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Manhar N, Singh SK, Yadav P, Bishnolia M, Khurana A, Bhatti JS, Navik U. Methyl Donor Ameliorates CCl 4-Induced Nephrotoxicity by Inhibiting Oxidative Stress, Inflammation, and Fibrosis Through the Attenuation of Kidney Injury Molecule 1 and Neutrophil Gelatinase-Associated Lipocalin Expression. J Biochem Mol Toxicol 2025; 39:e70188. [PMID: 39987517 DOI: 10.1002/jbt.70188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 01/21/2025] [Accepted: 02/08/2025] [Indexed: 02/25/2025]
Abstract
Carbon tetrachloride (CCl4), a volatile organic compound, is harmful to multi-organs, including the liver, lungs, muscles, and kidneys. Methyl donors, such as methionine, choline, betaine, and folic acid, are vital to one-carbon metabolism and have great potential to alleviate oxidative stress and inflammation, thus mitigating disease onset. Hence, the current study aims to examine the therapeutic effect of methyl donors against CCl4-induced nephrotoxicity. Nephrotoxicity was developed in male Sprague Dawley rats using CCl4 at a dose of 1 mL/kg (4-week model induction) twice a week via the intraperitoneal route. Thereafter, methyl donor treatments through oral gavage were given for the next 6 weeks with a continuation of CCl4 administration. Biochemical, oxidative stress parameters, histopathological, and qRT-PCR analyses were done at the completion of the 10-week. Biochemical analyses revealed that CCl4 induces nephrotoxicity, as evidenced by increased urea and creatinine levels and decreased albumin levels. These detrimental effects were significantly ameliorated by methyl donor treatment. Moreover, CCl4 decreased the antioxidant enzyme activity (superoxide dismutase; SOD and catalase; CAT) while increasing oxidative stress markers (malondialdehyde; MDA and nitrite). Methyl donor treatment effectively mitigated these oxidative changes. Histopathological analysis demonstrated the nephroprotective effect of methyl donors against CCl4-induced nephrotoxicity, showing reduced tissue damage and protection of renal architecture. At the molecular level, methyl donor treatment alleviated the CCl4-induced increase in kidney injury biomarkers (Kidney injury molecule 1; KIM-1 and Neutrophil gelatinase-associated lipocalin; NGAL), as well as inflammatory (IL-6 and TNF-α) and fibrosis-related genes (Acta-2 and TGF-β). In conclusion, our findings suggest that methyl donors possess anti-inflammatory and anti-fibrotic properties. They protect against CCl4-induced oxidative damage to renal cells, likely due to their reactive oxygen species scavenging capabilities and their ability to restore key early renal injury biomarkers (KIM-1 and NGAL). Methyl donors hold great promise as a cutting-edge therapy approach for preventing CCl4-induced nephrotoxicity.
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Affiliation(s)
- Nirmal Manhar
- Department of Pharmacology, Central University of Punjab, Bathinda, India
| | - Sumeet Kumar Singh
- Department of Pharmacology, Central University of Punjab, Bathinda, India
| | - Poonam Yadav
- Department of Pharmacology, Central University of Punjab, Bathinda, India
| | - Manish Bishnolia
- Department of Pharmacology, Central University of Punjab, Bathinda, India
| | - Amit Khurana
- Department of Pharmacology, Central University of Punjab, Bathinda, India
| | - Jasvinder Singh Bhatti
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India
| | - Umashanker Navik
- Department of Pharmacology, Central University of Punjab, Bathinda, India
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Bishnolia M, Yadav P, Singh SK, Manhar N, Rajput S, Khurana A, Bhatti JS, Navik U. Methyl donor ameliorates CCl 4-induced liver fibrosis by inhibiting inflammation, and fibrosis through the downregulation of EGFR and DNMT-1 expression. Food Chem Toxicol 2025; 196:115230. [PMID: 39736447 DOI: 10.1016/j.fct.2024.115230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Revised: 12/16/2024] [Accepted: 12/26/2024] [Indexed: 01/01/2025]
Abstract
Methyl donors regulate the one-carbon metabolism and have significant potential to reduce oxidative stress and inflammation. Therefore, this study aims to investigate the protective effect of methyl donors against CCl4-induced liver fibrosis. Liver fibrosis was induced in male Sprague Dawley rats using CCl4 at a dose of 1 ml/kg (twice a week for a 4-week, via intraperitoneal route). Subsequently, methyl donor treatments were given orally for the next six weeks while continuing CCl4 administration. After 10 weeks, biochemical, histopathology, immunohistochemistry, western blotting, and qRT-PCR were performed. Methyl donor treatment significantly ameliorated ALT, AST, ALP levels, and oxidative stress associated with CCl4-induced liver injury. The histopathological investigation also demonstrated the hepatoprotective effect of methyl donors against CCl4-induced liver fibrosis, showing reduced tissue damage, collagen deposition, and attenuating the expression of the COL1A1 gene. Further, methyl donors inhibited the CCl4-induced increase in DNMT-1 and NF-κB p65 expression with an upregulation of AMPK. Methyl donor downregulated the CCl4-induced increase in inflammatory and fibrosis related gene expression and inhibited the apoptosis with a downregulation of EGFR expression. Here, we provide the first evidence that methyl donor combinations prevent liver fibrosis by attenuating oxidative stress, inflammation, and fibrosis through DNMT-1 and EGFR downregulation.
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Affiliation(s)
- Manish Bishnolia
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, India
| | - Poonam Yadav
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, India
| | - Sumeet Kumar Singh
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, India
| | - Nirmal Manhar
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, India
| | - Sonu Rajput
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, India
| | - Amit Khurana
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, India
| | - Jasvinder Singh Bhatti
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India.
| | - Umashanker Navik
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, India.
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Cesarini L, Grignaffini F, Alisi A, Pastore A. Alterations in Glutathione Redox Homeostasis in Metabolic Dysfunction-Associated Fatty Liver Disease: A Systematic Review. Antioxidants (Basel) 2024; 13:1461. [PMID: 39765791 PMCID: PMC11672975 DOI: 10.3390/antiox13121461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 11/18/2024] [Accepted: 11/25/2024] [Indexed: 01/11/2025] Open
Abstract
Low molecular weight (LMW) thiols, particularly glutathione, play pathogenic roles in various multiorgan diseases. The liver is central for the production and systemic distribution of LMW thiols; thus, it is particularly susceptible to the imbalance of redox status that may determine increased oxidative stress and trigger the liver damage observed in metabolic dysfunction-associated steatotic liver disease (MASLD) models and humans. Indeed, increased LMW thiols at the cellular and extracellular levels may be associated with the severity of MASLD. Here, we present a systematic literature review of recent studies assessing the levels of LMW thiols in MASLD in in vivo and in vitro models and human subjects. Based on the PRISMA 2020 criteria, a search was conducted using PubMed and Scopus by applying inclusion/exclusion filters. The initial search returned 1012 documents, from which 165 eligible studies were selected, further described, and qualitatively analysed. Of these studies, most focused on animal and cellular models, while a minority used human fluids. The analysis of these studies revealed heterogeneity in the methods of sample processing and measurement of LMW thiol levels, which hinder cut-off values for diagnostic use. Standardisation of the analysis and measure of LMW thiol is necessary to facilitate future studies.
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Affiliation(s)
| | | | - Anna Alisi
- Research Unit of Genetics of Complex Phenotypes, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (L.C.); (F.G.); (A.P.)
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Fu Y, Wang Z, Qin H. Examining the Pathogenesis of MAFLD and the Medicinal Properties of Natural Products from a Metabolic Perspective. Metabolites 2024; 14:218. [PMID: 38668346 PMCID: PMC11052500 DOI: 10.3390/metabo14040218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 04/06/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD), characterized primarily by hepatic steatosis, has become the most prevalent liver disease worldwide, affecting approximately two-fifths of the global population. The pathogenesis of MAFLD is extremely complex, and to date, there are no approved therapeutic drugs for clinical use. Considerable evidence indicates that various metabolic disorders play a pivotal role in the progression of MAFLD, including lipids, carbohydrates, amino acids, and micronutrients. In recent years, the medicinal properties of natural products have attracted widespread attention, and numerous studies have reported their efficacy in ameliorating metabolic disorders and subsequently alleviating MAFLD. This review aims to summarize the metabolic-associated pathological mechanisms of MAFLD, as well as the natural products that regulate metabolic pathways to alleviate MAFLD.
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Affiliation(s)
| | | | - Hong Qin
- Department of Nutrition and Food Hygiene, Xiangya School of Public Health, Central South University, Changsha 410006, China; (Y.F.); (Z.W.)
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Oriquat G, Masoud IM, Kamel MA, Aboudeya HM, Bakir MB, Shaker SA. The Anti-Obesity and Anti-Steatotic Effects of Chrysin in a Rat Model of Obesity Mediated through Modulating the Hepatic AMPK/mTOR/lipogenesis Pathways. Molecules 2023; 28:molecules28041734. [PMID: 36838721 PMCID: PMC9962978 DOI: 10.3390/molecules28041734] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 02/06/2023] [Accepted: 02/08/2023] [Indexed: 02/16/2023] Open
Abstract
BACKGROUND Obesity is a complex multifactorial disease characterized by excessive adiposity, and is linked to an increased risk of nonalcoholic fatty liver disease (NAFLD). Flavonoids are natural polyphenolic compounds that exert interesting pharmacological effects as antioxidant, anti-inflammatory, and lipid-lowering agents. In the present study, we investigated the possible therapeutic effects of the flavonoid chrysin on obesity and NAFLD in rats, and the role of AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathways in mediating these effects. METHOD Thirty-two Wistar male rats were divided into two groups: the control group and the obese group. Obesity was induced by feeding with an obesogenic diet for 3 months. The obese rats were subdivided into four subgroups, comprising an untreated group, and three groups treated orally with different doses of chrysin (25, 50, and 75 mg/kg/day for one month). Results revealed that chrysin treatment markedly ameliorated the histological changes and significantly and dose-dependently reduced the weight gain, hyperglycemia, and insulin resistance in the obese rats. Chrysin, besides its antioxidant boosting effects (increased GSH and decreased malondialdehyde), activated the AMPK pathway and suppressed the mTOR and lipogenic pathways, and stimulated expression of the genes controlling mitochondrial biogenesis in the hepatic tissues in a dose-dependent manner. In conclusion, chrysin could be a promising candidate for the treatment of obesity and associated NAFLD, aiding in attenuating weight gain and ameliorating glucose and lipid homeostasis and adipokines, boosting the hepatic mitochondrial biogenesis, and modulating AMPK/mTOR/SREBP-1c signaling pathways.
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Affiliation(s)
- Ghaleb Oriquat
- Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman 19328, Jordan
| | - Inas M. Masoud
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria 21311, Egypt
| | - Maher A. Kamel
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt
- Correspondence: (M.A.K.); (S.A.S.)
| | | | - Marwa B. Bakir
- Department of Pharmacology and Experimental Therapeutics, Alexandria University, Alexandria 21561, Egypt
| | - Sara A. Shaker
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt
- Correspondence: (M.A.K.); (S.A.S.)
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Maternal One-Carbon Supplement Reduced the Risk of Non-Alcoholic Fatty Liver Disease in Male Offspring. Nutrients 2022; 14:nu14122545. [PMID: 35745277 PMCID: PMC9228996 DOI: 10.3390/nu14122545] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/10/2022] [Accepted: 06/15/2022] [Indexed: 12/03/2022] Open
Abstract
Recent studies have suggested that prevention of obesity and non-alcoholic fatty liver disease (NAFLD) should start with maternal dietary management. We previously reported disrupted methionine cycle, associated with NAFLD, in male offspring liver due to maternal high-fat (HF) diet, thus we hypothesize that maternal one-carbon supplement may reduce the risk of NAFLD in offspring via the normalizing methionine cycle. To test it, female mice (F0) were exposed to either a maternal normal-fat diet (NF group) a maternal HF diet (HF group), or a maternal methyl donor supplement (H1S or H2S group) during gestation and lactation. The offspring male mice (F1) were exposed to a postweaning HF diet to promote NAFLD. While the HF offspring displayed obesity, glucose intolerance and hepatic steatosis, the H1S and H2S offspring avoided hepatic steatosis. This phenotype was associated with the normalization of the methionine cycle and the restoration of L-carnitine and AMPK activity. Furthermore, maternal HF diet induced epigenetic regulation of important genes involved in fatty acid oxidation and oxidative phosphorylation via DNA methylation modifications, which were recovered by maternal one-carbon supplementation. Our study provides evidence that maternal one-carbon supplement can reverse/block the adverse effects of maternal HF diet on promoting offspring NAFLD, suggesting a potential nutritional strategy that is administered to mothers to prevent NAFLD in the offspring.
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Boonma T, Navasumrit P, Parnlob V, Waraprasit S, Ruchirawat M. SAM and folic acid prevent arsenic-induced oxidative and nitrative DNA damage in human lymphoblast cells by modulating expression of inflammatory and DNA repair genes. Chem Biol Interact 2022; 361:109965. [PMID: 35490796 DOI: 10.1016/j.cbi.2022.109965] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 04/18/2022] [Accepted: 04/25/2022] [Indexed: 11/27/2022]
Abstract
Growing evidence suggests that arsenic exposure increases the risk of developing a variety of inflammation-associated chronic diseases and cancers. Our previous study revealed that increased transcript levels of inflammatory genes (i.e. COX2, EGR1, and SOCS3) coupled with hypomethylation of the promoter regions of these genes was associated with increased DNA damage in arsenic-exposed newborns through their early childhood. This study further investigated the ability of the methyl group donors, S-adenosyl methionine (SAM) and folic acid, to prevent promoter hypomethylation that results in decreased mRNA expression of inflammatory genes (COX2, EGR1, and SOCS3), and a reduction in arsenic-induced oxidative and nitrative DNA damage in human lymphoblast cells. Pretreatment with SAM (100 nM, 2 days) increased promoter methylation, reduced the mRNA levels of these inflammatory genes, and decreased both 8-hydroxydeoxyguanosine (8-OHdG) and 8-nitroguanine levels by 50% (p < 0.01) in arsenic-treated cells. In addition, pretreatment with folic acid (10 μM, 7 days), a micronutrient, led to a significant increase in promoter methylation associated with the reduction in mRNA levels of these inflammatory genes and decreased levels of 8-OHdG and 8-nitroguanine by 80% and 90% (p < 0.01), respectively, compared with arsenic treatment alone. Moreover, pretreatments with these methyl group donors increased mRNA expression of an antioxidant defense regulator (Nrf2) and DNA repair genes (hOGG1, XRCC1, and PARP1). This study shows for the first time that SAM or folic acid supplementation can prevent arsenic-induced oxidative and nitrative DNA damage. This suggests the potential use of SAM or folic acid for prevention of arsenic toxicity in human populations.
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Affiliation(s)
- Tiwapan Boonma
- Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok, 10210, Thailand; Chulabhorn Graduate Institute, Bangkok, 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), OPS, MHESI, Thailand
| | - Panida Navasumrit
- Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok, 10210, Thailand; Chulabhorn Graduate Institute, Bangkok, 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), OPS, MHESI, Thailand
| | - Varabhorn Parnlob
- Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok, 10210, Thailand
| | - Somchamai Waraprasit
- Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok, 10210, Thailand
| | - Mathuros Ruchirawat
- Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok, 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), OPS, MHESI, Thailand.
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The regulation of HBP1, SIRT1, and SREBP-1c genes and the related microRNAs in non-alcoholic fatty liver rats: The association with the folic acid anti-steatosis. PLoS One 2022; 17:e0265455. [PMID: 35417465 PMCID: PMC9007334 DOI: 10.1371/journal.pone.0265455] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 03/02/2022] [Indexed: 01/20/2023] Open
Abstract
Folic acid is one of the vital micronutrients that contribute to the genetic stability and other biological activities. In addition, microRNAs regulate gene expression through a multittude of pathways. Our current work aimd to explore the possible ameliorative potency of folic acid and its association with the hepatic miR-21, -34a, and -122 expression as well as their targeted genes, HBP1, SIRT1, and SREBP-1c in rats with non-alcoholic fatty liver disease (NAFL). A total of 50 Wistar rats were randomly divided into two groups, a control group (n = 10) and NAFL group (n = 40). Rats in NAFL group were fed a high-fat diet (HFD) containing 20% fats for 14 weeks. The NAFL group was further subdivided into four groups (n = 10/group), one untreated and three orally folic acid-treated groups (25, 50, and 75 μg/Kg b.wt). NAFL characteristics was evaluated in rats in addition to the miR-21, -34a, and -122 profile as well as the transcriptional levels of HBP1, SIRT1, and SREBP-1c genes. NAFL rats exhibited the classic traits of fatty liver disease profile and dysregulation in the pattern of miR-21, -34a, and -122 expression as well as their targeted genes (HBP1, SIRT1, and SREBP-1c, respectively) in the liver. Additionally, NAFL rats had altered levels of TNF-α and adiponectin. These alterations were significantly ameliorated in a dose-dependent pattern following the folic acid treatments. In conclusions, the anti-steatotic, insulin-sensitizing, glucose-lowering and lipotropic potencies of folic acid in NAFL rats may be linked to the epigenetic modulation of the hepatic microRNAs (miR-21, -34a, and -122) and the expression of their target genes (HBP1, SIRT1, and SREBP-1c).
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Pan X, Wu Y, Peng H, Cai X, Hu Z, Lin X, Peng XE. Genome-wide DNA methylation profiling in nonalcoholic fatty liver reveals predictive aberrant methylation in PRKCE and SEC14L3 promoters. Dig Liver Dis 2022; 54:521-528. [PMID: 34108094 DOI: 10.1016/j.dld.2021.05.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/06/2021] [Accepted: 05/07/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Optimal non-invasive biomarkers for diagnosis and treatment of nonalcoholic fatty liver disease (NAFLD) remain to be identified. AIMS To identify potential DNA methylation biomarkers for NAFLD. METHODS Genome-wide DNA methylation profiling was performed to identify differentially methylated CpG sites in peripheral blood leukocytes. Differentially methylated regions were validated using the MassCLEAVE assay. The expression levels of candidate genes were explored by Gene Expression Omnibus database. RESULTS The hypomethylation of PRKCE CpG 4.5 and CpG 18.19 was associated with nonalcoholic fatty liver (NAFL), the odds ratio (OR) and 95% confidence interval (CI) were 0.129 (0.026-0.639) and 0.231 (0.069-0.768). The methylation level of CpG 1.2 and average methylation level of SEC14L3 were correlated with NAFL, with OR (95% CI) being 0.283 (0.093-0.865) and 0.264 (0.087-0.799). PRKCE CpG 4.5 and cg17802464 of SEC14L3 were correlated with body mass index, waist circumference, total triglyceride, high-density lipoprotein cholesterol, alanine aminotransferase and aspartate aminotransferase. All selected datasets showed high expression levels of PRKCE and SEC14L3 in patients with NAFLD. CONCLUSIONS Our findings suggest that the hypomethylation of PRKCE and SEC14L3 promoters represent attractive biomarkers for NAFLD. Further studies are warranted to validate these biomarkers as molecular tools for diagnosis of NAFLD and therapeutic targets.
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Affiliation(s)
- Xinting Pan
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, PR China; The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, PR China
| | - Yunli Wu
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, PR China
| | - Hewei Peng
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, PR China
| | - Xiaoling Cai
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, PR China
| | - Zhijian Hu
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, PR China
| | - Xu Lin
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, PR China
| | - Xian-E Peng
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, PR China; Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, PR China.
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Ali MA, Mahmoud SA, Alkhedaide A, Soliman MM, Al-Shafie TA, El-Sayed YS, Shukry M, Ghamry HI, Elblehi SS. Boosting effects of Cranberry and Cinnamaldehyde for pioglitazone amelioration of liver steatosis in rat via suppression of HIF-1α/Smad/β-catenin signaling. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.104973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Rodríguez-Sanabria JS, Escutia-Gutiérrez R, Rosas-Campos R, Armendáriz-Borunda JS, Sandoval-Rodríguez A. An Update in Epigenetics in Metabolic-Associated Fatty Liver Disease. Front Med (Lausanne) 2022; 8:770504. [PMID: 35087844 PMCID: PMC8787199 DOI: 10.3389/fmed.2021.770504] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 12/02/2021] [Indexed: 12/17/2022] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) is characterized by hepatic steatosis accompanied by one of three features: overweight or obesity, T2DM, or lean or normal weight with evidence of metabolic dysregulation. It is distinguished by excessive fat accumulation in hepatocytes, and a decrease in the liver's ability to oxidize fats, the accumulation of ectopic fat, and the activation of proinflammatory pathways. Chronic damage will keep this pathophysiologic cycle active causing progression from hepatic steatosis to cirrhosis and eventually, hepatocarcinoma. Epigenetics affecting gene expression without altering DNA sequence allows us to study MAFLD pathophysiology from a different perspective, in which DNA methylation processes, histone modifications, and miRNAs expression have been closely associated with MAFLD progression. However, these considerations also faced us with the circumstance that modifying those epigenetics patterns might lead to MAFLD regression. Currently, epigenetics is an area of great interest because it could provide new insights in therapeutic targets and non-invasive biomarkers. This review comprises an update on the role of epigenetic patterns, as well as innovative therapeutic targets and biomarkers in MAFLD.
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Affiliation(s)
- J Samael Rodríguez-Sanabria
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Guadalajara, Mexico
| | - Rebeca Escutia-Gutiérrez
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Guadalajara, Mexico
| | - Rebeca Rosas-Campos
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Guadalajara, Mexico
| | - Juan S Armendáriz-Borunda
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Guadalajara, Mexico.,School of Medicine and Health Sciences, Tecnologico de Monterrey, Campus Guadalajara, Zapopan, Mexico
| | - Ana Sandoval-Rodríguez
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Guadalajara, Mexico
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Pascale RM, Simile MM, Calvisi DF, Feo CF, Feo F. S-Adenosylmethionine: From the Discovery of Its Inhibition of Tumorigenesis to Its Use as a Therapeutic Agent. Cells 2022; 11:409. [PMID: 35159219 PMCID: PMC8834208 DOI: 10.3390/cells11030409] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 01/10/2022] [Accepted: 01/14/2022] [Indexed: 02/07/2023] Open
Abstract
Alterations of methionine cycle in steatohepatitis, cirrhosis, and hepatocellular carcinoma induce MAT1A decrease and MAT2A increase expressions with the consequent decrease of S-adenosyl-L-methionine (SAM). This causes non-alcoholic fatty liver disease (NAFLD). SAM administration antagonizes pathological conditions, including galactosamine, acetaminophen, and ethanol intoxications, characterized by decreased intracellular SAM. Positive therapeutic effects of SAM/vitamin E or SAM/ursodeoxycholic acid in animal models with NAFLD and intrahepatic cholestasis were not confirmed in humans. In in vitro experiments, SAM and betaine potentiate PegIFN-alpha-2a/2b plus ribavirin antiviral effects. SAM plus betaine improves early viral kinetics and increases interferon-stimulated gene expression in patients with viral hepatitis non-responders to pegIFNα/ribavirin. SAM prevents hepatic cirrhosis, induced by CCl4, inhibits experimental tumors growth and is proapoptotic for hepatocellular carcinoma and MCF-7 breast cancer cells. SAM plus Decitabine arrest cancer growth and potentiate doxorubicin effects on breast, head, and neck cancers. Furthermore, SAM enhances the antitumor effect of gemcitabine against pancreatic cancer cells, inhibits growth of human prostate cancer PC-3, colorectal cancer, and osteosarcoma LM-7 and MG-63 cell lines; increases genomic stability of SW480 cells. SAM reduces colorectal cancer progression and inhibits the proliferation of preneoplastic rat liver cells in vivo. The discrepancy between positive results of SAM treatment of experimental tumors and modest effects against human disease may depend on more advanced human disease stage at moment of diagnosis.
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Affiliation(s)
- Rosa M. Pascale
- Department of Medical, Surgical and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy; (M.M.S.); (D.F.C.); (F.F.)
| | - Maria M. Simile
- Department of Medical, Surgical and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy; (M.M.S.); (D.F.C.); (F.F.)
| | - Diego F. Calvisi
- Department of Medical, Surgical and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy; (M.M.S.); (D.F.C.); (F.F.)
| | - Claudio F. Feo
- Department of Medical, Surgical and Experimental Sciences, Division of Surgery, University of Sassari, 07100 Sassari, Italy;
| | - Francesco Feo
- Department of Medical, Surgical and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy; (M.M.S.); (D.F.C.); (F.F.)
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Li F, Ou Q, Lai Z, Pu L, Chen X, Wang L, Sun L, Liang X, Wang Y, Xu H, Wei J, Wu F, Zhu H, Wang L. The Co-occurrence of Chronic Hepatitis B and Fibrosis Is Associated With a Decrease in Hepatic Global DNA Methylation Levels in Patients With Non-alcoholic Fatty Liver Disease. Front Genet 2021; 12:671552. [PMID: 34335686 PMCID: PMC8318039 DOI: 10.3389/fgene.2021.671552] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 06/01/2021] [Indexed: 01/23/2023] Open
Abstract
Global DNA hypomethylation has been reported in patients with chronic hepatitis B (CHB) and non-alcoholic fatty-liver disease (NAFLD). However, the global DNA methylation profile of patients with concurrent NAFLD and CHB (NAFLD + CHB) is still unclear. We aimed to detect the hepatic global DNA methylation levels of NAFLD + CHB patients and assess the associated risk factors. Liver biopsies were collected from 55 NAFLD patients with or without CHB. The histological characteristics of the biopsy were then assessed. Hepatic global DNA methylation levels were quantified by fluorometric method. The hepatic global DNA methylation levels in NAFLD + CHB group were significantly lower than that in NAFLD group. Participants with fibrosis showed lower levels of hepatic global DNA methylation than those without fibrosis. Participants with both CHB and fibrosis had lower levels of hepatic global DNA methylation than those without either CHB or fibrosis. The co-occurrence of CHB and fibrosis was significantly associated with a reduction in global DNA methylation levels compared to the absence of both CHB and fibrosis. Our study suggests that patients with NAFLD + CHB exhibited lower levels of global DNA methylation than patients who had NAFLD alone. The co-occurrence of CHB and liver fibrosis in NAFLD patients was associated with a decrease in global DNA methylation levels.
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Affiliation(s)
- FangYuan Li
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - Qian Ou
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - ZhiWei Lai
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - LiuZhen Pu
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - XingYi Chen
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - LiRong Wang
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - LiuQiao Sun
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - XiaoPing Liang
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - YaoYao Wang
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - Hang Xu
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
| | - Jun Wei
- Department of Science and Technology, Guangzhou Customs, Guangzhou, China
| | - Feng Wu
- Department of Science and Technology, Guangzhou Customs, Guangzhou, China
| | - HuiLian Zhu
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - LiJun Wang
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, China
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Arumugam MK, Paal MC, Donohue TM, Ganesan M, Osna NA, Kharbanda KK. Beneficial Effects of Betaine: A Comprehensive Review. BIOLOGY 2021; 10:456. [PMID: 34067313 PMCID: PMC8224793 DOI: 10.3390/biology10060456] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/06/2021] [Accepted: 05/19/2021] [Indexed: 02/05/2023]
Abstract
Medicinal herbs and many food ingredients possess favorable biological properties that contribute to their therapeutic activities. One such natural product is betaine, a stable, nontoxic natural substance that is present in animals, plants, and microorganisms. Betaine is also endogenously synthesized through the metabolism of choline or exogenously consumed through dietary intake. Betaine mainly functions as (i) an osmolyte and (ii) a methyl-group donor. This review describes the major physiological effects of betaine in whole-body health and its ability to protect against both liver- as well as non-liver-related diseases and conditions. Betaine's role in preventing/attenuating both alcohol-induced and metabolic-associated liver diseases has been well studied and is extensively reviewed here. Several studies show that betaine protects against the development of alcohol-induced hepatic steatosis, apoptosis, and accumulation of damaged proteins. Additionally, it can significantly prevent/attenuate progressive liver injury by preserving gut integrity and adipose function. The protective effects are primarily associated with the regulation of methionine metabolism through removing homocysteine and maintaining cellular SAM:SAH ratios. Similarly, betaine prevents metabolic-associated fatty liver disease and its progression. In addition, betaine has a neuroprotective role, preserves myocardial function, and prevents pancreatic steatosis. Betaine also attenuates oxidant stress, endoplasmic reticulum stress, inflammation, and cancer development. To conclude, betaine exerts significant therapeutic and biological effects that are potentially beneficial for alleviating a diverse number of human diseases and conditions.
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Affiliation(s)
- Madan Kumar Arumugam
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (MK.A.); (M.C.P.); (T.M.D.J.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Matthew C. Paal
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (MK.A.); (M.C.P.); (T.M.D.J.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Terrence M. Donohue
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (MK.A.); (M.C.P.); (T.M.D.J.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (MK.A.); (M.C.P.); (T.M.D.J.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (MK.A.); (M.C.P.); (T.M.D.J.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (MK.A.); (M.C.P.); (T.M.D.J.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Tan J, Sun M, Luo Q, Sun H, Wang M, Jiang C, Li S, He Y. Arsenic exposure increased expression of HOTAIR and LincRNA-p21 in vivo and vitro. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:587-596. [PMID: 32816178 DOI: 10.1007/s11356-020-10487-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 08/10/2020] [Indexed: 06/11/2023]
Abstract
Arsenic is an environmental contaminant, its multiple effects on human tend to increase the rate of disease, cancer and other health problems. Some of long non-coding RNAs (lncRNAs) can be induced in major cellular processes such as necrosis, proliferation, and mutation. While the toxicity of arsenic is well established, the association between arsenic exposure and long non-coding RNAs has not been studied enough. This study investigated the association between arsenic and the expression of HOTAIR and LincRNA-p21 in vivo and vitro. In epidemiological studies, the expression of HOTAIR and LincRNA-p21 was increased after long-term arsenic exposure. HOTAIR and LincRNA-p21 expression were positively linked to monomethylarsenic acid (MMA), dimethylarsenic acid (DMA), inorganic arsenic (iAs), total arsenic (tAs), and MMA% and negatively linked to secondary methylation index (SMI). In A549 cells, arsenic exposure resulted in enhanced HOTAIR and LincRNA-p21 expression dose-dependently. The expression of HOTAIR was considerably high in the presence of NaAsO2 and MMA but showed no difference in DMA compared with control group. And LincRNA-p21 expression was increased in the presence of NaAsO2, MMA, and DMA. The expression of HOTAIR and LincRNA-p21 induced by iAs was much higher than that induced by MMA and DMA. Compared with the control group, treatment of A549 cells with NaAsO2/S-adenosylmethionine (SAM) and NaAsO2/glutathione (GSH) combination increased HOTAIR and LincRNA-p21 expression. The expression of LincRNA-p21 in combination of NaAsO2/GSH was significantly decreased compared with NaAsO2 alone. Besides, in the presence of arsenic, both of HOTAIR and LincRNA-p21 were upregulated significantly when P53 was knocked down. We revealed that inorganic arsenic, its methylated metabolites, and arsenic metabolism efficiency affect the expression of HOTAIR and LincRNA-p21.
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Affiliation(s)
- Jingwen Tan
- School of Public Health, Kunming Medical University, No.1168 Chunrongxi Road Chenggong District, Kunming, Yunnan Province, China
| | - Mingjun Sun
- School of Public Health, Kunming Medical University, No.1168 Chunrongxi Road Chenggong District, Kunming, Yunnan Province, China
| | - Quan Luo
- School of Public Health, Kunming Medical University, No.1168 Chunrongxi Road Chenggong District, Kunming, Yunnan Province, China
| | - Huiwen Sun
- School of Public Health, Kunming Medical University, No.1168 Chunrongxi Road Chenggong District, Kunming, Yunnan Province, China
| | - Mengjie Wang
- School of Public Health, Kunming Medical University, No.1168 Chunrongxi Road Chenggong District, Kunming, Yunnan Province, China
| | - Chenglan Jiang
- School of Public Health, Kunming Medical University, No.1168 Chunrongxi Road Chenggong District, Kunming, Yunnan Province, China
| | - Shuting Li
- School of Public Health, Kunming Medical University, No.1168 Chunrongxi Road Chenggong District, Kunming, Yunnan Province, China
| | - Yuefeng He
- School of Public Health, Kunming Medical University, No.1168 Chunrongxi Road Chenggong District, Kunming, Yunnan Province, China.
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Sachinvala ND, Teramoto N, Stergiou A. Proposed Neuroimmune Roles of Dimethyl Fumarate, Bupropion, S-Adenosylmethionine, and Vitamin D 3 in Affording a Chronically Ill Patient Sustained Relief from Inflammation and Major Depression. Brain Sci 2020; 10:E600. [PMID: 32878267 PMCID: PMC7563300 DOI: 10.3390/brainsci10090600] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/23/2020] [Accepted: 08/25/2020] [Indexed: 12/14/2022] Open
Abstract
We had discussed earlier that, after most of the primary author's multiple sclerosis (MS) symptoms were lessened by prior neuroimmune therapies, use of dimethyl fumarate (DMF) gradually subdued his asthma and urticaria symptoms, as well as his MS-related intercostal cramping; and bupropion supplemented with S-adenosylmethionine (SAMe) and vitamin D3 (vit-D3) helped remit major depression (MD). Furthermore, the same cocktail (bupropion plus supplements), along with previously discussed routines (yoga, meditation, physical exercises, and timely use of medications for other illnesses), continued to subdue MD during new difficulties with craniopharyngioma, which caused bitemporal vision loss; sphenoid sinus infections, which caused cranial nerve-VI (CN6) palsy and diplopia; and through their treatments. Impressed by the benefit the four compounds provided, in this manuscript, we focus on explaining current neuroimmune literature proposals on how: (1) DMF impedes inflammation, oxidative stress, and cell death in CNS and peripheral tissues; (2) Bupropion curbs anxiety, MD, and enhances alertness, libido, and moods; (3) SAMe silences oxidative stress and depression by multiple mechanisms; and (4) Vit-D3 helps brain development and functioning and subdues inflammation. we realize that herein we have reviewed proposed mechanisms of remedies we discovered by literature searches and physician assisted auto-experimentation; and our methods might not work with other patients. We present our experiences so readers are heartened to reflect upon their own observations in peer-reviewed forums and make available a wide body of information for the chronically ill and their physicians to benefit from.
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Affiliation(s)
| | - Naozumi Teramoto
- Department of Applied Chemistry, Faculty of Engineering, Chiba Institute of Technology, 2-17-1, Tsudanuma, Narashino, Chiba 275-0016, Japan;
| | - Angeline Stergiou
- Department of Medicine, Fairfield Medical Center, 401 North Ewing, Lancaster, OH 43130, USA;
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Xin FZ, Zhao ZH, Zhang RN, Pan Q, Gong ZZ, Sun C, Fan JG. Folic acid attenuates high-fat diet-induced steatohepatitis via deacetylase SIRT1-dependent restoration of PPARα. World J Gastroenterol 2020; 26:2203-2220. [PMID: 32476787 PMCID: PMC7235203 DOI: 10.3748/wjg.v26.i18.2203] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 03/27/2020] [Accepted: 04/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Folic acid has been shown to improve non-alcoholic steatohepatitis (NASH), but its roles in hepatic lipid metabolism, hepatic one-carbon metabolism, and gut microbiota are still unknown. AIM To demonstrate the role of folic acid in lipid metabolism and gut microbiota in NASH. METHODS Twenty-four Sprague-Dawley rats were assigned into three groups: Chow diet, high-fat diet (HFD), and HFD with folic acid administration. At the end of 16 wk, the liver histology, the expression of hepatic genes related to lipid metabolism, one-carbon metabolism, and gut microbiota structure analysis of fecal samples based on 16S rRNA sequencing were measured to evaluate the effect of folic acid. Palmitic acid-exposed Huh7 cell line was used to evaluate the role of folic acid in hepatic lipid metabolism. RESULTS Folic acid treatment attenuated steatosis, lobular inflammation, and hepatocellular ballooning in rats with HFD-induced steatohepatitis. Genes related to lipid de novo lipogenesis, β-oxidation, and lipid uptake were improved in HFD-fed folic acid-treated rats. Furthermore, peroxisome proliferator-activated receptor alpha (PPARα) and silence information regulation factor 1 (SIRT1) were restored by folic acid in HFD-fed rats and palmitic acid-exposed Huh7 cell line. The restoration of PPARα by folic acid was blocked after transfection with SIRT1 siRNA in the Huh7 cell line. Additionally, folic acid administration ameliorated depleted hepatic one-carbon metabolism and restored the diversity of the gut microbiota in rats with HFD-induced steatohepatitis. CONCLUSION Folic acid improves hepatic lipid metabolism by upregulating PPARα levels via a SIRT1-dependent mechanism and restores hepatic one-carbon metabolism and diversity of gut microbiota, thereby attenuating HFD-induced NASH in rats.
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Affiliation(s)
- Feng-Zhi Xin
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Ze-Hua Zhao
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Rui-Nan Zhang
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Qin Pan
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Zi-Zhen Gong
- Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
- Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Chao Sun
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Jian-Gao Fan
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
- Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
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18
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Ali MA, Kamel MA. Modulation of the hepatic expression of miR-33 and miR-34a possibly mediates the metabolic effects of estrogen in ovariectomized female rats. Eur J Pharmacol 2020; 873:173006. [PMID: 32045601 DOI: 10.1016/j.ejphar.2020.173006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 02/05/2020] [Accepted: 02/07/2020] [Indexed: 12/30/2022]
Abstract
Estrogen and the estrogen receptors (ERs) are well-known regulators of several aspects of glucose and lipid metabolism. Meanwhile, the underlying mechanistic role of estrogens in regulating metabolic health remains largely unknown. Hence, the study was designed to tackle the possible contribution of the hepatic expression of miR-33, miR-21 and miR-34a and their target genes as the underlying mechanism of the metabolic effects of estrogen in ovariectomized rats. Forty female rats were ovariectomized (OVX), treated with estrogen and/or fulvestrant for 28 days and compared with untreated or treated sham operated rats. Estradiol amended the metabolic abnormalities in the OVX rats, witnessed by decreasing blood sugar, insulin and HOMA-IR as well as correcting the disrupted serum and hepatic lipids. Estradiol increased the hepatic expression of miR-33 and inhibited that of miR-34a and miR-21, leading to adjusting the gene expression and the protein level of their targets, sterol regulatory element-binding proteins-1c (SREBP-1c), fatty acid synthase (FASN), high mobility group (HMG) Box Transcription Factor 1 (HBP1) and Sirtuin 1 (SIRT1), receptively. However, estrogen had no significant effects on HBP1 protein. These effects were almost completely inhibited by fulvestrant, an estrogen receptor blocker, to the extent that fulvestrant had similar metabolic disorders to that of ovariectomization. In conclusion, estrogen replacement therapy in OVX females significantly ameliorated the metabolic derangements of insulin resistance, dyslipidemia and hepatic fat accumulation possibly via corrections of hepatic expression of miR-33 and miR-34a; effects that were mediated through the receptor-mediated signaling of ERs as confirmed by fulvestrant.
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Affiliation(s)
- Mennatallah A Ali
- Department of Pharmacology &Therapeutics, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, Alexandria, Egypt.
| | - Maher A Kamel
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt
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19
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Lai Z, Chen J, Ding C, Wong K, Chen X, Pu L, Huang Q, Chen X, Cheng Z, Liu Y, Tan X, Zhu H, Wang L. Association of Hepatic Global DNA Methylation and Serum One-Carbon Metabolites with Histological Severity in Patients with NAFLD. Obesity (Silver Spring) 2020; 28:197-205. [PMID: 31785086 DOI: 10.1002/oby.22667] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 09/10/2019] [Indexed: 12/26/2022]
Abstract
OBJECTIVE Clinical relevance of global DNA methylation and one-carbon metabolite levels with histological severity remains uncertain in patients with nonalcoholic fatty liver disease (NAFLD). This study aimed to evaluate hepatic global DNA methylation and serum one-carbon metabolite concentrations in patients with NAFLD and the possible associations of these parameters with liver histology. METHODS Liver biopsies from 18 control participants and 47 patients with NAFLD were evaluated. RESULTS The hepatic global DNA methylation level was significantly lower in the NAFLD group than in the control group among participants with overweight. Participants with moderate inflammation and mild fibrosis had significantly lower levels of global DNA methylation than those without these characteristics. Participants with borderline nonalcoholic steatohepatitis had significantly lower global DNA methylation levels than controls. The hepatic global DNA methylation level tended to decrease with the increasing hepatic inflammation grade and disease progression. The NAFLD group had a significantly higher serum homocysteine concentration than the control group among participants with overweight. This level tended to increase with increasing hepatic steatosis grade and disease progression. CONCLUSIONS Patients with NAFLD exhibited lower hepatic levels of global DNA methylation and elevated serum homocysteine concentrations, which are associated with the histological severity of NAFLD.
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Affiliation(s)
- Zhiwei Lai
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, People's Republic of China
| | - Junliang Chen
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, People's Republic of China
| | - Chenghe Ding
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, People's Republic of China
| | - Kwanshu Wong
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, People's Republic of China
| | - Xingyi Chen
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, People's Republic of China
| | - Liuzhen Pu
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, People's Republic of China
| | - Qiangwei Huang
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, People's Republic of China
| | - Xiaolin Chen
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, People's Republic of China
| | - Zijian Cheng
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, People's Republic of China
| | - Yan Liu
- Shenzhen Hospital, Southern Medical University, Shenzhen, People's Republic of China
| | - Xuying Tan
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Huilian Zhu
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Lijun Wang
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, People's Republic of China
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20
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Radziejewska A, Muzsik A, Milagro FI, Martínez JA, Chmurzynska A. One-Carbon Metabolism and Nonalcoholic Fatty Liver Disease: The Crosstalk between Nutrients, Microbiota, and Genetics. Lifestyle Genom 2019; 13:53-63. [PMID: 31846961 DOI: 10.1159/000504602] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 10/30/2019] [Indexed: 01/02/2023] Open
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Its etiology includes nutritional, genetic, and lifestyle factors. Several mechanisms may link one-carbon metabolism - the associated metabolic pathways of folate, methionine, and choline - to the onset of NAFLD. In this review, we attempted to assess how choline, folate, methionine, and betaine affect NAFLD development, mainly through their role in the secretion of very low-density lipoproteins (VLDL) from the liver. We also reviewed recent articles that have described the relation between microbiota metabolism and NAFLD progression. Moreover, we describe the effect of single-nucleotide polymorphisms (SNP) in genes related to one-carbon metabolism and disease prevalence. We additionally seek SNP identified by genome-wide associations that may increase the risk of this disease. Even though the evidence available is not entirely consistent, it seems that the concentrations of choline, methionine, folate, and betaine may affect the progression of NAFLD. Since there is no effective therapy for NAFLD, further investigations into the link between nutrition, gut microbiota, genetic factors, and NAFLD are still necessary, with a particular emphasis on methyl donors.
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Affiliation(s)
- Anna Radziejewska
- Institute of Human Nutrition and Dietetics, Poznań University of Life Sciences, Poznań, Poland
| | - Agata Muzsik
- Institute of Human Nutrition and Dietetics, Poznań University of Life Sciences, Poznań, Poland
| | - Fermín I Milagro
- Department of Nutrition, Food Science and Physiology, Centre for Nutrition Research, University of Navarra, Pamplona, Spain.,Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - J Alfredo Martínez
- Department of Nutrition, Food Science and Physiology, Centre for Nutrition Research, University of Navarra, Pamplona, Spain.,Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - Agata Chmurzynska
- Institute of Human Nutrition and Dietetics, Poznań University of Life Sciences, Poznań, Poland,
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21
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Youssry S, Kamel MA. Effect of folate supplementation on immunological and autophagy markers in experimental nonalcoholic fatty liver disease. Eur Cytokine Netw 2019; 30:135-143. [PMID: 32096475 DOI: 10.1684/ecn.2019.0437] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND AND AIMS Chronic hepatic inflammation is an important pathogenic mediator of nonalcoholic fatty liver disease (NAFLD) that contributes to disease severity. It is commonly suggested that autophagy dysfunction may be an underlying cause of nonalcoholic fatty liver disease. However, the exact role of autophagy in lipid metabolism remains controversial. There has been a growing interest in the role of folate supplementation for the treatment and/or prevention of NAFLD. We aimed in this study to investigate the effects of different doses of folate supplementation on several immune markers and autophagy trying to explore the complex role of IL-22 and autophagy in NAFLD. METHODS Fifty Wistar rats were randomly separated into experimental (n = 40) and control groups (n = 10), which were fed for eight weeks with a high-fat diet (HFD) containing 40% fats or a standard diet, respectively. The experimental group was further subdivided into four subgroups where the first subgroup was left untreated while the other three were treated with different doses of folate (50, 100, and 150 μg/kg of body weight, respectively). At the end of the experimental period, animals from each group were sacrificed for blood and tissue analyses. RESULTS NAFLD rats showed decreased IL-22 serum levels and increased LC3B expression as compared to controls. Folate treatment was significantly associated with improvement in disease parameters, reduced presence of the pro-inflammatory cytokines TNF-α and CXCL8 and LC3B expression, and increased IL-22 levels in a dose-dependent manner. CONCLUSION These results highlight the capacity of folate to modulate the production of several pro-inflammatory cytokines and autophagy thereby having a favorable impact disease progression.
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Affiliation(s)
- Sara Youssry
- Lecturer of Immunology and Allergy, Medical Research Institute, Alexandria University, Egypt
| | - Maher A Kamel
- Professor of Biochemistry, Medical Research Institute, Alexandria University, Egypt
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