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Shuai R, He Y, Yang D, Zhang Y, Zhang L. Association between the atherogenic index of plasma and non-alcoholic fatty liver disease in Korean pregnant women: secondary analysis of a prospective cohort study. Front Nutr 2025; 12:1511952. [PMID: 39957769 PMCID: PMC11825326 DOI: 10.3389/fnut.2025.1511952] [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: 10/15/2024] [Accepted: 01/21/2025] [Indexed: 02/18/2025] Open
Abstract
Background Recent studies have shown an association between atherogenic index of plasma (AIP) and nonalcoholic fatty liver disease (NAFLD), but the association in a population of pregnant women remains unclear. Objectives Our study aimed to examine the association between AIP and NAFLD in pregnant Korean women. Methods Our study used publicly available data from Korea, which recruited singleton pregnant women between November 2014 and September 2016 who were at 10-14 weeks of gestation. The presence of NAFLD was diagnosed by liver ultrasound. AIP was calculated as log10 (TG/HDL). Participants were grouped according to AIP tertile: T1 (< 0.16, n = 195), T2 (0.16-0.32, n = 195), and T3 (>0.32, n = 196). Logistic regression models were used to estimate the relationship between AIP and NAFLD. Subgroup and sensitivity analyses were conducted to explore the stability of this relationship. Restricted cubic spline (RCS) curve fitting was employed to investigate potential non-linear associations. Results After excluding data on missing variables, 586 singleton pregnant women were finally included. The subjects included in the study had an average AIP of 0.22 (0.11, 0.37), and NAFLD occurred in 110 (18.8%) pregnant women. We observed a positive linear association between AIP and NAFLD (OR = 1.33, 95% CI: 1.19-1.48), which persisted after adjusting for potential confounders (OR = 1.2, 95% CI: 1.06-1.37). When AIP was used as a categorical variable, after adjusting for covariates, the NAFLD risk was significantly higher in the highest tertile of AIP than in the lowest group (OR = 2.02, 95% CI: 1.11-3.68). Their correlations were stable across subgroups and sensitivity analyses. Conclusion In this secondary analysis of a prospective cohort study of pregnant Korean women, AIP was found to be positively associated with NAFLD. These outcomes might be used to screen for NAFLD in pregnant women.
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Affiliation(s)
- Rong Shuai
- Department of Laboratory Medicine, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, China
| | - Yuxing He
- Department of Laboratory Medicine, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, China
| | - Dongqian Yang
- Department of Laboratory Medicine, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, China
| | - Yingying Zhang
- Department of Laboratory Medicine, Affiliated Wuxi Fifth Hospital of Jiangnan University, Wuxi, China
| | - Li Zhang
- Department of Laboratory Medicine, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, China
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Amirkhizi F, Taghizadeh M, Khalese-Ranjbar B, Hamedi-Shahraki S, Asghari S. The clinical value of serum sirtuin-1 concentration in the diagnosis of metabolic dysfunction-associated steatotic liver disease. BMC Gastroenterol 2025; 25:27. [PMID: 39844087 PMCID: PMC11753077 DOI: 10.1186/s12876-025-03613-8] [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: 08/28/2024] [Accepted: 01/14/2025] [Indexed: 01/24/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease and can affect individuals without producing any symptoms. We aimed to explore the value of serum sirtuin-1 (Sirt-1) in the diagnosis of MASLD. METHODS This case-control study analyzed data collected from 190 individuals aged 20 to 60 years. Anthropometric parameters, demographic information, and serum biochemical variables-including glycemic parameters, lipid profiles, liver enzymes, and Sirt-1 levels-were assessed. The correlation between serum Sirt-1 and biochemical variables was examined using Pearson's correlation coefficient. Receiver operating characteristic (ROC) curve analysis was employed to evaluate the diagnostic value of serum Sirt-1 in the context of MASLD. RESULTS Serum Sirt-1 levels was significantly lower in the MASLD group (p < 0.001) and was inversely correlated with serum insulin (r = -0.163, p = 0.025), HOMA-IR (r = -0.169, p = 0.020) and triglyceride (r = -0.190, p = 0.009) and positively correlated with serum levels of high-density lipoprotein cholesterol (HDL-C) (r = 0.214, p = 0.003). The area under the curve (AUC) of Sirt-1 to predict the presence of MASLD was 0.76 (p < 0.001, 95% CI: 0.69, 0.82) with a sensitivity of 78.9, specificity of 61.1, positive predictive value (PPV) of 67.0%, and negative predictive value (NPV) of 74.0%. The optimal cutoff, determined using Youden's index, was 23.75 ng/mL. This indicates that serum Sirt-1 levels below 23.75 ng/mL may be indicative of MASLD. CONCLUSIONS The present study demonstrated that serum Sirt-1 levels were significantly lower in patients with MASLD. Furthermore, these levels were correlated with various metabolic parameters, including insulin resistance and the serum lipid profile. A serum Sirt-1 level below the cutoff of 23.75 ng/mL exhibited a significant association with the presence of MASLD, suggesting its potential utility in identifying patients with this condition.
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Affiliation(s)
- Farshad Amirkhizi
- Department of Nutrition, School of Public Health, Zabol University of Medical Sciences, Zabol, Iran
| | - Mahdiyeh Taghizadeh
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, No#44, Hojjatdoust St., Naderi St., Keshavarz Blvd, Tehran, 141556117, Iran
| | - Banafshe Khalese-Ranjbar
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, No#44, Hojjatdoust St., Naderi St., Keshavarz Blvd, Tehran, 141556117, Iran
| | - Soudabeh Hamedi-Shahraki
- Department of Epidemiology and Biostatistics, School of Public Health, Zabol University of Medical Sciences, Zabol, Iran
| | - Somayyeh Asghari
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, No#44, Hojjatdoust St., Naderi St., Keshavarz Blvd, Tehran, 141556117, Iran.
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Elhemiely AA, Darwish A. Pharmacological and biochemical insights into lead-induced hepatotoxicity: Pathway interplay and the protective effects of arbutin via the oral and intraperitoneal routes in silico and in vivo. Int Immunopharmacol 2024; 142:112968. [PMID: 39226827 DOI: 10.1016/j.intimp.2024.112968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 08/12/2024] [Accepted: 08/15/2024] [Indexed: 09/05/2024]
Abstract
INTRODUCTION Lead acetate (PbAc), a hazardous heavy metal, poses significant threats to human health and the environment because of widespread industrial exposure. PbAc exposure leads to liver injury primarily through oxidative stress and the disruption of key regulatory pathways. Understanding these mechanisms and exploring protective agents are vital for mitigating PbAc-induced hepatotoxicity. Therefore, we aimed to investigate the molecular pathways implicated in PbAc-induced liver damage, focusing on Sirt-1, Nrf2 (HO-1, NQO1, and SOD), Akt-1/GSK3β, m-TOR, and P53. Additionally, we aimed to assess the hepatoprotective effects of arbutin, which is administered orally and intraperitoneally, to determine the most effective delivery method. METHODOLOGY In silico analyses were conducted to identify relevant protein networks associated with Sirt-1 and AKT-1/GSK-3B pathways. The pharmacodynamic properties of arbutin were examined, followed by molecular docking studies to elucidate its interactions with the selected protein network. In vivo preclinical studies were carried out on adult male rats randomly assigned to 6 different treatment groups, including PbAc exposure and PbAc exposure treated with arbutin either orally or intraperitoneally. RESULTS PbAc exposure led to hepatic oxidative stress, as evidenced by elevated MDA levels and SIRT-1 inhibition, disrupting antioxidant pathways and activating antiautophagic and proapoptotic pathways, ultimately resulting in hepatocyte necrosis. Both oral and intraperitoneal arbutin administration effectively modifed these effects, with intraperitoneal delivery showing superior efficacy in mitigating PbAc-induced histological, immunological, and biochemical alterations. CONCLUSION This study provides insights into the molecular mechanisms underlying PbAc-induced liver injury and highlights the hepatoprotective potential of arbutin. These findings suggest that arbutin, particularly when administered intraperitoneally, holds promise as a therapeutic agent for combating PbAc-induced hepatotoxicity.
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Affiliation(s)
| | - Alshaymaa Darwish
- Department of Biochemistry, Faculty of Pharmacy, Sohag University, Sohag, Egypt.
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Lei Y, Ma XL, Liu T, Wang MJ, Kang JS, Yang J, Mi N. Lactucin ameliorates FFA-induced steatosis in HepG2 cells by modulating mitochondrial homeostasis through the SIRT1/PGC-1α signaling axis. Heliyon 2024; 10:e39890. [PMID: 39524853 PMCID: PMC11550614 DOI: 10.1016/j.heliyon.2024.e39890] [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: 05/08/2024] [Revised: 10/25/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024] Open
Abstract
Nonalcoholic fatty liver disease is a complex disease involving abnormal liver metabolism. Its strong association with metabolic dysfunction has led to a change in nomenclature to metabolism dysfunction-associated fatty liver disease (MAFLD). MAFLD pathogenesis involves abnormal accumulation of hepatic lipids that lead to the production of excess free fatty acids (FFAs), which in turn cause an imbalance in hepatic mitochondrial function. Lactucin, a natural compound extracted from Cichorium glandulosum Boiss. et Huet, regulates liver metabolism and protects the liver. However, the potential mechanisms underlying the lactucin-mediated effects in MAFLD require further investigation. In the present study, HepG2 cells were treated with FFAs to establish an in vitro model of MAFLD. Parameters related to lipid accumulation and mitochondrial function, including triglycerides (TG), oil red O-stained lipid droplets, reactive oxygen species (ROS), mitochondrial membrane potential (JC-1), adenine triphosphate (ATP), and complex III were analysed. Morphology of the mitochondria were evaluated by transmission electron microscopy. Furthermore, key proteins in the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) signalling axis and mitochondrial quality control were analysed. The SIRT1 inhibitor EX-527 was used to verify the key role of the SIRT1 signalling pathway. Western blotting showed that lactucin upregulated the expression of SIRT-1, PGC-1α, Nrf1, Tfam, Mfn2, and Opa1, and promoted mitochondrial biosynthesis and kinetics. The results suggest that lactucin restores mitochondrial dynamic homeostasis by upregulating the SIRT1/PGC-1α signalling axis, thereby reducing FFA-induced lipid accumulation in HepG2 cells.
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Affiliation(s)
- Yi Lei
- College of Pharmacy, Xinjiang Medical University, Urumqi, 830011, China
| | - Xiao-li Ma
- College of Pharmacy, Xinjiang Medical University, Urumqi, 830011, China
- Key Laboratory of Active Components of Xinjiang Natural Medicine and Drug Release Technology, Urumqi, 830000, China
| | - Tong Liu
- Basic Medical College, Xinjiang Medical University, Urumqi, 830011, China
| | - Meng-jiao Wang
- College of Pharmacy, Xinjiang Medical University, Urumqi, 830011, China
| | - Jin-sen Kang
- College of Pharmacy, Xinjiang Medical University, Urumqi, 830011, China
- Key Laboratory of Active Components of Xinjiang Natural Medicine and Drug Release Technology, Urumqi, 830000, China
| | - Jian Yang
- College of Pharmacy, Xinjiang Medical University, Urumqi, 830011, China
- Key Laboratory of Active Components of Xinjiang Natural Medicine and Drug Release Technology, Urumqi, 830000, China
| | - Na Mi
- Key Laboratory of Active Components of Xinjiang Natural Medicine and Drug Release Technology, Urumqi, 830000, China
- Clinical Medicine Research Institute, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China
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Dadkhah Nikroo N, Jafarinejad H, Yousefi Z, Abdolvahabi Z, Malek M, Mortazavi P, Pazouki A, Mokhber S, Nourbakhsh M. Elevated mir-141 in obesity: Insights into the interplay with sirtuin 1 and non-alcoholic fatty liver disease. Obes Sci Pract 2024; 10:e70007. [PMID: 39345780 PMCID: PMC11427942 DOI: 10.1002/osp4.70007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 08/21/2024] [Accepted: 08/25/2024] [Indexed: 10/01/2024] Open
Abstract
Background Changes in gene expression related to obesity are linked to microRNAs, such as miR-141, which play a crucial role in metabolic homeostasis. Sirtuin 1 (SIRT1), an enzyme that plays a crucial role in regulating various cellular functions and metabolism, is implicated in obesity and the ensuing non-alcoholic fatty liver disease (NAFLD). The aim of this research was to evaluate the levels of miR-141 and its relationship with SIRT1 and NAFLD. Methods A group of 100 adults (50 with obesity and 50 with normal-weight) were selected and underwent complete clinical evaluation and anthropometric measurements. Biochemical parameters were assessed in blood serum, and the levels of miR-141 in plasma were measured by real-time PCR. The expression of the SIRT1 gene was also evaluated in the peripheral blood mononuclear cells using Real-time PCR. The ELISA technique was used to determine insulin levels. Liver steatosis was assessed by ultrasound. Results The results showed that levels of miR-141 were significantly increased in participants with obesity compared with the control group. Conversely, the expression of the SIRT1 gene in individuals with obesity was lower than that in control participants. A strong negative correlation was observed between miR-141 and SIRT1 and a strong positive association was observed between miR-141 and metabolic parameters. Furthermore, participants with fatty liver had significantly elevated levels of miR-141 gene expression and lower expression of SIRT1 gene, compared to those without fatty liver. Conclusion elevated levels of miR-141 in individuals with obesity might be a contributing factor in the repression of SIRT1 in obesity and its consequences, including NAFLD. Therefore, miR-141 might serve as a suitable diagnostic and therapeutic target in obesity and NAFLD.
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Affiliation(s)
- Nikta Dadkhah Nikroo
- Finetech in Medicine Research CenterIran University of Medical SciencesTehranIran
| | - Habib Jafarinejad
- Cancer Research Center and Department of ImmunologySchool of MedicineSemnan University of Medical SciencesSemnanIran
- Legal Medicine Research CenterLegal Medicine OrganizationTehranIran
| | - Zeynab Yousefi
- Department of Clinical BiochemistryFaculty of Medical ScienceTarbiat Modares UniversityTehranIran
| | - Zohreh Abdolvahabi
- Cellular and Molecular Research CentreResearch Institute for Prevention of Non‐Communicable DiseasesQazvin University of Medical SciencesQazvinIran
| | - Mojtaba Malek
- Research Center for Prevention of Cardiovascular DiseaseInstitute of Endocrinology and MetabolismIran University of Medical SciencesTehranIran
| | - Pejman Mortazavi
- Department of PathobiologyFaculty of Veterinary MedicineScience and Research BranchIslamic Azad UniversityTehranIran
| | - Abdolreza Pazouki
- Minimally Invasive Surgery Research CenterIran University of Medical SciencesTehranIran
| | - Somayeh Mokhber
- Minimally Invasive Surgery Research CenterIran University of Medical SciencesTehranIran
| | - Mitra Nourbakhsh
- Finetech in Medicine Research CenterIran University of Medical SciencesTehranIran
- Department of BiochemistrySchool of MedicineIran University of Medical SciencesTehranIran
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McGinty G, Przemioslo R. Effects of excess high-normal alanine aminotransferase levels in relation to new-onset metabolic dysfunction-associated fatty liver disease: Clinical implications. World J Gastroenterol 2024; 30:3264-3267. [PMID: 39086753 PMCID: PMC11287414 DOI: 10.3748/wjg.v30.i27.3264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 05/29/2024] [Accepted: 06/21/2024] [Indexed: 07/11/2024] Open
Abstract
In this editorial, we comment on the article by Chen et al recently published in 2024. We focus the debate on whether reducing the upper limit of normal of alanine aminotransferase (ALT) would effectively identify cases of fibrosis in metabolic-dysfunction associated fatty liver disease (MAFLD). This is important given the increasing prevalence of MAFLD and obesity globally. Currently, a suitable screening test to identify patients in the general population does not exist and most patients are screened after the finding of an abnormal ALT. The authors of this paper challenge the idea of what a normal ALT is and whether that threshold should be lowered, particularly as their study found that 83.12% of their study population with a diagnosis of MAFLD had a normal ALT. The main advantages of screening would be to identify patients and provide intervention early, the mainstay of this being changing modifiable risk factors and monitoring for liver fibrosis. However, there is not enough suitable therapeutic options available as of yet although this is likely to change in the coming years with more targets for therapy being discovered. Semaglutide is one example of this which has demonstrated benefit with an acceptable side effect profile for those patients with MAFLD and obesity, although studies have not yet shown a significant improvement in fibrosis regression. It would also require a huge amount of resource if a reduced ALT level alone was used as criteria; it is more likely that current scoring systems such as fibrosis-4 may be amended to represent this additional risk. Currently, there is not a good argument to recommend widespread screening with a reduced ALT level as this is unlikely to be cost-effective. This is compounded by the fact that there is a significant heterogeneity in what is considered a normal ALT between laboratories. Although studies previously have suggested a more pragmatic approach in screening those over the age of 60, this is likely to change with the increasing incidence of obesity within the younger age groups. The main message from this study is that those who have hypercholesterolemia and high body metabolic index should have these risk factors modified to maintain a lower level of ALT to reduce the risk of progression to fibrosis and cirrhosis.
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Affiliation(s)
- Giovanna McGinty
- Department of Gastroenterology, North Bristol Trust, Southmead Hospital, Bristol BS10 5NB, United Kingdom
| | - Robert Przemioslo
- Department of Gastroenterology and Hepatology, North Bristol Trust, Southmead Hospital, Bristol BS10 5NB, United Kingdom
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Li S, Xiong F, Zhang S, Liu J, Gao G, Xie J, Wang Y. Oligonucleotide therapies for nonalcoholic steatohepatitis. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102184. [PMID: 38665220 PMCID: PMC11044058 DOI: 10.1016/j.omtn.2024.102184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/28/2024]
Abstract
Nonalcoholic steatohepatitis (NASH) represents a severe disease subtype of nonalcoholic fatty liver disease (NAFLD) that is thought to be highly associated with systemic metabolic abnormalities. It is characterized by a series of substantial liver damage, including hepatocellular steatosis, inflammation, and fibrosis. The end stage of NASH, in some cases, may result in cirrhosis and hepatocellular carcinoma (HCC). Nowadays a large number of investigations are actively under way to test various therapeutic strategies, including emerging oligonucleotide drugs (e.g., antisense oligonucleotide, small interfering RNA, microRNA, mimic/inhibitor RNA, and small activating RNA) that have shown high potential in treating this fatal liver disease. This article systematically reviews the pathogenesis of NASH/NAFLD, the promising druggable targets proven by current studies in chemical compounds or biological drug development, and the feasibility and limitations of oligonucleotide-based therapeutic approaches under clinical or pre-clinical studies.
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Affiliation(s)
- Sixu Li
- Department of Pathophysiology, West China College of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610066, China
| | - Feng Xiong
- Department of Cardiology, The Third People’s Hospital of Chengdu, Chengdu 610031, China
| | - Songbo Zhang
- Department of Breast Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, China
| | - Jinghua Liu
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Guangping Gao
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Viral Vector Core, University of Massachusetts Chan Medical, School, Worcester, MA 01605, USA
| | - Jun Xie
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Viral Vector Core, University of Massachusetts Chan Medical, School, Worcester, MA 01605, USA
| | - Yi Wang
- Department of Pathophysiology, West China College of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610066, China
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BinMowyna MN, AlFaris NA, Al-Sanea EA, AlTamimi JZ, Aldayel TS. Resveratrol attenuates against high-fat-diet-promoted non-alcoholic fatty liver disease in rats mainly by targeting the miR-34a/SIRT1 axis. Arch Physiol Biochem 2024; 130:300-315. [PMID: 35254877 DOI: 10.1080/13813455.2022.2046106] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/18/2022] [Indexed: 11/09/2022]
Abstract
This study evaluated if miR-34a/SIRT1 signalling mediates the anti-hepatosteatotic effect of resveratrol (RSV) in high-fat-diet (HFD)-fed rats. Rats were divided into seven groups (n = 6/each) as control, control + miR-34a agomir negative control, HFD, HFD + miR-34a, HFD + RSV, HFD + RSV + Ex-527 (a SIRT1 inhibitor), and HFD + RSV + miR-34a agomir. After 8 weeks, RSV suppressed dyslipidemia, lowered fasting glucose and insulin levels, improved insulin sensitivity, and prevented hepatic lipid accumulation. These effects were associated with hepatic downregulation of SREBP1 and SREBP2, upregulation of PPARα, and acetylation of Nrf2 (activation) and NF-κβ p65 (inhibition). Also, RSV reduced the transcription of miR-34a and increased the nuclear localisation of SIRT1 in the livers, muscles, and adipose tissues of HFD-fed rats. All these effects were prevented by EX-527 and miR-34a agmir. In conclusion, RSV prevents HFD-induced insulin resistance and hepatic steatosis by suppressing miR-34a-induced activation of SIRT1.
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Affiliation(s)
- Mona N BinMowyna
- College of Applied Medical Sciences, Shaqra University, Shaqra, Saudi Arabia
| | - Nora A AlFaris
- Department of Physical Sport Science, College of Education, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Ekram A Al-Sanea
- Department of Biology, College of Sciences, Ibb University, Ibb, Yemen
| | - Jozaa Z AlTamimi
- Department of Physical Sport Science, College of Education, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Tahany S Aldayel
- Department of Physical Sport Science, College of Education, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
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Sedik AA, Elgohary R, Khalifa E, Khalil WKB, I Shafey H, B Shalaby M, S O Gouida M, M Tag Y. Lauric acid attenuates hepato-metabolic complications and molecular alterations in high-fat diet-induced nonalcoholic fatty liver disease in rats. Toxicol Mech Methods 2024; 34:454-467. [PMID: 38166588 DOI: 10.1080/15376516.2023.2301344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/29/2023] [Accepted: 12/29/2023] [Indexed: 01/04/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as a major chronic liver illness characterized by increase of lipid content in the liver. This study investigated the role of lauric acid to treat NAFLD in male adult Sprague Dawley rats. In this study, to induce NAFLD in the rats, a high-fat diet (HFD) was administered for eight consecutive weeks. Lauric acid groups received lauric acid (250 and 500 mg/kg; orally), concurrently with HFD for eight consecutive weeks. Lauric acid could ameliorate the serum levels of TG, TC, ALT, AST, blood glucose, and insulin. Moreover, lauric acid significantly elevated the levels of SOD, GSH, catalase, and IL-10. Additionally, it lowered the hepatic levels of MDA, ROS, MPO, 4-HNE, interleukin (IL)-1β, and tumor necrosis factor (TNF-α). Furthermore, lauric acid significantly up-regulated the hepatic expression of IRS1, AMPK, PI3K, and SIRT1 genes. In parallel, lauric acid could improve the histopathological picture of the liver and reduce the liver apoptosis via decreasing the expression of annexin V (Anx V). Finally, our data proposed that lauric acid could be an effective candidate for the NAFLD treatment.
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Affiliation(s)
- Ahmed A Sedik
- Pharmacology Department, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Rania Elgohary
- Narcotics, Ergogenics and Poisons Department, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Eman Khalifa
- Oral Biology Department, Faculty of Oral and Dental Medicine, Delta University for Science and Technology, Mansoura, Egypt
| | | | - Heba I Shafey
- Cell Biology Department, National Research Centre, Giza, Egypt
| | - Mohamed B Shalaby
- Toxicology Research Department, Research Institute of Medical Entomology (RIME), General Organisation of Teaching Hospitals and Institutes (GOTHI), Ministry of Health and Population (MoHP), Cairo, Egypt
| | - Mona S O Gouida
- Genetics Unit, Faculty of Medicine, Children Hospital, Mansoura University, Mansoura, Egypt
| | - Yasmin M Tag
- Oral Biology Department, Faculty of Oral and Dental Medicine, Delta University for Science and Technology, Mansoura, Egypt
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She Y, Guo Z, Zhai Q, Liu J, Du Q, Zhang Z. CDK4/6 inhibitors in drug-induced liver injury: a pharmacovigilance study of the FAERS database and analysis of the drug-gene interaction network. Front Pharmacol 2024; 15:1378090. [PMID: 38633610 PMCID: PMC11021785 DOI: 10.3389/fphar.2024.1378090] [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: 01/29/2024] [Accepted: 03/20/2024] [Indexed: 04/19/2024] Open
Abstract
Objective The aim of this study was to investigate the potential risk of drug-induced liver injury (DILI) caused by the CDK4/6 inhibitors (CDK4/6is abemaciclib, ribociclib, and palbociclib by comprehensively analyzing the FDA Adverse Event Reporting System (FAERS) database. Moreover, potential toxicological mechanisms of CDK4/6is-related liver injury were explored via drug-gene network analysis. Methods In this retrospective observational study, we collected reports of DILI associated with CDK4/6i use from the FAERS dated January 2014 to March 2023. We conducted disproportionality analyses using the reporting odds ratio (ROR) with a 95% confidence interval (CI). Pathway enrichment analysis and drug-gene network analyses were subsequently performed to determine the potential mechanisms underlying CDK4/6i-induced liver injury. Results We found positive signals for DILI with ribociclib (ROR = 2.60) and abemaciclib (ROR = 2.37). DILIs associated with liver-related investigations, signs, and symptoms were confirmed in all three reports of CDK4/6is. Moreover, ascites was identified as an unlisted hepatic adverse effect of palbociclib. We isolated 189 interactive target genes linking CDK4/6 inhibitors to hepatic injury. Several key genes, such as STAT3, HSP90AA1, and EP300, were revealed via protein-protein analysis, emphasizing their central roles within the network. KEGG pathway enrichment of these genes highlighted multiple pathways. Conclusion Our study revealed variations in hepatobiliary toxicity among the different CDK4/6 inhibitors, with ribociclib showing the highest risk of liver injury, followed by abemaciclib, while palbociclib appeared relatively safe. Our findings emphasize the need for cautious use of CDK4/6 inhibitors, and regular liver function monitoring is recommended for long-term CDK4/6 inhibitor use.
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Affiliation(s)
- Youjun She
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zihan Guo
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qing Zhai
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jiyong Liu
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qiong Du
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhongwei Zhang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Critical Care, Fudan University Shanghai Cancer Center, Shanghai, China
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11
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Ulubasoglu H, Hancerliogullari N, Tokmak A, Keskin LH, Candar T, Moraloglu Tekin O. Low sirtuin-1 levels are associated with gestational diabetes mellitus. Minerva Endocrinol (Torino) 2023; 48:282-287. [PMID: 36285745 DOI: 10.23736/s2724-6507.22.03868-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
BACKGROUND The aim of this study was to determine whether sirtuin-1 (SIRT1), which has a regulatory role in glucose and lipid metabolism with its deacetylase activity, has a decisive role in predicting gestational diabetes (GDM). METHODS This study was performed at the antenatal outpatient clinic of Ankara City Hospital between January 2021 and May 2021. A total of 525 women with low-risk pregnancy underwent the 75 g oral glucose tolerance test (OGTT) between 24th-28th weeks of pregnancy during the study period. Fasting serum SIRT1 levels of patients diagnosed with GDM according to OGTT results were compared some of those without GDM. RESULTS Of the 525 pregnant women who underwent 75 g OGTT, 50 (9.6%) were diagnosed with GDM. The data of pregnant women with GDM were compared with age and Body Mass Index matched 122 controls. While serum SIRT1 levels were 22.0 (19.9-24.3) ng/mL in the GDM group, it was 34.7 (28.8-54.6) ng/mL in the control group (P<0.001). ROC curve analysis showed that a threshold level for serum SIRT1 equal to or greater than 27.3 ng/mL may predict GDM with a sensitivity of 86% and specificity of 80%. CONCLUSIONS Second-trimester low serum SIRT1 levels are associated with GDM. It may be a diagnostic marker for GDM.
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Affiliation(s)
- Hasan Ulubasoglu
- Department of Obstetrics and Gynecology, Ankara Bilkent City Hospital, Ankara, Türkiye
| | | | - Aytekin Tokmak
- Department of Obstetrics and Gynecology, Ankara Bilkent City Hospital, Ankara, Türkiye
| | - Levent H Keskin
- Department of Obstetrics and Gynecology, Ankara Bilkent City Hospital, Ankara, Türkiye
| | - Tuba Candar
- Department of Medical Biochemistry, Ufuk University, Ankara, Türkiye
| | - Ozlem Moraloglu Tekin
- Department of Obstetrics and Gynecology, Ankara Bilkent City Hospital, Ankara, Türkiye
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12
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Liu J, Gao S, Zhou W, Chen Y, Wang Z, Zeng Z, Zhou H, Lin T. Dihydrotrichodimerol Purified from the Marine Fungus Acremonium citrinum Prevents NAFLD by Targeting PPARα. JOURNAL OF NATURAL PRODUCTS 2023; 86:1189-1201. [PMID: 37083418 DOI: 10.1021/acs.jnatprod.2c00990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2023]
Abstract
The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is closely linked to the imbalance of lipid and glucose metabolism, in which peroxisome proliferator-activated receptors (PPARs) play essential roles. The clinical trials have shown the beneficial effects of the PPARs' ligands on NAFLD. In this study, we screen the extracts from the marine fungus Acremonium citrinum and identify the natural compounds dihydrotrichodimerol (L1A) and trichodimerol (L1B) as the ligands of PPARs, of which L1A is a dual PPARα/γ agonist, whereas L1B is a selective PPARγ agonist. L1A but not L1B significantly prevents hepatic lipid accumulation in an oleic acid-induced NAFLD cell model as well as in a high-fat-diet-induced NAFLD mouse model. Moreover, L1A potently inhibits hepatic steatosis in a PPARα-dependent manner in another NAFLD mouse model constructed by using a choline-deficient and amino acid-defined diet. Mechanistically, L1A transcriptionally up-regulates the expression of SIRT1 in a PPARα-dependent manner, followed by the activation of AMPK and inactivation of ACC, resulting in the inhibition of lipid anabolism and the increase of lipid catabolism. Taken together, our study reveals a dual ligand of PPARα/γ with a distinct structure and therapeutic effect on NAFLD, providing a potential drug candidate bridging the currently urgent need for the management of NAFLD.
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Affiliation(s)
- Jie Liu
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen, Fujian 361102, China
| | - Shuo Gao
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen, Fujian 361102, China
| | - Wanxuan Zhou
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen, Fujian 361102, China
| | - Yongyan Chen
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen, Fujian 361102, China
| | - Zhenwu Wang
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen, Fujian 361102, China
- High Throughput Drug Screening Platform, Xiamen University, Xiamen, Fujian 361102, China
| | - Zhiping Zeng
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen, Fujian 361102, China
- High Throughput Drug Screening Platform, Xiamen University, Xiamen, Fujian 361102, China
| | - Hu Zhou
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen, Fujian 361102, China
- High Throughput Drug Screening Platform, Xiamen University, Xiamen, Fujian 361102, China
| | - Ting Lin
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen, Fujian 361102, China
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13
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Pal SC, Méndez-Sánchez N. Screening for MAFLD: who, when and how? Ther Adv Endocrinol Metab 2023; 14:20420188221145650. [PMID: 36699945 PMCID: PMC9869195 DOI: 10.1177/20420188221145650] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 11/26/2022] [Indexed: 01/22/2023] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) is a highly prevalent disease with increasing prevalence worldwide. Currently, no universal screening methods have been standardized, even when this disease poses a major health burden. MAFLD as a spectrum of diseases can range from simple steatosis, and steatohepatitis to fibrosis and hepatocellular carcinoma. Its extra-hepatic manifestations are vast and include cardiovascular diseases, extra-hepatic malignancies, cognitive and respiratory alterations. Given its extensive damage targets as well as its high prevalence, timely identification of the high-risk population presenting metabolic dysfunction should undergo universal non-invasive screening methods, which can be carried out through blood tests, easy and effective imaging techniques, such as ultrasound, score calculation and general clinical information brought together from primary patient-physician contact.
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Affiliation(s)
- Shreya C. Pal
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
- Liver Research Unit, Medica Sur Clinic Foundation, Mexico City, Mexico
| | - Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic Foundation, Puente de Piedra 150, 14050 Mexico City, Mexico
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
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14
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Mechanisms of Action of Mesenchymal Stem Cells in Metabolic-Associated Fatty Liver Disease. Stem Cells Int 2023; 2023:3919002. [PMID: 36644008 PMCID: PMC9839417 DOI: 10.1155/2023/3919002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 11/15/2022] [Accepted: 12/09/2022] [Indexed: 01/09/2023] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) is currently the most common chronic liver disease worldwide. However, its pathophysiological mechanism is complicated, and currently, it has no FDA-approved pharmacological therapies. In recent years, mesenchymal stem cell (MSC) therapy has attracted increasing attention in the treatment of hepatic diseases. MSCs are multipotent stromal cells that originated from mesoderm mesenchyme, which have self-renewal and multipotent differentiation capability. Recent experiments and studies have found that MSCs have the latent capacity to be used for MAFLD treatment. MSCs have the potential to differentiate into hepatocytes, which could be induced into hepatocyte-like cells (HLCs) with liver-specific morphology and function under appropriate conditions to promote liver tissue regeneration. They can also reduce liver tissue injury and reverse the development of MAFLD by regulating immune response, antifibrotic activities, and lipid metabolism. Moreover, several advantages are attributed to MSC-derived exosomes (MSC-exosomes), such as targeted delivery, reliable reparability, and poor immunogenicity. After entering the target cells, MSC-exosomes help regulate cell function and signal transduction; thus, it is expected to become an emerging treatment for MAFLD. In this review, we comprehensively discussed the roles of MSCs in MAFLD, main signaling pathways of MSCs that affect MAFLD, and mechanisms of MSC-exosomes on MAFLD.
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15
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Pal SC, Eslam M, Mendez-Sanchez N. Detangling the interrelations between MAFLD, insulin resistance, and key hormones. Hormones (Athens) 2022; 21:573-589. [PMID: 35921046 DOI: 10.1007/s42000-022-00391-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 07/19/2022] [Indexed: 11/04/2022]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) has increasingly become a significant and highly prevalent cause of chronic liver disease, displaying a wide array of risk factors and pathophysiologic mechanisms of which only a few have so far been clearly elucidated. A bidirectional interaction between hormonal discrepancies and metabolic-related disorders, including obesity, type 2 diabetes mellitus (T2DM), and polycystic ovarian syndrome (PCOS) has been described. Since the change in nomenclature from non-alcoholic fatty liver disease (NAFLD) to MAFLD is based on the clear impact of metabolic elements on the disease, the reciprocal interactions of hormones such as insulin, adipokines (leptin and adiponectin), and estrogens have strongly pointed to the intrinsic links that lead to the heterogeneous epidemiology, clinical presentations, and risk factors involved in MAFLD in different populations. The objective of this work is twofold. Firstly, there is a brief discussion regarding the change in nomenclature as well as epidemiology, risk factors, and pathophysiologic mechanisms other than hormonal effects, which include nutrition and the gut microbiome, as well as genetic and epigenetic influences. Secondly, we review the basis of the most important hormonal factors involved in the development and progression of MAFLD that act both independently and in an interrelated manner.
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Affiliation(s)
- Shreya C Pal
- Faculty of Medicine, National Autonomous University of Mexico, Av. Universidad 3000, Coyoacán, 4510, Mexico City, Mexico
- Liver Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150. Col. Toriello Guerra, 14050, Tlalpan, Mexico City, Mexico
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital, University of Sydney, Sydney, NSW, Australia
| | - Nahum Mendez-Sanchez
- Faculty of Medicine, National Autonomous University of Mexico, Av. Universidad 3000, Coyoacán, 4510, Mexico City, Mexico.
- Liver Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150. Col. Toriello Guerra, 14050, Tlalpan, Mexico City, Mexico.
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16
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Harchegani AB, Rostami S, Mohsenifar Z, Dafchahi AB, Moghadam FM, Jaafarzadeh M, Saraabestan SS, Ranji N. Anti-apoptotic properties of N-Acetyl cysteine and its effects on of Liver X receptor and Sirtuin 1 expression in the liver of rats exposed to Lead. J Trace Elem Med Biol 2022; 74:127070. [PMID: 36155419 DOI: 10.1016/j.jtemb.2022.127070] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 05/22/2022] [Accepted: 09/08/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND This study aimed to evaluate the expression of Liver X receptor (Lxr), Sirtuin 1 (Sirt1), apoptotic-related genes, and the protective role of N-acetylcysteine (NAC) in the liver of rats treated with Lead (Pb). METHODS Rats were randomly divided into 5 groups, including G1 (control), G2 (single dose of Pb), G3 (continuous dose of Pb), G4 (single dose of Pb + NAC), and G5 (continuous dose of Pb + NAC). Lipid profiles and liver specific enzymes were assessed. Expression of Lxr, Sirt1, Bax and Caspase-3 genes was considered using RT-PCR. RESULTS Exposure to Pb caused a significant accumulation of Pb in the blood and liver tissue, increase in serum AST, ALT and ALP enzymes, as well as lipid profiles. Chronic exposure to Pb caused a significant decrease in Lxr (3.15-fold; p < 0.001) and Sirt1 (2.78-fold; p = 0.009), but significant increase in expression of Bax (4.49-fold; p < 0.001) and Caspase-3 (4.10-fold; p < 0.001) genes when compared to the control. Combined therapy with Pb + NAC in rats caused a significant decrease in AST, ALT and ALP values (28.93%, 20.80% and 28.86%, respectively) in the blood as compared to rats treated with Pb alone. Co-treated with Pb + NAC significantly increased the expression of Lxr (1.72-fold; p = 0.043) and Sirt1 (2.45-fold; p = 0.008), but decreased the expression of Bax (1.96-fold; p = 0.03) and Caspase 3 (2.22-fold; p = 0.029) genes when compared to rats treated with Pb alone. CONCLUSION Chronic exposure to Pb is strongly associated with accumulation of Pb in the blood and liver, hepatic cells apoptosis, down-expression of Lxr and Sirt1 genes and consequently liver injury and abnormal lipid profiles. NAC reversed the Pb-induced toxicity on the liver tissue.
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Affiliation(s)
- Asghar Beigi Harchegani
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Sareh Rostami
- Department of Biology, Faculty of Sciences, Rasht Branch, Islamic Azad University, Rasht, Iran.
| | - Zhaleh Mohsenifar
- Ayatollah Taleghani Educational Hospital, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Alireza Beheshti Dafchahi
- Department of Environmental Science and Engineering, Faculty of Agriculture, Tabriz Branch, Islamic Azad University, Tabriz, Iran.
| | | | - Mohammad Jaafarzadeh
- Department of Biology, Faculty of Sciences, Rasht Branch, Islamic Azad University, Rasht, Iran.
| | | | - Najmeh Ranji
- Department of Biology, Faculty of Sciences, Rasht Branch, Islamic Azad University, Rasht, Iran.
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17
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Pu'er raw tea extract alleviates lipid deposition in both LO2 cells and Caenorhabditis elegans. FOOD BIOSCI 2022. [DOI: 10.1016/j.fbio.2022.102172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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18
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Shen W, Wan X, Hou J, Liu Z, Mao G, Xu X, Yu C, Zhu X, Ju Z. Peroxisome proliferator-activated receptor γ coactivator 1α maintains NAD + bioavailability protecting against steatohepatitis. LIFE MEDICINE 2022; 1:207-220. [PMID: 39871927 PMCID: PMC11749270 DOI: 10.1093/lifemedi/lnac031] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 08/16/2022] [Indexed: 01/11/2025]
Abstract
Hepatic metabolic derangements are pivotal incidences in the occurrence of hepatic steatosis, inflammation, and fibrosis. Peroxisome proliferator-activated receptor-γ, coactivator-1α (PGC-1α), a master regulator that mediates adipose metabolism and mitochondrial biogenesis, its role in hepatic steatosis and progression to steatohepatitis remains elusive. By surveying genomic data on nonalcoholic steatohepatitis (NASH) patients available in the Gene Expression Omnibus, we found that PGC-1α was significantly down-regulated compared with healthy controls, implicating the restoration of PGC-1α may ameliorate the hepatopathy. Using a hepatocyte-specific PGC-1α overexpression (LivPGC1α) mouse model, we demonstrated that PGC-1α attenuated hepatic steatosis induced by methionine-choline-deficient diet (MCD). Biochemical measurements and histological examination indicated less inflammatory infiltration, collagen deposition, NF-kB activation, and less lipid accumulation in LivPGC1α liver fed MCD. Further analyses indicated that the NAD+-dependent deacetylase sirtuin 2 (SIRT2) interacted with and deacetylated PGC-1α. Congruently, ablation of SIRT2 accelerated the NASH progression in mice fed MCD, while NAD+ repletion via its precursor mimicked the beneficial effect of PGC-1α overexpression and was sufficient to alleviate NASH in mice. These findings indicate that hepatic-specific overexpression of PGC-1α exerts a beneficial role in the regulation of steatohepatitis and that pharmacological activation of the SIRT2-PGC-1α-NAD+ axis may help to treat NASH.
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Affiliation(s)
- Weiyan Shen
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China
- Key Laboratory of Regenerative Medicine of Ministry of Education, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China
| | - Xingyong Wan
- Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Jiahui Hou
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China
| | - Zhu Liu
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China
| | - Genxiang Mao
- Zhejiang Provincial Key Lab of Geriatrics & Geriatrics Research Institute of Zhejiang Province, Department of Geriatrics, Zhejiang Hospital, Hangzhou 310013, China
| | - Xiaogang Xu
- Zhejiang Provincial Key Lab of Geriatrics & Geriatrics Research Institute of Zhejiang Province, Department of Geriatrics, Zhejiang Hospital, Hangzhou 310013, China
| | - Chaohui Yu
- Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Xudong Zhu
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China
| | - Zhenyu Ju
- Key Laboratory of Regenerative Medicine of Ministry of Education, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China
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All Roads Lead to Cathepsins: The Role of Cathepsins in Non-Alcoholic Steatohepatitis-Induced Hepatocellular Carcinoma. Biomedicines 2022; 10:biomedicines10102351. [PMID: 36289617 PMCID: PMC9598942 DOI: 10.3390/biomedicines10102351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/16/2022] [Accepted: 09/16/2022] [Indexed: 11/17/2022] Open
Abstract
Cathepsins are lysosomal proteases that are essential to maintain cellular physiological homeostasis and are involved in multiple processes, such as immune and energy regulation. Predominantly, cathepsins reside in the lysosomal compartment; however, they can also be secreted by cells and enter the extracellular space. Extracellular cathepsins have been linked to several pathologies, including non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). NASH is an increasingly important risk factor for the development of HCC, which is the third leading cause of cancer-related deaths and poses a great medical and economic burden. While information regarding the involvement of cathepsins in NASH-induced HCC (NASH-HCC) is limited, data to support the role of cathepsins in either NASH or HCC is accumulating. Since cathepsins play a role in both NASH and HCC, it is likely that the role of cathepsins is more significant in NASH-HCC compared to HCC derived from other etiologies. In the current review, we provide an overview on the available data regarding cathepsins in NASH and HCC, argue that cathepsins play a key role in the transition from NASH to HCC, and shed light on therapeutic options in this context.
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20
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Zeng C, Chen M. Progress in Nonalcoholic Fatty Liver Disease: SIRT Family Regulates Mitochondrial Biogenesis. Biomolecules 2022; 12:1079. [PMID: 36008973 PMCID: PMC9405760 DOI: 10.3390/biom12081079] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 08/02/2022] [Accepted: 08/03/2022] [Indexed: 11/16/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance, mitochondrial dysfunction, inflammation, and oxidative stress. As a group of NAD+-dependent III deacetylases, the sirtuin (SIRT1-7) family plays a very important role in regulating mitochondrial biogenesis and participates in the progress of NAFLD. SIRT family members are distributed in the nucleus, cytoplasm, and mitochondria; regulate hepatic fatty acid oxidation metabolism through different metabolic pathways and mechanisms; and participate in the regulation of mitochondrial energy metabolism. SIRT1 may improve NAFLD by regulating ROS, PGC-1α, SREBP-1c, FoxO1/3, STAT3, and AMPK to restore mitochondrial function and reduce steatosis of the liver. Other SIRT family members also play a role in regulating mitochondrial biogenesis, fatty acid oxidative metabolism, inflammation, and insulin resistance. Therefore, this paper comprehensively introduces the role of SIRT family in regulating mitochondrial biogenesis in the liver in NAFLD, aiming to further explain the importance of SIRT family in regulating mitochondrial function in the occurrence and development of NAFLD, and to provide ideas for the research and development of targeted drugs. Relatively speaking, the role of some SIRT family members in NAFLD is still insufficiently clear, and further research is needed.
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Affiliation(s)
| | - Mingkai Chen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhidong Road, Wuhan 430060, China
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21
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Sodum N, Rao V, Cheruku SP, Kumar G, Sankhe R, Kishore A, Kumar N, Rao CM. Amelioration of high-fat diet (HFD) + CCl4 induced NASH/NAFLD in CF-1 mice by activation of SIRT-1 using cinnamoyl sulfonamide hydroxamate derivatives: in-silico molecular modelling and in-vivo prediction. 3 Biotech 2022; 12:147. [PMID: 35720958 PMCID: PMC9200928 DOI: 10.1007/s13205-022-03192-5] [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: 12/11/2021] [Accepted: 04/28/2022] [Indexed: 11/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the major hepatic metabolic disorders that occurs because of the accumulation of lipids in hepatocytes in the form of free fatty acids (FFA) and triglycerides (TG) which become non-alcoholic steatohepatitis (NASH). NOTCH-1 receptors act as novel targets for the development of NAFLD/NASH, where overexpression of NOTCH-1 receptor alters the lipid metabolism in hepatocytes leading to NAFLD. SIRT-1 deacetylates the NOTCH-1 receptor and inhibits NAFLD. Hence, computer-aided drug design (CADD) was used to check the SIRT-1 activation ability of cinnamic sulfonyl hydroxamate derivatives (NMJ 1–8), resveratrol, and vorinostat. SIRT-1 (PDB ID: 5BTR) was docked with eight hydroxamate derivatives and vorinostat using Schrödinger software. Based on binding energy obtained (– 26.31 to – 47.34 kcal/mol), vorinostat, NMJ-2, NMJ-3, NMJ-5 were selected for induced-fit docking (IFD) and results were within – 750.70 to – 753.22 kcal/mol. Qikprop tool was used to analyse the pre pharmacokinetic parameters (ADME analysis) of all hydroxamate compounds. As observed in the molecular dynamic (MD) study, NMJ-2, NMJ-3 were showing acceptable results for activation of SIRT-1. Based on these predictions, in-vivo studies were conducted in CF1 mice, where NMJ-3 showed significant (p < 0.05) changes in lipid profile and anti-oxidant parameters (Catalase, SOD, GSH, nitrite, and LPO) and plasma insulin levels. NMJ-3 treatment also reduced inflammation, fibrosis, and necrosis in liver samples.
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Affiliation(s)
- Nalini Sodum
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104 Karnataka India
| | - Vanishree Rao
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104 Karnataka India
| | - Sri Pragnya Cheruku
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104 Karnataka India
| | - Gautam Kumar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104 Karnataka India
| | - Runali Sankhe
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104 Karnataka India
| | - Anoop Kishore
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104 Karnataka India
| | - Nitesh Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Export Promotions Industrial Park (EPIP), Industrial Area Hajipur, Vaishali District, Hajipur, 844102 Bihar India
| | - C Mallikarjuna Rao
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104 Karnataka India
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Effects of Resveratrol Supplementation and Exercise on Apoptosis, Lipid Profile, and Expression of Farnesoid X Receptor, Liver X Receptor and Sirtuin 1 Genes in the Liver of Type 1 Diabetic Rats. MEDICAL LABORATORY JOURNAL 2022. [DOI: 10.52547/mlj.16.4.39] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2023] Open
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23
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Wei K, Wei Y, Xu W, Lu F, Ma H. Corn peptides improved obesity-induced non-alcoholic fatty liver disease through relieving lipid metabolism, insulin resistance and oxidative stress. Food Funct 2022; 13:5782-5793. [PMID: 35537139 DOI: 10.1039/d2fo00199c] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is increasingly threatening human health. The remarkable effects of corn peptides (CPs) as bioactive peptides on liver protection have attracted much attention. Nevertheless, the specific effect of CPs on NAFLD remains unclear. The present study was designed to investigate the efficacy of CPs in the prevention and auxiliary treatment of high-fat diet (HFD)-induced NAFLD in SD rats, and puerarin was used as the positive control. SD rats were fed a high-fat diet to establish the NAFLD rat model, and LO2 cells were treated with a high concentration of fructose to simulate the NAFLD cell model. NAFLD was comprehensively examined in terms of body weight, liver function markers, serum biochemistry and liver histology. Protein expression was determined using western blot analysis. The results of animal experiments showed that CPs could effectively inhibit the rate of weight gain, reduce the blood lipid level and liver index, and enhance glucose tolerance. The results of cell experiments showed that CPs could effectively reduce the accumulation of lipids in LO2 cells and inhibit the accumulation of reactive oxygen species (ROS). In addition, CPs could markedly reduce liver lipid accumulation in the liver cell and liver tissue, as further evidenced by the reduced expression of SREBP-1c in human non-tumour hepatic (LO2) cells. Meanwhile, the increased expression of SIRT1/PPAR-α and Nrf2/HO-1 pathways under the pretreatment of CPs in LO2 cells indicated that CPs could markedly relieve high fat-induced fatty liver injury, regulate insulin sensitivity, and reduce production of ROS. The results of in vivo and in vitro experiments demonstrated that CPs provided potential prevention and auxiliary treatment for NAFLD through reducing lipid accumulation, alleviating insulin resistance, and inhibiting oxidative stress. This study investigated the biological activity of CPs and laid the theoretical basis for the development of CP-based functional foods and dietary supplements.
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Affiliation(s)
- Kang Wei
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, 212013, P. R. China.
| | - Yang Wei
- School of Agriculture and Biology, Shanghai Jiaotong University, Shanghai, 200204, P. R. China
| | - Weidong Xu
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, 212013, P. R. China.
| | - Feng Lu
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, 212013, P. R. China.
| | - Haile Ma
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, 212013, P. R. China.
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Pedroza-Diaz J, Arroyave-Ospina JC, Serna Salas S, Moshage H. Modulation of Oxidative Stress-Induced Senescence during Non-Alcoholic Fatty Liver Disease. Antioxidants (Basel) 2022; 11:antiox11050975. [PMID: 35624839 PMCID: PMC9137746 DOI: 10.3390/antiox11050975] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/18/2022] [Accepted: 05/05/2022] [Indexed: 01/10/2023] Open
Abstract
Non-alcoholic fatty liver disease is characterized by disturbed lipid metabolism and increased oxidative stress. These conditions lead to the activation of different cellular response mechanisms, including senescence. Cellular senescence constitutes an important response to injury in the liver. Recent findings show that chronic oxidative stress can induce senescence, and this might be a driving mechanism for NAFLD progression, aggravating the disturbance of lipid metabolism, organelle dysfunction, pro-inflammatory response and hepatocellular damage. In this context, the modulation of cellular senescence can be beneficial to ameliorate oxidative stress-related damage during NAFLD progression. This review focuses on the role of oxidative stress and senescence in the mechanisms leading to NAFLD and discusses the possibilities to modulate senescence as a therapeutic strategy in the treatment of NAFLD.
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Affiliation(s)
- Johanna Pedroza-Diaz
- University Medical Center Groningen, Department of Gastroenterology and Hepatology, University of Groningen, 9712 CP Groningen, The Netherlands; (J.P.-D.); (S.S.S.); (H.M.)
- Grupo de Investigación e Innovación Biomédica GI2B, Facultad de Ciencias Exactas y Aplicadas, Instituto Tecnológico Metropolitano, Medellín 050536, Colombia
| | - Johanna C. Arroyave-Ospina
- University Medical Center Groningen, Department of Gastroenterology and Hepatology, University of Groningen, 9712 CP Groningen, The Netherlands; (J.P.-D.); (S.S.S.); (H.M.)
- Correspondence:
| | - Sandra Serna Salas
- University Medical Center Groningen, Department of Gastroenterology and Hepatology, University of Groningen, 9712 CP Groningen, The Netherlands; (J.P.-D.); (S.S.S.); (H.M.)
| | - Han Moshage
- University Medical Center Groningen, Department of Gastroenterology and Hepatology, University of Groningen, 9712 CP Groningen, The Netherlands; (J.P.-D.); (S.S.S.); (H.M.)
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Yin Y, Li D, Liu F, Wang X, Cui Y, Li S, Li X. The Ameliorating Effects of Apple Polyphenol Extract on High-Fat-Diet-Induced Hepatic Steatosis Are SIRT1-Dependent: Evidence from Hepatic-Specific SIRT1 Heterozygous Mutant C57BL/6 Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:5579-5594. [PMID: 35485931 DOI: 10.1021/acs.jafc.2c01461] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Apple polyphenol extract (APE) has been reported to possess protective effects against hepatic steatosis. To explore whether APE-induced alleviation of hepatic steatosis is SIRT1-dependent, the present study was carried out using wild-type and hepatic SIRT1 heterozygous mutant (Sirt1+/-) C57BL/6 mice. On consideration of the sex disparity related to hepatic steatosis morbidity, both male and female mice were included in the study. Six to eight week old mice were fed a high-fat diet (HFD) and randomly assigned to one of the following groups: (1) wild-type mice (wt+HFD), (2) Sirt1+/- mice (Sirt1+/-+HFD), and (3) Sirt1+/- mice with 500 mg/(kg·bw·d) APE intragastric administration (Sirt1+/-+HAP). HFD-induced weight gain and triglyceride accumulation was more prominent in Sirt1+/- mice in comparison to wild-type mice. Following APE treatment, these effects were significantly reduced along with the alleviation of hepatic steatosis via upregulated expression of SIRT1 at the protein and mRNA levels in both male and female mice. However, APE differentially regulated the genes related to lipid metabolism (Lkb1, Ampk, Hsl, Srebp-1c, Abcg1, and Cd36) in a sex-specific manner. Moreover, APE treatment altered gut microbiota composition, with an increased relative abundance of Akkermansia and a decreased Firmicutes/Bacterodetes ratio. Thus, our study provided new evidence supporting our hypothesis that APE-induced alleviation of hepatic steatosis is SIRT1-dependent.
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Affiliation(s)
- Yan Yin
- School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
| | - Deming Li
- School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
| | - Fang Liu
- School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
| | - Xinjing Wang
- School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
| | - Yuan Cui
- School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
| | - Shilan Li
- School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
| | - Xinli Li
- School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215006, People's Republic of China
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26
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Prikhodko VA, Bezborodkina NN, Okovityi SV. Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates. Biomedicines 2022; 10:274. [PMID: 35203484 PMCID: PMC8869100 DOI: 10.3390/biomedicines10020274] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/22/2022] [Accepted: 01/24/2022] [Indexed: 02/08/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), or metabolic (dysfunction)-associated fatty liver disease (MAFLD), is characterized by high global incidence and prevalence, a tight association with common metabolic comorbidities, and a substantial risk of progression and associated mortality. Despite the increasingly high medical and socioeconomic burden of NAFLD, the lack of approved pharmacotherapy regimens remains an unsolved issue. In this paper, we aimed to provide an update on the rapidly changing therapeutic landscape and highlight the major novel approaches to the treatment of this disease. In addition to describing the biomolecules and pathways identified as upcoming pharmacological targets for NAFLD, we reviewed the current status of drug discovery and development pipeline with a special focus on recent evidence from clinical trials.
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Affiliation(s)
- Veronika A. Prikhodko
- Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical and Pharmaceutical University, 14A Prof. Popov Str., 197022 St. Petersburg, Russia;
| | - Natalia N. Bezborodkina
- Zoological Institute, Russian Academy of Sciences, 1 Universitetskaya emb., 199034 St. Petersburg, Russia;
| | - Sergey V. Okovityi
- Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical and Pharmaceutical University, 14A Prof. Popov Str., 197022 St. Petersburg, Russia;
- Scientific, Clinical and Educational Center of Gastroenterology and Hepatology, Saint Petersburg State University, 7/9 Universitetskaya emb., 199034 St. Petersburg, Russia
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27
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Cha Y, Kim T, Jeon J, Jang Y, Kim PB, Lopes C, Leblanc P, Cohen BM, Kim KS. SIRT2 regulates mitochondrial dynamics and reprogramming via MEK1-ERK-DRP1 and AKT1-DRP1 axes. Cell Rep 2021; 37:110155. [PMID: 34965411 PMCID: PMC8780843 DOI: 10.1016/j.celrep.2021.110155] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 10/01/2021] [Accepted: 12/01/2021] [Indexed: 02/08/2023] Open
Abstract
During somatic reprogramming, cellular energy metabolism fundamentally switches from predominantly mitochondrial oxidative phosphorylation toward glycolysis. This metabolic reprogramming, also called the Warburg effect, is critical for the induction of pluripotency, but its molecular mechanisms remain poorly defined. Notably, SIRT2 is consistently downregulated during the reprogramming process and regulates glycolytic switch. Here, we report that downregulation of SIRT2 increases acetylation of mitogen-activated protein kinase (MAPK) kinase-1 (MEK1) at Lys175, resulting in activation of extracellular signal-regulated kinases (ERKs) and subsequent activation of the pro-fission factor dynamin-related protein 1 (DRP1). In parallel, downregulation of SIRT2 hyperacetylates the serine/threonine protein kinase AKT1 at Lys20 in a non-canonical way, activating DRP1 and metabolic reprogramming. Together, our study identified two axes, SIRT2-MEK1-ERK-DRP1 and SIRT2-AKT1-DRP1, that critically link mitochondrial dynamics and oxidative phosphorylation to the somatic reprogramming process. These upstream signals, together with SIRT2’s role in glycolytic switching, may underlie the Warburg effect observed in human somatic cell reprogramming. Mitochondrial remodeling has critical roles for the somatic cell reprogramming process. Cha et al. report the functional role of SIRT2 in mitochondrial dynamics and remodeling during the human somatic cell reprogramming process. They identify two axes, SIRT2-MEK1-ERK-DRP1 and SIRT2-AKT1-DRP1, that link SIRT2 downregulation to mitochondrial remodeling and somatic cell reprogramming.
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Affiliation(s)
- Young Cha
- Department of Psychiatry and Molecular Neurobiology Laboratory, McLean Hospital and Program in Neuroscience, Harvard Medical School, Belmont, MA 02478, USA.
| | - Taewoo Kim
- Department of Psychiatry and Molecular Neurobiology Laboratory, McLean Hospital and Program in Neuroscience, Harvard Medical School, Belmont, MA 02478, USA
| | - Jeha Jeon
- Department of Psychiatry and Molecular Neurobiology Laboratory, McLean Hospital and Program in Neuroscience, Harvard Medical School, Belmont, MA 02478, USA
| | - Yongwoo Jang
- Department of Psychiatry and Molecular Neurobiology Laboratory, McLean Hospital and Program in Neuroscience, Harvard Medical School, Belmont, MA 02478, USA; Department of Biomedical Engineering, Hanyang University, Seoul 04763, Korea
| | - Patrick B Kim
- Department of Psychiatry and Molecular Neurobiology Laboratory, McLean Hospital and Program in Neuroscience, Harvard Medical School, Belmont, MA 02478, USA
| | - Claudia Lopes
- Department of Psychiatry and Molecular Neurobiology Laboratory, McLean Hospital and Program in Neuroscience, Harvard Medical School, Belmont, MA 02478, USA
| | - Pierre Leblanc
- Department of Psychiatry and Molecular Neurobiology Laboratory, McLean Hospital and Program in Neuroscience, Harvard Medical School, Belmont, MA 02478, USA
| | - Bruce M Cohen
- Department of Psychiatry and Program for Neuropsychiatric Research, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA
| | - Kwang-Soo Kim
- Department of Psychiatry and Molecular Neurobiology Laboratory, McLean Hospital and Program in Neuroscience, Harvard Medical School, Belmont, MA 02478, USA.
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28
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Exercise Intervention Mitigates Pathological Liver Changes in NAFLD Zebrafish by Activating SIRT1/AMPK/NRF2 Signaling. Int J Mol Sci 2021; 22:ijms222010940. [PMID: 34681600 PMCID: PMC8536011 DOI: 10.3390/ijms222010940] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/05/2021] [Accepted: 10/05/2021] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common disease that causes serious liver damage. Exercise is recognized as a non-pharmacological tool to improve the pathology of NAFLD. However, the antioxidative effects and mechanisms by which exercise ameliorates NAFLD remain unclear. The present study conducted exercise training on zebrafish during a 12-week high-fat feeding period to study the antioxidant effect of exercise on the liver. We found that swimming exercise decreased lipid accumulation and improved pathological changes in the liver of high-fat diet-fed zebrafish. Moreover, swimming alleviated NOX4-derived reactive oxygen species (ROS) overproduction and reduced methanedicarboxylic aldehyde (MDA) levels. We also examined the anti-apoptotic effects of swimming and found that it increased the expression of antiapoptotic factor bcl2 and decreased the expression of genes associated with apoptosis (caspase3, bax). Mechanistically, swimming intervention activated SIRT1/AMPK signaling-mediated lipid metabolism and inflammation as well as enhanced AKT and NRF2 activation and upregulated downstream antioxidant genes. In summary, exercise attenuates pathological changes in the liver induced by high-fat diets. The underlying mechanisms might be related to NRF2 and mediated by SIRT1/AMPK signaling.
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29
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Shen L, Xie L, Chen L, Liu L, Shi X, Wang X, Chen D, Wang H, Quan S, Wang Z. Resveratrol reverses the programmed high-susceptibility to non-alcoholic fatty liver disease by targeting the hepatic SIRT1-SREBP1c pathway in prenatal ethanol-exposed rat offspring. J Toxicol Sci 2021; 46:413-423. [PMID: 34470993 DOI: 10.2131/jts.46.413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
An increased susceptibility to non-alcoholic fatty liver disease (NAFLD) in female rat offspring that experienced prenatal ethanol exposure (PEE) has been previously demonstrated. The present study further investigated the potential mechanism. Based on the results from both fetal and adult studies of offspring rats that experienced PEE (4 g/kg/day), the fetal weight, serum glucose and triglyceride levels decreased significantly and hepatocellular ultra-structure was altered. Fetal livers exhibited inhibited expression and activity of sirtuin 1 (SIRT1), enhanced expression of lipogenic genes: sterol regulatory element binding protein 1c (SREBP1c), fatty acid synthase (FASN), acetyl-coenzyme A carboxylase α (ACCα), stearyl-coenzyme A desaturase 1 (SCD1). In adult offspring fed with high-fat diet, the PEE offspring revealed obviously catch-up growth, increased food intake, elevated serum metabolic phenotypes, suppressed hepatic SIRT1-SREBP1c pathway, and formation of NAFLD. Resveratrol (the chemical activator of SIRT1) could remarkably reverse the serum metabolic phenotypes and alleviate the hepatocyte steatosis in relation to the PEE offspring through activating the hepatic SIRT1-SREBP1c pathway. Therefore, increased susceptibility to diet-induced NAFLD in PEE offspring appears to be mediated by intrauterine programming of hepatic lipogenesis via the SIRT1-SREBP1c pathway. This altered programming effect could partially be reversed by resveratrol intervention after birth in PEE offspring rats.
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Affiliation(s)
- Lang Shen
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, China
| | - Lijia Xie
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, China
| | - Li Chen
- Guangzhou Institute of Pediateics, Guangzhou Women and Children's Medical Center, China
| | - Li Liu
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, China
| | - Xiao Shi
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, China
| | - Xiaocong Wang
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, China
| | - Donghong Chen
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, China
| | - Hui Wang
- Department of Pharmacology, Basic Medical School of Wuhan University, China.,Hubei Provincial Key Laboratory of Developmentally Originated Disease, China
| | - Song Quan
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, China
| | - Zhijian Wang
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, China
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Phytotherapy as Multi-Hit Therapy to Confront the Multiple Pathophysiology in Non-Alcoholic Fatty Liver Disease: A Systematic Review of Experimental Interventions. ACTA ACUST UNITED AC 2021; 57:medicina57080822. [PMID: 34441028 PMCID: PMC8400978 DOI: 10.3390/medicina57080822] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/02/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated fatty liver disease (MAFLD), is a metabolic condition distinguished by fat deposition in the hepatocytes. It has a prevalence of about 25% worldwide and is associated with other conditions such as diabetes mellitus, obesity, hypertension, etc. Background and Objectives: There is currently no approved drug therapy for NAFLD. Current measures in the management of NAFLD include lifestyle modification such as an increase in physical activity or weight loss. Development of NAFLD involves a number of parallel hits: including genetic predisposition, insulin resistance, disordered lipid metabolism, mitochondrial dysfunction, lipotoxicity, oxidative stress, etc. Herbal therapy may have a role to play in the treatment of NAFLD, due to their numerous bioactive constituents and the multiple pharmacological actions they exhibit. Therefore, this systematic review aims to investigate the potential multi-targeting effects of plant-derived extracts in experimental models of NAFLD. Materials and Methods: We performed a systematic search on databases and web search engines from the earliest available date to 30 April 2021, using relevant keywords. The study included articles published in English, assessing the effects of plant-derived extracts, fractions, or polyherbal mixtures in the treatment of NAFLD in animal models. These include their effects on at least disordered lipid metabolism, insulin resistance/type 2 diabetes mellitus (T2DM), and histologically confirmed steatosis with one or more of the following: oxidative stress, inflammation, hepatocyte injury, obesity, fibrosis, and cardiometabolic risks factors. Results: Nine articles fulfilled our inclusion criteria and the results demonstrated the ability of phytomedicines to simultaneously exert therapeutic actions on multiple targets related to NAFLD. Conclusions: These findings suggest that herbal extracts have the potential for effective treatment or management of NAFLD.
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Pathogenetic mechanisms of nonalcoholic fatty liver disease and inhibition of the inflammasome as a new therapeutic target. Clin Res Hepatol Gastroenterol 2021; 45:101710. [PMID: 33930586 DOI: 10.1016/j.clinre.2021.101710] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 03/30/2021] [Accepted: 03/31/2021] [Indexed: 02/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and its incidence is increasing. Nonalcoholic steatohepatitis (NASH), the progressive form of the disease, can lead to end-stage liver disease. The pathogenesis of the disease is not fully understood, and there is currently no specific treatment. Therefore, an effective and reliable treatment modality is needed. In recent years, the inflammasome has been shown to play a vital role in many stages of NAFLD pathogenesis. In particular, the detection, by toll-like receptors, of pathogen-associated molecular patterns induced by the gut-liver axis triggers the formation of the NLRP3 (NLR family pyrin domain-containing protein 3) inflammasome. Stimulation of damage-associated molecular patterns also activates the NLRP3 inflammasome. The activated inflammasome has caspase-1 activity, which leads to the release of interleukin (IL)-1 and IL-18 and formation of pores in the cell wall. This process spreads the inflammatory process to the outside of the cell and induces inflammatory cell death (pyroptosis). Subsequent progression of the inflammatory process leads to fibrosis. Recent evidence suggests that the NLRP3 inflammasome may be a potential target for the treatment of NASH. The discovery of specific NLRP3 inflammasome blockers in recent years and evidence of their positive effects in experimental models support this therapeutic approach. In this article, we discuss recent evidence on the pathogenesis of NAFLD, the role of the inflammasome in the pathogenesis of NAFLD, and the potential effects of inhibition of the inflammasome.
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Yefimenko T, Mykytyuk M. Non-alcoholic fatty liver disease: time for changes. INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (UKRAINE) 2021; 17:334-345. [DOI: 10.22141/2224-0721.17.4.2021.237350] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The review contains updated information on the epidemiology, etiology, pathogenesis, diagnosis, treatment and prevention of non-alcoholic fatty liver disease (NAFLD). We searched for terms including NAFLD, non-alcoholic steatohepatitis (NASH), metabolic syndrome and type 2 diabetes mellitus in literature published over the past 5 years using the Scopus, Web of Science, CyberLeninka, PubMed databases. The concept of NAFLD includes two morphological forms of the disease with different prognosis: non-alcoholic fatty hepatosis and NASH. The severity of NASH is quite variable, including fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD, a spectrum of fatty liver disorders of viral, autoimmune, drug-induced, and genetic origin, which are not caused by alcohol abuse, has recently been renamed as metabolic (dysfunction) associated fatty liver disease (MAFLD). The average prevalence of NAFLD is approximately 25% among the adult population worldwide, and in some regions exceeds 30%. An increase in the prevalence of this pathology is in parallel with the global epidemic of obesity and type 2 diabetes mellitus in the world. It is time to reach a general consensus in the scientific community on changing the nomenclature and moving from a negative to a positive definition of NAFLD/NASH. The new nomenclature points to the “positive” determinants of the disease, namely the close relationship with metabolic disorders, instead of defining it as what it is not (ie. non-alcoholic). The MAFLD abbreviation more accurately discloses existing knowledge about fatty liver diseases associated with metabolic dysfunction and should replace NAFLD/NASH, as this will stimulate the research community’s efforts to update the disease nomenclature and subphenotype and accelerate the transition to new treatments. It is important that primary care physicians, endocrinologists, and other specialists are aware of the extent and long-term consequences of NAFLD. Early identification of patients with NASH can help improve treatment outcomes, avoid liver transplantation in patients with decompensated cirrhosis. There are currently no effective treatments for NAFLD, so it is important to follow a multidisciplinary approach, which means using measures to improve prognosis, reduce the risk of death associated with NAFLD, the development of cirrhosis or hepatocellular carcinoma. Epidemiological data suggest a close relationship between unhealthy lifestyles and NAFLD, so lifestyle adjustments are needed to all patients. Insulin sensitizers, statins, ezetimibe, a cholesterol absorption inhibitor, hepatoprotectors, antioxidants, incretin analogues, dipeptidyl peptidase 4 inhibitors, pentoxifylline, probiotics, angiotensin-converting enzyme inhibitors, and endocannabinoid antagonists are used in the treatment of NAFLD.
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Cano R, Pérez JL, Dávila LA, Ortega Á, Gómez Y, Valero-Cedeño NJ, Parra H, Manzano A, Véliz Castro TI, Albornoz MPD, Cano G, Rojas-Quintero J, Chacín M, Bermúdez V. Role of Endocrine-Disrupting Chemicals in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: A Comprehensive Review. Int J Mol Sci 2021; 22:4807. [PMID: 34062716 PMCID: PMC8125512 DOI: 10.3390/ijms22094807] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/21/2021] [Accepted: 03/22/2021] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disorder, affecting around 25% of the population worldwide. It is a complex disease spectrum, closely linked with other conditions such as obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome, which may increase liver-related mortality. In light of this, numerous efforts have been carried out in recent years in order to clarify its pathogenesis and create new prevention strategies. Currently, the essential role of environmental pollutants in NAFLD development is recognized. Particularly, endocrine-disrupting chemicals (EDCs) have a notable influence. EDCs can be classified as natural (phytoestrogens, genistein, and coumestrol) or synthetic, and the latter ones can be further subdivided into industrial (dioxins, polychlorinated biphenyls, and alkylphenols), agricultural (pesticides, insecticides, herbicides, and fungicides), residential (phthalates, polybrominated biphenyls, and bisphenol A), and pharmaceutical (parabens). Several experimental models have proposed a mechanism involving this group of substances with the disruption of hepatic metabolism, which promotes NAFLD. These include an imbalance between lipid influx/efflux in the liver, mitochondrial dysfunction, liver inflammation, and epigenetic reprogramming. It can be concluded that exposure to EDCs might play a crucial role in NAFLD initiation and evolution. However, further investigations supporting these effects in humans are required.
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Affiliation(s)
- Raquel Cano
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela; (R.C.); (J.L.P.); (Á.O.); (Y.G.); (H.P.); (A.M.); (M.P.D.A.)
| | - José L. Pérez
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela; (R.C.); (J.L.P.); (Á.O.); (Y.G.); (H.P.); (A.M.); (M.P.D.A.)
| | - Lissé Angarita Dávila
- Escuela de Nutrición y Dietética, Facultad de Medicina, Universidad Andres Bello, Sede Concepción 4260000, Chile;
| | - Ángel Ortega
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela; (R.C.); (J.L.P.); (Á.O.); (Y.G.); (H.P.); (A.M.); (M.P.D.A.)
| | - Yosselin Gómez
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela; (R.C.); (J.L.P.); (Á.O.); (Y.G.); (H.P.); (A.M.); (M.P.D.A.)
| | - Nereida Josefina Valero-Cedeño
- Carrera de Laboratorio Clínico, Facultad de Ciencias de la Salud, Universidad Estatal del Sur de Manabí, Jipijapa E482, Ecuador; (N.J.V.-C.); (T.I.V.C.)
| | - Heliana Parra
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela; (R.C.); (J.L.P.); (Á.O.); (Y.G.); (H.P.); (A.M.); (M.P.D.A.)
| | - Alexander Manzano
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela; (R.C.); (J.L.P.); (Á.O.); (Y.G.); (H.P.); (A.M.); (M.P.D.A.)
| | - Teresa Isabel Véliz Castro
- Carrera de Laboratorio Clínico, Facultad de Ciencias de la Salud, Universidad Estatal del Sur de Manabí, Jipijapa E482, Ecuador; (N.J.V.-C.); (T.I.V.C.)
| | - María P. Díaz Albornoz
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela; (R.C.); (J.L.P.); (Á.O.); (Y.G.); (H.P.); (A.M.); (M.P.D.A.)
| | - Gabriel Cano
- Insitute für Pharmazie, Freie Universitänt Berlin, Königin-Louise-Strabe 2-4, 14195 Berlin, Germany;
| | - Joselyn Rojas-Quintero
- Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;
| | - Maricarmen Chacín
- Facultad de Ciencias de la Salud. Barranquilla, Universidad Simón Bolívar, Barranquilla 55-132, Colombia;
| | - Valmore Bermúdez
- Facultad de Ciencias de la Salud. Barranquilla, Universidad Simón Bolívar, Barranquilla 55-132, Colombia;
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Epigenetics in NAFLD/NASH: Targets and therapy. Pharmacol Res 2021; 167:105484. [PMID: 33771699 DOI: 10.1016/j.phrs.2021.105484] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 12/15/2022]
Abstract
Recently non-alcoholic fatty liver disease (NAFLD) has grabbed considerable scientific attention, owing to its rapid increase in prevalence worldwide and growing burden on end-stage liver diseases. Metabolic syndrome including obesity, diabetes, and hypertension poses a grave risk to NAFLD etiology and progression. With no drugs available, the mainstay of NAFLD management remains lifestyle changes with exercise and dietary modifications. Nonselective drugs such as metformin, thiazolidinediones (TZDs), ursodeoxycholic acid (UDCA), silymarin, etc., are also being used to target the interrelated pathways for treating NAFLD. Considering the enormous disease burden and the unmet need for drugs, fresh insights into pathogenesis and drug discovery are required. The emergence of the field of epigenetics offers a convincing explanation for the basis of lifestyle, environmental, and other risk factors to influence NAFLD pathogenesis. Therefore, understanding these epigenetic modifications to target the primary cause of the disease might prove a rational strategy to prevent the disease and develop novel therapeutic interventions. Apart from describing the role of epigenetics in the pathogenesis of NAFLD as in other reviews, this review additionally provides an elaborate discussion on exploiting the high plasticity of epigenetic modifications in response to environmental cues, for developing novel therapeutics for NAFLD. Besides, this extensive review provides evidence for epigenetic mechanisms utilized by several potential drugs for NAFLD.
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Soni SK, Basu P, Singaravel M, Sharma R, Pandi-Perumal SR, Cardinali DP, Reiter RJ. Sirtuins and the circadian clock interplay in cardioprotection: focus on sirtuin 1. Cell Mol Life Sci 2021; 78:2503-2515. [PMID: 33388853 PMCID: PMC11073088 DOI: 10.1007/s00018-020-03713-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 10/09/2020] [Accepted: 11/16/2020] [Indexed: 02/06/2023]
Abstract
Chronic disruption of circadian rhythms which include intricate molecular transcription-translation feedback loops of evolutionarily conserved clock genes has serious health consequences and negatively affects cardiovascular physiology. Sirtuins (SIRTs) are nuclear, cytoplasmic and mitochondrial histone deacetylases that influence the circadian clock with clock-controlled oscillatory protein, NAMPT, and its metabolite NAD+. Sirtuins are linked to the multi-organ protective role of melatonin, particularly in acute kidney injury and in cardiovascular diseases, where melatonin, via upregulation of SIRT1 expression, inhibits the apoptotic pathway. This review focuses on SIRT1, an NAD+-dependent class III histone deacetylase which counterbalances the intrinsic histone acetyltransferase activity of one of the clock genes, CLOCK. SIRT1 is involved in the development of cardiomyocytes, regulation of voltage-gated cardiac sodium ion channels via deacetylation, prevention of atherosclerotic plaque formation in the cardiovascular system, protection against oxidative damage and anti-thrombotic actions. Overall, SIRT1 has a see-saw effect on cardioprotection, with low levels being cardioprotective and higher levels leading to cardiac hypertrophy.
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Affiliation(s)
- Sanjeev Kumar Soni
- Chronobiology Laboratory, Department of Zoology, Institute of Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Priyoneel Basu
- Chronobiology Laboratory, Department of Zoology, Institute of Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Muniyandi Singaravel
- Chronobiology Laboratory, Department of Zoology, Institute of Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Ramaswamy Sharma
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | | | - Daniel P Cardinali
- Faculty of Medical Sciences, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA.
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Azarmehr Z, Ranji N, Khazaei Koohpar Z, Habibollahi H. The effect of N-Acetyl cysteine on the expression of Fxr (Nr1h4), LXRα (Nr1h3) and Sirt1 genes, oxidative stress, and apoptosis in the liver of rats exposed to different doses of cadmium. Mol Biol Rep 2021; 48:2533-2542. [PMID: 33772418 DOI: 10.1007/s11033-021-06300-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 03/18/2021] [Indexed: 10/21/2022]
Abstract
The aim of this study was to consider the expression of farnesoid X receptor (Fxr), liver X receptor (LXRα) and sirtuin 1 (Sirt1), oxidative stress, inflammation, apoptosis, and the protective role of N-acetylcysteine (NAC) in the liver of rats treated with cadmium (Cd). 30 Wistar rats were divided into 5 groups: G1 (control), G2 (single dose of Cd), G3 (continuous dose of Cd), G4 (single dose of Cd + continuous dose of NAC), and G5 (continuous dose of Cd + continuous dose of NAC). The apoptosis of hepatic cells was measured using the TUNEL assay. Levels of malondialdehyde (MDA), IL-10, TNF-α, and total antioxidant capacity (TAC) were measured by specific kits. The expression of Fxr, LXRα, and Sirt1 genes and ratio of Bax/Bcl2 was considered using RT-PCR. While NAC treatment improved TAC and IL-10 values, it decreased MDA and TNF-α levels in the liver of rats exposed to Cd (P < 0.001). NAC decreased Bax/Bcl2 in the liver of G4 and G5 groups (P < 0.001). Exposure to a continuous dose of Cd decreased Fxr, LXRα, and Sirt1 expression by 36.65- (P < 0.001), 12.52- (P < 0.001) and 11.34-fold (P < 0.001) compared to control, respectively. NAC increased Fxr, LXRα, and Sirt1 expression (P < 0.01) and decreased Cd concentrations in both serum and tissue samples in G4 and G5 groups. Our results suggested that NAC protects liver tissue against Cd toxicity by elevating antioxidant capacity, mitigating oxidative stress, inflammation, apoptosis and up-regulation of FXR, LXR, and SIRT1 genes.
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Affiliation(s)
- Zahra Azarmehr
- Department of Biology, Faculty of Sciences, Rasht Branch, Islamic Azad University, P.O. Box, 3516-41335, Rasht, Iran
| | - Najmeh Ranji
- Department of Biology, Faculty of Sciences, Rasht Branch, Islamic Azad University, P.O. Box, 3516-41335, Rasht, Iran.
| | - Zeinab Khazaei Koohpar
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
| | - Hadi Habibollahi
- Department of Biology, Faculty of Sciences, Rasht Branch, Islamic Azad University, P.O. Box, 3516-41335, Rasht, Iran
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Heydari H, Ghiasi R, Hamidian G, Ghaderpour S, Keyhanmanesh R. Voluntary exercise improves sperm parameters in high fat diet receiving rats through alteration in testicular oxidative stress, mir-34a/SIRT1/p53 and apoptosis. Horm Mol Biol Clin Investig 2021; 42:253-263. [PMID: 33638320 DOI: 10.1515/hmbci-2020-0085] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 01/19/2021] [Indexed: 01/07/2023]
Abstract
OBJECTIVES High fat diet can lead to testicular structural and functional disturbances, spermatogenesis disorders as well as infertility. So, the present investigation was proposed to clarify whether voluntary exercise could prevent high fat diet induced reproductive complications in rats through testicular stress oxidative and apoptosis. METHODS Forty male Wistar rats were randomly divided into four groups; control (C), voluntary exercise (VE), high fat diet (HFD) and high fat diet and voluntary exercise (VE + HFD) groups. The rats in the VE and VE + HFD groups were accommodated in apart cages that had running wheels and the running distance was assessed daily for 10 weeks. In VE + HFD group, animals were fed with HFD for five weeks before commencing exercise. The sperm parameters, the expressions of testicular miR-34a gene, and P53 and SIRT1 proteins as well as testicular apoptosis were analyzed in all groups. RESULTS The results indicated that voluntary exercise in VE + HFD group led to significantly increased GPX and SOD activities, SIRT1 protein expression, sperm parameters, and decreased the expression of miR34a gene and Acp53 protein, and cellular apoptosis index compared to HFD group (p<0.001 to p<0.05). The SOD and catalase activities, SIRT1 protein expression, sperm parameters in VE + HFD group were lower than of those of VE group, however, MDA content, expression of Acp53 protein, apoptosis indexes in VE + HFD group was higher than that of VE group (p<0.001 to p<0.05). CONCLUSION This study revealed that voluntary exercise improved spermatogenesis, in part by decreasing the testicular oxidative stress status, apoptosis through alteration in miR-34a/SIRT1/p53 pathway.
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Affiliation(s)
- Hamed Heydari
- Department of Physiology, Tabriz Faculty of Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rafighe Ghiasi
- Department of Physiology, Tabriz Faculty of Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Gholamreza Hamidian
- Department of Basic Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Saber Ghaderpour
- Department of Physiology, Tabriz Faculty of Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rana Keyhanmanesh
- Department of Physiology, Tabriz Faculty of Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Le Carbone prevents liver damage in non-alcoholic steatohepatitis-hepatocellular carcinoma mouse model via AMPKα-SIRT1 signaling pathway activation. Heliyon 2021; 7:e05888. [PMID: 33490669 PMCID: PMC7803657 DOI: 10.1016/j.heliyon.2020.e05888] [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: 10/23/2020] [Revised: 11/30/2020] [Accepted: 12/24/2020] [Indexed: 12/12/2022] Open
Abstract
Le Carbone (LC), a fiber-enriched activated charcoal dietary supplement, claimed to be effective against inflammation associated with colitis, trimethylaminuria, and sclerosis. The study aimed to investigate the underlying mechanisms of LC to protect liver damage and its progression in non-alcoholic steatohepatitis-hepatocellular carcinoma (NASH-HCC) mice. To induce this model, C57BL/6J male baby mice were injected with a low-dose of streptozotocin and fed with a high-fat diet (HFD) 32 during 4 weeks–16 weeks of age. The LC suspension was administered orally at a dose of 5 mg/mouse/day started at the age of 6 weeks and continued until 16 weeks of age along with HFD32 feeding. At the end of the experiment, serum and liver tissues were collected for the biochemical, histological, and molecular analysis. We found that LC suspension improved the histopathological changes, serum aminotransferases in NASH mice. The hepatic expression of metabolic proteins, p-AMPKα and sirtuin 1, and proteins responsible for β-oxidation of fatty acids, peroxisome proliferator-activated receptor (PPAR) γ coactivator-α, PPARα were significantly repressed in NASH mice. LC treatment markedly restored these expressions. LC treatment significantly reduced the hepatic proteins expressions of PPARγ, tissue inhibitor of metalloproteinases 4, p47phox, p-JNK, p-ERK1/2, glypican-3, and prothrombin in NASH mice. Our findings demonstrate that LC prevents the liver damage and progression of NASH, possibly by enhancing the AMPK-SIRT1 signaling pathway.
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Xu T, Song Q, Zhou L, Yang W, Wu X, Qian Q, Chai H, Han Q, Pan H, Dou X, Li S. Ferulic acid alleviates lipotoxicity-induced hepatocellular death through the SIRT1-regulated autophagy pathway and independently of AMPK and Akt in AML-12 hepatocytes. Nutr Metab (Lond) 2021; 18:13. [PMID: 33468182 PMCID: PMC7814733 DOI: 10.1186/s12986-021-00540-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 01/02/2021] [Indexed: 02/07/2023] Open
Abstract
Background Lipotoxicity-induced cell death plays a detrimental role in the pathogenesis of metabolic diseases. Ferulic acid, widespread in plant-based food, is a radical scavenger with multiple bioactivities. However, the benefits of ferulic acid against hepatic lipotoxicity are largely unclear. Here, we investigated the protective effect of ferulic acid against palmitate-induced lipotoxicity and clarified its potential mechanisms in AML-12 hepatocytes. Methods AML-12 mouse hepatocytes were exposed to palmitate to mimic lipotoxicity. Different doses (25, 50, and 100 μM) of ferulic acid were added 2 h before palmitate treatment. Cell viability was detected by measuring lactate dehydrogenase release, nuclear staining, and the expression of cleaved-caspase-3. Intracellular reactive oxygen species content and mitochondrial membrane potential were analysed by fluorescent probes. The potential mechanisms were explored by molecular biological methods, including Western blotting and quantitative real-time PCR, and were further verified by siRNA interference. Results Our data showed that ferulic acid significantly inhibited palmitate-induced cell death, rescued mitochondrial membrane potential, reduced reactive oxygen species accumulation, and decreased inflammatory factor activation, including IL-6 and IL-1beta. Ferulic acid significantly stimulated autophagy in hepatocytes, whereas autophagy suppression blocked the protective effect of ferulic acid against lipotoxicity. Ferulic acid-activated autophagy, which was triggered by SIRT1 upregulation, was mechanistically involved in its anti-lipotoxicity effects. SIRT1 silencing blocked most beneficial changes induced by ferulic acid. Conclusions We demonstrated that the phytochemical ferulic acid, which is found in plant-based food, protected against hepatic lipotoxicity, through the SIRT1/autophagy pathway. Increased intake of ferulic acid-enriched food is a potential strategy to prevent and/or improve metabolic diseases with lipotoxicity as a typical pathological feature.
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Affiliation(s)
- Tiantian Xu
- College of Basic Medicine and Public Health, Zhejiang Chinese Medical University, Hangzhou, 310053, China.,College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Qing Song
- College of Basic Medicine and Public Health, Zhejiang Chinese Medical University, Hangzhou, 310053, China.,College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China.,Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Li Zhou
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China.,The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Wenwen Yang
- College of Basic Medicine and Public Health, Zhejiang Chinese Medical University, Hangzhou, 310053, China.,College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Xiangyao Wu
- College of Basic Medicine and Public Health, Zhejiang Chinese Medical University, Hangzhou, 310053, China.,College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Qianyu Qian
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China.,Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Hui Chai
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China.,Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Qiang Han
- College of Basic Medicine and Public Health, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Hongzhi Pan
- Collaborative Research Center, Shanghai University of Medicine and Health Sciences, Shanghai, 201399, China
| | - Xiaobing Dou
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China. .,Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
| | - Songtao Li
- College of Basic Medicine and Public Health, Zhejiang Chinese Medical University, Hangzhou, 310053, China. .,Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
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Darvishzadeh Mahani F, Khaksari M, Raji-Amirhasani A. Renoprotective effects of estrogen on acute kidney injury: the role of SIRT1. Int Urol Nephrol 2021; 53:2299-2310. [PMID: 33458788 DOI: 10.1007/s11255-020-02761-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 12/15/2020] [Indexed: 01/23/2023]
Abstract
Acute kidney injury (AKI) is a common syndrome associated with high morbidity and mortality, despite progress in medical care. Many studies have shown that there are sex differences and different role of sex hormones particularly estrogens in kidney injury. In this regard, the incidence and rate of progression of kidney diseases are higher in men compared with women. These observations suggest that female sex hormone may be renoprotective. Silent information regulator 2 homolog 1 (SIRT1) is a histone deacetylase, which is implicated in multiple biologic processes in several organisms. In the kidneys, SIRT1 inhibits renal cell apoptosis, inflammation, and fibrosis. Studies have reported a link between SIRT1 and estrogen. In addition, SIRT1 regulates ERα expression and inhibition of SIRT1 activity suppresses ERα expression. This effect leads to inhibition of estrogen-responsive gene expression. In this text, we review the role of SIRT1 in mediating the protective effects of estrogen in the onset and progression of AKI.
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Affiliation(s)
- Fatemeh Darvishzadeh Mahani
- Physiology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Khaksari
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran.
| | - Alireza Raji-Amirhasani
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
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Ramos LF, Silva CM, Pansa CC, Moraes KCM. Non-alcoholic fatty liver disease: molecular and cellular interplays of the lipid metabolism in a steatotic liver. Expert Rev Gastroenterol Hepatol 2021; 15:25-40. [PMID: 32892668 DOI: 10.1080/17474124.2020.1820321] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) affects ~25% of world population and cases have increased in recent decades. These anomalies have several etiologies; however, obesity and metabolic dysfunctions are the most relevant causes. Despite being considered a public health problem, no effective therapeutic approach to treat NAFLD is available. For that, a deep understanding of metabolic routes that support hepatic diseases is needed. AREAS COVERED This review covers aspects of the onset of NAFLD. Thereby, biochemistry routes as well as cellular and metabolic effects of the gut microbiota in body's homeostasis and epigenetics are contextualized. EXPERT OPINION Recently, the development of biological sciences has generated innovative knowledge, bringing new insights and perspectives to clarify the systems biology of liver diseases. A detailed comprehension of epigenetics mechanisms will offer possibilities to develop new therapeutic and diagnostic strategies for NAFLD. Different epigenetic processes have been reported that are modulated by the environment such as gut microbiota, suggesting strong interplays between cellular behavior and pathology. Thus, a more complete description of such mechanisms in hepatic diseases will help to clarify how to control the establishment of fatty liver, and precisely describe molecular interplays that potentially control NAFLD.
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Affiliation(s)
- Letícia F Ramos
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
| | - Caio M Silva
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
| | - Camila C Pansa
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
| | - Karen C M Moraes
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
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Xu N, Luo H, Li M, Wu J, Wu X, Chen L, Gan Y, Guan F, Li M, Su Z, Chen J, Liu Y. β-patchoulene improves lipid metabolism to alleviate non-alcoholic fatty liver disease via activating AMPK signaling pathway. Biomed Pharmacother 2020; 134:111104. [PMID: 33341045 DOI: 10.1016/j.biopha.2020.111104] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/30/2020] [Accepted: 12/02/2020] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has been a leading cause of chronic metabolic disease, seriously posing healthy burdens to the public, whereas interventions available for it are limited to date. Patchouli oil had been reported to attenuate hepatic steatosis in our previous study. β-patchoulene (β-PAE) is a representative component separated from patchouli oil with multiple activities, but its effect against NAFLD is still unknown. To investigate the effect and potential mechanism of β-PAE on NAFLD, we used high fat diet (HFD) in vivo and free fatty acid (FFA) in vitro to induce hepatic steatosis in rats and L02 cells, respectively. Histological examination was evaluated via Hematoxylin-eosin and oil red O staining. The parameters for hepatic steatosis were estimated via biochemical kits, western blotting and quantitative real-time PCR. Compound C, the inhibitor of AMPK, was applied further to examine the precise mechanism of β-PAE on NAFLD. Our results indicated that β-PAE significantly attenuated HFD-induced weight gain, hepatic injury, lipid deposition in serum and hepatic tissue as well as FFA induced-lipid accumulation. Besides, β-PAE markedly improved the expression of AMP-activated protein kinase (AMPK) and its downstream factors which correlate with hepatic lipid synthesis and oxidation in vivo and in vitro. Nevertheless, Compound C abrogated the benefits derived from β-PAE in L02 cells. In conclusion, these results suggest that β-PAE exerts AMPK agonist-like effect to regulate hepatic lipid synthesis and oxidation, eventually prevent NAFLD progression.
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Affiliation(s)
- Nan Xu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Huijuan Luo
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Minyao Li
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Jiazhen Wu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Xue Wu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macau, China
| | - Liping Chen
- Faculty of Health Sciences, University of Macau, Macau, China
| | - Yuxuan Gan
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510120, China
| | - Fengkun Guan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Mengyao Li
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Ziren Su
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Dongguan & Guangzhou University of Chinese Medicine Cooperative Academy of Mathematical Engineering for Chinese Medicine, Dongguan, 523808, China
| | - Jiannan Chen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
| | - Yuhong Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Dongguan & Guangzhou University of Chinese Medicine Cooperative Academy of Mathematical Engineering for Chinese Medicine, Dongguan, 523808, China.
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Zhu S, Guan L, Tan X, Li G, Sun C, Gao M, Zhang B, Xu L. Hepatoprotective Effect and Molecular Mechanisms of Hengshun Aromatic Vinegar on Non-Alcoholic Fatty Liver Disease. Front Pharmacol 2020; 11:585582. [PMID: 33343352 PMCID: PMC7747854 DOI: 10.3389/fphar.2020.585582] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 11/09/2020] [Indexed: 12/11/2022] Open
Abstract
Aromatic vinegar with abundant bioactive components can be used as a food additive to assist the treatment of various diseases. However, its effect on non-alcoholic fatty liver disease (NAFLD) is still unknown. The purpose of this study was to investigate the mechanism of Hengshun aromatic vinegar in preventing NAFLD in vivo and in vitro. Aromatic vinegar treatment was applied to rats fed with a high-fat diet (HFD) and HepG2 cells challenged with palmitic acid (PA). Our results showed that aromatic vinegar markedly improved cell viabilities and attenuated cell damage in vitro. The levels of TC, TG, FFA, AST, ALT, and malondialdehyde (MDA) in HFD-induced rats were significantly decreased by aromatic vinegar. Mechanism investigation revealed that aromatic vinegar markedly up-regulated the level of silent information regulator of transcription 1 (Sirt1), and thereby inhibited inflammation of the pathway through down-regulating the expressions of high mobility group box 1, toll-likereceptor-4, nuclear transcription factor-κB, tumor necrosis factor receptor-associated factor-6, and inflammatory factors. Aromatic vinegar simultaneously increased the expression of farnesoid X receptor and suppressed expressions of lipogenesis related proteins, including fatty acid synthase, acetyl-CoA carboxylase-1, sterol regulatory element binding transcription factor 1, and stearoyl-CoA desaturase-1. These results were further validated by knockdown of Sirt1 using siRNAs silencing in vitro. In conclusion, Hengshun aromatic vinegar showed protective effects against NAFLD by enhancing the activity of SIRT1 and thereby inhibiting lipogenesis and inflammation pathways, which is expected to become a new assistant strategy for NAFLD therapy in the future.
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Affiliation(s)
- Shenghu Zhu
- Jiangsu Hengshun Vinegar Industry Co., Ltd., Zhenjiang, China
| | - Linshu Guan
- College of Pharmacy, Dalian Medical University, Dalian, China
| | - Xuemei Tan
- College of Pharmacy, Dalian Medical University, Dalian, China
| | - Guoquan Li
- Jiangsu Hengshun Vinegar Industry Co., Ltd., Zhenjiang, China
| | - Changjie Sun
- College of Pharmacy, Dalian Medical University, Dalian, China
| | - Meng Gao
- College of Pharmacy, Dalian Medical University, Dalian, China
| | - Bao Zhang
- Jiangsu Hengshun Vinegar Industry Co., Ltd., Zhenjiang, China
| | - Lina Xu
- College of Pharmacy, Dalian Medical University, Dalian, China
- Key Laboratory for Basic and Applied Research on Pharmacodynamic Substances of Traditional Chinese Medicine of Liaoning Province, Dalian Medical University, Dalian, China
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The Role of Histone Acetylation-/Methylation-Mediated Apoptotic Gene Regulation in Hepatocellular Carcinoma. Int J Mol Sci 2020; 21:ijms21238894. [PMID: 33255318 PMCID: PMC7727670 DOI: 10.3390/ijms21238894] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 10/31/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023] Open
Abstract
Epigenetics, an inheritable phenomenon, which influences the expression of gene without altering the DNA sequence, offers a new perspective on the pathogenesis of hepatocellular carcinoma (HCC). Nonalcoholic steatohepatitis (NASH) is projected to account for a significant share of HCC incidence due to the growing prevalence of various metabolic disorders. One of the major molecular mechanisms involved in epigenetic regulation, post-translational histone modification seems to coordinate various aspects of NASH which will further progress to HCC. Mounting evidence suggests that the orchestrated events of cellular and nuclear changes during apoptosis can be regulated by histone modifications. This review focuses on the current advances in the study of acetylation-/methylation-mediated histone modification in apoptosis and the implication of these epigenetic regulations in HCC. The reversibility of epigenetic alterations and the agents that can target these alterations offers novel therapeutic approaches and strategies for drug development. Further molecular mechanistic studies are required to enhance information governing these epigenetic modulators, which will facilitate the design of more effective diagnosis and treatment options.
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Cha SH, Hwang Y, Heo SJ, Jun HS. Diphlorethohydroxycarmalol Attenuates Palmitate-Induced Hepatic Lipogenesis and Inflammation. Mar Drugs 2020; 18:E475. [PMID: 32962167 PMCID: PMC7551772 DOI: 10.3390/md18090475] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 09/11/2020] [Accepted: 09/15/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease, encompassing a range of conditions caused by lipid deposition within liver cells, and is also associated with obesity and metabolic diseases. Here, we investigated the protective effects of diphlorethohydroxycarmalol (DPHC), which is a polyphenol isolated from an edible seaweed, Ishige okamurae, on palmitate-induced lipotoxicity in the liver. DPHC treatment repressed palmitate-induced cytotoxicity, triglyceride content, and lipid accumulation. DPHC prevented palmitate-induced mRNA and protein expression of SREBP (sterol regulatory element-binding protein) 1, C/EBP (CCAAT-enhancer-binding protein) α, ChREBP (carbohydrate-responsive element-binding protein), and FAS (fatty acid synthase). In addition, palmitate treatment reduced the expression levels of phosphorylated AMP-activated protein kinase (AMPK) and sirtuin (SIRT)1 proteins, and DPHC treatment rescued this reduction. Moreover, DPHC protected palmitate-induced liver toxicity and lipogenesis, as well as inflammation, and enhanced AMPK and SIRT1 signaling in zebrafish. These results suggest that DPHC possesses protective effects against palmitate-induced toxicity in the liver by preventing lipogenesis and inflammation. DPHC could be used as a potential therapeutic or preventive agent for fatty liver diseases.
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Affiliation(s)
- Seon-Heui Cha
- Department of Marine Bio and Medical Sciences, Hanseo University, Chungcheongnam-do 31962, Korea
| | - Yongha Hwang
- Gachon Medical and Convergence Institute, Gachon Gil Medical Center, Incheon 21999, Korea;
| | - Soo-Jin Heo
- Jeju Marine Research Center, Korea Institute of Ocean Science and Technology (KIOST), Jeju 63349, Korea;
- Department of Biology, University of Science and Technology (UST), Daejeon 34113, Korea
| | - Hee-Sook Jun
- Gachon Medical and Convergence Institute, Gachon Gil Medical Center, Incheon 21999, Korea;
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea
- College of Pharmacy, Gachon University, Incheon 21999, Korea
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Nassir F. Role of acetylation in nonalcoholic fatty liver disease: a focus on SIRT1 and SIRT3. EXPLORATION OF MEDICINE 2020. [DOI: 10.37349/emed.2020.00017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent liver chronic disease worldwide. The pathogenesis of NAFLD is complex and involves many metabolic enzymes and multiple pathways. Posttranslational modifications of proteins (PMPs) added another layer of complexity to the pathogenesis of NAFLD. PMPs change protein properties and regulate many biological functions, including cellular localization, stability, intracellular signaling, and protein function. Lysine acetylation is a common reversible PMP that consists of the transfer of an acetyl group from acetyl-coenzyme A (CoA) to a lysine residue on targeted proteins. The deacetylation reaction is catalyzed by deacetylases called sirtuins. This review summarizes the role of acetylation in NAFLD with a focus on sirtuins 1 and 3.
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Affiliation(s)
- Fatiha Nassir
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, USA
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Kundu A, Dey P, Park JH, Kim IS, Kwack SJ, Kim HS. EX-527 Prevents the Progression of High-Fat Diet-Induced Hepatic Steatosis and Fibrosis by Upregulating SIRT4 in Zucker Rats. Cells 2020; 9:1101. [PMID: 32365537 PMCID: PMC7290750 DOI: 10.3390/cells9051101] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 04/25/2020] [Accepted: 04/27/2020] [Indexed: 02/07/2023] Open
Abstract
Sirtuin (SIRT) is known to prevent nonalcoholic fatty liver disease (NAFLD); however, the role of SIRT4 in the progression of hepatic fibrosis remains unknown. We hypothesize that EX-527, a selective SIRT1 inhibitor, can inhibit the progression of high-fat diet (HFD)-induced hepatic fibrosis. We found that SIRT4 expression in the liver of NAFLD patients is significantly lower than that in normal subjects. In this study, EX-527 (5 µg/kg), administered to HFD rats twice a week for ten weeks, reduced the serum levels of triglyceride (TG), total cholesterol, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) and attenuated hepatic fibrosis evidenced by Masson's trichrome and hepatic fat by oil red-O staining. EX-527 upregulated SIRT2, SIRT3, and SIRT4 expression in the liver of HFD fed rats but downregulated transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) expression. It decreased proinflammatory cytokine production and hydroxyproline levels in the serum and SMAD4 expression and restored apoptotic protein (Bcl-2, Bax, and cleaved caspase-3) expression. These data propose a critical role for the SIRT4/SMAD4 axis in hepatic fibrogenesis. SIRT4 upregulation has the potential to counter HFD-induced lipid accumulation, inflammation, and fibrogenesis. We demonstrate that EX-527 is a promising candidate in inhibiting the progression of HFD-induced liver fibrosis.
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Affiliation(s)
- Amit Kundu
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea; (A.K.); (P.D.); (J.H.P.); (I.S.K.)
| | - Prasanta Dey
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea; (A.K.); (P.D.); (J.H.P.); (I.S.K.)
| | - Jae Hyeon Park
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea; (A.K.); (P.D.); (J.H.P.); (I.S.K.)
| | - In Su Kim
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea; (A.K.); (P.D.); (J.H.P.); (I.S.K.)
| | - Seung Jun Kwack
- Department of Biochemistry and Health Science, Changwon National University, Gyeongnam 51140, Korea;
| | - Hyung Sik Kim
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea; (A.K.); (P.D.); (J.H.P.); (I.S.K.)
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Enhanced GIP Secretion in Obesity Is Associated with Biochemical Alteration and miRNA Contribution to the Development of Liver Steatosis. Nutrients 2020; 12:nu12020476. [PMID: 32069846 PMCID: PMC7071278 DOI: 10.3390/nu12020476] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 02/03/2020] [Accepted: 02/06/2020] [Indexed: 12/16/2022] Open
Abstract
Nutrient excess enhances glucose-dependent insulinotropic polypeptide (GIP) secretion, which may in turn contribute to the development of liver steatosis. We hypothesized that elevated GIP levels in obesity may affect markers of liver injury through microRNAs. The study involved 128 subjects (body mass index (BMI) 25–40). Fasting and postprandial GIP, glucose, insulin, and lipids, as well as fasting alanine aminotransferase (ALT), γ-glutamyltransferase (GGT), cytokeratin-18, fibroblast growth factor (FGF)-19, and FGF-21 were determined. TaqMan low density array was used for quantitative analysis of blood microRNAs. Fasting GIP was associated with ALT [β = 0.16 (confidence interval (CI): 0.01–0.32)], triglycerides [β = 0.21 (95% CI: 0.06–0.36], and FGF-21 [β = 0.20 (95%CI: 0.03–0.37)]; and postprandial GIP with GGT [β = 0.17 (95%CI: 0.03–0.32)]. The odds ratio for elevated fatty liver index (>73%) was 2.42 (95%CI: 1.02–5.72) for high GIP versus low GIP patients. The miRNAs profile related to a high GIP plasma level included upregulated miR-136-5p, miR-320a, miR-483-5p, miR-520d-5p, miR-520b, miR-30e-3p, and miR-571. Analysis of the interactions of these microRNAs with gene expression pathways suggests their potential contribution to the regulation of the activity of genes associated with insulin resistance, fatty acids metabolism, and adipocytokines signaling. Exaggerated fasting and postprandial secretion of GIP in obesity are associated with elevated liver damage markers as well as FGF-21 plasma levels. Differentially expressed microRNAs suggest additional, epigenetic factors contributing to the gut–liver cross-talk.
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Chinese Herbal Medicine Formula Shenling Baizhu San Ameliorates High-Fat Diet-Induced NAFLD in Rats by Modulating Hepatic MicroRNA Expression Profiles. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2019:8479680. [PMID: 31915454 PMCID: PMC6935448 DOI: 10.1155/2019/8479680] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 11/24/2019] [Accepted: 11/26/2019] [Indexed: 12/19/2022]
Abstract
Objective The purpose of present study was to investigate the potential mechanism underlying the protective effect of Shenling Baizhu San (SLBZS) on nonalcoholic fatty liver disease (NAFLD) by microRNA (miRNA) sequencing. Methods Thirty male Wistar rats were randomly divided into a normal control (NC) group, a high-fat diet (HFD) group, and an SLBZS group. After 12 weeks, the biochemical parameters and liver histologies of the rats were assessed. The Illumina HiSeq 2500 sequencing platform was used to analyse the hepatic miRNA expression profiles. Representative differentially expressed miRNAs were further validated by qRT-PCR. The functions of the differentially expressed miRNAs were analysed by bioinformatics. Results Our results identified 102 miRNAs that were differentially expressed in the HFD group compared with the NC group. Among those differentially expressed miRNAs, the expression levels of 28 miRNAs were reversed by SLBZS administration, suggesting the modulation effect of SLBZS on hepatic miRNA expression profiles. The qRT-PCR results confirmed that the expression levels of miR-155-5p, miR-146b-5p, miR-132-3p, and miR-34a-5p were consistent with those detected by sequencing. Bioinformatics analyses indicated that the target genes of the differentially expressed miRNAs reversed by SLBZS were mainly related to metabolic pathways. Conclusion This study provides novel insights into the mechanism of SLBZS in protecting against NAFLD; this mechanism may be partly related to the modulation of hepatic miRNA expression and their target pathways.
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Tekin K, Tekin MI. Oxidative stress and diabetic retinopathy. Pathology 2020. [DOI: 10.1016/b978-0-12-815972-9.00003-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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