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Srikanth Y, Reddy DH, Anusha VL, Dumala N, Viswanadh MK, Chakravarthi G, Nalluri BN, Yadagiri G, Ramakrishna K. Unveiling the Multifaceted Pharmacological Actions of Indole-3-Carbinol and Diindolylmethane: A Comprehensive Review. PLANTS (BASEL, SWITZERLAND) 2025; 14:827. [PMID: 40094833 PMCID: PMC11902694 DOI: 10.3390/plants14050827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Revised: 02/28/2025] [Accepted: 03/04/2025] [Indexed: 03/19/2025]
Abstract
Cruciferae family vegetables are remarkably high in phytochemicals such as Indole-3-carbinol (I3C) and Diindolylmethane (DIM), which are widely known as nutritional supplements. I3C and DIM have been studied extensively in different types of cancers like breast, prostate, endometrial, colorectal, gallbladder, hepatic, and cervical, as well as cancers in other tissues. In this review, we summarized the protective effects of I3C and DIM against cardiovascular, neurological, reproductive, metabolic, bone, respiratory, liver, and immune diseases, infections, and drug- and radiation-induced toxicities. Experimental evidence suggests that I3C and DIM offer protection due to their antioxidant, anti-inflammatory, antiapoptotic, immunomodulatory, and xenobiotic properties. Apart from the beneficial effects, the present review also discusses the possible toxicities of I3C and DIM that are reported in various preclinical investigations. So far, most of the reports about I3C and DIM protective effects against various diseases are only from preclinical studies; this emphasizes the dire need for large-scale clinical trials on these phytochemicals against human diseases. Further, in-depth research is required to improve the bioavailability of these two phytochemicals to achieve the desirable protective effects. Overall, our review emphasizes that I3C and DIM may become potential drug candidates for combating dreadful human diseases.
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Affiliation(s)
- Yadava Srikanth
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram 522302, India; (Y.S.); (D.H.R.); (V.L.A.); (N.D.); (M.K.V.); (G.C.); (B.N.N.)
| | - Dontiboina Harikrishna Reddy
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram 522302, India; (Y.S.); (D.H.R.); (V.L.A.); (N.D.); (M.K.V.); (G.C.); (B.N.N.)
| | - Vinjavarapu Lakshmi Anusha
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram 522302, India; (Y.S.); (D.H.R.); (V.L.A.); (N.D.); (M.K.V.); (G.C.); (B.N.N.)
| | - Naresh Dumala
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram 522302, India; (Y.S.); (D.H.R.); (V.L.A.); (N.D.); (M.K.V.); (G.C.); (B.N.N.)
| | - Matte Kasi Viswanadh
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram 522302, India; (Y.S.); (D.H.R.); (V.L.A.); (N.D.); (M.K.V.); (G.C.); (B.N.N.)
| | - Guntupalli Chakravarthi
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram 522302, India; (Y.S.); (D.H.R.); (V.L.A.); (N.D.); (M.K.V.); (G.C.); (B.N.N.)
| | - Buchi N. Nalluri
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram 522302, India; (Y.S.); (D.H.R.); (V.L.A.); (N.D.); (M.K.V.); (G.C.); (B.N.N.)
| | - Ganesh Yadagiri
- Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Kakarla Ramakrishna
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram 522302, India; (Y.S.); (D.H.R.); (V.L.A.); (N.D.); (M.K.V.); (G.C.); (B.N.N.)
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Tian C, Deng S, Yang M, Bai B, Pan Y, Xie G, Zhao D, Wei L. Indole-3-carbinol and its main derivative 3,3'-diindolylmethane: Regulatory roles and therapeutic potential in liver diseases. Biomed Pharmacother 2024; 180:117525. [PMID: 39388997 DOI: 10.1016/j.biopha.2024.117525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 10/01/2024] [Accepted: 10/04/2024] [Indexed: 10/12/2024] Open
Abstract
Indole-3-carbinol (I3C), a compound found in cruciferous vegetables, has shown significant efficacy in treating both cancerous and non-cancerous diseases. Its primary derivative, 3,3'-diindolylmethane (DIM), formed during digestion, also exhibits similar therapeutic benefits. In liver disorders, I3C and DIM exhibit dual roles by inhibiting and promoting hepatocellular carcinoma (HCC) and providing relief for nonmalignant liver diseases, such as acute liver injury (ALI), hepatic fibrosis, nonalcoholic fatty liver disease (NAFLD), and alcohol-related liver disease (ALD). Mechanistically, I3C and DIM modulate various pathophysiological processes, including cell proliferation, apoptosis, oxidative stress, and lipogenesis. This review aims to enhance researchers' understanding of the regulatory roles of I3C and DIM in these liver diseases and explore the potential of plant-derived substances in liver disease treatment.
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Affiliation(s)
- Chao Tian
- Hepatopancreatobiliary Center, Ministry of Education Key Laboratory of Digital Intelligence Hepatology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine of Tsinghua University, Beijing 102218, China
| | - Shizhou Deng
- Hepatopancreatobiliary Center, Ministry of Education Key Laboratory of Digital Intelligence Hepatology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine of Tsinghua University, Beijing 102218, China; Research and Development Department, Guangdong Longsee Biomedical Corporation, Guangzhou 510700, China
| | - Ming Yang
- Hepatopancreatobiliary Center, Ministry of Education Key Laboratory of Digital Intelligence Hepatology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine of Tsinghua University, Beijing 102218, China
| | - Baochen Bai
- Department of Cardiology, Peking University People's hospital, Beijing 100044, China
| | - Yi Pan
- Hepatopancreatobiliary Center, Ministry of Education Key Laboratory of Digital Intelligence Hepatology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine of Tsinghua University, Beijing 102218, China
| | - Gangqiao Xie
- Hepatopancreatobiliary Center, Ministry of Education Key Laboratory of Digital Intelligence Hepatology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine of Tsinghua University, Beijing 102218, China; Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Dongliang Zhao
- Hepatopancreatobiliary Center, Ministry of Education Key Laboratory of Digital Intelligence Hepatology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine of Tsinghua University, Beijing 102218, China
| | - Lai Wei
- Hepatopancreatobiliary Center, Ministry of Education Key Laboratory of Digital Intelligence Hepatology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine of Tsinghua University, Beijing 102218, China.
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Xue X, Li Y, Yao Y, Zhang S, Peng C, Li Y. A comprehensive review of miR-21 in liver disease: Big impact of little things. Int Immunopharmacol 2024; 134:112116. [PMID: 38696909 DOI: 10.1016/j.intimp.2024.112116] [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: 02/21/2024] [Revised: 04/10/2024] [Accepted: 04/17/2024] [Indexed: 05/04/2024]
Abstract
microRNAs (miRNAs), a class of non-coding RNA with 20-24 nucleotides, are defined as the powerful regulators for gene expression. miR-21 is a multifunctional miRNA enriched in the circulatory system and multiple organs, which not only serves as a non-invasive biomarker in disease diagnosis, but also participates in many cellular activities. In various chronic liver diseases, the increase of miR-21 affects glycolipid metabolism, viral infection, inflammatory and immune cell activation, hepatic stellate cells activation and tissue fibrosis, and autophagy. Moreover, miR-21 is also a liaison in the deterioration of chronic liver disease to hepatocellular carcinoma (HCC), and it impacts on cell proliferation, apoptosis, migration, invasion, angiogenesis, immune escape, and epithelial-mesenchymal transformation by regulating target genes expression in different signaling pathways. In current research on miRNA therapy, some natural products can exert the hepatoprotective effects depending on the inhibition of miR-21 expression. In addition, miR-21-based therapeutic also play a role in regulating intracellular miR-21 levels and enhancing the efficacy of chemotherapy drugs. Herein, we systemically summarized the recent progress of miR-21 on biosynthesis, biomarker function, molecular mechanism and miRNA therapy in chronic liver disease and HCC, and looked forward to outputting some information to enable it from bench to bedside.
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Affiliation(s)
- Xinyan Xue
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yanzhi Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yuxin Yao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Shenglin Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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Wu X, Miao X, Xue X, Qiao S, Dai Y, Wei Z. Aryl Hydrocarbon Receptor Activation Limits the Fatty Acid Synthesis and Subsequent "miR-193a-3p-HDAC3-FASN" Signals to Alleviate Intestinal Fibrosis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:13069-13082. [PMID: 38809951 DOI: 10.1021/acs.jafc.4c00976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2024]
Abstract
Intestinal fibrosis is a common complication of Crohn's disease and characterized by excessive extracellular matrix (ECM) deposition. The aryl hydrocarbon receptor (AhR) detects micronutrients and microbial metabolites in diet and can attenuate intestinal fibrosis with unclear mechanisms. In this study, AhR activation was demonstrated to downregulate the transcription of collagen I and fibronectin in a Sp1- but not Sp3- or AP-1-dependent manner. A suppressed fatty acid synthesis was highlighted using untargeted metabolomics analyses, and synthetic products, palmitic acid (PA), were used as the intermediary agent. After a screening study, fatty acid synthase (FASN) was identified as the main targeted protein, and AhR activation regulated "HDAC3-acetylation" signals but not glycosylation to enhance FASN degradation. Furthermore, results of bioinformatics analysis and others showed that after being activated, AhR targeted miR-193a-3p to control HDAC3 transcription. Collectively, AhR activation inhibited ECM deposition and alleviated intestinal fibrosis by limiting fatty acid synthesis subsequent to the inhibition of "miR-193a-3p-HDAC3-FASN" signals.
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Affiliation(s)
- Xiaoqian Wu
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
| | - Xiaohong Miao
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
| | - Xinru Xue
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
| | - Simiao Qiao
- Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510655, China
| | - Yue Dai
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
| | - Zhifeng Wei
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
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Sahu R, Goswami S, Narahari Sastry G, Rawal RK. The Preventive and Therapeutic Potential of the Flavonoids in Liver Cirrhosis: Current and Future Perspectives. Chem Biodivers 2023; 20:e202201029. [PMID: 36703592 DOI: 10.1002/cbdv.202201029] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 01/12/2023] [Indexed: 01/28/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) may vary from moderately mild non-alcohol fatty liver (NAFL) towards the malignant variant known as non-alcoholic steatohepatitis (NASH), which is marked by fatty liver inflammation and may progress to liver cirrhosis (LC), liver cancer, fibrosis, or liver failure. Flavonoids can protect the liver from toxins through their anti-inflammatory, antioxidant, anti-cancer, and antifibrogenic pharmacological activities. Furthermore, flavonoids protect against LC by regulation of hepatic stellate cells (HSCs) trans-differentiation, inhibiting growth factors like TGF-β and platelets-derived growth factor (PDGF), vascular epithelial growth factor (VEGF), viral infections like hepatitis-B, C and D viruses (HBV, HCV & HDV), autoimmune-induced, alcohol-induced, metabolic disorder-induced, causing by apoptosis, and regulating MAPK pathways. These flavonoids may be explored in the future as a therapeutic solution for hepatic diseases.
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Affiliation(s)
- Rakesh Sahu
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India
| | - Sourav Goswami
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India
| | - G Narahari Sastry
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, Uttar Pradesh, India
| | - Ravindra K Rawal
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, Uttar Pradesh, India
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Yang T, Wu E, Zhu X, Leng Y, Ye S, Dong R, Liu J, Zhong J, Zheng Y, Xu W, Luo J, Kong L, Zhang H. TKF, a mexicanolide-type limonoid derivative, suppressed hepatic stellate cells activation and liver fibrosis through inhibition of the YAP/Notch3 pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 107:154466. [PMID: 36182796 DOI: 10.1016/j.phymed.2022.154466] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 08/02/2022] [Accepted: 09/18/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND Liver fibrosis is a common scarring response and may ultimately lead to liver cancer, unfortunately, there is currently no effective antifibrotic drug approved for human use. Limonoids exhibit a broad spectrum of biological activities; however, the potential role of limonoids against fibrosis is largely unknown. PURPOSE This study investigates the antifibrotic activities and potential mechanisms of TKF (3-tigloyl-khasenegasin F), a natural mexicanolide-type limonoid derivative. STUDY DESIGN/METHODS Two well-established mouse models (CCl4 challenge and bile duct ligation) were used to assess anti-fibrotic effects of TKF in vivo. Human hepatic stellate cell (HSC) line LX-2 and mouse primary hepatic stellate cells (pHSCs) also served as in vitro liver fibrosis models. RESULT TKF administration significantly attenuated hepatic histopathological injury and collagen accumulation and suppressed fibrogenesis-associated gene expression including Col1a1, Acta2, and Timp1. In LX-2 cells and mouse pHSCs, TKF dose-dependently suppressed HSC activation and the expression levels of fibrogenic markers. Mechanistic studies showed that TKF inhibited Notch3-Hes1 and YAP signalings in vivo and in vitro. Furthermore, YAP inhibition or knockdown downregulated the Notch3 expression; however, Notch3 inhibition or knockdown did not affect the level of YAP in activated HSC. We revealed that TKF inhibited Notch3-Hes1 activation and downregulated hepatic fibrogenic gene expression via inhibiting YAP. CONCLUSION The therapeutic benefit of TKF against liver fibrosis results from inhibition of YAP and Notch3-Hes1 pathways, indicating that TKF may be a novel therapeutic candidate for liver fibrosis.
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Affiliation(s)
- Ting Yang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Enyi Wu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiaoyun Zhu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yingrong Leng
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Shengtao Ye
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Ruirui Dong
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jiaman Liu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jiawen Zhong
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Ying Zheng
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Wenjun Xu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jun Luo
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Lingyi Kong
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.
| | - Hao Zhang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.
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Sun Q, Xiao L, Cui Z, Yang Y, Ma J, Huang Z, Zhang J, Chen J. 3,3'-Diindolylmethane improves antitumor immune responses of PD-1 blockade via inhibiting myeloid-derived suppressor cells. Chin Med 2022; 17:81. [PMID: 35773674 PMCID: PMC9245307 DOI: 10.1186/s13020-022-00638-z] [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: 04/18/2022] [Accepted: 06/18/2022] [Indexed: 11/16/2022] Open
Abstract
Background Immune checkpoint inhibitors that target programmed cell death protein 1 (PD-1) have obtained encouraging results, but a fraction of tumor patients failed to respond to anti-PD-1 treatment due to the existence of multiple immune suppressive elements such as myeloid-derived suppressor cells (MDSCs). Traditional Chinese medicine or natural products from medicinal plants could enhance immunity and may be helpful for cancer immunotherapy. As a digestive metabolite from cruciferous plants, 3,3′-diindolylmethane (DIM) has been widely used in chemotherapy, but its influence on cancer immunotherapy remains unclear. Here we investigate the function of DIM on MDSCs and examine the therapeutic effects of DIM in conjunction with PD-1 antibody against mouse tumors. Methods Flow cytometry analysis, Western blot analysis and qRT-PCR assay were used to examine the inhibitory effects and mechanisms of DIM on MDSCs in vitro and in vivo. The therapeutic effects of DIM on cancer immunotherapy by PD-1 antibody were evaluated in mouse models of breast cancer and melanoma tumor. Results DIM exerted the inhibitory effect on MDSCs via downregulating miR-21 level and subsequently activating PTEN/PIAS3-STAT3 pathways. Adoptive transfer of MDSCs impaired the therapeutic effects of DIM, indicating that the antitumor activity of DIM might be due to the suppression of MDSCs. Furthermore, in mouse models of breast cancer and melanoma tumor, the addition of DIM can enhance the therapeutic effect of PD-1 antibody through promoting T cells responses, and thereby inhibiting tumor growth. Conclusions Overall, the strategy based on the combination treatment of anti-PD-1 antibody and DIM may provide a new approach for cancer immunotherapy. Cruciferae plants-rich diet which contains high amount of DIM precursor may be beneficial for cancer patients that undergo the anti-PD-1 treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s13020-022-00638-z.
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Affiliation(s)
- Qi Sun
- State Key Laboratory of Analytical Chemistry for Life Sciences and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210023, Nanjing, China
| | - Lin Xiao
- State Key Laboratory of Analytical Chemistry for Life Sciences and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210023, Nanjing, China
| | - Zhiying Cui
- State Key Laboratory of Analytical Chemistry for Life Sciences and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210023, Nanjing, China
| | - Yaping Yang
- State Key Laboratory of Analytical Chemistry for Life Sciences and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210023, Nanjing, China
| | - Junting Ma
- State Key Laboratory of Analytical Chemistry for Life Sciences and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210023, Nanjing, China. .,Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, 230032, Hefei, China.
| | - Zhen Huang
- State Key Laboratory of Analytical Chemistry for Life Sciences and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210023, Nanjing, China.
| | - Junfeng Zhang
- State Key Laboratory of Analytical Chemistry for Life Sciences and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210023, Nanjing, China
| | - Jiangning Chen
- State Key Laboratory of Analytical Chemistry for Life Sciences and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210023, Nanjing, China.
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Shen DF, Cheng H, Cai BZ, Cai WF, Wang B, Zhu Q, Wu YB, Liu M, Chen RJ, Gao FF, Zhang YM, Niu YD, Shi GG. N-n-Butyl haloperidol iodide ameliorates liver fibrosis and hepatic stellate cell activation in mice. Acta Pharmacol Sin 2022; 43:133-145. [PMID: 33758354 PMCID: PMC8724321 DOI: 10.1038/s41401-021-00630-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 02/17/2021] [Indexed: 02/05/2023]
Abstract
N-n-Butyl haloperidol iodide (F2) is a novel compound that has antiproliferative and antifibrogenic activities. In this study we investigated the therapeutic potential of F2 against liver fibrosis in mice and the underlying mechanisms. Two widely used mouse models of fibrosis was established in mice by injection of either carbon tetrachloride (CCl4) or thioacetamide (TAA). The mice received F2 (0.75, 1.5 or 3 mg·kg-1·d-1, ip) for 4 weeks of fibrosis induction. We showed that F2 administration dose-dependently ameliorated CCl4- or TAA-induced liver fibrosis, evidenced by significant decreases in collagen deposition and c-Jun, TGF-β receptor II (TGFBR2), α-smooth muscle actin (α-SMA), and collagen I expression in the liver. In transforming growth factor beta 1 (TGF-β1)-stimulated LX-2 cells (a human hepatic stellate cell line) and primary mouse hepatic stellate cells, treatment with F2 (0.1, 1, 10 μM) concentration-dependently inhibited the expression of α-SMA, and collagen I. In LX-2 cells, F2 inhibited TGF-β/Smad signaling through reducing the levels of TGFBR2; pretreatment with LY2109761 (TGF-β signaling inhibitor) or SP600125 (c-Jun signaling inhibitor) markedly inhibited TGF-β1-induced induction of α-SMA and collagen I. Knockdown of c-Jun decreased TGF-β signaling genes, including TGFBR2 levels. We revealed that c-Jun was bound to the TGFBR2 promoter, whereas F2 suppressed the binding of c-Jun to the TGFBR2 promoter to restrain TGF-β signaling and inhibit α-SMA and collagen I upregulation. In conclusion, the therapeutic benefit of F2 against liver fibrosis results from inhibition of c-Jun expression to reduce TGFBR2 and concomitant reduction of the responsiveness of hepatic stellate cells to TGF-β1. F2 may thus be a potentially new effective pharmacotherapy for human liver fibrosis.
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Affiliation(s)
- Dai-Fei Shen
- Department of Pharmacology, Shantou University Medical College, Shantou, 515041, China
| | - He Cheng
- Qingyuan Maternal and Child Health Hospital, Qingyuan, 511515, China
| | - Bo-Zhi Cai
- Laboratory of Molecular Cardiology, The First Affiliated Hospital, Shantou University Medical College, Shantou, 515041, China
| | - Wen-Feng Cai
- Department of Pharmacology, Shantou University Medical College, Shantou, 515041, China
| | - Bin Wang
- Department of Pharmacology, Shantou University Medical College, Shantou, 515041, China
| | - Qing Zhu
- Department of Pharmacology, Shantou University Medical College, Shantou, 515041, China
| | - Yue-Bin Wu
- Department of Pharmacology, Shantou University Medical College, Shantou, 515041, China
| | - Man Liu
- Department of Pharmacology, Shantou University Medical College, Shantou, 515041, China
| | - Run-Ji Chen
- Department of Pharmacology, Shantou University Medical College, Shantou, 515041, China
| | - Fen-Fei Gao
- Department of Pharmacology, Shantou University Medical College, Shantou, 515041, China
| | - Yan-Mei Zhang
- Department of Pharmacology, Shantou University Medical College, Shantou, 515041, China
| | - Yong-Dong Niu
- Department of Pharmacology, Shantou University Medical College, Shantou, 515041, China
| | - Gang-Gang Shi
- Department of Pharmacology, Shantou University Medical College, Shantou, 515041, China
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Abstract
The aryl hydrocarbon receptor (AHR) is a ubiquitously expressed ligand-activated transcription factor with multifaceted physiological functions. In the immune system, AHR has been unequivocally identified as a key regulatory factor that can integrate environmental, dietary, or microbial signals into innate and adaptive immune responses. Correspondingly, AHR activity seems to be most important at barrier organs, such as the gut, skin, and lung. The liver is likewise prominently exposed to gut-derived dietary or microbial AHR ligands and, moreover, generates plenty of AHR ligands itself. Yet, surprisingly little is known about the role of AHR in the regulation of hepatic immune responses, which are normally biased towards tolerance, preventing harmful inflammation in response to innocuous stimuli. In this review, we summarize the current knowledge about the role of AHR in hepatic immune responses in the healthy liver as well as in inflammatory liver disease. Moreover, we discuss AHR as a potential therapeutic target in hepatic disorders, including autoimmune liver disease, liver fibrosis, and liver cancer.
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Nikulin SV, Alekseev BY, Sergeeva NS, Karalkin PA, Nezhurina EK, Kirsanova VA, Sviridova IK, Akhmedova SA, Volchenko NN, Bolotina LV, Osipyants AI, Hushpulian DM, Topchiy MA, Asachenko AF, Koval AP, Shcherbo DS, Kiselev VI, Mikhaylenko DS, Schumacher U, Poloznikov AA. Breast cancer organoid model allowed to reveal potentially beneficial combinations of 3,3'-diindolylmethane and chemotherapy drugs. Biochimie 2020; 179:217-227. [PMID: 33098909 DOI: 10.1016/j.biochi.2020.10.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 10/13/2020] [Accepted: 10/19/2020] [Indexed: 02/07/2023]
Abstract
Epigenetic alterations represent promising therapeutic targets in cancer treatment. Recently it was revealed that small molecules have the potential to act as microRNA silencers. Capacity to bind the discrete stem-looped structure of pre-miR-21 and prevent its maturation opens opportunities to utilize such compounds for the prevention of initiation, progression, and chemoresistance of cancer. Molecular simulations performed earlier identified 3,3'-diindolylmethane (DIM) as a potent microRNA-21 antagonist. However, data on DIM and microRNA-21 interplay is controversial, which may be caused by the limitations of the cell lines.
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Affiliation(s)
- Sergey V Nikulin
- Faculty of Biology and Biotechnologies, Higher School of Economics, Moscow, 101000, Russia; P. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, 125284, Russia
| | - Boris Ya Alekseev
- P. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, 125284, Russia
| | - Nataliya S Sergeeva
- P. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, 125284, Russia
| | - Pavel A Karalkin
- P. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, 125284, Russia
| | - Elizaveta K Nezhurina
- P. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, 125284, Russia
| | - Valentina A Kirsanova
- P. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, 125284, Russia
| | - Irina K Sviridova
- P. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, 125284, Russia
| | - Suraja A Akhmedova
- P. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, 125284, Russia
| | - Nadezhda N Volchenko
- P. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, 125284, Russia
| | - Larisa V Bolotina
- P. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, 125284, Russia
| | - Andrey I Osipyants
- School of Biomedicine, Far Eastern Federal University, Vladivostok, 690091, Russia
| | - Dmitry M Hushpulian
- School of Biomedicine, Far Eastern Federal University, Vladivostok, 690091, Russia; Institute of Nanotechnology of Microelectronics, 32A Leninsky Prospekt, Moscow, 119991, Russia
| | - Maxim A Topchiy
- A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, Moscow, 119991, Russia
| | - Andrey F Asachenko
- A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov str. 28, Moscow, 119991, Russia
| | - Anastasia P Koval
- Molecular Oncology Laboratory, Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, 117997, Russia
| | - Dmitry S Shcherbo
- Molecular Oncology Laboratory, Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, 117997, Russia
| | - Vsevolod I Kiselev
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Moscow, 117997, Russia
| | - Dmitry S Mikhaylenko
- Institute of Molecular Medicine, Biomedical Science and Technology Park, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Russia; Research Centre for Medical Genetics, Moscow, 115522, Russia
| | - Udo Schumacher
- Institute of Anatomy and Experimental Morphology, University Medical Center, Hamburg-Eppendorf, Hamburg, 20246, Germany
| | - Andrey A Poloznikov
- Faculty of Biology and Biotechnologies, Higher School of Economics, Moscow, 101000, Russia; P. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, 125284, Russia.
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11
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Riaz F, Li D. Non-coding RNA Associated Competitive Endogenous RNA Regulatory Network: Novel Therapeutic Approach in Liver Fibrosis. Curr Gene Ther 2020; 19:305-317. [PMID: 31696817 DOI: 10.2174/1566523219666191107113046] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 10/21/2019] [Accepted: 10/28/2019] [Indexed: 12/19/2022]
Abstract
Liver fibrosis or scarring is the most common pathological feature caused by chronic liver injury, and is widely considered one of the primary causes of morbidity and mortality. It is primarily characterised by hepatic stellate cells (HSC) activation and excessive extracellular matrix (ECM) protein deposition. Overwhelming evidence suggests that the dysregulation of several noncoding RNAs (ncRNAs), mainly long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs) contributes to the activation of HSC and progression of liver fibrosis. These ncRNAs not only bind to their target genes for the development and regression of liver fibrosis but also act as competing endogenous RNAs (ceRNAs) by sponging with miRNAs to form signaling cascades. Among these signaling cascades, lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA are critical modulators for the initiation, progression, and regression of liver fibrosis. Thus, targeting these interacting ncRNA cascades can serve as a novel and potential therapeutic target for inhibition of HSC activation and prevention and regression of liver fibrosis.
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Affiliation(s)
- Farooq Riaz
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, China
| | - Dongmin Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, China
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12
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Chang T, Ho HL, Hsu SJ, Chang CC, Tsai MH, Huo TI, Huang HC, Lee FY, Hou MC, Lee SD. Glucobrassicin Metabolites Ameliorate the Development of Portal Hypertension and Cirrhosis in Bile Duct-Ligated Rats. Int J Mol Sci 2019; 20:ijms20174161. [PMID: 31454890 PMCID: PMC6747388 DOI: 10.3390/ijms20174161] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 08/11/2019] [Accepted: 08/24/2019] [Indexed: 01/24/2023] Open
Abstract
Patients suffering from liver cirrhosis are often complicated with the formation of portosystemic collateral vessels, which is associated with the progression of a splanchnic hyperdynamic circulatory state. Alleviating pathological angiogenesis has thus been proposed to be a feasible treatment strategy. Indole-3-carbinol (C9H9NO, I3C) and 3,3'-diindolymethane (DIM), formed by the breakdown of glucosinolate glucobrassicin, are prevalent in cruciferous vegetables and have anti-angiogenesis properties. We aimed to evaluate their influences on portal hypertension, the severity of mesenteric angiogenesis, and portosystemic collaterals in cirrhosis. Sprague-Dawley rats with common bile duct ligation (CBDL)-induced liver cirrhosis or sham operation (surgical control) were randomly allocated to receive I3C (20 mg/kg/3 day), DIM (5 mg/kg/day) or vehicle for 28 days. The systemic and portal hemodynamics, severity of portosystemic shunting, mesenteric angiogenesis, and mesenteric proangiogenic factors protein expressions were evaluated. Compared to vehicle, both DIM and I3C significantly reduced portal pressure, ameliorated liver fibrosis, and down-regulated mesenteric protein expressions of vascular endothelial growth factor and phosphorylated Akt. DIM significantly down-regulated pErk, and I3C down-regulated NFκB, pIκBα protein expressions, and reduced portosystemic shunting degree. The cruciferous vegetable byproducts I3C and DIM not only exerted a portal hypotensive effect but also ameliorated abnormal angiogenesis and portosystemic collaterals in cirrhotic rats.
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Affiliation(s)
- Ting Chang
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Hsin-Ling Ho
- Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Lotong Poh-Ai Hospital, Yilan 26546, Taiwan
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan
| | - Shao-Jung Hsu
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Ching-Chih Chang
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
- Division of Gastroenterology and Hepatology, Department of Medicine, Lotong Poh-Ai Hospital, Yilan 26546, Taiwan.
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan.
| | - Ming-Hung Tsai
- Chang Gung University College of Medicine and Division of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Teh-Ia Huo
- Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Hui-Chun Huang
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Fa-Yauh Lee
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Ming-Chih Hou
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Shou-Dong Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan
- Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei 11217, Taiwan
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13
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Wu X, Peng K, Huang H, Li Z, Xiang W, Deng W, Liu L, Li W, Zhang T. MiR-21b-3p protects NS2OY cells against oxygen-glucose deprivation/reperfusion-induced injury by down-regulating cyclooxygenase-2. Am J Transl Res 2019; 11:3007-3017. [PMID: 31217870 PMCID: PMC6556624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 12/23/2018] [Indexed: 06/09/2023]
Abstract
Recent studies have shown abnormal expression levels of cyclooxygenase-2 (COX-2) and miR-21b-3p in cerebral ischemia-reperfusion (I/R) rat models. Decreased COX-2 expression could reduce brain injury and thus could be a target of miR-21b-3p according to the miRNA databases (miRDB) analysis. However, its functions and underlying mechanisms in I/R injury remain unclear. In our study, we have established an oxygen/glucose deprivation and reperfusion (OGD/R) model by using NS2OY cells. The expression of miR-21b-3p and COX-2 was determined by quantitative real-time PCR or Western blot, and the fluorescence intensities were detected by fluorescence in situ hybridization (FISH) or immunofluorescence. After transfection and OGD/R treatments, the functions of miR-21b-3p and COX-2 on cell viability and apoptosis were detected using cell-counting kit 8, Edu staining, flow cytometry and Hoechst staining, respectively. Finally, dual-luciferase reporter assay was used to explore the relationship between miR-21-b-3p and COX-2. The results have showed that COX-2 mRNA and protein expression were significantly increased; however, the expression of miR-21b-3p was remarkably reduced in NS2OY cells after OGD/R treatment. The changes were most remarkable in OGD 2 h/R24 group. Function analysis has showed that when NS2OY cells were exposed to OGD/R injury, overexpressed miR-21b-3p significantly downregulated COX-2 expression, increased cell viability and decreased apoptosis. In addition, knocking down the expression of COX-2 could also increase cell viability and decrease apoptosis. Dual-luciferase reporter assays showed miR-21b-3p as the target of 3'-UTR of COX-2. Therefore, we concluded that OGD/R-induced injury by down-regulating COX-2.
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Affiliation(s)
- Xiaona Wu
- Department of Neurology, General Hospital of Southern Theater Command, PLAGuangzhou, Guangdong, People’s Republic of China
| | - Kairun Peng
- Department of Neurology, General Hospital of Southern Theater Command, PLAGuangzhou, Guangdong, People’s Republic of China
| | - Huai Huang
- Department Two of Nerve Rehabilitation, Guangzhou General Hospital, Guangzhou Military RegionGuangzhou, Guangdong, People’s Republic of China
| | - Zhensheng Li
- Department of Neurology, General Hospital of Southern Theater Command, PLAGuangzhou, Guangdong, People’s Republic of China
| | - Wei Xiang
- Department of Neurology, General Hospital of Southern Theater Command, PLAGuangzhou, Guangdong, People’s Republic of China
| | - Wenting Deng
- Department of Neurology, General Hospital of Southern Theater Command, PLAGuangzhou, Guangdong, People’s Republic of China
| | - Liu Liu
- Department of Neurology, General Hospital of Southern Theater Command, PLAGuangzhou, Guangdong, People’s Republic of China
| | - Wei Li
- General Hospital of Northern Theater Command, PLAShenyang, Liaoning, People’s Republic of China
| | - Tao Zhang
- Department of Orthopaedics, General Hospital of Southern Theater Command, PLAGuangzhou, Guangdong, People’s Republic of China
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Xia ZE, Xi JL, Shi L. 3,3'-Diindolylmethane ameliorates renal fibrosis through the inhibition of renal fibroblast activation in vivo and in vitro. Ren Fail 2018; 40:447-454. [PMID: 30101622 PMCID: PMC6095015 DOI: 10.1080/0886022x.2018.1490322] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
3,3'-Diindolylmethane (DIM), a natural acid condensation extracted from cruciferous plants, exhibits anti-fibrotic effects in hepatic and cardiac fibrosis models. The effects of DIM on renal fibrosis, however, are unclear. This study aimed to explore the protective effects of DIM on renal fibrosis. Unilateral ureteral obstruction (UUO) and transforming growth factor (TGF)-β1-stimulated normal rat kidney (NRK)-49F fibroblast cell mouse models were established. The models were then treated with DIM for the assessment of its anti-fibrotic effects and mechanisms. Results of HE and Masson staining showed that DIM reduced kidney injury and production of interstitial collagens fibrosis. CTS also inhibited expression of fibronectin, collagen-1 but retain E-cadherin in the UUO model. Furthermore, DIM suppressed local fibroblast activation, as evidenced by the suppressed expression of the myofibroblast markers α-SMA and vimentin in vivo and in vitro. In addition, DIM significantly inhibited the TGF-β1-induced proliferation of NRK49F cells in a time- and dose-dependent manner. DIM decreased Smad2/3 phosphorylation but increased Smad7 expression. Results suggested that DIM inhibits TGF-β/Smad2/3 signaling to attenuate renal interstitial fibrosis via inhibiting local fibroblast activation. This mechanism is likely related to Smad7 induction.
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Affiliation(s)
- Zun-En Xia
- a Department of Clinical Laboratory , Renmin Hospital of Wuhan University , Wuhan , China
| | - Juan-Li Xi
- b Department of Gastroenterology , Wuhan Third Hospital , Wuhan , China
| | - Lei Shi
- c Department of Oncology , Renmin Hospital of Wuhan University , Wuhan , China
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15
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Huang Q, Zhang X, Bai F, Nie J, Wen S, Wei Y, Wei J, Huang R, He M, Lu Z, Lin X. Methyl helicterte ameliorates liver fibrosis by regulating miR-21-mediated ERK and TGF-β1/Smads pathways. Int Immunopharmacol 2018; 66:41-51. [PMID: 30419452 DOI: 10.1016/j.intimp.2018.11.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 10/26/2018] [Accepted: 11/05/2018] [Indexed: 12/28/2022]
Abstract
Methyl helicterate (MH) has been reported to have protective effects against CCl4-induced hepatic injury and fibrosis in rats, but its protective mechanism, especially on hepatic stallete cells (HSCs), remains unclear. Recently, our pilot experiment showed that MH could inhibit miR-21 expression in HSC-T6 cells, suggesting that miR-21 may be one of the targets of MH to intervene liver fibrosis. To verify the hypothesis, the present study would focus on the regulatory effect of MH on the miR-21-mediated ERK and TGF-β1/Smads pathways. Briefly, rats were intraperitoneally injected with 0.5 ml porcine serum (PS) twice a week for 24 weeks to induce liver fibrosis, and meanwhile, the rats were treated with MH from weeks 16 to 24. In vitro experiment, miR-21 expression in HSC-T6 cells was up- or down-regulated using lentiviral transfection assay. Collagen accumulation, inflammatory cytokines, cell apoptosis, miR-21 expression, and activation of the ERK and TGF-β1/smad2/3 pathways were then assessed. The results showed that MH treatment markedly alleviated PS-induced liver injury, as evidenced by the attenuation of histopathological changes and the decrease in serum alanine and aspartate aminotransferases activity. MH significantly decreased the content of inflammatory cytokines and recruited the anti-oxidative defense system. Moreover, MH treatment significantly decreased miR-21 expression and inhibited the activation of the ERK and TGF-β1/smad2/3 pathways in liver tissues. In vitro experiments showed that MH strongly inhibited HSC-T6 cell activation and reduced collagen accumulation. Interestingly, miR-21 overexpression significantly promoted HSC-T6 cell proliferation, reduced HSC apoptosis, and increased collagenation, while these abnormal changes induced by miR-21overexpression were significantly reversed by MH treatment. Furthermore, miR-21 overexpression notably activated the ERK and TGF-β1/Smads pathways via repressing SPRY2 and Smad7 expression respectively, however, these effects were largely abolished by MH treatment. In conclusion, our study demonstrates that MH significantly alleviates PS-induced liver injury and fibrosis by inhibiting miR-21-mediated ERK and TGF-β1/Smads pathways.
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Affiliation(s)
- Quanfang Huang
- The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, China
| | | | - Facheng Bai
- Guangxi Medical University, Nanning 530021, China
| | - Jinlan Nie
- Guangxi Medical University, Nanning 530021, China
| | - Shujuan Wen
- Guangxi Medical University, Nanning 530021, China
| | - Yuanyuan Wei
- Guangxi Medical University, Nanning 530021, China
| | - Jinbin Wei
- Guangxi Medical University, Nanning 530021, China
| | - Renbin Huang
- Guangxi Medical University, Nanning 530021, China
| | - Min He
- Guangxi Medical University, Nanning 530021, China
| | - Zhongpeng Lu
- Department of Biochemistry, University of Arkansas Medical School, 4301 W. Markham, Little Rock, AR 72205-7199, USA
| | - Xing Lin
- Guangxi Medical University, Nanning 530021, China.
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16
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Islam MS, Segars JH, Castellucci M, Ciarmela P. Dietary phytochemicals for possible preventive and therapeutic option of uterine fibroids: Signaling pathways as target. Pharmacol Rep 2017; 69:57-70. [DOI: 10.1016/j.pharep.2016.10.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 10/03/2016] [Accepted: 10/19/2016] [Indexed: 02/07/2023]
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Zou XZ, Liu T, Gong ZC, Hu CP, Zhang Z. MicroRNAs-mediated epithelial-mesenchymal transition in fibrotic diseases. Eur J Pharmacol 2016; 796:190-206. [PMID: 27916556 DOI: 10.1016/j.ejphar.2016.12.003] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Revised: 11/24/2016] [Accepted: 12/01/2016] [Indexed: 12/19/2022]
Abstract
MicroRNAs (miRNAs), a large family of small and highly conserved non-coding RNAs, regulate gene expression through translational repression or mRNA degradation. Aberrant expression of miRNAs underlies a spectrum of diseases including organ fibrosis. Recent evidence suggests that miRNAs contribute to organ fibrosis through mediating epithelial-mesenchymal transition (EMT). Alleviation of EMT has been proposed as a promising strategy against fibrotic diseases given the key role of EMT in fibrosis. miRNAs impact the expression of specific ligands, receptors, and signaling pathways, thus modulating EMT and consequently influencing fibrosis. This review summarizes the current knowledge concerning how miRNAs regulate EMT and highlights the specific roles that miRNAs-regulated EMT plays in fibrotic diseases as diverse as pulmonary fibrosis, hepatic fibrosis, renal fibrosis and cardiac fibrosis. It is desirable that a more comprehensive understanding of the functions of miRNAs-regulated EMT will facilitate the development of novel diagnostic and therapeutic strategies for various debilitating organ fibrosis.
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Affiliation(s)
- Xiao-Zhou Zou
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China
| | - Ting Liu
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China
| | - Zhi-Cheng Gong
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Chang-Ping Hu
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, Hunan 410078, China.
| | - Zheng Zhang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, Hunan 410078, China.
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18
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Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice. J Transl Med 2016; 96:1256-1267. [PMID: 27775690 PMCID: PMC5121007 DOI: 10.1038/labinvest.2016.112] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 09/22/2016] [Accepted: 09/26/2016] [Indexed: 12/12/2022] Open
Abstract
Cholestasis is a condition that leads to chronic hepatobiliary inflammation, fibrosis, and eventually cirrhosis. Many microRNAs (miRs) are known to have a role in fibrosis progression; however, the role of miR-21 during cholestasis remains unknown. Therefore, the aim of this study was to elucidate the role of miR-21 during cholestasis-induced biliary hyperplasia and hepatic fibrosis. Wild-type (WT) and miR-21-/- mice underwent Sham or bile duct ligation (BDL) for 1 week, before evaluating liver histology, biliary proliferation, hepatic stellate cell (HSC) activation, fibrotic response, and small mothers against decapentaplegic 7 (Smad-7) expression. In vitro, immortalized murine biliary cell lines (IMCLs) and human hepatic stellate cell line (hHSC) were treated with either miR-21 inhibitor or control before analyzing proliferation, apoptosis, and fibrotic responses. In vivo, the levels of miR-21 were increased in total liver and cholangiocytes after BDL, and loss of miR-21 decreased the amount of BDL-induced biliary proliferation and intrahepatic biliary mass. In addition, loss of miR-21 decreased BDL-induced HSC activation, collagen deposition, and expression of the fibrotic markers transforming growth factor-β1 and α-smooth muscle actin. In vitro, IMCL and hHSCs treated with miR-21 inhibitor displayed decreased proliferation and expression of fibrotic markers and enhanced apoptosis when compared with control treated cells. Furthermore, mice lacking miR-21 show increased Smad-7 expression, which may be driving the decrease in biliary hyperplasia and hepatic fibrosis. During cholestatic injury, miR-21 is increased and leads to increased biliary proliferation and hepatic fibrosis. Local modulation of miR-21 may be a therapeutic option for patients with cholestasis.
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Blaya D, Coll M, Rodrigo-Torres D, Vila-Casadesús M, Altamirano J, Llopis M, Graupera I, Perea L, Aguilar-Bravo B, Díaz A, Banales JM, Clària J, Lozano JJ, Bataller R, Caballería J, Ginès P, Sancho-Bru P. Integrative microRNA profiling in alcoholic hepatitis reveals a role for microRNA-182 in liver injury and inflammation. Gut 2016; 65:1535-45. [PMID: 27196584 DOI: 10.1136/gutjnl-2015-311314] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 04/17/2016] [Indexed: 12/12/2022]
Abstract
OBJECTIVE MicroRNAs (miRNAs) are well-known regulators of disease pathogenesis and have great potential as biomarkers and therapeutic targets. We aimed at profiling miRNAs in alcoholic hepatitis (AH) and identifying miRNAs potentially involved in liver injury. DESIGN MiRNA profiling was performed in liver samples from patients with AH, alcohol liver disease, non-alcoholic steatohepatitis, HCV disease and normal liver tissue. Expression of miRNAs was assessed in liver and serum from patients with AH and animal models. Mimic and decoy miR-182 were used in vitro and in vivo to evaluate miR-182's biological functions. RESULTS MiRNA expression profile in liver was highly altered in AH and distinctive from alcohol-induced cirrhotic livers. Moreover, we identified a set of 18 miRNAs predominantly expressed in AH as compared with other chronic liver conditions. Integrative miRNA-mRNA functional analysis revealed the association of AH-altered miRNAs with nuclear receptors, IGF-1 signalling and cholestasis. Interestingly, miR-182 was the most highly expressed miRNA in AH, which correlated with degree of ductular reaction, disease severity and short-term mortality. MiR-182 mimic induced an upregulation of inflammatory mediators in biliary cells. At experimental level, miR-182 was increased in biliary cells in mice fed with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet but not upregulated by alcohol intake or fibrosis. Inhibition of miR-182 in DDC-fed mice reduced liver damage, bile acid accumulation and inflammatory response. CONCLUSIONS AH is characterised by a deregulated miRNA profile, including miR-182, which is associated with disease severity and liver injury. These results highlight the potential of miRNAs as therapeutic targets and biomarkers in AH.
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Affiliation(s)
- Delia Blaya
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Mar Coll
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Daniel Rodrigo-Torres
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Maria Vila-Casadesús
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - José Altamirano
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Marta Llopis
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Isabel Graupera
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Luis Perea
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Beatriz Aguilar-Bravo
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Alba Díaz
- Department of Pathology, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Jesus M Banales
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, San Sebastian, Spain
| | - Joan Clària
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Department of Biochemistry and Molecular Genetics, Hospital Clínic and Department of Physiological Sciences I, University of Barcelona, Barcelona, Spain
| | - Juan José Lozano
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Ramon Bataller
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Juan Caballería
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain Liver Unit, Hospital Clínic, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Pere Ginès
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain Liver Unit, Hospital Clínic, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Pau Sancho-Bru
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
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20
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Hepatic Stellate Cells and microRNAs in Pathogenesis of Liver Fibrosis. J Clin Med 2016; 5:jcm5030038. [PMID: 26999230 PMCID: PMC4810109 DOI: 10.3390/jcm5030038] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Revised: 02/23/2016] [Accepted: 03/07/2016] [Indexed: 12/18/2022] Open
Abstract
microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by either blocking translation or inducing degradation of target mRNA. miRNAs play essential roles in diverse biological and pathological processes, including development of hepatic fibrosis. Hepatic stellate cells (HSCs) play a central role in development of hepatic fibrosis and there are intricate regulatory effects of miRNAs on their activation, proliferation, collagen production, migration, and apoptosis. There are multiple differentially expressed miRNAs in activated HSCs, and in this review we aim to summarize current data on miRNAs that participate in the development of hepatic fibrosis. Based on this review, miRNAs may serve as biomarkers for diagnosis of liver disease, as well as markers of disease progression. Most importantly, dysregulated miRNAs may potentially be targeted by novel therapies to treat and reverse progression of hepatic fibrosis.
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21
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Ahmad A, Li Y, Sarkar FH. The bounty of nature for changing the cancer landscape. Mol Nutr Food Res 2016; 60:1251-63. [PMID: 26799714 DOI: 10.1002/mnfr.201500867] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 01/11/2016] [Accepted: 01/11/2016] [Indexed: 12/18/2022]
Abstract
The landscape of cancer has changed considerably in past several years, due mainly to aggressive screening, accumulation of data from basic and epidemiological studies, and the advances in translational research. Natural anticancer agents have always been a part and parcel of cancer research. The initial focus on natural anticancer agents was in context of their cancer chemopreventive properties but their ability to selectively target oncogenic signaling pathways has also been recognized. In light of the rapid advancements in our understanding of the role of microRNAs, cancer stem cells, and epigenetic events in cancer initiation and progression, a number of natural anticancer agents are showing promise in vitro, in vivo as well as in preclinical studies. Moreover, parent structures of natural agents are being extensively modified with the hope of improving efficacy, specificity, and bioavailability. In this article, we focus on two natural agents, 3,3'-diindolylmethane and garcinol, along with 3,4-difluorobenzo curcumin, a synthetic analog of natural agent curcumin. We showcase how these anticancer agents are changing cancer landscape by modulating novel microRNAs, epigenetic factors, and cancer stem cell markers. These activities are relevant and being appreciated for overcoming drug resistance and inhibition of metastases, the two overarching clinical challenges in modern medicine.
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Affiliation(s)
- Aamir Ahmad
- Department of Pathology, Wayne State University School of Medicine and Karmanos Cancer Institute, Detroit, MI, USA
| | - Yiwei Li
- Department of Pathology, Wayne State University School of Medicine and Karmanos Cancer Institute, Detroit, MI, USA
| | - Fazlul H Sarkar
- Department of Pathology, Wayne State University School of Medicine and Karmanos Cancer Institute, Detroit, MI, USA.,Department of Oncology, Wayne State University School of Medicine and Karmanos Cancer Institute, Detroit, MI, USA
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22
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Liu RH, Ning B, Ma XE, Gong WM, Jia TH. Regulatory roles of microRNA-21 in fibrosis through interaction with diverse pathways (Review). Mol Med Rep 2016; 13:2359-66. [PMID: 26846276 DOI: 10.3892/mmr.2016.4834] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 01/05/2016] [Indexed: 02/04/2023] Open
Abstract
MicroRNA-21 (miR-21) is a small, non-coding RNA which can regulate gene expression at the post‑transcriptional level. While the fibrogenic process is vital in tissue repair, proliferation and transition of fibrogenic cells combined with an imbalance of secretion and degradation of the extracellular matrix results in excessive tissue remodeling and fibrosis. Recent studies have indicated that miR‑21 is overexpressed during fibrosis and can regulate the fibrogenic process in a variety of organs and tissues via diverse pathways. The present review summarized the significant roles of miR-21 in fibrosis and discussed the underlying key pathways.
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Affiliation(s)
- Rong-Han Liu
- Department of Spinal Surgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Bin Ning
- Department of Spinal Surgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Xiao-En Ma
- Department of Spinal Surgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Wei-Ming Gong
- Department of Spinal Surgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Tang-Hong Jia
- Department of Spinal Surgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
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23
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TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis: Updated. CURRENT PATHOBIOLOGY REPORTS 2015. [DOI: 10.1007/s40139-015-0089-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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24
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Dattaroy D, Pourhoseini S, Das S, Alhasson F, Seth RK, Nagarkatti M, Michelotti GA, Diehl AM, Chatterjee S. Micro-RNA 21 inhibition of SMAD7 enhances fibrogenesis via leptin-mediated NADPH oxidase in experimental and human nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 2015; 308:G298-312. [PMID: 25501551 PMCID: PMC4329476 DOI: 10.1152/ajpgi.00346.2014] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatic fibrosis in nonalcoholic steatohepatitis (NASH) is the common pathophysiological process resulting from chronic liver inflammation and oxidative stress. Although significant research has been carried out on the role of leptin-induced NADPH oxidase in fibrogenesis, the molecular mechanisms that connect the leptin-NADPH oxidase axis in upregulation of transforming growth factor (TGF)-β signaling have been unclear. We aimed to investigate the role of leptin-mediated upregulation of NADPH oxidase and its subsequent induction of micro-RNA 21 (miR21) in fibrogenesis. Human NASH livers and a high-fat (60% kcal) diet-fed chronic mouse model, where hepatotoxin bromodichloromethane was used to induce NASH, were used for this study. To prove the role of the leptin-NADPH oxidase-miR21 axis, mice deficient in genes for leptin, p47phox, and miR21 were used. Results showed that wild-type mice and human livers with NASH had increased oxidative stress, increased p47phox expression, augmented NF-κB activation, and increased miR21 levels. These mice and human livers showed increased TGF-β, SMAD2/3-SMAD4 colocalizations in the nucleus, increased immunoreactivity against Col1α, and α-SMA with a concomitant decrease in protein levels of SMAD7. Mice that were deficient in leptin or p47phox had decreased activated NF-κB and miR21 levels, suggesting the role of leptin and NADPH oxidase in inducing NF-κB-mediated miR21 expression. Further miR21 knockout mice had decreased colocalization events of SMAD2/3-SMAD4 in the nucleus, increased SMAD7 levels, and decreased fibrogenesis. Taken together, the studies show the novel role of leptin-NADPH oxidase induction of miR21 as a key regulator of TGF-β signaling and fibrogenesis in experimental and human NASH.
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Affiliation(s)
- Diptadip Dattaroy
- 1Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, South Carolina;
| | - Sahar Pourhoseini
- 1Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, South Carolina;
| | - Suvarthi Das
- 1Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, South Carolina;
| | - Firas Alhasson
- 1Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, South Carolina;
| | - Ratanesh Kumar Seth
- 1Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, South Carolina;
| | - Mitzi Nagarkatti
- 2Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina;
| | | | - Anna Mae Diehl
- 3Division of Gastroenterology, Duke University, Durham, North Carolina
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, South Carolina;
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25
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Page A, Mann DA, Mann J. The mechanisms of HSC activation and epigenetic regulation of HSCs phenotypes. CURRENT PATHOBIOLOGY REPORTS 2014; 2:163-170. [PMID: 27413631 DOI: 10.1007/s40139-014-0052-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Epigenetics is a dynamically expanding field of science entailing numerous regulatory mechanisms controlling changes of gene expression in response to environmental factors. Over the recent years there has been a great interest in epigenetic marks as a potential diagnostic and prognostic tool or future target for treatment of various human diseases. There is an increasing body of published research to suggest that epigenetic events regulate progression of chronic liver disease. Experimental manipulation of epigenetic signatures such as DNA methylation, histone acetylation / methylation and the activities of proteins that either annotate or interpret these epigenetic marks can have profound effects on the activation and phenotype of HSC, key cells responsible for onset and progression of liver fibrosis. This review presents recent advances in epigenetic alterations, which could provide mechanistic insight into the pathogenesis of chronic liver disease and provide novel clinical applications.
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Affiliation(s)
- Agata Page
- Institute of Cellular Medicine, Faculty of Medical Sciences, 4 Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK
| | - Derek A Mann
- Institute of Cellular Medicine, Faculty of Medical Sciences, 4 Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK
| | - Jelena Mann
- Institute of Cellular Medicine, Faculty of Medical Sciences, 4 Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK
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26
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Tang PMK, Lan HY. MicroRNAs in TGF-β/Smad-mediated Tissue Fibrosis. CURRENT PATHOBIOLOGY REPORTS 2014. [DOI: 10.1007/s40139-014-0060-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Zhou WC, Zhang QB, Qiao L. Pathogenesis of liver cirrhosis. World J Gastroenterol 2014; 20:7312-7324. [PMID: 24966602 PMCID: PMC4064077 DOI: 10.3748/wjg.v20.i23.7312] [Citation(s) in RCA: 380] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 03/16/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis. Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions.
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