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1
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Coutinho-Wolino KS, Brito ML, Trigueira PC, de Menezes LO, do Nascimento CS, Stockler-Pinto MB. Genetic Signature of a Healthy Lifestyle: New Horizons for Preventing Noncommunicable Chronic Diseases by Modulating MicroRNA-155. Nutr Rev 2024:nuae142. [PMID: 39383044 DOI: 10.1093/nutrit/nuae142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/11/2024] Open
Abstract
The development and progression of several noncommunicable diseases (NCDs) are associated with microRNA (miR) 155 (miR-155) activation, which promotes inflammation and oxidative stress. In particular, miR-155 regulates nuclear transcription factor-kappa B (NF-κB) by silencing gene expression of proteins involved in NF-κB suppression, such as suppressor of cytokine signaling 1 (SOCS1) and SH-2 containing inositol 5' polyphosphate 1 (SHIP1), increases the production of reactive oxygen species, and suppresses gene expression of antioxidant enzymes through nuclear factor erythroid 2-related factor 2 (Nrf2) inhibition. In this context, a healthy lifestyle based on a diet rich in nutrients and bioactive compounds as well as regular physical activity may modulate the activity of several miRs. Following this concept, studies involving nutrients, bioactive compounds, and physical activity have been developed to modulate miR-155 activation. This narrative review aims to discuss how a healthy lifestyle based on a diet rich in nutrients, bioactive compounds, and physical activity may modulate the miR-155 pathway and consequently prevent the development and progression of NCDs. Nutrients and bioactive compounds from food may act by inhibiting pathways that promote miR-155 activation such as NF-κB and promote activation of pathways that are associated with the downregulation of miR-155, such as Nrf2, and SOCS1 pathways. Regular physical activity also seems to influence miR-155 levels through an improvement in the immune system during muscle recovery. There is relevant evidence that shows a positive effect of nutrients, bioactive compounds, and physical activity with the modulation of miR-155, which can potentially provide benefits in the clinical setting in cases of NCDs.
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Affiliation(s)
- Karen S Coutinho-Wolino
- Postgraduate Program in Cardiovascular Sciences, Fluminense Federal University, Niterói, Rio de Janeiro, 24070-090, Brazil
| | - Michele L Brito
- Postgraduate Program in Pathology, Fluminense Federal University, Niterói, Rio de Janeiro, 24070-090, Brazil
| | - Pricilla C Trigueira
- Postgraduate Program in Pathology, Fluminense Federal University, Niterói, Rio de Janeiro, 24070-090, Brazil
| | - Larissa O de Menezes
- Graduate Program in Nutrition, Faculty of Nutrition, Fluminense Federal University, Niterói, 24020-140, Brazil
| | - Clara S do Nascimento
- Graduate Program in Biomedicine, Faculty of Biomedicine, Fluminense Federal University, Niterói, 24020-140, Brazil
| | - Milena B Stockler-Pinto
- Postgraduate Program in Cardiovascular Sciences, Fluminense Federal University, Niterói, Rio de Janeiro, 24070-090, Brazil
- Postgraduate Program in Pathology, Fluminense Federal University, Niterói, Rio de Janeiro, 24070-090, Brazil
- Postgraduate Program in Nutrition Sciences, Faculty of Nutrition, Fluminense Federal University, Niterói, 24020-140, Brazil
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2
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Latini A, Benedittis GD, Ciccacci C, Novelli G, Spallone V, Borgiani P. Low expression levels of miRNA-155 and miRNA-499a are associated with obesity in Type 2 diabetes. Epigenomics 2024; 16:85-91. [PMID: 38221897 DOI: 10.2217/epi-2023-0320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2024] Open
Abstract
Background & aims: This study investigated a possible correlation between three circulating miRNAs, previously observed to be associated to diabetic polyneuropathy, and the obesity condition. Methods & results: The expression levels of miR-128a, miR-155 and miR499a were evaluated in 49 participants with Type 2 diabetes, divided into different groups based on the presence or absence of obesity and central obesity. The analyses revealed a significant decrease of miR-155 and miR-499a expression levels in obese subjects. In particular, the reduction appears to be even more significant in Type 2 diabetes subjects with central obesity. Conclusion: The results suggest that these miRNAs could be involved in obesity-driven pathogenetic mechanisms.
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Affiliation(s)
- Andrea Latini
- Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, Rome, 00133, Italy
| | - Giada De Benedittis
- Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, Rome, 00133, Italy
| | - Cinzia Ciccacci
- UniCamillus, Saint Camillus International University of Health Sciences, Rome, 00131, Italy
| | - Giuseppe Novelli
- Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, Rome, 00133, Italy
- IRCCS NEUROMED, Pozzilli, IS, 86077, Italy
- School of Medicine, Department of Pharmacology, Reno University of Nevada, NV 89557, USA
| | - Vincenza Spallone
- Department of Systems Medicine, Endocrinology Section, University of Rome Tor Vergata, Rome, 00133, Italy
| | - Paola Borgiani
- Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, Rome, 00133, Italy
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3
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Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Kobara H, Ono M, Himoto T, Masaki T. MicroRNAs and Nonalcoholic Steatohepatitis: A Review. Int J Mol Sci 2023; 24:14482. [PMID: 37833930 PMCID: PMC10572537 DOI: 10.3390/ijms241914482] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/19/2023] [Accepted: 09/21/2023] [Indexed: 10/15/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a clinicopathologic syndrome caused by fat deposition in hepatocytes. Patients with nonalcoholic steatohepatitis (NASH), an advanced form of NAFLD with severe fibrosis, are at high risk for liver-related complications, including hepatocellular carcinoma (HCC). However, the mechanism of progression from simple fat deposition to NASH is complex, and previous reports have linked NAFLD to gut microbiota, bile acids, immunity, adipokines, oxidative stress, and genetic or epigenetic factors. NASH-related liver injury involves multiple cell types, and intercellular signaling is thought to be mediated by extracellular vesicles. MicroRNAs (miRNAs) are short, noncoding RNAs that play important roles as post-transcriptional regulators of gene expression and have been implicated in the pathogenesis of various diseases. Recently, many reports have implicated microRNAs in the pathogenesis of NALFD/NASH, suggesting that exosomal miRNAs are potential non-invasive and sensitive biomarkers and that the microRNAs involved in the mechanism of the progression of NASH may be potential therapeutic target molecules. We are interested in which miRNAs are involved in the pathogenesis of NASH and which are potential target molecules for therapy. We summarize targeted miRNAs associated with the etiology and progression of NASH and discuss each miRNA in terms of its pathophysiology, potential therapeutic applications, and efficacy as a NASH biomarker.
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Affiliation(s)
| | | | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Japan; (A.M.); (K.O.); (K.F.); (J.T.); (H.K.); (M.O.); (T.H.); (T.M.)
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4
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Dlouha D, Blaha M, Huckova P, Lanska V, Hubacek JA, Blaha V. Long-Term LDL-Apheresis Treatment and Dynamics of Circulating miRNAs in Patients with Severe Familial Hypercholesterolemia. Genes (Basel) 2023; 14:1571. [PMID: 37628623 PMCID: PMC10454435 DOI: 10.3390/genes14081571] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/26/2023] [Accepted: 07/29/2023] [Indexed: 08/27/2023] Open
Abstract
Lipoprotein apheresis (LA) is a therapeutic option for patients with severe hypercholesterolemia who have persistently elevated LDL-C levels despite attempts at drug therapy. MicroRNAs (miRNAs), important posttranscriptional gene regulators, are involved in the pathogenesis of atherosclerosis. Our study aimed to monitor the dynamics of twenty preselected circulating miRNAs in patients under long-term apheresis treatment. Plasma samples from 12 FH patients (men = 50%, age = 55.3 ± 12.2 years; mean LA overall treatment time = 13.1 ± 7.8 years) were collected before each apheresis therapy every sixth month over the course of four years of treatment. Eight complete follow-up (FU) samples were measured in each patient. Dynamic changes in the relative quantity of 6 miRNAs (miR-92a, miR-21, miR-126, miR-122, miR-26a, and miR-185; all p < 0.04) during FU were identified. Overall apheresis treatment time influenced circulating miR-146a levels (p < 0.04). In LDLR mutation homozygotes (N = 5), compared to heterozygotes (N = 7), we found higher plasma levels of miR-181, miR-126, miR-155, and miR-92a (all p < 0.03). Treatment with PCSK9 inhibitors (N = 6) affected the plasma levels of 7 miRNAs (miR-126, miR-122, miR-26a, miR-155, miR-125a, miR-92a, and miR-27a; all p < 0.04). Long-term monitoring has shown that LA in patients with severe familial hypercholesterolemia influences plasma circulating miRNAs involved in endothelial dysfunction, cholesterol homeostasis, inflammation, and plaque development. The longer the treatment using LA, the better the miRNA milieu depicting the potential cardiovascular risk.
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Affiliation(s)
- Dana Dlouha
- Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (P.H.); (J.A.H.)
| | - Milan Blaha
- 4th Department of Internal Medicine—Hematology, University Hospital Hradec Králové, 50005 Hradec Králové, Czech Republic;
- Faculty of Medicine in Hradec Králové, Charles University, 50003 Hradec Králové, Czech Republic;
| | - Pavlina Huckova
- Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (P.H.); (J.A.H.)
| | - Vera Lanska
- Statistical Unit, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic;
| | - Jaroslav Alois Hubacek
- Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (P.H.); (J.A.H.)
- 1st Faculty of Medicine, Charles University, 12108 Prague, Czech Republic
| | - Vladimir Blaha
- Faculty of Medicine in Hradec Králové, Charles University, 50003 Hradec Králové, Czech Republic;
- 3rd Department of Internal Medicine—Metabolism and Gerontology, University Hospital Hradec Králové, 50005 Hradec Králové, Czech Republic
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5
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Bartiromo M, Nardolillo M, Ferrara S, Russo G, Miraglia Del Giudice E, Di Sessa A. The challenging role of micro-RNAs in non-alcoholic fatty liver disease in children with obesity: is it time for a new era? Expert Rev Gastroenterol Hepatol 2023; 17:817-824. [PMID: 37497846 DOI: 10.1080/17474124.2023.2242245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 07/04/2023] [Accepted: 07/26/2023] [Indexed: 07/28/2023]
Abstract
INTRODUCTION As the pediatric obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in childhood. Pediatric NAFLD pathophysiology is tangled and still unclear, but insulin resistance (IR), genetics, epigenetics, oxidative stress, and inflammation act as key players. Due to the increased cardiometabolic risk of these patients, several biomarkers have been proposed for early NAFLD identification, but their clinical utility is poor. Recently, hepatic dysregulation of microRNAs (miRNAs) has been linked to metabolic dysfunction, which in turn implied in NAFLD development. Evidence on the intriguing role of miRNAs in NAFLD pathogenesis has emerging especially in at-risk children such as those with obesity. However, pediatric evidence supporting their potential use as early noninvasive NAFLD tools is still limited but promising. AREAS COVERED We provided an overview on the emerging role of miRNAs in pediatric NAFLD by addressing some issues regarding their pathophysiological link with the metabolic milieu and their role as reliable NAFLD markers in children with obesity. EXPERT OPINION Strong evidence supports a potential role of miRNAs as early biomarkers of NAFLD in children with obesity. They might represent a valid diagnostic and targeted therapeutic tool due to its close pathogenic link with the metabolic milieu.
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Affiliation(s)
- Mario Bartiromo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Michele Nardolillo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Serena Ferrara
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giuseppina Russo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Emanuele Miraglia Del Giudice
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Anna Di Sessa
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
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6
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Zhu Y, Tan JK, Wong SK, Goon JA. Therapeutic Effects of microRNAs on Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH): A Systematic Review and Meta-Analysis. Int J Mol Sci 2023; 24:ijms24119168. [PMID: 37298120 DOI: 10.3390/ijms24119168] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/26/2023] [Accepted: 04/28/2023] [Indexed: 06/12/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as a global health problem that affects people even at young ages due to unhealthy lifestyles. Without intervention, NAFLD will develop into nonalcoholic steatohepatitis (NASH) and eventually liver cirrhosis and hepatocellular carcinoma. Although lifestyle interventions are therapeutic, effective implementation remains challenging. In the efforts to establish effective treatment for NAFLD/NASH, microRNA (miRNA)-based therapies began to evolve in the last decade. Therefore, this systematic review aims to summarize current knowledge on the promising miRNA-based approaches in NAFLD/NASH therapies. A current systematic evaluation and a meta-analysis were conducted according to the PRISMA statement. In addition, a comprehensive exploration of PubMed, Cochrane, and Scopus databases was conducted to perform article searches. A total of 56 different miRNAs were reported as potential therapeutic agents in these studies. miRNA-34a antagonist/inhibitor was found to be the most studied variant (n = 7), and it significantly improved the hepatic total cholesterol, total triglyceride, Aspartate Aminotransferase (AST), and Alanine Transaminase (ALT) levels based on a meta-analysis. The biological processes mediated by these miRNAs involved hepatic fat accumulation, inflammation, and fibrosis. miRNAs have shown enormous therapeutic potential in the management of NAFLD/NASH, wherein miRNA-34a antagonist has been found to be an exceptional potential agent for the treatment of NAFLD/NASH.
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Affiliation(s)
- Yuezhi Zhu
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Jen Kit Tan
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Sok Kuan Wong
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Jo Aan Goon
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
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7
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Xu K, Xia P, Chen X, Ma W, Yuan Y. ncRNA-mediated fatty acid metabolism reprogramming in HCC. Trends Endocrinol Metab 2023; 34:278-291. [PMID: 36890041 DOI: 10.1016/j.tem.2023.02.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 02/14/2023] [Accepted: 02/16/2023] [Indexed: 03/08/2023]
Abstract
The challenges of hepatocellular carcinoma (HCC) pathogenesis, diagnosis, treatment, and prognosis evaluation are obvious. Hepatocyte-specific fatty acid (FA) metabolic reprogramming is an important marker of liver carcinogenesis and progression; elucidating its mechanism will help unravel the complexity of HCC pathogenesis. Noncoding RNAs (ncRNAs) play important roles in HCC development. Moreover, ncRNAs are important mediators of FA metabolism and are directly involved in the reprogramming of FA metabolism in HCC cells. Here we review significant new advances in understanding the mechanisms regulating HCC metabolism by focusing on ncRNA-mediated post-translational modifications of metabolic enzymes, metabolism-related transcription factors, and other proteins in associated signaling pathways. We also discuss the great therapeutic potential of targeting ncRNA-mediated FA metabolism reprogramming in HCC.
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Affiliation(s)
- Kequan Xu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China
| | - Peng Xia
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China
| | - Xi Chen
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China
| | - Weijie Ma
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China.
| | - Yufeng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China.
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8
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Xue X, Wang J, Fu K, Dai S, Wu R, Peng C, Li Y. The role of miR-155 on liver diseases by modulating immunity, inflammation and tumorigenesis. Int Immunopharmacol 2023; 116:109775. [PMID: 36753984 DOI: 10.1016/j.intimp.2023.109775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 01/18/2023] [Accepted: 01/20/2023] [Indexed: 02/08/2023]
Abstract
The liver is a well-known metabolic organ that can be susceptible to external stimuli to affect its normal physiological function. Worldwide, the morbidity and mortality of liver diseases are skyrocketing every year, causing human health crises. Recently, new approaches such as biotechnology have been introduced to achieve optimal treatment and prognostic management of liver diseases. microRNAs (miRNAs), a kind of small non-coding RNA molecule, have the advantages of biodiversity, wide distribution and numerous members. Among these miRNAs, miR-155 is an important regulator of inflammation, immunity and tumorigenesis. In this review, the PubMed and Web of Science databases were searched from 2009 to 2022. After inclusion and exclusion, 64 articles were selected for a systematic review to comprehensively summarize the mechanisms of miR-155 regulating inflammation, immunity and tumorigenesis in liver diseases and liver cancer, covering in vitro, in vivo and clinical studies. Existing preclinical studies and clinical trials have listed that the up-regulation and down-regulation of miR-155 are significant in alcoholic liver injury, viral hepatitis, autoimmune hepatitis, infectious liver injury, liver transplantation and liver cancer. The immune and inflammation effects of miR-155 are manifested by regulating macrophage polarization, NK cell killing, Th17 cell and Th1/Th2 cell differentiation. Additionally, miR-155 is also committed to participating in the cell cycle, invasion and metastasis, immune escape and other processes to promote and intensify the development of liver cancer. In conclusion, miR-155 is not only a biomarker for the diagnosis and prognosis of liver diseases, but also plays a therapeutic role via regulating immunity, inflammation and tumorigenesis.
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Affiliation(s)
- Xinyan Xue
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jing Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Ke Fu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Shu Dai
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Rui Wu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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Sarangi R, Mishra S, Das S, Mishra A. Nonalcoholic Fatty Liver Disease and MicroRNAs: A Weighty Consideration. BIOMEDICAL AND BIOTECHNOLOGY RESEARCH JOURNAL (BBRJ) 2023. [DOI: 10.4103/bbrj.bbrj_319_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/17/2023]
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10
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Rana M, Saini M, Das R, Gupta S, Joshi T, Mehta DK. Circulating MicroRNAs: Diagnostic Value as Biomarkers in the Detection of Non-alcoholic Fatty Liver Diseases and Hepatocellular Carcinoma. Microrna 2023; 12:99-113. [PMID: 37005546 DOI: 10.2174/2211536612666230330083146] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 01/09/2023] [Accepted: 01/20/2023] [Indexed: 04/04/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD), a metabolic-related disorder, is the most common cause of chronic liver disease which, if left untreated, can progress from simple steatosis to advanced fibrosis and eventually cirrhosis or hepatocellular carcinoma, which is the leading cause of hepatic damage globally. Currently available diagnostic modalities for NAFLD and hepatocellular carcinoma are mostly invasive and of limited precision. A liver biopsy is the most widely used diagnostic tool for hepatic disease. But due to its invasive procedure, it is not practicable for mass screening. Thus, noninvasive biomarkers are needed to diagnose NAFLD and HCC, monitor disease progression, and determine treatment response. Various studies indicated that serum miRNAs could serve as noninvasive biomarkers for both NAFLD and HCC diagnosis because of their association with different histological features of the disease. Although microRNAs are promising and clinically useful biomarkers for hepatic diseases, larger standardization procedures and studies are still required.
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Affiliation(s)
- Minakshi Rana
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Manisha Saini
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Rina Das
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Sumeet Gupta
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Tanishq Joshi
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Dinesh Kumar Mehta
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
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11
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Zaiou M. Noncoding RNAs as additional mediators of epigenetic regulation in nonalcoholic fatty liver disease. World J Gastroenterol 2022; 28:5111-5128. [PMID: 36188722 PMCID: PMC9516672 DOI: 10.3748/wjg.v28.i35.5111] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 07/28/2022] [Accepted: 08/26/2022] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common cause of chronic liver disorder worldwide. It represents a spectrum that includes a continuum of different clinical entities ranging from simple steatosis to nonalcoholic steatohepatitis, which can evolve to cirrhosis and in some cases to hepatocellular carcinoma, ultimately leading to liver failure. The pathogenesis of NAFLD and the mechanisms underlying its progression to more pathological stages are not completely understood. Besides genetic factors, evidence indicates that epigenetic mechanisms occurring in response to environmental stimuli also contribute to the disease risk. Noncoding RNAs (ncRNAs), including microRNAs, long noncoding RNAs, and circular RNAs, are one of the epigenetic factors that play key regulatory roles in the development of NAFLD. As the field of ncRNAs is rapidly evolving, the present review aims to explore the current state of knowledge on the roles of these RNA species in the pathogenesis of NAFLD, highlight relevant mechanisms by which some ncRNAs can modulate regulatory networks implicated in NAFLD, and discuss key challenges and future directions facing current research in the hopes of developing ncRNAs as next-generation non-invasive diagnostics and therapies in NAFLD and subsequent progression to hepatocellular carcinoma.
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Affiliation(s)
- Mohamed Zaiou
- Institut Jean Lamour, UMR CNRS 7198, CNRS, University of Lorraine, Nancy 54011, France
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12
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Factors influencing circulating microRNAs as biomarkers for liver diseases. Mol Biol Rep 2022; 49:4999-5016. [DOI: 10.1007/s11033-022-07170-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 01/19/2022] [Indexed: 11/09/2022]
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13
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Lin H, Mercer KE, Ou X, Mansfield K, Buchmann R, Børsheim E, Tas E. Circulating microRNAs Are Associated With Metabolic Markers in Adolescents With Hepatosteatosis. Front Endocrinol (Lausanne) 2022; 13:856973. [PMID: 35498403 PMCID: PMC9047938 DOI: 10.3389/fendo.2022.856973] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 03/14/2022] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Altered hepatic microRNA (miRNA) expression may play a role in the development of insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). Circulating miRNAs could mirror the liver metabolism. OBJECTIVE This study aimed to assess the relationship between serum miRNA profile in children with obesity, IR, and NAFLD. METHODS Adolescents with obesity (n = 31) were stratified based on insulin resistance and NAFLD status. One-hundred seventy-nine miRNAs were determined in the serum by quantitative RT-PCR. Differentially expressed miRNAs were compared between groups, and log-transformed levels correlated with metabolic markers and intrahepatic triglyceride. RESULTS Serum miR-21-5p, -22-3p, -150-5p, and -155-5p levels were higher in children with IR and NAFLD, and their expression levels correlated with hepatic fat and serum triglyceride. In patients with NAFLD, miR-155-5p correlated with ALT (r = 0.68, p<0.01) and AST (r = 0.64, p<0.01) and miR-21-5p and -22-3p levels correlated with plasma adiponectin (r = -0.71 and r = -0.75, respectively, p<0.05) and fibroblast growth factor-21 (r = -0.73 and r = -0.89, respectively, p<0.01). miR-27-3a level was higher in children without IR and NAFLD. CONCLUSIONS Several miRNAs are differentially expressed in children with IR and NAFLD. Determining their mechanistic roles may provide newer diagnostic tools and therapeutic targets for pediatric NAFLD.
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Affiliation(s)
- Haixia Lin
- Arkansas Children’s Nutrition Center, Little Rock, AR, United States
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Kelly E. Mercer
- Arkansas Children’s Nutrition Center, Little Rock, AR, United States
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Center for Childhood Obesity and Prevention, Arkansas Children’s Research Institute, Little Rock, AR, United States
| | - Xiawei Ou
- Arkansas Children’s Nutrition Center, Little Rock, AR, United States
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Center for Childhood Obesity and Prevention, Arkansas Children’s Research Institute, Little Rock, AR, United States
- Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Kori Mansfield
- Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Robert Buchmann
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Elisabet Børsheim
- Arkansas Children’s Nutrition Center, Little Rock, AR, United States
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Center for Childhood Obesity and Prevention, Arkansas Children’s Research Institute, Little Rock, AR, United States
| | - Emir Tas
- Arkansas Children’s Nutrition Center, Little Rock, AR, United States
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Center for Childhood Obesity and Prevention, Arkansas Children’s Research Institute, Little Rock, AR, United States
- Endocrinology and Diabetes, Arkansas Children’s Hospital, Little Rock, AR, United States
- *Correspondence: Emir Tas,
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14
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Abstract
Abstract
Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease, worldwide. The molecular pathogenesis of NAFLD is complex, involving numerous signalling molecules including microRNAs (miRNAs). Dysregulation of miRNA expression is associated with hepatic inflammation, fibrosis and hepatocellular carcinoma. Although miRNAs are also critical to the cellular response to vitamin D, mediating regulation of the vitamin D receptor (VDR) and vitamin D’s anticancer effects, a role for vitamin D regulated miRNAs in NAFLD pathogenesis has been relatively unexplored. Therefore, this review aimed to critically assess the evidence for a potential subset of miRNAs that are both dysregulated in NAFLD and modulated by vitamin D. Comprehensive review of 89 human studies identified 25 miRNAs found dysregulated in more than one NAFLD study. In contrast, only 17 studies, including a protocol for a trial in NAFLD, had examined miRNAs in relation to vitamin D status, response to supplementation, or vitamin D in the context of the liver. This paper summarises these data and reviews the biological roles of six miRNAs (miR-21, miR-30, miR-34, miR-122, miR-146, miR-200) found dysregulated in multiple independent NAFLD studies. While modulation of miRNAs by vitamin D has been understudied, integrating the data suggests seven vitamin D modulated miRNAs (miR-27, miR-125, miR-155, miR-192, miR-223, miR-375, miR-378) potentially relevant to NAFLD pathogenesis. Our summary tables provide a significant resource to underpin future hypothesis-driven research, and we conclude that the measurement of serum and hepatic miRNAs in response to vitamin D supplementation in larger trials is warranted.
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15
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Bala S, Ganz M, Babuta M, Zhuang Y, Csak T, Calenda CD, Szabo G. Steatosis, inflammasome upregulation, and fibrosis are attenuated in miR-155 deficient mice in a high fat-cholesterol-sugar diet-induced model of NASH. J Transl Med 2021; 101:1540-1549. [PMID: 34453120 PMCID: PMC9272486 DOI: 10.1038/s41374-021-00626-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 06/02/2021] [Accepted: 06/04/2021] [Indexed: 12/19/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease globally. miRNAs (miRs) regulate various cellular events that lead to NAFLD. In this study we tested the hypothesis that miR-155 is an important regulator of steatohepatitis and fibrosis pathways. Wild type (WT) or miR-155 deficient (KO) mice received a high fat-high cholesterol-high sugar-diet (HF-HC-HS) for 34 weeks and liver tissues were analyzed. In patients with nonalcoholic steatohepatitis and in the mouse model of HF-HC-HS diet we found increased miR-155 levels in the liver compared to normal livers. Upon HF-HC-HS diet feeding, miR-155 KO mice displayed less liver injury, decreased steatosis, and attenuation in fibrosis compared to WT mice. ALT, triglyceride levels, and genes involved in fatty acid metabolic pathway were increased in WT mice whereas miR-155 KO mice showed attenuation in these parameters. HF-HC-HS diet-induced significant increase in the expression of NLRP3 inflammasome components in the livers of WT mice compared to chow fed diet. Compared to WT mice, miR-155 KO showed attenuated induction in the NLRP3, ASC, and caspase1 inflammasome expression on HF-HC-HS diet. Fibrosis markers such as collagen content and deposition, αSMA, Zeb2, and vimentin were all increased in WT mice and miR-155 KO mice showed attenuated fibrosis marker expression. Overall, our findings highlight a role for miR-155 in HF-HC-HS diet-induced steatosis and liver fibrosis.
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Affiliation(s)
- Shashi Bala
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, 02215, MA, USA
| | - Michal Ganz
- Department of Medicine, University of Massachusetts Medical School, Worcester, 01605, MA, USA
| | - Mrigya Babuta
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, 02215, MA, USA
| | - Yuan Zhuang
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, 02215, MA, USA
| | - Timea Csak
- Department of Medicine, University of Massachusetts Medical School, Worcester, 01605, MA, USA
| | - Charles D Calenda
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, 02215, MA, USA
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, 02215, MA, USA.
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16
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López-Sánchez GN, Dóminguez-Pérez M, Uribe M, Chávez-Tapia NC, Nuño-Lámbarri N. Non-alcoholic fatty liver disease and microRNAs expression, how it affects the development and progression of the disease. Ann Hepatol 2021; 21:100212. [PMID: 32533953 DOI: 10.1016/j.aohep.2020.04.012] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 04/30/2020] [Indexed: 02/07/2023]
Abstract
The obesity pandemic that affects the global population generates one of the most unfavorable microenvironmental conditions in the hepatocyte, which triggers the metabolic hepatopathy known as non-alcoholic fatty liver; its annual rates increase in its prevalence and does not seem to improve in the future. The international consortia, LITMUS by the European Union and NIMBLE by the United States of America, have started a race for the development of hepatic steatosis and steatohepatitis reliable biomarkers to have an adequate diagnosis. MicroRNAs have been proposed as diagnostic and prognostic biomarkers involved in adaptation to changes in the liver microenvironment, which could improve clinical intervention strategies in patients with hepatic steatosis.
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Affiliation(s)
- Guillermo Nahúm López-Sánchez
- Traslational Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra, Tlalpan, Z.C. 14050 Mexico City, Mexico
| | - Mayra Dóminguez-Pérez
- Genomics of Cardiovascular Diseases Laboratory, National Institute of Genomic Medicine, Periferico Sur 4809, Arenal Tepepan, Tlalpan, Z.C. 14610 Mexico City, Mexico
| | - Misael Uribe
- Obesity and Digestive Diseases Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra, Tlalpan, Z.C. 14050 Mexico City, Mexico
| | - Norberto Carlos Chávez-Tapia
- Traslational Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra, Tlalpan, Z.C. 14050 Mexico City, Mexico; Obesity and Digestive Diseases Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra, Tlalpan, Z.C. 14050 Mexico City, Mexico
| | - Natalia Nuño-Lámbarri
- Traslational Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra, Tlalpan, Z.C. 14050 Mexico City, Mexico.
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17
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Targeting miRNA by Natural Products: A Novel Therapeutic Approach for Nonalcoholic Fatty Liver. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6641031. [PMID: 34426744 PMCID: PMC8380168 DOI: 10.1155/2021/6641031] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 08/02/2021] [Indexed: 02/07/2023]
Abstract
The increasing prevalence of nonalcoholic fatty liver disease (NAFLD) as multifactorial chronic liver disease and the lack of a specific treatment have begun a new era in its treatment using gene expression changes and microRNAs. This study aimed to investigate the potential therapeutic effects of natural compounds in NAFLD by regulating miRNA expression. MicroRNAs play essential roles in regulating the cell's biological processes, such as apoptosis, migration, lipid metabolism, insulin resistance, and adipocyte differentiation, by controlling the posttranscriptional gene expression level. The impact of current NAFLD pharmacological management, including drug and biological therapies, is uncertain. In this context, various dietary fruits or medicinal herbal sources have received worldwide attention versus NAFLD development. Natural ingredients such as berberine, lychee pulp, grape seed, and rosemary possess protective and therapeutic effects against NAFLD by modifying the gene's expression and noncoding RNAs, especially miRNAs.
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18
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Feng X, Bao J, Song C, Xie L, Tan X, Li J, Jia H, Tian M, Qi J, Qin C, Bian H. Functional role of miR‑155 in physiological and pathological processes of liver injury (Review). Mol Med Rep 2021; 24:714. [PMID: 34396452 DOI: 10.3892/mmr.2021.12353] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 07/09/2021] [Indexed: 11/05/2022] Open
Abstract
There are several types of liver injury, including alcohol‑induced liver injury, drug‑induced liver injury, infectious liver injury, cirrhosis, liver ischemia/reperfusion injury and liver failure. In recent years, accumulated data have demonstrated that microRNAs (miRNAs/miRs) may be involved in the occurrence and development of a variety of systemic diseases, such as immune diseases, tumors and nervous system diseases. miR‑155 is a key miRNA, which has been studied extensively and has been shown to target different genes. In the present review, the potential effects and mechanisms of miR‑155 on the physiological and pathological processes of liver injury were reviewed from the perspective of cell stress, inflammation and activation of fibrosis. In addition, the potential benefits of miR‑155 as a therapeutic target and predictor of liver injury were summarized.
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Affiliation(s)
- Xiao Feng
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
| | - Jiaying Bao
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
| | - Chunxia Song
- Department of Emergency Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
| | - Ling Xie
- Department of Obstetrics and Gynecology, Jinan Zhangqiu District Maternal and Child Health Hospital, Jinan, Shandong 250200, P.R. China
| | - Xu Tan
- Department of Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
| | - Jiaqi Li
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
| | - Huimin Jia
- Department of Emergency Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
| | - Miaomiao Tian
- Department of Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
| | - Jianni Qi
- Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
| | - Chengyong Qin
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
| | - Hongjun Bian
- Department of Emergency Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
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19
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Mastiha has efficacy in immune-mediated inflammatory diseases through a microRNA-155 Th17 dependent action. Pharmacol Res 2021; 171:105753. [PMID: 34224858 DOI: 10.1016/j.phrs.2021.105753] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 06/30/2021] [Accepted: 06/30/2021] [Indexed: 02/08/2023]
Abstract
Mastiha is a natural nutritional supplement with known anti-inflammatory properties. Non-alcoholic fatty liver disease (NAFLD) and Inflammatory bowel disease (IBD) are immune mediated inflammatory diseases that share common pathophysiological features. Mastiha has shown beneficial effects in both diseases. MicroRNAs have emerged as key regulators of inflammation and their modulation by phytochemicals have been extensively studied over the last years. Therefore, the aim of this study was to investigate whether a common route exists in the anti-inflammatory activity of Mastiha, specifically through the regulation of miRNA levels. Plasma miR-16, miR-21 and miR-155 were measured by Real-Time PCR before and after two double blinded and placebo-controlled randomized clinical trials with Mastiha. In IBD and particularly in ulcerative colitis patients in relapse, miR-155 increased in the placebo group (p = 0.054) whereas this increase was prevented by Mastiha. The mean changes were different in the two groups even after adjusting for age, sex and BMI (p = 0.024 for IBD and p = 0.042). Although the results were not so prominent in NAFLD, miR-155 displayed a downward trend in the placebo group (p = 0.054) whereas the levels did not changed significantly in the Mastiha group in patients with less advanced fibrosis. Our results propose a regulatory role for Mastiha in circulating levels of miR-155, a critical player in T helper-17 (Th17) differentiation and function.
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20
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Wu J, Nagy LE, Liangpunsakul S, Wang L. Non-coding RNA crosstalk with nuclear receptors in liver disease. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166083. [PMID: 33497819 PMCID: PMC7987766 DOI: 10.1016/j.bbadis.2021.166083] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 12/28/2020] [Accepted: 01/16/2021] [Indexed: 02/06/2023]
Abstract
The dysregulation of nuclear receptors (NRs) underlies the pathogenesis of a variety of liver disorders. Non-coding RNAs (ncRNAs) are defined as RNA molecules transcribed from DNA but not translated into proteins. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are two types of ncRNAs that have been extensively studied for regulating gene expression during diverse cellular processes. NRs as therapeutic targets in liver disease have been exemplified by the successful application of their pharmacological ligands in clinics. MiRNA-based reagents or drugs are emerging as flagship products in clinical trials. Advancing our understanding of the crosstalk between NRs and ncRNAs is critical to the development of diagnostic and therapeutic strategies. This review summarizes recent findings on the reciprocal regulation between NRs and ncRNAs (mainly on miRNAs and lncRNAs) and their implication in liver pathophysiology, which might be informative to the translational medicine of targeting NRs and ncRNAs in liver disease.
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Affiliation(s)
- Jianguo Wu
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America; Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, United States of America.
| | - Laura E Nagy
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America; Department of Gastroenterology and Hepatology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America; Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, United States of America
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America; Roudebush Veterans Administration Medical Center, Indianapolis, IN, United States of America; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - Li Wang
- Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT, United States of America
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21
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Peripheral Blood miRome Identified miR-155 as Potential Biomarker of MetS and Cardiometabolic Risk in Obese Patients. Int J Mol Sci 2021; 22:ijms22031468. [PMID: 33540559 PMCID: PMC7867145 DOI: 10.3390/ijms22031468] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 01/10/2021] [Accepted: 01/11/2021] [Indexed: 12/26/2022] Open
Abstract
This study explored circulating miRNAs and target genes associated with metabolic syndrome (MetS) and cardiometabolic risk in obese patients. Small-RNA sequencing was used to assess the peripheral blood miRNome of 12 obese subjects (6 MetS and 6 non-MetS). Differentially expressed miRNAs and target genes were further analyzed by qPCR in a larger sample of obese patients (48 MetS and 32 non-MetS). miRNA:mRNA interactions were studied using in silico tools. miRNome analysis identified 10 downregulated miRNAs in MetS compared to non-Met patients (p < 0.05). In silico studies revealed three miRNAs (miR-155, miR-181a, and let-7a) and their predictive targets (CCAAT/enhancer-binding protein beta-CEBPB, KRAS proto-oncogene, GTPase-KRAS and suppressor of cytokine signaling 1-SOCS1) with a potential role in the insulin receptor signaling pathway. miR-155 expression was reduced and CEBPB mRNA levels were increased in MetS patients (p < 0.05), and these effects were correlated with the number of MetS diagnostic criteria (p < 0.05). Increased HOMA-IR (>7.6) was associated with low miR-155 levels, high CEBPB expression, and serum hsCRP (p < 0.05). miR-155 was negatively correlated with CEBPB, HOMA-IR, and plasma fibrinogen, and positively correlated with serum adiponectin (p < 0.05). Downregulation of circulating miR-155 is associated with insulin resistance, poor glycemic control, and increased MetS-related cardiometabolic risk, and these effects are potentially mediated by interaction with CEBPB.
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22
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Mandala A, Janssen RC, Palle S, Short KR, Friedman JE. Pediatric Non-Alcoholic Fatty Liver Disease: Nutritional Origins and Potential Molecular Mechanisms. Nutrients 2020; 12:E3166. [PMID: 33081177 PMCID: PMC7602751 DOI: 10.3390/nu12103166] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/12/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the number one chronic liver disease worldwide and is estimated to affect nearly 40% of obese youth and up to 10% of the general pediatric population without any obvious signs or symptoms. Although the early stages of NAFLD are reversible with diet and lifestyle modifications, detecting such stages is hindered by a lack of non-invasive methods of risk assessment and diagnosis. This absence of non-invasive means of diagnosis is directly related to the scarcity of long-term prospective studies of pediatric NAFLD in children and adolescents. In the majority of pediatric NAFLD cases, the mechanisms driving the origin and rapid progression of NAFLD remain unknown. The progression from NAFLD to non-alcoholic steatohepatitis (NASH) in youth is associated with unique histological features and possible immune processes and metabolic pathways that may reflect different mechanisms compared with adults. Recent data suggest that circulating microRNAs (miRNAs) are important new biomarkers underlying pathways of liver injury. Several factors may contribute to pediatric NAFLD development, including high-sugar diets, in utero exposures via epigenetic alterations, changes in the neonatal microbiome, and altered immune system development and mitochondrial function. This review focuses on the unique aspects of pediatric NAFLD and how nutritional exposures impact the immune system, mitochondria, and liver/gastrointestinal metabolic health. These factors highlight the need for answers to how NAFLD develops in children and for early stage-specific interventions.
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Affiliation(s)
- Ashok Mandala
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (A.M.); (R.C.J.); (K.R.S.)
| | - Rachel C. Janssen
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (A.M.); (R.C.J.); (K.R.S.)
| | - Sirish Palle
- Department of Pediatrics, Section of Gastroenterology, Hepatology & Nutrition, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Kevin R. Short
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (A.M.); (R.C.J.); (K.R.S.)
- Department of Pediatrics, Section of Diabetes and Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Jacob E. Friedman
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (A.M.); (R.C.J.); (K.R.S.)
- Department of Pediatrics, Section of Diabetes and Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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23
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Xin S, Zhan Q, Chen X, Xu J, Yu Y. Efficacy of serum miRNA test as a non-invasive method to diagnose nonalcoholic steatohepatitis: a systematic review and meta-analysis. BMC Gastroenterol 2020; 20:186. [PMID: 32532204 PMCID: PMC7291448 DOI: 10.1186/s12876-020-01334-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Accepted: 06/03/2020] [Indexed: 02/07/2023] Open
Abstract
Background Nonalcoholic steatohepatitis (NASH) is a key turning point during the progression of nonalcoholic fatty liver disease (NAFLD). Recent studies have shown that serum miRNA tests may be effective in the diagnosis of NAFLD. We conducted a meta-analysis to assess the evidence for the diagnostic efficacy of serum miRNAs in patients with NAFLD and its subtype, NASH, in particular. Methods After a systematic review, sensitivity, specificity, and area under the receiver operating characteristics curve (AUROC) were pooled to determine the efficacy of serum miRNA test for the diagnosis of NAFLD and NASH. Clinical utility was evaluated by Fagan’s nomogram and likelihood ratio scattergram. Heterogeneity was evaluated by subgroup analysis and meta-regression. Publication bias was detected by Deeks’ funnel plot. Results We included 27 trials containing 1775 NAFLD patients (including simple steatosis and NASH) and 586 NASH patients. For NAFLD vs NASH, the pooled sensitivity, specificity, and AUROC were (0.71 vs. 0.74), (0.76 vs. 0.85) and (0.80 vs. 0.86), respectively. Serum miRNA had high accuracy for distinguishing NASH from simple steatosis, with an AUROC of 0.91. Among the most commonly studied serum miRNAs, miRNA-34a showed moderate diagnostic accuracy for NAFLD and the lowest heterogeneity (sensitivity I2 = 5.73%, specificity I2 = 33.16%, AUROC = 0.85). According to subgroup analysis and meta-regression, a lower BMI (< 30 kg/m2) might be a crucial source of heterogeneity. Conclusions As a novel non-invasive method, serum miRNA test exhibited robust diagnostic efficacy for NASH. Among these well-studied miRNAs, miRNA-34a was more available for diagnosis. Diagnosis of NAFLD by serum miRNA is more likely to be accurate in patients with BMI ≥ 30 kg/m2.
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Affiliation(s)
- Shengliang Xin
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Qiao Zhan
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Xiaofan Chen
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Jinghang Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Yanyan Yu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China.
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24
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Abstract
Obesity is a worldwide epidemic and contributes to global morbidity and mortality mediated via the development of nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), cardiovascular (CVD) and other diseases. It is a consequence of an elevated caloric intake, a sedentary lifestyle and a genetic as well as an epigenetic predisposition. This review summarizes changes in DNA methylation and microRNAs identified in blood cells and different tissues in obese human and rodent models. It includes information on epigenetic alterations which occur in response to fat-enriched diets, exercise and metabolic surgery and discusses the potential of interventions to reverse epigenetic modifications.
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Affiliation(s)
- Meriem Ouni
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Annette Schürmann
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
- Institute of Nutritional Science, University of Potsdam, Potsdam, Germany.
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Ando Y, Yamazaki M, Yamada H, Munetsuna E, Fujii R, Mizuno G, Ichino N, Osakabe K, Sugimoto K, Ishikawa H, Ohashi K, Teradaira R, Ohta Y, Hamajima N, Hashimoto S, Suzuki K. Association of circulating miR-20a, miR-27a, and miR-126 with non-alcoholic fatty liver disease in general population. Sci Rep 2019; 9:18856. [PMID: 31827150 PMCID: PMC6906495 DOI: 10.1038/s41598-019-55076-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Accepted: 11/22/2019] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is closely associated with obesity, metabolic syndrome, and type II diabetes mellitus. Recently, circulating microRNAs (miRNAs) have been proposed as useful disease biomarkers. We examined whether circulating miRNAs, such as miR-20a, miR-27a, and miR-126, were useful biomarkers for NAFLD. We conducted a cross-sectional analysis of 527 subjects aged 39 years or older who had undergone a health examination in the Yakumo Study. Of the residents, 92 were diagnosed with NAFLD using a registered medical sonographer. Serum miR-20a, miR-27a and miR-126 levels were measured by quantitative real-time PCR. We then calculated the odds ratios for serum miRNA level changes according to the severity of NAFLD using normal liver status as the reference group. Serum levels of miR-20a and 27a, but not miR-126, were significantly lower in NAFLD subjects than normal subjects. Serum miR-20a and miR-27a levels were significantly lower in both male and female severe NAFLD subjects. Logistic regression analysis showed a significant relationship between low circulating miR-20a and 27a levels and severe NAFLD. Down-regulated circulating miR-20a and 27a levels were significantly associated with severe NAFLD in the general population. Circulating miR-20a and miR-27a may be useful biomarkers for severe NAFLD.
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Affiliation(s)
- Yoshitaka Ando
- Department of Biomedical and Analytical Sciences, Fujita Health University School of Medical Sciences, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Mirai Yamazaki
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, 281-1, Murechohara, Takamatsu, Kagawa, 761-0123, Japan
| | - Hiroya Yamada
- Department of Hygiene, Fujita Health University School of Medicine, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.
| | - Eiji Munetsuna
- Department of Biochemistry, Fujita Health University School of Medicine, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Ryosuke Fujii
- Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Genki Mizuno
- Department of Joint Research Laboratory of Clinical Medicine, Fujita Health University Hospital, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Naohiro Ichino
- Department of Clinical Physiology and Functional Imaging, Fujita Health University School of Medical Sciences, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Keisuke Osakabe
- Department of Clinical Physiology and Functional Imaging, Fujita Health University School of Medical Sciences, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Keiko Sugimoto
- Department of Clinical Physiology and Functional Imaging, Fujita Health University School of Medical Sciences, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Hiroaki Ishikawa
- Department of Biomedical and Analytical Sciences, Fujita Health University School of Medical Sciences, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Koji Ohashi
- Department of Biomedical and Analytical Sciences, Fujita Health University School of Medical Sciences, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Ryoji Teradaira
- Department of Biomedical and Analytical Sciences, Fujita Health University School of Medical Sciences, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Yoshiji Ohta
- Department of Chemistry, Fujita Health University School of Medicine, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Nobuyuki Hamajima
- Department of Healthcare Administration, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Shuji Hashimoto
- Department of Hygiene, Fujita Health University School of Medicine, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Koji Suzuki
- Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.
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Expression Profile Analysis of Differentially Expressed Circular RNAs in Steroid-Induced Osteonecrosis of the Femoral Head. DISEASE MARKERS 2019; 2019:8759642. [PMID: 31827647 PMCID: PMC6885284 DOI: 10.1155/2019/8759642] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 09/23/2019] [Accepted: 10/08/2019] [Indexed: 02/07/2023]
Abstract
Background A growing number of studies have suggested that circular RNAs (circRNAs) serve as potential diagnostic biomarkers in many diseases. However, the role of circRNAs in steroid-induced osteonecrosis of the femoral head (SONFH) has not been reported. Methods Secondary sequencing was performed to profile circRNA expression in peripheral blood samples from three SONFH patients and three healthy individuals. We confirmed our preliminary findings by qRT-PCR. Bioinformatics analysis was conducted to predict their functions. Results The result showed 345 dysregulated circRNAs. qRT-PCR of eight selected circRNAs preliminarily confirmed the results, which were consistent with RNA sequencing. Bioinformatics analyses were performed to predict the functions of circRNAs to target the genes of miRNAs and the networks of circRNA-miRNA-mRNA interactions. Conclusions This study provides a new and fundamental circRNA profile of SONFH and a theoretical basis for further studies on the functions of circRNAs in SONFH.
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Klieser E, Mayr C, Kiesslich T, Wissniowski T, Fazio PD, Neureiter D, Ocker M. The Crosstalk of miRNA and Oxidative Stress in the Liver: From Physiology to Pathology and Clinical Implications. Int J Mol Sci 2019; 20:ijms20215266. [PMID: 31652839 PMCID: PMC6862076 DOI: 10.3390/ijms20215266] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/14/2019] [Accepted: 10/21/2019] [Indexed: 02/07/2023] Open
Abstract
The liver is the central metabolic organ of mammals. In humans, most diseases of the liver are primarily caused by an unhealthy lifestyle-high fat diet, drug and alcohol consumption- or due to infections and exposure to toxic substances like aflatoxin or other environmental factors. All these noxae cause changes in the metabolism of functional cells in the liver. In this literature review we focus on the changes at the miRNA level, the formation and impact of reactive oxygen species and the crosstalk between those factors. Both, miRNAs and oxidative stress are involved in the multifactorial development and progression of acute and chronic liver diseases, as well as in viral hepatitis and carcinogenesis, by influencing numerous signaling and metabolic pathways. Furthermore, expression patterns of miRNAs and antioxidants can be used for biomonitoring the course of disease and show potential to serve as possible therapeutic targets.
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Affiliation(s)
- Eckhard Klieser
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Cancer Cluster Salzburg, 5020 Salzburg, Austria.
| | - Christian Mayr
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Institute of Physiology and Pathophysiology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
| | - Tobias Kiesslich
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Institute of Physiology and Pathophysiology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
| | - Till Wissniowski
- Department of Gastroenterology and Endocrinology, Philipps University Marburg, 35043 Marburg, Germany.
| | - Pietro Di Fazio
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, 35043 Marburg, Germany.
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Cancer Cluster Salzburg, 5020 Salzburg, Austria.
| | - Matthias Ocker
- Translational Medicine Oncology, Bayer AG, 13353 Berlin, Germany.
- Department of Gastroenterology CBF, Charité University Medicine Berlin, 12200 Berlin, Germany.
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Huang PS, Wang CS, Yeh CT, Lin KH. Roles of Thyroid Hormone-Associated microRNAs Affecting Oxidative Stress in Human Hepatocellular Carcinoma. Int J Mol Sci 2019; 20:E5220. [PMID: 31640265 PMCID: PMC6834183 DOI: 10.3390/ijms20205220] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 10/17/2019] [Accepted: 10/18/2019] [Indexed: 02/07/2023] Open
Abstract
Oxidative stress occurs as a result of imbalance between the generation of reactive oxygen species (ROS) and antioxidant genes in cells, causing damage to lipids, proteins, and DNA. Accumulating damage of cellular components can trigger various diseases, including metabolic syndrome and cancer. Over the past few years, the physiological significance of microRNAs (miRNA) in cancer has been a focus of comprehensive research. In view of the extensive level of miRNA interference in biological processes, the roles of miRNAs in oxidative stress and their relevance in physiological processes have recently become a subject of interest. In-depth research is underway to specifically address the direct or indirect relationships of oxidative stress-induced miRNAs in liver cancer and the potential involvement of the thyroid hormone in these processes. While studies on thyroid hormone in liver cancer are abundantly documented, no conclusive information on the potential relationships among thyroid hormone, specific miRNAs, and oxidative stress in liver cancer is available. In this review, we discuss the effects of thyroid hormone on oxidative stress-related miRNAs that potentially have a positive or negative impact on liver cancer. Additionally, supporting evidence from clinical and animal experiments is provided.
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Affiliation(s)
- Po-Shuan Huang
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan.
- Department of Biomedical Sciences, College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan.
| | - Chia-Siu Wang
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan.
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 33302, Taiwan.
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan.
- Department of Biomedical Sciences, College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan.
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 33302, Taiwan.
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33302, Taiwan.
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Role of Noncoding RNA in Development of Nonalcoholic Fatty Liver Disease. BIOMED RESEARCH INTERNATIONAL 2019; 2019:8690592. [PMID: 30931332 PMCID: PMC6413411 DOI: 10.1155/2019/8690592] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 02/13/2019] [Indexed: 12/13/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is increasing in prevalence globally, but little is known about its specific molecular mechanisms. During the past decade, noncoding RNAs (ncRNAs) have been linked to NAFLD initiation and progression. They are a class of RNAs that play an important role in regulating gene expression despite not encoding proteins. This review summarizes recent research on the relationship between ncRNAs and NAFLD. We discussed the potential applicability of ncRNAs as a biomarker for early NAFLD diagnosis and assessment of disease severity. With further study, ncRNAs should prove to be valuable new targets for NAFLD treatment and benefit the development of noninvasive diagnostic methods.
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Yu J, Peng J, Luan Z, Zheng F, Su W. MicroRNAs as a Novel Tool in the Diagnosis of Liver Lipid Dysregulation and Fatty Liver Disease. Molecules 2019; 24:molecules24020230. [PMID: 30634538 PMCID: PMC6358728 DOI: 10.3390/molecules24020230] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Revised: 12/23/2018] [Accepted: 12/24/2018] [Indexed: 02/07/2023] Open
Abstract
In recent years, metabolic disorder, especially fatty liver disease, has been considered a major challenge to global health. The attention of researchers focused on expanding knowledge of the regulation mechanism behind these diseases and towards the new diagnostics tools and treatments. The pathophysiology of the fatty liver disease is undoubtedly complex. Abnormal hepatic lipid accumulation is a major symptom of most metabolic diseases. Therefore, the identification of novel regulation factors of lipid metabolism is important and meaningful. As a new diagnostic tool, the function of microRNAs during fatty liver disease has recently come into notice in biological research. Accumulating evidence supports the influence of miRNAs in lipid metabolism. In this review, we discuss the potential role of miRNAs in liver lipid metabolism and the pathogenesis of fatty liver disease.
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Affiliation(s)
- Jingwei Yu
- Shenzhen University Medical Center, Shenzhen University Health Science Center, Shenzhen 518060, China.
- Department of Biology, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Jun Peng
- Shenzhen University Medical Center, Shenzhen University Health Science Center, Shenzhen 518060, China.
| | - Zhilin Luan
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, China.
| | - Feng Zheng
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, China.
| | - Wen Su
- Shenzhen University Medical Center, Shenzhen University Health Science Center, Shenzhen 518060, China.
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Liu CH, Ampuero J, Gil-Gómez A, Montero-Vallejo R, Rojas Á, Muñoz-Hernández R, Gallego-Durán R, Romero-Gómez M. miRNAs in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis. J Hepatol 2018; 69:1335-1348. [PMID: 30142428 DOI: 10.1016/j.jhep.2018.08.008] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Revised: 07/21/2018] [Accepted: 08/07/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS microRNAs (miRNAs) are deregulated in non-alcoholic fatty liver disease (NAFLD) and have been proposed as useful markers for the diagnosis and stratification of disease severity. We conducted a meta-analysis to identify the potential usefulness of miRNA biomarkers in the diagnosis and stratification of NAFLD severity. METHODS After a systematic review, circulating miRNA expression consistency and mean fold-changes were analysed using a vote-counting strategy. The sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio and area under the curve (AUC) for the diagnosis of NAFLD or non-alcoholic steatohepatitis (NASH) were pooled using a bivariate meta-analysis. Deeks' funnel plot was used to assess the publication bias. RESULTS Thirty-seven studies of miRNA expression profiles and six studies of diagnostic accuracy were ultimately included in the quantitative analysis. miRNA-122 and miRNA-192 showed consistent upregulation. miRNA-122 was upregulated in every scenario used to distinguish NAFLD severity. The miRNA expression correlation between the serum and liver tissue was inconsistent across studies. miRNA-122 distinguished NAFLD from healthy controls with an AUC of 0.82 (95% CI 0.75-0.89), and miRNA-34a distinguished non-alcoholic steatohepatitis (NASH) from non-alcoholic fatty liver (NAFL) with an AUC of 0.78 (95% CI 0.67-0.88). CONCLUSION miRNA-34a, miRNA-122 and miRNA-192 were identified as potential diagnostic markers to segregate NAFL from NASH. Both miRNA-122, in distinguishing NAFLD from healthy controls, and miRNA-34a, in distinguishing NASH from NAFL, showed moderate diagnostic accuracy. miRNA-122 was upregulated in every scenario of NAFL, NASH and fibrosis. LAY SUMMARY: microRNAs are deregulated in non-alcoholic fatty liver disease. The microRNAs, miRNA-34a, miRNA-122 and miRNA-192, were identified as potential biomarkers of non-alcoholic fatty liver and non-alcoholic steatohepatitis, at different stages of disease severity. The correlation between miRNA expression in the serum and in liver tissue was inconsistent, or even inverse.
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Affiliation(s)
- Chang-Hai Liu
- Institute of Biomedicine of Seville, Sevilla, Spain; University of Seville, Seville, Spain
| | - Javier Ampuero
- Institute of Biomedicine of Seville, Sevilla, Spain; Unit of Digestive Diseases and Ciberehd, University Hospital Virgen del Rocío, Seville, Spain; University of Seville, Seville, Spain
| | - Antonio Gil-Gómez
- Institute of Biomedicine of Seville, Sevilla, Spain; University of Seville, Seville, Spain
| | - Rocío Montero-Vallejo
- Institute of Biomedicine of Seville, Sevilla, Spain; University of Seville, Seville, Spain
| | - Ángela Rojas
- Institute of Biomedicine of Seville, Sevilla, Spain
| | | | | | - Manuel Romero-Gómez
- Institute of Biomedicine of Seville, Sevilla, Spain; Unit of Digestive Diseases and Ciberehd, University Hospital Virgen del Rocío, Seville, Spain; University of Seville, Seville, Spain.
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Torres JL, Novo-Veleiro I, Manzanedo L, Alvela-Suárez L, Macías R, Laso FJ, Marcos M. Role of microRNAs in alcohol-induced liver disorders and non-alcoholic fatty liver disease. World J Gastroenterol 2018; 24:4104-4118. [PMID: 30271077 PMCID: PMC6158486 DOI: 10.3748/wjg.v24.i36.4104] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 06/25/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate multiple physiological and pathological functions through the modulation of gene expression at the post-transcriptional level. Accumulating evidence has established a role for miRNAs in the development and pathogenesis of liver disease. Specifically, a large number of studies have assessed the role of miRNAs in alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), two diseases that share common underlying mechanisms and pathological characteristics. The purpose of the current review is to summarize and update the body of literature investigating the role of miRNAs in liver disease. In addition, the potential use of miRNAs as biomarkers and/or therapeutic targets is discussed. Among all miRNAs analyzed, miR-34a, miR-122 and miR-155 are most involved in the pathogenesis of NAFLD. Of note, these three miRNAs have also been implicated in ALD, reinforcing a common disease mechanism between these two entities and the pleiotropic effects of specific miRNAs. Currently, no single miRNA or panel of miRNAs has been identified for the detection of, or staging of ALD or NAFLD. While promising results have been shown in murine models, no therapeutic based-miRNA agents have been developed for use in humans with liver disease.
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Affiliation(s)
- Jorge-Luis Torres
- Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca-IBSAL, Salamanca 37007, Spain
- Spanish Working Group on Alcohol and Alcoholism, Spanish Society of Internal Medicine, Madrid 28016, Spain
| | - Ignacio Novo-Veleiro
- Department of Internal Medicine, University Hospital of Santiago de Compostela, A Coruña 15706, Spain
- Spanish Working Group on Alcohol and Alcoholism, Spanish Society of Internal Medicine, Madrid 28016, Spain
| | - Laura Manzanedo
- Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca-IBSAL, Salamanca 37007, Spain
| | - Lucía Alvela-Suárez
- Department of Internal Medicine, HM Rosaleda Hospital, Santiago de Compostela, A Coruña 15701, Spain
| | - Ronald Macías
- Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca-IBSAL, Salamanca 37007, Spain
| | - Francisco-Javier Laso
- Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca-IBSAL, Salamanca 37007, Spain
- Department of Medicine, Faculty of Medicine, University of Salamanca, Salamanca 37007, Spain
- Spanish Working Group on Alcohol and Alcoholism, Spanish Society of Internal Medicine, Madrid 28016, Spain
| | - Miguel Marcos
- Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca-IBSAL, Salamanca 37007, Spain
- Department of Medicine, Faculty of Medicine, University of Salamanca, Salamanca 37007, Spain
- Spanish Working Group on Alcohol and Alcoholism, Spanish Society of Internal Medicine, Madrid 28016, Spain
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Zhou LY, Zeng H, Wang S, Chen JX. Regulatory Role of Endothelial PHD2 in the Hepatic Steatosis. Cell Physiol Biochem 2018; 48:1003-1011. [PMID: 30036883 PMCID: PMC6350253 DOI: 10.1159/000491968] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 05/25/2018] [Indexed: 12/11/2022] Open
Abstract
Background/Aims: Liver disease is a leading cause of high mortality and morbidity worldwide. The aim of the present study is to investigate the regulatory role of prolyl hydroxylase-2 (PHD2)-hypoxia-inducible factor-2α (HIF-2α) axis on nonalcoholic fatty liver disease (NAFLD) and to explore the potential mechanisms by which endothelial (EC)-specific PHD2 deficiency regulates hepatic steatosis and fibrosis. Methods: In the endothelial-specific PHD2 knockout (PHD2ECKO) mouse fed with normal diet or high fat diet (HFD), liver lipid accumulation and fibrosis were measured by Oil Red O and Masson trichrome staining. The fat and body weight (FW/BW) ratio and glucose tolerance were measured. The expression of HIF-2α, atrial natriuretic peptide (ANP), angiopoietin-2 (Ang-2), and transforming growth factor-β (TGF-β) were analyzed by western blot analysis. Results: The steatosis and fibrosis were significantly increased in the PHD2ECKO mice. FW/BW ratio was significantly increased in the PHD2ECKO mice. Moreover, knockout of endothelial PHD2 resulted in an impairment of glucose tolerance in mice. Western blot analysis showed that the expression of HIF-2α in liver tissues was not significantly increased. Interestingly, the expression of ANP was decreased, and Ang-2 and TGF-β levels were significantly increased in the liver of PHD2ECKO mice. The FW/BW ratio was also significantly increased in the PHD2ECKO mice fed with HFD for 16 weeks. Feeding HFD resulted in a significant increase in hepatic steatosis in the control PHD2f/f mice, but did not further enhance hepatic steatosis in the PHD2ECKO mice. Conclusions: We concluded that the endothelial PHD2 plays a critical role in hepatic steatosis and fibrosis, which may be involved in the regulation of ANP and Ang-2/TGF-β signaling pathway, but not the HIF-2α expression.
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Affiliation(s)
- Li-Ying Zhou
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, Mississippi, USA.,Department of Reproduction, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Heng Zeng
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, Mississippi, USA
| | - Shuo Wang
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, Mississippi, USA.,Key laboratory of cerebral cardiopulmonary Resuscitation, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Jian-Xiong Chen
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, Mississippi, USA
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Miao C, Xie Z, Chang J. Critical Roles of microRNAs in the Pathogenesis of Fatty Liver: New Advances, Challenges, and Potential Directions. Biochem Genet 2018; 56:423-449. [PMID: 29951838 DOI: 10.1007/s10528-018-9870-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 06/20/2018] [Indexed: 12/17/2022]
Abstract
In this review, we summarize the current understanding of microRNA (miRNA)-mediated modulation of the gene expression in the fatty liver as well as related signaling pathways. Because of the breadth and diversity of miRNAs, miRNAs may have a very wide variety of biological functions, and much evidence has confirmed that miRNAs are involved in the pathogenesis of fatty liver. In the pathophysiological mechanism of fatty liver, miRNAs may be regulated by upstream regulators, and have their own regulatory targets. miRNAs display important roles in the pathological mechanisms of alcoholic liver disease and non-alcoholic fatty liver disease. At present, most of the miRNA studies are focused on cell and tissue levels, and in vivo studies will help us elucidate the regulation of miRNAs and help us evaluate the potential of miRNAs as diagnostic markers and therapeutic targets. Furthermore, there is evidence that miRNAs are involved in the mechanism of natural medicine treatment in fatty liver. Given the important roles of miRNAs in the pathogenesis of fatty liver, we predict that studies of miRNAs in the pathogenesis of fatty liver will contribute to the elucidation of fatty liver pathology and the treatment of fatty liver patients.
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Affiliation(s)
- Chenggui Miao
- Department of Pharmacy, School of Life and Health Science, Anhui Science and Technology University, Fengyang, 233100, China
| | - Zhongwen Xie
- State Key Laboratory of Tea Biochemistry and Biotechnology, School of Science and Technology of Tea and Food, Anhui Agricultural University, No. 130, Changjiang West Road, Hefei, 230036, Anhui, China.
| | - Jun Chang
- Fourth Affiliated Hospital, Anhui Medical University, Hefei, 230032, China
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López P, Castro A, Flórez M, Miranda K, Aranda P, Sánchez-González C, Llopis J, Arredondo M. miR-155 and miR-122 Expression of Spermatozoa in Obese Subjects. Front Genet 2018; 9:175. [PMID: 29896216 PMCID: PMC5986881 DOI: 10.3389/fgene.2018.00175] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 04/27/2018] [Indexed: 01/20/2023] Open
Abstract
Obesity is characterized by mild chronic inflammation that is linked with impaired iron homeostasis. Studies in human and murine show that there is a transgenerational epigenetic inheritance via the gametes in obesity; however, there is little information on changes in the expression of microRNAs related to inflammation and iron homeostasis in spermatozoa from obese subjects. The present study investigated the expression of microRNAs related to inflammation (miR-21 y miR-155) and iron nutrition (miR-122 and miR-200b) in plasma, peripheral blood mononuclear cells (PBMC) and spermatozoa from normozoospermic controls (Cn; n = 17; BMI: 24.6 ± 2.0) and obese (Ob; n = 17; BMI: 32.6 ± 4.4) men. To determine the inflammation levels, we measured IL-6, TNF-α, and monocyte chemoattractant protein-1 (MCP1) by Magnetic Luminex® Assay. mRNA expression of IL6, TNF-α, and hepcidin (HAMP) in PBMC were evaluated by RT-qPCR. The analysis of microRNAs was performed using the Taqman® assays. The iron content in PBMC, seminal plasma, and spermatozoa was determined by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). High serum IL6, TNF-α, and MCP1 levels were observed in Ob group (p < 0.05). Gene expression analysis showed an increased abundance relative of TNF-α (p = 0.018), HAMP (p = 0.03), and IL6 (p = 0.02) in PBMC from obese subjects. Also, we observed high levels of serum ferritin (p = 0.03), iron content in seminal plasma (p = 0.04), and spermatozoa (p = 0.002), but lower serum Fe (p = 0.007) in obese subjects. In the Ob group, a high expression of miR-155 (p = 0.02) and miR-21 (p = 0.03) was observed in PBMC and miR-122 (p = 0.03) in plasma. In sperm, both miR-155 (p = 0.004) and miR-122 (p = 0.028) were high in the Ob group. Our results showed that obese subjects have increased expressions of miR-155 and miR-122, two microRNAs that were previously related with inflammation and iron metabolism, respectively, at both the systemic and sperm levels.
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Affiliation(s)
- Paulina López
- Micronutrient Laboratory, Institute of Nutrition and Food Technology, University of Chile, Santiago, Chile
| | - Andrea Castro
- Institute of Maternal and Child Research, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Martha Flórez
- Institute of Maternal and Child Research, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Karen Miranda
- Micronutrient Laboratory, Institute of Nutrition and Food Technology, University of Chile, Santiago, Chile
| | - Pilar Aranda
- CIBM, INYTA, IMUDS, Department of Physiology, Faculty of Pharmacy, University of Granada, Granada, Spain
| | - Cristina Sánchez-González
- CIBM, INYTA, IMUDS, Department of Physiology, Faculty of Pharmacy, University of Granada, Granada, Spain
| | - Juan Llopis
- CIBM, INYTA, IMUDS, Department of Physiology, Faculty of Pharmacy, University of Granada, Granada, Spain
| | - Miguel Arredondo
- Micronutrient Laboratory, Institute of Nutrition and Food Technology, University of Chile, Santiago, Chile
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Su Q, Kumar V, Sud N, Mahato RI. MicroRNAs in the pathogenesis and treatment of progressive liver injury in NAFLD and liver fibrosis. Adv Drug Deliv Rev 2018; 129:54-63. [PMID: 29391222 DOI: 10.1016/j.addr.2018.01.009] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 01/05/2018] [Accepted: 01/13/2018] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) increases the risk of various liver injuries, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis, and ultimately hepatocellular carcinoma (HCC). Ample evidence has suggested that aberrant expression of microRNAs (miRNAs) is functionally involved in the activation of cellular stress, inflammation and fibrogenesis in hepatic cells, including hepatocytes, Kupffer and hepatic stellate cells (HSCs), at different pathological stages of NAFLD and liver fibrosis. Here, we overview recent findings on the potential role of miRNAs in the pathogenesis of NAFLD, including lipotoxicity, oxidative stress, metabolic inflammation and fibrogenesis. We critically assess the literatures on both human subjects and animal models of NAFLD and liver fibrosis with miRNA dysregulation and their mechanisms of actions in liver damage. We further highlight the potential use of miRNA mimics or antimiRNAs as therapeutic approaches for the prevention and treatment of NAFLD and liver fibrosis.
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Affiliation(s)
- Qiaozhu Su
- Department of Nutrition and Health Sciences, University of Nebraska, Lincoln, NE 68583, USA.
| | - Virender Kumar
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Neetu Sud
- Department of Nutrition and Health Sciences, University of Nebraska, Lincoln, NE 68583, USA
| | - Ram I Mahato
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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