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1
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Devasia AG, Ramasamy A, Leo CH. Current Therapeutic Landscape for Metabolic Dysfunction-Associated Steatohepatitis. Int J Mol Sci 2025; 26:1778. [PMID: 40004240 PMCID: PMC11855529 DOI: 10.3390/ijms26041778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 01/31/2025] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
In recent years, "metabolic dysfunction-associated steatotic liver disease" (MASLD) has been proposed to better connect liver disease to metabolic dysfunction, which is the most common chronic liver disease worldwide. MASLD affects more than 30% of individuals globally, and it is diagnosed by the combination of hepatic steatosis and obesity, type 2 diabetes, or two metabolic risk factors. MASLD begins with the buildup of extra fat, often greater than 5%, within the liver, causing liver hepatocytes to become stressed. This can proceed to a more severe form, metabolic dysfunction-associated steatohepatitis (MASH), in 20-30% of people, where inflammation in the liver causes tissue fibrosis, which limits blood flow over time. As fibrosis worsens, MASH may lead to cirrhosis, liver failure, or even liver cancer. While the pathophysiology of MASLD is not fully known, the current "multiple-hits" concept proposes that dietary and lifestyle factors, metabolic factors, and genetic or epigenetic factors contribute to elevated oxidative stress and inflammation, causing liver fibrosis. This review article provides an overview of the pathogenesis of MASLD and evaluates existing therapies as well as pharmacological drugs that are currently being studied in clinical trials for MASLD or MASH.
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Affiliation(s)
- Arun George Devasia
- Science, Math & Technology, Singapore University of Technology & Design, Singapore 487372, Singapore;
- Genome Institute of Singapore (GIS), Agency for Science Technology and Research (A*STAR), 60 Biopolis Street, Singapore 138672, Singapore;
| | - Adaikalavan Ramasamy
- Genome Institute of Singapore (GIS), Agency for Science Technology and Research (A*STAR), 60 Biopolis Street, Singapore 138672, Singapore;
| | - Chen Huei Leo
- Department of Biomedical Engineering, College of Design & Engineering, National University of Singapore, 9 Engineering Drive 1, Singapore 117576, Singapore
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2
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Njei B, Al-Ajlouni YA, Ameyaw P, Njei LP, Boateng S. Role of ammonia and glutamine in the pathogenesis and progression of metabolic dysfunction-associated steatotic liver disease: A systematic review. J Gastroenterol Hepatol 2024; 39:1788-1808. [PMID: 38763916 DOI: 10.1111/jgh.16603] [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: 02/01/2024] [Revised: 04/10/2024] [Accepted: 04/24/2024] [Indexed: 05/21/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of the global population, with a significant risk of advancing to liver cirrhosis and hepatocellular carcinoma. The roles of ammonia and glutamine in MASLD's pathogenesis are increasingly recognized, prompting this systematic review. This systematic review was conducted through a meticulous search of literature on December 21, 2023, across five major databases, focusing on studies that addressed the relationship between ammonia or glutamine and MASLD. The quality of the included studies was evaluated using CASP checklists. This study is officially registered in the PROSPERO database (CRD42023495619) and was conducted without external funding or sponsorship. Following PRISMA guidelines, 13 studies were included in this review. The studies were conducted globally, with varying sample sizes and study designs. The appraisal indicated a mainly low bias, confirming the reliability of the evidence. Glutamine's involvement in MASLD emerged as multifaceted, with its metabolic role being critical for liver function and disease progression. Variable expressions of glutamine synthetase and glutaminase enzymes highlight metabolic complexity whereas ammonia's impact through urea cycle dysfunction suggests avenues for therapeutic intervention. However, human clinical trials are lacking. This review emphasizes the necessity of glutamine and ammonia in understanding MASLD and identifies potential therapeutic targets. The current evidence, while robust, points to the need for human studies to corroborate preclinical findings. A personalized approach to treatment, informed by metabolic differences in MASLD patients, is advocated, alongside future large-scale clinical trials for a deeper exploration into these metabolic pathways.
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Affiliation(s)
- Basile Njei
- International Medicine Program, Section of Digestive Diseases, Yale University, New Haven, Connecticut, USA
| | | | - Prince Ameyaw
- Yale Affiliated Hospitals Program, Bridgeport, Connecticut, USA
| | - Lea-Pearl Njei
- University of Maryland Baltimore County, Baltimore, Maryland, USA
| | - Sarpong Boateng
- Yale Affiliated Hospitals Program, Bridgeport, Connecticut, USA
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3
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Wu H, Wei J, Wang S, Chen L, Zhang J, Wang N, Tan X. Dietary pattern modifies the risk of MASLD through metabolomic signature. JHEP Rep 2024; 6:101133. [PMID: 39081700 PMCID: PMC11286987 DOI: 10.1016/j.jhepr.2024.101133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 05/24/2024] [Accepted: 05/30/2024] [Indexed: 08/02/2024] Open
Abstract
Background & Aims The EAT-Lancet Commission in 2019 advocated a plant-centric diet for health and environmental benefits, but its relation to metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. We aimed to discover the metabolite profile linked to the EAT-Lancet diet and its association with MASLD risk, considering genetic predisposition. Methods We analyzed data from 105,752 UK Biobank participants with detailed dietary and metabolomic information. We constructed an EAT-Lancet diet index and derived a corresponding metabolomic signature through elastic net regression. A weighted polygenic risk score for MASLD was computed from associated risk variants. The Cox proportional hazards model was employed to estimate hazard ratios (HRs) and 95% CIs for the risk of MASLD (defined as hospital admission or death). Results During a median follow-up period of 11.6 years, 1,138 cases of MASLD were documented. Participants in the highest group for the EAT-Lancet diet index had a multivariable HR of 0.79 (95% CI 0.66-0.95) for MASLD compared to the lowest group. The diet's impact was unaffected by genetic predisposition to MASLD (p = 0.42). Moreover, a robust correlation was found between the metabolomic signature and the EAT-Lancet diet index (Pearson r = 0.29; p <0.0001). Participants in the highest group for the metabolomic signature had a multivariable HR of 0.46 (95% CI 0.37-0.58) for MASLD, in comparison to those in the lowest group. Conclusions Higher intake of the EAT-Lancet diet and its associated metabolite signature are both linked to a reduced risk of MASLD, independently of traditional risk factors. Impact and implications Our analysis leveraging the UK Biobank study showed higher adherence to the EAT-Lancet diet was associated with a reduced risk of metabolic dysfunction-associated steatotic liver disease (MASLD). We identified a unique metabolite signature comprising 81 metabolites associated with the EAT-Lancet diet, potentially underlying the diet's protective mechanism against MASLD. These findings suggest the EAT-Lancet diet may offer substantial protective benefits against MASLD.
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Affiliation(s)
- Hanzhang Wu
- Department of Big Data in Health Science, Zhejiang University School of Public Health, Hangzhou, China. Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Hangzhou, China
| | - Jiahe Wei
- Department of Big Data in Health Science, Zhejiang University School of Public Health, Hangzhou, China. Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Hangzhou, China
| | - Shuai Wang
- Department of Big Data in Health Science, Zhejiang University School of Public Health, Hangzhou, China. Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Hangzhou, China
| | - Liangkai Chen
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jihui Zhang
- Center for Sleep and Circadian Medicine, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China; Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Ningjian Wang
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao Tan
- Department of Big Data in Health Science, Zhejiang University School of Public Health, Hangzhou, China. Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Hangzhou, China
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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4
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Tinkov AA, Korobeinikova TV, Morozova GD, Aschner M, Mak DV, Santamaria A, Rocha JBT, Sotnikova TI, Tazina SI, Skalny AV. Association between serum trace element, mineral, and amino acid levels with non-alcoholic fatty liver disease (NAFLD) in adult women. J Trace Elem Med Biol 2024; 83:127397. [PMID: 38290269 DOI: 10.1016/j.jtemb.2024.127397] [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: 11/30/2023] [Revised: 12/29/2023] [Accepted: 01/13/2024] [Indexed: 02/01/2024]
Abstract
The objective of the present study is assessment of serum trace element and amino acid levels in non-alcoholic fatty liver disease (NAFLD) patients with subsequent evaluation of its independent associations with markers of liver injury and metabolic risk. MATERIALS AND METHODS 140 women aged 20-90 years old with diagnosed NAFLD and 140 healthy women with a respective age range were enrolled in the current study. Analysis of serum and hair levels of trace elements and minerals was performed with inductively-coupled plasma mass-spectrometry (ICP-MS). Serum amino acid concentrations were evaluated by high-pressure liquid chromatography (HPLC) with UV-detection. In addition, routine biochemical parameters including liver damage markers, alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT), were assessed spectrophotometrically. RESULTS The findings demonstrated that patients with NAFLD were characterized by higher ALT, GGT, lactate dehydrogenase (LDH) and cholinesterase (CE) activity, as well as increased levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and uric acid. NAFLD patients were characterized by reduced serum and hair Co, Se, and Zn levels, as well as hair Cu content and serum Mn concentrations in comparison to controls. Circulating Ala, Cit, Glu, Gly, Ile, Leu, Phe, and Tyr levels in NAFLD patients exceeded those in the control group. Multiple linear regression demonstrated that serum and hair trace element levels were significantly associated with circulating amino acid levels after adjustment for age, BMI, and metabolic parameters including liver damage markers. CONCLUSION It is proposed that altered trace element handling may contribute to NAFLD pathogenesis through modulation of amino acid metabolism.
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Affiliation(s)
- Alexey A Tinkov
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University, 150003 Yaroslavl, Russia; Department of Medical Elementology, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia.
| | - Tatiana V Korobeinikova
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; Department of Medical Elementology, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia
| | - Galina D Morozova
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, 10461 Bronx, NY, USA
| | - Daria V Mak
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia
| | - Abel Santamaria
- Faculty of Sciencies, National Autonomous University of Mexico, 04510 Mexico City, Mexico
| | - Joao B T Rocha
- Departamento de Bioquímica e Biologia Molecular, CCNE, Universidade Federal de Santa Maria, Santa Maria 97105-900 RS, Brazil
| | - Tatiana I Sotnikova
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; City Clinical Hospital n. a. S.P. Botkin of the Moscow City Health Department, 125284 Moscow, Russia
| | - Serafima Ia Tazina
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; City Clinical Hospital n. a. S.P. Botkin of the Moscow City Health Department, 125284 Moscow, Russia
| | - Anatoly V Skalny
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University, 150003 Yaroslavl, Russia; Department of Medical Elementology, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia
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Tain YL, Hsu CN. Amino Acids during Pregnancy and Offspring Cardiovascular-Kidney-Metabolic Health. Nutrients 2024; 16:1263. [PMID: 38732510 PMCID: PMC11085482 DOI: 10.3390/nu16091263] [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: 04/19/2024] [Accepted: 04/22/2024] [Indexed: 05/13/2024] Open
Abstract
Amino acids are essential for normal pregnancy and fetal development. Disruptions in maternal amino acid metabolism have been associated with various adult diseases later in life, a phenomenon referred to as the developmental origins of health and disease (DOHaD). In this review, we examine the recent evidence highlighting the significant impact of amino acids on fetal programming, their influence on the modulation of gut microbiota, and their repercussions on offspring outcomes, particularly in the context of cardiovascular-kidney-metabolic (CKM) syndrome. Furthermore, we delve into experimental studies that have unveiled the protective effects of therapies targeting amino acids. These interventions have demonstrated the potential to reprogram traits associated with CKM in offspring. The discussion encompasses the challenges of translating the findings from animal studies to clinical applications, emphasizing the complexity of this process. Additionally, we propose potential solutions to overcome these challenges. Ultimately, as we move forward, future research endeavors should aim to pinpoint the most effective amino-acid-targeted therapies, determining the optimal dosage and mode of administration. This exploration is essential for maximizing the reprogramming effects, ultimately contributing to the enhancement of cardiovascular-kidney-metabolic health in offspring.
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Affiliation(s)
- You-Lin Tain
- Division of Pediatric Nephrology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan;
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Chien-Ning Hsu
- Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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Yuan Y, Zhang Y, Lu X, Li J, Wang M, Zhang W, Zheng M, Sun Z, Xing Y, Li Y, Qu Y, Jiao Y, Han H, Xie C, Mao T. Novel insights into macrophage immunometabolism in nonalcoholic steatohepatitis. Int Immunopharmacol 2024; 131:111833. [PMID: 38503012 DOI: 10.1016/j.intimp.2024.111833] [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: 01/07/2024] [Revised: 02/29/2024] [Accepted: 03/07/2024] [Indexed: 03/21/2024]
Abstract
Nonalcoholic steatohepatitis (NASH), an inflammatory subtype of nonalcoholic fatty liver disease (NAFLD), is characterized by liver steatosis, inflammation, hepatocellular injury and different degrees of fibrosis, and has been becoming the leading cause of liver-related morbidity and mortality worldwide. Unfortunately, the pathogenesis of NASH has not been completely clarified, and there are no approved therapeutic drugs. Recent accumulated evidences have revealed the involvement of macrophage in the regulation of host liver steatosis, inflammation and fibrosis, and different phenotypes of macrophages have different metabolic characteristics. Therefore, targeted regulation of macrophage immunometabolism may contribute to the treatment and prognosis of NASH. In this review, we summarized the current evidences of the role of macrophage immunometabolism in NASH, especially focused on the related function conversion, as well as the strategies to promote its polarization balance in the liver, and hold promise for macrophage immunometabolism-targeted therapies in the treatment of NASH.
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Affiliation(s)
- Yali Yuan
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, PR China
| | - Ye Zhang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, PR China
| | - Xinyu Lu
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, PR China
| | - Junxiang Li
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, PR China
| | - Muyuan Wang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, PR China
| | - Wenji Zhang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, PR China
| | | | | | - Yunqi Xing
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, PR China
| | - Yitong Li
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, PR China
| | - Yingdi Qu
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, PR China
| | - Yao Jiao
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, PR China
| | - Haixiao Han
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, PR China.
| | - Chune Xie
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, PR China; Shenzhen Bao'an Traditional Chinese Medicine Hospital, Shenzhen, PR China.
| | - Tangyou Mao
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, PR China.
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7
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Zou J, Song Q, Shaw PC, Zuo Z. Dendrobium officinale regulate lipid metabolism in diabetic mouse liver via PPAR-RXR signaling pathway: Evidence from an integrated multi-omics analysis. Biomed Pharmacother 2024; 173:116395. [PMID: 38460364 DOI: 10.1016/j.biopha.2024.116395] [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: 12/28/2023] [Revised: 03/04/2024] [Accepted: 03/06/2024] [Indexed: 03/11/2024] Open
Abstract
Dendrobium officinale (DEN) is recognized as a kind of functional food that can effectively ameliorate endocrine and metabolic disruptions. This study delved into the pharmacological mechanism of DEN on hepatic lipotoxicity associated with Type II diabetes mellitus (T2DM). In vivo study experiments on db/db mice indicated that DEN treatment notably enhanced liver function, decreased blood lipid levels, and improved insulin sensitivity. Non-targeted metabolomics analysis revealed that DEN significantly ameliorated metabolism pathways, including lipoic acid, linoleic acid, bile secretion, and the alanine/aspartate/glutamate metabolism, as well as taurine and hypotaurine metabolism. Transcriptomics analysis demonstrated DEN treatment could modulate the expression of genes such as Cpt1b, Scd1, G6pc2, Fos, Adrb2, Atp2a1, Ppp1r1b, and Cyp7a1. Furthermore, Proteomics analysis indicated that the beneficial effect of DEN on lipid metabolism was linked to pathways like AMPK and PPAR signaling. The integrative analysis of multi-omics revealed that the PPAR-RXR signaling was critical to the therapeutic effect of DEN on T2DM-induced fatty liver. Additionally, in vitro study on AML-12 cells confirmed that DEN counteract PA-induced lipid accumulation by activating the PPAR-RXR pathway. Overall, these findings suggested that DEN exhibited the potential to mitigate T2DM-induced hepatic lipo-toxicity and manage lipid imbalances in T2DM.
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Affiliation(s)
- Junju Zou
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China; Hunan University of Chinese Medicine, The Hunan University of Chinese Medicine, PR China
| | - Qianbo Song
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China
| | - Pang Chui Shaw
- Li Dak Sum Yip Yio Chin R&D Center for Chinese Medicine and School of Life Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China
| | - Zhong Zuo
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China.
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Zhou X, Zhang J, Sun Y, Shen J, Sun B, Ma Q. Glutamine Ameliorates Liver Steatosis via Regulation of Glycolipid Metabolism and Gut Microbiota in High-Fat Diet-Induced Obese Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:15656-15667. [PMID: 37847053 DOI: 10.1021/acs.jafc.3c05566] [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: 10/18/2023]
Abstract
Obesity and its associated conditions, such as nonalcoholic fatty liver disease (NAFLD), are risk factors for health. The aim of this study was to explore the effects of glutamine (Gln) on liver steatosis induced by a high-fat diet (HFD) and HEPG2 cells induced by oleic acid. Gln demonstrated a positive influence on hepatic homeostasis by suppressing acetyl CoA carboxylase (ACC) and fatty acid synthase (FAS) and promoting sirtuin 1 (SIRT1) expression while improving glucose metabolism by regulating serine/threonine protein kinase (AKT)/factor forkhead box O1 (FOXO1) signals in vivo and in vitro. Obese Gln-fed mice had higher colonic short-chain fatty acid (SCFA) contents and lower inflammation factor protein levels in the liver, HEPG2 cells, and jejunum. Gln-treated obese mice had an effective decrease in Firmicutes abundance. These findings indicate that Gln serves as a nutritional tool in managing obesity and related disorders.
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Affiliation(s)
- Xinbo Zhou
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Junjie Zhang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Yutong Sun
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Jian Shen
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Bo Sun
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Qingquan Ma
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
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Mansouri RA, Ahmed AM, Alshaibi HF, Al-Bazi MM, Banjabi AA, Alsufiani HM, Aloqbi AA, Aboubakr EM. A new cirrhotic animal protocol combining carbon tetrachloride with methotrexate to address limitations of the currently used chemical-induced models. Front Pharmacol 2023; 14:1201583. [PMID: 37397479 PMCID: PMC10308223 DOI: 10.3389/fphar.2023.1201583] [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: 04/06/2023] [Accepted: 05/31/2023] [Indexed: 07/04/2023] Open
Abstract
Background: Chemically induced cirrhotic animal models are commonly used. However, they have limitations such as high mortalities and low yield of cirrhotic animals that limit their uses. Aims: To overcome limitations of the chemically induced cirrhotic animal model via combined administration of methotrexate (MTX) with CCl4 and decrease their commonly used doses depending on the proposed synergetic cirrhotic effect. Methods: Rats were divided into six groups: normal (4 weeks), normal (8 weeks), MTX, CCl4 (4 weeks), CCl4 (8 weeks), and MTX + CCl4 (4 weeks) groups. Animals' hepatic morphology and histopathological characterization were explored. Hepatic Bcl2 and NF-κB-p65 tissue contents were determined using the immunostaining technique, and hepatic tissue damage, oxidative status, and inflammatory status biochemical parameters were determined. Results: CCl4 + MTX combined administration produced prominent cirrhotic liver changes, further confirmed by a substantial increase in oxidative stress and inflammatory parameters, whereas mortalities were significantly lower than in other treated groups. Conclusion: The present study introduced a new model that can significantly improve the major limitations of chemically induced cirrhotic animal models with new pathological features that mimic human cirrhosis. Compared to other chemically induced methods, the present model can save time, cost, and animal suffering.
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Affiliation(s)
- Rasha A. Mansouri
- Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Adel M. Ahmed
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, South Valley University, Qena, Egypt
| | - Huda F. Alshaibi
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Embryonic Stem Cell Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Maha M. Al-Bazi
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Abeer A. Banjabi
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hadeil Muhanna Alsufiani
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Akram Ahmed Aloqbi
- Department of Biology, Faculty of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Esam M. Aboubakr
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, South Valley University, Qena, Egypt
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10
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Nasri M, Adibhesami G, Mahdavifard S, Babaeenezhad E, Ahmadvand H. Exogenous glutamine ameliorates diabetic nephropathy in a rat model of type 2 diabetes mellitus through its antioxidant and anti-inflammatory activities. Arch Physiol Biochem 2023; 129:363-372. [PMID: 33021829 DOI: 10.1080/13813455.2020.1828478] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
This study aimed to evaluate the effects of glutamine (Gln) on diabetic nephropathy and other complications in a rat model of type 2 diabetes mellitus. Streptozotocin/nicotinamide induced diabetic rats were enrolled as an animal model of type 2 diabetes mellitus. Animals were divided into control, diabetic, and Gln (1000 mg/l in drinking water, eight weeks) treated diabetic groups. Gln alleviated renal inflammatory and oxidative stress biomarkers (tumour necrosis factor-alpha, interleukin 6, glutathione peroxidase, total superoxide dismutase, and glutathione), decreased serum uric acid and creatinine, and restored renal histopathological changes (glomerular volume, sclerosis, and leukocyte infiltration). Additionally, Gln ameliorated other complications, including systemic oxidative stress (serum malondialdehyde and nitric oxide, serum and liver glutathione, glutathione peroxidase, and total superoxide dismutase, and liver catalase), insulin resistance, hyperglycaemia, and hyperlipidaemia. Collectively, Gln attenuates diabetic nephropathy and other complications in type 2 diabetes mellitus in rats through its antioxidant and anti-inflammatory activities.
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Affiliation(s)
- Maryam Nasri
- Razi Herbal Medicine Research Center, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
- Department of Biochemistry and Genetics, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Glavizh Adibhesami
- Department of Biochemistry and Genetics, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Sina Mahdavifard
- Department of Clinical Biochemistry, Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Esmaeel Babaeenezhad
- Department of Biochemistry, School of Medicine, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hassan Ahmadvand
- Razi Herbal Medicine Research Center, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
- Department of Biochemistry and Genetics, Lorestan University of Medical Sciences, Khorramabad, Iran
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Abstract
The epidemic of obesity, type 2 diabetes and nonalcoholic liver disease (NAFLD) favors drug consumption, which augments the risk of adverse events including liver injury. For more than 30 years, a series of experimental and clinical investigations reported or suggested that the common pain reliever acetaminophen (APAP) could be more hepatotoxic in obesity and related metabolic diseases, at least after an overdose. Nonetheless, several investigations did not reproduce these data. This discrepancy might come from the extent of obesity and steatosis, accumulation of specific lipid species, mitochondrial dysfunction and diabetes-related parameters such as ketonemia and hyperglycemia. Among these factors, some of them seem pivotal for the induction of cytochrome P450 2E1 (CYP2E1), which favors the conversion of APAP to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). In contrast, other factors might explain why obesity and NAFLD are not always associated with more frequent or more severe APAP-induced acute hepatotoxicity, such as increased volume of distribution in the body, higher hepatic glucuronidation and reduced CYP3A4 activity. Accordingly, the occurrence and outcome of APAP-induced liver injury in an obese individual with NAFLD would depend on a delicate balance between metabolic factors that augment the generation of NAPQI and others that can mitigate hepatotoxicity.
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Zhu M, Wang X, Wang K, Zhao Z, Dang Y, Ji G, Li F, Zhou W. Lingguizhugan decoction improves non-alcoholic steatohepatitis partially by modulating gut microbiota and correlated metabolites. Front Cell Infect Microbiol 2023; 13:1066053. [PMID: 36779187 PMCID: PMC9908757 DOI: 10.3389/fcimb.2023.1066053] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 01/12/2023] [Indexed: 01/27/2023] Open
Abstract
Background Lingguizhugan decoction is a traditional Chinese medicine prescription that has been used to improve non-alcoholic fatty liver disease and its progressive form, non-alcoholic steatohepatitis (NASH). However, the anti-NASH effects and underlying mechanisms of Lingguizhugan decoction remain unclear. Methods Male Sprague-Dawley rats were fed a methionine- and choline-deficient (MCD) diet to induce NASH, and then given Lingguizhugan decoction orally for four weeks. NASH indexes were evaluated by histopathological analysis and biochemical parameters including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver triglycerides (TG), etc. Fecal samples of rats were subjected to profile the changes of gut microbiota and metabolites using 16S rRNA sequencing and ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS). Bioinformatics was used to identify Lingguizhugan decoction reversed candidates, and Spearman's correlation analysis was performed to uncover the relationship among gut microbiota, fecal metabolites, and NASH indexes. Results Four-week Lingguizhugan decoction treatment ameliorated MCD diet-induced NASH features, as evidenced by improved hepatic steatosis and inflammation, as well as decreased serum AST and ALT levels. Besides, Lingguizhugan decoction partially restored the changes in gut microbial community composition in NASH rats. Meanwhile, the relative abundance of 26 genera was significantly changed in NASH rats, and 11 genera (such as odoribacter, Ruminococcus_1, Ruminococcaceae_UCG-004, etc.) were identified as significantly reversed by Lingguizhugan decoction. Additionally, a total of 99 metabolites were significantly altered in NASH rats, and 57 metabolites (such as TDCA, Glutamic acid, Isocaproic acid, etc.) enriched in different pathways were reversed by Lingguizhugan decoction. Furthermore, Spearman's correlation analyses revealed that most of the 57 metabolites were significantly correlated with 11 genera and NASH indexes. Conclusion Lingguizhugan decoction may exert protective effects on NASH partially by modulating gut microbiota and correlated metabolites.
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Affiliation(s)
- Mingzhe Zhu
- Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xue Wang
- Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Kai Wang
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhiqiang Zhao
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yanqi Dang
- Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guang Ji
- Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fenghua Li
- Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenjun Zhou
- Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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13
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Mahdavifard S, Sekhavatmand N. Glutamine Is a Superior Protector Against Lead-Induced Hepatotoxicity in Rats via Antioxidant, Anti-inflammatory, and Chelating Properties. Biol Trace Elem Res 2022; 200:4726-4732. [PMID: 35478087 DOI: 10.1007/s12011-021-03046-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 11/22/2021] [Indexed: 11/29/2022]
Abstract
Lead acetate-motivated oxidative stress can affect all organ systems, particularly the liver. Glutamine (Gln) has both antioxidant and chelating properties. Therefore, we investigated for the first time the effect of Gln on the biochemical and histopathological alternations in a rat model of lead toxicity. Thirty-two rats were divided into four groups (eight rats in each): untreated normal, lead poisoning, and two similar groups receiving Gln (0.1% in drinking water for 4 weeks). To induce lead poisoning, rats received 50 mg/L lead acetate in drinking water for 4 weeks. Oxidative stress indices (total glutathione, the ratio of reduced glutathione to oxidized glutathione, advanced protein oxidation products, malondialdehyde, and ferric ion reducing power) and inflammatory markers (hepatic nuclear factor-kβ expression, interleukin 1β level, and myeloperoxidase activity) were measured. Furthermore, biochemical markers of hepatotoxicity (alanine transaminase, aspartate transaminase, alkaline phosphatase, gamma-glutamyl transpeptidase, total bilirubin, total protein, albumin, and globulins) were measured. Histopathological examination evaluated lead-induced liver damage. The treatment compensated lead-induced biochemical and histopathological alternations in rat liver. Furthermore, it decreased lead acetate level, the NF-kβ gene expression, oxidative stress, and inflammatory markers. Moreover, the treatment elevated total glutathione and reduced glutathione in the sera and liver homogenates of treated groups (p < 0.001). Glutamine could protect the liver against lead intoxication via antioxidant, anti-inflammatory, and chelating properties. In addition, its downregulating effect on the hepatic NF-kβ signaling pathway confirms its hepatoprotective activity.
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Affiliation(s)
- Sina Mahdavifard
- Department of Clinical Biochemistry, Ardabil University of Medical Sciences, P.O. Box, 56189-85991, Ardabil, Iran.
| | - Negar Sekhavatmand
- Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
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14
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He Y, Song Z, Ji Y, Tso P, Wu Z. Preventive Effects of l-Glutamine on High-Fat Diet-Induced Metabolic Disorders Linking with Regulation of Intestinal Barrier Integrity, Hepatic Lipid Metabolism, and Gut Microbiota in Rats. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:11923-11934. [PMID: 36122193 DOI: 10.1021/acs.jafc.2c01975] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
The present study was conducted to investigate the effects of l-glutamine (Gln) on a high-fat diet (HFD)-induced lipid metabolic abnormality and explore its possible mechanisms. The results demonstrated that Gln administration reduced body weight, improved serum lipids, and decreased glucose tolerance in HFD-fed rats. Meanwhile, Gln administration alleviated liver injury, reduced the hepatic inflammatory response by inhibiting NLRP3 inflammasome activation, and decreased hepatic lipid accumulation by promoting VLDL secretion and fatty acid β-oxidation, as well as reduced bile acid synthesis by activating hepatic and ileal FXR in HFD-fed rats. Moreover, Gln administration restored HFD-induced intestinal barrier dysfunction, promoted intestinal fat absorption, suppressed intestinal inflammation, and also reshaped the gut microbiota composition in HFD-fed rats by downregulating the abundance of potential pathogens Escherichia-Shigella and upregulating the abundance of beneficial bacteria such as Akkermansia. To conclude, the present results showed that Gln may be a potential option for preventing HFD-induced metabolic disorders via the gut-liver axis.
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Affiliation(s)
- Yu He
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing 100193, China
| | - Zhuan Song
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing 100193, China
| | - Yun Ji
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing 100193, China
| | - Patrick Tso
- Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, 2120 E. Galbraith Road, Building A, Cincinnati, Ohio 45237, United States
| | - Zhenlong Wu
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing 100193, China
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing 100193, China
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15
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da Purificação NRC, Garcia VB, Frez FCV, Sehaber CC, Lima KRDA, de Oliveira Lima MF, de Carvalho Vasconcelos R, de Araujo AA, de Araújo Júnior RF, Lacchini S, de Oliveira F, Perles JVCM, Zanoni JN, de Sousa Lopes MLD, Clebis NK. Combined use of systemic quercetin, glutamine and alpha-tocopherol attenuates myocardial fibrosis in diabetic rats. Biomed Pharmacother 2022; 151:113131. [PMID: 35643067 DOI: 10.1016/j.biopha.2022.113131] [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: 03/23/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 11/02/2022] Open
Abstract
This study aimed to analyze the effects of the quercetin (100 mg/kg), 1% glutamine and 1% α-tocopherol antioxidants in the myocardium of rats with streptozotocin-induced diabetes mellitus. Twenty male rats were subdivided into four groups (n = 5): N (normoglycemic); D (diabetic); NT (normoglycemic treated with antioxidants); and DT (diabetic treated with antioxidants) treated for 60 days. Clinical parameters, oxidative stress markers, inflammatory cytokines, myocardial collagen fibers and immunoexpression of superoxide dismutase 1 (SOD-1), glutathione peroxidase-1 (GPx-1), interleukin-1β (IL-1-β), transforming growth factor-beta (TGF-β), and fibroblast growth factor-2 (FGF-2) were evaluated. Results showed reduced body weight, hyperphagia, polydipsia and hyperglycemic state in groups D and DT. The levels of glutathione (GSH) were higher in NT and DT compared to N (p < 0.01) and D (p < 0.001) groups, respectively. Greater GSH levels were found in DT when compared to N animals (p < 0.001). In DT, there was an increase in IL-10 in relation to N, D and NT (p < 0.05), while GPx-1 expression was similar to N and lower compared to D (p < 0.001). TGF-β expression in DT was greater than N (p < 0.001) group, whereas FGF-2 in DT was higher than in the other groups (p < 0.001). A significant reduction in collagen fibers (type I) was found in DT compared to D (p < 0.05). The associated administration of quercetin, glutamine and α-tocopherol increased the levels of circulating interleukin-10 (IL-10) and GSH, and reduced the number of type I collagen fibers. Combined use of systemic quercetin, glutamine and alpha-tocopherol attenuates myocardial fibrosis in diabetic rats.
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Affiliation(s)
| | | | | | | | - Kaio Ramon De Aguiar Lima
- Postgraduate Program in Functional & Structural Biology, Departament of Morphology, UFRN, Natal, RN, Brazil
| | | | | | - Aurigena Antunes de Araujo
- Postgraduate Program in Pharmaceutical Sciences, Postgraduate Program in Dental Sciences, Department of Pharmacology and Biophysical, UFRN, Natal, RN, Brazil.
| | - Raimundo Fernandes de Araújo Júnior
- Postgraduate Program in Health Sciences, Postgraduate Program in Functional & Structural Biology, Departament of Morphology, UFRN, Natal, RN, Brazil
| | - Silvia Lacchini
- Postgraduate Program in Morphology Science, Departamento of Anatomy, São Paulo University, São Paulo, SP, Brazil
| | - Flávia de Oliveira
- Departament of Biocience, Federal University of São Paulo (UNIFESP), Santos, SP, Brazil
| | | | | | | | - Naianne Kelly Clebis
- Postgraduate Program in Functional & Structural Biology, Departament of Morphology, UFRN, Natal, RN, Brazil
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16
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Shen M, Pan H, Ke J, Zhao F. NF-κB-upregulated miR-155-5p promotes hepatocyte mitochondrial dysfunction to accelerate the development of nonalcoholic fatty liver disease through downregulation of STC1. J Biochem Mol Toxicol 2022; 36:e23025. [PMID: 35603999 DOI: 10.1002/jbt.23025] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 01/07/2022] [Indexed: 12/30/2022]
Abstract
Previous studies have highlighted the involvement of nuclear factor kappa B (NF-κB) in the development of nonalcoholic fatty liver disease (NAFLD). The purpose of our investigation is to explore the interaction among NF-κB, microRNA-155-5p (miR-155-5p), and Stanniocalcin 1 (STC1), and its effects on NAFLD by establishing a NAFLD model in Sprague Dawley rats. A highly-expressed miR-155-5p and NF-κB was revealed in the liver tissues of NAFLD rats, and a positive correlation was identified between miR-155-5p and NF-κB. Next, the expression of NF-κB and STC1 was altered in the modeled rats through lentivirus injection, followed by determination on the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol, triglycerides, and low-density lipoprotein cholesterol. Furthermore, the hepatocyte mitochondria were separated to measure the activities of adenosine triphosphate (ATP), reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and mitochondrial respiratory chain complex, and to observe the number, length and ultrastructural length of mitochondrial cristae. The results demonstrated that NF-κB overexpression induced mitochondrial dysfunction, increased ROS level, decreased ATP and MMP contents, as well as inhibited the number and length of mitochondrial cristae in the hepatocyte mitochondria of NAFLD rats. Besides, miR-155-5p was found to negatively regulate STC1 expression based on dual luciferase reporter gene assay, which exert inhibition on mitochondrial activity of hepatocytes in NAFLD rats. These results uncover the possible involvement of NF-κB/miR-155-5p/STC1 axis in NAFLD progression, that NF-κB could increase miR-155-5p expression to inhibit STC1 expression, thus inducing hepatic mitochondrial dysfunction and promoting the occurrence and development of NAFLD.
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Affiliation(s)
- Miao Shen
- Health Management Center, Department of Gastroenterology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310000, Zhejiang, China
| | - Hanghai Pan
- Health Management Center, Department of Gastroenterology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310000, Zhejiang, China
| | - Jinjing Ke
- Health Management Center, Department of Gastroenterology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310000, Zhejiang, China
| | - Fei Zhao
- Health Management Center, Department of Gastroenterology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310000, Zhejiang, China
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17
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Jin W, Cho S, Laxi N, Bao T, Dai L, Yu H, Qi R, Zhang J, Ba G, Fu M. Hepatoprotective Effects of Ixeris chinensis on Nonalcoholic Fatty Liver Disease Induced by High-Fat Diet in Mice: An Integrated Gut Microbiota and Metabolomic Analysis. Molecules 2022; 27:molecules27103148. [PMID: 35630624 PMCID: PMC9147883 DOI: 10.3390/molecules27103148] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/05/2022] [Accepted: 05/13/2022] [Indexed: 12/10/2022] Open
Abstract
Ixeris chinensis (Thunb.) Nakai (IC) is a folk medicinal herb used in Mongolian medical clinics for the treatment of hepatitis and fatty liver diseases even though its pharmacological mechanism has not been well characterized. This study investigated the hepatoprotective mechanism of IC on mice with nonalcoholic fatty liver disease (NAFLD) by integrating gut microbiota and metabolomic analysis. A high-fat diet (HFD) was used to develop nonalcoholic fatty liver disease, after which the mice were treated with oral IC (0.5, 1.5 and 3.0 g/kg) for 10 weeks. HFD induced NAFLD and the therapeutic effects were characterized by pathological and histological evaluations, and the serum indicators were analyzed by ELISA. The gut microbial and metabolite profiles were studied by 16S rRNA sequencing and untargeted metabolomic analysis, respectively. The results showed that the administration of IC resulted in significant decreases in body weight; liver index; serum biomarkers such as ALT, TG, and LDL-C; and the liver inflammatory factors IL-1β, IL-6, and TNF-α. The 16S rRNA sequencing results showed that administration of IC extract altered both the composition and abundance of the gut microbiota. Untargeted metabolomic analysis of liver samples detected a total of 212 metabolites, of which 128 were differentially expressed between the HFD and IC group. IC was found to significantly alter the levels of metabolites such as L-glutamic acid, pyridoxal, ornithine, L-aspartic acid, D-proline, and N4-acetylaminobutanal, which are involved in the regulation of glutamine and glutamate, Vitamin B6 metabolism, and arginine and proline metabolic pathways. Correlation analysis indicated that the effects of the IC extract on metabolites were associated with alterations in the abundance of Akkermansiaceae, Lachnospiraceae, and Muribaculaceae. Our study revealed that IC has a potential hepatoprotective effect in NAFLD and that its function might be linked to improvements in the composition of gut microbiota and their metabolites.
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Affiliation(s)
- Wenjie Jin
- NMPA Key Laboratory of Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China; (W.J.); (S.C.); (N.L.); (T.B.); (L.D.); (H.Y.); (R.Q.)
| | - Sungbo Cho
- NMPA Key Laboratory of Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China; (W.J.); (S.C.); (N.L.); (T.B.); (L.D.); (H.Y.); (R.Q.)
| | - Namujila Laxi
- NMPA Key Laboratory of Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China; (W.J.); (S.C.); (N.L.); (T.B.); (L.D.); (H.Y.); (R.Q.)
| | - Terigele Bao
- NMPA Key Laboratory of Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China; (W.J.); (S.C.); (N.L.); (T.B.); (L.D.); (H.Y.); (R.Q.)
| | - Lili Dai
- NMPA Key Laboratory of Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China; (W.J.); (S.C.); (N.L.); (T.B.); (L.D.); (H.Y.); (R.Q.)
| | - Hongzhen Yu
- NMPA Key Laboratory of Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China; (W.J.); (S.C.); (N.L.); (T.B.); (L.D.); (H.Y.); (R.Q.)
| | - Rigeer Qi
- NMPA Key Laboratory of Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China; (W.J.); (S.C.); (N.L.); (T.B.); (L.D.); (H.Y.); (R.Q.)
| | - Junqing Zhang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, Haikou 571199, China;
| | - Genna Ba
- NMPA Key Laboratory of Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China; (W.J.); (S.C.); (N.L.); (T.B.); (L.D.); (H.Y.); (R.Q.)
- Correspondence: (G.B.); (M.F.)
| | - Minghai Fu
- NMPA Key Laboratory of Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China; (W.J.); (S.C.); (N.L.); (T.B.); (L.D.); (H.Y.); (R.Q.)
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, Haikou 571199, China;
- Correspondence: (G.B.); (M.F.)
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18
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Dong YW, Jiang WD, Wu P, Liu Y, Kuang SY, Tang L, Tang WN, Zhou XQ, Feng L. Novel Insight Into Nutritional Regulation in Enhancement of Immune Status and Mediation of Inflammation Dynamics Integrated Study In Vivo and In Vitro of Teleost Grass Carp ( Ctenopharyngodon idella): Administration of Threonine. Front Immunol 2022; 13:770969. [PMID: 35359991 PMCID: PMC8963965 DOI: 10.3389/fimmu.2022.770969] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 02/09/2022] [Indexed: 12/02/2022] Open
Abstract
This study aims to investigate the effects of threonine (Thr) on immunoregulation in vivo and in vitro of teleost grass carp (Ctenopharyngodon idella). Juveniles (9.53 ± 0.02 g) were reared for 8 weeks with respective Thr diet (3.99, 7.70, 10.72, 14.10, 17.96, and 21.66 g/kg) and then challenged with Aeromonas hydrophila for in vivo study. Macrophages isolated from head kidney were treated in vitro for 48 h with L-Thr (0, 0.5, 1.0, 2.0, 4.0, and 8.0 mM) after 6 h of lipopolysaccharide induction. The results showed that, compared with Thr deficiency (3.99 g/kg), the optimal dietary Thr (14.10g/kg) affected the immunocyte activation in the head kidney (HK) and spleen (SP) by downregulating the mRNA expressions of MHC-II and upregulating CD4 (not CD8), and it mediated the innate immune by enhancing the activities of lysozyme (LZ), acid phosphatase content of complement 3 (C3) and C4, increasing the mRNA abundances of hepcidin, liver expressed antimicrobial peptide-2A (LEAP-2A), LEAP-2B, β-defensin1, downregulating tumor necrosis factor α (TNF-α), IL-6, IL-1β, IL-12p35, IL-12p40, IL-17AF1, and IL-17D partly by attenuating RORγ1 transcriptional factor and nuclear factor kappa B p65 (NF-κBp65) signaling cascades [IKKβ/IκBα/NF-κBp65] and upregulating transforming growth factor β1 (TGF-β1), IL-4/13A, -4/13B, IL-10, and IL-22 partly by GATA-3. Besides these, the optimal dietary Thr regulated the adaptive immune by upregulating the mRNAs of immunoglobulin M (IgM) and IgZ (not IgD). Moreover, 2 mM Thr downregulated in vitro the mRNA abundances of colony stimulating factor-1, inducible nitric oxide synthase, mannose receptor 1, matrix metalloproteinase2 (MMP-2), and MMP-9 significantly (P < 0.05), indicating that Thr could attenuate the M1-type macrophages’ activation. Moreover, L-Thr downregulated the mRNA transcripts of TNF-α, IL-6, and IL-1β associated with impairing the SOCS1/STAT1 signaling and upregulated IL-10 and TGF-β1 partly by accentuating the SOCS3/STAT3 pathway. The above-mentioned observations suggested that Thr improved the immune status in the immune organs of fish by enhancing the immune defense and mediating the inflammation process. Finally, based on the immune indices of LZ activity in HK and C3 content in SP, the optimal Thr for immune enhancement in juvenile grass carp (9.53–53.43 g) was determined to be 15.70 g/kg diet (4.85 g/100 g protein) and 14.49 g/kg diet (4.47 g/100 g protein), respectively.
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Affiliation(s)
- Yu-Wen Dong
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Wei-Dan Jiang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Pei Wu
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Yang Liu
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Sheng-Yao Kuang
- Animal Nutrition Institute, Sichuan Academy of Animal Science, Chengdu, China
| | - Ling Tang
- Animal Nutrition Institute, Sichuan Academy of Animal Science, Chengdu, China
| | - Wu-Neng Tang
- Animal Nutrition Institute, Sichuan Academy of Animal Science, Chengdu, China
| | - Xiao-Qiu Zhou
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Lin Feng
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China
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19
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Delgado TC, de las Heras J, Martínez-Chantar ML. Understanding gut-liver axis nitrogen metabolism in Fatty Liver Disease. Front Endocrinol (Lausanne) 2022; 13:1058101. [PMID: 36589817 PMCID: PMC9797658 DOI: 10.3389/fendo.2022.1058101] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 11/21/2022] [Indexed: 12/23/2022] Open
Abstract
The homeostasis of the most important nitrogen-containing intermediates, ammonia and glutamine, is a tightly regulated process in which the gut-liver axis plays a central role. Several studies revealed that nitrogen metabolism is altered in Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD), a consensus-driven novel nomenclature for Non-Alcoholic Fatty Liver Disease (NAFLD), the most common chronic liver disease worldwide. Both increased ammonia production by gut microbiota and decreased ammonia hepatic removal due to impaired hepatic urea cycle activity or disrupted glutamine synthetase activity may contribute to hepatic ammonia accumulation underlying steatosis, which can eventually progress to hyperammonemia in more advanced stages of steatohepatitis and overt liver fibrosis. Furthermore, our group recently showed that augmented hepatic ammoniagenesis via increased glutaminase activity and overexpression of the high activity glutaminase 1 isoenzyme occurs in Fatty Liver Disease. Overall, the improved knowledge of disrupted nitrogen metabolism and metabolic miscommunication between the gut and the liver suggests that the reestablishment of altered gut-liver axis nitrogenous balance is an appealing and attractive therapeutic approach to tackle Fatty Liver Disease, a growing and unmet health problem.
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Affiliation(s)
- Teresa C. Delgado
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Bizkaia, Spain
- Congenital Metabolic Disorders, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- *Correspondence: Teresa C. Delgado,
| | - Javier de las Heras
- Congenital Metabolic Disorders, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Division of Pediatric Metabolism, Department of Pediatrics, CIBERer, Cruces University Hospital, Barakaldo, Spain
- Department of Pediatrics, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - María L. Martínez-Chantar
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Bizkaia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain
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Zhao YH, Zhang SW, Zhao HJ, Qin HY, Wu F, Zhang J, Zhang YQ, Liu XL, Liang S, Zhang H, Wu JD, Zhao ZY, Wang HZ, Shao M, Liu J, Dong JT, Zhang WJ. Gadolinium chloride pre-treatment reduces the inflammatory response and preserves intestinal barrier function in a rat model of sepsis. Exp Ther Med 2021; 22:1143. [PMID: 34504589 PMCID: PMC8393272 DOI: 10.3892/etm.2021.10577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 10/09/2019] [Indexed: 11/12/2022] Open
Abstract
The inflammatory response is closely associated with sepsis occurrence and progression. Damage to the function of the intestinal mucosal barrier is considered to be the ῾initiation factor᾿ for the development of multiple organ dysfunction syndrome, which is the most severe progression of sepsis. The aim of the present study was to investigate whether gadolinium chloride (GdCl3) could alleviate the systemic inflammatory response and protect the function of the intestinal mucosal barrier in a rat model of sepsis. The mechanism underlying this protective effect was also explored. Sprague-Dawley rats were divided into four groups: Sham, sham + GdCl3, cecal ligation and puncture (CLP; a model of sepsis) and CLP + GdCl3. In each group, blood was collected from the abdominal aorta, and intestinal tissue was collected after 6, 12 and 24 h of successful modeling. Levels of tumor necrosis factor-α, interleukin (IL)-6 and IL-1β were determined using ELISA. Western blot analysis was used to determine levels of occludin, tight junction protein ZO-1 (ZO-1), myosin light chain kinase 3 (MLCK), NF-κB and caspase-3 in intestinal tissues. Hematoxylin-eosin staining was used to observe the degree of damage to intestinal tissue. The results indicated that in CLP sepsis model rats treated with GdCl3, the release of systemic and intestinal pro-inflammatory factors was reduced and tissue damage was alleviated when compared with untreated CLP rats. Additionally, the expression of occludin and ZO-1 was increased, while that of NF-κB, MLCK, and caspase-3 was reduced in the CLP + GdCl3 rats compared with the CLP rats. GdCl3 may alleviate systemic and intestinal inflammatory responses and reduce the expression of MLCK through inhibition of the activation of NF-kB. The results of the present study also indicated that GdCl3 promoted the expression of occludin and ZO-1. GdCl3 was also demonstrated to reduce cell apoptosis through the inhibition of caspase-3 expression.
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Affiliation(s)
- Yan Heng Zhao
- Department of Critical Care Medicine, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, P.R. China
| | - Shun Wen Zhang
- Department of Thoracic Surgery, The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Hai Jun Zhao
- Department of Critical Care Medicine, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, P.R. China
| | - Hui Yuan Qin
- Department of Thoracic Surgery, The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Fang Wu
- Department of Pathophysiology, Shihezi University School of Medicine, The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi, Xinjiang 832002, P.R. China
| | - Jie Zhang
- Department of Critical Care Medicine, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, P.R. China
| | - Yu Qing Zhang
- Department of Critical Care Medicine, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, P.R. China
| | - Xiao Ling Liu
- Department of Pathophysiology, Shihezi University School of Medicine, The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi, Xinjiang 832002, P.R. China
| | - Su Liang
- Department of Critical Care Medicine, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, P.R. China
| | - Hui Zhang
- Department of Pathophysiology, Shihezi University School of Medicine, The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi, Xinjiang 832002, P.R. China
| | - Jiang Dong Wu
- Department of Pathophysiology, Shihezi University School of Medicine, The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi, Xinjiang 832002, P.R. China
| | - Zheng Yong Zhao
- Department of Pathophysiology, Shihezi University School of Medicine, The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi, Xinjiang 832002, P.R. China
| | - Hong Zhou Wang
- Department of Pathophysiology, Shihezi University School of Medicine, The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi, Xinjiang 832002, P.R. China
| | - Meng Shao
- Department of Pathophysiology, Shihezi University School of Medicine, The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi, Xinjiang 832002, P.R. China
| | - Jing Liu
- Department of Pathophysiology, Shihezi University School of Medicine, The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi, Xinjiang 832002, P.R. China
| | - Jiang Tao Dong
- Department of Critical Care Medicine, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, P.R. China
| | - Wan Jiang Zhang
- Department of Pathophysiology, Shihezi University School of Medicine, The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi, Xinjiang 832002, P.R. China
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Vairetti M, Di Pasqua LG, Cagna M, Richelmi P, Ferrigno A, Berardo C. Changes in Glutathione Content in Liver Diseases: An Update. Antioxidants (Basel) 2021; 10:364. [PMID: 33670839 PMCID: PMC7997318 DOI: 10.3390/antiox10030364] [Citation(s) in RCA: 130] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 02/22/2021] [Accepted: 02/24/2021] [Indexed: 02/07/2023] Open
Abstract
Glutathione (GSH), a tripeptide particularly concentrated in the liver, is the most important thiol reducing agent involved in the modulation of redox processes. It has also been demonstrated that GSH cannot be considered only as a mere free radical scavenger but that it takes part in the network governing the choice between survival, necrosis and apoptosis as well as in altering the function of signal transduction and transcription factor molecules. The purpose of the present review is to provide an overview on the molecular biology of the GSH system; therefore, GSH synthesis, metabolism and regulation will be reviewed. The multiple GSH functions will be described, as well as the importance of GSH compartmentalization into distinct subcellular pools and inter-organ transfer. Furthermore, we will highlight the close relationship existing between GSH content and the pathogenesis of liver disease, such as non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), chronic cholestatic injury, ischemia/reperfusion damage, hepatitis C virus (HCV), hepatitis B virus (HBV) and hepatocellular carcinoma. Finally, the potential therapeutic benefits of GSH and GSH-related medications, will be described for each liver disorder taken into account.
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Affiliation(s)
| | - Laura Giuseppina Di Pasqua
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (M.V.); (M.C.); (P.R.); (C.B.)
| | | | | | - Andrea Ferrigno
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (M.V.); (M.C.); (P.R.); (C.B.)
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22
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Jia R, Cao LP, Du JL, He Q, Gu ZY, Jeney G, Xu P, Yin GJ. Effects of high-fat diet on antioxidative status, apoptosis and inflammation in liver of tilapia (Oreochromis niloticus) via Nrf2, TLRs and JNK pathways. FISH & SHELLFISH IMMUNOLOGY 2020; 104:391-401. [PMID: 32553566 DOI: 10.1016/j.fsi.2020.06.025] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 06/09/2020] [Accepted: 06/12/2020] [Indexed: 06/11/2023]
Abstract
Fatty liver injury (or disease) is a common disease in farmed fish, but its pathogenic mechanism is not fully understood. Therefore the present study aims to investigate high-fat diet (HFD)-induced liver injury and explore the underlying mechanism in fish. The tilapia were fed on control diet and HFD for 90 days, and then the blood and liver tissues were collected to determine biochemical parameter, gene expression and protein level. The results showed that HFD feeding signally increased the levels of plasma aminotransferases and pro-inflammatory factors after 60 days. In liver and plasma, HFD feeding significantly suppressed antioxidant ability, but enhanced lipid peroxidation formation, protein oxidation and DNA damage after 60 or 90 days. Further, the Nrf2 pathway and antioxidative function-related genes were adversely changed in liver of HFD-fed tilapia after 60 and/or 90 days. Meanwhile, HFD treatment induced apoptosis via initiating mitochondrial pathway in liver after 90 days. Furthermore, after 90 days of feeding, the expression of genes or proteins related to JNK pathway and TLRs-Myd88-NF-κB pathway was clearly upregulated in HFD treatment. Similarly, the mRNA levels of inflammatory factors including tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8 and IL-10 were also upregulated in liver of HFD-fed tilapia after 60 and/or 90 days. In conclusion, the current study suggested that HFD feeding impaired antioxidant defense system, induced apoptosis, enhanced inflammation and led to liver injury. The adverse influences of HFD in the liver might be due to the variation of Nrf2, JNK and TLRs-Myd88-NF-κB signaling pathways.
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Affiliation(s)
- Rui Jia
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China; International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China.
| | - Li-Ping Cao
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China; International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Jin-Liang Du
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China; International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Qin He
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Zheng-Yan Gu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Galina Jeney
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China; National Agricultural Research Center, Research Institute for Fisheries and Aquaculture, Anna Light 8, Szarvas, 5440, Hungary
| | - Pao Xu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China; International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China.
| | - Guo-Jun Yin
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China; International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China.
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Qiu S, Zhang AH, Guan Y, Sun H, Zhang TL, Han Y, Yan GL, Wang XJ. Functional metabolomics using UPLC-Q/TOF-MS combined with ingenuity pathway analysis as a promising strategy for evaluating the efficacy and discovering amino acid metabolism as a potential therapeutic mechanism-related target for geniposide against alcoholic liver disease. RSC Adv 2020; 10:2677-2690. [PMID: 35496090 PMCID: PMC9048633 DOI: 10.1039/c9ra09305b] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 12/03/2019] [Indexed: 12/13/2022] Open
Abstract
Metabolomics has been used as a strategy to evaluate the efficacy of and potential targets for natural products.
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Affiliation(s)
- Shi Qiu
- National Chinmedomics Research Center
- Sino-America Chinmedomics Technology Collaboration Center
- National TCM Key Laboratory of Serum Pharmacochemistry
- Metabolomics Laboratory
- Department of Pharmaceutical Analysis
| | - Ai-hua Zhang
- National Chinmedomics Research Center
- Sino-America Chinmedomics Technology Collaboration Center
- National TCM Key Laboratory of Serum Pharmacochemistry
- Metabolomics Laboratory
- Department of Pharmaceutical Analysis
| | - Yu Guan
- National Chinmedomics Research Center
- Sino-America Chinmedomics Technology Collaboration Center
- National TCM Key Laboratory of Serum Pharmacochemistry
- Metabolomics Laboratory
- Department of Pharmaceutical Analysis
| | - Hui Sun
- National Chinmedomics Research Center
- Sino-America Chinmedomics Technology Collaboration Center
- National TCM Key Laboratory of Serum Pharmacochemistry
- Metabolomics Laboratory
- Department of Pharmaceutical Analysis
| | - Tian-lei Zhang
- National Chinmedomics Research Center
- Sino-America Chinmedomics Technology Collaboration Center
- National TCM Key Laboratory of Serum Pharmacochemistry
- Metabolomics Laboratory
- Department of Pharmaceutical Analysis
| | - Ying Han
- National Chinmedomics Research Center
- Sino-America Chinmedomics Technology Collaboration Center
- National TCM Key Laboratory of Serum Pharmacochemistry
- Metabolomics Laboratory
- Department of Pharmaceutical Analysis
| | - Guang-li Yan
- National Chinmedomics Research Center
- Sino-America Chinmedomics Technology Collaboration Center
- National TCM Key Laboratory of Serum Pharmacochemistry
- Metabolomics Laboratory
- Department of Pharmaceutical Analysis
| | - Xi-jun Wang
- National Chinmedomics Research Center
- Sino-America Chinmedomics Technology Collaboration Center
- National TCM Key Laboratory of Serum Pharmacochemistry
- Metabolomics Laboratory
- Department of Pharmaceutical Analysis
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Olaniyi KS, Amusa OA, Oniyide AA, Ajadi IO, Akinnagbe NT, Babatunde SS. Protective role of glutamine against cadmium-induced testicular dysfunction in Wistar rats: Involvement of G6PD activity. Life Sci 2019; 242:117250. [PMID: 31899225 DOI: 10.1016/j.lfs.2019.117250] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/14/2019] [Accepted: 12/29/2019] [Indexed: 01/28/2023]
Abstract
BACKGROUND Endocrine disruptor such as cadmium has been widely reported to cause testicular toxicity, which contributes to recent decline in male fertility worldwide. Glutamine, the most abundant amino acid in the body has been demonstrated to exert protective effects in cellular toxicity. However, its role in testicular toxicity is unknown. The present study is therefore aimed at investigating the effects of glutamine supplementation on cadmium-induced testicular toxicity, and the possible involvement of glucose-6-phosphate dehydrogenase (G6PD) activity. MATERIALS AND METHOD Male Wistar rats weighing 160-190 g were allotted into 4 groups (n = 5/group): The groups received vehicle (distilled water; p.o.), glutamine (1gkg-1; p.o.), cadmium chloride (5mgkg-1p.o.) and Cadmium chloride plus glutamine respectively, daily for 30 days. Biochemical and histological analyses were performed with appropriate method. RESULTS Administration of cadmium significantly decreased body weight, sperm count, motility and viability, as well as altered sperm morphology and progressivity. Cadmium also caused atrophy of the seminiferous tubule in addition to disrupted testicular architecture, lumen, Sertoli cells and spermatogonia. Similarly, serum and testicular aspartate transaminase, and malondialdehyde significantly increased, and G6PD, glutathione, nicotinamide adenine dinucleotide phosphate and nitric oxide significantly decreased with corresponding decrease in follicle stimulating hormone, luteinizing hormone and testosterone in cadmium-treated animals compared with control groups. However, supplementation with glutamine attenuated these alterations. CONCLUSION The present study demonstrates that cadmium induces testicular dysfunction that is attributable to defective G6PD and accompanied by increased lipid peroxidation and impaired NO-dependent endothelial function. Interestingly, glutamine supplementation ameliorates cadmium-induced testicular dysfunction through enhancement of G6PD activity.
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Affiliation(s)
- Kehinde S Olaniyi
- Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria; School of Laboratory Medicine & Medical Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Private Bag X54001, Congella 4013, Westville, Durban, South Africa; Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria.
| | - Oluwatobi A Amusa
- Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria
| | - Adesola A Oniyide
- Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria
| | - Isaac O Ajadi
- Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria; School of Laboratory Medicine & Medical Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Private Bag X54001, Congella 4013, Westville, Durban, South Africa
| | - Nifesimi T Akinnagbe
- Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria
| | - Salam S Babatunde
- Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
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Nemati A, Alipanah-Moghadam R, Molazadeh L, Naghizadeh Baghi A. The Effect of Glutamine Supplementation on Oxidative Stress and Matrix Metalloproteinase 2 and 9 After Exhaustive Exercise. DRUG DESIGN DEVELOPMENT AND THERAPY 2019; 13:4215-4223. [PMID: 31849453 PMCID: PMC6912001 DOI: 10.2147/dddt.s218606] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 12/04/2019] [Indexed: 12/14/2022]
Abstract
Background Glutamine is the most abundant amino acid in plasma and skeletal muscles and an important fuel for immune system cells. It has beneficial anti-inflammatory and antioxidant properties which may be considered as a potentially useful supplement for athletes. The present study was conducted to investigate the effect of glutamine supplementation on oxidative stress and matrix metalloproteinase 2 and 9 after exhaustive exercise in young healthy males. Materials and methods In this study, 30 healthy males (supplement =15 and control=15) were randomly assigned into two groups. The supplement group received 0.3 g/kg BW of glutamine along with 25 gr of sugar dissolved in 250 cc water per day. The control group received 25 gr of sugar in 250 cc water per day. Fasting blood samples were taken at baseline and at the end of 14 days of intervention. The participants underwent exercise until experiencing full-body exhaustive fatigue for 16 ± 2.84 mins, and then fasting blood samples were taken. Serum levels of TAC, MDA, MMP2, MMP9, glutathione, and hs-CRP were measured. Results Serum levels of MDA and hs-CRP significantly decreased in the supplement group (p< 0.05). The serum level of TAC significantly increased in the supplement group (p< 0.05). Glutathione serum levels significantly increased after exhaustive exercise (p< 0.05). Serum levels of MMP2 and MMP9 remained unchanged. Conclusion Results of this study showed that, some biochemical factors are time-dependent and can increase or decrease over time, as well as, serum levels of hs-CRP and MDA decreased with glutamine supplementation along with the increase in the TAC serum levels, but this supplementation had no effect on serum levels of MMP2 and MMP9 in exhaustive exercise.
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Affiliation(s)
- Ali Nemati
- Ardabil University of Medical Sciences, School of Medicine, Department of Clinical Biochemistry, Ardabil, Iran
| | - Reza Alipanah-Moghadam
- Ardabil University of Medical Sciences, School of Medicine, Department of Clinical Biochemistry, Ardabil, Iran
| | - Leila Molazadeh
- Ardabil University of Medical Sciences, School of Medicine, Department of Clinical Biochemistry, Ardabil, Iran
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Engel MMS, Kusumastuty I, Anita KW, Handayani D. The Effect of High Fat High Fructose Diet (Modification of AIN-93M) on Nuclear Factor Kappa Beta Expression in the Liver Tissue of Male Sprague Dawley Rats. ACTA ACUST UNITED AC 2019. [DOI: 10.1088/1742-6596/1374/1/012042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Abstract
Metabolic inflammation (low-grade inflammation) remains an etiopathogenic key factor in the development of metabolic syndrome. Nuclear Factor Kappa Beta (NF-κβ) is a transcription regulator of genes having a role in immunity, the inflammatory response which can be associated with obesity-related pathological conditions like nonalcoholic fatty liver (NAFLD). Various stimuli, such as metabolic stress (hyperglycemia, ROS, fat metabolism) and proinflammatory cytokines (TNF-α, IL-6, IL-1β) could activate NF-κβ. This study was aimed to investigate the underlying molecular mechanisms of NAFLD in rats fed a modified AIN-93M HFHF (High Fat High Fructose) diet. The design of this study was experimental post-test only controlled group design. Thirty male Sprague Dawley rats were distributed into 2 treatment groups by a completely randomized design (CRD) technique. The sacrifice was performed after 17 weeks of treatment. NF-κβ expression was assessed by an immunohistochemical method (IRS score). The results showed there were significant differences in feed intake and energy intake between groups P1 and P2 (p = 0,000, p = 0,000). The average NF-κβ expression in the P2 group was significantly higher (p = 0.000) compared to the control group (P1). The correlation test between dietary intake and NF-κβ expression proved that there was a positive correlation between energy, carbohydrate and fat intake on NF-κβ expression (p = 0.001, 0.000, 0.046). However, there was a negative relationship between protein intake and NF-κβ expression (p = 0.000). This study concluded the modified AIN-93M HFHF diet increased NF-κβ expression in the liver tissue of male Sprague Dawley rats.
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Metabolomic Biomarkers in the Diagnosis of Non-Alcoholic Fatty Liver Disease. HEPATITIS MONTHLY 2019. [DOI: 10.5812/hepatmon.92244] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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Pitaloka DMIFA, Ko CH, Lin MT, Yeh SL, Yeh CL. Glutamine administration promotes hepatic glucose homeostasis through regulating the PI3K/Akt pathway in high-fat diet-induced obese mice with limb ischemia. Nutr Res 2019; 68:45-53. [DOI: 10.1016/j.nutres.2019.05.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 05/23/2019] [Accepted: 05/25/2019] [Indexed: 01/27/2023]
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Abboud KY, Reis SK, Martelli ME, Zordão OP, Tannihão F, de Souza AZZ, Assalin HB, Guadagnini D, Rocha GZ, Saad MJA, Prada PO. Oral Glutamine Supplementation Reduces Obesity, Pro-Inflammatory Markers, and Improves Insulin Sensitivity in DIO Wistar Rats and Reduces Waist Circumference in Overweight and Obese Humans. Nutrients 2019; 11:nu11030536. [PMID: 30832230 PMCID: PMC6471297 DOI: 10.3390/nu11030536] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 02/18/2019] [Accepted: 02/24/2019] [Indexed: 12/16/2022] Open
Abstract
In the present study, we aimed to investigate whether chronic oral glutamine (Gln) supplementation may alter metabolic parameters and the inflammatory profile in overweight and obese humans as well as whether Gln may modulate molecular pathways in key tissues linked to the insulin action in rats. Thirty-nine overweight/obese volunteers received 30 g of Gln or alanine (Ala-control) for 14 days. Body weight (BW), waist circumference (WC), hormones, and pro-inflammatory markers were evaluated. To investigate molecular mechanisms, Gln or Ala was given to Wistar rats on a high-fat diet (HFD), and metabolic parameters, euglycemic hyperinsulinemic clamp with tracers, and Western blot were done. Gln reduced WC and serum lipopolysaccharide (LPS) in overweight volunteers. In the obese group, Gln diminished WC and serum insulin. There was a positive correlation between the reduction on WC and LPS. In rats on HFD, Gln reduced adiposity, improved insulin action and signaling, and reversed both defects in glucose metabolism in the liver and muscle. Gln supplementation increased muscle glucose uptake and reversed the increased hepatic glucose production, in parallel with a reduced glucose uptake in adipose tissue. This insulin resistance in AT was accompanied by enhanced IRS1 O-linked-glycosamine association in this tissue, but not in the liver and muscle. These data suggest that Gln supplementation leads to insulin resistance specifically in adipose tissue via the hexosamine pathway and reduces adipose mass, which is associated with improvement in the systemic insulin action. Thus, further investigation with Gln supplementation should be performed for longer periods in humans before prescribing as a beneficial therapeutic approach for individuals who are overweight and obese.
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Affiliation(s)
- Kahlile Youssef Abboud
- School of Applied Sciences, State University of Campinas (UNICAMP), Limeira 13484-350 SP, Brazil.
| | - Sabrina Karen Reis
- School of Applied Sciences, State University of Campinas (UNICAMP), Limeira 13484-350 SP, Brazil.
| | - Maria Eduarda Martelli
- School of Applied Sciences, State University of Campinas (UNICAMP), Limeira 13484-350 SP, Brazil.
| | - Olivia Pizetta Zordão
- Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas 13083-887 SP, Brazil.
| | - Fabiana Tannihão
- School of Applied Sciences, State University of Campinas (UNICAMP), Limeira 13484-350 SP, Brazil.
| | | | - Heloisa Balan Assalin
- Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas 13083-887 SP, Brazil.
| | - Dioze Guadagnini
- Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas 13083-887 SP, Brazil.
| | - Guilherme Zweig Rocha
- Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas 13083-887 SP, Brazil.
| | - Mario Jose Abdalla Saad
- Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas 13083-887 SP, Brazil.
| | - Patricia Oliveira Prada
- School of Applied Sciences, State University of Campinas (UNICAMP), Limeira 13484-350 SP, Brazil.
- Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas 13083-887 SP, Brazil.
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Ding Y, Yanagi K, Cheng C, Alaniz RC, Lee K, Jayaraman A. Interactions between gut microbiota and non-alcoholic liver disease: The role of microbiota-derived metabolites. Pharmacol Res 2019; 141:521-529. [PMID: 30660825 PMCID: PMC6392453 DOI: 10.1016/j.phrs.2019.01.029] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 01/15/2019] [Accepted: 01/15/2019] [Indexed: 02/07/2023]
Abstract
There is increasing evidence that the intestinal microbiota plays a mechanistic role in the etiology of non-alcoholic fatty liver disease (NAFLD). Animal and human studies have linked small molecule metabolites produced by commensal bacteria in the gut contribute to not only intestinal inflammation, but also to hepatic inflammation. These immunomodulatory metabolites are capable of engaging host cellular receptors, and may mediate the observed association between gut dysbiosis and NAFLD. This review focuses on the effects and potential mechanisms of three specific classes of metabolites that synthesized or modified by gut bacteria: short chain fatty acids, amino acid catabolites, and bile acids. In particular, we discuss their role as ligands for cell surface and nuclear receptors regulating metabolic and inflammatory pathways in the intestine and liver. Studies reveal that the metabolites can both agonize and antagonize their cognate receptors to reduce or exacerbate liver steatosis and inflammation, and that the effects are metabolite- and context-specific. Further studies are warranted to more comprehensively understand bacterial metabolite-mediated gut-liver in NAFLD. This understanding could help identify novel therapeutics and therapeutic targets to intervene in the disease through the gut microbiota.
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Affiliation(s)
- Yufang Ding
- Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843, USA
| | - Karin Yanagi
- Department of Chemical and Biological Engineering, Tufts University, Medford, MA, 02155, USA
| | - Clint Cheng
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX, 77807, USA
| | - Robert C Alaniz
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX, 77807, USA
| | - Kyongbum Lee
- Department of Chemical and Biological Engineering, Tufts University, Medford, MA, 02155, USA.
| | - Arul Jayaraman
- Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843, USA; Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX, 77807, USA; Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, Texas, 77843, USA.
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Abstract
L-ornithine L-aspartate (LOLA) has been known as an effective ammonia-lowering agent for more than 50 years with good evidence in hepatic encephalopathy. Administration of LOLA removes ammonia via two distinct mechanisms: by synthesis of urea and by the synthesis of glutamine via the enzyme glutamine synthetase. While LOLA has been used in cirrhosis and acute liver injury settings, it is less clear if LOLA could be used in non-alcoholic fatty liver disease (NAFLD). NAFLD and the progressive form non-alcoholic steatohepatitis (NASH) are currently the leading causes of chronic liver disease worldwide, with roughly 25% of the world population affected by NAFLD. Consequences of NASH are end-stage liver disease and cardiovascular morbidity and mortality. As the basis for NAFLD is excess calorie uptake and excess adipose tissue mass, the conservative therapeutic approach is weight loss by intense lifestyle change. However, no pharmacological treatment options are currently approved. LOLA is being investigated as a pharmacological tool to ameliorate liver injury in NAFLD on the basis that it lowers liver ammonia concentrations and supplies anti-oxidative glutamine and glutathione. Indirect hepatoprotective effects currently under investigation could also be beneficial.
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Affiliation(s)
- Ali Canbay
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany.
| | - Jan-Peter Sowa
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany
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Cheng K, Song Z, Zhang H, Li S, Wang C, Zhang L, Wang T. The therapeutic effects of resveratrol on hepatic steatosis in high-fat diet-induced obese mice by improving oxidative stress, inflammation and lipid-related gene transcriptional expression. Med Mol Morphol 2019; 52:187-197. [PMID: 30673851 DOI: 10.1007/s00795-019-00216-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Accepted: 01/13/2019] [Indexed: 12/12/2022]
Abstract
So far, the majority of the previous animal studies have focused on the preventive effects of resveratrol (RSV) on non-alcoholic fatty liver disease (NAFLD) rather than the therapeutic effects. In this study, the therapeutic effects of RSV on hepatic oxidative stress (OS), inflammation, and lipid metabolism-related gene expression of obese mice induced by a high-fat diet (HFD) were investigated. Male C57BL/6 mice were fed a HFD for 8 weeks to induce obesity-related NAFLD model. And then, NAFLD mice were treated with daily RSV oral gavage at the dose of 100 mg/kg body weight for an additional 4 weeks. HFD-induced the elevation of serum total cholesterol, high-density lipoprotein cholesterol, glucose, insulin, aspartate aminotransferase and alanine aminotransferase levels, and homeostasis model assessment of insulin resistance, hepatic histology changes, the increases in hepatic triglyceride, malondialdehyde and tumor necrosis factor alpha concentrations, as well as the higher mRNA expression of hepatic toll-like receptor 4 and cluster of differentiation 36 in mice, were restored by RSV. The therapeutic effects of RSV against hepatic steatosis of HFD obese mice were attributed to the reduction of OS, inflammation and free fatty acid uptake.
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Affiliation(s)
- Kang Cheng
- College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang, Nanjing, 210095, China
| | - Zhihua Song
- College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang, Nanjing, 210095, China
- School of electrical and Electronic Engineering, Anhui Science and Technology University, No. 1501 Mount Huangshan Avenue, Bengbu, 233100, China
| | - Hao Zhang
- College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang, Nanjing, 210095, China
| | - Simian Li
- College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang, Nanjing, 210095, China
| | - Chao Wang
- College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang, Nanjing, 210095, China
| | - Lili Zhang
- College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang, Nanjing, 210095, China
| | - Tian Wang
- College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang, Nanjing, 210095, China.
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Biochemical and Physiological Parameters in Rats Fed with High-Fat Diet: The Protective Effect of Chronic Treatment with Purple Grape Juice (Bordo Variety). BEVERAGES 2018. [DOI: 10.3390/beverages4040100] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
High-fat-diet (HFD) has been related to metabolic and cardiovascular diseases. Consumption of grapes and their byproducts containing phenolic compounds has been reported due to the benefits they produce for human health. The purpose of this study was to investigate the antioxidant and protective effect of chronic intake of purple grape juice on certain biochemical and physiological changes promoted by the consumption of HFD. Forty male rats were randomly divided into four groups to receive standard or HFD diet and/or conventional (CGJ) or organic grape juice (OGJ) for three months. Dietary intake, body weight gain, cardiometabolic parameters, and serum lipoperoxidation were investigated. Results showed that consumption of CGJ and OGJ changed the pattern of food and drink intake of the animals. There was a reduction in the body weight of animals that consumed grape juices and an increase in the weight gain in HFD and OGJ rats. HFD increased abdominal fat and the abdominal fat/weight ratio, and both grape juices prevented these modifications. HFD increased hepatic enzymes levels (aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT)) and reduced urea. Purple grape juices prevented some of these changes. HFD enhanced lipid peroxidation (thiobarbituric acid reactive substances (TBARS)) in serum and CGJ and OGJ prevented this increase. The consumption of purple grape juice has the potential to prevent and ameliorate most of the alterations provoked by HFD, therefore regular intake of grape products could promote beneficial effects.
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Butterworth RF, Canbay A. Hepatoprotection by L-Ornithine L-Aspartate in Non-Alcoholic Fatty Liver Disease. Dig Dis 2018; 37:63-68. [PMID: 30016770 PMCID: PMC6390461 DOI: 10.1159/000491429] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 06/21/2018] [Indexed: 02/02/2023]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the leading chronic hepatic condition worldwide and new approaches to management and treatment are limited. SUMMARY L-ornithine L-aspartate (LOLA) has hepatoprotective properties in patients with fatty liver of diverse etiology and results of a multicenter randomized clinical trial reveal that 12 weeks treatment with oral LOLA (6-9 g/d) results in a dose-related reduction in activities of liver enzymes and triglycerides together with significant improvements of liver/spleen CT ratios. A preliminary report described improvements of hepatic microcirculation in patients with non-alcoholic steatohepatitis (NASH) following treatment with LOLA. Mechanisms responsible for the beneficial effects of LOLA in NAFLD/NASH involve, in addition to its established ammonia-lowering effect, metabolic transformations of the LOLA-constituent amino acids L-ornithine and L-aspartate into L-glutamine, L-arginine, and glutathione. These metabolites have well-established actions implicated in the prevention of lipid peroxidation, improvement of hepatic microcirculation in addition to anti-inflammatory, and anti-oxidant properties. Key Messages: (1) LOLA is effective for the treatment of key indices in NAFLD/NASH. (2) Mechanisms other than LOLA's ammonia-lowering action have been postulated. (3) Further assessments in the clinical setting are now required.
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Affiliation(s)
- Roger F. Butterworth
- University of Montreal (St-Luc Hospital), Montreal, Québec, Canada,*Roger F. Butterworth, PhD, DSc, University of Montreal (St-Luc Hospital), 45143 Cabot Trail, Englishtown, Nova Scotia, Montreal, QC B0C 1H0 (Canada), E-Mail
| | - Ali Canbay
- University of Magdeburg (University Hospital), Magdeburg, Germany
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Cruzat V, Macedo Rogero M, Noel Keane K, Curi R, Newsholme P. Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation. Nutrients 2018; 10:nu10111564. [PMID: 30360490 PMCID: PMC6266414 DOI: 10.3390/nu10111564] [Citation(s) in RCA: 632] [Impact Index Per Article: 90.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Revised: 10/13/2018] [Accepted: 10/16/2018] [Indexed: 02/07/2023] Open
Abstract
Glutamine is the most abundant and versatile amino acid in the body. In health and disease, the rate of glutamine consumption by immune cells is similar or greater than glucose. For instance, in vitro and in vivo studies have determined that glutamine is an essential nutrient for lymphocyte proliferation and cytokine production, macrophage phagocytic plus secretory activities, and neutrophil bacterial killing. Glutamine release to the circulation and availability is mainly controlled by key metabolic organs, such as the gut, liver, and skeletal muscles. During catabolic/hypercatabolic situations glutamine can become essential for metabolic function, but its availability may be compromised due to the impairment of homeostasis in the inter-tissue metabolism of amino acids. For this reason, glutamine is currently part of clinical nutrition supplementation protocols and/or recommended for immune suppressed individuals. However, in a wide range of catabolic/hypercatabolic situations (e.g., ill/critically ill, post-trauma, sepsis, exhausted athletes), it is currently difficult to determine whether glutamine supplementation (oral/enteral or parenteral) should be recommended based on the amino acid plasma/bloodstream concentration (also known as glutaminemia). Although the beneficial immune-based effects of glutamine supplementation are already established, many questions and evidence for positive in vivo outcomes still remain to be presented. Therefore, this paper provides an integrated review of how glutamine metabolism in key organs is important to cells of the immune system. We also discuss glutamine metabolism and action, and important issues related to the effects of glutamine supplementation in catabolic situations.
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Affiliation(s)
- Vinicius Cruzat
- School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences, Curtin University, Perth 6102, Australia.
- Faculty of Health, Torrens University, Melbourne 3065, Australia.
| | - Marcelo Macedo Rogero
- Department of Nutrition, Faculty of Public Health, University of São Paulo, Avenida Doutor Arnaldo 715, São Paulo 01246-904, Brazil.
| | - Kevin Noel Keane
- School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences, Curtin University, Perth 6102, Australia.
| | - Rui Curi
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil.
| | - Philip Newsholme
- School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences, Curtin University, Perth 6102, Australia.
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Cruzat V, Macedo Rogero M, Noel Keane K, Curi R, Newsholme P. Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation. Nutrients 2018. [PMID: 30360490 DOI: 10.20944/preprints201809.0459.v1] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Glutamine is the most abundant and versatile amino acid in the body. In health and disease, the rate of glutamine consumption by immune cells is similar or greater than glucose. For instance, in vitro and in vivo studies have determined that glutamine is an essential nutrient for lymphocyte proliferation and cytokine production, macrophage phagocytic plus secretory activities, and neutrophil bacterial killing. Glutamine release to the circulation and availability is mainly controlled by key metabolic organs, such as the gut, liver, and skeletal muscles. During catabolic/hypercatabolic situations glutamine can become essential for metabolic function, but its availability may be compromised due to the impairment of homeostasis in the inter-tissue metabolism of amino acids. For this reason, glutamine is currently part of clinical nutrition supplementation protocols and/or recommended for immune suppressed individuals. However, in a wide range of catabolic/hypercatabolic situations (e.g., ill/critically ill, post-trauma, sepsis, exhausted athletes), it is currently difficult to determine whether glutamine supplementation (oral/enteral or parenteral) should be recommended based on the amino acid plasma/bloodstream concentration (also known as glutaminemia). Although the beneficial immune-based effects of glutamine supplementation are already established, many questions and evidence for positive in vivo outcomes still remain to be presented. Therefore, this paper provides an integrated review of how glutamine metabolism in key organs is important to cells of the immune system. We also discuss glutamine metabolism and action, and important issues related to the effects of glutamine supplementation in catabolic situations.
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Affiliation(s)
- Vinicius Cruzat
- School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences, Curtin University, Perth 6102, Australia. .,Faculty of Health, Torrens University, Melbourne 3065, Australia.
| | - Marcelo Macedo Rogero
- Department of Nutrition, Faculty of Public Health, University of São Paulo, Avenida Doutor Arnaldo 715, São Paulo 01246-904, Brazil.
| | - Kevin Noel Keane
- School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences, Curtin University, Perth 6102, Australia.
| | - Rui Curi
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil.
| | - Philip Newsholme
- School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences, Curtin University, Perth 6102, Australia.
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Sellmann C, Baumann A, Brandt A, Jin CJ, Nier A, Bergheim I. Oral Supplementation of Glutamine Attenuates the Progression of Nonalcoholic Steatohepatitis in C57BL/6J Mice. J Nutr 2017; 147:2041-2049. [PMID: 28931589 DOI: 10.3945/jn.117.253815] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Revised: 06/22/2017] [Accepted: 08/17/2017] [Indexed: 11/14/2022] Open
Abstract
Background: Universally accepted therapeutic strategies for the treatment of nonalcoholic steatohepatitis (NASH) are still lacking. Studies suggest a preventive effect of oral Gln supplementation on the development of NASH; however, whether Gln also has therapeutic potential for pre-existing NASH has not yet been clarified.Objective: The aim of the present study was to determine whether Gln prevents the progression of diet-induced NASH in mice.Methods: For 8 wk, female C57BL/6J mice (6-8 wk old) were pair-fed a liquid Western-style diet [WSD, 25% of energy from fat, 50% wt:wt fructose, 0.16% wt:wt cholesterol] or control diet (C diet) to induce liver damage. From week 8 to 13, they were pair-fed the C diet or WSD alone or supplemented with l-Gln to provide 2.1 g/kg body weight (C diet + Gln or WSD + Gln). Energy intake was adjusted to the group with the lowest energy intake. Indexes of liver damage and inflammation, intestinal barrier function, and toll-like receptor 4 (Tlr4) signaling in the liver were determined.Results: The liver histology scores significantly increased from 8 to 13 wk (+31%) in WSD-fed mice and were significantly higher than in controls (P ≤ 0.05 for both time comparisons), whereas scores did not differ between C diet-fed and WSD + Gln-fed mice after 13 wk of feeding. The occludin protein concentrations in the small intestinal tissue were similarly reduced in both WSD-fed groups when compared with controls [WSD compared with C diet (-53%) and C diet + Gln (-42%), P ≤ 0.05; WSD + Gln compared with C diet + Gln (-34%), P ≤ 0.05] after 13 wk, whereas the expression of myeloid differentiation primary response gene 88 mRNA and concentration of inducible nitric oxide synthase and 4-hydroxynonenal protein adducts were significantly higher only in livers of WSD-fed mice (P ≤ 0.05 for the WSD group compared with all other groups; WSD + Gln group compared with the C diet groups: NS).Conclusion: Taken together, our data suggest that oral Gln supplementation protects mice from the progression of pre-existing, WSD-induced NASH.
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Affiliation(s)
- Cathrin Sellmann
- Institute of Nutritional Sciences, SD Model Systems of Molecular Nutrition, Friedrich-Schiller University Jena, Jena, Germany; and
| | - Anja Baumann
- Molecular Nutritional Science Division, Department of Nutritional Sciences, University of Vienna, Vienna, Austria
| | - Annette Brandt
- Molecular Nutritional Science Division, Department of Nutritional Sciences, University of Vienna, Vienna, Austria
| | - Cheng Jun Jin
- Institute of Nutritional Sciences, SD Model Systems of Molecular Nutrition, Friedrich-Schiller University Jena, Jena, Germany; and
| | - Anika Nier
- Molecular Nutritional Science Division, Department of Nutritional Sciences, University of Vienna, Vienna, Austria
| | - Ina Bergheim
- Institute of Nutritional Sciences, SD Model Systems of Molecular Nutrition, Friedrich-Schiller University Jena, Jena, Germany; and .,Molecular Nutritional Science Division, Department of Nutritional Sciences, University of Vienna, Vienna, Austria
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Mejía SÁ, Gutman LAB, Camarillo CO, Navarro RM, Becerra MCS, Santana LD, Cruz M, Pérez EH, Flores MD. Nicotinamide prevents sweet beverage-induced hepatic steatosis in rats by regulating the G6PD, NADPH/NADP + and GSH/GSSG ratios and reducing oxidative and inflammatory stress. Eur J Pharmacol 2017; 818:499-507. [PMID: 29069580 DOI: 10.1016/j.ejphar.2017.10.048] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 10/19/2017] [Accepted: 10/20/2017] [Indexed: 12/28/2022]
Abstract
The disruption of redox state homeostasis, the overexpression of lipogenic transcription factors and enzymes, and the increase in lipogenic precursors induced by sweetened beverages are determinants of the development of nonalcoholic fatty liver disease. This study evaluated the action of nicotinamide (NAM) on the expression of glucose-6-phosphate dehydrogenase (G6PD) and redox, oxidative, and inflammatory states in a model of nonalcoholic hepatic steatosis induced by high and chronic consumption of carbohydrates. Male rats were provided drinking water with 30% glucose or fructose ad libitum for 12 weeks. Additionally, 30 days after the beginning of carbohydrate administration, some rats were simultaneously provided water with 0.06% or 0.12% NAM for 5h daily over the next 8 weeks. Biochemical profiles and expression levels of G6PD, tumor necrosis factor α (TNFα), and NADPH oxidase 4 (NOX4) were evaluated together with glutathione/glutathione disulfide (GSH/GSSG) and reduced nicotinamide adenine dinucleotide (phosphate)/nicotinamide adenine dinucleotide (phosphate) [NAD(P)H/NAD(P)] ratios and thiobarbituric acid reactive substances (TBARS). The results showed that hepatic steatosis induced by the chronic consumption of glucose or fructose was associated with body weight gain and increased levels of serum glucose, insulin, triacylglycerols, free fatty acids, transaminases, and TBARS. In the liver, the expression and activity of G6PD increased along with the GSSG, TBARS, and TG concentrations. These alterations were reduced by NAM treatment through the attenuation of increases in G6PD expression and activity and in the NADPH/NADP+ ratio, thereby slowing liver steatosis. NAM prevents redox, oxidative, and inflammatory alterations induced by high carbohydrate consumption.
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Affiliation(s)
- Selene Ángeles Mejía
- División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana Unidad Iztapalapa, Ciudad de México, México; Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México; Universidad Autónoma Metropolitana Unidad Iztapalapa, Departamento de Ciencias de la Salud, Ciudad de México, México
| | - Luis Arturo Baiza Gutman
- Laboratorio en Biología del Desarrollo, Unidad de Morfología y Función, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Estado de México, México
| | - Clara Ortega Camarillo
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Rafael Medina Navarro
- Departamento de Metabolismo Experimental, Centro para la Investigación Biomédica de Michoacán (CIBIMI-IMSS), Michoacán, México
| | - Martha Catalina Sánchez Becerra
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Leticia Damasio Santana
- Unidad de Investigación Médica en Enfermedades Endocrinas, Hospital de Especialidades "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Miguel Cruz
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Elizabeth Hernández Pérez
- Universidad Autónoma Metropolitana Unidad Iztapalapa, Departamento de Ciencias de la Salud, Ciudad de México, México
| | - Margarita Díaz Flores
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México.
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姚 笑, 夏 凡, 唐 外, 周 本. [Effect of Hugan Qingzhi tablets on AMPK pathway activation and NF-κB-p65 protein expression in the liver of rats with nonalcoholic fatty liver disease]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2017; 37:56-62. [PMID: 28109099 PMCID: PMC6765763 DOI: 10.3969/j.issn.1673-4254.2017.01.10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Indexed: 06/06/2023]
Abstract
OBJECTIVE To investigate the effect of Hugan Qingzhi tablets on lipid metabolism and inflammation in rats fed on high-fat diet and explore the underlying mechanisms. METHODS Sixty male Sprague-Dawley rats were randomly divided into 6 groups, namely HFD group (with high-fat diet and distilled water), control group (with normal diet and distilled water), fenofibrate group (with high-fat diet and treatment with 0.1 g<kg fenofibrate suspension), and low-, moderate- and high-dose Hugan Qingzhi tablet groups (with high-fat diet and treatment with 0.54, 1.08, and 2.16 g<kg Hugan Qingzhi suspension). After daily corresponding treatments for 12 weeks, the histological changes in the liver were observed with HE staining. The serum levels of triglyceride (TG), cholesterol (CHOL), alanine transaminase (ALT), and aspartate aminotransferase (AST), and the levels of TG and CHOL in the hepatic tissue were assayed. The proinflammatory cytokines TNF-α, IL-6 and CRP were detected with enzyme-linked immunoassay, and p-AMPK, SREBP-1c, FASN and NF-αB-p65 expression levels in the liver were determined with qRT-PCR or Western blotting. RESULTS At high and moderate doses, Hugan Qingzhi effectively decreased the levels of ALT, AST, TG and CHOL levels in the serum, lowered the hepatic levels of TNF-α, IL-6 and CRP, enhanced p-AMPK, and reduced the expression of SREBP-1c, FASN and Ac-NF-αB-p65 in the liver of rats fed on high-fat diet. CONCLUSION Hugan Qingzhi tablets alleviates hyperlipidemia and inflammation in rats fed with high-fat diet possibly by activating AMPK pathway and suppress NF-αB activity to arrest the progression of nonalcoholic fatty liver disease.
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Affiliation(s)
- 笑睿 姚
- />南方医科大学珠江医院药学部，广东 广州 510282Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - 凡 夏
- />南方医科大学珠江医院药学部，广东 广州 510282Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - 外姣 唐
- />南方医科大学珠江医院药学部，广东 广州 510282Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - 本杰 周
- />南方医科大学珠江医院药学部，广东 广州 510282Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
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de Oliveira DC, da Silva Lima F, Sartori T, Santos ACA, Rogero MM, Fock RA. Glutamine metabolism and its effects on immune response: molecular mechanism and gene expression. ACTA ACUST UNITED AC 2016. [DOI: 10.1186/s41110-016-0016-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Irie M, Sohda T, Anan A, Fukunaga A, Takata K, Tanaka T, Yokoyama K, Morihara D, Takeyama Y, Shakado S, Sakisaka S. Reduced Glutathione suppresses Oxidative Stress in Nonalcoholic Fatty Liver Disease. Euroasian J Hepatogastroenterol 2016; 6:13-18. [PMID: 29201718 PMCID: PMC5578552 DOI: 10.5005/jp-journals-10018-1159] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 10/22/2015] [Indexed: 12/24/2022] Open
Abstract
Background and aims Insulin resistance and cytokine production are key mechanisms leading to fatty change in the liver and may produce nonalcoholic steatohepatitis (NASH). Oxidative stress may also contribute to clinical progression from simple fatty liver (FL) to NASH. A therapy for insulin resistance and antioxidant has been applied to treat NASH, yet these treatments are not fully established. In the present study, we have evaluated whether an antioxidant agent, glutathione, prevents the development of NASH from FL. Materials and methods Five patients with FL and 10 with NASH were enrolled in the study. Three hundred milligrams per day of glutathione was given orally to patients with nonalcoholic fatty liver disease (NAFLD) every day, and an oxidative stress marker and biochemical tests were analyzed before treatment and 1 and 3 months after starting the treatment. We measured serum levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) and gamma-glutamyltranspeptidase (GGT). Immunohistochemistry for glutathione was performed on formalin fixed liver specimens obtained from liver biopsies. Results Before treatment, the NASH group had higher serum 8-OHdG and lower serum glutathione levels than the FL group. Immunohistochemistry revealed that a strong expression of glutathione was observed in zone 3 in both NASH and FL before treatment. Serum levels of alanine transaminase and 8-OHdG were significantly decreased after treatment in the NASH group. Gamma-glutamyltranspeptidase was decreased after treatment, although the decrease was statistically not significant. Discussion The present pilot study demonstrated that antioxidant therapy with glutathione may reduce the pathological oxidative stress in the liver in NASH, preventing the progression from NAFLD to NASH. How to cite this article Irie M, Sohda T, Anan A, Fukunaga A, Takata K, Tanaka T, Yokoyama K, Morihara D, Takeyama Y, Shakado S, Sakisaka S. Reduced Glutathione suppresses Oxidative Stress in Nonalcoholic Fatty Liver Disease. Euroasian J Hepato-Gastroenterol 2016;6(1):13-18.
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Affiliation(s)
- Makoto Irie
- Department of Gastroenterology and Medicine, Fukuoka University, Faculty of Medicine, Fukuoka, Japan
| | - Tetsuro Sohda
- Department of Gastroenterology and Medicine, Fukuoka University, Faculty of Medicine, Fukuoka, Japan
| | - Akira Anan
- Department of Gastroenterology and Medicine, Fukuoka University, Faculty of Medicine, Fukuoka, Japan
| | - Atsushi Fukunaga
- Department of Gastroenterology and Medicine, Fukuoka University, Faculty of Medicine, Fukuoka, Japan
| | - Kazuhide Takata
- Department of Gastroenterology and Medicine, Fukuoka University, Faculty of Medicine, Fukuoka, Japan
| | - Takashi Tanaka
- Department of Gastroenterology and Medicine, Fukuoka University, Faculty of Medicine, Fukuoka, Japan
| | - Keiji Yokoyama
- Department of Gastroenterology and Medicine, Fukuoka University, Faculty of Medicine, Fukuoka, Japan
| | - Daisuke Morihara
- Department of Gastroenterology and Medicine, Fukuoka University, Faculty of Medicine, Fukuoka, Japan
| | - Yasuaki Takeyama
- Department of Gastroenterology and Medicine, Fukuoka University, Faculty of Medicine, Fukuoka, Japan
| | - Satoshi Shakado
- Department of Gastroenterology and Medicine, Fukuoka University, Faculty of Medicine, Fukuoka, Japan
| | - Shotaro Sakisaka
- Department of Gastroenterology and Medicine, Fukuoka University, Faculty of Medicine, Fukuoka, Japan
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Abruzzese GA, Heber MF, Ferreira SR, Velez LM, Reynoso R, Pignataro OP, Motta AB. Prenatal hyperandrogenism induces alterations that affect liver lipid metabolism. J Endocrinol 2016; 230:67-79. [PMID: 27179108 DOI: 10.1530/joe-15-0471] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 05/13/2016] [Indexed: 12/22/2022]
Abstract
Prenatal hyperandrogenism is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). PCOS patients have high risk of developing fatty liver and steatosis. This study aimed to evaluate the role of prenatal hyperandrogenism in liver lipid metabolism and fatty liver development. Pregnant rats were hyperandrogenized with testosterone. At pubertal age, the prenatally hyperandrogenized (PH) female offspring displayed both ovulatory (PHov) and anovulatory (PHanov) phenotypes that mimic human PCOS features. We evaluated hepatic transferases, liver lipid content, the balance between lipogenesis and fatty acid oxidation pathway, oxidant/antioxidant balance and proinflammatory status. We also evaluated the general metabolic status through growth rate curve, basal glucose and insulin levels, glucose tolerance test, HOMA-IR index and serum lipid profile. Although neither PH group showed signs of liver lipid content, the lipogenesis and fatty oxidation pathways were altered. The PH groups also showed impaired oxidant/antioxidant balance, a decrease in the proinflammatory pathway (measured by prostaglandin E2 and cyclooxygenase-2 levels), decreased glucose tolerance, imbalance of circulating lipids and increased risk of metabolic syndrome. We conclude that prenatal hyperandrogenism generates both PHov and PHanov phenotypes with signs of liver alterations, imbalance in lipid metabolism and increased risk of developing metabolic syndrome. The anovulatory phenotype showed more alterations in liver lipogenesis and a more impaired balance of insulin and glucose metabolism, being more susceptible to the development of steatosis.
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Affiliation(s)
- Giselle Adriana Abruzzese
- Laboratorio de Fisio-patología OváricaCentro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
| | - Maria Florencia Heber
- Laboratorio de Fisio-patología OváricaCentro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
| | - Silvana Rocio Ferreira
- Laboratorio de Fisio-patología OváricaCentro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
| | - Leandro Martin Velez
- Laboratorio de Fisio-patología OváricaCentro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
| | - Roxana Reynoso
- Laboratorio de EndocrinologíaDepartamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
| | - Omar Pedro Pignataro
- Laboratorio de Endocrinología Molecular y Transducción de SeñalesInstituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
| | - Alicia Beatriz Motta
- Laboratorio de Fisio-patología OváricaCentro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
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Barros MAP, Vasconcelos PRL, Souza CM, Andrade GM, Moraes MO, Costa PEG, Coelho GR, Garcia JHP. L-Alanyl-Glutamine Attenuates Oxidative Stress in Liver Transplantation Patients. Transplant Proc 2016; 47:2478-82. [PMID: 26518955 DOI: 10.1016/j.transproceed.2015.08.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 07/08/2015] [Accepted: 08/03/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Ischemia/reperfusion injury during liver transplantation can cause severe damage to the graft. The objective of this randomized, double-blind study was to evaluate the possible protective effects of L-alanyl-glutamine on the liver graft. METHODS The sample included 33 patients from a liver transplantation service in Northeastern Brazil. Before cold ischemia, the patients received 50 g of L-alanyl-glutamine (treatment group) or saline (control group) through the portal vein. The graft was biopsied at the time of recovery, at the beginning of warm ischemia, and at the end of transplantation to determine malondialdehyde (MDA), heat-shock protein (Hsp)70, nuclear factor kappa-beta (NFkB), superoxide dismutase (SOD), and reduced glutathione (GSH) levels. RESULTS The blood parameters were similar in the two groups. In the treatment group, MDA did not increase at the beginning of cold ischemia and decreased at the end of transplantation. This phenomenon was not observed in the control group. GSH, SOD, Hsp70, and NFkB levels were similar in the two groups. CONCLUSIONS Our findings suggest that preconditioning with L-alanyl-glutamine attenuates the effects of ischemia/reperfusion-related oxidative stress and reduces lipid peroxidation in the grafts of liver transplantation patients.
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Affiliation(s)
- M A P Barros
- Department of Surgery, HUWC (University Hospital), Universidade Federal do Ceará, Fortaleza, Ceará, Brazil.
| | - P R L Vasconcelos
- Department of Surgery, HUWC (University Hospital), Universidade Federal do Ceará, Fortaleza, Ceará, Brazil
| | - C M Souza
- Department of Physiology and Pharmacology, School of Medicine, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil
| | - G M Andrade
- Department of Physiology and Pharmacology, School of Medicine, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil
| | - M O Moraes
- Department of Physiology and Pharmacology, School of Medicine, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil
| | - P E G Costa
- Department of Surgery, HUWC (University Hospital), Universidade Federal do Ceará, Fortaleza, Ceará, Brazil
| | - G R Coelho
- Department of Surgery, HUWC (University Hospital), Universidade Federal do Ceará, Fortaleza, Ceará, Brazil
| | - J H P Garcia
- Department of Surgery, HUWC (University Hospital), Universidade Federal do Ceará, Fortaleza, Ceará, Brazil
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Tarantino G, Finelli C. Lipids, Low-Grade Chronic Inflammation and NAFLD. HANDBOOK OF LIPIDS IN HUMAN FUNCTION 2016:731-759. [DOI: 10.1016/b978-1-63067-036-8.00028-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Relevant Aspects of Nutritional and Dietary Interventions in Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2015; 16:25168-98. [PMID: 26512643 PMCID: PMC4632797 DOI: 10.3390/ijms161025168] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Revised: 09/29/2015] [Accepted: 10/14/2015] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the main cause of liver disease worldwide. NAFLD is linked to circumstances such as type 2 diabetes, insulin resistance, obesity, hyperlipidemia, and hypertension. Since the obesity figures and related comorbidities are increasing, NAFLD has turned into a liver problem that has become progressively more common. Currently, there is no effective drug therapy for NAFLD; therefore, interventions in lifestyles remain the first line of treatment. Bearing in mind that adherence rates to this type of treatment are poor, great efforts are currently focused on finding novel therapeutic agents for the prevention in the development of hepatic steatosis and its progression to nonalcoholic steatohepatitis and cirrhosis. This review presents a compilation of the scientific evidence found in the last years showing the results of interventions in lifestyle, diet, and behavioral therapies and research results in human, animal and cell models. Possible therapeutic agents ranging from supplementation with vitamins, amino acids, prebiotics, probiotics, symbiotics, polyunsaturated fatty acids and polyphenols to interventions with medicinal plants are analyzed.
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Sellmann C, Jin CJ, Degen C, De Bandt JP, Bergheim I. Oral Glutamine Supplementation Protects Female Mice from Nonalcoholic Steatohepatitis. J Nutr 2015; 145:2280-6. [PMID: 26246326 DOI: 10.3945/jn.115.215517] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 07/15/2015] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Genetic factors, a diet rich in fat and sugar, and an impaired intestinal barrier function are critical in the development of nonalcoholic steatohepatitis (NASH). The nonessential amino acid glutamine (Gln) has been suggested to have protective effects on intestinal barrier function but also against the development of liver diseases of various etiologies. OBJECTIVE The effect of oral Gln supplementation on the development of Western-style diet (WSD)-induced NASH in mice was assessed. METHODS Female 6- to 8-wk-old C57BL/6J mice were pair-fed a control (C) diet or a WSD alone or supplemented with 2.1 g l-Gln/kg body weight for 6 wk (C+Gln or WSD+Gln). Indexes of liver damage, lipid peroxidation, and glucose metabolism and endotoxin concentrations were measured. RESULTS Although Gln supplementation had no effect on the loss of the tight junction protein occludin, the increased portal endotoxin and fasting glucose concentrations found in WSD-fed mice, markers of liver damage (e.g., nonalcoholic fatty liver disease activity score and number of neutrophils in the liver) were significantly lower in the WSD+Gln group than in the WSD group (~47% and ~60% less, respectively; P < 0.05). Concentrations of inducible nitric oxide synthase (iNOS) protein and 3-nitrotyrosin protein adducts were significantly higher in livers of WSD-fed mice than in all other groups (~8.6- and ~1.9-fold higher, respectively, compared with the C group; P < 0.05) but did not differ between WSD+Gln-, C-, and C+Gln-fed mice. Hepatic tumor necrosis factor α and plasminogen activator inhibitor 1 concentrations were significantly higher in WSD-fed mice (~1.6- and ~1.8-fold higher, respectively; P < 0.05) but not in WSD+Gln-fed mice compared with C mice. CONCLUSION Our data suggest that the protective effects of oral Gln supplementation on the development of WSD-induced NASH in mice are associated with protection against the induction of iNOS and lipid peroxidation in the liver.
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Affiliation(s)
- Cathrin Sellmann
- Institute of Nutritional Sciences, SD Model Systems of Molecular Nutrition, Friedrich-Schiller University Jena, Jena, Germany
| | - Cheng Jun Jin
- Institute of Nutritional Sciences, SD Model Systems of Molecular Nutrition, Friedrich-Schiller University Jena, Jena, Germany
| | - Christian Degen
- Institute of Nutritional Sciences, SD Model Systems of Molecular Nutrition, Friedrich-Schiller University Jena, Jena, Germany
| | - Jean-Pascal De Bandt
- Nutrition Biology Laboratory EA4466, Faculty of Pharmacy, Paris Descartes University, Sorbonne Paris Cité, Paris, France; and Clinical Chemistry Department, Paris Center University Hospitals, Public Assistance Hospitals of Paris, Paris, France
| | - Ina Bergheim
- Institute of Nutritional Sciences, SD Model Systems of Molecular Nutrition, Friedrich-Schiller University Jena, Jena, Germany;
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Aydin M, Yildiz A, Ibiloglu I, Ekinci A, Ulger BV, Yuksel M, Bilik MZ, Ozaydogdu N, Ekinci C, Yazgan UC. The protective role of glutamine against acute induced toxicity in rats. Toxicol Mech Methods 2015; 25:296-301. [DOI: 10.3109/15376516.2015.1025349] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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Gündüz E, Ülger BV, İbiloğlu İ, Ekinci A, Dursun R, Zengin Y, İçer M, Uslukaya Ö, Ekinci C, Güloğlu C. Glutamine provides effective protection against deltamethrin-induced acute hepatotoxicity in rats but not against nephrotoxicity. Med Sci Monit 2015; 21:1107-14. [PMID: 25890620 PMCID: PMC4413811 DOI: 10.12659/msm.893180] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Background The aim of this study was to investigate the protective effects of L-glutamine (GLN) against liver and kidney injury caused by acute toxicity of deltamethrin (DLM). Material/Methods Thirty-two rats were indiscriminately separated into 4 groups with 8 rats each: control group (distilled water; 10 ml/kg, perorally [p.o.]), DLM group (35 mg/kg p.o. one dose.), GLN group (1.5 gr/kg, p.o. single dose.) and DLM (35 mg/kg p.o. one dose.) + GLN group (1.5 gr/kg, p.o. one dose after 4 hours.). Testing for total antioxidant status (TAS), total oxidant status (TOS), interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) analyses were performed on tissue samples, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), urea, and creatinine were analyzed on serum samples. Liver and kidney samples were histopathologically analyzed. Results The TOS level in liver was significantly higher in the DLM group than in the control group, and the level in DLM+GLN group was considerably lower than in the DLM group. The TAS level in the DLM+GLN group was considerably higher than in the control and DLM groups. The TAS level in kidney tissues was considerably lower in the DLM group than in controls, but was similar to other groups. Histopathological analyses of liver tissues established a significant difference between DLM and DLM+GLN groups in terms of grade 2 hepatic injury. However, no significant difference was found between DLM and DLM+GLN groups in terms of kidney injury. Conclusions Glutamine leads to significant improvement in deltamethrin-induced acute hepatotoxicity in terms of histopathologic results, tissue oxidative stress parameters, and serum liver function marker enzymes.
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Affiliation(s)
- Ercan Gündüz
- Department of Emergency Medicine, Faculty of Medicine, Dicle University, Diyarbakır, Turkey
| | - Burak Veli Ülger
- Department of General Surgery, Faculty of Medicine, Dicle University, Diyarbakır, Turkey
| | - İbrahim İbiloğlu
- Department of Pathology, Faculty of Medicine, Dicle University, Diyarbakır, Turkey
| | - Aysun Ekinci
- Department of Biochemistry, Faculty of Medicine, Dicle University, Diyarbakır, Turkey
| | - Recep Dursun
- Department of Emergency Medicine, Faculty of Medicine, Dicle University, Diyarbakır, Turkey
| | - Yılmaz Zengin
- Department of Emergency Medicine, Faculty of Medicine, Dicle University, Diyarbakır, Turkey
| | - Mustafa İçer
- Department of Emergency Medicine, Faculty of Medicine, Dicle University, Diyarbakır, Turkey
| | - Ömer Uslukaya
- Department of General Surgery, Faculty of Medicine, Dicle University, Diyarbakır, Turkey
| | - Cenap Ekinci
- Department of Histology, Faculty of Medicine, Dicle University, Diyarbakır, Turkey
| | - Cahfer Güloğlu
- Department of Emergency Medicine, Faculty of Medicine, Dicle University, Diyarbakır, Turkey
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Stojsavljević S, Gomerčić Palčić M, Virović Jukić L, Smirčić Duvnjak L, Duvnjak M. Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20:18070-18091. [PMID: 25561778 PMCID: PMC4277948 DOI: 10.3748/wjg.v20.i48.18070] [Citation(s) in RCA: 247] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 10/21/2014] [Accepted: 11/18/2014] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient with no history of alcohol abuse or other causes for secondary hepatic steatosis. The pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) has not been fully elucidated. The "two-hit" hypothesis is probably a too simplified model to elaborate complex pathogenetic events occurring in patients with NASH. It should be better regarded as a multiple step process, with accumulation of liver fat being the first step, followed by the development of necroinflammation and fibrosis. Adipose tissue, which has emerged as an endocrine organ with a key role in energy homeostasis, is responsive to both central and peripheral metabolic signals and is itself capable of secreting a number of proteins. These adipocyte-specific or enriched proteins, termed adipokines, have been shown to have a variety of local, peripheral, and central effects. In the current review, we explore the role of adipocytokines and proinflammatory cytokines in the pathogenesis of NAFLD. We particularly focus on adiponectin, leptin and ghrelin, with a brief mention of resistin, visfatin and retinol-binding protein 4 among adipokines, and tumor necrosis factor-α, interleukin (IL)-6, IL-1, and briefly IL-18 among proinflammatory cytokines. We update their role in NAFLD, as elucidated in experimental models and clinical practice.
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Zhou J, Fan S, Cao Y, Zhu M, Han Y, Cao X, Li Y. Tumor necrosis factor-α suppresses the protein fractional synthesis rate of the small intestine stimulated by glutamine in rats. Exp Ther Med 2014; 9:547-552. [PMID: 25574232 PMCID: PMC4280961 DOI: 10.3892/etm.2014.2129] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2014] [Accepted: 10/21/2014] [Indexed: 12/21/2022] Open
Abstract
The objective of this study was to examine whether and how TNF-α affects glutamine-enhanced protein synthesis and the expression of the amino acid transporter ASCT2 in the small intestine at the mRNA and protein levels. A total of 30 male Sprague-Dawley rats were randomly assigned into three groups, namely the total parenteral nutrition (TPN; control), glutamine-treated (Gln), and glutamine- and tumor necrosis factor-α (TNF-α)-treated (TNF-α) groups. At 30 min prior to examination, all rats were mainlined with [L-15N]leucine. The concentration of TNF-α in plasma and of glutamine in plasma and the small intestine was measured. The fractional synthesis rate (FSR) of protein and the mRNA and protein expression levels of ASCT2 in the small intestine were assessed. The level of TNF-α was highest in the TNF-α group and the glutamine concentration was elevated to a greater extent in the TNF-α group than in the other two groups. However, the FSR of protein in the small intestine was significantly higher in the Gln group compared with that in the TNF-α group. The mRNA and protein expression levels of ASCT2 in the experimental groups were significantly higher that those in the control group, but did not differ significantly between the Gln and TNF-α groups. These results indicate that TNF-α may attenuate glutamine-stimulated protein synthesis in the small intestine in the early stage of sepsis in rats. The mechanism may be that TNF-α inhibits the function of the glutamine transporter in the uptake the glutamine into target cells for protein synthesis. This inhibition may occur at or following protein translation.
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Affiliation(s)
- Jihong Zhou
- Department of Burns and Plastic Surgery, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, P.R. China
| | - Shengxian Fan
- Department of General Surgery, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, P.R. China
| | - Yacheng Cao
- Institute of Soil Science, Chinese Academy of Sciences, Nanjing, Jiangsu 210002, P.R. China
| | - Mingfang Zhu
- Institute of Soil Science, Chinese Academy of Sciences, Nanjing, Jiangsu 210002, P.R. China
| | - Yong Han
- Institute of Soil Science, Chinese Academy of Sciences, Nanjing, Jiangsu 210002, P.R. China
| | - Xueying Cao
- Department of Burns and Plastic Surgery, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, P.R. China
| | - Yousheng Li
- Department of General Surgery, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, P.R. China
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