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Ren S, Wang J, Wang Y, Luo Q, Pu W, Meng X, Liu S. Oxidative stress and type 2 diabetes: a review of lactic acid bacteria as potential prophylactic and therapeutic interventions. Food Sci Biotechnol 2025; 34:2403-2416. [PMID: 40492034 PMCID: PMC12145373 DOI: 10.1007/s10068-024-01775-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 11/18/2024] [Accepted: 11/25/2024] [Indexed: 06/11/2025] Open
Abstract
Oxidative stress, which results from the overproduction of reactive oxygen species (ROS) that induce protein, lipid, and DNA oxidation, has emerged as a key factor in the pathogenesis of various diseases, including type 2 diabetes (T2D). Recently, the relationship between oxidative stress and T2D has gained considerable attention. Widely utilized as probiotics in fermented foods and beverages, lactic acid bacteria (LAB) exhibit potent antioxidant properties. However, the precise mechanisms enabling LAB to behave as antioxidants remain elusive. LAB play a pivotal role in promoting and maintaining host health while mitigating the development and progression of various disorders, including T2D. Against the backdrop of a large number of studies highlighting the beneficial role of LAB in mitigating oxidative stress-related diseases, this review explores potential biomarkers for the prevention of oxidative stress and examines the potential contribution of LAB to the fight against T2D.
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Affiliation(s)
- Siheng Ren
- Institute of Public Health, Chengdu University of Traditional Chinese Medicine, No.1166, Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
| | - Juan Wang
- Institute of Public Health, Chengdu University of Traditional Chinese Medicine, No.1166, Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
| | - Yuxi Wang
- Institute of Public Health, Chengdu University of Traditional Chinese Medicine, No.1166, Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
| | - Qian Luo
- Institute of Public Health, Chengdu University of Traditional Chinese Medicine, No.1166, Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
| | - Wei Pu
- Institute of Public Health, Chengdu University of Traditional Chinese Medicine, No.1166, Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
| | - Xiao Meng
- Institute of Public Health, Chengdu University of Traditional Chinese Medicine, No.1166, Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
| | - Shukun Liu
- Institute of Public Health, Chengdu University of Traditional Chinese Medicine, No.1166, Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
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2
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Wade H, Pan K, Zhang B, Zheng W, Su Q. Mechanistic role of long non-coding RNAs in the pathogenesis of metabolic dysfunction-associated steatotic liver disease and fibrosis. EGASTROENTEROLOGY 2024; 2:e100115. [PMID: 39872125 PMCID: PMC11729351 DOI: 10.1136/egastro-2024-100115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/29/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease, encompasses a broad range of hepatic metabolic disorders primarily characterised by the disruption of hepatic lipid metabolism, hepatic lipid accumulation and steatosis. Severe cases of MASLD might progress to metabolic dysfunction-associated steatohepatitis, characterised by hepatic inflammation, hepatocyte ballooning degeneration, activation of hepatic stellate cells (HSCs) and fibrogenesis. It may further progress to hepatocellular carcinoma. In the liver, long non-coding RNAs (lncRNAs) target multiple metabolic pathways in hepatocytes, HSCs, and Kupffer cells at different stages of MASLD and liver fibrosis. In this study, we overview recent findings on the potential role of lncRNAs in the pathogenesis of MASLD and liver fibrosis via modulation of de novo lipid synthesis, fatty acid β-oxidation, lipotoxicity, oxidative stress, metabolic inflammation, mammalian target of rapamycin signalling, apoptosis, ubiquitination and fibrogenesis. We critically assess the literature reports that investigate the complex interplay between lncRNA, microRNA and key mediators in liver injury, in both human participants and animal models of MASLD and liver fibrosis. We also highlight the therapeutic potential of lncRNAs in chronic liver diseases.
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Affiliation(s)
- Henry Wade
- School of Biological Sciences, Queen’s University Belfast, Belfast, UK
| | - Kaichao Pan
- Endocrinology Group, Advocate Illinois Masonic Medical Center, Chicago, Illinois, USA
| | - Bingrui Zhang
- School of Biological Sciences, Queen’s University Belfast, Belfast, UK
| | - Wenhua Zheng
- Faculty of Health Science, University of Macau, Macau, China
| | - Qiaozhu Su
- School of Biological Sciences, Queen’s University Belfast, Belfast, UK
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3
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Li S, Zhang Y, Ishfaq M, Liu R, Wei G, Zhang X. Curcumin alleviates Aflatoxin B1-triggered chicken liver necroptosis by targeting the LOC769044/miR-1679/STAT1 axis. Poult Sci 2024; 103:103883. [PMID: 38865767 PMCID: PMC11223116 DOI: 10.1016/j.psj.2024.103883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 05/05/2024] [Accepted: 05/17/2024] [Indexed: 06/14/2024] Open
Abstract
Aflatoxin B1 (AFB1) is an unavoidable environmental toxin. The accumulation of AFB1 and its metabolites in the liver poses a threat to both human and animal health. Curcumin exhibits anti-oxidative, anti-tumor, and anti-inflammatory properties. There is no report on the mechanism regarding how curcumin relived liver necroptosis in chickens induced by AFB1 based on the regulatory network of ceRNA. To explore this, we performed transmission electron microscopy and sequenced lncRNA and mRNA in chicken livers treated with AFB1 and/or curcumin for 28 d in vivo. We observed substantial alterations in the lncRNA and mRNA expression profiles within the chicken liver, indicating that curcumin can mitigate AFB1-induced necroptosis both in vivo and in vitro. Further analysis, including the establishment of an lncRNA-miRNA-mRNA network and the utilization of a dual luciferase reporter assay, revealed that LOC769044 acts as a competing endogenous RNA (ceRNA) for miR-1679. In addition, STAT1 was identified as a direct target of miR-1679. Modulating miR-1679 levels through overexpression, and silencing LOC769044 and STAT1, effectively reversed the necroptotic effects induced by AFB1, a reversal that was also observed with curcumin supplementation. In conclusion, our data demonstrate that curcumin alleviates AFB1-induced liver necroptosis through the LOC769044/miR-1679/STAT1 signaling axis. This study suggests that LOC769044 may serve as a novel therapeutic target for managing AFB1-mediated liver toxicity.
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Affiliation(s)
- Sihong Li
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development. Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Xiangfang District, Harbin, China; Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, Zhejiang Province 311300, China
| | - Yixin Zhang
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development. Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Xiangfang District, Harbin, China
| | - Muhammad Ishfaq
- Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
| | - Ruimeng Liu
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development. Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Xiangfang District, Harbin, China
| | - Gaoqiang Wei
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development. Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Xiangfang District, Harbin, China
| | - Xiuying Zhang
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development. Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Xiangfang District, Harbin, China.
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4
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Shao JL, Wang LJ, Xiao J, Yang JF. Non-coding RNAs: The potential biomarker or therapeutic target in hepatic ischemia-reperfusion injury. World J Gastroenterol 2023; 29:4927-4941. [PMID: 37731999 PMCID: PMC10507504 DOI: 10.3748/wjg.v29.i33.4927] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 07/22/2023] [Accepted: 08/18/2023] [Indexed: 09/01/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is the major complication of liver surgery and liver transplantation, that may increase the postoperative morbidity, mortality, tumor progression, and metastasis. The underlying mechanisms have been extensively investigated in recent years. Among these, oxidative stress, inflammatory responses, immunoreactions, and cell death are the most studied. Non-coding RNAs (ncRNAs) are defined as the RNAs that do not encode proteins, but can regulate gene expressions. In recent years, ncRNAs have emerged as research hotspots for various diseases. During the progression of HIRI, ncRNAs are differentially expressed, while these dysregulations of ncRNAs, in turn, have been verified to be related to the above pathological processes involved in HIRI. ncRNAs mainly contain microRNAs, long ncRNAs, and circular RNAs, some of which have been reported as biomarkers for early diagnosis or assessment of liver damage severity, and as therapeutic targets to attenuate HIRI. Here, we briefly summarize the common pathophysiology of HIRI, describe the current knowledge of ncRNAs involved in HIRI in animal and human studies, and discuss the potential of ncRNA-targeted therapeutic strategies. Given the scarcity of clinical trials, there is still a long way to go from pre-clinical to clinical application, and further studies are needed to uncover their potential as therapeutic targets.
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Affiliation(s)
- Jia-Li Shao
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Li-Juan Wang
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Ji Xiao
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Jin-Feng Yang
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
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Moradi M, Mard SA, Farbood Y, Dianat M, Goudarzi G, Khorsandi L, Seyedian SS. The protective effect of p-Coumaric acid on hepatic injury caused by particulate matter in the rat and determining the role of long noncoding RNAs MEG3 and HOTAIR. J Biochem Mol Toxicol 2023:e23364. [PMID: 37183931 DOI: 10.1002/jbt.23364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 12/30/2022] [Accepted: 03/20/2023] [Indexed: 05/16/2023]
Abstract
Increasing air pollution is associated with serious human health problems. P-coumaric acid (PC) is a herbal phenolic compound that exhibits beneficial pharmacological potentials. Here, the protective effect of PC on liver injury induced by air pollution was examined. Thirty-two adult male Wistar rats (200-250 g) were divided randomly into four groups (n = 8). The groups were; Control (rats received DMSO and then exposed to clean air), PC (rats received PC and then exposed to clean air), DMSO + Dust (rats received DMSO and then exposed to dust), and PC + Dust (the animals received PC and then exposed to dust). The clean air, DMSO, PC, and dust were administrated 3 days a week for 6 consecutive weeks. The rats were anesthetized and their blood samples and liver sections were taken to conduct molecular, biomedical, and histopathological tests. Dust exposure increased the liver enzymes, bilirubin, triglyceride, cholesterol, and the production of liver malondialdehyde, and decreased in liver total anti-oxidant capacity and serum high-density lipoprotein. It also increased the mRNA expression of inflammatory-related cytokines, decreased the mRNA expression of SIRT-1, decreased the expression levels of miR-20b5p, and MEG3 while increased the expression levels of miR-34a, and HOTAIR. Dust exposure also increased the liver content of three cytokines TNF-α, NF-κB, HMGB-1, and ATG-7 proteins. PC enhanced liver function against adverse effects of dust through recovering almost all the studied variables. Exposure to dust damaged the liver through induction of oxidative stress, inflammation, and autophagy. PC protected the liver against dust-induced cytotoxicity.
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Affiliation(s)
- Mojtaba Moradi
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyyed A Mard
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Yaghoob Farbood
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mahin Dianat
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Gholamreza Goudarzi
- Air Pollution and Respiratory Diseases Research Center, Ahvaz Jundishapour University of Medical Sciences, Ahvaz, Iran. Environmental Technologies Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Layasadat Khorsandi
- Department of Anatomical Sciences, School of Medicine, Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed S Seyedian
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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LncRNA MEG3 alleviates interstitial cystitis in rats by upregulating Nrf2 and inhibiting the p38/NF-κB pathway. Cytokine 2023; 165:156169. [PMID: 36933397 DOI: 10.1016/j.cyto.2023.156169] [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: 06/08/2022] [Revised: 02/27/2023] [Accepted: 03/01/2023] [Indexed: 03/18/2023]
Abstract
PURPOSE Interstitial cystitis (IC), a chronic pain syndrome characterized by urinary frequency, urgency, and bladder or pelvic floor pain, severely affects the quality of life of patients. The aim of this study was to investigate the role and mechanism of long noncoding RNA Maternally Expressed Gene3 (lncRNA MEG3) in IC. METHODS An IC rat model was established by intraperitoneal injection of cyclophosphamide combined with bladder perfusion of fisetin and tumor necrosis factor-α (TNF-α) to mimic IC. An in vitro model was established using TNF-α-induced rat bladder epithelium cells. H&E staining was used to assess bladder tissue damage and ELISA was used to measure inflammatory cytokine levels. Western blot analysis was used to examine Nrf2, Bax, Bcl-2, cleaved caspase-3, p-p38, p38, p-NF-κB and NF-κB protein expression levels. RNA immunoprecipitation and RNA pull-down assays were used to examine the interaction between MEG3 and Nrf2. RESULTS MEG3 levels were upregulated in IC tissues and bladder epithelial cells, whereas Nrf2 expression was found to be downregulated. Knockdown of MEG3 reduced bladder tissue injury, inflammation, oxidative stress and apoptosis. MEG3 was negatively correlated with Nrf2. Downregulation of MEG3 alleviated IC inflammation and injury by upregulating Nrf2 and inhibiting the p38/NF-κB pathway. CONCLUSION Downregulation of MEG3 alleviated inflammation and injury in IC rats by upregulating Nrf2 and inhibiting the p38/NF-κB pathway.
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Zhu SF, Yuan W, Du YL, Wang BL. Research progress of lncRNA and miRNA in hepatic ischemia-reperfusion injury. Hepatobiliary Pancreat Dis Int 2023; 22:45-53. [PMID: 35934611 DOI: 10.1016/j.hbpd.2022.07.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 07/18/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatic ischemia-reperfusion injury (HIRI) is a common complication of liver surgeries, such as hepatectomy and liver transplantation. In recent years, several non-coding RNAs (ncRNAs) including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been identified as factors involved in the pathological progression of HIRI. In this review, we summarized the latest research on lncRNAs, miRNAs and the lncRNA-miRNA regulatory networks in HIRI. DATA SOURCES The PubMed and Web of Science databases were searched for articles published up to December 2021 using the following keywords: "hepatic ischemia-reperfusion injury", "lncRNA", "long non-coding RNA", "miRNA" and "microRNA". The bibliography of the selected articles was manually screened to identify additional studies. RESULTS The mechanism of HIRI is complex, and involves multiple lncRNAs and miRNAs. The roles of lncRNAs such as AK139328, CCAT1, MALAT1, TUG1 and NEAT1 have been established in HIRI. In addition, numerous miRNAs are associated with apoptosis, autophagy, oxidative stress and cellular inflammation that accompany HIRI pathogenesis. Based on the literature, we conclude that four lncRNA-miRNA regulatory networks mediate the pathological progression of HIRI. Furthermore, the expression levels of some lncRNAs and miRNAs undergo significant changes during the progression of HIRI, and thus are potential prognostic markers and therapeutic targets. CONCLUSIONS Complex lncRNA-miRNA-mRNA networks regulate HIRI progression through mutual activation and antagonism. It is necessary to screen for more HIRI-associated lncRNAs and miRNAs in order to identify novel therapeutic targets.
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Affiliation(s)
- Shan-Fei Zhu
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China
| | - Wei Yuan
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China
| | - Yong-Liang Du
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China
| | - Bai-Lin Wang
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China.
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Liang C, Peng Y, Sun H, Wang L, Jiang L, Zou S. Silencing lncRNA KCNQ1OT1 reduced hepatic ischemia reperfusion injury-induced pyroptosis by regulating miR-142a-3p/HMGB1 axis. Mol Cell Biochem 2022; 478:1293-1305. [PMID: 36308669 DOI: 10.1007/s11010-022-04586-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 10/11/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND Based on pre-existing evidence, KCNQ1OT1 has been pointed out to be closely related to myocardial and cerebral ischemia reperfusion injury diseases. Herein, the objective of our study is to probe into the potential function as well as the underlying mechanism of KCNQ1OT1 on hepatic ischemia reperfusion injury (HIRI). METHODS Using C57BL/6 J mice and primary mouse hepatocytes were conducted to establish HIRI model in vivo and in vitro. Cell viability was examined using CCK-8 assay and EdU assay. Flow cytometric analysis was performed to evaluate the pyroptosis. Dual-luciferase reporter assay was employed to verify the interaction relationships. qRT-PCR and Western blot were adopted to analyze the mRNA and protein level. Histopathological alteration of liver tissue was evaluated by HE staining. Immunohistochemistry (IHC) was performed to measure NLRP3 and caspase 1. RESULTS Our data revealed that KCNQ1OT1 expression was ascending in hepatic tissue of HIRI mouse. Moreover, deprivation of KCNQ1OT1 mitigated I/R-induced hepatic injury and pyroptosis in vivo. Further experiments demonstrated that silencing KCNQ1OT1 promoted proliferation and inhibited pyroptosis in hypoxia/reoxygenation (H/R)-induced primary mouse hepatocytes. Mechanistically, KCNQ1OT1 functioned as a competing endogenous RNA which sponged miR-142a-3p, therefore promoted HMGB1 expression to activate TLR4/NF-κB signaling pathway in HIRI. CONCLUSION LncRNA KCNQ1OT1 elevated HMGB1 expression through binding to miR-142a-3p, thereby promoting pyroptosis in HIRI.
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Affiliation(s)
- Canxin Liang
- Department of Anesthesiology, Hunan Cancer Hospital, Hunan Province, No. 283 Tongzipo Road, Changsha, 410013, China
| | - Yanhua Peng
- Department of Anesthesiology, Hunan Cancer Hospital, Hunan Province, No. 283 Tongzipo Road, Changsha, 410013, China
| | - Huiping Sun
- Department of Anesthesiology, Hunan Cancer Hospital, Hunan Province, No. 283 Tongzipo Road, Changsha, 410013, China
| | - Lijuan Wang
- Department of Anesthesiology, Hunan Cancer Hospital, Hunan Province, No. 283 Tongzipo Road, Changsha, 410013, China
| | - Liubing Jiang
- Department of Anesthesiology, Hunan Cancer Hospital, Hunan Province, No. 283 Tongzipo Road, Changsha, 410013, China
| | - Shuangfa Zou
- Department of Anesthesiology, Hunan Cancer Hospital, Hunan Province, No. 283 Tongzipo Road, Changsha, 410013, China.
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Song Z, He C, Wen J, Yang J, Chen P. Long Non-coding RNAs: Pivotal Epigenetic Regulators in Diabetic Retinopathy. Curr Genomics 2022; 23:246-261. [PMID: 36777876 PMCID: PMC9875540 DOI: 10.2174/1389202923666220531105035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/07/2022] [Accepted: 05/16/2022] [Indexed: 11/22/2022] Open
Abstract
Diabetic retinopathy (DR) is a severe complication of diabetes; however, its mechanism is not fully understood. Evidence has recently revealed that long non-coding RNAs (lncRNAs) are abnormally expressed in DR, and lncRNAs may function as pivotal regulators. LncRNAs are able to modulate gene expression at the epigenetic level by acting as scaffolds of histone modification complexes and sponges of binding with microRNAs (miRNAs). LncRNAs are believed to be important epigenetic regulators, which may become beneficial in the diagnosis and therapy of DR. However, the mechanisms of lncRNAs in DR are still unclear. In this review, we summarize the possible functions and mechanisms of lncRNAs in epigenetic regulation to target genes in the progression of DR.
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Affiliation(s)
- Zhaoxia Song
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Chang He
- Department of Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Jianping Wen
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Jianli Yang
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Peng Chen
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun, China;,Address correspondence to this author at the Department of Medical Genetics, College of Basic Medical Sciences, Jilin University. Address: Room 413, 126 Xinmin Street, Changchun, Jilin 130021, China; Tel/Fax: 0086-18584362191; E-mail:
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Sadrkhanloo M, Entezari M, Orouei S, Zabolian A, Mirzaie A, Maghsoudloo A, Raesi R, Asadi N, Hashemi M, Zarrabi A, Khan H, Mirzaei S, Samarghandian S. Targeting Nrf2 in ischemia-reperfusion alleviation: From signaling networks to therapeutic targeting. Life Sci 2022; 300:120561. [PMID: 35460707 DOI: 10.1016/j.lfs.2022.120561] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 03/28/2022] [Accepted: 04/13/2022] [Indexed: 12/15/2022]
Abstract
The nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of redox balance and it responds to various cell stresses that oxidative stress is the most well-known one. The Nrf2 should undergo nuclear translocation to exert its protective impacts and decrease ROS production. On the other hand, ischemic/reperfusion (I/R) injury is a pathological event resulting from low blood flow to an organ and followed by reperfusion. The I/R induces cell injury and organ dysfunction. The present review focuses on Nrf2 function in alleviation of I/R injury. Stimulating of Nrf2 signaling ameliorates I/R injury in various organs including lung, liver, brain, testis and heart. The Nrf2 enhances activity of antioxidant enzymes to reduce ROS production and prevent oxidative stress-mediated cell death. Besides, Nrf2 reduces inflammation via decreasing levels of pro-inflammatory factors including IL-6, IL-1β and TNF-α. Nrf2 signaling is beneficial in preventing apoptosis and increasing cell viability. Nrf2 induces autophagy to prevent apoptosis during I/R injury. Furthermore, it can interact with other molecular pathways including PI3K/Akt, NF-κB, miRNAs, lncRNAs and GSK-3β among others, to ameliorate I/R injury. The therapeutic agents, most of them are phytochemicals such as resveratrol, berberine and curcumin, induce Nrf2 signaling in I/R injury alleviation.
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Affiliation(s)
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Sima Orouei
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Amirhossein Zabolian
- Resident of Orthopedics, Department of Orthopedics, School of Medicine, 5th Azar Hospital, Golestan University of Medical Sciences, Golestan, Iran.
| | - Amirreza Mirzaie
- Young Researchers and Elite Club, Damghan Branch, Islamic Azad University, Damghan, Iran
| | - Amin Maghsoudloo
- Young Researchers and Elite Club, Damghan Branch, Islamic Azad University, Damghan, Iran
| | - Rasoul Raesi
- Mashhad University of Medical Sciences, Mashhad, Iran
| | - Neda Asadi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Sariyer, Istanbul 34396, Turkey.
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, 23200, Pakistan
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran.
| | - Saeed Samarghandian
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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11
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Sun Q, Gong J, Wu J, Hu Z, Zhang Q, Zhu X. SNHG1-miR-186-5p-YY1 feedback loop alleviates hepatic ischemia/reperfusion injury. Cell Cycle 2022; 21:1267-1279. [PMID: 35275048 PMCID: PMC9132488 DOI: 10.1080/15384101.2022.2046984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/20/2021] [Accepted: 02/23/2022] [Indexed: 11/03/2022] Open
Abstract
As a common cause of liver injury, hepatic ischemia/reperfusion injury (HIRI) happens in various clinical conditions including trauma, hepatectomy and liver transplantation. Since transcription factor Yin Yang 1 (YY1) was reported to be downregulated after ischemia/reperfusion (I/R) injury, we focused on YY1 to explore its function in HIRI by functional assays like Cell Counting Kit-8 (CCK-8) assays and flow cytometry assays. The RT-qPCR assay revealed that YY1 was downregulated in hepatocytes after I/R injury. The function assays disclosed that YY1 facilitated cell viability and proliferation, but hindered cell apoptosis in hepatocytes after I/R injury. Through mechanism assays including luciferase reporter assay, RIP and RNA pulldown assay, miR-186-5p was found to bind with YY1 and promote hepatocyte apoptosis by targeting YY1. Subsequently, we verified that small nucleolar RNA host gene 1 (SNHG1) could sponge miR-186-5p to upregulate YY1. Importantly, we figured out that YY1 had a positive regulation on SNHG1. Along the way, YY1 was identified as the upstream transcription factor for SNHG1. In conclusion, our study unveiled a novel competing endogenous RNA (ceRNA) pattern of SNHG1/miR-186-5p/YY1 positive feedback loop in hepatic I/R injury, which might provide new insight into prevention of HIRI during liver transplantation or hepatic surgery.
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Affiliation(s)
- Qiang Sun
- General Surgery Department 1, Zhongshan Hospital, Sun Yat-sen University, Zhongshan, Guangdong, China
| | - Jinlong Gong
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jianlong Wu
- General Surgery Department 1, Zhongshan Hospital, Sun Yat-sen University, Zhongshan, Guangdong, China
| | - Zhipeng Hu
- General Surgery Department 1, Zhongshan Hospital, Sun Yat-sen University, Zhongshan, Guangdong, China
| | - Qiao Zhang
- General Surgery Department 1, Zhongshan Hospital, Sun Yat-sen University, Zhongshan, Guangdong, China
| | - Xiaofeng Zhu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
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Sun Q, Gong J, Gong X, Wu J, Hu Z, Zhang Q, Zhu X. Long non-coding RNA MALAT1 aggravated liver ischemia-reperfusion injury via targeting miR-150-5p/AZIN1. Bioengineered 2022; 13:13422-13436. [PMID: 36700468 PMCID: PMC9275989 DOI: 10.1080/21655979.2022.2073124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a crucial role in the process of renal ischemia-reperfusion (IR) injury and myocardial IR injury. However, its mechanism in liver IR injury is not clear. IR and hypoxia/reoxygenation (H/R) model were built on C57BL/6 mice. Blood samples were obtained from the inferior vena cava of the model mice. MALAT1 expression was detected in IR model and H/R model. Supported by experimental results, the impacts of MALAT1 on viability, apoptosis, and inflammation of H/R model cells were detected. The correlation between MALAT1 and downstream genes was analyzed by mechanism assays. MALAT1 was detected to be upregulated in IR model and H/R model. MALAT1 knockdown had inhibitory effects on apoptosis and inflammatory reaction while promoting liver cell viability in H/R condition. Meanwhile, MALAT1 targeted miR-150-5p to regulate antizyme inhibitor 1 (AZIN1) in liver cells. Finally, MALAT1 regulated viability, apoptosis, and inflammatory reaction of liver cells by targeting miR-150-5p and AZIN1. To conclude, MALAT1 targeted miR-150-5p/AZIN1 to accelerate liver IR injury, suggesting that MALAT1 might be a novel target for liver IR injury.
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Affiliation(s)
- Qiang Sun
- General Surgery Department 1, Zhongshan People’s Hospital, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, Guangdong, China
| | - Jinlong Gong
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xueyi Gong
- General Surgery Department 1, Zhongshan People’s Hospital, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, Guangdong, China
| | - Jianlong Wu
- General Surgery Department 1, Zhongshan People’s Hospital, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, Guangdong, China
| | - Zhipeng Hu
- General Surgery Department 1, Zhongshan People’s Hospital, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, Guangdong, China
| | - Qiao Zhang
- General Surgery Department 1, Zhongshan People’s Hospital, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, Guangdong, China
| | - Xiaofeng Zhu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China,CONTACT Xiaofeng Zhu Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Second Road, Yuexiu District, Guangzhou510000Guangdong, China
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LncRNA MEG3 up-regulates SIRT6 by ubiquitinating EZH2 and alleviates nonalcoholic fatty liver disease. Cell Death Dis 2022; 8:103. [PMID: 35256601 PMCID: PMC8901640 DOI: 10.1038/s41420-022-00889-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 01/13/2022] [Accepted: 02/10/2022] [Indexed: 12/24/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a global health threat. Here, we presented the significant role of a novel signaling axis comprising long non-coding RNA maternally expressed gene 3 (MEG3), enhancer of zeste homolog 2 (EZH2), and sirtuin 6 (SIRT6) in controlling lipid accumulation, inflammation, and the progression of NAFLD. Mice fed with high-fat diet (HFD) were established as in vitro and in vivo NAFLD models, respectively. Lipid accumulation was measured by oil red O staining and assays for triglycerides or cholesterol. Inflammation was examined by ELISA for pro-inflammatory cytokines. Gene expressions were examined by RT-qPCR or Western blot. Interactions between key signaling molecules were examined by combining expressional analysis, RNA immunoprecipitation, cycloheximide stability assay, co-immunoprecipitation, and chromatin immunoprecipitation. MEG3 level was reduced in FFA-challenged hepatocytes or liver from HFD-fed mice, and the reduction paralleled the severity of NAFLD in clinic. Overexpressing MEG3 suppressed FFA-induced lipid accumulation or inflammation in hepatocytes. By promoting the ubiquitination and degradation of EZH2, MEG3 upregulated SIRT6, an EZH2 target. SIRT6 essentially mediated the protective effects of MEG3 in hepatocytes. Consistently, overexpressing MEG3 alleviated HFD-induced NAFLD in vivo. By controlling the expressions of genes involved in lipid metabolism and inflammation, the MEG3/EZH2/SIRT6 axis significantly suppressed lipid accumulation and inflammation in vitro, and NAFLD development in vivo. Therefore, boosting MEG3 level may benefit the treatment of NAFLD.
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LncRNA XR_596701 protects H9c2 cells against intermittent hypoxia-induced injury through regulation of the miR-344b-5p/FAIM3 axis. Cell Death Dis 2022; 8:42. [PMID: 35091561 PMCID: PMC8799738 DOI: 10.1038/s41420-022-00834-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 12/31/2021] [Accepted: 01/13/2022] [Indexed: 11/23/2022]
Abstract
Long noncoding RNAs (lncRNAs) participate in various biological processes and cardiovascular diseases. Recently, a novel lncRNA XR_596701 was found to be differentially expressed in obstructive sleep apnea (OSA)-induced myocardial tissue compared to normal myocardial tissues. However, the pathological effect and regulatory mechanism of XR_596701 in intermittent hypoxia (IH)-mediated cardiomyocytes damage have not been studied. The subcellular localization of XR_596701 was determined by fluorescence in situ hybridization (FISH). Gene expressions of XR_596701 and miR-344b-5p were detected by quantitative real-time polymerase chain reaction (qRT-PCR) in IH-induced H9c2 cells. Cell proliferation was measured by 5-ethynyl-2′-deoxyuridine (EdU) staining assay. Cell apoptosis was detected by Hoechst 33342/PI staining and immunofluorescence (IF). Apoptotic protein of H9c2 cells was measured by western blot. The direct interaction between XR_596701 and miR-344b-5p as well as miR-344b-5p and Fas apoptotic inhibitory molecule 3 (FAIM3) were examined using dual-luciferase reporter assay. The significance of XR_596701 and miR-344b-5p on cell proliferation and apoptosis was evaluated by using gain-of-function and loss-of-function approaches. XR_596701 was upregulated, while miR-344b-5p downregulated in IH-induced H9c2 cells. Functionally, suppression of XR_596701 and overexpression of miR-344b-5p inhibited cell proliferation and promoted cell apoptosis in H9c2 cells. The roles of XR_596701 were achieved by sponging miR-344b-5p. And the function of miR-344b-5p was reversed by targeting FAIM3. Additionally, FAIM3 mediated IH-induced H9c2 cells damage by XR_596701. XR_596701 was serve as a novel lncRNA that indicated protective roles on proliferation and apoptosis of IH-induced H9c2 cells through the miR-344b-5p/FAIM3 axis.
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Xu Y, Li Z, Lu S, Wang C, Ke S, Li X, Yin B, Yu H, Zhou M, Pan S, Jiang H, Ma Y. Integrative Analysis of the Roles of lncRNAs and mRNAs in Itaconate-Mediated Protection Against Liver Ischemia-Reperfusion Injury in Mice. J Inflamm Res 2021; 14:4519-4536. [PMID: 34526799 PMCID: PMC8435882 DOI: 10.2147/jir.s327467] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/19/2021] [Indexed: 12/30/2022] Open
Abstract
Purpose Itaconate is well known for its strong anti-inflammatory and antioxidant effect, but little is known about the potential role of long non-coding RNAs (lncRNAs) in the underlying mechanisms of hepatic ischemia-reperfusion (IR) injury. The aim of our study is to identify lncRNAs related to IR injury and itaconate-mediated protection and to demonstrate the mechanism by which itaconate acts in liver IR injury from the new perspective of lncRNAs. Methods 4-Octyl itaconate (OI), a membrane-permeable derivative of itaconate, was used as a substitute for itaconate in our study. By using a mouse model of hepatic IR injury, serum and liver samples were collected to measure indexes of liver injury. Then, the liver samples of the mice were subjected to RNA sequencing (RNA-seq) and subsequent bioinformatics analysis. Results Itaconate attenuated liver IR injury. A total of 138 lncRNAs and 156 messenger RNAs (mRNAs) were markedly differentially expressed in the IR-damaged liver tissues pretreated with OI compared with the matched liver tissues treated with vehicle. Functional analysis indicated that lncRNAs may indirectly participate in the effects of itaconate. Furthermore, 41 mRNAs were examined for the protein-protein interaction (PPI) network analysis, and a key gene cluster was defined. Then, combined the coexpression analysis and the cis and trans regulatory function prediction of lncRNAs, some "candidate" lncRNA-mRNA pairs which might relate to itaconate-mediated liver protection were identified, while the relationship requires future validation. Conclusion Our study revealed that itaconate could protect the liver against IR injury and that lncRNAs might play a role in this process. Our study provides a novel way to investigate the mechanism by which itaconate affects hepatic IR injury and exerts its anti-inflammatory and antioxidative stress effects.
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Affiliation(s)
- Yanan Xu
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Zihao Li
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Shounan Lu
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Chaoqun Wang
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Shanjia Ke
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Xinglong Li
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Bing Yin
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Hongjun Yu
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Menghua Zhou
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Shangha Pan
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Hongchi Jiang
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Yong Ma
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
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Xu Y, Huang X, Luo Q, Zhang X. MicroRNAs Involved in Oxidative Stress Processes Regulating Physiological and Pathological Responses. Microrna 2021; 10:164-180. [PMID: 34279211 DOI: 10.2174/2211536610666210716153929] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 05/16/2021] [Accepted: 05/18/2021] [Indexed: 11/22/2022]
Abstract
Oxidative stress influences several physiological and pathological cellular events, including cell differentiation, excessive growth, proliferation, apoptosis, and the inflammatory response. Therefore, oxidative stress is involved in the pathogenesis of various diseases, including pulmonary fibrosis, epilepsy, hypertension, atherosclerosis, Parkinson's disease, cardiovascular disease, and Alzheimer's disease. Recent studies have shown that several microRNAs (miRNAs) are involved in developing various diseases caused by oxidative stress and that miRNAs may be helpful to determine the inflammatory characteristics of immune responses during infection and disease. This review describes the known effects of miRNAs on reactive oxygen species to induce oxidative stress and the miRNA regulatory mechanisms involved in the uncoupling of Keap1-Nrf2 complexes. Finally, we summarized the functions of miRNAs in several antioxidant genes. Understanding the crosstalk between miRNAs and oxidative stress-inducing factors during physiological and pathological cellular events may have implications for designing more effective treatments for immune diseases.
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Affiliation(s)
- Yongjie Xu
- Guangdong Provincial Key Laboratory of Conservation and Precision Utilization of Characteristic Agricultural Resources in Mountainous Areas, School of Life Science of Jiaying University, Guangdong Innovation Centre for Science and Technology of Wuhua Yellow Chicken, Meizhou 514015, China
| | - Xunhe Huang
- Guangdong Provincial Key Laboratory of Conservation and Precision Utilization of Characteristic Agricultural Resources in Mountainous Areas, School of Life Science of Jiaying University, Guangdong Innovation Centre for Science and Technology of Wuhua Yellow Chicken, Meizhou 514015, China
| | - Qingbin Luo
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science/ Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou 510642, China
| | - Xiquan Zhang
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science/ Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou 510642, China
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Ning JZ, He KX, Cheng F, Li W, Yu WM, Li HY, Rao T, Ruan Y. Long Non-coding RNA MEG3 Promotes Pyroptosis in Testicular Ischemia-Reperfusion Injury by Targeting MiR-29a to Modulate PTEN Expression. Front Cell Dev Biol 2021; 9:671613. [PMID: 34222244 PMCID: PMC8249820 DOI: 10.3389/fcell.2021.671613] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 05/24/2021] [Indexed: 01/14/2023] Open
Abstract
Increasing evidence shows that the abnormal long non-coding RNAs (lncRNAs) expression is closely related to ischemia-reperfusion injury (I/R) progression. Studies have previously described that lncRNA MEG3 regulates pyroptosis in various organs I/R. Nevertheless, the related mechanisms of MEG3 in testicular I/R has not been clarified. The aim of this research is to unravel underlying mechanisms of the regulation of pyroptosis mediated by MEG3 during testicular I/R. We have established a testicular torsion/detorsion (T/D) model and an oxygen-glucose deprivation/reperfusion (OGD/R)-treated spermatogenic cell model. Testicular ischemic injury was assessed by H&E staining. Western blotting, quantitative real-time PCR, MDA, and SOD tests and immunohistochemistry measured the expression of MEG3 and related proteins and the level of ROS production in testicular tissues. Quantitative real-time PCR and western blotting determined the relative expression of MEG3, miR-29a, and relevant proteins in GC-1. Cell viability and cytotoxicity were measured by CCK-8 and LDH assays. Secretion and expression levels of inflammatory proteins were determined by ELISA, immunofluorescence and western blotting. The interaction among MEG3, miR-29a, and PTEN was validated through a dual luciferase reporter assay and Ago2-RIP. In this research, we identified that MEG3 was upregulated in animal specimens and GC-1. In loss of function or gain of function assays, we verified that MEG3 could promote pyroptosis. Furthermore, we found that MEG3 negatively regulated miR-29a expression at the posttranscriptional level and promoted PTEN expression, and further promoted pyroptosis. Therefore, we explored the interaction among MEG3, miR-29a and PTEN and found that MEG3 directly targeted miR-29a, and miR-29a targeted PTEN. Overexpression of miR-29a effectively eliminated the upregulation of PTEN induced by MEG3, indicating that MEG3 regulates PTEN expression by targeting miR-29a. In summary, our research indicates that MEG3 contributes to pyroptosis by regulating miR-29a and PTEN during testicular I/R, indicating that MEG3 may be a potential therapeutic target in testicular torsion.
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Affiliation(s)
- Jin-Zhuo Ning
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Kai-Xiang He
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Fan Cheng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wei Li
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wei-Min Yu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hao-Yong Li
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ting Rao
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yuan Ruan
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
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Tian C, Gao L, Zucker IH. Regulation of Nrf2 signaling pathway in heart failure: Role of extracellular vesicles and non-coding RNAs. Free Radic Biol Med 2021; 167:218-231. [PMID: 33741451 PMCID: PMC8096694 DOI: 10.1016/j.freeradbiomed.2021.03.013] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 02/26/2021] [Accepted: 03/11/2021] [Indexed: 12/11/2022]
Abstract
The balance between pro- and antioxidant molecules has been established as an important driving force in the pathogenesis of cardiovascular disease. Chronic heart failure is associated with oxidative stress in the myocardium and globally. Redox balance in the heart and brain is controlled, in part, by antioxidant proteins regulated by the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2), which is reduced in the heart failure state. Nrf2 can, in turn, be regulated by a variety of mechanisms including circulating microRNAs (miRNAs) encapsulated in extracellular vesicles (EVs) derived from multiple cell types in the heart. Here, we review the role of the Nrf2 and antioxidant enzyme signaling pathway in mediating redox balance in the myocardium and the brain in the heart failure state. This review focuses on Nrf2 and antioxidant protein regulation in the heart and brain by miRNA-enriched EVs in the setting of heart failure. We discuss EV-mediated intra- and inter-organ communications especially, communication between the heart and brain via an EV pathway that mediates cardiac function and sympatho-excitation in heart failure. Importantly, we speculate how engineered EVs with specific miRNAs or antagomirs may be used in a therapeutic manner in heart failure.
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Affiliation(s)
- Changhai Tian
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Lie Gao
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, 68198-5850, USA
| | - Irving H Zucker
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, 68198-5850, USA.
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Liu D, Liu Y, Zheng X, Liu N. c-MYC-induced long noncoding RNA MEG3 aggravates kidney ischemia-reperfusion injury through activating mitophagy by upregulation of RTKN to trigger the Wnt/β-catenin pathway. Cell Death Dis 2021; 12:191. [PMID: 33602903 PMCID: PMC7892540 DOI: 10.1038/s41419-021-03466-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/17/2020] [Accepted: 01/19/2021] [Indexed: 02/08/2023]
Abstract
Ischemia-reperfusion injury (IRI)-induced acute kidney injury (AKI) is a life-threatening disease. The activation of mitophagy was previously identified to play an important role in IRI. Maternally expressed 3 (MEG3) can promote cerebral IRI and hepatic IRI. The present study was designed to study the role of MEG3 in renal IRI. Renal IRI mice models were established, and HK-2 cells were used to construct the in vitro models of IRI. Hematoxylin-eosin staining assay was applied to reveal IRI-triggered tubular injury. MitoTracker Green FM staining and an ALP kit were employed for detection of mitophagy. TdT-mediated dUTP-biotin nick-end labeling assay was used to reveal cell apoptosis. The results showed that renal cortex of IRI mice contained higher expression of MEG3 than that of sham mice. MEG3 expression was also elevated in HK-2 cells following IRI, suggesting that MEG3 might participate in the development of IRI. Moreover, downregulation of MEG3 inhibited the apoptosis of HK-2 cells after IRI. Mitophagy was activated by IRI, and the inhibition of MEG3 can restore mitophagy activity in IRI-treated HK-2 cells. Mechanistically, we found that MEG3 can bind with miR-145-5p in IRI-treated cells. In addition, rhotekin (RTKN) was verified to serve as a target of miR-145-5p. MEG3 upregulated RTKN expression by binding with miR-145-5p. Further, MEG3 activated the Wnt/β-catenin pathway by upregulation of RTKN. The downstream effector of Wnt/β-catenin pathway, c-MYC, served as the transcription factor to activate MEG3. In conclusion, the positive feedback loop of MEG3/miR-145-5p/RTKN/Wnt/β-catenin/c-MYC promotes renal IRI by activating mitophagy and inducing apoptosis, which might offer a new insight into the therapeutic methods for renal IRI in the future.
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Affiliation(s)
- Dajun Liu
- Department of Nephrology, Shengjing Hospital of China Medical University, 110022, Shenyang, Liaoning, China.
| | - Ying Liu
- Department of Nephrology, Shengjing Hospital of China Medical University, 110022, Shenyang, Liaoning, China
| | - Xiaotong Zheng
- Department of Nephrology, Shengjing Hospital of China Medical University, 110022, Shenyang, Liaoning, China
| | - Naiquan Liu
- Department of Nephrology, Shengjing Hospital of China Medical University, 110022, Shenyang, Liaoning, China
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Padmavathi G, Ramkumar KM. MicroRNA mediated regulation of the major redox homeostasis switch, Nrf2, and its impact on oxidative stress-induced ischemic/reperfusion injury. Arch Biochem Biophys 2021; 698:108725. [PMID: 33326800 DOI: 10.1016/j.abb.2020.108725] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/21/2020] [Accepted: 12/11/2020] [Indexed: 12/13/2022]
Abstract
Ischemia/reperfusion injury (IRI) initiates from oxidative stress caused by lack of blood supply and subsequent reperfusion. It is often associated with sterile inflammation, cell death and microvascular dysfunction, which ultimately results in myocardial, cerebral and hepatic IRIs. Reportedly, deregulation of Nrf2 pathway plays a significant role in the oxidative stress-induced IRIs. Further, microRNAs (miRNAs/miRs) are proved to regulate the expression and activation of Nrf2 by targeting either the 3'-UTR or the upstream regulators of Nrf2. Additionally, compounds (crocin, ZnSO4 and ginsenoside Rg1) that modulate the levels of the Nrf2-regulating miRNAs were found to exhibit a protective effect against IRIs of different organs. Therefore, the current review briefs the impact of ischemia reperfusion (I/R) pathogenesis in various organs, role of miRNAs in the regulation of Nrf2 and the I/R protective effect of compounds that alter their expression.
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Affiliation(s)
- Ganesan Padmavathi
- SRM Research Institute, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - Kunka Mohanram Ramkumar
- SRM Research Institute, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India; Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India.
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Bao S, He C, Ku P, Xie M, Lin J, Lu S, Nie X. Effects of triclosan on the RedoximiRs/Sirtuin/Nrf2/ARE signaling pathway in mosquitofish (Gambusia affinis). AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2021; 230:105679. [PMID: 33227666 DOI: 10.1016/j.aquatox.2020.105679] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 11/05/2020] [Accepted: 11/07/2020] [Indexed: 06/11/2023]
Abstract
Triclosan (TCS) has been widely used in daily life for its broad-spectrum antibacterial property and subsequently detected frequently in aquatic waterborne. Environmental relevant concentrations of TCS in water (ng-μg/L) may pose potential unexpected impact on non-target aquatic organisms. In the present work, we investigated the transcriptional responses of Nrf2 as well as its downstream genes, sirtuins and redox-sensitive microRNAs (RedoximiRs) in livers of the small freshwater fish mosquitofish (Gambusia affinis) which were exposed to environmental relevant concentrations of TCS (0.05 μg/L, 0.5 μg/L and 5 μg/L for 24 h and 168 h). Results showed there were similar up-regulations in Nrf2 and its target genes (e. g. NQO1, CAT and SOD) at transcriptional, enzymatic and protein levels, reflecting oxidative stress of TCS to mosquitofish. Meanwhile, up-regulations of Sirt1, Sirt2 and down-regulations of miR-34b, miR-200b-5p and miR-21 could modulate antioxidant system via the Nrf2/ARE signaling pathway by the post-transcriptional regulations. Some oxidative stress-related biomarkers displayed in concentration-dependent manners (e. g. NQO1 mRNA, CAT mRNA) and/or time-dependent manners (e. g. GSH contents). This study indicated that the RedoximiRs/Sirtuin/Nrf2/ARE signaling pathway played a crucial role in mosquitofish exposed to TCS, and there might be potentially profound effects for TCS on the aquatic ecological safety.
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Affiliation(s)
- Shuang Bao
- Department of Ecology/Hydrobiology Research Institute, Jinan University, Guangzhou, 510632, China
| | - Cuiping He
- Department of Ecology/Hydrobiology Research Institute, Jinan University, Guangzhou, 510632, China
| | - Peijia Ku
- Department of Biology, University of North Carolina at Greensboro, Greensboro, NC 27402, United States
| | - Meinan Xie
- Department of Ecology/Hydrobiology Research Institute, Jinan University, Guangzhou, 510632, China
| | - Jiawei Lin
- Department of Ecology/Hydrobiology Research Institute, Jinan University, Guangzhou, 510632, China
| | - Songhui Lu
- Research Center of Harmful Algae and Marine Biology, Jinan University, Guangzhou, 510632, China.
| | - Xiangping Nie
- Department of Ecology/Hydrobiology Research Institute, Jinan University, Guangzhou, 510632, China.
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22
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Gong C, Zhou X, Lai S, Wang L, Liu J. Long Noncoding RNA/Circular RNA-miRNA-mRNA Axes in Ischemia-Reperfusion Injury. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8838524. [PMID: 33299883 PMCID: PMC7710414 DOI: 10.1155/2020/8838524] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 09/30/2020] [Accepted: 10/30/2020] [Indexed: 12/18/2022]
Abstract
Ischemia-reperfusion injury (IRI) elicits tissue injury involved in a wide range of pathologies. Multiple studies have demonstrated that noncoding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs), participate in the pathological development of IRI, and they may act as biomarkers, therapeutic targets, or prognostic indicators. Nonetheless, the specific molecular mechanisms of ncRNAs in IRI have not been completely elucidated. Regulatory networks among lncRNAs/circRNAs, miRNAs, and mRNAs have been the focus of attention in recent years. Studies on the underlying molecular mechanisms have contributed to the discovery of therapeutic targets or strategies in IRI. In this review, we comprehensively summarize the current research on the lncRNA/circRNA-miRNA-mRNA axes and highlight the important role of these axes in IRI.
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Affiliation(s)
- Chengwu Gong
- Department of Cardiothoracic Surgery, Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Xueliang Zhou
- Department of Cardiothoracic Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Songqing Lai
- Department of Cardiothoracic Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Lijun Wang
- Department of Cardiothoracic Surgery, Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Jichun Liu
- Department of Cardiothoracic Surgery, Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, China
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23
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Shi R, Chen Y, Liao Y, Li R, Lin C, Xiu L, Yu H, Ding Y. Research Status of Differentially Expressed Noncoding RNAs in Type 2 Diabetes Patients. BIOMED RESEARCH INTERNATIONAL 2020; 2020:3816056. [PMID: 33274206 PMCID: PMC7683115 DOI: 10.1155/2020/3816056] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/26/2020] [Accepted: 10/19/2020] [Indexed: 12/18/2022]
Abstract
AIMS Noncoding RNAs (ncRNAs) play an important role in the occurrence and development of type 2 diabetes mellitus (T2DM). This paper summarized the current evidences of the involvement microRNAs, long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) in the differential expressions and their interaction with each other in T2DM. METHODS The differentially expressed miRNAs, lncRNAs, and circRNAs in the blood circulation (plasma, serum, whole blood, and peripheral blood mononuclear cells) of patients with T2DM were found in PubMed, GCBI, and other databases. The interactions between ncRNAs were predicted based on the MiRWalk and the DIANA Tools databases. The indirect and direct target genes of lncRNAs and circRNAs were predicted based on the starBase V2.0, DIANA Tools, and LncRNA-Target databases. Then, GO and KEGG analysis on all miRNA, lncRNA, and circRNA target genes was performed using the mirPath and Cluster Profile software package in R language. The lncRNA-miRNA and circRNA-miRNA interaction diagram was constructed with Cytoscape. The aim of this investigation was to construct a mechanism diagram of lncRNA involved in the regulation of target genes on insulin signaling pathways and AGE-RAGE signaling pathways of diabetic complications. RESULTS A total of 317 RNAs, 283 miRNAs, and 20 lncRNAs and circRNAs were found in the circulation of T2DM. Dysregulated microRNAs and lncRNAs were found to be involved in signals related to metabolic disturbances, insulin signaling, and AGE-RAGE signaling in T2DM. In addition, lncRNAs participate in the regulation of key genes in the insulin signaling and AGE-RAGE signaling pathways through microRNAs, which leads to insulin resistance and diabetic vascular complications. CONCLUSION Noncoding RNAs participate in the occurrence and development of type 2 diabetes and lead to its vascular complications by regulating different signaling pathways.
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Affiliation(s)
- Rou Shi
- Department of Epidemiology and Medical Statistics, Guangdong Medical University, Dongguan, Guangdong 523808, China
- Huizhou Central People's Hospital, Department of Endocrinology, Huizhou, Guangdong 516008, China
| | - Yingjian Chen
- Institute of Medical Systems Biology, Guangdong Medical University, Dongguan, Guangdong 523808, China
| | - Yuanjun Liao
- Institute of Medical Systems Biology, Guangdong Medical University, Dongguan, Guangdong 523808, China
| | - Rang Li
- Institute of Medical Systems Biology, Guangdong Medical University, Dongguan, Guangdong 523808, China
| | - Chunwen Lin
- Department of Epidemiology and Medical Statistics, Guangdong Medical University, Dongguan, Guangdong 523808, China
| | - Liangchang Xiu
- Department of Epidemiology and Medical Statistics, Guangdong Medical University, Dongguan, Guangdong 523808, China
| | - Haibing Yu
- Department of Epidemiology and Medical Statistics, Guangdong Medical University, Dongguan, Guangdong 523808, China
| | - Yuanlin Ding
- Department of Epidemiology and Medical Statistics, Guangdong Medical University, Dongguan, Guangdong 523808, China
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24
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Fawzy MS, Ibrahiem AT, AlSel BTA, Alghamdi SA, Toraih EA. Analysis of microRNA-34a expression profile and rs2666433 variant in colorectal cancer: a pilot study. Sci Rep 2020; 10:16940. [PMID: 33037254 PMCID: PMC7547073 DOI: 10.1038/s41598-020-73951-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 09/23/2020] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) are implicated in every stage of carcinogenesis and play an essential role as genetic biomarkers of cancer. We aimed to evaluate microRNA-34a gene (MIR34A) expression in colorectal cancer (CRC) tissues compared with non-cancer one and to preliminarily explore the association of one related variant to CRC risk. A total of 116 paraffin-embedded colon specimens were enrolled. MiR-34a was quantified by qPCR, and rs2666433 (A/G) genotyping was performed by TaqMan Real-Time PCR. Also, the somatic mutation burden was assessed. MIR34A expression in the CRC specimens was significantly upregulated (median = 21.50, IQR: 7.0-209.2; P = 0.001) relative to the non-cancer tissues. Allele (A) was highly prevalent in CRC tissues represented 0.56 (P < 0.001). AA/AG genotype carriers were 5.7 and 2.8 more likely to develop cancer than GG carriers. Tumor-normal tissue paired analysis revealed genotype concordance in 33 out of 58 tissue samples. Approximately 43% of the specimens showed a tendency for G to A shift. Additionally, a higher frequency of somatic mutation (92%) was observed in adenocarcinoma (P = 0.006). MIR34A expression and gene variant did not show associations with the clinicopathological data. However, G > A somatic mutation carriers had more prolonged DFS and OS. Bioinformatics analysis revealed miR-34a could target 30 genes that are implied in all steps of CRC tumorigenesis. In conclusion, this study confirms MIR34A upregulation in CRC tissues, and its rs2666433 (A/G) variant showed association with CRC and a high somatic mutation rate in cancer tissues. MiR-34a could provide a novel targeted therapy after validation in large-scale studies.
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Affiliation(s)
- Manal S Fawzy
- Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar, 1321, Saudi Arabia.
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt.
| | - Afaf T Ibrahiem
- Department of Pathology, Faculty of Medicine, Northern Border University, Arar, 1321, Saudi Arabia
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Baraah T Abu AlSel
- Department of Microbiology, Faculty of Medicine, Northern Border University, Arar, 1321, Saudi Arabia
| | - Saleh A Alghamdi
- Medical Genetics, Clinical Laboratory Department, College of Applied Medical Sciences, Taif University, Taif, 21944,, Saudi Arabia
| | - Eman A Toraih
- Department of Surgery, School of Medicine, Tulane University, New Orleans, LA, 70112, USA
- Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt
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25
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Bhattacharjee S, Li J, Dashwood RH. Emerging crosstalk between long non-coding RNAs and Nrf2 signaling. Cancer Lett 2020; 490:154-164. [DOI: 10.1016/j.canlet.2020.07.011] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 07/08/2020] [Accepted: 07/11/2020] [Indexed: 12/17/2022]
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26
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Ghafouri-Fard S, Shoorei H, Taheri M. Non-coding RNAs participate in the ischemia-reperfusion injury. Biomed Pharmacother 2020; 129:110419. [PMID: 32563988 DOI: 10.1016/j.biopha.2020.110419] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 06/11/2020] [Accepted: 06/13/2020] [Indexed: 02/07/2023] Open
Abstract
Ischemia, being defined as blood supply deficiency is involved in the pathogenesis of a number of life-threatening conditions such as myocardial infarction and cerebral stroke. Assessment of the molecular pathology of these conditions has led to identification of the role of reperfusion in induction and aggravation of tissue injury and necrosis. Thus, the term "ischemia/ reperfusion (I/R) injury" has been introduced. This process involves aberrant regulation of the mitochondrial function, apoptotic and autophagic pathways and signal transducers. More recently, non-coding RNAs including long non-coding RNAs (lncRNAs) ad microRNAs (miRNAs) have been shown to influence I/R injury. Animal studies and clinical investigations have shown up-/down-regulation of tens of lncRNAs and miRNAs in this process. In the current study, we summarize the role of these transcripts in the pathophysiology of I/R injury and their potential as biomarkers for detection of extent of tissue injury.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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27
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Ashrafizadeh M, Ahmadi Z, Samarghandian S, Mohammadinejad R, Yaribeygi H, Sathyapalan T, Sahebkar A. MicroRNA-mediated regulation of Nrf2 signaling pathway: Implications in disease therapy and protection against oxidative stress. Life Sci 2020; 244:117329. [PMID: 31954747 DOI: 10.1016/j.lfs.2020.117329] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 01/12/2020] [Accepted: 01/15/2020] [Indexed: 12/15/2022]
Abstract
MicroRNAs (miRs) are small non-coding pieces of RNA that are involved in a variety of physiologic processes such as apoptosis, cell proliferation, cell differentiation, cell cycle and cell survival. These multifunctional nucleotides are also capable of preventing oxidative damages by modulating antioxidant defense systems in a variety of milieu, such as in diabetes. Although the exact molecular mechanisms by which miRs modulate the antioxidant defense elements are unclear, some evidence suggests that they may exert these effects via nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. This intracellular mechanism is crucial in the maintenance of the physiologic redox balance by regulating the expression and activity of various cellular antioxidative defense elements and thereby plays a pivotal role in the development of oxidative stress. Any impairment in the Nrf2 signaling pathway may result in oxidative damage-dependent complications such as various diabetic complications, neurological disorders and cancer. In the current review, we discuss the modulatory effects of miRs on the Nrf2 signaling pathway, which can potentially be novel therapeutic targets.
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Affiliation(s)
- Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Zahra Ahmadi
- Department of Basic Science, Shoushtar Branch, Islamic Azad University, Shoushtar, Iran
| | - Saeed Samarghandian
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Reza Mohammadinejad
- Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran.
| | - Thozhukat Sathyapalan
- Department of Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull, UK
| | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA, Tehran, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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28
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Lu J, Miao J, Sun J. LncRNA np_5318 promotes renal ischemia-reperfusion injury through the TGF-β/Smad signaling pathway. Exp Ther Med 2020; 19:2833-2840. [PMID: 32256767 PMCID: PMC7086211 DOI: 10.3892/etm.2020.8534] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 08/16/2019] [Indexed: 12/24/2022] Open
Abstract
Long noncoding (Lnc)RNA np_5318 has been proved to be involved in renal injury, while its functionality in renal ischemia-reperfusion (I/R) injury is unknown. Therefore, the present study aimed to investigate the role of lncRNA np_5318 in the development of renal I/R injury. Renal I/R injury model and I/R cell model were established in vitro. The expression of np_5318 in I/R cell was inhibited by small interfering (si)-np_5318 and increased by pc-np_5318. Renal function was detected and evaluated by automatic biochemical tests. Immunohistochemical staining was performed to detect the expression cluster of differentiation (CD)31, transforming growth factor (TGF)-β1 and (mothers against decapentaplegic homolog 3) Smad3 in renal tissue. The interaction between np_5318 and Smad3 was verified by chromatin immunoprecipitation (ChIP). Western blotting was performed to detect the expression levels of TGF-β1, Smad3 and phosphorylated (p)-Smad3 in renal tissue and renal cells. Expression of np_5318 in renal tissue and renal cells was detected by reverse transcription-quantitative PCR. Relative cell viability was confirmed by MTT assay. Renal function was impaired and pathological changes in renal tissue were observed in the renal I/R injury group, indicating the renal I/R injury model was successfully established. Compared with the sham group, the expression level of np_5318 significantly increased in the renal I/R injury group. ChIP data confirmed the interaction between np_5318 and Smad3. The expression of TGF-β1, Smad3 and p-Smad3 in renal tissue was also significantly increased in the renal I/R injury group. Furthermore, the I/R cell model in vitro was successfully constructed and np_5318 in I/R group was significantly increased compared with the control group. Cell growth was significantly suppressed in the I/R group compared with the control group. Additionally, transfection with pc-np_5318 significantly inhibited cell growth of I/R cells at 48 and 72 h. While inhibition of np_5318 by si-np_5318 significantly increased the cell growth of I/R cells at 48 and 72 h. Moreover, the level of TGF-β1, p-Smad3 and Smad3 was significantly increased in the I/R group compared with the control group, and transfection with pc-np_5318 significantly increased the level of TGF-β1, p-Smad3 and Smad3. While inhibition of np_5318 by si-np_5318 significantly suppressed the level of TGF-β1, p-Smad3 and Smad3. LncRNA np_5318 may participate in the development of renal I/R injury through TGF-β/Smad signaling pathway.
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Affiliation(s)
- Jing Lu
- Department of Nephropathy, Yucheng People's Hospital, Yucheng, Shandong 251200, P.R. China
| | - Jiangang Miao
- Department of CT, Yucheng People's Hospital, Yucheng, Shandong 251200, P.R. China
| | - Jianhua Sun
- Department of Hemodialysis, Yucheng People's Hospital, Yucheng, Shandong 251200, P.R. China
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29
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Li X, Zhang W, Xu K, Lu J. miR-34a promotes liver fibrosis in patients with chronic hepatitis via mediating Sirt1/p53 signaling pathway. Pathol Res Pract 2020; 216:152876. [PMID: 32089410 DOI: 10.1016/j.prp.2020.152876] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 01/19/2020] [Accepted: 02/11/2020] [Indexed: 01/15/2023]
Abstract
PURPOSE This research aimed to explore the correlation between miR-34a expression in peripheral blood and clinical characteristics of patients with chronic hepatitis C (CHC) as well as the diagnostic and prognostic values of serum miR-34a in CHC. METHODS Serum samples of 41 CHC patients and 18 normal participants were collected to examine the expression levels of miR-34a using qRT-PCR. The changes of serum TBA, liver enzyme AST and ALT were also determined by enzyme colorimetry and rate method. The levels of serum fibrotic markers hyaluronic acid (HA), type III procollagen (PCIII), type IV collagen (IV-C) and laminin (LN) were detected by radioimmunoassay. Degree of liver fibrosis was examined by liver biopsy. Western blot analysis was used to investigate the expression of ac-p53, p53 and Sirt1 in the liver tissues of CHC patients. RESULTS MiR-34a was significantly increased in the serum of CHC patients than that in healthy participants, and serum miR-34a was correlated with liver fibrosis index. Serum TBA, AST and ALT levels, and AST/ALT ratios in patients with CHC were increased with increasing degree of fibrosis, and were positively associated with serum miR-34a. Furthermore, the liver tissues of CHC patients showed low Sirt1 protein expression and highly ac-p53 protein expression. CONCLUSIONS Serum miR-34a in patients with CHC could promote liver fibrosis through mediating the Sirt1/p53 pathway and might function as pivotal biomarker on the prognosis and diagnosis of CHC patients.
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Affiliation(s)
- Xiaojie Li
- The Seventh Inpatient Area, Qingdao Sixth People's Hospital, No. 9, Fushun Road, Shibei District, Qingdao City, Shandong Province, 266033, China
| | - Weiying Zhang
- Department of Inspection, Qingdao Sixth People's Hospital, No. 9, Fushun Road, Shibei District, Qingdao City, Shandong Province, 266033, China
| | - Kun Xu
- Department of Physiotherapy, Qingdao Sixth People's Hospital, No. 9, Fushun Road, Shibei District, Qingdao City, Shandong Province, 266033, China
| | - Jing Lu
- Department of Inspection, Qingdao Sixth People's Hospital, No. 9, Fushun Road, Shibei District, Qingdao City, Shandong Province, 266033, China.
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30
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Magenta A, Lorde R, Syed SB, Capogrossi MC, Puca A, Madeddu P. Molecular therapies delaying cardiovascular aging: disease- or health-oriented approaches. VASCULAR BIOLOGY 2020; 2:R45-R58. [PMID: 32923974 PMCID: PMC7439942 DOI: 10.1530/vb-19-0029] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 01/16/2020] [Indexed: 12/11/2022]
Abstract
Regenerative medicine is a new therapeutic modality that aims to mend tissue damage by encouraging the reconstitution of physiological integrity. It represents an advancement over conventional therapies that allow reducing the damage but result in disease chronicization. Age-related decline in spontaneous capacity of repair, especially in organs like the heart that have very limited proliferative capacity, contributes in reducing the benefit of conventional therapy. ncRNAs are emerging as key epigenetic regulators of cardiovascular regeneration. Inhibition or replacement of miRNAs may offer reparative solutions to cardiovascular disease. The first part of this review article is devoted to illustrating novel therapies emerging from research on miRNAs. In the second part, we develop new therapeutic concepts emerging from genetics of longevity. Prolonged survival, as in supercentenarians, denotes an exceptional capacity to repair and cope with risk factors and diseases. These characteristics are shared with offspring, suggesting that the regenerative phenotype is heritable. New evidence indicates that genetic traits responsible for prolongation of health span in humans can be passed to and benefit the outcomes of animal models of cardiovascular disease. Genetic studies have also focused on determinants of accelerated senescence and related druggable targets. Evolutionary genetics assessing the genetic basis of adaptation and comparing successful and unsuccessful genetic changes in response to selection within populations represent a powerful basis to develop novel therapies aiming to prolong cardiovascular and whole organism health.
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Affiliation(s)
| | - Reggio Lorde
- Bristol Medical School (Translational Health Sciences), Bristol Heart Institute, University of Bristol, Bristol, UK
| | - Sunayana Begum Syed
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA
| | - Maurizio C Capogrossi
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.,Division of Cardiology, Johns Hopkins Bayview Medical Center, Baltimore, Maryland, USA
| | - Annibale Puca
- Ageing Unit, IRCCS MultiMedica, Milan, Italy.,Department of Medicine, Surgery and Dentistry, 'Scuola Medica Salernitana' University of Salerno, Baronissi, Italy
| | - Paolo Madeddu
- Bristol Medical School (Translational Health Sciences), Bristol Heart Institute, University of Bristol, Bristol, UK
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31
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Fang H, Zhang FX, Li HF, Yang M, Liao R, Wang RR, Wang QY, Zheng PC, Zhang JP. PRR34-AS1 overexpression promotes protection of propofol pretreatment against ischemia/reperfusion injury in a mouse model after total knee arthroplasty via blockade of the JAK1-dependent JAK-STAT signaling pathway. J Cell Physiol 2019; 235:2545-2556. [PMID: 31556112 DOI: 10.1002/jcp.29158] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 08/23/2019] [Indexed: 02/05/2023]
Abstract
Long noncoding RNAs have been documented to be protective against ischemia/reperfusion (I/R) injury. However, few research works have focused on the protective effects of PRR34-AS1 on I/R injury after total knee arthroplasty (TKA). The objective of the present study was to investigate the possible effect of PRR34-AS1 on I/R injury after TKA. A mouse model with I/R injury after TKA was established. The interaction between PRR34-AS1 and Janus kinase 1 (JAK1) was examined and thoroughly investigated. Next, the effects of PRR34-AS1 on the expression of apoptosis-related proteins, JAS-signal transducer and activator of transcription (STAT) signaling pathways, and inflammation-related genes, chondrocyte proliferation, and apoptosis were analyzed after gain- and loss-of-function experiments. Attenuated symptoms were observed in mice pretreated with propofol, which was evidenced by decreased positive expression rate of JAK1 protein and superoxide dismutase content along with increased malondialdehyde content and IL-10 levels. PRR34-AS1 was poorly expressed in mice with I/R injury after TKA. JAK1 was a target of PRR34-AS1. Upregulated PRR34-AS1 diminished expression of JAK1, STAT1, JAK2, and STAT3 as well as cell apoptosis, while enhancing cell proliferation in vitro. Furthermore, JAK1 silencing could reverse the suppressed cell proliferation and enhanced cell apoptosis of chondrocytes imposed by silencing PRR34-AS1. Upregulation of PRR34-AS1 can potentially relieve I/R injury after TKA in mice pretreated with propofol through inhibition of the JAS-STAT signaling pathway by targeting JAK1.
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Affiliation(s)
- Hua Fang
- Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, China.,Department of Anesthesiology, Guizhou University People's Hospital, Guiyang, China
| | - Fang-Xiang Zhang
- Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, China.,Department of Anesthesiology, Guizhou University People's Hospital, Guiyang, China
| | - Hua-Feng Li
- Department of Anesthesiology, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Miao Yang
- Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, China.,Department of Anesthesiology, Guizhou University People's Hospital, Guiyang, China
| | - Ren Liao
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Ru-Rong Wang
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Quan-Yun Wang
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Peng-Cheng Zheng
- Guizhou University Research Center for Analysis of Drugs and Metabolites, Guizhou University, Guiyang, China
| | - Jian-Ping Zhang
- Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, China.,Department of Anesthesiology, Guizhou University People's Hospital, Guiyang, China
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32
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Long noncoding RNA-MEG3 contributes to myocardial ischemia-reperfusion injury through suppression of miR-7-5p expression. Biosci Rep 2019; 39:BSR20190210. [PMID: 31366567 PMCID: PMC6702358 DOI: 10.1042/bsr20190210] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 07/21/2019] [Accepted: 07/26/2019] [Indexed: 12/13/2022] Open
Abstract
Long noncoding RNA (lncRNA) maternally expressed gene 3 (MEG3) plays an important role in protection of ischemia–reperfusion (I/R) injury in brain and liver. However, role of MEG3 in myocardial I/R injury remains unclear. Here, the role of MEG3 in protection of myocardial I/R injury and its association with microRNA-7-5p (miR-7-5p) was investigated using rat cardiac I/R model and myocardial I/R cell model. Our results showed that MEG3 was significantly up-regulated and miR-7-5p was significantly down-regulated after I/R. Following I/R, the levels of intact PARP and intact caspase-3 were reduced, while the cleaved fragments of PARP and caspase-3 were increased. TUNEL assay showed an increase in cardiomyocyte apoptosis after I/R. The levels of I/R-induced creatine kinase (CK) and lactate dehydrogenase (LDH) were inhibited by knockdown of MEG3 (siMEG3). SiMEG3 increased cell proliferation and inhibited cell apoptosis after I/R. In contrast, overexpression of MEG3 increased the I/R-induced CK and LDH activities and cell apoptosis and decreased cell proliferation. The dual-luciferase reporter system showed a direct binding of MEG3 to miR-7-5p. The level of miR-7-5p was negatively associated with the change in levels of MEG3 in H9c2 cells. The levels of intact RARP1 and caspase-3 were significantly increased by knockdown of MEG3. Co-transfection of miR-7-5p inhibitor with siMEG3 activates CK and LDH, significantly decreased cell proliferation, increased cell apoptosis, and decreased intact poly(ADP-ribose) polymerase 1 (PARP1) and caspase-3. In summary, down-regulation of MEG3 protects myocardial cells against I/R-induced apoptosis through miR-7-5p/PARP1 pathway, which might provide a new therapeutic target for treatment of myocardial I/R injury.
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Zhang X, Wu N, Wang J, Li Z. LncRNA MEG3 inhibits cell proliferation and induces apoptosis in laryngeal cancer via miR-23a/APAF-1 axis. J Cell Mol Med 2019; 23:6708-6719. [PMID: 31328388 PMCID: PMC6787452 DOI: 10.1111/jcmm.14549] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 06/12/2019] [Accepted: 06/13/2019] [Indexed: 12/14/2022] Open
Abstract
Long non‐coding RNA (LncRNA) MEG3 serves a regulatory role in the progression of several types of cancer, but the role of MEG3 in laryngeal cancer is still unknown. The aim of this study was to explore the regulatory role and mechanism of MEG3 in laryngeal cancer. MEG3 expression in 50 laryngeal cancer tissue samples was detected by reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR). The effects of MEG3 overexpression on laryngeal cancer cells were investigated in vitro and in vivo. The mechanism of competitive endogenous RNA (ceRNA) was validated through luciferase reporter assay, RT‐qPCR and Western blotting. MEG3 was down‐regulated in laryngeal cancer tissues, and the low MEG3 expression was associated with advanced clinical stage. Additionally, MEG3 overexpression inhibited the proliferation and induced the apoptosis of laryngeal cancer cells in vitro and in vivo. Particularly, MEG3 bound to miR‐23a specifically and a reciprocal negative regulation existed between miR‐23a and MEG3. Moreover, MEG3 up‐regulated apoptotic protease activating factor‐1 (APAF‐1), a known miR‐23a's target, thereby leading to the activation of caspase‐9 and caspase‐3. Meanwhile, these activated effects were rescued by miR‐23a overexpression. In conclusion, the present study demonstrated that MEG3 functions as a novel tumour suppressive LncRNA in laryngeal cancer for the first time. Furthermore, MEG3 may act as a ceRNA to regulate APAF‐1 expression by competitive binding to miR‐23a, thereby regulating the progression of laryngeal cancer.
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Affiliation(s)
- Xiaowen Zhang
- Medical Research Center, Shengjing Hospital of China Medical University, Shenyang, China.,Key Laboratory of Research and Application of Animal Model for Environmental and Metabolic Diseases, Shenyang, China
| | - Nan Wu
- The Central Laboratory of the First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jin Wang
- The ENT Department, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhijie Li
- Medical Research Center, Shengjing Hospital of China Medical University, Shenyang, China.,Key Laboratory of Research and Application of Animal Model for Environmental and Metabolic Diseases, Shenyang, China
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Dar WA, Sullivan E, Bynon JS, Eltzschig H, Ju C. Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms. Liver Int 2019; 39:788-801. [PMID: 30843314 PMCID: PMC6483869 DOI: 10.1111/liv.14091] [Citation(s) in RCA: 261] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 02/13/2019] [Accepted: 02/22/2019] [Indexed: 12/11/2022]
Abstract
Liver disease causing end organ failure is a growing cause of mortality. In most cases, the only therapy is liver transplantation. However, liver transplantation is a complex undertaking and its success is dependent on a number of factors. In particular, liver transplantation is subject to the risks of ischaemia-reperfusion injury (IRI). Liver IRI has significant effects on the function of a liver after transplantation. The cellular and molecular mechanisms governing IRI in liver transplantation are numerous. They involve multiple cells types such as liver sinusoidal endothelial cells, hepatocytes, Kupffer cells, neutrophils and platelets acting via an interconnected network of molecular pathways such as activation of toll-like receptor signalling, alterations in micro-RNA expression, production of ROS, regulation of autophagy and activation of hypoxia-inducible factors. Interestingly, the cellular and molecular events in liver IRI can be correlated with clinical risk factors for IRI in liver transplantation such as donor organ steatosis, ischaemic times, donor age, and donor and recipient coagulopathy. Thus, understanding the relationship of the clinical risk factors for liver IRI to the cellular and molecular mechanisms that govern it is critical to higher levels of success after liver transplantation. This in turn will help in the discovery of therapeutics for IRI in liver transplantation - a process that will lead to improved outcomes for patients suffering from end-stage liver disease.
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Affiliation(s)
- Wasim A. Dar
- Department of Surgery, McGovern Medical School at UT Health, Houston, TX
| | - Elise Sullivan
- Department of Anesthesia, McGovern Medical School at UT Health, Houston, TX
| | - John S. Bynon
- Department of Surgery, McGovern Medical School at UT Health, Houston, TX
| | - Holger Eltzschig
- Department of Anesthesia, McGovern Medical School at UT Health, Houston, TX
| | - Cynthia Ju
- Department of Anesthesia, McGovern Medical School at UT Health, Houston, TX
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Wei GJ, Yuan MQ, Jiang LH, Lu YL, Liu CH, Luo HC, Huang HT, Qi ZQ, Wei YS. A Genetic Variant of miR-34a Contributes to Susceptibility of Ischemic Stroke Among Chinese Population. Front Physiol 2019; 10:432. [PMID: 31068831 PMCID: PMC6491571 DOI: 10.3389/fphys.2019.00432] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 03/28/2019] [Indexed: 12/22/2022] Open
Abstract
miRNAs are small non-coding RNAs modulating gene expression, and variants in miRNA genes are involved in the pathogenesis of ischemic stroke (IS). However, the effect of miR-34a polymorphisms on IS susceptibility has rarely been reported. In the present study, we investigated the association between rs12128240, rs2666433, and rs6577555 of the miR-34a gene and IS susceptibility. Snapshot assay was used to detect miR-34a polymorphisms in 548 IS patients and 560 controls. Relative expression of miR-34a was measured by quantitative real-time PCR. We found that rs2666433 was associated with a significantly increased risk of IS (AA vs. GG: OR = 1.61, 95% CI = 1.05-2.52, P = 0.031; AA vs. GG+GA: OR = 1.58, 95% CI = 1.05-2.45, P = 0.026). For the IS subtypes, rs2666433 was associated with large artery atherosclerosis (AA vs. GG: OR = 2.09, 95% CI = 1.16-3.51, P = 0.007; AA vs. GG+GA: OR = 2.02, 95% CI = 1.15-3.33, P = 0.007; A vs. G: OR = 1.36, 95% CI = 1.07-1.81, P = 0.021). Additionally, the level of miR-34a was significantly up-regulated in IS patients compared to the controls (P < 0.001), and patients with rs2666433 AA genotype had a higher level of miR-34a than those with GG+GA genotypes (P < 0.001). Furthermore, increased level of homocysteine was observed in IS patients compared to the controls (P < 0.001), especially in patients carrying the rs2666433AA genotype compared to those carrying the rs2666433 GG+GA genotypes (P < 0.001). However, no significant association between rs12128240 or rs6577555 and IS was found. Collectively, our study found the association between miR-34a polymorphisms and the risk of IS among the Chinese population. The results may provide an explanation for etiology of IS and a potential biomarker or therapeutic target for IS. HIGHLIGHTS-MiR-34a rs2666433 polymorphism was associated with an increased risk of ischemic stroke.-The level of miR-34a was significantly up-regulated in ischemic stroke patients compared with controls, and patients with rs2666433 AA genotype had a higher level miR-34a than those with GG+GA genotypes.-Furthermore, increased level of homocysteine was showed in IS patients compared to controls, and in patients carrying the rs2666433AA compared to those carrying the rs2666433 GG+GA.
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Affiliation(s)
- Gui-Jiang Wei
- Department of Cell Biology, Medical College of Guangxi University, Nanning, China
- Department of Medical Laboratory, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Ming-Qing Yuan
- Department of Cell Biology, Medical College of Guangxi University, Nanning, China
| | - Li-He Jiang
- Department of Cell Biology, Medical College of Guangxi University, Nanning, China
| | - Yu-Lan Lu
- Department of Medical Laboratory, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Chun-Hong Liu
- Department of Medical Laboratory, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Hong-Cheng Luo
- Department of Medical Laboratory, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Hua-Tuo Huang
- Department of Medical Laboratory, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Zong-Quan Qi
- Department of Cell Biology, Medical College of Guangxi University, Nanning, China
| | - Ye-Sheng Wei
- Department of Cell Biology, Medical College of Guangxi University, Nanning, China
- Department of Medical Laboratory, Affiliated Hospital of Guilin Medical University, Guilin, China
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Dehaini H, Awada H, El-Yazbi A, Zouein FA, Issa K, Eid AA, Ibrahim M, Badran A, Baydoun E, Pintus G, Eid AH. MicroRNAs as Potential Pharmaco-targets in Ischemia-Reperfusion Injury Compounded by Diabetes. Cells 2019; 8:152. [PMID: 30759843 PMCID: PMC6406262 DOI: 10.3390/cells8020152] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 02/06/2019] [Accepted: 02/10/2019] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Ischemia-Reperfusion (I/R) injury is the tissue damage that results from re-oxygenation of ischemic tissues. There are many players that contribute to I/R injury. One of these factors is the family of microRNAs (miRNAs), which are currently being heavily studied. This review aims to critically summarize the latest papers that attributed roles of certain miRNAs in I/R injury, particularly in diabetic conditions and dissect their potential as novel pharmacologic targets in the treatment and management of diabetes. METHODS PubMed was searched for publications containing microRNA and I/R, in the absence or presence of diabetes. All papers that provided sufficient evidence linking miRNA with I/R, especially in the context of diabetes, were selected. Several miRNAs are found to be either pro-apoptotic, as in the case of miR-34a, miR-144, miR-155, and miR-200, or anti-apoptotic, as in the case of miR-210, miR-21, and miR-146a. Here, we further dissect the evidence that shows diverse cell-context dependent effects of these miRNAs, particularly in cardiomyocytes, endothelial, or leukocytes. We also provide insight into cases where the possibility of having two miRNAs working together to intensify a given response is noted. CONCLUSIONS This review arrives at the conclusion that the utilization of miRNAs as translational agents or pharmaco-targets in treating I/R injury in diabetic patients is promising and becoming increasingly clearer.
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Affiliation(s)
- Hassan Dehaini
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon.
| | - Hussein Awada
- Department of Biology, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon.
| | - Ahmed El-Yazbi
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon.
- Department of Pharmacology and Toxicology, Alexandria University, Alexandria P.O. Box 21521, El-Mesallah, Egypt.
| | - Fouad A Zouein
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon.
| | - Khodr Issa
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon.
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon.
| | - Maryam Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon.
| | - Adnan Badran
- Department of Nutrition, University of Petra, Amman P.O Box 961343 Amman, Jordan.
| | - Elias Baydoun
- Department of Biology, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon.
| | - Gianfranco Pintus
- Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha P.O. Box 2713, Qatar.
- Biomedical Research Center, Qatar University, Doha P.O. Box 2713, Qatar.
| | - Ali H Eid
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon.
- Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha P.O. Box 2713, Qatar.
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Wang X, Yuan B, Cheng B, Liu Y, Zhang B, Wang X, Lin X, Yang B, Gong G. Crocin Alleviates Myocardial Ischemia/Reperfusion-Induced Endoplasmic Reticulum Stress via Regulation of miR-34a/Sirt1/Nrf2 Pathway. Shock 2019; 51:123-130. [DOI: 10.1097/shk.0000000000001116] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Tong P, Peng QH, Gu LM, Xie WW, Li WJ. LncRNA-MEG3 alleviates high glucose induced inflammation and apoptosis of retina epithelial cells via regulating miR-34a/SIRT1 axis. Exp Mol Pathol 2018; 107:102-109. [PMID: 30529346 DOI: 10.1016/j.yexmp.2018.12.003] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 11/22/2018] [Accepted: 12/06/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Diabetic retinopathy (DR) is the serious complication of diabetes, which could lead to blindness. Inflammation and apoptosis are hallmark of DR, but mechanism of their regulation is little known. LncRNA-MEG3 is associated with multiple biological processes including proliferation, apoptosis and inflammation response, and is dramatically decreased in DR. However, the role and underlying mechanism of MEG3 in DR is unclear. This study is aimed to reveal the signaling mechanisms of MEG3 in inflammation and apoptosis of DR. METHODS ARPE-19 cells were applied for this research. MEG3 was cloned into pcDNA3.1. miR-34a was overexpressed and inhibited by transfecting with mimics and inhibitor, respectively. The expression level was detected by qRT-PCR and western blotting. The targeted regulatory relationship was analyzed by dual luciferase assay. Cytokine secretion, cell viability and apoptosis were detected by ELISA assay, MTT assay and flow cytometry analysis, respectively. RESULTS High glucose (HG) inhibited MEG3 and SIRT1 expression and enhanced miR-34a expression. MEG3 could promote SIRT1 expression by targeting miR-34a. MEG3 overexpression and miR-34a knockdown could inhibit HG-induced apoptosis and secretion of inflammation cytokines including IL-1β, IL-6 and TNF-α, but miR-34a overexpression alleviated such effects of MEG3. Furthermore, MEG3 overexpression also inhibited NF-κB signaling pathway and increased Bcl-2/Bax ratio via down-regulating miR-34a. CONCLUSION MEG3 could alleviate HG-inducing apoptosis and inflammation via inhibiting NF-κB signaling pathway by targeting miR-34a/SIRT1 axis. This finding illustrated the function and mechanism of MEG3 in DR, and MEG3 might serve as potential therapeutic target for DR.
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Affiliation(s)
- Ping Tong
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha 410011, PR China
| | - Qing-Hua Peng
- Hunan Provincial Key Laboratory of Ophthalmology and Otorhinolaryngology in Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, PR China
| | - Li-Min Gu
- Department of Ophthalmology, The Third Affiliated Hospital of Second Military Medical University, Shanghai 200438, PR China
| | - Wei-Wei Xie
- Ningbo Eye Hospital, Ningbo 315040, PR China
| | - Wen-Jie Li
- Department of Ophthalmology, The Third Xiangya Hospital of Central South University, Changsha 410013, PR China.
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Zhu X, Li H, Wu Y, Zhou J, Yang G, Wang W, Kang D, Ye S. CREB-upregulated lncRNA MEG3 promotes hepatic gluconeogenesis by regulating miR-302a-3p-CRTC2 axis. J Cell Biochem 2018; 120:4192-4202. [PMID: 30260029 DOI: 10.1002/jcb.27706] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 08/27/2018] [Indexed: 12/29/2022]
Abstract
Hepatic gluconeogenesis is the major contributor to hyperglycemia in diabetes. Long noncoding RNA (lncRNA) maternally expressed gene 3 (MEG3) has been shown to promote hepatic insulin resistance; however, the underlying mechanism involving hepatic gluconeogenesis remains unclear. This study aims to investigate the potential role of MEG3 in hepatic gluconeogenesis. Mouse primary hepatocytes were used in this study. Cell transfection was performed for the overexpression or knockdown of specific genes. Expressions of MEG3, miR-302a-3p, CREB-regulated transcriptional coactivator 2 (CRTC2), protein kinase A (PKA), cAMP-response element binding protein (CREB), PPARγ coactivator-1α (PGC-1α), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pc) were determined by quantitative real-time polymerase chain reaction (qRT-qPCR) and Western blot analysis, respectively. The association among MEG3, miR-302a-3p, and CRTC2 was disclosed by dual-luciferase reporter assay. MEG3 was highly expressed in high glucagon-treated mouse primary hepatocytes. CREB-induced MEG3 upregulation increased gluconeogenic gene expression in high glucagon-treated primary hepatocytes, while MEG3 interference led to an opposite effect. MEG3 served as a competing endogenous RNA (ceRNA) to upregulate CRTC2 by targeting miR-302a-3p in primary hepatocytes, thereby increasing PGC-1α-PEPCK/G6Pc. CREB-upregulated MEG3-enhanced hepatic gluconeogenesis via mediating miR-302a-3p-CRTC2 axis, revealing that MEG3 might be a potential target and therapeutic strategy for diabetes.
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Affiliation(s)
- Xiang Zhu
- School of Medicine, Shandong University, Jinan, Shandong, China.,Department of Gerontology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Hongqi Li
- Department of Gerontology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Yuanbo Wu
- Department of Neurology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Jian Zhou
- Department of Gerontology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Guangwei Yang
- Department of Endocrinology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Weidong Wang
- Department of Gerontology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Dongmei Kang
- Department of Gerontology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Shandong Ye
- Department of Endocrinology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
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Yang R, Liu S, Wen J, Xue L, Zhang Y, Yan D, Wang G, Liu Z. Inhibition of maternally expressed gene 3 attenuated lipopolysaccharide-induced apoptosis through sponging miR-21 in renal tubular epithelial cells. J Cell Biochem 2018; 119:7800-7806. [PMID: 29923218 DOI: 10.1002/jcb.27163] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 05/18/2018] [Indexed: 12/20/2022]
Abstract
Acute kidney injury (AKI) results in retention of waste products and dysregulation of extracellular volume and electrolytes, thus leading to a variety of complications. Recent advances in long noncoding RNAs suggested their close relationship with disease progression. In the current study, we investigated the role and mechanism of maternally expressed gene 3 (MEG3) on AKI pathogenesis. Real-time polymerase chain reaction found that the expression of MEG3 was significantly increased in both kidney tissues and TKPTS cells induced by lipopolysaccharide (LPS). Western blot assay showed that the expression of apoptosis regulator Bcl-2 was increased in MEG3-inhibited TKPTS cells. Flow cytometry assay confirmed that LPS-induced apoptosis was significantly attenuated after transfection of si-MEG3. The RNAhybrid informatics algorithm predicted that there was a strong binding capacity between miR-21 and MEG3. Luciferase reporter assay confirmed that MEG3 could function as a competing endogenous RNA of miR-21. The antiapoptotic effect of si-MEG3 could be neutralized by a miR-21 inhibitor, demonstrated by the decreased expression of Bcl-2 and flow cytometry results. Further investigation showed that programmed cell death protein 4 (PDCD4), a validated target of miR-21, was highly expressed in both injured kidney tissues and LPS-stimulated TKPTS cells. Meanwhile, the protein expression of PDCD4 was significantly reduced by inhibition of MEG3, but retrieved by coinhibition of MEG3 and miR-21. In conclusion, our results demonstrated that inhibition of MEG3 could attenuate LPS-induced apoptosis in TKPTS cells by regulating the miR-21/PDCD4 pathway, suggesting that the MEG3/miR-21/PDCD4 axis could be developed as a potential therapeutic target of AKI.
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Affiliation(s)
- Ru Yang
- Department of Rheumatology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Suxuan Liu
- Department of Cardiovascular Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Jian Wen
- Department of Rheumatology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Leixi Xue
- Department of Rheumatology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yi Zhang
- Department of Rheumatology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Dong Yan
- Department of Rheumatology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Guokun Wang
- Department of Cardiovascular Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Zhichun Liu
- Department of Rheumatology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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