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Zhao J, Yang J, Yang F, Wang Y, Xia Q, Ren F, Zhang Y. An integrated zebrafish model and network pharmacology to investigate the mechanism of Chrysanthemum for treating metabolic dysfunction-associated fatty liver disease. Food Chem 2025; 473:143134. [PMID: 39893923 DOI: 10.1016/j.foodchem.2025.143134] [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: 09/18/2024] [Revised: 01/25/2025] [Accepted: 01/27/2025] [Indexed: 02/04/2025]
Abstract
Chrysanthemum (Chrysanthemum morifolium Ramat) is a food, which serves both as a medicinal and culinary resource in China; however, its active ingredients and mechanisms underlying its hepatoprotective effects remain elusive. This study aimed to investigate the protective effect of water extract from chrysanthemum flowers (WEFC) against metabolic dysfunction-associated fatty liver induced by thioacetamide (TAA) in zebrafish and its underlying mechanisms. The protective effect of WEFC against TAA-induced liver injury was investigated using the liver-specific transgenic zebrafish line, Tg(fabp10a:DsRed). Network pharmacology was used to analyze the potential targets and ingredients. Quantitative polymerase chain reaction was used to verify the associated mechanisms. Molecular protein docking was performed to identify the targets. WEFC and its component prunin attenuated TAA-induced liver injury and reversed the changes in lipid pathway-related gene expression induced by TAA. Therefore, prunin may play an important role in protecting the liver through RAC-alpha serine/threonine-protein kinase (AKT1) activation.
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Affiliation(s)
- Jingcheng Zhao
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 Jingshidong Road, Licheng District, Jinan 250103, China; Uygur Medical Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830049, China
| | - Jing Yang
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 Jingshidong Road, Licheng District, Jinan 250103, China
| | - Fei Yang
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 Jingshidong Road, Licheng District, Jinan 250103, China
| | - Yuanhao Wang
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 Jingshidong Road, Licheng District, Jinan 250103, China
| | - Qing Xia
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 Jingshidong Road, Licheng District, Jinan 250103, China
| | - Fengming Ren
- Chongqing Pharmaceutical Planting Research Institute, Chongqing 408435, China
| | - Yun Zhang
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 Jingshidong Road, Licheng District, Jinan 250103, China.
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Yu G, Wen W, Li Q, Chen H, Zhang S, Huang H, Zhang Q, Fu L. Heat-Processed Diet Rich in Advanced Glycation End Products Induced the Onset and Progression of NAFLD via Disrupting Gut Homeostasis and Hepatic Lipid Metabolism. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:2510-2526. [PMID: 39635825 DOI: 10.1021/acs.jafc.4c08360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
Epidemiologic studies have suggested an association between the consumption of dietary advanced glycation end products (dAGEs) and the incidence of nonalcoholic fatty liver disease (NAFLD). However, the precise mechanism by which dAGEs induce NAFLD development, particularly the pathogenic role of the gut-liver axis, remains poorly understood. In this study, by establishing a high-AGE diet (HAD)-fed C57BL/6 mouse model, we employed multiomics approaches combined with a series of biological analyses to investigate the effect of HAD on NAFLD in vivo. Our results showed that exposure to HAD led to fat accumulation, oxidative stress, inflammation, and fibrosis in the liver of mice. Transcriptome analysis further revealed that HAD exposure disrupted lipid metabolism and activated inflammation-related signaling pathways in the liver. Additionally, exposure to HAD induced perturbations in gut homeostasis, as evidenced by the compromised gut barrier function, reduced probiotic abundance, and increases in pathogenic bacterial proportions. Dysbiosis of gut homeostasis may further act as a trigger for the initiation and progression of NAFLD via the gut-liver axis. This study sheds light on the underlying mechanisms through which dAGEs contribute to the development of NAFLD and helps to understand the detrimental effects of food ultraprocessing products in modern diets. Future studies are needed to explore the in-depth mechanisms related to the gut-liver axis to consolidate our conclusions.
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Affiliation(s)
- Gang Yu
- School of Statistics and Mathematics and Collaborative Innovation Centre of Statistical Data, School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, P. R. China
| | - Wenjiabao Wen
- School of Statistics and Mathematics and Collaborative Innovation Centre of Statistical Data, School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, P. R. China
| | - Qianqian Li
- School of Statistics and Mathematics and Collaborative Innovation Centre of Statistical Data, School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, P. R. China
| | - Hongbo Chen
- National Pre-packaged Food Quality Supervision and Inspection Center, Zhejiang Fangyuan Test Group Co., LTD., Hangzhou 310018, China
| | - Shuifeng Zhang
- National Pre-packaged Food Quality Supervision and Inspection Center, Zhejiang Fangyuan Test Group Co., LTD., Hangzhou 310018, China
| | - Hua Huang
- Quzhou Institute for Food and Drug Control, Quzhou 324000, China
| | - Qiaozhi Zhang
- School of Statistics and Mathematics and Collaborative Innovation Centre of Statistical Data, School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, P. R. China
| | - Linglin Fu
- School of Statistics and Mathematics and Collaborative Innovation Centre of Statistical Data, School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, P. R. China
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Li Q, Sheng J, Baruscotti M, Liu Z, Wang Y, Zhao L. Identification of Senkyunolide I as a novel modulator of hepatic steatosis and PPARα signaling in zebrafish and hamster models. JOURNAL OF ETHNOPHARMACOLOGY 2025; 336:118743. [PMID: 39209000 DOI: 10.1016/j.jep.2024.118743] [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: 07/01/2024] [Revised: 08/19/2024] [Accepted: 08/25/2024] [Indexed: 09/04/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver-related morbidity and mortality, with hepatic steatosis being the hallmark symptom. Salvia miltiorrhiza Bunge (Smil, Dan-Shen) and Ligusticum striatum DC (Lstr, Chuan-Xiong) are commonly used to treat cardiovascular diseases and have the potential to regulate lipid metabolism. However, whether Smil/Lstr combo can be used to treat NAFLD and the mechanisms underlying its lipid-regulating properties remain unclear. PURPOSE To assess the feasibility and reliability of a short-term high-fat diet (HFD) induced zebrafish model for evaluating hepatic steatosis phenotype and to investigate the liver lipid-lowering effects of Smil/Lstr, as well as its active components. METHODS The phenotypic alterations of liver and multiple other organ systems were examined in the HFD zebrafish model using fluorescence imaging and histochemistry. The liver-specific lipid-lowering effects of Smil/Lstr combo were evaluated endogenously. The active molecules and functional mechanisms were further explored in zebrafish, human hepatocytes, and hamster models. RESULTS In 5-day HFD zebrafish, significant lipid accumulation was detected in the blood vessels and the liver, as evidenced by increased staining with Oil Red O and fluorescent lipid probes. Hepatic hypertrophy was observed in the model, along with macrovesicular steatosis. Smil/Lstr combo administration effectively restored the lipid profile and alleviated hepatic hypertrophy in the HFD zebrafish. In oleic-acid stimulated hepatocytes, Smil/Lstr combo markedly reduced lipid accumulation and cell damage. Subsequently, based on zebrafish phenotypic screening, the natural phthalide senkyunolide I (SEI) was identified as a major molecule mediating the lipid-lowering activities of Smil/Lstr combo in the liver. Moreover, SEI upregulated the expression of the lipid metabolism regulator PPARα and downregulated fatty acid translocase CD36, while a PPARα antagonist sufficiently blocked the regulatory effect of SEI on hepatic steatosis. Finally, the roles of SEI on hepatic lipid accumulation and PPARα signaling were further verified in the hamster model. CONCLUSIONS We proposed a zebrafish-based screening strategy for modulators of hepatic steatosis and discovered the regulatory roles of Smil/Lstr combo and its component SEI on liver lipid accumulation and PPARα signaling, suggesting their potential value as novel candidates for NAFLD treatment.
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Affiliation(s)
- Qingquan Li
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Jian Sheng
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Mirko Baruscotti
- Department of Biosciences, University of Milano, Milan, 1-20133, Italy
| | - Zhenjie Liu
- Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University Medical School, Hangzhou, 310003, China
| | - Yi Wang
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310020, China
| | - Lu Zhao
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University Medical School, Hangzhou, 310003, China; State Key Laboratory of Chinese Medicine Modernization, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
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Mahmoud M, Kawtharany H, Awali M, Mahmoud N, Mohamed I, Syn WK. The Effects of Testosterone Replacement Therapy in Adult Men With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Systematic Review and Meta-analysis. Clin Transl Gastroenterol 2025; 16:e00787. [PMID: 39503363 PMCID: PMC11756880 DOI: 10.14309/ctg.0000000000000787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 10/30/2024] [Indexed: 11/08/2024] Open
Abstract
INTRODUCTION Sex steroids modulate metabolic dysfunction-associated steatotic liver disease (MASLD) pathobiology. We hypothesized that testosterone treatment (TT) modulates progression of MASLD and performed a systematic review to evaluate the efficacy of TT on liver steatosis and fibrosis. METHODS We searched PubMed and Embase from inception until November 2023. We screened 1,489 studies and identified 9 eligible studies. We assessed risk of bias for randomized trials using RoB-2 "Cochrane risk of bias tool for randomized trials," nonrandomized studies using ROBINS-I tool "Risk of Bias In Nonrandomized Studies-of Interventions," and Murad's tool for single-arm studies. We pooled estimates using RevMan 5. RESULTS Three randomized controlled trials|, 4 nonrandomized studies, and 2 single-arm studies were identified. The population of interest comprised men with MASLD. TT was administered at varying doses, routes, and frequencies, with follow-up ranging from 12 weeks to 8 years. Liver fibrosis and steatosis were assessed using liver biopsy in 3 studies, CT/MRI in 5, and serum scores in 2. All studies provided evidence of reduction in liver steatosis with TT compared with no TT. In addition, the LiFT (randomized controlled trials) trial demonstrated a resolution of MASLD/ metabolic dysfunction-associated steatohepatitis and a regression in liver fibrosis. TT led to decrease in liver enzymes. Studies were heterogenous in terms of population characteristics, treatment modalities, endpoints, and follow-up. Adverse events were comparable between the 2 groups. DISCUSSION TT is a promising treatment option for men with MASLD and low testosterone. It may improve liver steatosis and reduce liver fibrosis. Large, double-blinded randomized placebo-controlled trials are needed.
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Affiliation(s)
- Maya Mahmoud
- Department of Internal Medicine, Saint Louis University, St Louis, Missouri, USA
| | - Hassan Kawtharany
- Evidence-Based Practice and Impact Center, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Mohamed Awali
- Department of Radiology, Washington University in Saint Louis, St Louis, Missouri, USA
| | - Nadine Mahmoud
- Pulmonary and Critical Care Medicine, Department of Internal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Islam Mohamed
- Department of Internal Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA
| | - Wing-Kin Syn
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University, St Louis, Missouri, USA
- Department of Physiology, Faculty of Medicine and Nursing, University of Basque Country UPV/EHU, Leioa, Spain
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Tian J, Cao Y, Zhang W, Wang A, Yang X, Dong Y, Zhou X. The potential of insulin resistance indices to predict non-alcoholic fatty liver disease in patients with type 2 diabetes. BMC Endocr Disord 2024; 24:261. [PMID: 39633354 PMCID: PMC11616383 DOI: 10.1186/s12902-024-01794-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 11/28/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND The triglyceride-glucose (TyG) index and related parameters, as well as the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), have been developed as insulin resistance markers to identify individuals at risk for non-alcoholic fatty liver disease (NAFLD). However, its use for predicting NAFLD in patients with type 2 diabetes mellitus (T2DM) remains unclear. In this study, we aimed to observe the performance of insulin resistance indices in diagnosing NAFLD combined with T2DM and to compare their diagnostic values in clinical practice. PATIENTS AND METHODS Overall, 268 patients with T2DM from the Endocrinology Department of Jiangsu Provincial Hospital of Traditional Chinese Medicine were enrolled in this study and divided into two groups: an NAFLD group (T2DM with NAFLD) and a T2DM group (T2DM without NAFLD). General information and blood indicators of the participants were collected, and insulin resistance indices were calculated based on these data. Receiver operating characteristic (ROC) analysis was conducted to calculate the area under the curve (AUC) for insulin resistance-related indices, aiming to assess their ability to discriminate between T2DM patients with and without NAFLD. RESULTS ROC analysis revealed that among the five insulin resistance-related indices, four parameters (TyG, TyG-body mass index [BMI], TyG-waist circumference [WC], and TyG- (waist-hip ratio [WHR]) exhibited high predictive performance for identifying NAFLD, except for HOMA-IR (AUCs:0.710,0.738,0.737 and 0.730, respectivly). TyG-BMI demonstrated superior predictive value, especially in males. For males, the AUC for TyG-BMI was 0.764 (95% confidence interval [CI] 0.691-0.827). The sensitivity and specificity for male NAFLD were 90.32% and 47.89%, respectively. Moreover, in the Generalized linear regression models, there were positive associations of TyG, TyG-BMI, TyG-WC, TyG-WHR, and HOMA-IR with controlled attenuation parameter (CAP), with β values of 21.30, 0.745, 0.247, and 2.549 (all P < 0.001), respectively. CONCLUSION TyG-BMI is a promising predictor of NAFLD combined with T2DM, particularly in lean male patients.
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Affiliation(s)
- Jie Tian
- School of Nursing, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yutian Cao
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenhui Zhang
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Aiyao Wang
- School of Nursing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xinyi Yang
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yinfeng Dong
- Department of Pathology and Pathophysiology, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
| | - Xiqiao Zhou
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
- The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, China.
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Cao J, Shon A, Yoon L, Kamaya A, Tse JR. Diagnostic performance of CT/MRI LI-RADS v2018 in non-cirrhotic steatotic liver disease. Eur Radiol 2024; 34:7622-7631. [PMID: 38951191 DOI: 10.1007/s00330-024-10846-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 03/21/2024] [Accepted: 04/23/2024] [Indexed: 07/03/2024]
Abstract
OBJECTIVE To assess the performance of computed tomography (CT)/magnetic resonance imaging (MRI) Liver Imaging Reporting and Data System (LI-RADS) among patients with non-cirrhotic steatotic liver disease (SLD). MATERIALS AND METHODS This IRB-approved, retrospective study included 119 observations from 77 adult patients (36 women, 41 men; median 64 years) who underwent liver CT or MRI from 2010 to 2023. All patients had histopathologic evidence of SLD without cirrhosis. Three board-certified abdominal radiologists blinded to tissue diagnosis and imaging follow-up assessed observations with LI-RADS. The positive predictive value (PPV), sensitivity, specificity, accuracy, and inter-reader agreement were calculated. RESULTS Seventy-five observations (63%) were benign and 44 (37%) were malignant. PPV for hepatocellular carcinoma (HCC) was 0-0% for LR-1, 0-0% for LR-2, 0-7% for LR-3, 11-20% for LR-4, 75-88% for LR-5, 0-8% for LR-M, and 50-75% for LR-TIV. For LR-5 in identifying HCC, sensitivity was 79-83%, specificity was 91-97%, and accuracy was 89-92%. For composite categories of LR-5, LR-M, or LR-TIV in identifying malignancy, sensitivity was 86-89%, specificity was 85-96%, and accuracy was 86-93%. The most common false positives for LR-5 were hepatocellular adenomas. Only 59-65% of HCCs showed non-peripheral washout at CT versus 67-83% at MRI, though nearly all had an enhancing capsule. PPV and accuracy of LR-5 for HCC did not differ by modality. Inter-reader agreement for major features ranged from 0.667 to 0.830 and was 0.766 for the final category. CONCLUSION Despite challenges such as the lower prevalence of non-peripheral washout at CT and overlapping imaging features between HCC and hepatocellular adenomas, LI-RADS may serve as an effective tool in assessing focal liver lesions in SLD. CLINICAL RELEVANCE STATEMENT LI-RADS in non-cirrhotic steatotic liver disease can effectively diagnose hepatocellular carcinoma and malignancy at computed tomography and magnetic resonance imaging, thereby guiding clinical management decisions and expediting patient care pathways. KEY POINTS Performance of LI-RADS is unknown in non-cirrhotic patients with steatotic liver disease. LI-RADS 5 category showed a high pooled specificity of 91-97% for hepatocellular carcinoma. LI-RADS can non-invasively risk stratify focal liver observations in non-cirrhotic patients with steatotic liver disease.
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Affiliation(s)
- Jennie Cao
- Department of Radiology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA
| | - Andy Shon
- Department of Radiology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA
| | - Luke Yoon
- Department of Radiology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA
| | - Aya Kamaya
- Department of Radiology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA
| | - Justin R Tse
- Department of Radiology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA.
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López-Tenorio II, Aguilar-Villegas ÓR, Espinoza-Palacios Y, Segura-Real L, Peña-Aparicio B, Amedei A, Aguirre-García MM. Primary Prevention Strategy for Non-Communicable Diseases (NCDs) and Their Risk Factors: The Role of Intestinal Microbiota. Biomedicines 2024; 12:2529. [PMID: 39595097 PMCID: PMC11591598 DOI: 10.3390/biomedicines12112529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 10/22/2024] [Accepted: 11/01/2024] [Indexed: 11/28/2024] Open
Abstract
Non-communicable diseases (NCDs) are the leading cause of morbidity and mortality worldwide. These conditions have numerous health consequences and significantly impact patients' lifestyles. Effective long-term treatment is essential since NCDs are irreversible. Therefore, primary healthcare must be both exclusive and of the highest quality, ensuring comprehensive care. The primary goal should be to improve quality of life with a focus on patients, families, and communities, as most of these diseases can be prevented and controlled, although not cured. Several factors have been linked to individual health, including social, cultural, and economic aspects, lifestyle, and certain environmental factors, including work, that can have positive or negative effects. More of these variables may contribute to the onset of NCDs, which are defined by their chronic nature, propensity for prolongation, and generally slow rate of progression. Examples of NCDs include hypertension, type 2 diabetes (T2D), dyslipidemia, and fatty liver disease linked to metabolic dysfunction. The onset of these diseases has been associated with an imbalance in certain microbial niches, such as the gut, which hosts billions of microorganisms performing multiple metabolic functions, such as the production of metabolites like bile acids (BAs), short-chain fatty acids (SCFAs), and trimethylamine N-oxide (TMAO). Therefore, lifestyle changes and personal habits can significantly impact the gut microbiota (GM), potentially preventing chronic diseases associated with metabolism. NCDs are highly prevalent worldwide, prompting increased attention to strategies for modifying the intestinal microbiota (IM). Approaches such as probiotics, prebiotics, synbiotics, and fecal transplantation (FMT) have demonstrated improvements in the quality of life for individuals with these conditions. Additionally, lifestyle changes and the adoption of healthy habits can significantly impact IM and may help prevent chronic diseases related to metabolism. Therefore, the main aim of this review is to analyze and understand the importance of microbiota intervention in the prevention of non-communicable diseases. R3:A1.
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Affiliation(s)
- Itzel Ivonn López-Tenorio
- Unidad de Investigación UNAM-INC, División de Investigación, Facultad de Medicina UNAM, Instituto Nacional de Cardiología Ignacio Cháve, Mexico City 14080, Mexico; (I.I.L.-T.); (Ó.R.A.-V.); (Y.E.-P.); (L.S.-R.)
| | - Óscar Rodrigo Aguilar-Villegas
- Unidad de Investigación UNAM-INC, División de Investigación, Facultad de Medicina UNAM, Instituto Nacional de Cardiología Ignacio Cháve, Mexico City 14080, Mexico; (I.I.L.-T.); (Ó.R.A.-V.); (Y.E.-P.); (L.S.-R.)
| | - Yoshua Espinoza-Palacios
- Unidad de Investigación UNAM-INC, División de Investigación, Facultad de Medicina UNAM, Instituto Nacional de Cardiología Ignacio Cháve, Mexico City 14080, Mexico; (I.I.L.-T.); (Ó.R.A.-V.); (Y.E.-P.); (L.S.-R.)
| | - Lorena Segura-Real
- Unidad de Investigación UNAM-INC, División de Investigación, Facultad de Medicina UNAM, Instituto Nacional de Cardiología Ignacio Cháve, Mexico City 14080, Mexico; (I.I.L.-T.); (Ó.R.A.-V.); (Y.E.-P.); (L.S.-R.)
| | - Berenice Peña-Aparicio
- Consulta Externa Endocrinología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Mexico;
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy;
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), 50134 Florence, Italy
| | - María Magdalena Aguirre-García
- Unidad de Investigación UNAM-INC, División de Investigación, Facultad de Medicina UNAM, Instituto Nacional de Cardiología Ignacio Cháve, Mexico City 14080, Mexico; (I.I.L.-T.); (Ó.R.A.-V.); (Y.E.-P.); (L.S.-R.)
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Abdel-Razeq R, Bitar L, Bitar ER, Onwuzo C, Abu-Hammour MN, Eren B, Mohamed I, Johnson A, Boustany A, Onwuzo S, Asaad I. Prevalence and risk factors associated with metabolic dysfunction-associated steatohepatitis in patients with Helicobacter pylori infection: A population-based study. World J Hepatol 2024; 16:1349-1356. [DOI: 10.4254/wjh.v16.i10.1349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 09/03/2024] [Accepted: 09/23/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) is associated with the development of gastrointestinal disorders ranging from gastritis to gastric cancer. The evidence of the association between metabolic dysfunction-associated steatohepatitis (MASH) and H. pylori infection in the literature is scarce. Therefore, we aim to evaluate the risk of developing MASH in patients who have had a diagnosis of H. pylori infection independently of any confounding variables.
AIM To evaluate the risk of developing MASH in patients who have had a diagnosis of H. pylori infection.
METHODS This study used a validated multicenter research database of over 360 hospitals across 26 healthcare systems across the United States from 1999 to 2022. Multivariate regression analysis assessed the risk of developing MASH, adjusting for confounders including H. pylori infection, obesity, type 2 diabetes, hypertension, dyslipidemia, and male gender. A two-sided P value < 0.05 was considered as statistically significant, and all statistical analyses were performed using R version 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria, 2008).
RESULTS A total of 79476132 individuals were screened in the database and 69232620 were selected in the final analysis after accounting for inclusion and exclusion criteria. Smokers (14.30%), patients with hyperlipidemia (70.35%), hypertension (73.86%), diabetes mellitus type 2 (56.46%), and obese patients (58.15%) were more common in patients with MASH compared to control. Using a multivariate regression analysis, the risk of MASH was increased in diabetics [odds ratio (OR): 3.55; 95%CI: 3.48-3.62], obese (OR: 5.93; 95%CI: 5.81-6.04), males (OR: 1.49; 95%CI: 1.46-1.52), individuals with hyperlipidemia (OR: 2.43; 95%CI: 2.38-2.49) and H. pylori infection (OR: 2.51; 95%CI: 2.31-2.73).
CONCLUSION This is the largest population-based study in the United States illustrating an increased prevalence and odds of developing MASH in patients with H. pylori infection after adjusting for risk factors.
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Affiliation(s)
- Rashid Abdel-Razeq
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44111, United States
| | - Lynn Bitar
- Faculty of Medicine, Saint Joseph University of Beirut, Beirut 1104 2020, Lebanon
| | - Elio R Bitar
- Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Chidera Onwuzo
- Department of Medicine & Surgery, General Hospital Lagos Island, Lagos Island 101223, Lagos, Nigeria
| | - Mohamad-Noor Abu-Hammour
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44111, United States
| | - Barish Eren
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44111, United States
| | - Islam Mohamed
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44111, United States
| | - Adejoke Johnson
- Department of Internal Medicine, Jacobi Medical Center/North Central Bronx Hospital, Bronx, NY 10461, United States
| | - Antoine Boustany
- Division of Gastroenterology, Department of Internal Medicine, University of Florida College of Medicine, Jacksonville, FL 32209, United States
| | - Somtochukwu Onwuzo
- Department of Gastroenterology, Allegheny General Hospital, Pittsburgh, PA 15212, United States
| | - Imad Asaad
- Department of Gastroenterology, Firelands Health, Sandusky, OH 44870, United States
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Abdel-Razeq R, Bitar L, Bitar ER, Onwuzo C, Abu-Hammour MN, Eren B, Mohamed I, Johnson A, Boustany A, Onwuzo S, Asaad I. Prevalence and risk factors associated with metabolic dysfunction-associated steatohepatitis in patients with Helicobacter pylori infection: A population-based study. World J Hepatol 2024; 16:1169-1176. [PMID: 39474577 PMCID: PMC11514611 DOI: 10.4254/wjh.v16.i10.1169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 09/03/2024] [Accepted: 09/23/2024] [Indexed: 10/21/2024] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) is associated with the development of gastrointestinal disorders ranging from gastritis to gastric cancer. The evidence of the association between metabolic dysfunction-associated steatohepatitis (MASH) and H. pylori infection in the literature is scarce. Therefore, we aim to evaluate the risk of developing MASH in patients who have had a diagnosis of H. pylori infection independently of any confounding variables.
AIM To evaluate the risk of developing MASH in patients who have had a diagnosis of H. pylori infection.
METHODS This study used a validated multicenter research database of over 360 hospitals across 26 healthcare systems across the United States from 1999 to 2022. Multivariate regression analysis assessed the risk of developing MASH, adjusting for confounders including H. pylori infection, obesity, type 2 diabetes, hypertension, dyslipidemia, and male gender. A two-sided P value < 0.05 was considered as statistically significant, and all statistical analyses were performed using R version 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria, 2008).
RESULTS A total of 79476132 individuals were screened in the database and 69232620 were selected in the final analysis after accounting for inclusion and exclusion criteria. Smokers (14.30%), patients with hyperlipidemia (70.35%), hypertension (73.86%), diabetes mellitus type 2 (56.46%), and obese patients (58.15%) were more common in patients with MASH compared to control. Using a multivariate regression analysis, the risk of MASH was increased in diabetics [odds ratio (OR): 3.55; 95%CI: 3.48-3.62], obese (OR: 5.93; 95%CI: 5.81-6.04), males (OR: 1.49; 95%CI: 1.46-1.52), individuals with hyperlipidemia (OR: 2.43; 95%CI: 2.38-2.49) and H. pylori infection (OR: 2.51; 95%CI: 2.31-2.73).
CONCLUSION This is the largest population-based study in the United States illustrating an increased prevalence and odds of developing MASH in patients with H. pylori infection after adjusting for risk factors.
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Affiliation(s)
- Rashid Abdel-Razeq
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44111, United States
| | - Lynn Bitar
- Faculty of Medicine, Saint Joseph University of Beirut, Beirut 1104 2020, Lebanon
| | - Elio R Bitar
- Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Chidera Onwuzo
- Department of Medicine & Surgery, General Hospital Lagos Island, Lagos Island 101223, Lagos, Nigeria
| | - Mohamad-Noor Abu-Hammour
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44111, United States
| | - Barish Eren
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44111, United States
| | - Islam Mohamed
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44111, United States
| | - Adejoke Johnson
- Department of Internal Medicine, Jacobi Medical Center/North Central Bronx Hospital, Bronx, NY 10461, United States
| | - Antoine Boustany
- Division of Gastroenterology, Department of Internal Medicine, University of Florida College of Medicine, Jacksonville, FL 32209, United States
| | - Somtochukwu Onwuzo
- Department of Gastroenterology, Allegheny General Hospital, Pittsburgh, PA 15212, United States
| | - Imad Asaad
- Department of Gastroenterology, Firelands Health, Sandusky, OH 44870, United States
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10
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Basu D. Palmitoylethanolamide, an endogenous fatty acid amide, and its pleiotropic health benefits: A narrative review. J Biomed Res 2024; 38:1-15. [PMID: 39433509 DOI: 10.7555/jbr.38.20240053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2024] Open
Abstract
The global nutritional transition has led to high frequency and severity of chronic degenerative diseases worldwide, primarily driven by chronic inflammatory stress. At the mealtimes, various pharmaceutical products aim to prevent such an inflammatory stress, they usually cause various systemic side effects. Therefore, supplementation of natural and safe ingredients is a great strategy to reduce the risk and severity of inflammatory stress-related diseases. As a result, palmitoylethanolamide (PEA), an endocannabinoid-like mediator, has been extensively studied for its myriad of actions, including anti-inflammatory, anti-microbial, immunostimulatory, neuroprotective, and pain-reducing effects with high tolerability and safety of PEA in animals and humans. Because of the multiple molecular targets and mechanisms of action, PEA has shown therapeutic benefits in various diseases, including neurological, psychiatric, ophthalmic, metabolic, oncological, renal, hepatic, immunological, rheumatological, and gastrointestinal conditions. The current review highlights the roles and functions of PEA in various physiological and pathological conditions, further supporting the use of PEA as an important dietary agent.
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Affiliation(s)
- Debasis Basu
- Healious Global METTA Clinic, Kolkata, West Bengal 700029, India
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11
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Li P, Wang T, Qiu H, Zhang R, Yu C, Wang J. 6-Gingerol Inhibits De Novo Lipogenesis by Targeting Stearoyl-CoA Desaturase to Alleviate Fructose-Induced Hepatic Steatosis. Int J Mol Sci 2024; 25:11289. [PMID: 39457074 PMCID: PMC11508832 DOI: 10.3390/ijms252011289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 10/18/2024] [Accepted: 10/18/2024] [Indexed: 10/28/2024] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD), also known as non-alcoholic fatty liver disease (NAFLD), is a worldwide liver disease without definitive or widely used therapeutic drugs in clinical practice. In this study, we confirm that 6-gingerol (6-G), an active ingredient of ginger (Zingiber officinale Roscoe) in traditional Chinese medicine (TCM), can alleviate fructose-induced hepatic steatosis. It was found that 6-G significantly decreased hyperlipidemia caused by high-fructose diets (HFD) in rats, and reversed the increase in hepatic de novo lipogenesis (DNL) and triglyceride (TG) levels induced by HFD, both in vivo and in vitro. Mechanistically, chemical proteomics and cellular thermal shift assay (CETSA)-proteomics approaches revealed that stearoyl-CoA desaturase (SCD) is a direct binding target of 6-G, which was confirmed by further CETSA assay and molecular docking. Meanwhile, it was found that 6-G could not alter SCD expression (in either mRNA or protein levels), but inhibited SCD activity (decreasing the desaturation levels of fatty acids) in HFD-fed rats. Furthermore, SCD deficiency mimicked the ability of 6-G to reduce lipid accumulation in HF-induced HepG2 cells, and impaired the improvement in hepatic steatosis brought about by 6-G treatment in HFD supplemented with oleic acid diet-induced SCD1 knockout mice. Taken together, our present study demonstrated that 6-G inhibits DNL by targeting SCD to alleviate fructose diet-induced hepatic steatosis.
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Affiliation(s)
- Pan Li
- Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Medical University, Chongqing 400016, China; (P.L.); (T.W.)
- College of Pharmacy, Chongqing Medical University, Chongqing 400016, China;
| | - Tingting Wang
- Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Medical University, Chongqing 400016, China; (P.L.); (T.W.)
- College of Pharmacy, Chongqing Medical University, Chongqing 400016, China;
| | - Hongmei Qiu
- College of Pharmacy, Chongqing Medical University, Chongqing 400016, China;
| | - Ruoyu Zhang
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing Medical University, Chongqing 400016, China;
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong 999077, China
| | - Chao Yu
- Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Medical University, Chongqing 400016, China; (P.L.); (T.W.)
- College of Pharmacy, Chongqing Medical University, Chongqing 400016, China;
| | - Jianwei Wang
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing Medical University, Chongqing 400016, China;
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12
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Montoya-Buelna M, Ramirez-Lopez IG, San Juan-Garcia CA, Garcia-Regalado JJ, Millan-Sanchez MS, de la Cruz-Mosso U, Haramati J, Pereira-Suarez AL, Macias-Barragan J. Contribution of extracellular vesicles to steatosis-related liver disease and their therapeutic potential. World J Hepatol 2024; 16:1211-1228. [PMID: 39351515 PMCID: PMC11438597 DOI: 10.4254/wjh.v16.i9.1211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 07/31/2024] [Accepted: 08/13/2024] [Indexed: 09/23/2024] Open
Abstract
Extracellular vesicles (EVs) are small particles released by many cell types in different tissues, including the liver, and transfer specific cargo molecules from originating cells to receptor cells. This process generally culminates in activation of distant cells and inflammation and progression of certain diseases. The global chronic liver disease (CLD) epidemic is estimated at 1.5 billion patients worldwide. Cirrhosis and liver cancer are the most common risk factors for CLD. However, hepatitis C and B virus infection and obesity are also highly associated with CLD. Nonetheless, the etiology of many CLD pathophysiological, cellular, and molecular events are unclear. Changes in hepatic lipid metabolism can lead to lipotoxicity events that induce EV release. Here, we aimed to present an overview of EV features, from definition to types and biogenesis, with particular focus on the molecules related to steatosis-related liver disease, diagnosis, and therapy.
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Affiliation(s)
- Margarita Montoya-Buelna
- Laboratorio de Inmunología, Departamento de Fisiología, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Inocencia G Ramirez-Lopez
- Departamento de Ciencias de la Salud, Centro Universitario de los Valles, Universidad de Guadalajara, Ameca 46600, Jalisco, Mexico
| | - Cesar A San Juan-Garcia
- Doctorado en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Jose J Garcia-Regalado
- Laboratorio de Inmunología, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Mariana S Millan-Sanchez
- Laboratorio de Inmunología, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Ulises de la Cruz-Mosso
- Red de Inmunonutrición y Genómica Nutricional en las Enfermedades Autoinmunes, Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Jesse Haramati
- Laboratorio de Inmunobiología, Departamento de Biología Celular y Molecular, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara, Zapopan 45200, Jalisco, Mexico
| | - Ana L Pereira-Suarez
- Instituto de Investigación en Ciencias Biomédicas, Departamento de Microbiología y Patología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Jose Macias-Barragan
- Departamento de Ciencias de la Salud, Centro Universitario de los Valles, Universidad de Guadalajara, Ameca 46600, Jalisco, Mexico.
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13
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Koch RL, Stanton JB, McClatchy S, Churchill GA, Craig SW, Williams DN, Johns ME, Chase KR, Thiesfeldt DL, Flynt JC, Pazdro R. Discovery of genomic loci for liver health and steatosis reveals overlap with glutathione redox genetics. Redox Biol 2024; 75:103248. [PMID: 38917671 PMCID: PMC11254179 DOI: 10.1016/j.redox.2024.103248] [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: 03/08/2024] [Revised: 05/27/2024] [Accepted: 06/18/2024] [Indexed: 06/27/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition in the United States, encompassing a wide spectrum of liver pathologies including steatosis, steatohepatitis, fibrosis, and cirrhosis. Despite its high prevalence, there are no medications currently approved by the Food and Drug Administration for the treatment of NAFLD. Recent work has suggested that NAFLD has a strong genetic component and identifying causative genes will improve our understanding of the molecular mechanisms contributing to NAFLD and yield targets for future therapeutic investigations. Oxidative stress is known to play an important role in NAFLD pathogenesis, yet the underlying mechanisms accounting for disturbances in redox status are not entirely understood. To better understand the relationship between the glutathione redox system and signs of NAFLD in a genetically-diverse population, we measured liver weight, serum biomarkers aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and graded liver pathology in a large cohort of Diversity Outbred mice. We compared hepatic endpoints to those of the glutathione redox system previously measured in the livers and kidneys of the same mice, and we screened for statistical and genetic associations using the R/qtl2 software. We discovered several novel genetic loci associated with markers of liver health, including loci that were associated with both liver steatosis and glutathione redox status. Candidate genes within each locus point to possible new mechanisms underlying the complex relationship between NAFLD and the glutathione redox system, which could have translational implications for future studies targeting NAFLD pathology.
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Affiliation(s)
- Rebecca L Koch
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - James B Stanton
- Department of Pathology, University of Georgia, Athens, GA, USA, 30602
| | | | | | - Steven W Craig
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - Darian N Williams
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - Mallory E Johns
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - Kylah R Chase
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - Dana L Thiesfeldt
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - Jessica C Flynt
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - Robert Pazdro
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602.
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14
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Zhang M, Zhao W, Zhang Z, He M, Zhang Y, Song B, Liu J, Zhang H. FPS-ZM1 attenuates the deposition of lipid in the liver of diabetic mice by sterol regulatory element binding protein-1c. BMC Endocr Disord 2024; 24:164. [PMID: 39210356 PMCID: PMC11360499 DOI: 10.1186/s12902-024-01705-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 08/26/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) shares common pathogenic mechanisms of type 2 diabetes mellitus (T2DM) with upregulated advanced glycation end products (AGEs). Here, we aim to investigate the effect of FPS-ZM1, an inhibitor for receptor for AGEs (RAGE), on lipid deposition in the liver of mice. METHODS KK-Ay mice were used as models of T2DM with NAFLD, while C57BL/6j mice were controls. Additionally, KK-Ay mice were treated with DMSO (with a concentration of 1%), with or without FPS-ZM1 (3 mg/kg/day, i.p). Lipid deposition in hepatocytes was observed using oil red O stain. Levels of AGEs and RAGE were measured. Sterol regulatory element-binding protein-1c (SREBP-1c), as well as nuclear factor κB p65 (p65 nfκb) and mitogen-activated protein kinase p38 (p38 MAPK), were also detected. RESULTS Lipid deposition is increased in the hepatocytes of KK-Ay mice compared to C57BL/6j mice. In addition, not only were the levels of AGEs elevated in plasma, but also the levels of RAGE in liver tissue. Although total SREBP-1c levels did not change in the liver of diabetic mice, mature SREBP-1c increased in KK-Ay mice with diabetes mellitus. Moreover, diabetic mice showed increased levels of phosphorylated-p65 nfκb (p-p65 nfκb) and phosphorylated-p38 MAPK (p-p38 MAPK). On the contrary, FPS-ZM1 decreased lipid deposition in liver cells, as well as mature SREBP-1c, p-p65 nfκb and p-p38 MAPK levels in liver tissue. CONCLUSION Generally, FPS-ZM1 may attenuate lipid deposition in hepatocytes of diabetic mice via SREBP-1c down-regulation. This may depend on the downregulation of p65 nfκb and p38 MAPK phosphorylation.
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Affiliation(s)
- Mengshu Zhang
- The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Wanwan Zhao
- Department of Nephrology, The First Affiliated Hospital of USTC,Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Zhen Zhang
- Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Mengting He
- Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Ya Zhang
- Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Bing Song
- The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Jinlei Liu
- The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China.
| | - Haoqiang Zhang
- Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
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15
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Hara T, Watanabe T, Yamagami H, Miyataka K, Yasui S, Asai T, Kaneko Y, Mitsui Y, Masuda S, Kurahashi K, Otoda T, Yuasa T, Kuroda A, Endo I, Honda S, Kondo A, Matsuhisa M, Aihara KI. Development of Liver Fibrosis Represented by the Fibrosis-4 Index Is a Specific Risk Factor for Tubular Injury in Individuals with Type 2 Diabetes. Biomedicines 2024; 12:1789. [PMID: 39200252 PMCID: PMC11352124 DOI: 10.3390/biomedicines12081789] [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: 04/16/2024] [Revised: 07/22/2024] [Accepted: 08/05/2024] [Indexed: 09/02/2024] Open
Abstract
Although hyperglycemia and hypertension are well-known risk factors for glomerular injury in individuals with type 2 diabetes (T2D), specific risk factors for tubular injury remain unclear. We aimed to clarify the differences between risk factors for glomerular injury and risk factors for tubular injury in individuals with T2D. We categorized 1243 subjects into four groups based on urinary biomarkers, including the albumin-to-creatinine ratio (uACR) and L-type fatty acid-binding protein-to-creatinine ratio (uL-ABPCR) as a normal (N) group (uACR < 30 mg/gCr and uL-FABPCR < 5 μg/gCr; n = 637), a glomerular specific injury (G) group (uACR ≥ 30 mg/gCr and uL-FABPCR < 5 μg/gCr; n = 248), a tubular specific injury (T) group (uACR < 30 mg/gCr and uL-FABPCR ≥ 5 μg/gCr; n = 90), and a dual injury (D) group (uACR ≥ 30 mg/gCr and uL-FABPCR ≥ 5 μg/gCr; n = 268). Logistic regression analysis referencing the N group revealed that BMI, current smoking, and hypertension were risk factors for the G group, creatinine (Cr) and Fibrosis-4 (FIB-4) index were risk factors for the T group, and BMI, hypertension, HbA1c, Cr, and duration of diabetes were risk factors for the D group. While hypertension was a distinct specific risk factor for glomerular injury, the FIB-4 index was a specific contributor to the prevalence of tubular injury. On the other hand, the logistic regression analysis revealed that the hepatic steatosis index (HSI) did not show any significant association with the G group, T group, or D group. Taken together, the development of liver fibrosis rather than liver steatosis is an inherent threat relating to tubular injury in individuals with T2D.
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Affiliation(s)
- Tomoyo Hara
- Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (H.Y.); (S.Y.); (T.A.); (Y.M.); (S.M.); (K.K.)
| | - Takeshi Watanabe
- Department of Preventive Medicine, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Hiroki Yamagami
- Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (H.Y.); (S.Y.); (T.A.); (Y.M.); (S.M.); (K.K.)
| | - Kohsuke Miyataka
- Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (H.Y.); (S.Y.); (T.A.); (Y.M.); (S.M.); (K.K.)
- Department of Diabetology and Metabolism, Tokushima Prefectural Central Hospital, 1-10-3 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Saya Yasui
- Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (H.Y.); (S.Y.); (T.A.); (Y.M.); (S.M.); (K.K.)
| | - Takahito Asai
- Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (H.Y.); (S.Y.); (T.A.); (Y.M.); (S.M.); (K.K.)
| | - Yousuke Kaneko
- Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (H.Y.); (S.Y.); (T.A.); (Y.M.); (S.M.); (K.K.)
- Department of Internal Medicine, Tokushima Prefectural Kaifu Hospital, 266 Sugitani, Nakamura, Mugi-cho, Kaifu-gun, Tokushima 775-0006, Japan
| | - Yukari Mitsui
- Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (H.Y.); (S.Y.); (T.A.); (Y.M.); (S.M.); (K.K.)
| | - Shiho Masuda
- Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (H.Y.); (S.Y.); (T.A.); (Y.M.); (S.M.); (K.K.)
| | - Kiyoe Kurahashi
- Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (H.Y.); (S.Y.); (T.A.); (Y.M.); (S.M.); (K.K.)
| | - Toshiki Otoda
- Department of Community Medicine and Medical Science, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (T.O.); (T.Y.); (K.-i.A.)
| | - Tomoyuki Yuasa
- Department of Community Medicine and Medical Science, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (T.O.); (T.Y.); (K.-i.A.)
| | - Akio Kuroda
- Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (A.K.); (M.M.)
| | - Itsuro Endo
- Department of Bioregulatory Sciences, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan;
| | - Soichi Honda
- Minami Municipal National Insurance Hospital, 105-1 Tai, Minami-cho, Kaifu-gun, Tokushima 779-2109, Japan
| | - Akira Kondo
- Kondo Naika Hospital, 1-6-25 Nishi Shinharma-cho, Tokushima 770-8008, Japan
| | - Munehide Matsuhisa
- Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (A.K.); (M.M.)
| | - Ken-ichi Aihara
- Department of Community Medicine and Medical Science, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (T.O.); (T.Y.); (K.-i.A.)
- Department of Internal Medicine, Anan Medical Center, 6-1 Kawahara Takarada-cho, Anan 774-0045, Japan
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16
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Anbarasu CR, Williams-Perez S, Camp ER, Erstad DJ. Surgical Implications for Nonalcoholic Steatohepatitis-Related Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:2773. [PMID: 39199546 PMCID: PMC11352989 DOI: 10.3390/cancers16162773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 07/27/2024] [Accepted: 07/31/2024] [Indexed: 09/01/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive form of liver cancer that arises in a background of chronic hepatic injury. Metabolic syndrome-associated fatty liver disease (MAFLD) and its severe form, nonalcoholic steatohepatitis (NASH), are increasingly common mechanisms for new HCC cases. NASH-HCC patients are frequently obese and medically complex, posing challenges for clinical management. In this review, we discuss NASH-specific challenges and the associated implications, including benefits of minimally invasive operative approaches in obese patients; the value of y90 as a locoregional therapy; and the roles of weight loss and immunotherapy in disease management. The relevant literature was identified through queries of PubMed, Google Scholar, and clinicaltrials.gov. Provider understanding of clinical nuances specific to NASH-HCC can improve treatment strategy and patient outcomes.
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Affiliation(s)
| | | | - Ernest R. Camp
- Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Surgery, Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA
| | - Derek J. Erstad
- Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Surgery, Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA
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Lee HB, Park M, Lee SY, Ha SK, Kim Y, Lee KW, Park HY. Lactococcus lactis KF140 Ameliorates Nonalcoholic Fatty Liver Disease Induced by N ε-Carboxymethyl-Lysine and High-Fat Diet. Mol Nutr Food Res 2024; 68:e2400260. [PMID: 38962859 DOI: 10.1002/mnfr.202400260] [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: 04/08/2024] [Revised: 06/05/2024] [Indexed: 07/05/2024]
Abstract
SCOPE Long-term consumption of excessive dietary advanced glycation end-products such as Nε-carboxymethyl-lysine (CML), which are produced by the Maillard reaction during food thermal processing, leads to nonalcoholic fatty liver disease (NAFLD) along with high fat consumption. The study previously finds that administration of Lactococcus lactis KF140 (LL-KF140) detoxifies CML by decreasing CML absorption both in a rat model and clinical trial. METHODS AND RESULTS The present study evaluates the ameliorative effect of LL-KF140 on NAFLD and fatty liver-related biomarkers in a mouse model induced by CML and high fat. LL-KF140 is orally administered to mice at a concentration of 1 × 107 or 1 × 108 colony-forming unit (CFU) per mouse for 8 weeks. LL-KF140 administration ameliorates the NAFLD-related symptoms by reducing body weight and fat mass gain along with levels of serum aspartate transaminase, alanine transferase, and lipids as well as glucose intolerance and insulin resistance in CML-treated mice. In addition, histological analysis including staining and western blotting shows that LL-KF140 suppresses the lipogenesis pathway and CML absorption, thereby suppressing CML-induced NAFLD. CONCLUSION These findings suggest that LL-KF140 attenuates dietary CML-induced NAFLD by suppressing the de novo lipogenesis pathway, and it may be used as a probiotic strain.
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Affiliation(s)
- Hye-Bin Lee
- Food Functionality Research Division, Korea Food Research Institute, Jeollabuk-do, 55365, Republic of Korea
| | - Miri Park
- Food Functionality Research Division, Korea Food Research Institute, Jeollabuk-do, 55365, Republic of Korea
| | - So-Young Lee
- Food Functionality Research Division, Korea Food Research Institute, Jeollabuk-do, 55365, Republic of Korea
| | - Sang Keun Ha
- Food Functionality Research Division, Korea Food Research Institute, Jeollabuk-do, 55365, Republic of Korea
| | - Yoonsook Kim
- Food Functionality Research Division, Korea Food Research Institute, Jeollabuk-do, 55365, Republic of Korea
| | - Kwang-Won Lee
- Department of Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Ho-Young Park
- Food Functionality Research Division, Korea Food Research Institute, Jeollabuk-do, 55365, Republic of Korea
- Department of Food Biotechnology, Korea National University of Science and Technology, Daejeon, 34113, Republic of Korea
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18
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Kumar S, Mohanty A, Mantry P, Schwartz RE, Haff M, Therapondos G, Noureddin M, Dieterich D, Girgrah N, Cohn K, Savanth M, Fuchs M. Deploying a metabolic dysfunction-associated steatohepatitis consensus care pathway: findings from an educational pilot in three health systems. BMC PRIMARY CARE 2024; 25:265. [PMID: 39033284 PMCID: PMC11265102 DOI: 10.1186/s12875-024-02517-y] [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: 02/08/2024] [Accepted: 07/10/2024] [Indexed: 07/23/2024]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly referred to as nonalcoholic fatty liver disease, impacts 30% of the global population. This educational pilot focused on the role primary care providers may play in the delivery of guidelines-based metabolic dysfunction-associated steatohepatitis (MASH) care. OBJECTIVE Accelerate the application of guidelines-based MASH care pathways to clinical workflows. METHODS A panel of six hepatologists was convened in 2021 to develop the care pathway and the subsequent pilot occurred between 2022 - 2023. The pilot was conducted across three U.S. health systems: Boston Medical Center (Boston), Methodist Health System (Dallas), and Weill Cornell Medicine (New York). Clinicians were educated on the care pathway and completed baseline/follow-up assessments. 19 primary care clinicians participated in the educational pilot baseline assessment, nine primary care clinicians completed the two-month assessment, and 15 primary care clinicians completed the four-month assessment. The primary endpoint was to assess clinician-reported adherence to and satisfaction with the care pathway. The pilot was deemed exempt by the Western Consensus Group Institutional Review Board. RESULTS At baseline, 38.10% (n = 8) of respondents felt they had received sufficient training on when to refer a patient suspected of metabolic dysfunction-associated liver disease to hepatology, and 42.86% (n = 9) had not referred any patients suspected of metabolic dysfunction-associated liver disease to hepatology within a month. At four months post-intervention, 79% (n = 15) of respondents agreed or strongly agreed they received sufficient training on when to refer a patient suspected of metabolic dysfunction-associated liver disease to hepatology, and there was a 25.7% increase in self-reported adherence to the institution's referral guidelines. Barriers to care pathway adherence included burden of manually calculating fibrosis-4 scores and difficulty ordering non-invasive diagnostics. CONCLUSIONS With therapeutics anticipated to enter the market this year, health systems leadership must consider opportunities to streamline the identification, referral, and management of patients with metabolic dysfunction-associated steatohepatitis. Electronic integration of metabolic dysfunction-associated steatohepatitis care pathways may address implementation challenges.
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Affiliation(s)
- Sonal Kumar
- Weill Cornell Medicine, 1305 York Avenue, 4 Floor, New York, NY, 10021, USA
| | - Arpan Mohanty
- Boston Medical Center, 85 E. Concord Street, 7 Floor, Boston, MA, 02118, USA
| | - Parvez Mantry
- Methodist Health System, 1411 N Beckley Ave #268, Dallas, TX, 75203, USA
| | - Robert E Schwartz
- Weill Cornell Medicine, 1305 York Avenue, 4 Floor, New York, NY, 10021, USA
| | - Madeleine Haff
- Boston Medical Center, 85 E. Concord Street, 7 Floor, Boston, MA, 02118, USA
| | - George Therapondos
- Ochsner MultiOrgan Transplant Institute at Ochsner Health, 1514 Jefferson Hwy, New Orleans, LA, 70121, USA
| | - Mazen Noureddin
- Houston Research Institute, Houston Methodist Hospital, 1155 Dairy Ashford Rd, Suite 200, Houston, TX, 77079, USA
| | - Douglas Dieterich
- Icahn School of Medicine at Mount Sinai Health System, 1 Gustave L. Levy Place, New York, NY, 10029-5674, USA
| | - Nigel Girgrah
- Ochsner MultiOrgan Transplant Institute at Ochsner Health, 1514 Jefferson Hwy, New Orleans, LA, 70121, USA
| | - Kristi Cohn
- NASHNET, 29 Broadway, Floor 26, New York, NY, 10003, USA
| | | | - Michael Fuchs
- Central Virginia VA Health Care System, 1201 Broad Rock Blvd, Richmond, VA, 23249, USA
- Virginia Commonwealth University, 1200 E Broad Street, West Hospital, 14 Floor, Box 980341, Richmond, VA, 23298-0341, USA
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19
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Stauffer WT, Goodman AZ, Gallay PA. Cyclophilin inhibition as a strategy for the treatment of human disease. Front Pharmacol 2024; 15:1417945. [PMID: 39045055 PMCID: PMC11264201 DOI: 10.3389/fphar.2024.1417945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 06/14/2024] [Indexed: 07/25/2024] Open
Abstract
Cyclophilins (Cyps), characterized as peptidyl-prolyl cis-trans isomerases (PPIases), are highly conserved and ubiquitous, playing a crucial role in protein folding and cellular signaling. This review summarizes the biochemical pathways mediated by Cyps, including their involvement in pathological states such as viral replication, inflammation, and cancer progression, to underscore the therapeutic potential of Cyp inhibition. The exploration of Cyp inhibitors (CypI) in this review, particularly non-immunosuppressive cyclosporine A (CsA) derivatives, highlights their significance as therapeutic agents. The structural and functional nuances of CsA derivatives are examined, including their efficacy, mechanism of action, and the balance between therapeutic benefits and off-target effects. The landscape of CypI is evaluated to emphasize the clinical need for targeted approaches to exploit the complex biology of Cyps and to propose future directions for research that may enhance the utility of non-immunosuppressive CsA derivatives in treating diseases where Cyps play a key pathological role.
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Affiliation(s)
| | | | - Philippe A. Gallay
- Department of Immunology & Microbiology, The Scripps Research Institute, La Jolla, CA, United States
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20
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Mahmoudi A, Meidany P, Almahmeed W, Jamialahmadi T, Sahebkar A. Stem Cell Therapy as a Potential Treatment of Non-Alcoholic Steatohepatitis-Related End-Stage Liver Disease: A Narrative Review. CURRENT STEM CELL REPORTS 2024; 10:85-107. [DOI: 10.1007/s40778-024-00241-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/17/2024] [Indexed: 01/04/2025]
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21
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Chandrasekaran P, Weiskirchen S, Weiskirchen R. Perilipins: A family of five fat-droplet storing proteins that play a significant role in fat homeostasis. J Cell Biochem 2024; 125:e30579. [PMID: 38747370 DOI: 10.1002/jcb.30579] [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: 02/27/2024] [Revised: 04/18/2024] [Accepted: 04/30/2024] [Indexed: 06/12/2024]
Abstract
Lipid droplets are organelles with unique spherical structures. They consist of a hydrophobic neutral lipid core that varies depending on the cell type and tissue. These droplets are surrounded by phospholipid monolayers, along with heterogeneous proteins responsible for neutral lipid synthesis and metabolism. Additionally, there are specialized lipid droplet-associated surface proteins. Recent evidence suggests that proteins from the perilipin family (PLIN) are associated with the surface of lipid droplets and are involved in their formation. These proteins have specific roles in hepatic lipid droplet metabolism, such as protecting the lipid droplets from lipase action and maintaining a balance between lipid storage and utilization in specific cells. Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by the accumulation of lipid droplets in more than 5% of the hepatocytes. This accumulation can progress into metabolic dysfunction-associated steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. The accumulation of hepatic lipid droplets in the liver is associated with the progression of MASLD and other diseases such as sarcopenic obesity. Therefore, it is crucial to understand the role of perilipins in this accumulation, as these proteins are key targets for developing novel therapeutic strategies. This comprehensive review aims to summarize the structure and characteristics of PLIN proteins, as well as their pathogenic role in the development of hepatic steatosis and fatty liver diseases.
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Affiliation(s)
| | - Sabine Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), Rheinisch-Westfälische Technische Hochschule (RWTH), University Hospital Aachen, Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), Rheinisch-Westfälische Technische Hochschule (RWTH), University Hospital Aachen, Aachen, Germany
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22
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Ricchi P, Pistoia L, Positano V, Spasiano A, Casini T, Putti MC, Borsellino Z, Cossu A, Messina G, Keilberg P, Fatigati C, Costantini S, Renne S, Peritore G, Cademartiri F, Meloni A. Liver steatosis in patients with transfusion-dependent thalassaemia. Br J Haematol 2024; 204:2458-2467. [PMID: 38685724 DOI: 10.1111/bjh.19496] [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: 01/15/2024] [Accepted: 04/17/2024] [Indexed: 05/02/2024]
Abstract
We evaluated the prevalence and the clinical associations of liver steatosis (LS) in patients with transfusion-dependent thalassaemia (TDT). We considered 301 TDT patients (177 females, median age = 40.61 years) enrolled in the Extension-Myocardial Iron Overload in Thalassaemia Network, and 25 healthy subjects. Magnetic resonance imaging was used to quantify iron overload and hepatic fat fraction (FF) by T2* technique and cardiac function by cine images. The glucose metabolism was assessed by the oral glucose tolerance test (OGTT). Hepatic FF was significantly higher in TDT patients than in healthy subjects (median value: 1.48% vs. 0.55%; p = 0.013). In TDT, hepatic FF was not associated with age, gender, serum ferritin levels or liver function parameters, but showed a weak inverse correlation with high-density lipoprotein cholesterol. The 36.4% of TDT patients showed LS (FF >3.7%). Active hepatitis C virus (HCV) infection, increased body mass index and hepatic iron were independent determinants of LS. A hepatic FF >3.53% predicted the presence of an abnormal OGTT. Hepatic FF was not correlated with cardiac iron, biventricular volumes or ejection fractions, but was correlated with left ventricular mass index. In TDT, LS is a frequent finding, associated with iron overload, increased weight and HCV, and conveying an increased risk for the alterations of glucose metabolism.
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Affiliation(s)
- Paolo Ricchi
- Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli", Napoli, Italy
| | - Laura Pistoia
- U.O.C. Ricerca Clinica, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Vincenzo Positano
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Anna Spasiano
- Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli", Napoli, Italy
| | - Tommaso Casini
- Oncologia, Ematologia e Trapianto di Cellule Staminali Emopoietiche, Meyer Children's Hospital IRCCS, Firenze, Italy
| | - Maria Caterina Putti
- Dipartimento Della Salute Della Donna e del Bambino, Clinica di Emato-Oncologia Pediatrica, Azienda Ospedaliero-Università di Padova, Padova, Italy
| | - Zelia Borsellino
- Unità Operativa Complessa Ematologia Con Talassemia, ARNAS Civico "Benfratelli-Di Cristina", Palermo, Italy
| | - Antonella Cossu
- Servizio Immunoematologia e Medicina Trasfusionale - Dipartimento Dei Servizi, Presidio Ospedaliero "San Francesco" ASL Nuoro, Nuoro, Italy
| | - Giuseppe Messina
- Centro Microcitemie, Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli", Reggio Calabria, Italy
| | - Petra Keilberg
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Carmina Fatigati
- Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli", Napoli, Italy
| | - Silvia Costantini
- Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli", Napoli, Italy
| | - Stefania Renne
- Struttura Complessa di Cardioradiologia-UTIC, Presidio Ospedaliero "Giovanni Paolo II", Lamezia Terme, Italy
| | - Giuseppe Peritore
- Unità Operativa Complessa di Radiologia, ARNAS Civico "Benfratelli-Di Cristina", Palermo, Italy
| | - Filippo Cademartiri
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Antonella Meloni
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
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23
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Dutta T, Sasidharan K, Ciociola E, Pennisi G, Noto FR, Kovooru L, Kroon T, Lindblom A, Du Y, Pirmoradian M, Wallin S, Mancina RM, Lindén D, Romeo S. Mitochondrial amidoxime-reducing component 1 p.Ala165Thr increases protein degradation mediated by the proteasome. Liver Int 2024; 44:1219-1232. [PMID: 38375985 DOI: 10.1111/liv.15857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/15/2024] [Accepted: 01/19/2024] [Indexed: 02/21/2024]
Abstract
OBJECTIVE Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health concern with no effective and specific drug treatment available. The rs2642438 minor allele in mitochondrial amidoxime-reducing component 1 (MARC1) results in an aminoacidic substitution (p.Ala165Thr) and associates with protection against MASLD. However, the mechanisms behind this protective effect are unknown. In this study, we examined the consequences of this aminoacidic substitution on protein stability and subcellular localization. METHODS We overexpressed the human MARC1 A165 (wild-type) or 165T (mutant) in vivo in mice and in vitro in human hepatoma cells (HepG2 and HuH-7), generated several mutants at position 165 by in situ mutagenesis and then examined protein levels. We also generated HepG2 cells stably overexpressing MARC1 A165 or 165T to test the effect of this substitution on MARC1 subcellular localization. RESULTS MARC1 165T overexpression resulted in lower protein levels than A165 both in vivo and in vitro. Similarly, any mutant at position 165 showed lower protein levels compared to the wild-type protein. We showed that the 165T mutant protein is polyubiquitinated and its degradation is accelerated through lysine-48 ubiquitin-mediated proteasomal degradation. We also showed that the 165T substitution does not affect the MARC1 subcellular localization. CONCLUSIONS This study shows that alanine at position 165 in MARC1 is crucial for protein stability, and the threonine substitution at this position leads to a hypomorphic protein variant due to lower protein levels. Our result supports the notion that lowering hepatic MARC1 protein level may be a successful therapeutic strategy for treating MASLD.
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Affiliation(s)
- Tanmoy Dutta
- Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Kavitha Sasidharan
- Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Ester Ciociola
- Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Grazia Pennisi
- Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
- Section of Gastroenterology and Hepatology, Dipartimento Di Promozione Della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza (PROMISE), University of Palermo, Palermo, Italy
| | - Francesca R Noto
- Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
- Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy
| | - Lohitesh Kovooru
- Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Tobias Kroon
- Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Anna Lindblom
- Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Yue Du
- Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
| | - Mohammad Pirmoradian
- Translational Science and Experimental Medicine, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Simonetta Wallin
- Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Rosellina M Mancina
- Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Daniel Lindén
- Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
- Division of Endocrinology, Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
- Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy
- Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden
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24
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Zhou Q, Hu H, Hu L, Liu S, Chen J, Tong S. Association between processed and unprocessed red meat consumption and risk of nonalcoholic fatty liver disease: A systematic review and dose-response meta-analysis. J Glob Health 2024; 14:04060. [PMID: 38665062 PMCID: PMC11046257 DOI: 10.7189/jogh.14.04060] [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: 04/28/2024] Open
Abstract
Background The nature of the relationship between red meat consumption and nonalcoholic fatty liver disease (NAFLD) remains unclear. Through this meta-analysis, we aimed to determine the association and dose-response relationship between red meat consumption (both processed and unprocessed) and the risk of NAFLD. Methods We systematically searched CENTRAL, PubMed, Embase, Web of Science and Scopus from inception to February 2022 for observational studies in which the exposure of interest was red meat consumption; the outcome of interest was the risk of NAFLD; and where odds ratios (ORs) or risk ratios were provided or could be calculated. We used random-effects meta-analyses to pool the effect sizes and performed analyses to estimate the linearity of the dose-response relationships between red meat intake and NAFLD risk. Results We included 10 studies in this review. The meta-analysis showed a significant association between the intake of red meat (OR = 1.27; 95% confidence interval (CI) = 1.07-1.50, P = 0.000, I2 = 81%), processed red meat (OR = 1.20; 95% CI = 1.04-1.3, P = 0.162, I2 = 34.9%) or unprocessed red meat (OR = 1.28; 95% CI = 1.05-1.55, P = 0.001, I2 = 76.2%) and the risk of NAFLD. We also found a significant linear dose-response association between processed red meat intake and NAFLD, with each 25-g increment of processed red meat intake per day was associated with an 11.1% higher risk of NAFLD (OR = 1.11; 95% CI = 1.01-1.22, P = 0.029), and a nonlinear association between unprocessed meat intake and NAFLD (P = 0.003 for nonlinearity). Conclusions Our findings indicate a potential positive association between red meat consumption (both processed and unprocessed) and NAFLD risk, especially in relation to increased intake of processed red meat compared to unprocessed red meat. However, caution is advised in interpreting these results; further research could establish a clearer understanding of the relationship between red meat consumption and NAFLD risk. Registration PROSPERO: CRD42022332839.
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Affiliation(s)
- Qin Zhou
- Department of Clinical Nutrition, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Huaidong Hu
- Department of Endocrinology and Metabolism, Chongqing General Hospital, Chongqing, China
| | - Lina Hu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shuaibin Liu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jin Chen
- Department of Evidence-based Medicine and Clinical Epidemiology, West China Medical School of Medicine/West China Hospital, Sichuan University, Chengdu, China
| | - Shiwen Tong
- Department of Clinical Nutrition, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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25
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Etzion O, Bareket-Samish A, Yardeni D, Fishman P. Namodenoson at the Crossroad of Metabolic Dysfunction-Associated Steatohepatitis and Hepatocellular Carcinoma. Biomedicines 2024; 12:848. [PMID: 38672201 PMCID: PMC11047856 DOI: 10.3390/biomedicines12040848] [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: 02/26/2024] [Revised: 04/02/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Namodenoson (CF102) is a small, orally available, anti-inflammatory, and anti-cancer drug candidate currently in phase 2B trial for the treatment of metabolic dysfunction-associated steatohepatitis (MASH; formerly known as non-alcoholic steatohepatitis (NASH)) and in phase 3 pivotal clinical trial for the treatment of hepatocellular carcinoma (HCC). In both MASH and HCC, the mechanism-of-action of namodenoson involves targeting the A3 adenosine receptor (A3AR), resulting in deregulation of downstream signaling pathways and leading to inhibition of inflammatory cytokines (TNF-α, IL-1, IL-6, and IL-8) and stimulation of positive cytokines (G-CSF and adiponectin). Subsequently, inhibition of liver inflammation, steatosis, and fibrosis were documented in MASH experimental models, and inhibition of HCC growth was observed in vitro, in vivo, and in clinical studies. This review discusses the evidence related to the multifaceted mechanism of action of namodenoson, and how this mechanism is reflected in the available clinical data in MASH and HCC.
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Affiliation(s)
- Ohad Etzion
- Department of Gastroenterology and Liver Diseases, Sorkoa University Medical Center, Beer Sheva 84101, Israel; (O.E.); (D.Y.)
| | | | - David Yardeni
- Department of Gastroenterology and Liver Diseases, Sorkoa University Medical Center, Beer Sheva 84101, Israel; (O.E.); (D.Y.)
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26
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Stauffer WT, Bobardt M, Ure DR, Foster RT, Gallay P. Cyclophilin D knockout significantly prevents HCC development in a streptozotocin-induced mouse model of diabetes-linked NASH. PLoS One 2024; 19:e0301711. [PMID: 38573968 PMCID: PMC10994289 DOI: 10.1371/journal.pone.0301711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Accepted: 03/20/2024] [Indexed: 04/06/2024] Open
Abstract
A family of Peptidyl-prolyl isomerases (PPIases), called Cyclophilins, localize to numerous intracellular and extracellular locations where they contribute to a variety of essential functions. We previously reported that non-immunosuppressive pan-cyclophilin inhibitor drugs like reconfilstat (CRV431) or NV556 decreased multiple aspects of non-alcoholic fatty liver disease (NAFLD) in mice under two different non-alcoholic steatohepatitis (NASH) mouse models. Both CRV431 and NV556 inhibit several cyclophilin isoforms, among which cyclophilin D (CypD) has not been previously investigated in this context. It is unknown whether it is necessary to simultaneously inhibit multiple cyclophilin family members to achieve therapeutic benefits or if loss-of-function of one is sufficient. Furthermore, narrowing down the isoform most responsible for a particular aspect of NAFLD/NASH, such as hepatocellular carcinoma (HCC), would allow for more precise future therapies. Features of human diabetes-linked NAFLD/NASH can be reliably replicated in mice by administering a single high dose of streptozotocin to disrupt pancreatic beta cells, in conjunction with a high sugar, high fat, high cholesterol western diet over the course of 30 weeks. Here we show that while both wild-type (WT) and Ppif-/- CypD KO mice develop multipe severe NASH disease features under this model, the formation of HCC nodules was significantly blunted only in the CypD KO mice. Furthermore, of differentially expressed transcripts in a qPCR panel of select HCC-related genes, nearly all were downregulated in the CypD KO background. Cyclophilin inhibition is a promising and novel avenue of treatment for diet-induced NAFLD/NASH. This study highlights the impact of CypD loss-of-function on the development of HCC, one of the most severe disease outcomes.
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Affiliation(s)
- Winston T. Stauffer
- Department of Immunology & Microbiology, Scripps Research, La Jolla, California, United States of America
| | - Michael Bobardt
- Department of Immunology & Microbiology, Scripps Research, La Jolla, California, United States of America
| | - Daren R. Ure
- Hepion Pharmaceuticals, Edison, New Jersey, United States of America
| | - Robert T. Foster
- Hepion Pharmaceuticals, Edison, New Jersey, United States of America
| | - Philippe Gallay
- Department of Immunology & Microbiology, Scripps Research, La Jolla, California, United States of America
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Yuan X, Liu J, Nie C, Ma Q, Wang C, Liu H, Chen Z, Zhang M, Li J. Comparative Study of the Effects of Dietary-Free and -Bound Nε-Carboxymethyllysine on Gut Microbiota and Intestinal Barrier. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:5014-5025. [PMID: 38388339 DOI: 10.1021/acs.jafc.3c09395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/24/2024]
Abstract
Nε-carboxymethyllysine (CML) is produced by a nonenzymatic reaction between reducing sugar and ε-amino group of lysine in food and exists as free and bound forms with varying digestibility and absorption properties in vivo, causing diverse interactions with gut microbiota. The effects of different forms of dietary CML on the gut microbiota and intestinal barrier of mice were explored. Mice were exposed to free and bound CML for 12 weeks, and colonic morphology, gut microbiota, fecal short-chain fatty acids (SCFAs), intestinal barrier, and receptor for AGE (RAGE) signaling cascades were measured. The results indicated that dietary-free CML increased the relative abundance of SCFA-producing genera including Blautia, Faecalibacterium, Agathobacter, and Roseburia. In contrast, dietary-bound CML mainly increased the relative abundance of Akkermansia. Moreover, dietary-free and -bound CML promoted the gene and protein expression of zonula occludens-1 and claudin-1. Additionally, the intake of free and bound CML caused an upregulation of RAGE expression but did not activate downstream inflammatory pathways due to the upregulation of oligosaccharyl transferase complex protein 48 (AGER1) expression, indicating a delicate balance between protective and proinflammatory effects in vivo. Dietary-free and -bound CML could modulate the gut microbiota community and increase tight-junction expression, and dietary-free CML might exert a higher potential benefit on gut microbiota and SCFAs than dietary-bound CML.
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Affiliation(s)
- Xiaojin Yuan
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Juan Liu
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Chenxi Nie
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Qingyu Ma
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Chaoqi Wang
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Huicui Liu
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Zhifei Chen
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Min Zhang
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Juxiu Li
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi 712100, China
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Shi A, Ji X, Li W, Dong L, Wu Y, Zhang Y, Liu X, Zhang Y, Wang S. The Interaction between Human Microbes and Advanced Glycation End Products: The Role of Klebsiella X15 on Advanced Glycation End Products' Degradation. Nutrients 2024; 16:754. [PMID: 38474882 DOI: 10.3390/nu16050754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 03/03/2024] [Accepted: 03/04/2024] [Indexed: 03/14/2024] Open
Abstract
Previous studies have shown that advanced glycation end products (AGEs) are implicated in the occurrence and progression of numerous diseases, with dietary AGEs being particularly associated with intestinal disorders. In this study, methylglyoxal-beta-lactoglobulin AGEs (MGO-β-LG AGEs) were utilized as the exclusive nitrogen source to investigate the interaction between protein-bound AGEs and human gut microbiota. The high-resolution mass spectrometry analysis of alterations in peptides containing AGEs within metabolites before and after fermentation elucidated the capacity of intestinal microorganisms to enzymatically hydrolyze long-chain AGEs into short-chain counterparts. The 16S rRNA sequencing revealed Klebsiella, Lactobacillus, Escherichia-Shigella, and other genera as dominant microbiota at different fermentation times. A total of 187 potential strains of AGE-metabolizing bacteria were isolated from the fermentation broth at various time points. Notably, one strain of Klebsiella exhibited the most robust growth capacity when AGEs served as the sole nitrogen source. Subsequently, proteomics was employed to compare the changes in protein levels of Klebsiella X15 following cultivation in unmodified proteins and proteins modified with AGEs. This analysis unveiled a remodeled amino acid and energy metabolism pathway in Klebsiella in response to AGEs, indicating that Klebsiella may possess a metabolic pathway specifically tailored to AGEs. This study found that fermenting AGEs in healthy human intestinal microbiota altered the bacterial microbiota structure, especially by increasing Klebsiella proliferation, which could be a key factor in AGEs' role in causing diseases, particularly intestinal inflammation.
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Affiliation(s)
- Aiying Shi
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Xuemeng Ji
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Wanhua Li
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Lu Dong
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Yuekun Wu
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Yunhui Zhang
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Xiaoxia Liu
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Yan Zhang
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Shuo Wang
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
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Stauffer WT, Goodman AZ, Bobardt M, Ure DR, Foster RT, Gallay P. Mice lacking cyclophilin B, but not cyclophilin A, are protected from the development of NASH in a diet and chemical-induced model. PLoS One 2024; 19:e0298211. [PMID: 38427624 PMCID: PMC10906846 DOI: 10.1371/journal.pone.0298211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 01/20/2024] [Indexed: 03/03/2024] Open
Abstract
Cyclophilins are a diverse family of peptidyl-prolyl isomerases (PPIases) of importance in a variety of essential cellular functions. We previously reported that the pan-cyclophilin inhibitor drug reconfilstat (CRV431) decreased disease in mice under the western-diet and carbon tetrachloride (CCl4) non-alcoholic steatohepatitis (NASH) model. CRV431 inhibits several cyclophilin isoforms, among which cyclophilin A (CypA) and B (CypB) are the most abundant. It is not known whether simultaneous inhibition of multiple cyclophilin family members is necessary for the observed therapeutic effects or if loss-of-function of one is sufficient. Identifying the responsible isoform(s) would enable future fine-tuning of drug treatments. Features of human liver fibrosis and complete NASH can be reliably replicated in mice by administration of intraperitoneal CCl4 alone or CCl4 in conjunction with high sugar, high cholesterol western diet, respectively. Here we show that while wild-type (WT) and Ppia-/- CypA KO mice develop severe NASH disease features under these models, Ppib-/- CypB KO mice do not, as measured by analysis of picrosirius red and hematoxylin & eosin-stained liver sections and TNFα immuno-stained liver sections. Cyclophilin inhibition is a promising and novel avenue of treatment for diet-induced NASH. In this study, mice without CypB, but not mice without CypA, were significantly protected from the development of the characteristic features of NASH. These data suggest that CypB is necessary for NASH disease progression. Further investigation is necessary to determine whether the specific role of CypB in the endoplasmic reticulum secretory pathway is of significance to its effect on NASH development.
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Affiliation(s)
- Winston T. Stauffer
- Department of Immunology & Microbiology, Scripps Research, La Jolla, California, United States of America
| | - Asha Z. Goodman
- Department of Immunology & Microbiology, Scripps Research, La Jolla, California, United States of America
| | - Michael Bobardt
- Department of Immunology & Microbiology, Scripps Research, La Jolla, California, United States of America
| | - Daren R. Ure
- Hepion Pharmaceuticals, Edison, New Jersey, United States of America
| | - Robert T. Foster
- Hepion Pharmaceuticals, Edison, New Jersey, United States of America
| | - Philippe Gallay
- Department of Immunology & Microbiology, Scripps Research, La Jolla, California, United States of America
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Bates EA, Kipp ZA, Lee WH, Martinez GJ, Weaver L, Becker KN, Pauss SN, Creeden JF, Anspach GB, Helsley RN, Xu M, Bruno MEC, Starr ME, Hinds TD. FOXS1 is increased in liver fibrosis and regulates TGFβ responsiveness and proliferation pathways in human hepatic stellate cells. J Biol Chem 2024; 300:105691. [PMID: 38280429 PMCID: PMC10878791 DOI: 10.1016/j.jbc.2024.105691] [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: 01/17/2024] [Accepted: 01/22/2024] [Indexed: 01/29/2024] Open
Abstract
Liver fibrosis commences with liver injury stimulating transforming growth factor beta (TGFβ) activation of hepatic stellate cells (HSCs), causing scarring and irreversible damage. TGFβ induces expression of the transcription factor Forkhead box S1 (FOXS1) in hepatocytes and may have a role in the pathogenesis of hepatocellular carcinoma (HCC). To date, no studies have determined how it affects HSCs. We analyzed human livers with cirrhosis, HCC, and a murine fibrosis model and found that FOXS1 expression is significantly higher in fibrotic livers but not in HCC. Next, we treated human LX2 HSC cells with TGFβ to activate fibrotic pathways, and FOXS1 mRNA was significantly increased. To study TGFβ-FOXS1 signaling, we developed human LX2 FOXS1 CRISPR KO and scrambled control HSCs. To determine differentially expressed gene transcripts controlled by TGFβ-FOXS1, we performed RNA-seq in the FOXS1 KO and control cells and over 400 gene responses were attenuated in the FOXS1 KO HSCs with TGFβ-activation. To validate the RNA-seq findings, we used our state-of-the-art PamGene PamStation kinase activity technology that measures hundreds of signaling pathways nonselectively in real time. Using our RNA-seq data, kinase activity data, and descriptive measurements, we found that FOXS1 controls pathways mediating TGFβ responsiveness, protein translation, and proliferation. Our study is the first to identify that FOXS1 may serve as a biomarker for liver fibrosis and HSC activation, which may help with early detection of hepatic fibrosis or treatment options for end-stage liver disease.
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Affiliation(s)
- Evelyn A Bates
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Zachary A Kipp
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Wang-Hsin Lee
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Genesee J Martinez
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Lauren Weaver
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - Kathryn N Becker
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Sally N Pauss
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Justin F Creeden
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Garrett B Anspach
- Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Robert N Helsley
- Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, USA; Saha Cardiovascular Research Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA; Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA; Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Mei Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Maria E C Bruno
- Division of Research, Department of Surgery, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Marlene E Starr
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA; Division of Research, Department of Surgery, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Terry D Hinds
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA; Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA; Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
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Chen C, He Y, Ni Y, Tang Z, Zhang W. Identification of crosstalk genes relating to ECM-receptor interaction genes in MASH and DN using bioinformatics and machine learning. J Cell Mol Med 2024; 28:e18156. [PMID: 38429902 PMCID: PMC10907849 DOI: 10.1111/jcmm.18156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 01/01/2024] [Accepted: 01/12/2024] [Indexed: 03/03/2024] Open
Abstract
This study aimed to identify genes shared by metabolic dysfunction-associated fatty liver disease (MASH) and diabetic nephropathy (DN) and the effect of extracellular matrix (ECM) receptor interaction genes on them. Datasets with MASH and DN were downloaded from the Gene Expression Omnibus (GEO) database. Pearson's coefficients assessed the correlation between ECM-receptor interaction genes and cross talk genes. The coexpression network of co-expression pairs (CP) genes was integrated with its protein-protein interaction (PPI) network, and machine learning was employed to identify essential disease-representing genes. Finally, immuno-penetration analysis was performed on the MASH and DN gene datasets using the CIBERSORT algorithm to evaluate the plausibility of these genes in diseases. We found 19 key CP genes. Fos proto-oncogene (FOS), belonging to the IL-17 signalling pathway, showed greater centrality PPI network; Hyaluronan Mediated Motility Receptor (HMMR), belonging to ECM-receptor interaction genes, showed most critical in the co-expression network map of 19 CP genes; Forkhead Box C1 (FOXC1), like FOS, showed a high ability to predict disease in XGBoost analysis. Further immune infiltration showed a clear positive correlation between FOS/FOXC1 and mast cells that secrete IL-17 during inflammation. Combining the results of previous studies, we suggest a FOS/FOXC1/HMMR regulatory axis in MASH and DN may be associated with mast cells in the acting IL-17 signalling pathway. Extracellular HMMR may regulate the IL-17 pathway represented by FOS through the Mitogen-Activated Protein Kinase 1 (ERK) or PI3K-Akt-mTOR pathway. HMMR may serve as a signalling carrier between MASH and DN and could be targeted for therapeutic development.
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Affiliation(s)
- Chao Chen
- Instrumentation and Service Center for Science and TechnologyBeijing Normal UniversityZhuhaiChina
| | - Yuxi He
- Pediatric Research InstituteThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Ying Ni
- Zhuhai Branch of State Key Laboratory of Earth Surface Processes and Resource Ecology, Advanced Institute of Natural SciencesBeijing Normal UniversityZhuhaiChina
- Engineering Research Center of Natural Medicine, Ministry of Education, Advanced Institute of Natural SciencesBeijing Normal UniversityZhuhaiChina
| | - Zhanming Tang
- Zhuhai Branch of State Key Laboratory of Earth Surface Processes and Resource Ecology, Advanced Institute of Natural SciencesBeijing Normal UniversityZhuhaiChina
- Engineering Research Center of Natural Medicine, Ministry of Education, Advanced Institute of Natural SciencesBeijing Normal UniversityZhuhaiChina
| | - Wensheng Zhang
- Zhuhai Branch of State Key Laboratory of Earth Surface Processes and Resource Ecology, Advanced Institute of Natural SciencesBeijing Normal UniversityZhuhaiChina
- Engineering Research Center of Natural Medicine, Ministry of Education, Advanced Institute of Natural SciencesBeijing Normal UniversityZhuhaiChina
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32
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Dietrich CG, Geier A. What is the impact of metabolic dysfunction-associated steatotic liver disease on drug transport and metabolism? Expert Opin Drug Metab Toxicol 2024; 20:107-110. [PMID: 38412106 DOI: 10.1080/17425255.2024.2324015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 02/23/2024] [Indexed: 02/29/2024]
Affiliation(s)
| | - Andreas Geier
- Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg (UKW), Würzburg, Germany
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Kim MH, Ahn S, Hur N, Oh SY, Son CG. The additive effect of herbal medicines on lifestyle modification in the treatment of non-alcoholic fatty liver disease: a systematic review and meta-analysis. Front Pharmacol 2024; 15:1362391. [PMID: 38464716 PMCID: PMC10920213 DOI: 10.3389/fphar.2024.1362391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 02/12/2024] [Indexed: 03/12/2024] Open
Abstract
Introduction: Non-alcoholic fatty liver disease (NAFLD) is difficult to manage because of its complex pathophysiological mechanism. There is still no effective treatment other than lifestyle modification (LM) such as dietary modifications, regular physical activity, and gradual weight loss. Herbal medicines from traditional Chinese Medicine and Korean Medicine have been shown to be effective in the treatment of NAFLD based on many randomized controlled trials. This systematic review and meta-analysis aims to evaluate the additive effects of herbal medicines on LM in the treatment of NAFLD. Methods: Two databases (PubMed and Cochrane library) were searched using keywords related to NAFLD and herbal medicines. Then the randomized controlled trials (RCTs) evaluating the therapeutic effects of herbal medicines combined with LM were selected. The pooled results were analyzed as mean difference (MD) with 95% confidence interval (CI) for continuous data, and risk ratio (RR) with 95% CI for dichotomous data. Results and Discussion: Eight RCTs with a total of 603 participants were included for this review study. Participants were administered with multi-herbal formulas (Yiqi Sanju Formula, Tiaogan Lipi Recipe, and Lingguizhugan Decoction) or single-herbal extracts (Glycyrrhiza glabra L., Magnoliae offcinalis, Trigonella Foenum-graecum L. semen, Portulaca oleracea L., and Rhus Coriaria L. fructus) along with LM for 12 weeks. The meta-analysis showed a significant improvement in ultrasoundbased liver steatosis measured by odds ratio (OR) in the herbal medicine group than those with LM alone (OR = 7.9, 95% CI 0.7 to 95.2, p < 0.1). In addition, herbal medicines decreased the levels of aspartate transferase (MD -7.5, 95% CI -13.4 to -1.7, p = 0.01) and total cholesterol (MD -16.0, 95% CI -32.7 to 0.7, p = 0.06) more than LM alone. The meta-analysis partially showed clinical evidence supporting the additive benefits of herbal medicines for NAFLD in combination with LM. Whereas, it is necessary to provide a solid basis through higher-quality studies using a specific herbal medicine.
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Affiliation(s)
- Myung-Ho Kim
- Liver and Immunology Research Center, Daejeon Korean Medicine Hospital of Daejeon University, Daejeon, Republic of Korea
- Department of Internal Korean Medicine, Woosuk University Medical Center, Jeonju, Republic of Korea
| | - Subin Ahn
- Department of Internal Korean Medicine, Woosuk University Medical Center, Jeonju, Republic of Korea
| | - Nayeon Hur
- Department of Internal Korean Medicine, Woosuk University Medical Center, Jeonju, Republic of Korea
| | - Seung-Yun Oh
- Department of Sasang Constitutional Medicine, Woosuk University Medical Center, Jeonju, Republic of Korea
| | - Chang-Gue Son
- Liver and Immunology Research Center, Daejeon Korean Medicine Hospital of Daejeon University, Daejeon, Republic of Korea
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Brandhorst S, Levine ME, Wei M, Shelehchi M, Morgan TE, Nayak KS, Dorff T, Hong K, Crimmins EM, Cohen P, Longo VD. Fasting-mimicking diet causes hepatic and blood markers changes indicating reduced biological age and disease risk. Nat Commun 2024; 15:1309. [PMID: 38378685 PMCID: PMC10879164 DOI: 10.1038/s41467-024-45260-9] [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: 03/17/2021] [Accepted: 01/18/2024] [Indexed: 02/22/2024] Open
Abstract
In mice, periodic cycles of a fasting mimicking diet (FMD) protect normal cells while killing damaged cells including cancer and autoimmune cells, reduce inflammation, promote multi-system regeneration, and extend longevity. Here, we performed secondary and exploratory analysis of blood samples from a randomized clinical trial (NCT02158897) and show that 3 FMD cycles in adult study participants are associated with reduced insulin resistance and other pre-diabetes markers, lower hepatic fat (as determined by magnetic resonance imaging) and increased lymphoid to myeloid ratio: an indicator of immune system age. Based on a validated measure of biological age predictive of morbidity and mortality, 3 FMD cycles were associated with a decrease of 2.5 years in median biological age, independent of weight loss. Nearly identical findings resulted from a second clinical study (NCT04150159). Together these results provide initial support for beneficial effects of the FMD on multiple cardiometabolic risk factors and biomarkers of biological age.
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Affiliation(s)
- Sebastian Brandhorst
- Longevity Institute, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA
| | - Morgan E Levine
- Department of Pathology, Yale School of Medicine, New Haven, CT, 06519, USA
| | - Min Wei
- Longevity Institute, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA
| | - Mahshid Shelehchi
- Longevity Institute, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA
| | - Todd E Morgan
- Longevity Institute, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA
| | - Krishna S Nayak
- Ming Hsieh Department of Electrical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, 90089, USA
| | - Tanya Dorff
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Kurt Hong
- Center of Clinical Nutrition and Applied Health Research, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA
| | - Eileen M Crimmins
- Longevity Institute, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA
- Center on Biodemography and Population Health, University of California Los Angeles and University of Southern California, Los Angeles, CA, 90089, USA
| | - Pinchas Cohen
- Longevity Institute, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA
| | - Valter D Longo
- Longevity Institute, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA.
- AIRC Institute of Molecular Oncology, Italian Foundation for Cancer Research Institute of Molecular Oncology, 20139, Milan, Italy.
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Lee S, Shaheen AA, Campbell DJT, Naugler C, Jiang J, Walker RL, Quan H, Lee J. Evaluating the coding accuracy of type 2 diabetes mellitus among patients with non-alcoholic fatty liver disease. BMC Health Serv Res 2024; 24:218. [PMID: 38365631 PMCID: PMC10874028 DOI: 10.1186/s12913-024-10634-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 01/24/2024] [Indexed: 02/18/2024] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) describes a spectrum of chronic fattening of liver that can lead to fibrosis and cirrhosis. Diabetes has been identified as a major comorbidity that contributes to NAFLD progression. Health systems around the world make use of administrative data to conduct population-based prevalence studies. To that end, we sought to assess the accuracy of diabetes International Classification of Diseases (ICD) coding in administrative databases among a cohort of confirmed NAFLD patients in Calgary, Alberta, Canada. METHODS The Calgary NAFLD Pathway Database was linked to the following databases: Physician Claims, Discharge Abstract Database, National Ambulatory Care Reporting System, Pharmaceutical Information Network database, Laboratory, and Electronic Medical Records. Hemoglobin A1c and diabetes medication details were used to classify diabetes groups into absent, prediabetes, meeting glycemic targets, and not meeting glycemic targets. The performance of ICD codes among these groups was compared to this standard. Within each group, the total numbers of true positives, false positives, false negatives, and true negatives were calculated. Descriptive statistics and bivariate analysis were conducted on identified covariates, including demographics and types of interacted physicians. RESULTS A total of 12,012 NAFLD patients were registered through the Calgary NAFLD Pathway Database and 100% were successfully linked to the administrative databases. Overall, diabetes coding showed a sensitivity of 0.81 and a positive predictive value of 0.87. False negative rates in the absent and not meeting glycemic control groups were 4.5% and 6.4%, respectively, whereas the meeting glycemic control group had a 42.2% coding error. Visits to primary and outpatient services were associated with most encounters. CONCLUSION Diabetes ICD coding in administrative databases can accurately detect true diabetic cases. However, patients with diabetes who meets glycemic control targets are less likely to be coded in administrative databases. A detailed understanding of the clinical context will require additional data linkage from primary care settings.
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Affiliation(s)
- Seungwon Lee
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4Z6, Canada.
- Centre for Health Informatics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
- Alberta Health Services, Calgary, AB, Canada.
- Data Intelligence for Health Lab, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
| | - Abdel Aziz Shaheen
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4Z6, Canada
- Centre for Health Informatics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - David J T Campbell
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4Z6, Canada
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Christopher Naugler
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4Z6, Canada
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Jason Jiang
- Centre for Health Informatics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Alberta Health Services, Calgary, AB, Canada
| | - Robin L Walker
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4Z6, Canada
- Centre for Health Informatics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Hude Quan
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4Z6, Canada
- Centre for Health Informatics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Joon Lee
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4Z6, Canada
- Centre for Health Informatics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Data Intelligence for Health Lab, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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Björnsdottir S, Ulfsdottir H, Gudmundsson EF, Sveinsdottir K, Isberg AP, Dobies B, Akerlie Magnusdottir GE, Gunnarsdottir T, Karlsdottir T, Bjornsdottir G, Sigurdsson S, Oddsson S, Gudnason V. User Engagement, Acceptability, and Clinical Markers in a Digital Health Program for Nonalcoholic Fatty Liver Disease: Prospective, Single-Arm Feasibility Study. JMIR Cardio 2024; 8:e52576. [PMID: 38152892 PMCID: PMC10905363 DOI: 10.2196/52576] [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: 09/12/2023] [Revised: 12/15/2023] [Accepted: 12/26/2023] [Indexed: 12/29/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the world. Common comorbidities are central obesity, type 2 diabetes mellitus, dyslipidemia, and metabolic syndrome. Cardiovascular disease is the most common cause of death among people with NAFLD, and lifestyle changes can improve health outcomes. OBJECTIVE This study aims to explore the acceptability of a digital health program in terms of engagement, retention, and user satisfaction in addition to exploring changes in clinical outcomes, such as weight, cardiometabolic risk factors, and health-related quality of life. METHODS We conducted a prospective, open-label, single-arm, 12-week study including 38 individuals with either a BMI >30, metabolic syndrome, or type 2 diabetes mellitus and NAFLD screened by FibroScan. An NAFLD-specific digital health program focused on disease education, lowering carbohydrates in the diet, food logging, increasing activity level, reducing stress, and healthy lifestyle coaching was offered to participants. The coach provided weekly feedback on food logs and other in-app activities and opportunities for participants to ask questions. The coaching was active throughout the 12-week intervention period. The primary outcome was feasibility and acceptability of the 12-week program, assessed through patient engagement, retention, and satisfaction with the program. Secondary outcomes included changes in weight, liver fat, body composition, and other cardiometabolic clinical parameters at baseline and 12 weeks. RESULTS In total, 38 individuals were included in the study (median age 59.5, IQR 46.3-68.8 years; n=23, 61% female). Overall, 34 (89%) participants completed the program and 29 (76%) were active during the 12-week program period. The median satisfaction score was 6.3 (IQR 5.8-6.7) of 7. Mean weight loss was 3.5 (SD 3.7) kg (P<.001) or 3.2% (SD 3.4%), with a 2.2 (SD 2.7) kg reduction in fat mass (P<.001). Relative liver fat reduction was 19.4% (SD 23.9%). Systolic blood pressure was reduced by 6.0 (SD 13.5) mmHg (P=.009). The median reduction was 0.14 (IQR 0-0.47) mmol/L for triglyceride levels (P=.003), 3.2 (IQR 0.0-5.4) µU/ml for serum insulin (s-insulin) levels (P=.003), and 0.5 (IQR -0.7 to 3.8) mmol/mol for hemoglobin A1c (HbA1c) levels (P=.03). Participants who were highly engaged (ie, who used the app at least 5 days per week) had greater weight loss and liver fat reduction. CONCLUSIONS The 12-week-long digital health program was feasible for individuals with NAFLD, receiving high user engagement, retention, and satisfaction. Improved liver-specific and cardiometabolic health was observed, and more engaged participants showed greater improvements. This digital health program could provide a new tool to improve health outcomes in people with NAFLD. TRIAL REGISTRATION Clinicaltrials.gov NCT05426382; https://clinicaltrials.gov/study/NCT05426382.
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Affiliation(s)
- Sigridur Björnsdottir
- Department of Endocrinology, Metabolism and Diabetes, Karolinska Institutet, Stockholm, Sweden
| | | | | | | | | | | | | | | | | | - Gudlaug Bjornsdottir
- Icelandic Heart Association, Kopavogur, Iceland
- School of Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Sigurdur Sigurdsson
- Icelandic Heart Association, Kopavogur, Iceland
- School of Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | | | - Vilmundur Gudnason
- Icelandic Heart Association, Kopavogur, Iceland
- School of Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
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Thilakarathna WPDW, Rupasinghe HPV. Proanthocyanidins-Based Synbiotics as a Novel Strategy for Nonalcoholic Fatty Liver Disease (NAFLD) Risk Reduction. Molecules 2024; 29:709. [PMID: 38338453 PMCID: PMC10856248 DOI: 10.3390/molecules29030709] [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: 12/23/2023] [Revised: 01/29/2024] [Accepted: 02/01/2024] [Indexed: 02/12/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), the most common liver disease worldwide, is a spectrum of liver abnormalities ranging from steatosis to nonalcoholic steatohepatitis (NASH) characterized by excessive lipid accumulation. The prevalence of NAFLD is predicted to increase rapidly, demanding novel approaches to reduce the global NAFLD burden. Flavonoids, the most abundant dietary polyphenols, can reduce the risk of NAFLD. The majority of dietary flavonoids are proanthocyanidins (PACs), which are oligomers and polymers of the flavonoid sub-group flavan-3-ols. The efficacy of PAC in reducing the NAFLD risk can be significantly hindered by low bioavailability. The development of synbiotics by combining PAC with probiotics may increase effectiveness against NAFLD by biotransforming PAC into bioavailable metabolites. PAC and probiotic bacteria are capable of mitigating steatosis primarily through suppressing de novo lipogenesis and promoting fatty acid β-oxidation. PAC and probiotic bacteria can reduce the progression of steatosis to NASH mainly through ameliorating hepatic damage and inflammation induced by hepatic oxidative stress, endoplasmic reticulum stress, and gut microbiota dysbiosis. Synbiotics of PAC are superior in reducing the risk of NAFLD compared to independent administration of PAC and probiotics. The development of PAC-based synbiotics can be a novel strategy to mitigate the increasing incidence of NAFLD.
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Affiliation(s)
- Wasitha P. D. W. Thilakarathna
- Department of Plant, Food, and Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, NS B2N 5E3, Canada;
| | - H. P. Vasantha Rupasinghe
- Department of Plant, Food, and Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, NS B2N 5E3, Canada;
- Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4H7, Canada
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Adeghate EA. GLP-1 receptor agonists in the treatment of diabetic non-alcoholic steatohepatitis patients. Expert Opin Pharmacother 2024; 25:223-232. [PMID: 38458647 DOI: 10.1080/14656566.2024.2328796] [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: 01/22/2024] [Accepted: 03/06/2024] [Indexed: 03/10/2024]
Abstract
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disease affecting almost 30% of the world population. Approximately 25% of people with NAFLD develop nonalcoholic steatohepatitis (NASH), the fulminant version of the disease. Diabetes mellitus is present in 22.5% of people with NAFLD and 44.60% of individuals with NASH. This review was undertaken to examine the current contribution of glucagon-like peptide 1 (GLP-1) receptor agonists to the pharmacotherapy of diabetic nonalcoholic steatohepatitis. AREAS COVERED The author analyzed the current status of GLP-1 receptor agonists for pharmacotherapy of diabetic NASH. Research data and literature reports were taken from the database and or websites of Diabetes UK, American Diabetes Association, ClinicalTrials.gov, PubMed, and Scopus. The keywords utilized included type 2 diabetes, GLP-1, NASH, NAFLD, and clinical trials. EXPERT OPINION Since diabetic NASH is associated with obesity, diabetes mellitus, oxidative stress and inflammation, drugs capable of mitigating all of these conditions simultaneously, are most ideal for the treatment of diabetic NASH. These drugs include (in order of relevance), GLP-1 receptor agonists, GLP-1 and GIP dual receptor agonists, sodium-glucose co-transporter-2 (SGLT2) inhibitors, and pioglitazone. The future, FDA-approved drug for diabetic NASH treatment will likely be GLP-1 agonist, which could be used as monotherapy or in combination with other drugs.
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Affiliation(s)
- Ernest A Adeghate
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- Zayed Centre for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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Calixto-Tlacomulco S, Luna-Reyes I, Delgado-Coello B, Gutiérrez-Vidal R, Reyes-Grajeda JP, Mas-Oliva J. CETP-derived Peptide Seq-1, the Key Component of HB-ATV-8 Vaccine Prevents Stress Responses, and Promotes Downregulation of Pro-Fibrotic Genes in Hepatocytes and Stellate Cells. Arch Med Res 2024; 55:102937. [PMID: 38301446 DOI: 10.1016/j.arcmed.2023.102937] [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: 09/01/2023] [Revised: 11/09/2023] [Accepted: 12/14/2023] [Indexed: 02/03/2024]
Abstract
BACKGROUND The nasal vaccine HB-ATV-8 has emerged as a promising approach for NAFLD (non-alcoholic fatty liver disease) and atherosclerosis prevention. HB-ATV-8 contains peptide seq-1 derived from the carboxy-end of the Cholesteryl Ester Transfer Protein (CETP), shown to reduce liver fibrosis, inflammation, and atherosclerotic plaque formation in animal models. Beyond the fact that this vaccine induces B-cell lymphocytes to code for antibodies against the seq-1 sequence, inhibiting CETP's cholesterol transfer activity, we have hypothesized that beyond the modulation of CETP activity carried out by neutralizing antibodies, the observed molecular effects may also correspond to the direct action of peptide seq-1 on diverse cellular systems and molecular features involved in the development of liver fibrosis. METHODS The HepG2 hepatoma-derived cell line was employed to establish an in vitro steatosis model. To obtain a conditioned cell medium to be used with hepatic stellate cell (HSC) cultures, HepG2 cells were exposed to fatty acids or fatty acids plus peptide seq-1, and the culture medium was collected. Gene regulation of COL1A1, ACTA2, TGF-β, and the expression of proteins COL1A1, MMP-2, and TIMP-2 were studied. AIM To establish an in vitro steatosis model employing HepG2 cells that mimics molecular processes observed in vivo during the onset of liver fibrosis. To evaluate the effect of peptide Seq-1 on lipid accumulation and pro-fibrotic responses. To study the effect of Seq-1-treated steatotic HepG2 cell supernatants on lipid accumulation, oxidative stress, and pro-fibrotic responses in HSC. RESULTS AND CONCLUSION Peptide seq-1-treated HepG2 cells show a downregulation of COLIA1, ACTA2, and TGF-β genes, and a decreased expression of proteins such as COL1A1, MMP-2, and TIMP-2, associated with the remodeling of extracellular matrix components. The same results are observed when HSCs are incubated with peptide Seq-1-treated steatotic HepG2 cell supernatants. The present study consolidates the nasal vaccine HB-ATV-8 as a new prospect in the treatment of NASH directly associated with the development of cardiovascular disease.
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Affiliation(s)
| | - Ismael Luna-Reyes
- Cellular Physiology Institute, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Blanca Delgado-Coello
- Cellular Physiology Institute, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Roxana Gutiérrez-Vidal
- Researchers Program for Mexico CONAHCYT, Mexico City, Mexico; Laboratory of Metabolic Diseases, Cinvestav Unidad Monterey, Apodaca, Nuevo León, Mexico
| | | | - Jaime Mas-Oliva
- Cellular Physiology Institute, Universidad Nacional Autónoma de México, Mexico City, Mexico.
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Xie F, Zhao J, Liu D, Wan Z, Sun K, Wang Y. Associations of dietary advanced glycation end products with liver steatosis via vibration controlled transient elastography in the United States: a nationwide cross-sectional study. Eur J Nutr 2024; 63:173-183. [PMID: 37779113 DOI: 10.1007/s00394-023-03253-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 09/08/2023] [Indexed: 10/03/2023]
Abstract
PURPOSE Large population-based studies for the associations between dietary advanced glycation end products (dAGEs) intake and liver steatosis remain lacking. It is necessary to clarify the relationship of dAGEsintake with liver steatosis through the National Health and Nutrition Survey (NHANES). METHODS A total of 5856 participants in the NHANES 2017-2018 were included. The dietary AGEs intake, including ε-(carboxymethyl)lysine(CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated using the combination of ultra-performance LC-tandem MS dietary AGEs database and two 24-h dietary recall interviews. Liver steatosis was assessed by controlled attenuation parameter via transient elastography. Logistic regression model was adopted to explore the relationships between dAGEs intake and hepatic steatosis. RESULTS Compared with individuals of total dAGEs, CML, MG-H1 in the lowest tertile, those in the highest tertile had highest risk of hepatic steatosis, and the corresponding odds radios(ORs) (95% confidence interval(CI)) were 1.37 (1.01, 1.84), 1.36 (1.04,1.78) and 1.40 (1.06, 1.85), respectively. Subgroups analysis found that the positive association between dAGEs, CML, CEL and MG-H1 and hepatic steatosis appeared stronger in subjects with obesity and those with abnormal waist circumference (WC). CONCLUSION There was a positive correlation between dAGEs, CML, MG-H1, and hepatic steatosis, and this association mainly existed in subjects with obesity and those with abnormal WC. Dietary AGEs restriction might be of high priority for subjects with obesity for the prevention of fatty liver disease. Further longitudinal studies are required to confirm the causal associations and explore the potential mechanisms.
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Affiliation(s)
- Fangfei Xie
- Physical Examination Center, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, 242 Guangji Road, Suzhou, 215008, China
| | - Jing Zhao
- Physical Examination Center, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, 242 Guangji Road, Suzhou, 215008, China
| | - Di Liu
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, 199 Ren'ai Road, Suzhou, 215123, China
| | - Zhongxiao Wan
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, 199 Ren'ai Road, Suzhou, 215123, China
| | - Kangyun Sun
- Physical Examination Center, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, 242 Guangji Road, Suzhou, 215008, China.
| | - Yun Wang
- Physical Examination Center, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, 242 Guangji Road, Suzhou, 215008, China.
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Sasidharan K, Caddeo A, Jamialahmadi O, Noto FR, Tomasi M, Malvestiti F, Ciociola E, Tavaglione F, Mancina RM, Cherubini A, Bianco C, Mirarchi A, Männistö V, Pihlajamäki J, Kärjä V, Grimaudo S, Luukkonen PK, Qadri S, Yki-Järvinen H, Petta S, Manfrini S, Vespasiani-Gentilucci U, Bruni V, Valenti L, Romeo S. IL32 downregulation lowers triglycerides and type I collagen in di-lineage human primary liver organoids. Cell Rep Med 2024; 5:101352. [PMID: 38232700 PMCID: PMC10829727 DOI: 10.1016/j.xcrm.2023.101352] [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: 10/13/2022] [Revised: 09/26/2023] [Accepted: 12/05/2023] [Indexed: 01/19/2024]
Abstract
Steatotic liver disease (SLD) prevails as the most common chronic liver disease yet lack approved treatments due to incomplete understanding of pathogenesis. Recently, elevated hepatic and circulating interleukin 32 (IL-32) levels were found in individuals with severe SLD. However, the mechanistic link between IL-32 and intracellular triglyceride metabolism remains to be elucidated. We demonstrate in vitro that incubation with IL-32β protein leads to an increase in intracellular triglyceride synthesis, while downregulation of IL32 by small interfering RNA leads to lower triglyceride synthesis and secretion in organoids from human primary hepatocytes. This reduction requires the upregulation of Phospholipase A2 group IIA (PLA2G2A). Furthermore, downregulation of IL32 results in lower intracellular type I collagen levels in di-lineage human primary hepatic organoids. Finally, we identify a genetic variant of IL32 (rs76580947) associated with lower circulating IL-32 and protection against SLD measured by non-invasive tests. These data suggest that IL32 downregulation may be beneficial against SLD.
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Affiliation(s)
- Kavitha Sasidharan
- Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Andrea Caddeo
- Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Oveis Jamialahmadi
- Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Francesca Rita Noto
- Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden; Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy
| | - Melissa Tomasi
- Precision Medicine Lab, Biological Resource Center Unit, Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Francesco Malvestiti
- Precision Medicine Lab, Biological Resource Center Unit, Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
| | - Ester Ciociola
- Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Federica Tavaglione
- Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden; Operative Unit of Clinical Medicine and Hepatology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy; Research Unit of Clinical Medicine and Hepatology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Rosellina M Mancina
- Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden; Research Unit of Clinical Medicine and Hepatology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Alessandro Cherubini
- Precision Medicine Lab, Biological Resource Center Unit, Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Cristiana Bianco
- Precision Medicine Lab, Biological Resource Center Unit, Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Angela Mirarchi
- Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy
| | - Ville Männistö
- Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Jussi Pihlajamäki
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Clinical Nutrition and Obesity Centre, Kuopio University Hospital, Kuopio, Finland
| | - Vesa Kärjä
- Department of Pathology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Stefania Grimaudo
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Panu K Luukkonen
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Internal Medicine, Yale University, New Haven, CT, USA
| | - Sami Qadri
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Hannele Yki-Järvinen
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Salvatore Petta
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Silvia Manfrini
- Operative Unit of Endocrinology and Diabetes, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy; Research Unit of Endocrinology and Diabetes, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Umberto Vespasiani-Gentilucci
- Operative Unit of Clinical Medicine and Hepatology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy; Research Unit of Clinical Medicine and Hepatology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Vincenzo Bruni
- Operative Unit of Bariatric Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Luca Valenti
- Precision Medicine Lab, Biological Resource Center Unit, Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy.
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden; Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy; Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
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Ding KR, Lakshmanan S, Holda M, Kinninger A, Manubolu VS, Joshi T, Golub I, Mao SS, Budoff MJ, Roy SK. Methods and Reproducibility of Liver Fat Measurement Using 3-Dimensional Liver Segmentation From Noncontrast Computed Tomography in EVAPORATE Cohort. J Comput Assist Tomogr 2024; 48:49-54. [PMID: 37531634 DOI: 10.1097/rct.0000000000001521] [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: 08/04/2023]
Abstract
OBJECTIVE Nonalcoholic fatty liver disease not only shares multiple risk factors with cardiovascular disease but also independently predicts its increased risk and related outcomes. Here, we evaluate reproducibility of 3-dimensional (3D) liver volume segmentation method to identify fatty liver on noncontrast cardiac computed tomography (CT) and compare measures with previously validated 2-dimensional (2D) segmentation CT criteria for the measurement of liver fat. METHODS The study included 68 participants enrolled in the EVAPORATE trial and underwent serial noncontrast cardiac CT. Liver attenuation < 40 Hounsfield units (HU) was used for diagnosing fatty liver, as done in the MESA study. Two-dimensional and 3D segmentation of the liver were performed by Philips software. Bland-Altman plot analysis was used to assess reproducibility. RESULTS Interreader reproducibility of 3D liver mean HU measurements was 96% in a sample of 111 scans. Reproducibility of 2D and 3D liver mean HU measurements was 93% in a sample of 111 scans. Reproducibility of change in 2D and 3D liver mean HU was 94% in 68 scans. Kappa, a measure of agreement in which the 2D and 3D measures both identified fatty liver, was excellent at 96.4% in 111 scans. CONCLUSIONS Fatty liver can be reliably diagnosed and measured serially in a stable and reproducible way by 3D liver segmentation of noncontrast cardiac CT scans. Future studies need to explore the sensitivity and stability of measures for low liver fat content by 3D segmentation, over the current 2D methodology. This measure can serve as an imaging biomarker to understand mechanistic correlations between atherosclerosis, fatty liver, and cardiovascular disease risk.
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Affiliation(s)
- Kimberly R Ding
- From the Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA
| | - Suvasini Lakshmanan
- Department of Cardiology, Harbor-UCLA Medical Center Lundquist Institute, Torrance, CA
| | - Mateusz Holda
- Department of Cardiology, Harbor-UCLA Medical Center Lundquist Institute, Torrance, CA
| | - April Kinninger
- Department of Cardiology, Harbor-UCLA Medical Center Lundquist Institute, Torrance, CA
| | - Venkat S Manubolu
- Department of Cardiology, Harbor-UCLA Medical Center Lundquist Institute, Torrance, CA
| | - Tej Joshi
- Department of Cardiology, Harbor-UCLA Medical Center Lundquist Institute, Torrance, CA
| | - Ilana Golub
- Department of Cardiology, Harbor-UCLA Medical Center Lundquist Institute, Torrance, CA
| | - Song S Mao
- Department of Cardiology, Harbor-UCLA Medical Center Lundquist Institute, Torrance, CA
| | - Matthew J Budoff
- Department of Cardiology, Harbor-UCLA Medical Center Lundquist Institute, Torrance, CA
| | - Sion K Roy
- Department of Cardiology, Harbor-UCLA Medical Center Lundquist Institute, Torrance, CA
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Singha PS, Ghosh S, Ghosh D. Levothyroxine and Non-alcoholic Fatty Liver Disease: A Mini Review. Mini Rev Med Chem 2024; 24:128-138. [PMID: 36918791 DOI: 10.2174/1389557523666230314113543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/24/2022] [Accepted: 11/29/2022] [Indexed: 03/16/2023]
Abstract
Levothyroxine or l-thyroxine is artificially manufactured thyroxine, which is used as a drug to treat underactive thyroid conditions in humans. The drug, levothyroxine, is consumed daily in a prescribed dose to replace the missing thyroid hormone thyroxine in an individual with an underactive thyroid, and it helps to maintain normal physiological conditions. Though it is a life-maintaining drug, it replaces the missing thyroid hormone and performs the necessary daily metabolic functions in our body. Like all other allopathic drugs, it comes with certain side effects, which include joint pain, cramps in muscle, weight gain/loss, hair loss, etc. The thyroid hormone, thyroxine, is known to mobilize fat in our body, including the ones from the hepatic system. An underactive thyroid may cause an accumulation of fat in the liver, leading to a fatty liver, which is clinically termed Non-Alcoholic Fatty Liver Disease (NAFLD). The correlation between hypothyroidism and NAFLD is now well-studied and recognized. As levothyroxine performs the functions of the missing thyroxine, it is anticipated, based on certain preliminary studies, that the drug helps to mobilize hepatic fat and thus may have a crucial role in mitigating the condition of NAFDL.
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Affiliation(s)
| | - Suvendu Ghosh
- Department of Physiology, Hooghly Mohsin College, Chinsura, Hooghly, 712 101, West Bengal, India
| | - Debosree Ghosh
- Department of Physiology, Government General Degree College, West Bengal, India
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Grinshpan LS, Eilat-Adar S, Ivancovsky-Wajcman D, Kariv R, Gillon-Keren M, Zelber-Sagi S. Ultra-processed food consumption and non-alcoholic fatty liver disease, metabolic syndrome and insulin resistance: A systematic review. JHEP Rep 2024; 6:100964. [PMID: 38234408 PMCID: PMC10792654 DOI: 10.1016/j.jhepr.2023.100964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 10/12/2023] [Accepted: 10/31/2023] [Indexed: 01/19/2024] Open
Abstract
Background High ultra-processed food (UPF) consumption is associated with the development of various diet-related non-communicable diseases, especially obesity and type 2 diabetes. The present study aimed to systematically review the association between UPF consumption and non-alcoholic fatty liver disease (NAFLD) and its leading risk factors; metabolic syndrome (MetS) and insulin resistance (IR). Methods A comprehensive search was conducted in PubMed, Scopus, Embase, Web of Science, CINAHL, and Cochrane (March 2023), and references of the identified articles were checked. The search keywords were defined through an exploratory investigation in addition to MeSH and similarly controlled vocabulary thesauruses. Observational and interventional studies were included. Studies that focused only on specific groups of processed foods or overlapping dietary patterns were excluded. The quality assessment was conducted using the Joanna Briggs Institute's critical appraisal tools for observational studies and Cochrane's risk of bias 2 tool for randomized-control trials. A narrative synthesis was employed to report the results. Results Fifteen studies were included, with a total of 52,885 participants, one randomized-controlled trial, and fourteen observational studies (nine cross-sectional and five prospective). The review has shown a significant association between UPF consumption and NAFLD in three studies out of six, MetS in five out of eight, and IR in one out of three. All large-scale prospective cohorts that studied NAFLD or MetS outcomes demonstrated a positive association. In contrast, studies that did not demonstrate significant associations were mostly cross-sectional and small. The evidence for an association with IR was insufficient and conflicting. Conclusion The included studies are few, observational, and based upon self-reported dietary assessment tools. However, current evidence indicates that UPF is not only associated with obesity and type 2 diabetes but may also be a risk factor for NAFLD and MetS. UPF is a worldwide concern deserving further longitudinal research. Impact and implications Overconsumption of ultra-processed food (UPF) may lead to the development of obesity and type 2 diabetes, but the association with non-alcoholic fatty liver disease (NAFLD) is not well established. The present systematic review shows that UPF may be associated with NAFLD, although more large prospective studies are needed. These findings emphasize the importance of minimizing the consumption of UPF to prevent NAFLD and other metabolic diseases among the general adult population. This systematic review and further prospective studies, epidemiological or interventional, can help physicians provide patients with evidence-based nutritional recommendations and will support policymakers in restricting the marketing of UPF as well as promoting affordable, healthy, and minimally processed foods.
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Affiliation(s)
- Laura Sol Grinshpan
- School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel
- Department of Gastroenterology Tel-Aviv Medical Center, Tel-Aviv, Israel
| | | | - Dana Ivancovsky-Wajcman
- School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel
- Department of Gastroenterology Tel-Aviv Medical Center, Tel-Aviv, Israel
| | - Revital Kariv
- Department of Gastroenterology Tel-Aviv Medical Center, Tel-Aviv, Israel
- Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Michal Gillon-Keren
- Institute of Endocrinology and Diabetes, Schneider Children’s Medical Center, Petah Tikva, Israel
- Faculty of Sciences, Kibbutzim College of Education Technology and the Arts, Tel-Aviv, Israel
| | - Shira Zelber-Sagi
- School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel
- Department of Gastroenterology Tel-Aviv Medical Center, Tel-Aviv, Israel
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Armani S, Geier A, Forst T, Merle U, Alpers DH, Lunnon MW. Effect of changes in metabolic enzymes and transporters on drug metabolism in the context of liver disease: Impact on pharmacokinetics and drug-drug interactions. Br J Clin Pharmacol 2023. [PMID: 38148609 DOI: 10.1111/bcp.15990] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 12/07/2023] [Accepted: 12/13/2023] [Indexed: 12/28/2023] Open
Abstract
Changes in the pharmacokinetic and resulting pharmacodynamic properties of drugs are common in many chronic liver diseases, leading to adverse effects, drug interactions and increased risk of over- or underdosing of medications. Structural and functional hepatic impairment can have major effects on drug metabolism and transport. This review summarizes research on the functional changes in phase I and II metabolic enzymes and in transport proteins in patients with metabolic diseases such as type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis and cirrhosis, providing a clinical perspective on how these changes affect drug uptake and metabolism. Generally, a decrease in expression and/or activity of many enzymes of the cytochrome P450 family (e.g. CYP2E1 and CYP3A4), and of influx and efflux transporters (e.g. organic anion-transporting polypeptide [OATP]1B1, OATP2B1, OAT2 and bile salt export pump), has been recently documented in patients with liver disease. Decreased enzyme levels often correlate with increased severity of chronic liver disease. In subjects with hepatic impairment, there is potential for strong alterations of drug pharmacokinetics due to reduced absorption, increased volume of distribution, metabolism and extraction. Due to the altered pharmacokinetics, specific drug-drug interactions are also a potential issue to consider in patients with liver disease. Given the huge burden of liver disease in western societies, there is a need to improve awareness among all healthcare professionals and patients with liver disease to ensure appropriate drug prescriptions.
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Affiliation(s)
- Sara Armani
- CRS Clinical Research Services, Mannheim, Germany
| | - Andreas Geier
- Department of Internal Medicine and Hepatology, University Hospital, Würzburg, Germany
| | - Thomas Forst
- CRS Clinical Research Services, Mannheim, Germany
| | - Uta Merle
- Department of Internal Medicine IV, University Hospital, Heidelberg, Germany
| | - David H Alpers
- Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
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Castañé H, Jiménez-Franco A, Martínez-Navidad C, Placed-Gallego C, Cambra-Cortés V, Perta AM, París M, del Castillo D, Arenas M, Camps J, Joven J. Serum Arylesterase, Paraoxonase, and Lactonase Activities and Paraoxonase-1 Concentrations in Morbidly Obese Patients and Their Relationship with Non-Alcoholic Steatohepatitis. Antioxidants (Basel) 2023; 12:2038. [PMID: 38136158 PMCID: PMC10741051 DOI: 10.3390/antiox12122038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 11/15/2023] [Accepted: 11/22/2023] [Indexed: 12/24/2023] Open
Abstract
Paraoxonase-1 (PON1) is an antioxidant enzyme associated with high-density lipoproteins (HDL). Reduced serum PON1 activity is found in diseases marked by oxidative stress and inflammation, but its role in obesity remains unclear. This study investigated PON1 activities and concentrations in morbidly obese individuals and explored the impacts of the genetic polymorphism PON1 rs662 and non-alcoholic fatty liver disease on enzymatic properties. We recruited 1349 morbidly obese patients undergoing bariatric surgery and 823 non-obese volunteers. PON1-related variables, including arylesterase, paraoxonase, and lactonase activities and PON1 concentrations, were examined. Our results showed that morbidly obese individuals exhibited higher PON1 concentrations but lower enzymatic activities than non-obese individuals. We observed inverse associations of arylesterase and paraoxonase activities with waist circumference (rho = -0.24, p < 0.001, and rho = -0.30, p < 0.001, respectively) and body mass index (rho = -0.15, p = 0.001, and rho = -0.23, p < 0.001), as well as direct associations of arylesterase, paraoxonase, and lactonase activities with HDL cholesterol (rho = 0.11, p = 0.005, rho = 0.20, p < 0.001, and rho = 0.20, p < 0.001). No significant differences were observed regarding metabolic syndrome, type 2 diabetes mellitus, hypertension, dyslipidemia, rs662 polymorphism allele frequencies, or the diagnosis of non-alcoholic steatohepatitis. Nevertheless, correlations were found between certain PON1-related variables, steatosis, and ballooning. In conclusion, changes in PON1-related variables in morbidly obese patients are dependent on the disease itself and HDL levels. The relationships between these variables and specific liver histological changes raise intriguing questions for consideration in future studies.
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Affiliation(s)
- Helena Castañé
- Unitat de Recerca Biomédica, Hospital Universitari de Sant Joan, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Av. Dr. Josep Laporte 2, 43204 Reus, Spain; (H.C.); (A.J.-F.); (C.M.-N.); (C.P.-G.); (V.C.-C.); (A.-M.P.); (M.A.)
| | - Andrea Jiménez-Franco
- Unitat de Recerca Biomédica, Hospital Universitari de Sant Joan, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Av. Dr. Josep Laporte 2, 43204 Reus, Spain; (H.C.); (A.J.-F.); (C.M.-N.); (C.P.-G.); (V.C.-C.); (A.-M.P.); (M.A.)
| | - Cristian Martínez-Navidad
- Unitat de Recerca Biomédica, Hospital Universitari de Sant Joan, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Av. Dr. Josep Laporte 2, 43204 Reus, Spain; (H.C.); (A.J.-F.); (C.M.-N.); (C.P.-G.); (V.C.-C.); (A.-M.P.); (M.A.)
| | - Cristina Placed-Gallego
- Unitat de Recerca Biomédica, Hospital Universitari de Sant Joan, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Av. Dr. Josep Laporte 2, 43204 Reus, Spain; (H.C.); (A.J.-F.); (C.M.-N.); (C.P.-G.); (V.C.-C.); (A.-M.P.); (M.A.)
| | - Vicente Cambra-Cortés
- Unitat de Recerca Biomédica, Hospital Universitari de Sant Joan, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Av. Dr. Josep Laporte 2, 43204 Reus, Spain; (H.C.); (A.J.-F.); (C.M.-N.); (C.P.-G.); (V.C.-C.); (A.-M.P.); (M.A.)
| | - Adelina-Miruna Perta
- Unitat de Recerca Biomédica, Hospital Universitari de Sant Joan, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Av. Dr. Josep Laporte 2, 43204 Reus, Spain; (H.C.); (A.J.-F.); (C.M.-N.); (C.P.-G.); (V.C.-C.); (A.-M.P.); (M.A.)
| | - Marta París
- Department of Bariatric Surgery, Hospital Universitari de Sant Joan, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Av. Dr. Josep Laporte 2, 43204 Reus, Spain; (M.P.); (D.d.C.)
| | - Daniel del Castillo
- Department of Bariatric Surgery, Hospital Universitari de Sant Joan, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Av. Dr. Josep Laporte 2, 43204 Reus, Spain; (M.P.); (D.d.C.)
| | - Meritxell Arenas
- Unitat de Recerca Biomédica, Hospital Universitari de Sant Joan, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Av. Dr. Josep Laporte 2, 43204 Reus, Spain; (H.C.); (A.J.-F.); (C.M.-N.); (C.P.-G.); (V.C.-C.); (A.-M.P.); (M.A.)
- Department of Radiation Oncology, Hospital Universitari de Sant Joan, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Av. Dr. Josep Laporte 2, 43204 Reus, Spain
| | - Jordi Camps
- Unitat de Recerca Biomédica, Hospital Universitari de Sant Joan, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Av. Dr. Josep Laporte 2, 43204 Reus, Spain; (H.C.); (A.J.-F.); (C.M.-N.); (C.P.-G.); (V.C.-C.); (A.-M.P.); (M.A.)
| | - Jorge Joven
- Unitat de Recerca Biomédica, Hospital Universitari de Sant Joan, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Av. Dr. Josep Laporte 2, 43204 Reus, Spain; (H.C.); (A.J.-F.); (C.M.-N.); (C.P.-G.); (V.C.-C.); (A.-M.P.); (M.A.)
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Wang H, Solomon J, Reza SMS, Yang HJ, Chu WT, Crozier I, Sayre PJ, Lee BY, Mani V, Friedrich TC, O’Connor DH, Worwa G, Kuhn JH, Calcagno C, Castro MA. Repeatability of computed tomography liver radiomic features in a nonhuman primate model of diet-induced steatosis. J Med Imaging (Bellingham) 2023; 10:066004. [PMID: 38090646 PMCID: PMC10711681 DOI: 10.1117/1.jmi.10.6.066004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 11/17/2023] [Accepted: 11/20/2023] [Indexed: 02/01/2024] Open
Abstract
Purpose We describe a method to identify repeatable liver computed tomography (CT) radiomic features, suitable for detection of steatosis, in nonhuman primates. Criteria used for feature selection exclude nonrepeatable features and may be useful to improve the performance and robustness of radiomics-based predictive models. Approach Six crab-eating macaques were equally assigned to two experimental groups, fed regular chow or an atherogenic diet. High-resolution CT images were acquired over several days for each macaque. First-order and second-order radiomic features were extracted from six regions in the liver parenchyma, either with or without liver-to-spleen intensity normalization from images reconstructed using either a standard (B-filter) or a bone-enhanced (D-filter) kernel. Intrasubject repeatability of each feature was assessed using a paired t -test for all scans and the minimum p -value was identified for each macaque. Repeatable features were defined as having a minimum p -value among all macaques above the significance level after Bonferroni's correction. Features showing a significant difference with respect to diet group were identified using a two-sample t -test. Results A list of repeatable features was generated for each type of image. The largest number of repeatable features was achieved from spleen-normalized D-filtered images, which also produced the largest number of second-order radiomic features that were repeatable and different between diet groups. Conclusions Repeatability depends on reconstruction kernel and normalization. Features were quantified and ranked based on their repeatability. Features to be excluded for more robust models were identified. Features that were repeatable but different between diet groups were also identified.
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Affiliation(s)
- Hui Wang
- National Institutes of Health, National Institute of Allergy and Infectious Diseases, Integrated Research Facility at Fort Detrick, Fort Detrick, Frederick, Maryland, United States
| | - Jeffrey Solomon
- Frederick National Laboratory for Cancer Research, Clinical Monitoring Research Program Directorate, Frederick, Maryland, United States
| | - Syed M. S. Reza
- National Institutes of Health, Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, Bethesda, Maryland, United States
| | - Hee-Jeong Yang
- National Institutes of Health, National Institute of Allergy and Infectious Diseases, Integrated Research Facility at Fort Detrick, Fort Detrick, Frederick, Maryland, United States
| | - Winston T. Chu
- National Institutes of Health, Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, Bethesda, Maryland, United States
| | - Ian Crozier
- Frederick National Laboratory for Cancer Research, Clinical Monitoring Research Program Directorate, Frederick, Maryland, United States
| | - Philip J. Sayre
- National Institutes of Health, National Institute of Allergy and Infectious Diseases, Integrated Research Facility at Fort Detrick, Fort Detrick, Frederick, Maryland, United States
| | - Byeong Y. Lee
- National Institutes of Health, National Institute of Allergy and Infectious Diseases, Integrated Research Facility at Fort Detrick, Fort Detrick, Frederick, Maryland, United States
| | - Venkatesh Mani
- National Institutes of Health, National Institute of Allergy and Infectious Diseases, Integrated Research Facility at Fort Detrick, Fort Detrick, Frederick, Maryland, United States
| | - Thomas C. Friedrich
- University of Wisconsin–Madison, Department of Pathobiological Sciences, School of Veterinary Medicine, Madison, Wisconsin, United States
| | - David H. O’Connor
- University of Wisconsin–Madison, Department of Pathology and Laboratory Medicine, Madison, Wisconsin, United States
| | - Gabriella Worwa
- National Institutes of Health, National Institute of Allergy and Infectious Diseases, Integrated Research Facility at Fort Detrick, Fort Detrick, Frederick, Maryland, United States
| | - Jens H. Kuhn
- National Institutes of Health, National Institute of Allergy and Infectious Diseases, Integrated Research Facility at Fort Detrick, Fort Detrick, Frederick, Maryland, United States
| | - Claudia Calcagno
- National Institutes of Health, National Institute of Allergy and Infectious Diseases, Integrated Research Facility at Fort Detrick, Fort Detrick, Frederick, Maryland, United States
| | - Marcelo A. Castro
- National Institutes of Health, National Institute of Allergy and Infectious Diseases, Integrated Research Facility at Fort Detrick, Fort Detrick, Frederick, Maryland, United States
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Pal R, Bhadada SK. AGEs accumulation with vascular complications, glycemic control and metabolic syndrome: A narrative review. Bone 2023; 176:116884. [PMID: 37598920 DOI: 10.1016/j.bone.2023.116884] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 08/07/2023] [Accepted: 08/16/2023] [Indexed: 08/22/2023]
Abstract
BACKGROUND Multiple pathogenetic mechanisms are involved in the genesis of various microvascular and macrovascular complications of diabetes mellitus. Of all these, advanced glycation end products (AGEs) have been strongly implicated. OBJECTIVES The present narrative review aims to summarize the available literature on the genesis of AGEs and their potential role in the causation of both micro- and macrovascular complications of diabetes mellitus. RESULTS Uncontrolled hyperglycemia triggers the formation of AGEs through non-enzymatic glycation reactions between reducing sugars and proteins, lipids, or nucleic acids. AGEs accumulate in bloodstream and bodily tissues under chronic hyperglycemia. AGEs create irreversible cross-linkages of various intra- and extracellular molecules and activate the receptor for advanced glycation end products (RAGE), which stimulates downstream signaling pathways that generate reactive oxygen species (ROS) and contribute to oxidative stress. Additionally, intracellular glycation of mitochondrial respiratory chain proteins by AGEs contributes to the further generation of ROS, which, in turn, sets a vicious cycle that further promotes the production of endogenous AGEs. Through these pathways, AGEs play a principal role in the pathogenesis of various diabetic complications, including diabetic retinopathy, nephropathy, neuropathy, bone disease, atherosclerosis and non-alcoholic fatty liver disease. Multiple clinical studies and meta-analyses have revealed a positive association between tissue or circulating levels of AGEs and development of various diabetic complications. Besides, exogenous AGEs, primarily those derived from diets, promote insulin resistance, obesity, and metabolic syndrome. CONCLUSIONS AGEs, triggered by chronic hyperglycemia, play a pivotal role in the pathogenesis of various complications of diabetes mellitus.
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Affiliation(s)
- Rimesh Pal
- Department of Endocrinology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India
| | - Sanjay K Bhadada
- Department of Endocrinology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India.
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Kollet O, Sagi I. Glycation-driven matrix crosslinking in cirrhosis. Nat Biomed Eng 2023; 7:1343-1345. [PMID: 37919368 DOI: 10.1038/s41551-023-01119-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2023]
Affiliation(s)
- Orit Kollet
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Irit Sagi
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel.
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Zhuang S, Zhou X, Yang X, Chang D, Chen T, Sun Y, Wang C, Zhang C, Jiang J, Chen Y, Lin X, Wang X, Yu W, Lin X, He C, Zheng Y, Zhang J, Shi H. Dendrobium mixture ameliorates hepatic injury induced by insulin resistance in vitro and in vivo through the downregulation of AGE/RAGE/Akt signaling pathway. Heliyon 2023; 9:e22007. [PMID: 38034607 PMCID: PMC10685200 DOI: 10.1016/j.heliyon.2023.e22007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 11/01/2023] [Accepted: 11/01/2023] [Indexed: 12/02/2023] Open
Abstract
Dendrobium mixture (DM) is a patented Chinese herbal medicine which has been shown to ameliorate type 2 diabetes mellitus (T2DM) with non-alcoholic fatty liver disease (NAFLD) in vivo and in vitro. We aimed to investigate the underlying mechanism of DM as a therapeutic agent in attenuating liver steatosis in relation to type 2 diabetes mellitus (T2DM). DM (16.2 g/kg/d) was administered to db/db mice for 4 weeks. The db/m mice and db/db mice in the control and model groups were given normal saline. Additionally, DM (11.25 g/kg/d) was administered to Sprague-Dawley (SD) rats, and the serum was collected and used in an experiment involving palmitic acid (PA)-induced human liver HepG2 cells with abnormal lipid and glucose metabolism. In db/db mice, the administration of DM significantly alleviated liver steatosis, including histological damage and cell apoptosis. DM was found to prevent the upregulation of the RAGE and AKT1 proteins in liver tissues. The underlying mechanism of DM was further studied in PA-induced HepG2 cells. Post-DM administration serum from SD rats reduced lipid accumulation and regulated glucose metabolism in HepG2 cells. Consequently, it inhibited RAGE/AKT signaling and restored autophagy activity. The upregulated autophagy was associated with the mTOR-AMPK signaling pathway. Furthermore, post-DM administration serum reduced apoptosis of hepatocytes in PA-induced HepG2 cells. Our study supports the potential use of DM as a therapeutic agent for the treatment of NAFLD in T2DM. The mechanism underlying this therapeutic potential is associated with the downregulation of the AGE/RAGE/Akt signaling pathway.
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Affiliation(s)
- Shuting Zhuang
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Xian Zhou
- NICM Health Research Institute, Western Sydney University, Westmead, NSW, 2006, Australia
| | - Xiaowen Yang
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Dennis Chang
- NICM Health Research Institute, Western Sydney University, Westmead, NSW, 2006, Australia
| | - Tao Chen
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou, 350100, China
| | - Yibin Sun
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou, 350100, China
| | - Chenxiang Wang
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou, 350100, China
| | - Chutian Zhang
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Jichao Jiang
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Yong Chen
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Xiaohui Lin
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Xiaoning Wang
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Wenzhen Yu
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Xinjun Lin
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Caigu He
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Yanfang Zheng
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou, 350100, China
| | - Jieping Zhang
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Hong Shi
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
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