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Ahmed M. Ramadan Fasting and Complications of Metabolic Dysfunction-Associated Steatotic Liver Disease: Impacts on Liver Cirrhosis and Heart Failure. J Clin Med 2025; 14:1841. [PMID: 40142648 PMCID: PMC11942711 DOI: 10.3390/jcm14061841] [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: 02/17/2025] [Revised: 03/03/2025] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
BACKGROUND Metabolic-dysfunction-associated steatotic liver disease (MASLD) and heart failure are two intersecting growing pandemics. Studies have demonstrated a strong association between MASLD and heart failure. Liver cirrhosis is a well-recognized complication of MASLD. This study aimed to summarize the potential effects of Ramadan fasting on MASLD, liver cirrhosis, and heart failure. The author searched the SCOPUS and PubMed databases using specific terms. The literature review focused on research articles published in English from 2000 to 2024. Twenty-two articles were selected for this narrative review. Ramadan fasting reduced serum cholesterol serum levels, improved symptoms of heart failure and reduced anthropometric measurements. However, it increased ascitic fluid production and plasma bilirubin levels and might increase the risk of hepatic encephalopathy and upper gastrointestinal haemorrhage in liver cirrhosis. Ramadan fasting might improve symptoms of heart failure and might decrease the risk of heart failure in patients with MASLD. Further research studies are needed to confirm the efficacy and evaluate the safety of Ramadan fasting in patients with heart failure and liver cirrhosis.
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Affiliation(s)
- Musaab Ahmed
- College of Medicine, Ajman University, Ajman P.O. Box 346, United Arab Emirates;
- Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab Emirates
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Zhang X, Lau HCH, Yu J. Pharmacological treatment for metabolic dysfunction-associated steatotic liver disease and related disorders: Current and emerging therapeutic options. Pharmacol Rev 2025; 77:100018. [PMID: 40148030 DOI: 10.1016/j.pharmr.2024.100018] [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: 03/29/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as nonalcoholic fatty liver disease) is a chronic liver disease affecting over a billion individuals worldwide. MASLD can gradually develop into more severe liver pathologies, including metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and liver malignancy. Notably, although being a global health problem, there are very limited therapeutic options against MASLD and its related diseases. While a thyroid hormone receptor agonist (resmetirom) is recently approved for MASH treatment, other efforts to control these diseases remain unsatisfactory. Given the projected rise in MASLD and MASH incidence, it is urgent to develop novel and effective therapeutic strategies against these prevalent liver diseases. In this article, the pathogenic mechanisms of MASLD and MASH, including insulin resistance, dysregulated nuclear receptor signaling, and genetic risk factors (eg, patatin-like phospholipase domain-containing 3 and hydroxysteroid 17-β dehydrogenase-13), are introduced. Various therapeutic interventions against MASH are then explored, including approved medication (resmetirom), drugs that are currently in clinical trials (eg, glucagon-like peptide 1 receptor agonist, fibroblast growth factor 21 analog, and PPAR agonist), and those failed in previous trials (eg, obeticholic acid and stearoyl-CoA desaturase 1 antagonist). Moreover, given that the role of gut microbes in MASLD is increasingly acknowledged, alterations in the gut microbiota and microbial mechanisms in MASLD development are elucidated. Therapeutic approaches that target the gut microbiota (eg, dietary intervention and probiotics) against MASLD and related diseases are further explored. With better understanding of the multifaceted pathogenic mechanisms, the development of innovative therapeutics that target the root causes of MASLD and MASH is greatly facilitated. The possibility of alleviating MASH and achieving better patient outcomes is within reach. SIGNIFICANCE STATEMENT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, and it can progress to more severe pathologies, including steatohepatitis, cirrhosis, and liver cancer. Better understanding of the pathogenic mechanisms of these diseases has facilitated the development of innovative therapeutic strategies. Moreover, increasing evidence has illustrated the crucial role of gut microbiota in the pathogenesis of MASLD and related diseases. It may be clinically feasible to target gut microbes to alleviate MASLD in the future.
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Affiliation(s)
- Xiang Zhang
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Harry Cheuk-Hay Lau
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jun Yu
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
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Khattib A, Shmet M, Levi A, Hayek T, Halabi M, Khatib S. Bioactive lipids improve serum HDL and PON1 activities in coronary artery disease patients: Ex-vivo study. Vascul Pharmacol 2024; 157:107435. [PMID: 39419293 DOI: 10.1016/j.vph.2024.107435] [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: 09/01/2024] [Revised: 10/09/2024] [Accepted: 10/10/2024] [Indexed: 10/19/2024]
Abstract
BACKGROUND Atherosclerotic cardiovascular disease (CVD) remains a leading cause of vascular disease worldwide. Atherosclerosis is characterized by the accumulation of lipids and oxidized lipids on the blood vessel walls. Coronary artery disease (CAD) is the most common display of atherosclerotic CVD. OBJECTIVES We investigated the effects of the bioactive lipids as lyso-diacylglyceryltrimethylhomoserine (lyso-DGTS (20,5,0)) and its derivative oleoyl-N-trimethyl homoserine amide (oleoyl amide-MHS) on the properties and functionality of HDL and paraoxonase 1 (PON1) activities in the serum of individuals who exhibited arterial plaque as observed by coronary CT angiography (CCTA). METHODS The study included two independent groups comprising 40 patients who had undergone arterial CCTA scans at Ziv Medical Center for various medical indications. The CAD group included 20 patients with coronary artery plaques with luminal stenosis of more than 50 % in a major coronary vessel. The control group consisted of 20 healthy patients (patients without artery plaques). RESULTS Serum samples from CAD patients exhibited lower serum PON1 and cholesterol efflux activities and higher pro-inflammatory than the control group. HDL isolated from CAD patients contains elevated levels of oxidizing lipids (specifically lyso- phosphatidyl ethanolamines and lyso-phosphocholines(compared to the control. However, incubation of the CAD patients' serum with lyso-DGTS and oleoyl amide-MHS restored the antiatherogenic activities of HDL. The lipids increased serum PON1 activities, enhanced apoB-depleted serum cholesterol-efflux activity, and elevated the serum's anti-inflammatory properties. CONCLUSIONS The results of the present study suggest the potential of the bioactive lipids lyso-DGTS and oleoyl amide-MHS to attenuate atherosclerosis via the improvement of dysfunctional HDL properties and PON1 activities. Further, in-vivo experiments are needed to assess the athero-protective effect of the lipids.
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Affiliation(s)
- Ali Khattib
- Natural Products and Analytical Chemistry Laboratory, MIGAL-Galilee Research Institute, Kiryat Shmona, Israel; Department of Biotechnology, Tel-Hai College, Upper Galilee, Israel; Technion Israel Institute of Technology, The Ruth and Bruce Rappaport Faculty of Medicine, Haifa, Israel
| | - Manar Shmet
- Natural Products and Analytical Chemistry Laboratory, MIGAL-Galilee Research Institute, Kiryat Shmona, Israel; Department of Biotechnology, Tel-Hai College, Upper Galilee, Israel
| | - Achinoam Levi
- Natural Products and Analytical Chemistry Laboratory, MIGAL-Galilee Research Institute, Kiryat Shmona, Israel; Department of Biotechnology, Tel-Hai College, Upper Galilee, Israel
| | - Tony Hayek
- Technion Israel Institute of Technology, The Ruth and Bruce Rappaport Faculty of Medicine, Haifa, Israel
| | | | - Soliman Khatib
- Natural Products and Analytical Chemistry Laboratory, MIGAL-Galilee Research Institute, Kiryat Shmona, Israel; Department of Biotechnology, Tel-Hai College, Upper Galilee, Israel.
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Castelnuovo G, Perez-Diaz-Del-Campo N, Guariglia M, Poggiolini I, Armandi A, Rosso C, Caviglia GP, Bugianesi E. Prebiotics targeting gut-liver axis to treat non-alcoholic fatty liver disease. Minerva Gastroenterol (Torino) 2024; 70:446-453. [PMID: 36892817 DOI: 10.23736/s2724-5985.23.03361-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/10/2023]
Abstract
Non-alcoholic steatohepatitis (NASH) is a high-prevalence, rapidly growing form of non-alcoholic fatty liver disease (NAFLD), which is closely linked to obesity and metabolic disorders. Gut microbiota has been increasingly recognized as a key factor in the onset of NAFLD in recent years. The liver can be strongly influenced by changes in the gut microbiota through the portal vein, giving the gut-liver axis a very important role in understanding the pathophysiology of liver diseases. A healthy intestinal barrier is characterized by selective permeability to nutrients, metabolites, water and bacterial products and its impairment may be a predisposing or aggravating condition for the progression of NAFLD. In most cases, NAFLD patients follow a Western diet pattern, which is closely linked to obesity and associated metabolic diseases, promoting inflammation, structural and behavioral changes in the gut microbiota. In fact, factors such as age, gender, genetic or environmental factors may induce a dysbiotic microbiota that promotes epithelial barrier dysfunction and increased intestinal permeability, favoring the progression of NAFLD. In this context, new dietary approaches, such as prebiotics, are emerging to prevent disease and maintain health. In this review, we reported the role of the gut-liver axis in the pathogenesis of NAFLD and investigated the potential therapeutic effect of prebiotics on the enhancement of intestinal barrier dysfunction, hepatic steatosis and, consequently, the progression of NAFLD.
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Affiliation(s)
| | | | - Marta Guariglia
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Irene Poggiolini
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Angelo Armandi
- Department of Medical Sciences, University of Turin, Turin, Italy
- Metabolic Liver Disease Research Program, First Department of Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Chiara Rosso
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Gian P Caviglia
- Department of Medical Sciences, University of Turin, Turin, Italy -
| | - Elisabetta Bugianesi
- Department of Medical Sciences, University of Turin, Turin, Italy
- Unit of Gastroenterology, Molinette Hospital, Città della Salute e della Scienza, Turin, Italy
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Zhou W, Du Z. Oleuropein mitigates non-alcoholic fatty liver disease (NAFLD) and modulates liver metabolites in high-fat diet-induced obese mice via activating PPARα. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2024; 104:8634-8645. [PMID: 38952322 DOI: 10.1002/jsfa.13691] [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: 11/30/2023] [Revised: 04/08/2024] [Accepted: 04/10/2024] [Indexed: 07/03/2024]
Abstract
BACKGROUND This study aimed to elucidate the mechanism of oleuropein (OLE) ameliorates non-alcoholic fatty liver disease (NAFLD) and its underlying mechanisms. RESULTS Male C57BL/6J mice were fed either a low-fat diet (LFD), a high-fat diet (HFD), or a HFD supplemented with 0.03% (w/w) OLE for 16 weeks. OLE supplementation decreased body weight and liver weight, improved serum lipid profiles, and ameliorated HFD-induced hepatic dysfunction. Liver metabolomics analysis revealed that OLE increased the levels of nicotinamide, tauroursodeoxycholic acid, taurine, and docosahexaenoic acid, which were beneficial for lipid homeostasis and inflammation regulation. OLE exerted its protective effects by activating peroxisome proliferator-activated receptor alpha (PPARα), a key transcription factor that regulates fibroblast growth factor 21 (FGF21) expression and modulates lipid oxidation, lipogenesis and inflammation pathways. Importantly, OLE supplementation did not significantly affect body weight or liver weight in PPARα knockout (PPARα KO) mice, indicating that PPARα is essential for OLE-mediated NAFLD prevention. CONCLUSION Our results suggest that OLE alleviates NAFLD in mice by activating PPARα and modulating liver metabolites. © 2024 Society of Chemical Industry.
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Affiliation(s)
- Wei Zhou
- Center for Prevention and Treatment of Cardiovascular Diseases, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zheng Du
- The First People's Hospital of Lianyungang Public Health Department, Lianyungang, China
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Beyoğlu D, Popov YV, Idle JR. The Metabolomic Footprint of Liver Fibrosis. Cells 2024; 13:1333. [PMID: 39195223 PMCID: PMC11353060 DOI: 10.3390/cells13161333] [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: 07/06/2024] [Revised: 08/08/2024] [Accepted: 08/08/2024] [Indexed: 08/29/2024] Open
Abstract
Both experimental and clinical liver fibrosis leave a metabolic footprint that can be uncovered and defined using metabolomic approaches. Metabolomics combines pattern recognition algorithms with analytical chemistry, in particular, 1H and 13C nuclear magnetic resonance spectroscopy (NMR), gas chromatography-mass spectrometry (GC-MS) and various liquid chromatography-mass spectrometry (LC-MS) platforms. The analysis of liver fibrosis by each of these methodologies is reviewed separately. Surprisingly, there was little general agreement between studies within each of these three groups and also between groups. The metabolomic footprint determined by NMR (two or more hits between studies) comprised elevated lactate, acetate, choline, 3-hydroxybutyrate, glucose, histidine, methionine, glutamine, phenylalanine, tyrosine and citrate. For GC-MS, succinate, fumarate, malate, ascorbate, glutamate, glycine, serine and, in agreement with NMR, glutamine, phenylalanine, tyrosine and citrate were delineated. For LC-MS, only β-muricholic acid, tryptophan, acylcarnitine, p-cresol, valine and, in agreement with NMR, phosphocholine were identified. The metabolomic footprint of liver fibrosis was upregulated as regards glutamine, phenylalanine, tyrosine, citrate and phosphocholine. Several investigators employed traditional Chinese medicine (TCM) treatments to reverse experimental liver fibrosis, and a commentary is given on the chemical constituents that may possess fibrolytic activity. It is proposed that molecular docking procedures using these TCM constituents may lead to novel therapies for liver fibrosis affecting at least one-in-twenty persons globally, for which there is currently no pharmaceutical cure. This in-depth review summarizes the relevant literature on metabolomics and its implications in addressing the clinical problem of liver fibrosis, cirrhosis and its sequelae.
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Affiliation(s)
- Diren Beyoğlu
- Department of Pharmaceutical and Administrative Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA 01119, USA;
| | - Yury V. Popov
- Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA;
| | - Jeffrey R. Idle
- Department of Pharmaceutical and Administrative Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA 01119, USA;
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Sakurai M, Motoike IN, Hishinuma E, Aoki Y, Tadaka S, Kogure M, Orui M, Ishikuro M, Obara T, Nakaya N, Kumada K, Hozawa A, Kuriyama S, Yamamoto M, Koshiba S, Kinoshita K. Identifying critical age and gender-based metabolomic shifts in a Japanese population of the Tohoku Medical Megabank cohort. Sci Rep 2024; 14:15681. [PMID: 38977808 PMCID: PMC11231361 DOI: 10.1038/s41598-024-66180-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 06/27/2024] [Indexed: 07/10/2024] Open
Abstract
Understanding the physiological changes associated with aging and the associated disease risks is essential to establish biomarkers as indicators of biological aging. This study used the NMR-measured plasma metabolome to calculate age-specific metabolite indices. In doing so, the scope of the study was deliberately simplified to capture general trends and insights into age-related changes in metabolic patterns. In addition, changes in metabolite concentrations with age were examined in detail, with the period from 55-59 to 60-64 years being a period of significant metabolic change, particularly in men, and from 45-49 to 50-54 years in females. These results illustrate the different variations in metabolite concentrations by sex and provide new insights into the relationship between age and metabolic diseases.
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Affiliation(s)
- Miyuki Sakurai
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Ikuko N Motoike
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Information Sciences, Tohoku University, Sendai, Japan
| | - Eiji Hishinuma
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, Japan
| | - Yuichi Aoki
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Information Sciences, Tohoku University, Sendai, Japan
| | - Shu Tadaka
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Mana Kogure
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Masatsugu Orui
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Mami Ishikuro
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Taku Obara
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Medicine, Tohoku University, Sendai, Japan
- Tohoku University Hospital, Tohoku University, Sendai, Japan
| | - Naoki Nakaya
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Kazuki Kumada
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Atsushi Hozawa
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Shinichi Kuriyama
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Medicine, Tohoku University, Sendai, Japan
- International Research Institute of Disaster Science, Tohoku University, Sendai, Japan
| | - Masayuki Yamamoto
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Seizo Koshiba
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, Japan
| | - Kengo Kinoshita
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
- Graduate School of Information Sciences, Tohoku University, Sendai, Japan.
- Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, Japan.
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Ahmed M, Ahmed MH. Ramadan Fasting in Individuals with Metabolic Dysfunction-Associated Steatotic Liver Disease, Liver Transplant, and Bariatric Surgery: A Narrative Review. J Clin Med 2024; 13:3893. [PMID: 38999457 PMCID: PMC11242100 DOI: 10.3390/jcm13133893] [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: 05/22/2024] [Revised: 06/25/2024] [Accepted: 07/01/2024] [Indexed: 07/14/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease is a growing worldwide pandemic. A limited number of studies have investigated the potential effect of Ramadan fasting on metabolic dysfunction-associated steatotic liver disease (MASLD). There is no single medication for the treatment of MASLD. There is a growing interest in dietary intervention as potential treatment for metabolic diseases including MASLD. The aim of this study was to discuss the epidemiology, pathogenesis, and risk factors of MASLD and the potential effects of Ramadan fasting on MASLD, liver transplant, and bariatric surgery. We searched PubMed and SCOPUS databases using different search terms. The literature search was based on research studies published in English from the year 2000 to the 2024. Thirty-two studies were included in this review. Ramadan fasting reduced body weight and improved lipid profile, anthropometric indices, fasting plasma glucose, plasma insulin, and inflammatory cytokines. Ramadan fasting improved risk factors of nonalcoholic fatty liver disease and might improve MASLD through weight reduction. However, further studies are needed to assess the safety and effectiveness of Ramadan fasting in liver transplant recipients and bariatric surgery.
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Affiliation(s)
- Musaab Ahmed
- College of Medicine, Ajman University, Ajman P.O. Box 346, United Arab Emirates
| | - Mohamed H Ahmed
- Department of Medicine and HIV Metabolic Clinic, Milton Keynes University Hospital NHS Foundation Trust, Eagelstone, Milton Keynes MK6 5LD, UK
- Department of Geriatric Medicine, Milton Keynes University Hospital NHS Foundation Trust, Eagelstone, Milton Keynes MK6 5LD, UK
- Honorary Senior Lecturer of the Faculty of Medicine and Health Sciences, University of Buckingham, Buckingham MK18 1EG, UK
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Yang H, Suh DH, Jung ES, Lee Y, Liu KH, Do IG, Lee CH, Park CY. Ezetimibe, Niemann-Pick C1 like 1 inhibitor, modulates hepatic phospholipid metabolism to alleviate fat accumulation. Front Pharmacol 2024; 15:1406493. [PMID: 38953111 PMCID: PMC11215075 DOI: 10.3389/fphar.2024.1406493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 05/13/2024] [Indexed: 07/03/2024] Open
Abstract
Background Ezetimibe, which lowers cholesterol by blocking the intestinal cholesterol transporter Niemann-Pick C1 like 1, is reported to reduce hepatic steatosis in humans and animals. Here, we demonstrate the changes in hepatic metabolites and lipids and explain the underlying mechanism of ezetimibe in hepatic steatosis. Methods We fed Otsuka Long-Evans Tokushima Fatty (OLETF) rats a high-fat diet (60 kcal % fat) with or vehicle (control) or ezetimibe (10 mg kg-1) via stomach gavage for 12 weeks and performed comprehensive metabolomic and lipidomic profiling of liver tissue. We used rat liver tissues, HepG2 hepatoma cell lines, and siRNA to explore the underlying mechanism. Results In OLETF rats on a high-fat diet, ezetimibe showed improvements in metabolic parameters and reduction in hepatic fat accumulation. The comprehensive metabolomic and lipidomic profiling revealed significant changes in phospholipids, particularly phosphatidylcholines (PC), and alterations in the fatty acyl-chain composition in hepatic PCs. Further analyses involving gene expression and triglyceride assessments in rat liver tissues, HepG2 hepatoma cell lines, and siRNA experiments unveiled that ezetimibe's mechanism involves the upregulation of key phospholipid biosynthesis genes, CTP:phosphocholine cytidylyltransferase alpha and phosphatidylethanolamine N-methyl-transferase, and the phospholipid remodeling gene lysophosphatidylcholine acyltransferase 3. Conclusion This study demonstrate that ezetimibe improves metabolic parameters and reduces hepatic fat accumulation by influencing the composition and levels of phospholipids, specifically phosphatidylcholines, and by upregulating genes related to phospholipid biosynthesis and remodeling. These findings provide valuable insights into the molecular pathways through which ezetimibe mitigates hepatic fat accumulation, emphasizing the role of phospholipid metabolism.
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Affiliation(s)
- Hyekyung Yang
- Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dong Ho Suh
- Department of Bioscience and Biotechnology, Konkuk University, Seoul, Republic of Korea
| | - Eun Sung Jung
- Department of Bioscience and Biotechnology, Konkuk University, Seoul, Republic of Korea
| | - Yoonjin Lee
- Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kwang-Hyeon Liu
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - In-Gu Do
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Choong Hwan Lee
- Department of Bioscience and Biotechnology, Konkuk University, Seoul, Republic of Korea
| | - Cheol-Young Park
- Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Zhang F, Shan S, Fu C, Guo S, Liu C, Wang S. Advanced Mass Spectrometry-Based Biomarker Identification for Metabolomics of Diabetes Mellitus and Its Complications. Molecules 2024; 29:2530. [PMID: 38893405 PMCID: PMC11173766 DOI: 10.3390/molecules29112530] [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: 02/08/2024] [Revised: 04/15/2024] [Accepted: 04/16/2024] [Indexed: 06/21/2024] Open
Abstract
Over the years, there has been notable progress in understanding the pathogenesis and treatment modalities of diabetes and its complications, including the application of metabolomics in the study of diabetes, capturing attention from researchers worldwide. Advanced mass spectrometry, including gas chromatography-tandem mass spectrometry (GC-MS/MS), liquid chromatography-tandem mass spectrometry (LC-MS/MS), and ultra-performance liquid chromatography coupled to electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-Q-TOF-MS), etc., has significantly broadened the spectrum of detectable metabolites, even at lower concentrations. Advanced mass spectrometry has emerged as a powerful tool in diabetes research, particularly in the context of metabolomics. By leveraging the precision and sensitivity of advanced mass spectrometry techniques, researchers have unlocked a wealth of information within the metabolome. This technology has enabled the identification and quantification of potential biomarkers associated with diabetes and its complications, providing new ideas and methods for clinical diagnostics and metabolic studies. Moreover, it offers a less invasive, or even non-invasive, means of tracking disease progression, evaluating treatment efficacy, and understanding the underlying metabolic alterations in diabetes. This paper summarizes advanced mass spectrometry for the application of metabolomics in diabetes mellitus, gestational diabetes mellitus, diabetic peripheral neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic encephalopathy, diabetic cardiomyopathy, and diabetic foot ulcers and organizes some of the potential biomarkers of the different complications with the aim of providing ideas and methods for subsequent in-depth metabolic research and searching for new ways of treating the disease.
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Affiliation(s)
- Feixue Zhang
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Medical College, Hubei University of Science and Technology, Xianning 437100, China; (F.Z.); (C.F.); (S.G.)
| | - Shan Shan
- College of Life Science, National R&D Center for Freshwater Fish Processing, Jiangxi Normal University, Nanchang 330022, China;
| | - Chenlu Fu
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Medical College, Hubei University of Science and Technology, Xianning 437100, China; (F.Z.); (C.F.); (S.G.)
- School of Pharmacy, Medical College, Hubei University of Science and Technology, Xianning 437100, China
| | - Shuang Guo
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Medical College, Hubei University of Science and Technology, Xianning 437100, China; (F.Z.); (C.F.); (S.G.)
| | - Chao Liu
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Medical College, Hubei University of Science and Technology, Xianning 437100, China; (F.Z.); (C.F.); (S.G.)
| | - Shuanglong Wang
- Jiangxi Key Laboratory for Mass Spectrometry and Instrumentation, East China University of Technology, Nanchang 330013, China
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Yu M, Chen X, Huang X, Gao X. Assessing the causal association between sleep apnea and the human gut microbiome composition: A two-sample Mendelian randomization study. SAGE Open Med 2024; 12:20503121241248044. [PMID: 38711464 PMCID: PMC11072075 DOI: 10.1177/20503121241248044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 04/02/2024] [Indexed: 05/08/2024] Open
Abstract
Background Studies have linked gut microbiota dysbiosis with sleep apnea; however, no causal relationship was found in human subjects. Finding new targets for the pathophysiology of sleep apnea might be made possible by systematically investigating the causal relationship between the human gut microbiota and sleep apnea. Methods A two-sample Mendelian randomization analysis was conducted. The human gut microbiome composition data, spanning five taxonomic levels, were acquired from a genome-wide association study that included 18,340 participants from 24 cohorts. Genome-wide association study data for sleep apnea were obtained from the Sleep Disorder Knowledge Portal for primary analysis and the FinnGen consortium for meta-analysis. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. Results Using inverse-variance weighted analysis, eight microbial taxa were initially found to be substantially linked with the apnea-hypopnea index. Only three microbial taxa remained significant associations with sleep apnea when combined with the FinnGen consortium (the class Bacilli: B = 8.21%, 95% CI = 0.93%-15.49%; p = 0.03; the order Lactobacillales: B = 7.55%, 95% CI = 0.25%-4.85%; p = 0.04; the genus RuminococcaceaeUCG009: B = -21.63%, 95% CI = -41.47% to -1.80%; p = 0.03). Conclusions Sleep apnea may lead to gut dysbiosis as significant reductions in butyrate-producing bacteria and increases in lactate-producing bacteria. By integrating genomes and metabolism, the evidence that three microbiome species are causally linked to sleep apnea may offer a fresh perspective on the underlying mechanisms of the condition.
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Affiliation(s)
- Min Yu
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, P.R. China
- Center for Oral Therapy of Sleep Apnea, Peking University Hospital of Stomatology, Beijing, P.R. China
- National Center of Stomatology, Beijing, P.R. China
| | - Xuehui Chen
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, P.R. China
- Center for Oral Therapy of Sleep Apnea, Peking University Hospital of Stomatology, Beijing, P.R. China
- National Center of Stomatology, Beijing, P.R. China
| | - Xin Huang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, P.R. China
- Center for Oral Therapy of Sleep Apnea, Peking University Hospital of Stomatology, Beijing, P.R. China
- National Center of Stomatology, Beijing, P.R. China
| | - Xuemei Gao
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, P.R. China
- Center for Oral Therapy of Sleep Apnea, Peking University Hospital of Stomatology, Beijing, P.R. China
- National Center of Stomatology, Beijing, P.R. China
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12
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Wang Y, Hou J, Li X, Chen P, Chen F, Pan Y, Deng Z, Li J, Liu R, Luo T. Tyrosol regulates hepatic lipid metabolism in high-fat diet-induced NAFLD mice. Food Funct 2024; 15:3752-3764. [PMID: 38506160 DOI: 10.1039/d3fo05345h] [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: 03/21/2024]
Abstract
This study aimed to elucidate the effect of tyrosol (TYR) on the amelioration of nonalcoholic fatty liver disease (NAFLD). Male C57BL/6J mice were fed a low-fat diet (LFD), a high-fat diet (HFD), or a HFD supplemented with 0.025% (w/w) TYR (TYR) for 16 weeks. Following a 16-week intervention, the TYR cohort exhibited diminished final body weight and hepatic lipid accumulation, compared to HFD fed mice. Liver metabolomics analysis revealed that TYR increased the hepatic levels of spermidine, taurine, linoleic acid, malic acid and eicosapentaenoic acid (EPA), indicating the beneficial effect of TYR on lipid homeostasis. Using molecular docking analysis and the luciferase assay, we found that TYR acts as a ligand and binds with peroxisome proliferator-activated receptor-α (PPARα), which plays a pivotal role in the modulation of hepatic lipid metabolism, thereby activating the transcription of downstream genes. Our results suggest that TYR alleviates NAFLD in HFD-fed mice probably by the modulation of the PPARα signaling pathway.
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Affiliation(s)
- Yu Wang
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, Jiangxi, China.
| | - Jihang Hou
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, Jiangxi, China.
| | - Xiaoping Li
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, Jiangxi, China.
| | - Pan Chen
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, Jiangxi, China.
| | - Fang Chen
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, Jiangxi, China.
| | - Yao Pan
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, Jiangxi, China.
| | - Zeyuan Deng
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, Jiangxi, China.
| | - Jing Li
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, Jiangxi, China.
| | - Rong Liu
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, Jiangxi, China.
| | - Ting Luo
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, Jiangxi, China.
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13
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Heller T, Herlemann DPR, Plieth A, Kröger JC, Weber MA, Reiner J, Jaster R, Kreikemeyer B, Lamprecht G, Schäffler H. Liver cirrhosis and antibiotic therapy but not TIPS application leads to a shift of the intestinal bacterial communities: A controlled, prospective study. J Dig Dis 2024; 25:200-208. [PMID: 38597371 DOI: 10.1111/1751-2980.13262] [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: 09/25/2023] [Revised: 02/20/2024] [Accepted: 03/05/2024] [Indexed: 04/11/2024]
Abstract
OBJECTIVES The gut-liver axis is discussed to play an important role in hepatic cirrhosis. Decompensated liver cirrhosis is associated with portal hypertension, which can lead to a variety of complications. Transjugular intrahepatic portosystemic shunt (TIPS) is an established treatment option for the complications of portal hypertension. In this study we focused on the effect of TIPS on intestinal microbial composition in cirrhotic patients. METHODS Thirty patients with liver cirrhosis were compared to 18 healthy adults. Seventeen patients with cirrhosis and portal hypertension received a TIPS. Clinical characteristics, including age, sex, and liver function measured with a Child-Pugh score and model for end-stage liver disease score, were obtained. Intestinal microbial composition was assessed via 16S rRNA gene amplicon sequencing from stool probes before and after TIPS. RESULTS TIPS led to a reduction of hepatic venous pressure gradient. However, TIPS did not cause a shift in the intestinal bacterial communities. Independent from the application of TIPS, antibiotic therapy was associated with a significant difference in the intestinal bacterial microbiota and also a reduced α-diversity. In addition, a significant difference was observed in the intestinal bacterial composition between patients with liver cirrhosis and healthy controls. CONCLUSION The presence of liver cirrhosis and the use of antibiotic therapy, but not the application of TIPS, were associated with a significant shift of the intestinal bacterial communities, showing a high impact on the microbiota of patients with liver cirrhosis.
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Affiliation(s)
- Thomas Heller
- Institute of Diagnostic and Interventional Radiology, Pediatric Radiology and Neuroradiology, University Medical Center Rostock, Rostock, Germany
| | - Daniel P R Herlemann
- Microbial Ecophysiology, Chair of Hydrobiology and Fisheries, Institute of Agricultural and Environmental Sciences, Estonian University of Life Sciences, Tartu, Estonia
- Leibniz Institute for Baltic Sea Research, Rostock, Germany
| | - Anabel Plieth
- Division of Gastroenterology and Endocrinology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
| | - Jens-Christian Kröger
- Institute of Diagnostic and Interventional Radiology, Pediatric Radiology and Neuroradiology, University Medical Center Rostock, Rostock, Germany
| | - Marc-André Weber
- Institute of Diagnostic and Interventional Radiology, Pediatric Radiology and Neuroradiology, University Medical Center Rostock, Rostock, Germany
| | - Johannes Reiner
- Division of Gastroenterology and Endocrinology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
| | - Robert Jaster
- Division of Gastroenterology and Endocrinology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
| | - Bernd Kreikemeyer
- Institute of Medical Microbiology, Virology and Hygiene, University Medical Center, Rostock, Germany
| | - Georg Lamprecht
- Division of Gastroenterology and Endocrinology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
| | - Holger Schäffler
- Division of Gastroenterology and Endocrinology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
- Department of Gastroenterology and Internal Medicine, Rems-Murr-Klinikum Winnenden GmbH, Winnenden, Germany
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14
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Zhou Z, Liu J, Liu J. Application of Weighted Gene Co-Expression Network Analysis to Metabolomic Data from an ApoA-I Knockout Mouse Model. Molecules 2024; 29:694. [PMID: 38338438 PMCID: PMC10856800 DOI: 10.3390/molecules29030694] [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: 12/04/2023] [Revised: 01/30/2024] [Accepted: 01/31/2024] [Indexed: 02/12/2024] Open
Abstract
As the ability to collect profiling data in metabolomics increases substantially with the advances in Liquid Chromatography-Mass Spectrometry (LC-MS) instruments, it is urgent to develop new and powerful data analysis approaches to match the big data collected and to extract as much meaningful information as possible from tens of thousands of molecular features. Here, we applied weighted gene co-expression network analysis (WGCNA), an algorithm popularly used in microarray or RNA sequencing, to plasma metabolomic data and demonstrated several advantages of WGCNA over conventional statistical approaches such as principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA). By using WGCNA, a large number of molecular features were clustered into a few modules to reduce the dimension of a dataset, the impact of phenotypic traits such as diet type and genotype on the plasma metabolome was evaluated quantitatively, and hub metabolites were found based on the network graph. Our work revealed that WGCNA is a very powerful tool to decipher, interpret, and visualize metabolomic datasets.
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Affiliation(s)
- Zhe Zhou
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Jiao Liu
- Center of Medical and Health Analysis, Peking University Health Science Center, Beijing 100191, China
| | - Jia Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
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15
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Aziz N, Wal P, Sinha R, Shirode PR, Chakraborthy G, Sharma MC, Kumar P. A Comprehensive Review on the Significance of Cysteine in Various Metabolic Disorders; Particularly CVD, Diabetes, Renal Dysfunction, and Ischemic Stroke. Curr Protein Pept Sci 2024; 25:682-707. [PMID: 38766817 DOI: 10.2174/0113892037287215240424090908] [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: 12/19/2023] [Revised: 03/20/2024] [Accepted: 03/27/2024] [Indexed: 05/22/2024]
Abstract
Metabolic disorders have long been a challenge for medical professionals and are a leading cause of mortality in adults. Diabetes, cardiovascular disorders (CVD), renal dysfunction, and ischemic stroke are the most prevalent ailments contributing to a high mortality rate worldwide. Reactive oxygen species are one of the leading factors that act as a fundamental root cause of metabolic syndrome. All of these disorders have their respective treatments, which, to some degree, sabotage the pathological worsening of the disease and an inevitable death. However, they pose a perilous health hazard to humankind. Cysteine, a functional amino acid shows promise for the prevention and treatment of metabolic disorders, such as CVD, Diabetes mellitus, renal dysfunction, and ischemic stroke. In this review, we explored whether cysteine can eradicate reactive oxygen species and subsequently prevent and treat these diseases.
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Affiliation(s)
- Namra Aziz
- PSIT-Pranveer Singh Institute of Technology (Pharmacy), NH-19, Kanpur-209305, UP, India
| | - Pranay Wal
- PSIT-Pranveer Singh Institute of Technology (Pharmacy), NH-19, Kanpur-209305, UP, India
| | - Rishika Sinha
- PSIT-Pranveer Singh Institute of Technology (Pharmacy), NH-19, Kanpur-209305, UP, India
| | | | | | | | - Pankaj Kumar
- Department of Pharmacology, Adesh Institute of Pharmacy and Biomedical Sciences, Adesh 6 University, NH-7, Barnala Road, Bathinda 151001, India
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16
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Choubey J, Wolkenhauer O, Chatterjee T. Systems Biology Approach to Analyze Microarray Datasets for Identification of Disease-Causing Genes: Case Study of Oral Squamous Cell Carcinoma. Methods Mol Biol 2024; 2719:13-31. [PMID: 37803110 DOI: 10.1007/978-1-0716-3461-5_2] [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] [Indexed: 10/08/2023]
Abstract
The discovery of potential disease-causing genes can aid medical progress. The post-genomic era has made this a more difficult task. Modern high-throughput methods have not solved the problem of identifying disease genes. Conventional methods cannot be used to investigate many rare or lethal diseases. Monitoring gene expression values in different samples using microarray technology is one of the best and most accurate ways to identify disease-causing genes. One of the most recent advances in experimental molecular biology is microarrays, which allow researchers to simultaneously monitor the expression levels of thousands of genes. Statistical analysis of microarray data might aid gene discovery by revealing pathways related to the target gene and facilitating identification of candidate genes. Systems biology, an interdisciplinary approach, has emerged as a crucial analytic tool with the potential to reveal previously unidentified causes and consequences of human illness. Genetic, environmental, immunological, or neurological factors have been implicated in the developing complex disorders like cancer. Because of this, it is important to approach the study of such disease from a novel perspective. The system biology approach allows us to rapidly identify disease-causing genes and assess their viability as therapeutic targets. This chapter demonstrates systems biology approaches to identify candidate genes using public database. Oral squamous cell carcinoma (OSCC) is used as a model disease to show how systems biology can be used successfully to identify and prioritize disease genes.
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Affiliation(s)
| | - Olaf Wolkenhauer
- Department of Systems Biology & Bioinformatics, University of Rostock, Rostock, Germany
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17
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Mihuta MS, Paul C, Borlea A, Roi CM, Pescari D, Velea-Barta OA, Mozos I, Stoian D. Connections between serum Trimethylamine N-Oxide (TMAO), a gut-derived metabolite, and vascular biomarkers evaluating arterial stiffness and subclinical atherosclerosis in children with obesity. Front Endocrinol (Lausanne) 2023; 14:1253584. [PMID: 37850094 PMCID: PMC10577381 DOI: 10.3389/fendo.2023.1253584] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 09/12/2023] [Indexed: 10/19/2023] Open
Abstract
Introduction Childhood obesity leads to early subclinical atherosclerosis and arterial stiffness. Studying biomarkers like trimethylamine N-oxide (TMAO), linked to cardio-metabolic disorders in adults, is crucial to prevent long-term cardiovascular issues. Methods The study involved 70 children aged 4 to 18 (50 obese, 20 normal-weight). Clinical examination included BMI, waist measurements, puberty stage, the presence of acanthosis nigricans, and irregular menstrual cycles. Subclinical atherosclerosis was assessed by measuring the carotid intima-media thickness (CIMT), and the arterial stiffness was evaluated through surrogate markers like the pulse wave velocity (PWV), augmentation index (AIx), and peripheral and central blood pressures. The blood biomarkers included determining the values of TMAO, HOMA-IR, and other usual biomarkers investigating metabolism. Results The study detected significantly elevated levels of TMAO in obese children compared to controls. TMAO presented positive correlations to BMI, waist circumference and waist-to-height ratio and was also observed as an independent predictor of all three parameters. Significant correlations were observed between TMAO and vascular markers such as CIMT, PWV, and peripheral BP levels. TMAO independently predicts CIMT, PWV, peripheral BP, and central SBP levels, even after adding BMI, waist circumference, waist-to-height ratio, puberty development and age in the regression model. Obese children with high HOMA-IR presented a greater weight excess and significantly higher vascular markers, but TMAO levels did not differ significantly from the obese with HOMA-IR Conclusion Our study provides compelling evidence supporting the link between serum TMAO, obesity, and vascular damage in children. These findings highlight the importance of further research to unravel the underlying mechanisms of this connection.
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Affiliation(s)
- Monica Simina Mihuta
- Department of Doctoral Studies, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
- Center of Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Corina Paul
- Department of Pediatrics, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Andreea Borlea
- Center of Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
- 2nd Department of Internal Medicine, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Cristina Mihaela Roi
- Department of Doctoral Studies, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
- Center of Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Denisa Pescari
- Department of Doctoral Studies, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Oana-Alexandra Velea-Barta
- 3rd Department of Odontotherapy and Endodontics, Faculty of Dental Medicine, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Ioana Mozos
- Department of Functional Sciences—Pathophysiology, Center for Translational Research and Systems Medicine, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Dana Stoian
- Center of Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
- 2nd Department of Internal Medicine, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
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18
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Niazi SK. The Coming of Age of AI/ML in Drug Discovery, Development, Clinical Testing, and Manufacturing: The FDA Perspectives. Drug Des Devel Ther 2023; 17:2691-2725. [PMID: 37701048 PMCID: PMC10493153 DOI: 10.2147/dddt.s424991] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 08/24/2023] [Indexed: 09/14/2023] Open
Abstract
Artificial intelligence (AI) and machine learning (ML) represent significant advancements in computing, building on technologies that humanity has developed over millions of years-from the abacus to quantum computers. These tools have reached a pivotal moment in their development. In 2021 alone, the U.S. Food and Drug Administration (FDA) received over 100 product registration submissions that heavily relied on AI/ML for applications such as monitoring and improving human performance in compiling dossiers. To ensure the safe and effective use of AI/ML in drug discovery and manufacturing, the FDA and numerous other U.S. federal agencies have issued continuously updated, stringent guidelines. Intriguingly, these guidelines are often generated or updated with the aid of AI/ML tools themselves. The overarching goal is to expedite drug discovery, enhance the safety profiles of existing drugs, introduce novel treatment modalities, and improve manufacturing compliance and robustness. Recent FDA publications offer an encouraging outlook on the potential of these tools, emphasizing the need for their careful deployment. This has expanded market opportunities for retraining personnel handling these technologies and enabled innovative applications in emerging therapies such as gene editing, CRISPR-Cas9, CAR-T cells, mRNA-based treatments, and personalized medicine. In summary, the maturation of AI/ML technologies is a testament to human ingenuity. Far from being autonomous entities, these are tools created by and for humans designed to solve complex problems now and in the future. This paper aims to present the status of these technologies, along with examples of their present and future applications.
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19
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Microbiome and Metabolomics in Liver Cancer: Scientific Technology. Int J Mol Sci 2022; 24:ijms24010537. [PMID: 36613980 PMCID: PMC9820585 DOI: 10.3390/ijms24010537] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 12/12/2022] [Accepted: 12/19/2022] [Indexed: 12/30/2022] Open
Abstract
Primary liver cancer is a heterogeneous disease. Liver cancer metabolism includes both the reprogramming of intracellular metabolism to enable cancer cells to proliferate inappropriately and adapt to the tumor microenvironment and fluctuations in regular tissue metabolism. Currently, metabolomics and metabolite profiling in liver cirrhosis, liver cancer, and hepatocellular carcinoma (HCC) have been in the spotlight in terms of cancer diagnosis, monitoring, and therapy. Metabolomics is the global analysis of small molecules, chemicals, and metabolites. Metabolomics technologies can provide critical information about the liver cancer state. Here, we review how liver cirrhosis, liver cancer, and HCC therapies interact with metabolism at the cellular and systemic levels. An overview of liver metabolomics is provided, with a focus on currently available technologies and how they have been used in clinical and translational research. We also list scalable methods, including chemometrics, followed by pathway processing in liver cancer. We conclude that important drivers of metabolomics science and scientific technologies are novel therapeutic tools and liver cancer biomarker analysis.
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20
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Heinzer K, Lang S, Farowski F, Wisplinghoff H, Vehreschild MJGT, Martin A, Nowag A, Kretzschmar A, Scholz CJ, Roderburg C, Mohr R, Tacke F, Kasper P, Goeser T, Steffen HM, Demir M. Dietary omega-6/omega-3 ratio is not associated with gut microbiota composition and disease severity in patients with nonalcoholic fatty liver disease. Nutr Res 2022; 107:12-25. [PMID: 36162275 DOI: 10.1016/j.nutres.2022.07.006] [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: 12/29/2021] [Revised: 07/24/2022] [Accepted: 07/30/2022] [Indexed: 12/27/2022]
Abstract
In this cross-sectional study, we hypothesized that a high dietary ratio of omega-6 (n-6) to omega-3 (n-3) fatty acids could be associated with an altered gut bacterial composition and with the disease severity in patients with nonalcoholic fatty liver disease (NAFLD). A total of 101 NAFLD patients were included in the study, of which 63 underwent a liver biopsy. All 101 patients completed a 14-day food and activity record. Ebispro 2016 professional software was used to calculate individual macronutrients and micronutrients consumed. Patients were grouped into 3 quantiles (Q) according to a low (Q1: <6.1, n = 34), moderate (Q2: 6.1-7.8, n = 33), or high (Q3: >7.8, n = 34) dietary n-6/n-3 ratio. Stool samples were analyzed using 16S rRNA gene sequencing. Spearman correlation coefficients and principal coordinate analysis were used to detect differences in the bacterial composition of the gut microbiota. The median dietary n-6/n-3 ratio of all patients was 6.7 (range, 3.1-14.9). No significant associations between the dietary n-6/n-3 ratio and the gut microbiota composition or disease severity were observed. However, the abundance of specific bacteria such as Catenibacterium or Lactobacillus ruminis were found to be positively correlated and the abundance of Clostridium were negatively correlated with dietary n-6 fatty acid intake. The results indicate that a high dietary n-6/n-3 ratio is probably not a highly relevant factor in the pathogenesis of human NAFLD. Further studies are needed to clarify the importance of interactions between gut bacterial taxa and n-6 fatty acids in the pathophysiology of NAFLD.
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Affiliation(s)
- Kathrin Heinzer
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany
| | - Sonja Lang
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany; Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Fedja Farowski
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Cologne, Germany; German Centre for Infection Research (DZIF), partner site Bonn/Cologne; Department of Internal Medicine, Infectious Diseases, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Hilmar Wisplinghoff
- Wisplinghoff Laboratories, Cologne, Germany; University of Cologne, Faculty of Medicine, Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, Cologne, Germany; Institute for Virology and Medical Microbiology, University Witten/Herdecke, Witten, Germany
| | - Maria J G T Vehreschild
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Cologne, Germany; German Centre for Infection Research (DZIF), partner site Bonn/Cologne; Department of Internal Medicine, Infectious Diseases, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Anna Martin
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany
| | - Angela Nowag
- Wisplinghoff Laboratories, Cologne, Germany; University of Cologne, Faculty of Medicine, Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, Cologne, Germany
| | | | | | - Christoph Roderburg
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité Universitätsmedizin, Berlin, Germany
| | - Raphael Mohr
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité Universitätsmedizin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité Universitätsmedizin, Berlin, Germany
| | - Philipp Kasper
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany
| | - Tobias Goeser
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany
| | - Hans-Michael Steffen
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany
| | - Münevver Demir
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité Universitätsmedizin, Berlin, Germany.
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Montemayor S, Mascaró CM, Ugarriza L, Casares M, Gómez C, Martínez JA, Tur JA, Bouzas C. Intrahepatic Fat Content and COVID-19 Lockdown in Adults with NAFLD and Metabolic Syndrome. Nutrients 2022; 14:nu14173462. [PMID: 36079720 PMCID: PMC9457922 DOI: 10.3390/nu14173462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/18/2022] [Accepted: 08/19/2022] [Indexed: 11/16/2022] Open
Abstract
Background: COVID-19 lockdowns had a significant impact on people’s health, triggering levels of anxiety, perceived stress, and changes in food and nutritional status. Objectives: To assess the changes in dietary habits, metabolic syndrome (MetS) and liver parameters before and after the COVID-19 lockdown according to changes in intrahepatic fat content in adults with non-alcoholic fatty liver disease (NAFLD) and MetS. Design: Pre- and post-lockdown observation of the COVID-19 lockdown on fifty-nine 40–60-year-old participants with MetS and NAFLD, in a parallel group, randomised experiment intended to treat NAFLD. Methods: Anthropometrics, liver and MetS biochemical parameters, intrahepatic fat content by abdominal magnetic resonance imaging, and dietary assessment using a validated 148-item Food Frequency Questionnaire were collected pre-COVID-19 lockdown and post-lockdown. Results: COVID-19 lockdown led to negative changes in the liver of patients with NAFLD and MetS, with weight gain and increases in glycemia, ALT and intrahepatic fat content post lockdown. Participants with worsened liver status had low consumption of fibre, cheese, nuts and coffee, and high consumption of sweets and pastries. Participants who improved liver status ameliorated ALT values, waist circumference, and intrahepatic fat content, assessed by magnetic resonance imaging post-lockdown. Conclusions: The maintenance of healthy lifestyle habits is vital, especially for populations with NAFLD and MetS, to reduce unhealthy lifestyle patterns displayed during lockdown.
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Affiliation(s)
- Sofía Montemayor
- Research Group on Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain
- Health Institute of the Balearic Islands (IDISBA), 07120 Palma de Mallorca, Spain
| | - Catalina M. Mascaró
- Research Group on Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain
- Health Institute of the Balearic Islands (IDISBA), 07120 Palma de Mallorca, Spain
| | - Lucía Ugarriza
- Research Group on Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain
- Health Institute of the Balearic Islands (IDISBA), 07120 Palma de Mallorca, Spain
- Camp Redó Primary Health Care Center, 07010 Palma de Mallorca, Spain
| | - Miguel Casares
- Radiodiagnosis Service, Red Asistencial Juaneda, 07011 Palma de Mallorca, Spain
| | - Cristina Gómez
- Research Group on Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain
- Health Institute of the Balearic Islands (IDISBA), 07120 Palma de Mallorca, Spain
- Clinical Analysis Service, Universitary Hospital Son Espases, 07120 Palma de Mallorca, Spain
| | - J. Alfredo Martínez
- Center for Nutrition Research, Department of Nutrition, Food Sciences, and Physiology, University of Navarra, 31008 Pamplona, Spain
- Cardiometabolics Precision Nutrition Program, IMDEA Food, CEI UAM-CSIC, 28049 Madrid, Spain
| | - Josep A. Tur
- Research Group on Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain
- Health Institute of the Balearic Islands (IDISBA), 07120 Palma de Mallorca, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition CB12/03/30038), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Correspondence:
| | - Cristina Bouzas
- Research Group on Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain
- Health Institute of the Balearic Islands (IDISBA), 07120 Palma de Mallorca, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition CB12/03/30038), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
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22
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Milenkovic D, Capel F, Combaret L, Comte B, Dardevet D, Evrard B, Guillet C, Monfoulet LE, Pinel A, Polakof S, Pujos-Guillot E, Rémond D, Wittrant Y, Savary-Auzeloux I. Targeting the gut to prevent and counteract metabolic disorders and pathologies during aging. Crit Rev Food Sci Nutr 2022; 63:11185-11210. [PMID: 35730212 DOI: 10.1080/10408398.2022.2089870] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Impairment of gut function is one of the explanatory mechanisms of health status decline in elderly population. These impairments involve a decline in gut digestive physiology, metabolism and immune status, and associated to that, changes in composition and function of the microbiota it harbors. Continuous deteriorations are generally associated with the development of systemic dysregulations and ultimately pathologies that can worsen the initial health status of individuals. All these alterations observed at the gut level can then constitute a wide range of potential targets for development of nutritional strategies that can impact gut tissue or associated microbiota pattern. This can be key, in a preventive manner, to limit gut functionality decline, or in a curative way to help maintaining optimum nutrients bioavailability in a context on increased requirements, as frequently observed in pathological situations. The aim of this review is to give an overview on the alterations that can occur in the gut during aging and lead to the development of altered function in other tissues and organs, ultimately leading to the development of pathologies. Subsequently is discussed how nutritional strategies that target gut tissue and gut microbiota can help to avoid or delay the occurrence of aging-related pathologies.
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Affiliation(s)
- Dragan Milenkovic
- Human Nutrition Unit, UMR1019, University Clermont Auvergne, INRAE, Clermont-Ferrand, France
| | - Frédéric Capel
- Human Nutrition Unit, UMR1019, University Clermont Auvergne, INRAE, Clermont-Ferrand, France
| | - Lydie Combaret
- Human Nutrition Unit, UMR1019, University Clermont Auvergne, INRAE, Clermont-Ferrand, France
| | - Blandine Comte
- Human Nutrition Unit, UMR1019, University Clermont Auvergne, INRAE, Clermont-Ferrand, France
| | - Dominique Dardevet
- Human Nutrition Unit, UMR1019, University Clermont Auvergne, INRAE, Clermont-Ferrand, France
| | - Bertrand Evrard
- Human Nutrition Unit, UMR1019, University Clermont Auvergne, INRAE, Clermont-Ferrand, France
| | - Christelle Guillet
- Human Nutrition Unit, UMR1019, University Clermont Auvergne, INRAE, Clermont-Ferrand, France
| | | | - Alexandre Pinel
- Human Nutrition Unit, UMR1019, University Clermont Auvergne, INRAE, Clermont-Ferrand, France
| | - Sergio Polakof
- Human Nutrition Unit, UMR1019, University Clermont Auvergne, INRAE, Clermont-Ferrand, France
| | - Estelle Pujos-Guillot
- Human Nutrition Unit, UMR1019, University Clermont Auvergne, INRAE, Clermont-Ferrand, France
| | - Didier Rémond
- Human Nutrition Unit, UMR1019, University Clermont Auvergne, INRAE, Clermont-Ferrand, France
| | - Yohann Wittrant
- Human Nutrition Unit, UMR1019, University Clermont Auvergne, INRAE, Clermont-Ferrand, France
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23
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Suvannapruk W, Edney MK, Kim DH, Scurr DJ, Ghaemmaghami AM, Alexander MR. Single-Cell Metabolic Profiling of Macrophages Using 3D OrbiSIMS: Correlations with Phenotype. Anal Chem 2022; 94:9389-9398. [PMID: 35713879 PMCID: PMC9260720 DOI: 10.1021/acs.analchem.2c01375] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
![]()
Macrophages are important
immune cells that respond to environmental
cues acquiring a range of activation statuses represented by pro-inflammatory
(M1) and anti-inflammatory (M2) phenotypes at each end of their spectrum.
Characterizing the metabolic signature (metabolic profiling) of different
macrophage subsets is a powerful tool to understand the response of
the human immune system to different stimuli. Here, the recently developed
3D OrbiSIMS instrument is applied to yield useful insight into the
metabolome from individual cells after in vitro differentiation of
macrophages into naïve, M1, and M2 phenotypes using different
cytokines. This analysis strategy not only requires more than 6 orders
of magnitude less sample than traditional mass spectrometry approaches
but also allows the study of cell-to-cell variance. Characteristic
metabolites in macrophage subsets are identified using a targeted
lipid and data-driven multivariate approach highlighting amino acids
and other small molecules. The diamino acids alanylasparagine and
lipid sphingomyelin SM(d18/16:0) are uniquely found in M1 macrophages,
while pyridine and pyrimidine are observed at increased intensity
in M2 macrophages, findings which link to known biological pathways.
The first demonstration of this capability illustrates the great potential
of direct cell analysis for in situ metabolite profiling with the
3D OrbiSIMS to probe functional phenotype at the single-cell level
using molecular signatures and to understand the response of the human
body to implanted devices and immune diseases.
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Affiliation(s)
- Waraporn Suvannapruk
- Advanced Materials and Healthcare Technologies Division, School of Pharmacy, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom
| | - Max K Edney
- Department of Chemical and Environmental Engineering, Faculty of Engineering, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom
| | - Dong-Hyun Kim
- Advanced Materials and Healthcare Technologies Division, School of Pharmacy, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom
| | - David J Scurr
- Advanced Materials and Healthcare Technologies Division, School of Pharmacy, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom
| | - Amir M Ghaemmaghami
- Immunology & Immuno-bioengineering Group, School of Life Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom
| | - Morgan R Alexander
- Advanced Materials and Healthcare Technologies Division, School of Pharmacy, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom
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24
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Velenosi TJ, Ben-Yakov G, Podszun MC, Hercun J, Etzion O, Yang S, Nadal C, Haynes-Williams V, Huang WCA, Gonzalez-Hodar L, Brychta RJ, Takahashi S, Akkaraju V, Krausz KW, Walter M, Cai H, Walter PJ, Muniyappa R, Chen KY, Gonzalez FJ, Rotman Y. Postprandial Plasma Lipidomics Reveal Specific Alteration of Hepatic-derived Diacylglycerols in Nonalcoholic Fatty Liver Disease. Gastroenterology 2022; 162:1990-2003. [PMID: 35283114 PMCID: PMC9117487 DOI: 10.1053/j.gastro.2022.03.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 02/24/2022] [Accepted: 03/01/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND & AIMS Hepatic energy metabolism is a dynamic process modulated by multiple stimuli. In nonalcoholic fatty liver disease (NAFLD), human studies typically focus on the static fasting state. We hypothesized that unique postprandial alterations in hepatic lipid metabolism are present in NAFLD. METHODS In a prospective clinical study, 37 patients with NAFLD and 10 healthy control subjects ingested a standardized liquid meal with pre- and postprandial blood sampling. Postprandial plasma lipid kinetics were characterized at the molecular lipid species level by untargeted lipidomics, cluster analysis, and lipid particle isolation, then confirmed in a mouse model. RESULTS There was a specific increase of multiple plasma diacylglycerol (DAG) species at 4 hours postprandially in patients with NAFLD but not in controls. This was replicated in a nonalcoholic steatohepatitis mouse model, where postprandial DAGs increased in plasma and concomitantly decreased in the liver. The increase in plasma DAGs appears early in the disease course, is dissociated from NAFLD severity and obesity, and correlates with postprandial insulin levels. Immunocapture isolation of very low density lipoprotein in human samples and stable isotope tracer studies in mice revealed that elevated postprandial plasma DAGs reflect hepatic secretion of endogenous, rather than meal-derived lipids. CONCLUSIONS We identified a selective insulin-related increase in hepatic secretion of endogenously derived DAGs after a mixed meal as a unique feature of NAFLD. DAGs are known to be lipotoxic and associated with atherosclerosis. Although it is still unknown whether the increased exposure to hepatic DAGs contributes to extrahepatic manifestations and cardiovascular risk in NAFLD, our study highlights the importance of extending NAFLD research beyond the fasting state.
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Affiliation(s)
- Thomas J. Velenosi
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH)
| | - Gil Ben-Yakov
- Liver & Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH,Liver Diseases Branch, NIDDK, NIH
| | - Maren C. Podszun
- Liver & Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH,Liver Diseases Branch, NIDDK, NIH
| | | | | | | | | | | | | | - Lila Gonzalez-Hodar
- Liver & Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH,Liver Diseases Branch, NIDDK, NIH
| | | | - Shogo Takahashi
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH)
| | - Vikas Akkaraju
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH)
| | - Kristopher W. Krausz
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH)
| | | | - Hongyi Cai
- Clinical Mass Spectrometry Core, NIDDK, NIH
| | | | | | - Kong Y. Chen
- Diabetes, Endocrinology and Obesity Branch, NIDDK, NIH
| | - Frank J. Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH)
| | - Yaron Rotman
- Liver and Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland; Liver Diseases Branch, NIDDK, NIH, Bethesda, Maryland.
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25
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Haonon O, Liu Z, Dangtakot R, Pinlaor P, Puapairoj A, Cha'on U, Intuyod K, Pongking T, Chantawong C, Sengthong C, Chaidee A, Onsurathum S, Li JV, Pinlaor S. Opisthorchis viverrini infection induces metabolic disturbances in hamsters fed with high fat/high fructose diets: implications for liver and kidney pathologies. J Nutr Biochem 2022; 107:109053. [DOI: 10.1016/j.jnutbio.2022.109053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 02/15/2022] [Accepted: 04/19/2022] [Indexed: 02/07/2023]
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26
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Martin-Grau M, Marrachelli VG, Monleon D. Rodent models and metabolomics in non-alcoholic fatty liver disease: What can we learn? World J Hepatol 2022; 14:304-318. [PMID: 35317178 PMCID: PMC8891675 DOI: 10.4254/wjh.v14.i2.304] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/13/2021] [Accepted: 01/29/2022] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) prevalence has increased drastically in recent decades, affecting up to 25% of the world’s population. NAFLD is a spectrum of different diseases that starts with asymptomatic steatosis and continues with development of an inflammatory response called steatohepatitis, which can progress to fibrosis. Several molecular and metabolic changes are required for the hepatocyte to finally vary its function; hence a “multiple hit” hypothesis seems a more accurate proposal. Previous studies and current knowledge suggest that in most cases, NAFLD initiates and progresses through most of nine hallmarks of the disease, although the triggers and mechanisms for these can vary widely. The use of animal models remains crucial for understanding the disease and for developing tools based on biological knowledge. Among certain requirements to be met, a good model must imitate certain aspects of the human NAFLD disorder, be reliable and reproducible, have low mortality, and be compatible with a simple and feasible method. Metabolism studies in these models provides a direct reflection of the workings of the cell and may be a useful approach to better understand the initiation and progression of the disease. Metabolomics seems a valid tool for studying metabolic pathways and crosstalk between organs affected in animal models of NAFLD and for the discovery and validation of relevant biomarkers with biological understanding. In this review, we provide a brief introduction to NAFLD hallmarks, the five groups of animal models available for studying NAFLD and the potential role of metabolomics in the study of experimental NAFLD.
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Affiliation(s)
- Maria Martin-Grau
- Department of Pathology, University of Valencia, Valencia 46010, Spain
| | - Vannina G Marrachelli
- Department of Physiology, University of Valencia, Valencia 46010, Spain
- Health Research Institute INCLIVA, Valencia 46010, Spain
| | - Daniel Monleon
- Department of Pathology, University of Valencia, Valencia 46010, Spain
- Health Research Institute INCLIVA, Valencia 46010, Spain
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes), Madrid 28029, Spain
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27
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Longo L, Rampelotto PH, Filippi-Chiela E, de Souza VEG, Salvati F, Cerski CT, da Silveira TR, Oliveira CP, Uribe-Cruz C, Álvares-da-Silva MR. Gut dysbiosis and systemic inflammation promote cardiomyocyte abnormalities in an experimental model of steatohepatitis. World J Hepatol 2021; 13:2052-2070. [PMID: 35070008 PMCID: PMC8727214 DOI: 10.4254/wjh.v13.i12.2052] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 07/20/2021] [Accepted: 10/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cardiovascular disease is the main cause of death in metabolic-associated fatty liver disease, and gut microbiota dysbiosis is associated with both of them.
AIM To assess the relationship between gut dysbiosis and cardiovascular risk (CVR) in an experimental model of steatohepatitis.
METHODS Adult male Sprague-Dawley rats were randomized to a control group (n = 10) fed a standard diet and an intervention group (n = 10) fed a high-fat choline-deficient diet for 16 wk. Biochemical, molecular, hepatic, and cardiac histopathology. Gut microbiota variables were evaluated.
RESULTS The intervention group had a significantly higher atherogenic coefficient, Castelli’s risk index (CRI)-I and CRI-II, interleukin-1β, tissue inhibitor of metalloproteinase-1 (all P < 0.001), monocyte chemoattractant protein-1 (P = 0.005), and plasminogen activator inhibitor-1 (P = 0.037) than the control group. Gene expression of miR-33a increased (P = 0.001) and miR-126 (P < 0.001) decreased in the intervention group. Steatohepatitis with fibrosis was seen in the intervention group, and heart computerized histological imaging analysis showed a significant decrease in the percentage of cardiomyocytes with a normal morphometric appearance (P = 0.007), reduction in the mean area of cardiomyocytes (P = 0.037), and an increase of atrophic cardiomyocytes (P = 0.007). There were significant correlations between the cardiomyocyte morphometry markers and those of progression and severity of liver disease and CVR. The intervention group had a lower Shannon diversity index and fewer changes in the structural pattern of gut microbiota (both P < 0.001) than controls. Nine microbial families that are involved in lipid metabolism were differentially abundant in intervention group and were significantly correlated with markers of liver injury and CVR.
CONCLUSION The study found a link between gut dysbiosis and significant cardiomyocyte abnormalities in animals with steatohepatitis.
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Affiliation(s)
- Larisse Longo
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Rio Grande do Sul, Brazil
| | - Pabulo Henrique Rampelotto
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
- Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
| | - Eduardo Filippi-Chiela
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Rio Grande do Sul, Brazil
- Center of Biotechnology, Universidade Federal do Rio Grande do Sul, Porto Alegre 91501-970, Rio Grande do Sul, Brazil
- Department of Morphological Sciences, Universidade Federal do Rio Grande do SulPorto Alegre 90050-170, Rio Grande do Sul, Brazil
- Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
| | - Valessa Emanoele Gabriel de Souza
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
| | - Fernando Salvati
- School of Medicine, Instituto Meridional de Educação-IMED, Passo Fundo 99070-220, Rio Grande do Sul, Brazil
| | - Carlos Thadeu Cerski
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Rio Grande do Sul, Brazil
- Unit of Surgical Pathology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
| | - Themis Reverbel da Silveira
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
| | - Cláudia P Oliveira
- Department of Gastroenterology (LIM07), Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246903, Brazil
| | - Carolina Uribe-Cruz
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Rio Grande do Sul, Brazil
| | - Mário Reis Álvares-da-Silva
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Rio Grande do Sul, Brazil
- Division of Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
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28
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De Simone G, Balducci C, Forloni G, Pastorelli R, Brunelli L. Hippuric acid: Could became a barometer for frailty and geriatric syndromes? Ageing Res Rev 2021; 72:101466. [PMID: 34560280 DOI: 10.1016/j.arr.2021.101466] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 09/07/2021] [Accepted: 09/17/2021] [Indexed: 12/11/2022]
Abstract
Aging is a natural biological event that has some downsides such as increased frailty, decline in cognitive and physical functions leading to chronical diseases, and lower quality of life. There is therefore a pressing need of reliable biomarkers to identify populations at risk of developing age-associated syndromes in order to improve their quality of life, promote healthy ageing and a more appropriate clinical management, when needed. Here we discuss the importance of hippuric acid, an endogenous co-metabolite, as a possible hallmark of human aging and age-related diseases, summarizing the scientific literature over the last years. Hippuric acid, the glycine conjugate of benzoic acid, derives from the catabolism by means of intestinal microflora of dietary polyphenols found in plant-based foods (e.g. fruits, vegetables, tea and coffee). In healthy conditions hippuric acid levels in blood and/or urine rise significantly during aging while its excretion drops in conditions related with aging, including cognitive impairments, rheumatic diseases, sarcopenia and hypomobility. This literature highlights the utility of hippuric acid in urine and plasma as a plausible hallmark of frailty, related to low fruit and vegetable intake and changes in gut microflora.
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Affiliation(s)
- Giulia De Simone
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Claudia Balducci
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | | | | | - Laura Brunelli
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
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29
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Saydmohammed M, Jha A, Mahajan V, Gavlock D, Shun TY, DeBiasio R, Lefever D, Li X, Reese C, Kershaw EE, Yechoor V, Behari J, Soto-Gutierrez A, Vernetti L, Stern A, Gough A, Miedel MT, Lansing Taylor D. Quantifying the progression of non-alcoholic fatty liver disease in human biomimetic liver microphysiology systems with fluorescent protein biosensors. Exp Biol Med (Maywood) 2021; 246:2420-2441. [PMID: 33957803 PMCID: PMC8606957 DOI: 10.1177/15353702211009228] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 03/23/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic syndrome is a complex disease that involves multiple organ systems including a critical role for the liver. Non-alcoholic fatty liver disease (NAFLD) is a key component of the metabolic syndrome and fatty liver is linked to a range of metabolic dysfunctions that occur in approximately 25% of the population. A panel of experts recently agreed that the acronym, NAFLD, did not properly characterize this heterogeneous disease given the associated metabolic abnormalities such as type 2 diabetes mellitus (T2D), obesity, and hypertension. Therefore, metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed as the new term to cover the heterogeneity identified in the NAFLD patient population. Although many rodent models of NAFLD/NASH have been developed, they do not recapitulate the full disease spectrum in patients. Therefore, a platform has evolved initially focused on human biomimetic liver microphysiology systems that integrates fluorescent protein biosensors along with other key metrics, the microphysiology systems database, and quantitative systems pharmacology. Quantitative systems pharmacology is being applied to investigate the mechanisms of NAFLD/MAFLD progression to select molecular targets for fluorescent protein biosensors, to integrate computational and experimental methods to predict drugs for repurposing, and to facilitate novel drug development. Fluorescent protein biosensors are critical components of the platform since they enable monitoring of the pathophysiology of disease progression by defining and quantifying the temporal and spatial dynamics of protein functions in the biosensor cells, and serve as minimally invasive biomarkers of the physiological state of the microphysiology system experimental disease models. Here, we summarize the progress in developing human microphysiology system disease models of NAFLD/MAFLD from several laboratories, developing fluorescent protein biosensors to monitor and to measure NAFLD/MAFLD disease progression and implementation of quantitative systems pharmacology with the goal of repurposing drugs and guiding the creation of novel therapeutics.
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Affiliation(s)
- Manush Saydmohammed
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Anupma Jha
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Vineet Mahajan
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Dillon Gavlock
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Tong Ying Shun
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Richard DeBiasio
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Daniel Lefever
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Xiang Li
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Celeste Reese
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Erin E Kershaw
- Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Vijay Yechoor
- Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Jaideep Behari
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh, PA 15261, USA
- UPMC Liver Clinic, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Alejandro Soto-Gutierrez
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Larry Vernetti
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Andrew Stern
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Albert Gough
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Mark T Miedel
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - D Lansing Taylor
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
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Wang ZH, Zheng KI, Wang XD, Qiao J, Li YY, Zhang L, Zheng MH, Wu J. LC-MS-based lipidomic analysis in distinguishing patients with nonalcoholic steatohepatitis from nonalcoholic fatty liver. Hepatobiliary Pancreat Dis Int 2021; 20:452-459. [PMID: 34256994 DOI: 10.1016/j.hbpd.2021.05.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 05/19/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is one of the main liver diseases, and its pathologic profile includes nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). However, there is no reliable non-invasive parameter in distinguishing NASH from NAFL in clinical practice. The present study was to find a non-invasive way to differentiate these two categories of NAFLD via lipidomic analysis. METHODS Lipidomic analysis was used to determine the changes of lipid moieties in blood from 20 NAFL and 10 NASH patients with liver biopsy. Liver histology was evaluated after hematoxylin and eosin staining and Masson's trichrome staining. The profile of lipid metabolites in correlation with steatosis, inflammation, hepatocellular necroptosis, fibrosis, and NAFLD activity score (NAS) was analyzed. RESULTS Compared with NAFL patients, NASH patients had higher degree of steatosis, ballooning degeneration, lobular inflammation. A total of 434 different lipid molecules were identified, which were mainly composed of various phospholipids and triacylglycerols. Many lipids, such as phosphatidylcholine (PC) (P-22:0/18:1), sphingomyelin (SM) (d14:0/18:0), SM (d14:0/24:0), SM (d14:0/22:0), phosphatidylethanolamine (PE) (18:0/22:5), PC (O-22:2/12:0), and PC (26:1/11:0) were elevated in the NASH group compared to those in the NAFL group. Specific analysis revealed an overall lipidomic profile shift from NAFL to NASH, and identified valuable lipid moieties, such as PCs [PC (14:0/18:2), PE (18:0/22:5) and PC (26:1/11:0)] or plasmalogens [PC (O-22:0/0:0), PC (O-18:0/0:0), PC (O-16:0/0:0)], which were significantly altered in NASH patients. In addition, PC (14:0/18:2), phosphatidic acid (18:2/24:4) were positively correlated with NAS; whereas PC (18:0/0:0) was correlated positively with fibrosis score. CONCLUSIONS The present study revealed overall lipidomic profile shift from NAFL to NASH, identified valuable lipid moieties which may be non-invasive biomarkers in the categorization of NAFLD. The correlations between lipid moieties and NAS and fibrosis scores indicate that these lipid biomarkers may be used to predict the severity of the disease.
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Affiliation(s)
- Zhong-Hua Wang
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Kenneth I Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Xiao-Dong Wang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou 325000, China; The Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou 325000, China
| | - Jin Qiao
- Department of General Practice, Huaihai Middle Road Community Health Service Center of Huangpu District, Shanghai 200025, China
| | - Yang-Yang Li
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Li Zhang
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou 325000, China; The Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou 325000, China
| | - Jian Wu
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China; Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China; Laboratory of Fatty Liver and Metabolic Diseases, Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai 200032, China.
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31
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Zhou L, Yu D, Zheng S, Ouyang R, Wang Y, Xu G. Gut microbiota-related metabolome analysis based on chromatography-mass spectrometry. Trends Analyt Chem 2021. [DOI: 10.1016/j.trac.2021.116375] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Zheng Y, He JQ. Pathogenic Mechanisms of Trimethylamine N-Oxide-induced Atherosclerosis and Cardiomyopathy. Curr Vasc Pharmacol 2021; 20:29-36. [PMID: 34387163 DOI: 10.2174/1570161119666210812152802] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 05/24/2021] [Accepted: 06/25/2021] [Indexed: 11/22/2022]
Abstract
Trimethylamine N-oxide (TMAO) is a gut microbiota metabolite derived from trimethylamine-containing nutrient precursors such as choline, L-carnitine, and betaine, which are rich in many vegetables, fruits, nuts, dairy products, and meats. An increasing number of clinical studies have demonstrated a strong relationship between elevated plasma TMAO levels and adverse cardiovascular events. It is commonly agreed that TMAO acts as both an independent risk factor and a prognostic index for patients with cardiovascular disease. Although most animal (mainly rodent) data support the clinical findings, the mechanisms by which TMAO modulates the cardiovascular system are still not well understood. In this context, we provide an overview of the potential mechanisms underlying TMAO-induced cardiovascular disease at the cellular and molecular levels, with a focus on atherosclerosis. We also address the direct effects of TMAO on cardiomyocytes (a new and under-researched area) and finally propose TMAO as a potential biomarker and/or therapeutic target for diagnosis and treatment of patients with cardiovascular disease.
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Affiliation(s)
- Youjing Zheng
- Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061. United States
| | - Jia-Qiang He
- Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061. United States
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Comte B, Monnerie S, Brandolini-Bunlon M, Canlet C, Castelli F, Chu-Van E, Colsch B, Fenaille F, Joly C, Jourdan F, Lenuzza N, Lyan B, Martin JF, Migné C, Morais JA, Pétéra M, Poupin N, Vinson F, Thevenot E, Junot C, Gaudreau P, Pujos-Guillot E. Multiplatform metabolomics for an integrative exploration of metabolic syndrome in older men. EBioMedicine 2021; 69:103440. [PMID: 34161887 PMCID: PMC8237302 DOI: 10.1016/j.ebiom.2021.103440] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 05/20/2021] [Accepted: 06/01/2021] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Metabolic syndrome (MetS), a cluster of factors associated with risks of developing cardiovascular diseases, is a public health concern because of its growing prevalence. Considering the combination of concomitant components, their development and severity, MetS phenotypes are largely heterogeneous, inducing disparity in diagnosis. METHODS A case/control study was designed within the NuAge longitudinal cohort on aging. From a 3-year follow-up of 123 stable individuals, we present a deep phenotyping approach based on a multiplatform metabolomics and lipidomics untargeted strategy to better characterize metabolic perturbations in MetS and define a comprehensive MetS signature stable over time in older men. FINDINGS We characterize significant changes associated with MetS, involving modulations of 476 metabolites and lipids, and representing 16% of the detected serum metabolome/lipidome. These results revealed a systemic alteration of metabolism, involving various metabolic pathways (urea cycle, amino-acid, sphingo- and glycerophospholipid, and sugar metabolisms…) not only intrinsically interrelated, but also reflecting environmental factors (nutrition, microbiota, physical activity…). INTERPRETATION These findings allowed identifying a comprehensive MetS signature, reduced to 26 metabolites for future translation into clinical applications for better diagnosing MetS. FUNDING The NuAge Study was supported by a research grant from the Canadian Institutes of Health Research (CIHR; MOP-62842). The actual NuAge Database and Biobank, containing data and biologic samples of 1,753 NuAge participants (from the initial 1,793 participants), are supported by the Fonds de recherche du Québec (FRQ; 2020-VICO-279753), the Quebec Network for Research on Aging, a thematic network funded by the Fonds de Recherche du Québec - Santé (FRQS) and by the Merck-Frost Chair funded by La Fondation de l'Université de Sherbrooke. All metabolomics and lipidomics analyses were funded and performed within the metaboHUB French infrastructure (ANR-INBS-0010). All authors had full access to the full data in the study and accept responsibility to submit for publication.
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Affiliation(s)
- Blandine Comte
- Université Clermont Auvergne, INRAE, UNH, Plateforme d'Exploration du Métabolisme, MetaboHUB Clermont, Clermont-Ferrand, France
| | - Stéphanie Monnerie
- Université Clermont Auvergne, INRAE, UNH, Plateforme d'Exploration du Métabolisme, MetaboHUB Clermont, Clermont-Ferrand, France
| | - Marion Brandolini-Bunlon
- Université Clermont Auvergne, INRAE, UNH, Plateforme d'Exploration du Métabolisme, MetaboHUB Clermont, Clermont-Ferrand, France
| | - Cécile Canlet
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, MetaboHUB, Toulouse 31300, France
| | - Florence Castelli
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB, F-91191 Gif sur Yvette, France
| | - Emeline Chu-Van
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB, F-91191 Gif sur Yvette, France
| | - Benoit Colsch
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB, F-91191 Gif sur Yvette, France
| | - François Fenaille
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB, F-91191 Gif sur Yvette, France
| | - Charlotte Joly
- Université Clermont Auvergne, INRAE, UNH, Plateforme d'Exploration du Métabolisme, MetaboHUB Clermont, Clermont-Ferrand, France
| | - Fabien Jourdan
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, MetaboHUB, Toulouse 31300, France
| | - Natacha Lenuzza
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB, F-91191 Gif sur Yvette, France
| | - Bernard Lyan
- Université Clermont Auvergne, INRAE, UNH, Plateforme d'Exploration du Métabolisme, MetaboHUB Clermont, Clermont-Ferrand, France
| | - Jean-François Martin
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, MetaboHUB, Toulouse 31300, France
| | - Carole Migné
- Université Clermont Auvergne, INRAE, UNH, Plateforme d'Exploration du Métabolisme, MetaboHUB Clermont, Clermont-Ferrand, France
| | - José A Morais
- Division de Gériatrie, McGill University, Center de recherche du Center universitaire de santé McGill, Montreal, Canada
| | - Mélanie Pétéra
- Université Clermont Auvergne, INRAE, UNH, Plateforme d'Exploration du Métabolisme, MetaboHUB Clermont, Clermont-Ferrand, France
| | - Nathalie Poupin
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, MetaboHUB, Toulouse 31300, France
| | - Florence Vinson
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, MetaboHUB, Toulouse 31300, France
| | - Etienne Thevenot
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB, F-91191 Gif sur Yvette, France
| | - Christophe Junot
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB, F-91191 Gif sur Yvette, France
| | - Pierrette Gaudreau
- Center de Recherche du Center hospitalier de l'Université de Montréal, Montreal, Canada; Département de médecine, Université de Montréal, Montreal, Canada
| | - Estelle Pujos-Guillot
- Université Clermont Auvergne, INRAE, UNH, Plateforme d'Exploration du Métabolisme, MetaboHUB Clermont, Clermont-Ferrand, France.
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Ahmed M, Ahmed MH. Nonalcoholic fatty liver disease and COVID-19: An epidemic that begets pandemic. World J Clin Cases 2021; 9:4133-4142. [PMID: 34141776 PMCID: PMC8173420 DOI: 10.12998/wjcc.v9.i17.4133] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/24/2021] [Accepted: 04/26/2021] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic, affecting all the individuals across the planet. COVID-19 has gained significant attention due to its high prevalence among individuals with diabetes, nonalcoholic fatty liver disease (NAFLD), and metabolic syndrome. NAFLD is the hepatic manifestation of metabolic syndrome and can be associated with a high risk of developing type 2 diabetes. The association of COVID-19 and NAFLD has also gained more attention because NAFLD is highly associated with the epidemic of obesity. NAFLD is a potential risk factor for SARS-CoV-2 infection and severe COVID-19, independent of metabolic syndrome. Importantly, it is not yet clear whether the epidemics of obesity and NAFLD have perpetuated the current pandemic of COVID-19. Further research is urgently needed to assess the following: (1) Whether NAFLD is a high risk factor for SARS-CoV-2 infection; (2) Whether NAFLD is associated with the severe form of COVID-19; and (3) Whether the presence of NAFLD can explain the racial variation in the morbidity and mortality associated with COVID-19. This review summarizes the interactions between COVID-19 and NAFLD, mechanism of liver injury by COVID-19, and effect of lockdown due to COVID- 19 on patients with NAFLD.
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Affiliation(s)
- Musaab Ahmed
- College of Medicine, Ajman University, Ajman 346, United Arab Emirates
| | - Mohamed H Ahmed
- Department of Medicine and HIV Metabolic Clinic, Milton Keynes University Hospital NHS Foundation Trust, Milton Keynes MK5 6LD, United Kingdom
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Abstract
The clinical phenotypes of nonalcoholic fatty liver disease (NAFLD) encompass from simple steatosis to nonalcoholic steatohepatitis (NASH) with varying degrees of fibrosis or cirrhosis. Liver biopsy has been the standard to diagnose NASH. However, there has been strong need for precise and accurate noninvasive tests because of invasiveness and sampling variability of biopsy. Metabolomics has drawn attention as a promising diagnostic methodology in the field of NAFLD, particularly to unravel metabolic alterations which plays relevant roles in the progression of NASH. There have been numerous metabolomics researches to find new biomarker of NASH in the last decade, fueled by the recent advances in the metabolomics methodology. This review briefly covers recent research advances on the lipidomics, amino acids and bile acid metabolomics regarding continuing attempts to discover relevant biomarkers for NASH.
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Affiliation(s)
- Hwi Young Kim
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Korea
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36
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Farag MA, Meyer A, Ali SE. Bleaching effect in Sarcophyton spp. soft corals-is there a correlation to their diterpene content? ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:25594-25602. [PMID: 33459982 DOI: 10.1007/s11356-021-12483-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 01/11/2021] [Indexed: 06/12/2023]
Abstract
Rising seawater temperature is one of the greatest threats to the persistence of coral reefs. While great efforts have been made to understand the metabolic costs of thermal acclimation, the exact roles of many secondary metabolites involved in the immediate response exhibited by soft corals remain largely unknown. Herein, an untargeted metabolomics approach using ultra-performance liquid chromatography coupled to high-resolution mass spectrometry (UPLC-MS) was employed to investigate thermal stress-induced modifications to the de novo synthesis of secondary metabolites in two soft coral species, Sarcophyton ehrenbergi and S. glaucum. Exposure to elevated temperature resulted in symbiont photoinhibition primarily via either damage to photosystem II (PSII) or the loss of algal symbionts during coral bleaching. This was suggested by a decrease in pulse amplitude modulated (PAM) measurements of corals incubated at different temperatures. Thermal stress was also found to impair the production of diterpenoid secondary metabolites in soft corals. Principally, reduction in the levels of a number of diterpenes, viz. sarcophytoxide and deoxysarcophytoxide, in heat stressed S. ehrenbergi and S. glaucum was observed indicative that thermal acclimation is energetically costly and will necessitate downstream changes in secondary metabolic pathways. Our data suggest that, while the host controls the production of ecologically important terpenes, when energetic contribution from the algal symbiont is reduced or absent as a result of a bleaching event, energy reserves may be insufficient to maintain the production of such energetically cost chemicals. This study provides for the first time a holistic assessment of secondary metabolite changes imposed in soft corals during exposure and acclimation to elevated temperatures.
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Affiliation(s)
- Mohamed A Farag
- Pharmacognosy Department, College of Pharmacy, Cairo University, Kasr el Aini St. P.B., Cairo, 11562, Egypt.
- Department of Chemistry, School of Sciences & Engineering, The American University in Cairo (AUC), New Cairo, 11835, Egypt.
| | - Achim Meyer
- Leibniz Centre for Tropical Marine Research (ZMT), Fahrenheit Str. 6, 28359, Bremen, Germany
| | - Sara E Ali
- Department of Pharmaceutical Biology, Faculty of Pharmacy & Biotechnology, The German University in Cairo, New Cairo, 11432, Egypt
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Deutsch L, Osredkar D, Plavec J, Stres B. Spinal Muscular Atrophy after Nusinersen Therapy: Improved Physiology in Pediatric Patients with No Significant Change in Urine, Serum, and Liquor 1H-NMR Metabolomes in Comparison to an Age-Matched, Healthy Cohort. Metabolites 2021; 11:206. [PMID: 33808177 PMCID: PMC8065886 DOI: 10.3390/metabo11040206] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/25/2021] [Accepted: 03/29/2021] [Indexed: 02/07/2023] Open
Abstract
Spinal muscular atrophy (SMA) is a genetically heterogeneous group of rare neuromuscular diseases and was until recently the most common genetic cause of death in children. The effects of 2-month nusinersen therapy on urine, serum, and liquor 1H-NMR metabolomes in SMA males and females were not explored yet, especially not in comparison to the urine 1H-NMR metabolomes of matching male and female cohorts. In this prospective, single-centered study, urine, serum, and liquor samples were collected from 25 male and female pediatric patients with SMA before and after 2 months of nusinersen therapy and urine samples from a matching healthy cohort (n = 125). Nusinersen intrathecal application was the first therapy for the treatment of SMA by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Metabolomes were analyzed using targeted metabolomics utilizing 600 MHz 1H-NMR, parametric and nonparametric multivariate statistical analyses, machine learning, and modeling. Medical assessment before and after nusinersen therapy showed significant improvements of movement, posture, and strength according to various medical tests. No significant differences were found in metabolomes before and after nusinersen therapy in urine, serum, and liquor samples using an ensemble of statistical and machine learning approaches. In comparison to a healthy cohort, 1H-NMR metabolomes of SMA patients contained a reduced number and concentration of urine metabolites and differed significantly between males and females as well. Significantly larger data scatter was observed for SMA patients in comparison to matched healthy controls. Machine learning confirmed urinary creatinine as the most significant, distinguishing SMA patients from the healthy cohort. The positive effects of nusinersen therapy clearly preceded or took place devoid of significant rearrangements in the 1H-NMR metabolomic makeup of serum, urine, and liquor. Urine creatinine was successful at distinguishing SMA patients from the matched healthy cohort, which is a simple systemic novelty linking creatinine and SMA to the physiology of inactivity and diabetes, and it facilitates the monitoring of SMA disease in pediatric patients through non-invasive urine collection.
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Affiliation(s)
- Leon Deutsch
- Department of Animal Science, Biotechnical Faculty, University of Ljubljana, SI-1000 Ljubljana, Slovenia;
| | - Damjan Osredkar
- Department of Pediatric Neurology, University Children’s Hospital, University Medical Centre Ljubljana, SI-1000 Ljubljana, Slovenia;
- Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia
| | - Janez Plavec
- National Institute of Chemistry, NMR Center, SI-1000 Ljubljana, Slovenia;
| | - Blaž Stres
- Department of Animal Science, Biotechnical Faculty, University of Ljubljana, SI-1000 Ljubljana, Slovenia;
- Department of Automation, Biocybernetics and Robotics, Jožef Stefan Institute, SI-1000 Ljubljana, Slovenia
- Faculty of Civil and Geodetic Engineering, Institute of Sanitary Engineering, University of Ljubljana, SI-1000 Ljubljana, Slovenia
- Department of Microbiology, University of Innsbruck, A-6020 Innsbruck, Austria
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Clinical Evidence of Tai Chi Exercise Prescriptions: A Systematic Review. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5558805. [PMID: 33777155 PMCID: PMC7972853 DOI: 10.1155/2021/5558805] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/26/2021] [Accepted: 03/03/2021] [Indexed: 12/22/2022]
Abstract
Objectives This systematic review aims to summarize the existing literature on Tai Chi randomized controlled trials (RCTs) and recommend Tai Chi exercise prescriptions for different diseases and populations. Methods A systematic search for Tai Chi RCTs was conducted in five electronic databases (PubMed, Cochrane Library, EMBASE, EBSCO, and Web of Science) from their inception to December 2019. SPSS 20.0 software and Microsoft Excel 2019 were used to analyze the data, and the risk of bias tool in the RevMan 5.3.5 software was used to evaluate the methodological quality of RCTs. Results A total of 139 articles were identified, including diseased populations (95, 68.3%) and healthy populations (44, 31.7%). The diseased populations included the following 10 disease types: musculoskeletal system or connective tissue diseases (34.7%), circulatory system diseases (23.2%), mental and behavioral disorders (12.6%), nervous system diseases (11.6%), respiratory system diseases (6.3%), endocrine, nutritional or metabolic diseases (5.3%), neoplasms (3.2%), injury, poisoning and certain other consequences of external causes (1.1%), genitourinary system diseases (1.1%), and diseases of the eye and adnexa (1.1%). Tai Chi exercise prescription was generally classified as moderate intensity. The most commonly applied Tai Chi style was Yang style (92, 66.2%), and the most frequently specified Tai Chi form was simplified 24-form Tai Chi (43, 30.9%). 12 weeks and 24 weeks, 2-3 times a week, and 60 min each time was the most commonly used cycle, frequency, and time of exercise in Tai Chi exercise prescriptions. Conclusions We recommend the more commonly used Tai Chi exercise prescriptions for different diseases and populations based on clinical evidence of Tai Chi. Further clinical research on Tai Chi should be combined with principles of exercise prescription to conduct large-sample epidemiological studies and long-term prospective follow-up studies to provide more substantive clinical evidence for Tai Chi exercise prescriptions.
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Chambers A, Bury JJ, Minett T, Richardson CD, Brayne C, Ince PG, Shaw PJ, Garwood CJ, Heath PR, Simpson JE, Matthews FE, Wharton SB. Advanced Glycation End Product Formation in Human Cerebral Cortex Increases With Alzheimer-Type Neuropathologic Changes but Is Not Independently Associated With Dementia in a Population-Derived Aging Brain Cohort. J Neuropathol Exp Neurol 2021; 79:950-958. [PMID: 32766675 DOI: 10.1093/jnen/nlaa064] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 05/12/2020] [Accepted: 06/09/2020] [Indexed: 12/11/2022] Open
Abstract
Diabetes mellitus is a risk factor for dementia, and nonenzymatic glycosylation of macromolecules results in formation of advanced glycation end-products (AGEs). We determined the variation in AGE formation in brains from the Cognitive Function and Ageing Study population-representative neuropathology cohort. AGEs were measured on temporal neocortex by enzyme-linked immunosorbent assay (ELISA) and cell-type specific expression on neurons, astrocytes and endothelium was detected by immunohistochemistry and assessed semiquantitatively. Fifteen percent of the cohort had self-reported diabetes, which was not significantly associated with dementia status at death or neuropathology measures. AGEs were expressed on neurons, astrocytes and endothelium and overall expression showed a positively skewed distribution in the population. AGE measures were not significantly associated with dementia. AGE measured by ELISA increased with Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neurofibrillary tangle score (p = 0.03) and Thal Aβ phase (p = 0.04), while AGE expression on neurons (and astrocytes), detected immunohistochemically, increased with increasing Braak tangle stage (p < 0.001), CERAD tangle score (p = 0.002), and neuritic plaques (p = 0.01). Measures of AGE did not show significant associations with cerebral amyloid angiopathy, microinfarcts or neuroinflammation. In conclusion, AGE expression increases with Alzheimer's neuropathology, particular later stages but is not independently associated with dementia. AGE formation is likely to be important for impaired brain cell function in aging and Alzheimer's.
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Affiliation(s)
- Annabelle Chambers
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Joanna J Bury
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Thais Minett
- Institute of Public Health, University of Cambridge, Cambridge, UK
| | - Connor D Richardson
- Population Health Sciences Institute, University of Newcastle, Newcastle, UK
| | - Carol Brayne
- Institute of Public Health, University of Cambridge, Cambridge, UK
| | - Paul G Ince
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Pamela J Shaw
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Claire J Garwood
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Paul R Heath
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Julie E Simpson
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Fiona E Matthews
- Population Health Sciences Institute, University of Newcastle, Newcastle, UK
| | - Stephen B Wharton
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
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40
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Amin AM. The metabolic signatures of cardiometabolic diseases: Does the shared metabotype offer new therapeutic targets? LIFESTYLE MEDICINE 2021. [DOI: 10.1002/lim2.25] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Affiliation(s)
- Arwa M. Amin
- Department of Clinical and Hospital Pharmacy College of Pharmacy Taibah University Medina Saudi Arabia
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41
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Bury JJ, Chambers A, Heath PR, Ince PG, Shaw PJ, Matthews FE, Brayne C, Simpson JE, Wharton SB. Type 2 diabetes mellitus-associated transcriptome alterations in cortical neurones and associated neurovascular unit cells in the ageing brain. Acta Neuropathol Commun 2021; 9:5. [PMID: 33407907 PMCID: PMC7788898 DOI: 10.1186/s40478-020-01109-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 12/15/2020] [Indexed: 12/15/2022] Open
Abstract
Type 2 diabetes mellitus (T2D), characterised by peripheral insulin resistance, is a risk factor for dementia. In addition to its contribution to small and large vessel disease, T2D may directly damage cells of the brain neurovascular unit. In this study, we investigated the transcriptomic changes in cortical neurones, and associated astrocytes and endothelial cells of the neurovascular unit, in the ageing brain. Neurone, astrocyte, and endothelial cell-enriched mRNA, obtained by immuno-laser capture microdissection of temporal cortex (Brodmann area 21/22) from 6 cases with self-reported T2D in the Cognitive Function and Ageing Study neuropathology cohort, and an equal number of age and sex-matched controls, was assessed by microarray analysis. Integrated Molecular Pathway Level Analysis was performed using the Kyoto Encyclopaedia of Genes and Genomes database on significantly differentially expressed genes, defined as P < 0.05 and fold-change ± 1.2. Hub genes identified from Weighted Gene Co-expression Network Analysis were validated in neurones using the NanoString nCounter platform. The expression and cellular localisation of proteins encoded by selected candidate genes were confirmed by immunohistochemistry. 912, 2202, and 1227 genes were significantly differentially expressed between cases with self-reported T2D and controls in neurones, astrocytes, and endothelial cells respectively. Changes in cortical neurones included alterations in insulin and other signalling pathways, cell cycle, cellular senescence, inflammatory mediators, and components of the mitochondrial respiratory electron transport chain. Impaired insulin signalling was shared by neurovascular unit cells with, additionally, apoptotic pathway changes in astrocytes and dysregulation of advanced glycation end-product signalling in endothelial cells. Transcriptomic analysis identified changes in key cellular pathways associated with T2D that may contribute to neuronal damage and dysfunction. These effects on brain cells potentially contribute to a diabetic dementia, and may provide novel approaches for therapeutic intervention.
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Affiliation(s)
- Joanna J Bury
- Sheffield Institute for Translational Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK
| | - Annabelle Chambers
- Sheffield Institute for Translational Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK
| | - Paul R Heath
- Sheffield Institute for Translational Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK
| | - Paul G Ince
- Sheffield Institute for Translational Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK
| | - Pamela J Shaw
- Sheffield Institute for Translational Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK
| | - Fiona E Matthews
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Carol Brayne
- Institute of Public Health, University of Cambridge, Cambridge, UK
| | - Julie E Simpson
- Sheffield Institute for Translational Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK
| | - Stephen B Wharton
- Sheffield Institute for Translational Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
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Choudhari JK, Chatterjee T, Gupta S, Garcia-Garcia JG, Vera-González J. Network Biology Approaches in Ophthalmological Diseases: A Case Study of Glaucoma. SYSTEMS MEDICINE 2021. [DOI: 10.1016/b978-0-12-801238-3.11586-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
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Oliveira AG, Fiorotto R. Novel approaches to liver disease diagnosis and modeling. Transl Gastroenterol Hepatol 2021; 6:19. [PMID: 33824923 PMCID: PMC7829068 DOI: 10.21037/tgh-20-109] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 05/08/2020] [Indexed: 12/12/2022] Open
Abstract
Lack of a prompt and accurate diagnosis remains on top of the list of challenges faced by patients with rare liver diseases. Although rare liver diseases affect a significant percentage of the population as a group, when taken singularly they represent unique diseases and the approaches used for diagnosis of common liver diseases are insufficient. However, the development of new methods for the acquisition of molecular and clinical data (i.e., genomic, proteomics, metabolomics) and computational tools for their analysis and integration, together with advances in modeling diseases using stem cell-based technology [i.e., induced pluripotent stem cells (iPSCs) and tissue organoids] represent a promising and powerful tool to improve the clinical management of these patients. This is the goal of precision medicine, a novel approach of modern medicine that aims at delivering a specific treatment based on disease-specific biological insights and individual profile. This review will discuss the application and advances of these technologies and how they represent a new opportunity in hepatology.
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Affiliation(s)
- André G. Oliveira
- Department of Physiology and Biophysics, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Romina Fiorotto
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, USA
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Saigusa D, Matsukawa N, Hishinuma E, Koshiba S. Identification of biomarkers to diagnose diseases and find adverse drug reactions by metabolomics. Drug Metab Pharmacokinet 2020; 37:100373. [PMID: 33631535 DOI: 10.1016/j.dmpk.2020.11.008] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 11/24/2020] [Accepted: 11/25/2020] [Indexed: 12/12/2022]
Abstract
Metabolomics has been widely used for investigating the biological functions of disease expression and has the potential to discover biomarkers in circulating biofluids or tissue extracts that reflect in phenotypic changes. Metabolic profiling has advantages because of the use of unbiased techniques, including multivariate analysis, and has been applied in pharmacological studies to predict therapeutic and adverse reactions of drugs, which is called pharmacometabolomics (PMx). Nuclear magnetic resonance (NMR)- and mass spectrometry (MS)-based metabolomics has contributed to the discovery of recent disease biomarkers; however, the optimal strategy for the study purpose must be selected from many established protocols, methodologies and analytical platforms. Additionally, information on molecular localization in tissue is essential for further functional analyses related to therapeutic and adverse effects of drugs in the process of drug development. MS imaging (MSI) is a promising technology that can visualize molecules on tissue surfaces without labeling and thus provide localized information. This review summarizes recent uses of MS-based global and wide-targeted metabolomics technologies and the advantages of the MSI approach for PMx and highlights the PMx technique for the biomarker discovery of adverse drug effects.
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Affiliation(s)
- Daisuke Saigusa
- Department of Integrative Genomics, Tohoku University Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan; Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
| | - Naomi Matsukawa
- Department of Integrative Genomics, Tohoku University Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan; Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
| | - Eiji Hishinuma
- Department of Integrative Genomics, Tohoku University Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan; Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan.
| | - Seizo Koshiba
- Department of Integrative Genomics, Tohoku University Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan; Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan; Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan.
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45
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Farhangi MA. Gut microbiota-dependent trimethylamine N-oxide and all-cause mortality: Findings from an updated systematic review and meta-analysis. Nutrition 2020; 78:110856. [DOI: 10.1016/j.nut.2020.110856] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/20/2020] [Accepted: 04/13/2020] [Indexed: 12/16/2022]
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46
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Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat Rev Gastroenterol Hepatol 2020; 17:279-297. [PMID: 32152478 DOI: 10.1038/s41575-020-0269-9] [Citation(s) in RCA: 630] [Impact Index Per Article: 126.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/21/2020] [Indexed: 02/07/2023]
Abstract
Gut microbiota dysbiosis has been repeatedly observed in obesity and type 2 diabetes mellitus, two metabolic diseases strongly intertwined with non-alcoholic fatty liver disease (NAFLD). Animal studies have demonstrated a potential causal role of gut microbiota in NAFLD. Human studies have started to describe microbiota alterations in NAFLD and have found a few consistent microbiome signatures discriminating healthy individuals from those with NAFLD, non-alcoholic steatohepatitis or cirrhosis. However, patients with NAFLD often present with obesity and/or insulin resistance and type 2 diabetes mellitus, and these metabolic confounding factors for dysbiosis have not always been considered. Patients with different NAFLD severity stages often present with heterogeneous lesions and variable demographic characteristics (including age, sex and ethnicity), which are known to affect the gut microbiome and have been overlooked in most studies. Finally, multiple gut microbiome sequencing tools and NAFLD diagnostic methods have been used across studies that could account for discrepant microbiome signatures. This Review provides a broad insight into microbiome signatures for human NAFLD and explores issues with disentangling these signatures from underlying metabolic disorders. More advanced metagenomics and multi-omics studies using system biology approaches are needed to improve microbiome biomarkers.
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47
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Salvoza NC, Giraudi PJ, Tiribelli C, Rosso N. Sex differences in non-alcoholic fatty liver disease: hints for future management of the disease. EXPLORATION OF MEDICINE 2020; 1:51-74. [DOI: 10.37349/emed.2020.00005] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 04/16/2020] [Indexed: 01/04/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) remains a major cause of chronic liver disease worldwide. Despite extensive studies, the heterogeneity of the risk factors as well as different disease mechanisms complicate the goals toward effective diagnosis and management. Recently, it has been shown that sex differences play a role in the prevalence and progression of NAFLD. In vitro, in vivo, and clinical studies revealed that the lower prevalence of NAFLD in premenopausal as compared to postmenopausal women and men is mainly due to the protective effects of estrogen and body fat distribution. It has been also described that males and females present differential pathogenic features in terms of biochemical profiles and histological characteristics. However, the exact molecular mechanisms for the gender differences that exist in the pathogenesis of NAFLD are still elusive. Lipogenesis, oxidative stress, and inflammation play a key role in the progression of NAFLD. For NAFLD, only a few studies characterized these mechanisms at the molecular level. Therefore, we aim to review the reported differential molecular mechanisms that trigger such different pathogenesis in both sexes. Differences in lipid metabolism, glucose homeostasis, oxidative stress, inflammation, and fibrosis were discussed based on the evidence reported in recent publications. In conclusion, with this review, we hope to provide a new perspective for the development of future practice guidelines as well as a new avenue for the management of the disease.
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Affiliation(s)
- Noel C. Salvoza
- Fondazione Italiana Fegato ONLUS, Area Science Park Basovizza SS14 km 163.5, 34149 Trieste, Italy; Philippine Council for Health Research and Development, DOST Compound, Bicutan Taguig City 1631, Philippines
| | - Pablo J. Giraudi
- Fondazione Italiana Fegato ONLUS, Area Science Park Basovizza SS14 km 163.5, 34149 Trieste, Italy
| | - Claudio Tiribelli
- Fondazione Italiana Fegato ONLUS, Area Science Park Basovizza SS14 km 163.5, 34149 Trieste, Italy
| | - Natalia Rosso
- Fondazione Italiana Fegato ONLUS, Area Science Park Basovizza SS14 km 163.5, 34149 Trieste, Italy
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48
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Parry SA, Hodson L. Managing NAFLD in Type 2 Diabetes: The Effect of Lifestyle Interventions, a Narrative Review. Adv Ther 2020; 37:1381-1406. [PMID: 32146704 PMCID: PMC7140753 DOI: 10.1007/s12325-020-01281-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Indexed: 02/07/2023]
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) is increasing. As a strong association between these two diseases exist, it is unsurprising that the number of patients with coexisting NAFLD and T2D is also increasing. These patients display a deleterious metabolic profile (e.g. hypertriglyceridemia), and increased mortality rates relative to those with only NAFLD or T2D in isolation; therefore, effective treatment strategies are required. Here we review the available intervention studies that have investigated the effects of changes in lifestyle (diet and exercise/physical activity) on NAFLD in patients with both NAFLD and T2D. On the basis of the available evidence, it appears that the addition of any kind of exercise (i.e. resistance, aerobic, or high-intensity intermittent exercise) is beneficial for patients with both NAFLD and T2D. These effects appear to occur independently of changes in body weight. Hypocaloric diets leading to weight loss are also effective in improving metabolic parameters in patients with both NAFLD and T2D, with data indicating that ~ 7–10% weight loss is required in order to observe beneficial effects. It is unclear if multidisciplinary interventions incorporating changes in both diet and physical activity levels are a more effective treatment strategy in this population than diet or exercise interventions in isolation. In conclusion, it is clear that lifestyle interventions are an effective treatment strategy in patients with both NAFLD and T2D, although further research is required to optimise these interventions and determine their scalability.
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Affiliation(s)
- Siôn A Parry
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
- National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital Trusts, Oxford, UK
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Sanchez-Rodriguez E, Egea-Zorrilla A, Plaza-Díaz J, Aragón-Vela J, Muñoz-Quezada S, Tercedor-Sánchez L, Abadia-Molina F. The Gut Microbiota and Its Implication in the Development of Atherosclerosis and Related Cardiovascular Diseases. Nutrients 2020; 12:605. [PMID: 32110880 PMCID: PMC7146472 DOI: 10.3390/nu12030605] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 02/19/2020] [Accepted: 02/21/2020] [Indexed: 12/23/2022] Open
Abstract
The importance of gut microbiota in health and disease is being highlighted by numerous research groups worldwide. Atherosclerosis, the leading cause of heart disease and stroke, is responsible for about 50% of all cardiovascular deaths. Recently, gut dysbiosis has been identified as a remarkable factor to be considered in the pathogenesis of cardiovascular diseases (CVDs). In this review, we briefly discuss how external factors such as dietary and physical activity habits influence host-microbiota and atherogenesis, the potential mechanisms of the influence of gut microbiota in host blood pressure and the alterations in the prevalence of those bacterial genera affecting vascular tone and the development of hypertension. We will also be examining the microbiota as a therapeutic target in the prevention of CVDs and the beneficial mechanisms of probiotic administration related to cardiovascular risks. All these new insights might lead to novel analysis and CVD therapeutics based on the microbiota.
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Affiliation(s)
- Estefania Sanchez-Rodriguez
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain
- Institute of Nutrition and Food Technology “José Mataix”, Center of Biomedical Research, University of Granada, Avda. del Conocimiento s/n., 18016 Armilla, Granada, Spain;
| | - Alejandro Egea-Zorrilla
- Institute of Nutrition and Food Technology “José Mataix”, Center of Biomedical Research, University of Granada, Avda. del Conocimiento s/n., 18016 Armilla, Granada, Spain;
| | - Julio Plaza-Díaz
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain
- Institute of Nutrition and Food Technology “José Mataix”, Center of Biomedical Research, University of Granada, Avda. del Conocimiento s/n., 18016 Armilla, Granada, Spain;
- Instituto de Investigación Biosanitaria IBS.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain
| | - Jerónimo Aragón-Vela
- Department of Nutrition, Exercise and Sports (NEXS), Section of Integrative Physiology, University of Copenhagen, Nørre Allé 51, DK-2200 Copenhagen, Denmark;
| | - Sergio Muñoz-Quezada
- Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Santiago 6094411, Chile;
- National Agency for Medicines (ANAMED), Public Health Institute, Santiago 7780050, Chile
| | | | - Francisco Abadia-Molina
- Institute of Nutrition and Food Technology “José Mataix”, Center of Biomedical Research, University of Granada, Avda. del Conocimiento s/n., 18016 Armilla, Granada, Spain;
- Department of Cell Biology, School of Sciences, University of Granada, 18071 Granada, Spain
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50
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Associations between adipose tissue volume and small molecules in plasma and urine among asymptomatic subjects from the general population. Sci Rep 2020; 10:1487. [PMID: 32001750 PMCID: PMC6992585 DOI: 10.1038/s41598-020-58430-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 01/06/2020] [Indexed: 12/20/2022] Open
Abstract
Obesity is one of the major risk factor for cardiovascular and metabolic diseases. A disproportional accumulation of fat at visceral (VAT) compared to subcutaneous sites (SAT) has been suspected as a key detrimental event. We used non-targeted metabolomics profiling to reveal metabolic pathways associated with higher VAT or SAT amount among subjects free of metabolic diseases to identify possible contributing metabolic pathways. The study population comprised 491 subjects [mean (standard deviation): age 44.6 yrs (13.0), body mass index 25.4 kg/m² (3.6), 60.1% females] without diabetes, hypertension, dyslipidemia, the metabolic syndrome or impaired renal function. We associated MRI-derived fat amounts with mass spectrometry-derived metabolites in plasma and urine using linear regression models adjusting for major confounders. We tested for sex-specific effects using interactions terms and performed sensitivity analyses for the influence of insulin resistance on the results. VAT and SAT were significantly associated with 155 (101 urine) and 49 (29 urine) metabolites, respectively, of which 45 (27 urine) were common to both. Major metabolic pathways were branched-chain amino acid metabolism (partially independent of insulin resistance), surrogate markers of oxidative stress and gut microbial diversity, and cortisol metabolism. We observed a novel positive association between VAT and plasma levels of the potential pharmacological agent piperine. Sex-specific effects were only a few, e.g. the female-specific association between VAT and O-methylascorbate. In brief, higher VAT was associated with an unfavorable metabolite profile in a sample of healthy, mostly non-obese individuals from the general population and only few sex-specific associations became apparent.
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