Sao Paulo, Brazil
| | - Chanachai Sae-Lee
- Research Division, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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Tews HC, Schmelter F, Kandulski A, Büchler C, Schmid S, Schlosser S, Elger T, Loibl J, Sommersberger S, Fererberger T, Gunawan S, Kunst C, Gülow K, Bettenworth D, Föh B, Maaß C, Solbach P, Günther UL, Derer S, Marquardt JU, Sina C, Müller M. Unique Metabolomic and Lipidomic Profile in Serum From Patients With Crohn's Disease and Ulcerative Colitis Compared With Healthy Control Individuals. Inflamm Bowel Dis 2024; 30:2405-2417. [PMID: 38156773 PMCID: PMC11630276 DOI: 10.1093/ibd/izad298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND Accurate biomarkers for disease activity and progression in patients with inflammatory bowel disease (IBD) are a prerequisite for individual disease characterization and personalized therapy. We show that metabolic profiling of serum from IBD patients is a promising approach to establish biomarkers. The aim of this work was to characterize metabolomic and lipidomic serum profiles of IBD patients in order to identify metabolic fingerprints unique to the disease. METHODS Serum samples were obtained from 55 patients with Crohn's disease (CD), 34 patients with ulcerative colitis (UC), and 40 healthy control (HC) individuals and analyzed using proton nuclear magnetic resonance spectroscopy. Classification of patients and HC individuals was achieved by orthogonal partial least squares discriminant analysis and univariate analysis approaches. Disease activity was assessed using the Gastrointestinal Symptom Rating Scale. RESULTS Serum metabolome significantly differed between CD patients, UC patients, and HC individuals. The metabolomic differences of UC and CD patients compared with HC individuals were more pronounced than the differences between UC and CD patients. Differences in serum levels of pyruvic acid, histidine, and the branched-chain amino acids leucine and valine were detected. The size of low-density lipoprotein particles shifted from large to small dense particles in patients with CD. Of note, apolipoprotein A1 and A2 serum levels were decreased in CD and UC patients with higher fecal calprotectin levels. The Gastrointestinal Symptom Rating Scale is negatively associated with the concentration of apolipoprotein A2. CONCLUSIONS Metabolomic assessment of serum samples facilitated the differentiation of IBD patients and HC individuals. These differences were constituted by changes in amino acid and lipoprotein levels. Furthermore, disease activity in IBD patients was associated with decreased levels of the atheroprotective apolipoproteins A1 and A2.
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Affiliation(s)
- Hauke Christian Tews
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Franziska Schmelter
- Institute of Nutritional Medicine, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Arne Kandulski
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Christa Büchler
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Stephan Schmid
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Sophie Schlosser
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Tanja Elger
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Johanna Loibl
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Stefanie Sommersberger
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Tanja Fererberger
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Stefan Gunawan
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Claudia Kunst
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Karsten Gülow
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Dominik Bettenworth
- Department of Medicine B—Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany
- Practice for Internal Medicine, Münster, Germany
| | - Bandik Föh
- Department of Medicine I, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Carlos Maaß
- Department of Medicine I, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Philipp Solbach
- Department of Medicine I, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Ulrich L Günther
- Institute of Chemistry and Metabolomics, University of Lübeck, Lübeck, Germany
| | - Stefanie Derer
- Institute of Nutritional Medicine, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Jens U Marquardt
- Department of Medicine I, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Christian Sina
- Institute of Nutritional Medicine, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
- Department of Medicine I, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
- Fraunhofer Research Institution for Individualized and Cell-Based Medical Engineering, Lübeck, Germany
| | - Martina Müller
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
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Goo D, Lee J, Paneru D, Sharma MK, Rafieian-Naeini HR, Mahdavi FS, Gyawali I, Gudidoddi SR, Han G, Kim WK. Effects of branched-chain amino acid imbalance and dietary valine and isoleucine supplementation in modified corn-soybean meal diets with corn distillers dried grains with solubles on growth performance, carcass quality, intestinal health, and cecal microbiome in Cobb 500. Poult Sci 2024; 103:104483. [PMID: 39510006 PMCID: PMC11577229 DOI: 10.1016/j.psj.2024.104483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 10/29/2024] [Accepted: 10/30/2024] [Indexed: 11/15/2024] Open
Abstract
One important feature of corn distillers dried grains with solubles (DDGS) is its high leucine:lysine ratio, which can inhibit chicken growth by causing branched-chain amino acid (BCAA) antagonism. The current study was conducted to investigate the effects of BCAA imbalance of inclusion of DDGS and whether additional dietary valine and isoleucine could alleviate the negative effects in broilers. A total of 640 0-d-old male Cobb 500 broilers were allocated into 4 treatments with 8 replicates and reared until d 42. The four different dietary groups were as follows: 1) control (CON) group (corn-soybean meal-based diet); 2) 30% DDGS (30D) group (replacing soybean meal with 30% DDGS); 3) 30D + additional valine and isoleucine (30DB) group; and 4) the group of 30DB + additional valine and isoleucine to provide the same leucine:valine and leucine:isoleucine ratios as the CON group (30DBB). The analyzed leucine:lysine ratios of the CON group were 1.36/1.41/1.46 (starter/grower/finisher phase), whereas the average leucine:lysine ratios of the 30% DDGS groups were 1.61/1.70/1.78 (starter/grower/finisher phase). The 30% DDGS groups (30D, 30DB, and 30DBB) negatively affected body weight (BW) from d 7 to 42 and BW gain (BWG), feed intake, carcass weight, breast muscle weight, and jejunal and ileal villus height:crypt depth during the overall period (d 0 to 42) (P < 0.05). Furthermore, the 30% DDGS groups significantly altered expression levels of jejunal tight junction proteins, breast muscle mechanistic target of rapamycin (mTOR) pathway-related genes, BCAA catabolism genes, and AA transporters compared to the CON (P < 0.01). The 30% DDGS groups showed differences in beta-diversity indices compared to the CON group (P < 0.05). The 30DBB group showing the lowest d 21 and 42 BW and overall BWG had the largest differences compared to the CON group in most measurements. In conclusion, excessive replacement of soybean meal with DDGS can significantly increase leucine levels, which may negatively affect chicken growth. Additionally, inappropriate ratios of valine and isoleucine can further decrease growth performance.
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Affiliation(s)
- Doyun Goo
- Department of Poultry Science, University of Georgia, Athens, GA, United States
| | - Jihwan Lee
- Department of Poultry Science, University of Georgia, Athens, GA, United States
| | - Deependra Paneru
- Department of Poultry Science, University of Georgia, Athens, GA, United States
| | - Milan K Sharma
- Department of Poultry Science, University of Georgia, Athens, GA, United States
| | | | - Fatemeh S Mahdavi
- Department of Poultry Science, University of Georgia, Athens, GA, United States
| | - Ishwari Gyawali
- Department of Poultry Science, University of Georgia, Athens, GA, United States
| | | | - Gippeum Han
- Department of Poultry Science, University of Georgia, Athens, GA, United States
| | - Woo Kyun Kim
- Department of Poultry Science, University of Georgia, Athens, GA, United States.
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Chen S, He G, Zhang M, Tang N, Zeng Y. Causal relationship between branched-chain amino acids and leukemia risk: insights from a two-sample Mendelian randomization study. Hematology 2024; 29:2433904. [PMID: 39663823 DOI: 10.1080/16078454.2024.2433904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 11/20/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND Branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential amino acids involved in protein synthesis, energy metabolism, and immune regulation. While BCAAs are known to influence cancer biology, their role in leukemia remains unclear. This study employs Mendelian randomization (MR) analysis to explore the causal relationship between BCAA levels and four leukemia subtypes: acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). METHODS Data from genome-wide association studies (GWAS) were used to select single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for BCAA levels. The inverse-variance weighted (IVW) method served as the primary analytical approach, with heterogeneity assessed via Cochran's Q test and pleiotropy through MR-Egger intercept. Sensitivity analysis was performed using leave-one-out analysis. RESULTS A significant inverse association was observed between total BCAA levels, leucine, valine, and ALL risk. Total BCAA levels showed an odds ratio (OR) of 0.16 (95% CI: 0.05-0.54, p=0.003), leucine 0.17 (95% CI: 0.04-0.61, p=0.007), and valine 0.21 (95% CI: 0.07-0.61, p=0.004). No significant associations were found for AML, CLL, or CML. CONCLUSION This study suggests that BCAAs, particularly leucine and valine, may protect against ALL, offering insights into leukemia metabolic regulation and potential targets for prevention and therapy.
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Affiliation(s)
- Shupeng Chen
- School of Clinical Medicine, Jiangxi University of Chinese Medicine, Nanchang, People's Republic of China
| | - Guilian He
- School of Clinical Medicine, Jiangxi University of Chinese Medicine, Nanchang, People's Republic of China
| | - Meiling Zhang
- School of Clinical Medicine, Jiangxi University of Chinese Medicine, Nanchang, People's Republic of China
| | - Nana Tang
- Hematology Department, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, People's Republic of China
| | - Yingjian Zeng
- Hematology Department, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, People's Republic of China
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Rokop ZP, O’Connell TM, Munsch T, Nephew L, Orman E, Mihaylov P, Mangus RS, Kubal C. The rate of muscle wasting in liver transplant recipients on waiting list: post-transplant outcomes and associated serum metabolite patterns. Hepatobiliary Surg Nutr 2024; 13:962-973. [PMID: 39669082 PMCID: PMC11634410 DOI: 10.21037/hbsn-23-645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 05/22/2024] [Indexed: 12/14/2024]
Abstract
Background Sarcopenia at the time of liver transplantation (LT) is an established risk factor for mortality following LT. However, most studies in this context have defined sarcopenia by one-time, static measurements. The aims of this study were (I) to determine the impact of the rate of muscle loss in waitlisted LT recipients on post-LT outcomes and (II) to identify patterns of serum metabolites associated with patients with more progressive sarcopenia. Methods Patients undergoing liver transplant from 2008 to 2018 who received more than one computed tomography (CT) scans within 12 months prior to liver transplant were included (n=61). The psoas muscle index (PMI) was calculated using Slice-O-Matic software and corrected for patient height (m2). Patients were classified into two groups based the rate of reduction in PMI-high wasting [HW; change in PMI (ΔPMI) ≤-1%/month] and low wasting (LW; ΔPMI >-1%/month). Pre-transplant serum metabolic profiles were collected using nuclear magnetic resonance (NMR) spectroscopy. Living kidney donor sera was used as healthy controls. Results Median ΔPMI was -2.0%/month in HW and -0.15%/month in LW patients (P<0.001). Post-transplant 1-year mortality was significantly higher in HW patients. There were no significant differences in metabolite concentrations between HW and LW patients. However, perturbations in taurine, sarcosine, betaine and the aromatic amino acids (AAAs), were observed in patients with liver disease as compared to healthy controls. Liver disease was also associated with a decrease in lipoprotein profiles, especially high-density lipoprotein (HDL) particles. Conclusions In patients undergoing LT, the rate of progression of sarcopenia is a strong prognostic indicator of post-LT death. Serum metabolite profiles were not characteristically unique to HW patients, and most closely resemble derangements associated with chronic liver disease.
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Affiliation(s)
- Zachary P. Rokop
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Thomas M. O’Connell
- Department of Otolaryngology, Head & Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Taylor Munsch
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Lauren Nephew
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Eric Orman
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Plamen Mihaylov
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Richard S. Mangus
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Chandrashekhar Kubal
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
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Presset A, Bodard S, Lefèvre A, Millet A, Oujagir E, Dupuy C, Iazourène T, Bouakaz A, Emond P, Escoffre JM, Nadal-Desbarats L. Metabolomic profile of cerebral tissue after acoustically-mediated blood-brain barrier opening in a healthy rat model: a focus on the contralateral side. Front Mol Neurosci 2024; 17:1383963. [PMID: 39634608 PMCID: PMC11615074 DOI: 10.3389/fnmol.2024.1383963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 10/17/2024] [Indexed: 12/07/2024] Open
Abstract
Microbubble (MB)-assisted ultrasound (US) is an innovative modality for the non-invasive, targeted, and efficient delivery of therapeutic molecules into the brain. Previously, we reported the first metabolomic signature of blood-brain barrier opening (BBBO) induced by MB-assisted US. In the present study, the neurometabolic consequences of acoustically-mediated BBBO on cerebral tissue were investigated using multimodal metabolomics approaches. Sinusoid US waves (1 MHz, peak negative pressure 0.6 MPa, burst length 10 ms, total treatment time 30 s, MB bolus dose 0.7 × 105 MBs/g) were applied on the rats' right striatum (ipsilateral side). Brain was collected and both striata were then dissected 3 h, 2 days, and 1 week after BBBO. After tissue preparation, the samples were analyzed using nuclear magnetic resonance spectrometry (NMRS) and high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS). Our findings showed a slight disruption of metabolic pathways in contralateral striata of animals. Analyses of metabolic pathways indicated changes in amino acid metabolisms. In addition, tryptophan derivate dosages revealed the perturbation of a central metabolite of the kynurenine pathway (i.e., 3-hydroxy-kynurenine). In conclusion, the acoustically-mediated BBBO of the ipsilateral cerebral hemisphere induced significant change in metabolism of contralateral one.
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Affiliation(s)
- Antoine Presset
- UMR 1253, iBrain, Inserm, Université de Tours, Tours, France
| | - Sylvie Bodard
- UMR 1253, iBrain, Inserm, Université de Tours, Tours, France
| | - Antoine Lefèvre
- UMR 1253, iBrain, Inserm, Université de Tours, Tours, France
- Département Analyses Chimique et Métabolomique, PST Analyses des Systèmes Biologiques, Université de Tours, Tours, France
| | - Anaïs Millet
- UMR 1253, iBrain, Inserm, Université de Tours, Tours, France
| | - Edward Oujagir
- UMR 1253, iBrain, Inserm, Université de Tours, Tours, France
| | - Camille Dupuy
- UMR 1253, iBrain, Inserm, Université de Tours, Tours, France
- Département Analyses Chimique et Métabolomique, PST Analyses des Systèmes Biologiques, Université de Tours, Tours, France
| | - Tarik Iazourène
- UMR 1253, iBrain, Inserm, Université de Tours, Tours, France
| | - Ayache Bouakaz
- UMR 1253, iBrain, Inserm, Université de Tours, Tours, France
| | - Patrick Emond
- UMR 1253, iBrain, Inserm, Université de Tours, Tours, France
- Département Analyses Chimique et Métabolomique, PST Analyses des Systèmes Biologiques, Université de Tours, Tours, France
- CHRU Tours, Serv Med Nucl in Vitro, Tours, France
| | | | - Lydie Nadal-Desbarats
- UMR 1253, iBrain, Inserm, Université de Tours, Tours, France
- Département Analyses Chimique et Métabolomique, PST Analyses des Systèmes Biologiques, Université de Tours, Tours, France
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Karvinen S, Korhonen TMK, Kiviö R, Lensu S, Gajera B, Britton SL, Koch LG, Nieminen AI, Kainulainen H. Branched-chain amino acid supplementation and voluntary running have distinct effects on the serum metabolome of rats with high or low intrinsic aerobic capacity. Front Nutr 2024; 11:1450386. [PMID: 39628463 PMCID: PMC11611553 DOI: 10.3389/fnut.2024.1450386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 09/10/2024] [Indexed: 12/06/2024] Open
Abstract
Introduction A growing body of literature associates branched-chain amino acid (BCAA) catabolism to increased fatty acid oxidation and better metabolic health. Hence, BCAA-rich diets may improve body composition and muscle protein synthesis. However, the role of individual characteristics such as a low aerobic fitness, a well-established risk factor for cardio-metabolic diseases, has not been studied. Methods This study examined 64 female rats from the high-capacity runner (HCR) and low-capacity runner (LCR) rat model. Rats from each line (HCR or LCR) were divided into four groups; differing from diet (CTRL or BCAA) and from the opportunity to voluntarily run on a running wheel (NONRUNNER or RUNNER). Groups were matched for body mass and maximal running capacity within each line. We measured maximal running capacity and metabolism before and after the intervention of diet and voluntary running activity. After the end of the experiment, serum samples were collected for metabolome analysis. Results We are the first to show that BCAA supplementation has a more pronounced impact on LCRs compared to HCRs. Specifically, in LCR rats, BCAA supplementation led to reduced daily voluntary running distance and an enrichment of serine metabolism in the serum metabolome. While voluntary running increased food intake and energy expenditure, its effects on the serum metabolome were minimal in HCRs. Conclusion The present research highlights the benefit achieved by combining BCAA supplementation with running activity, especially in the LCR line. Importantly, our results underscore the interconnected role of BCAAs and fatty acid metabolism in promoting overall metabolic health.
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Affiliation(s)
- Sira Karvinen
- Gerontology Research Center and Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
| | - Tia-Marje K. Korhonen
- Gerontology Research Center and Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
| | - Ronja Kiviö
- Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, Finland
| | - Sanna Lensu
- Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
- Department of Psychology, University of Jyväskylä, Jyväskylä, Finland
| | - Bharat Gajera
- Metabolomics Unit, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Steven L. Britton
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
- Department of Anaesthesiology, University of Michigan, Ann Arbor, MI, United States
| | - Lauren G. Koch
- Department of Physiology and Pharmacology, College of Medicine and Life Sciences, The University of Toledo, Toledo, OH, United States
| | - Anni I. Nieminen
- Metabolomics Unit, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Heikki Kainulainen
- Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
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Humphries JE, Melvin SD, Lanctôt C, McCallum H, Newell D, Grogan LF. Chytridiomycosis disrupts metabolic responses in amphibians at metamorphic climax. Microbes Infect 2024:105438. [PMID: 39551241 DOI: 10.1016/j.micinf.2024.105438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 09/12/2024] [Accepted: 11/12/2024] [Indexed: 11/19/2024]
Abstract
The fungal disease chytridiomycosis (causative agent Batrachochytrium dendrobatidis [Bd]) is a primary contributor to amphibian species declines. The morphological and physiological reorganization that occurs during amphibian metamorphosis likely increases the vulnerability of metamorphs to Bd. To address this, we exposed pro-metamorphic tadpoles of Fleay's barred frog (Mixophyes fleayi) to Bd and sampled skin and liver sections from control and exposed animals throughout metamorphosis (Gosner stages 40, 42 and 45). We used an untargeted metabolomics approach to assess the metabolic impacts of Bd infection during the critical metamorphic stages, extracting metabolites from sampled tissues and analysing them via Nuclear Magnetic Resonance spectrometry. Most exposed animals became moribund at Gosner stage 45, while a subset seemingly cleared their infections. Metabolite abundance varied throughout development, with Gosner stage 45 samples distinct from previous stages. Clinically infected animals at Gosner stage 45 exhibited profound metabolic dysregulation (e.g., upregulation of amino acid biosynthesis and degradation) in comparison to uninfected groups (negative controls and 'cleared' animals). Despite showing parallels with previous metabolomic analyses of Bd-infected adult frogs, we identified variations in our results that could be attributed to the dramatic changes that characterise metamorphosis and may be driving the heightened vulnerability observed in metamorphic amphibians.
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Affiliation(s)
- Josephine E Humphries
- School of Environment and Science, Griffith University, Southport, Queensland, 4222, Australia; Centre for Planetary Health and Food Security, Griffith University, Southport, Queensland, 4222, Australia.
| | - Steven D Melvin
- School of Environment and Science, Griffith University, Southport, Queensland, 4222, Australia; Australian Rivers Institute, Griffith University, Southport, Queensland, 4222, Australia
| | - Chantal Lanctôt
- School of Environment and Science, Griffith University, Southport, Queensland, 4222, Australia; Australian Rivers Institute, Griffith University, Southport, Queensland, 4222, Australia
| | - Hamish McCallum
- Centre for Planetary Health and Food Security, Griffith University, Southport, Queensland, 4222, Australia
| | - David Newell
- Faculty of Science and Engineering, Southern Cross University, Lismore, New South Wales 2480, Australia
| | - Laura F Grogan
- School of Environment and Science, Griffith University, Southport, Queensland, 4222, Australia; Centre for Planetary Health and Food Security, Griffith University, Southport, Queensland, 4222, Australia; School of the Environment, University of Queensland, St Lucia, Queensland, 4067, Australia
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Sanchez SE, Chiarelli TJ, Park MA, Carlyon JA. Orientia tsutsugamushi infection reduces host gluconeogenic but not glycolytic substrates. Infect Immun 2024; 92:e0028424. [PMID: 39324805 PMCID: PMC11556148 DOI: 10.1128/iai.00284-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 08/20/2024] [Indexed: 09/27/2024] Open
Abstract
Orientia tsutsugamushi a causal agent of scrub typhus, is an obligate intracellular bacterium that, akin to other rickettsiae, is dependent on host cell-derived nutrients for survival and thus pathogenesis. Based on limited experimental evidence and genome-based in silico predictions, O. tsutsugamushi is hypothesized to parasitize host central carbon metabolism (CCM). Here, we (re-)evaluated O. tsutsugamushi dependency on host cell CCM as initiated by glucose and glutamine. Orientia infection had no effect on host glucose and glutamine consumption or lactate accumulation, indicating no change in overall flux through CCM. However, host cell mitochondrial activity and ATP levels were reduced during infection and correspond with lower intracellular glutamine and glutamate pools. To further probe the essentiality of host CCM in O. tsutsugamushi proliferation, we developed a minimal medium for host cell cultivation and paired it with chemical inhibitors to restrict the intermediates and processes related to glucose and glutamine metabolism. These conditions failed to negatively impact O. tsutsugamushi intracellular growth, suggesting the bacterium is adept at scavenging from host CCM. Accordingly, untargeted metabolomics was utilized to evaluate minor changes in host CCM metabolic intermediates across O. tsutsugamushi infection and revealed that pathogen proliferation corresponds with reductions in critical CCM building blocks, including amino acids and TCA cycle intermediates, as well as increases in lipid catabolism. This study directly correlates O. tsutsugamushi proliferation to alterations in host CCM and identifies metabolic intermediates that are likely critical for pathogen fitness.IMPORTANCEObligate intracellular bacterial pathogens have evolved strategies to reside and proliferate within the eukaryotic intracellular environment. At the crux of this parasitism is the balance between host and pathogen metabolic requirements. The physiological basis driving O. tsutsugamushi dependency on its mammalian host remains undefined. By evaluating alterations in host metabolism during O. tsutsugamushi proliferation, we discovered that bacterial growth is independent of the host's nutritional environment but appears dependent on host gluconeogenic substrates, including amino acids. Given that O. tsutsugamushi replication is essential for its virulence, this study provides experimental evidence for the first time in the post-genomic era of metabolic intermediates potentially parasitized by a scrub typhus agent.
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Affiliation(s)
- Savannah E. Sanchez
- Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Travis J. Chiarelli
- Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Margaret A. Park
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida, USA
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, Florida, USA
| | - Jason A. Carlyon
- Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
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Garip B, Khokhar JY, Kayir H. Plasma essential amino acid levels in first episode psychosis at baseline and after antipsychotic treatment. SCHIZOPHRENIA (HEIDELBERG, GERMANY) 2024; 10:103. [PMID: 39505892 PMCID: PMC11542070 DOI: 10.1038/s41537-024-00528-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 10/12/2024] [Indexed: 11/08/2024]
Abstract
This study assessed plasma levels of essential amino acids (EAA) in drug-naïve first episode psychosis (FEP) patients at diagnosis and after 10 weeks of antipsychotic treatment. Forty FEP patients were enrolled at baseline, with blood samples collected before and after a 10-week antipsychotic treatment period. Plasma EAA levels were measured using an LC/MS/MS method. Psychotic symptoms were evaluated using standardized inventories before and after treatment. A decrease in BPRS score of more than 40% was used to indicate treatment response. Thirty-five healthy volunteers served as the control group. Baseline plasma levels of Thr, Met, Leu, Lys, His, and Tyr were higher in FEP patients than in healthy controls. After 10 weeks of treatment, Leu, His, and Tyr increased further, primarily in treatment-responsive patients. Conversely, Val level was lower than controls in patients at baseline and remained unchanged after treatment. Increased EAA levels were correlated with lower (less severe) scores in positive symptom scales. Treatment non-responders had persistently low Tyr/large neutral amino acid (LNAA) ratio. Tyr/LNAA ratio increased after treatment, specifically in treatment-responders. Phe/Tyr ratio decreased post-treatment in both responder and non-responder groups. Elevated EAA levels in FEP patients may signify compensatory responses to increased physiological demand for neurotransmitters or energy. Combining specific EAA supplementation with antipsychotic treatment may enhance treatment response in these patients.
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Affiliation(s)
- Beyazit Garip
- Gulhane Training and Research Hospital, Department of Psychiatry, Ankara, Turkey
| | - Jibran Y Khokhar
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
| | - Hakan Kayir
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
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Akbay B, Omarova Z, Trofimov A, Sailike B, Karapina O, Molnár F, Tokay T. Double-Edge Effects of Leucine on Cancer Cells. Biomolecules 2024; 14:1401. [PMID: 39595578 PMCID: PMC11591885 DOI: 10.3390/biom14111401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 10/16/2024] [Accepted: 10/22/2024] [Indexed: 11/28/2024] Open
Abstract
Leucine is an essential amino acid that cannot be produced endogenously in the human body and therefore needs to be obtained from dietary sources. Leucine plays a pivotal role in stimulating muscle protein synthesis, along with isoleucine and valine, as the group of branched-chain amino acids, making them one of the most popular dietary supplements for athletes and gym-goers. The individual effects of leucine, however, have not been fully clarified, as most of the studies so far have focused on the grouped effects of branched-chain amino acids. In recent years, leucine and its metabolites have been shown to stimulate muscle protein synthesis mainly via the mammalian target of the rapamycin complex 1 signaling pathway, thereby improving muscle atrophy in cancer cachexia. Interestingly, cancer research suggests that leucine may have either anti-cancer or pro-tumorigenic effects. In the current manuscript, we aim to review leucine's roles in muscle protein synthesis, tumor suppression, and tumor progression, specifically summarizing the molecular mechanisms of leucine's action. The role of leucine is controversial in hepatocellular carcinoma, whereas its pro-tumorigenic effects have been demonstrated in breast and pancreatic cancers. In summary, leucine being used as nutritional supplement for athletes needs more attention, as its pro-oncogenic effects may have been identified by recent studies. Anti-cancer or pro-tumorigenic effects of leucine in various cancers should be further investigated to achieve clear conclusions.
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Affiliation(s)
| | | | | | | | | | | | - Tursonjan Tokay
- Department of Biology, School of Sciences and Humanities, Nazarbayev University, Kabanbay Batyr 53, Astana 010000, Kazakhstan; (B.A.); (Z.O.); (A.T.); (B.S.); (O.K.); (F.M.)
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Trillos-Almanza MC, Aguilar MM, Buist-Homan M, Bomer N, Gomez KA, de Meijer VE, van Vilsteren FGI, Blokzijl H, Moshage H. Branched-chain amino acids and their metabolites decrease human and rat hepatic stellate cell activation. Mol Biol Rep 2024; 51:1116. [PMID: 39495311 PMCID: PMC11534903 DOI: 10.1007/s11033-024-10027-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 10/15/2024] [Indexed: 11/05/2024]
Abstract
BACKGROUND End-stage liver diseases (ESLDs) are a significant global health challenge due to their high prevalence and severe health impacts. Despite the severe outcomes associated with ESLDs, therapeutic options remain limited. Targeting the activation of hepatic stellate cells (HSCs), key drivers of extracellular matrix accumulation during liver injury presents a novel therapeutic approach. In ESLDs patients, branched-chain amino acids (BCAAs, leucine, isoleucine and valine) levels are decreased, and supplementation has been proposed to attenuate liver fibrosis and improve regeneration. However, their effects on HSCs require further investigation. OBJECTIVE To evaluate the efficacy of BCAAs and their metabolites, branched-chain α-keto acids (BCKAs), in modulating HSCs activation in human and rat models. METHODS Primary HSCs from rats and cirrhotic and non-cirrhotic human livers, were cultured and treated with BCAAs or BCKAs to assess their effects on both preventing (from day 1 of isolation) and reversing (from day 7 of isolation) HSCs activation. RESULTS In rat HSCs, leucine and BCKAs significantly reduced fibrotic markers and cell proliferation. In human HSCs, the metabolite of isoleucine decreased cell proliferation around 85% and increased the expression of branched-chain ketoacid dehydrogenase. The other metabolites also showed antifibrotic effects in HSCs from non-cirrhotic human livers. CONCLUSION BCAAs and their respective metabolites inhibit HSC activation with species-specific responses. Further research is needed to understand how BCAAs influence liver fibrogenesis. BCKAs supplementation could be a strategic approach for managing ESLDs, considering the nutritional status and amino acid profiles of patients.
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Affiliation(s)
- Maria Camila Trillos-Almanza
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
| | - Magnolia Martinez Aguilar
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Manon Buist-Homan
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Nils Bomer
- Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Karla Arevalo Gomez
- Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Vincent E de Meijer
- Division of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Department of Surgery, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Frederike G I van Vilsteren
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Hans Blokzijl
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Han Moshage
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
- Department of Laboratory Medicine, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
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Sekiya M, Sakakibara Y, Hirota Y, Ito N, Chikamatsu S, Takei K, Nishijima R, Iijima KM. Decreased plasma nicotinamide and altered NAD + metabolism in glial cells surrounding Aβ plaques in a mouse model of Alzheimer's disease. Neurobiol Dis 2024; 202:106694. [PMID: 39374707 DOI: 10.1016/j.nbd.2024.106694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 10/03/2024] [Accepted: 10/03/2024] [Indexed: 10/09/2024] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease and a leading cause of senile dementia. Amyloid-β (Aβ) accumulation triggers chronic neuroinflammation, initiating AD pathogenesis. Recent clinical trials for anti-Aβ immunotherapy underscore that blood-based biomarkers have significant advantages and applicability over conventional diagnostics and are an unmet clinical need. To further advance ongoing clinical trials and identify novel therapeutic targets for AD, developing additional plasma biomarkers closely associated with pathogenic mechanisms downstream of Aβ accumulation is critically important. To identify plasma metabolites reflective of neuroinflammation caused by Aβ pathology, we performed untargeted metabolomic analyses of the plasma by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) and analyzed the potential roles of the identified metabolic changes in the brain neuroinflammatory response using the female App knock-in (AppNLGF) mouse model of Aβ amyloidosis. The CE-TOFMS analysis of plasma samples from female wild-type (WT) and AppNLGF mice revealed that plasma levels of nicotinamide, a nicotinamide adenine dinucleotide (NAD+) precursor, were decreased in AppNLGF mice, and altered metabolite profiles were enriched for nicotinate/nicotinamide metabolism. In AppNLGF mouse brains, NAD+ levels were unaltered, but mRNA levels of NAD+-synthesizing nicotinate phosphoribosyltransferase (Naprt) and NAD+-degrading Cd38 genes were increased. These enzymes were induced in reactive astrocytes and microglia surrounding Aβ plaques in the cortex and hippocampus of female AppNLGF mouse brains, suggesting neuroinflammation increases NAD+ metabolism. This study suggests plasma nicotinamide could be indicative of the neuroinflammatory response and that nicotinate and nicotinamide metabolism are potential therapeutic targets for AD, by targeting both neuroinflammation and neuroprotection.
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Affiliation(s)
- Michiko Sekiya
- Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; Department of Experimental Gerontology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
| | - Yasufumi Sakakibara
- Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan
| | - Yu Hirota
- Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; Reseach Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Naoki Ito
- Brain-Skeletal Muscle Connection in Aging Project Team, Geroscience Research Center, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan
| | - Sachie Chikamatsu
- Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; Department of Experimental Gerontology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
| | - Kimi Takei
- Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan
| | - Risa Nishijima
- Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan
| | - Koichi M Iijima
- Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; Department of Experimental Gerontology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
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Dos Santos K, Bertho G, Baudin M, Giraud N. Glutamine: A key player in human metabolism as revealed by hyperpolarized magnetic resonance. PROGRESS IN NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY 2024; 144-145:15-39. [PMID: 39645348 DOI: 10.1016/j.pnmrs.2024.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 05/17/2024] [Accepted: 05/28/2024] [Indexed: 12/09/2024]
Abstract
In recent years, there has been remarkable progress in the field of dissolution dynamic nuclear polarization (D-DNP). This method has shown significant potential for enhancing nuclear polarization by over 10,000 times, resulting in a substantial increase in sensitivity. The unprecedented signal enhancements achieved with D-DNP have opened new possibilities for in vitro analysis. This method enables the monitoring of structural and enzymatic kinetics with excellent time resolution at low concentrations. Furthermore, these advances can be straightforwardly translated to in vivo magnetic resonance imaging and magnetic resonance spectroscopy (MRI and MRS) experiments. D-DNP studies have used a range of 13C labeled molecules to gain deeper insights into the cellular metabolic pathways and disease hallmarks. Over the last 15 years, D-DNP has been used to analyze glutamine, a key player in the cellular metabolism, involved in many diseases including cancer. Glutamine is the most abundant amino acid in blood plasma and the major carrier of nitrogen, and it is converted to glutamate inside the cell, where the latter is the most abundant amino acid. It has been shown that increased glutamine consumption by cells is a hallmark of tumor cancer metabolism. In this review, we first highlight the significance of glutamine in metabolism, providing an in-depth description of its use at the cellular level as well as its specific roles in various organs. Next, we present a comprehensive overview of the principles of D-DNP. Finally, we review the state of the art in D-DNP glutamine analysis and its application in oncology, neurology, and perfusion marker studies.
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Affiliation(s)
- Karen Dos Santos
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques Université Paris Cité, 45 rue des Saints Pères, 75006 Paris, France
| | - Gildas Bertho
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques Université Paris Cité, 45 rue des Saints Pères, 75006 Paris, France
| | - Mathieu Baudin
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques Université Paris Cité, 45 rue des Saints Pères, 75006 Paris, France; Laboratoire des Biomolécules, LBM, Département de chimie, École Normale Supérieure, PSL Université, Sorbonne Université 45 rue d'Ulm, 75005 Paris, France
| | - Nicolas Giraud
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques Université Paris Cité, 45 rue des Saints Pères, 75006 Paris, France.
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Leibovitzh H, Sarbagili Shabat C, Hirsch A, Zittan E, Mentella MC, Petito V, Cohen NA, Ron Y, Fliss Isakov N, Pfeffer J, Yaakov M, Fanali C, Turchini L, Masucci L, Quaranta G, Kolonimos N, Godneva A, Weinberger A, Scaldaferri F, Maharshak N. Faecal Transplantation for Ulcerative Colitis From Diet Conditioned Donors Followed by Dietary Intervention Results in Favourable Gut Microbial Profile Compared to Faecal Transplantation Alone. J Crohns Colitis 2024; 18:1606-1614. [PMID: 38720628 DOI: 10.1093/ecco-jcc/jjae062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 02/17/2024] [Accepted: 05/08/2024] [Indexed: 10/17/2024]
Abstract
BACKGROUND AND AIMS Several faecal microbial transplantation [FMT] approaches for ulcerative colitis [UC] have been investigated with conflicting results. We have recently published the clinical outcomes from the CRAFT UC Trial using FMT with the UC Exclusion Diet [UCED], compared with FMT alone. Here we aimed to compare the two FMT strategies in terms of microbial profile and function. METHODS Subjects recruited to the CRAFT UC study with available pre- and post-intervention faecal samples were included. Donors received diet conditioning for 14 days based on the UCED principles. Group 1 received single FMT by colonoscopy [Day 1] and enemas [Days 2 and 14] without donors' dietary conditioning [N = 11]. Group 2 received FMT but with donors' dietary pre-conditioning and UCED for the patients [N = 10]. Faecal samples were assessed by DNA shotgun metagenomic sequencing. RESULTS Following diet conditioning, donors showed depletion in metabolic pathways involved in biosynthesis of sulphur-containing amino acids. Only Group 2 showed significant shifts towards the donors' microbial composition [ADONIS: R2 = 0.15, p = 0.008] and significantly increased Eubacterium_sp_AF228LB post-intervention [β-coefficient 2.66, 95% confidence interval 2.1-3.3, q < 0.05] which was inversely correlated with faecal calprotectin [rho = -0.52, p = 0.035]. Moreover, pathways involved in gut inflammation and barrier function including branched chain amino acids were enriched post-intervention in Group 2 and were significantly inversely correlated with faecal calprotectin. CONCLUSION FMT from diet conditioned donors followed by the UCED led to microbial alterations associated with favourable microbial profiles which correlated with decreased faecal calprotectin. Our findings support further exploration of the additive benefit of dietary intervention for both donors and patients undergoing FMT as a potential treatment of UC.
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Affiliation(s)
- Haim Leibovitzh
- Department of Gastroenterology and Hepatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Chen Sarbagili Shabat
- Pediatric Gastroenterology Unit, PIBD Research Center, Wolfson Medical Center, Holon, Israel
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Ayal Hirsch
- Department of Gastroenterology and Hepatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Eran Zittan
- Gastroenterology Institute, IBD Unit, Haemek Medical Center, Afula, Israel
| | - Maria Chiara Mentella
- UOC di Nutrizione Clinica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Valentina Petito
- Cemad [CENTER for Digestive Disease], UOC Medicina Internae Gastroenterologia, Fondazione Policlinico 'A. Gemelli' IRCCS, Rome, Italy
| | - Nathaniel Aviv Cohen
- Department of Gastroenterology and Hepatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Yulia Ron
- Department of Gastroenterology and Hepatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Naomi Fliss Isakov
- Department of Gastroenterology and Hepatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Department of Health, School of Public Health, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Jorge Pfeffer
- Department of Gastroenterology and Hepatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Michal Yaakov
- Pediatric Gastroenterology Unit, PIBD Research Center, Wolfson Medical Center, Holon, Israel
| | - Caterina Fanali
- Cemad [CENTER for Digestive Disease], UOC Medicina Internae Gastroenterologia, Fondazione Policlinico 'A. Gemelli' IRCCS, Rome, Italy
| | - Laura Turchini
- Cemad [CENTER for Digestive Disease], UOC Medicina Internae Gastroenterologia, Fondazione Policlinico 'A. Gemelli' IRCCS, Rome, Italy
| | - Luca Masucci
- Istituto di Microbiologia, Università Cattolica del Sacro Cuore - Fondazione Policlinico 'A. Gemelli' IRCSS, Rome, Italy
- Dipartimento Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Gianluca Quaranta
- Istituto di Microbiologia, Università Cattolica del Sacro Cuore - Fondazione Policlinico 'A. Gemelli' IRCSS, Rome, Italy
- Dipartimento Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Nitzan Kolonimos
- Gastroenterology Institute, IBD Unit, Haemek Medical Center, Afula, Israel
| | - Anastasia Godneva
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel
| | - Adina Weinberger
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel
| | - Franco Scaldaferri
- Cemad [CENTER for Digestive Disease], UOC Medicina Internae Gastroenterologia, Fondazione Policlinico 'A. Gemelli' IRCCS, Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore- Fondazione Policlinico 'A. Gemelli' IRCCS, Rome, Italy
| | - Nitsan Maharshak
- Department of Gastroenterology and Hepatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
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Lu N, Wei M, Yang X, Li Y, Sun H, Yan Q, Zhang H, He J, Ma J, Xia M, Zhang C. Growth-coupled production of L-isoleucine in Escherichia coli via metabolic engineering. Metab Eng 2024; 86:181-193. [PMID: 39413988 DOI: 10.1016/j.ymben.2024.10.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 10/02/2024] [Accepted: 10/12/2024] [Indexed: 10/18/2024]
Abstract
L-isoleucine, an essential amino acid, is widely used in the pharmaceutical and food industries. However, the current production efficiency is insufficient to meet the increasing demands. In this study, we aimed to develop an efficient L-isoleucine-producing strain of Escherichia coli. First, accumulation of L-isoleucine was achieved by employing feedback-resistant enzymes. Next, a growth-coupled L-isoleucine synthetic pathway was established by introducing the metA-metB-based α-ketobutyrate-generating bypass, which significantly increased L-isoleucine production to 7.4 g/L. Upon employing an activity-improved cystathionine γ-synthase mutant obtained from adaptive laboratory evolution, L-isoleucine production further increased to 8.5 g/L. Subsequently, the redox flux was improved by bypassing the NADPH-dependent aspartate aminotransferase pathway and employing the NADH-dependent pathway and transhydrogenase. Finally, L-isoleucine efflux was enhanced by modifying the transport system. After fed-batch fermentation for 48 h, the resultant strain, ISO-12, reached an L-isoleucine production titer of 51.5 g/L and yield of 0.29 g/g glucose. The strains developed in this study achieved a higher L-isoleucine production efficiency than those reported previously. These strategies will aid in the development of cell factories that produce L-isoleucine and related products.
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Affiliation(s)
- Nan Lu
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, Tianjin University of Science and Technology, Tianjin, 300457, China; College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Minhua Wei
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, Tianjin University of Science and Technology, Tianjin, 300457, China; College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Xuejing Yang
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, Tianjin University of Science and Technology, Tianjin, 300457, China; College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Yingzi Li
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, Tianjin University of Science and Technology, Tianjin, 300457, China; College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Hao Sun
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, Tianjin University of Science and Technology, Tianjin, 300457, China; College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Qianyu Yan
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, Tianjin University of Science and Technology, Tianjin, 300457, China; College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Haibin Zhang
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, Tianjin University of Science and Technology, Tianjin, 300457, China; College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Jilong He
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, Tianjin University of Science and Technology, Tianjin, 300457, China; College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Jie Ma
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, Tianjin University of Science and Technology, Tianjin, 300457, China; College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Menglei Xia
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, Tianjin University of Science and Technology, Tianjin, 300457, China; College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China.
| | - Chenglin Zhang
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, Tianjin University of Science and Technology, Tianjin, 300457, China; College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China.
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