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Boateng AO, Patel VB, Bligh SWA. The Hepatoprotective Properties of Gentiopicroside, Sweroside, and Swertiamarin Against Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Biomolecules 2025; 15:726. [PMID: 40427619 PMCID: PMC12109968 DOI: 10.3390/biom15050726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2025] [Revised: 04/28/2025] [Accepted: 04/29/2025] [Indexed: 05/29/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a metabolic disease characterised by the accumulation of fat in the liver. It is estimated that 30-38% of the world's adult population have MASLD, making it the most prevalent global chronic liver disease. Due to a lack of a therapy for MASLD, treatment has been mainly focussed on managing the conditions associated with the disease such as obesity, diabetes mellitus, and hyperlipidaemia. This study aimed to investigate the role played by Gentiana phytochemicals including the following: gentiopicroside, sweroside, and swertiamarin, in promoting hepatocyte protection against the cytotoxic effects of fatty acids. Gentiana species such as lutea, macrophylla, rigescens, and scabra are known to protect and enhance hepatocyte viability via their antioxidant, anti-inflammatory, and bitter components including the following: amarogentin gentianine, iso-orientin, swertiamarin, gentiopicroside, and sweroside. In this study, HepG2 cells pre-treated with phytochemicals gentiopicroside, sweroside, swertiamarin, and silymarin followed by an exposure to arachidonic acid (10, 30, 50 and 80 µM) were assessed for cell viability via MTT, mitochondrial function via seahorse assay, ROS levels via DCF assay, and annexin V-FITC for apoptosis. THLE-2 cells were also assayed for validation. The phytochemicals tested improved ATP production notably gentiopicroside, which improved ATP production by over 60% compared to untreated hepatocytes. Significant hepatocyte protection against lipotoxicity leading to apoptosis was also observed in gentiopicroside in the presence of 30 µM arachidonic acid with apoptosis reduced by over 50%. ROS production was reduced up to 60% by the pre-treatment of HepG2 cells with 20 µM, gentiopicroside, sweroside, swertiamarin, and silymarin, with the highest reduction observed in swertiamarin. It was concluded that phytochemicals gentiopicroside, sweroside, and swertiamarin play key roles in the hepatocyte protection against the cytotoxic effects of fatty acids. This protection is conferred by enhancing mitochondrial function in terms of increasing the maximal respiratory capacity in response to a high influx of fatty acids, promoting ATP production as well as scavenging ROS produced as a result of high fatty acid influx and increased mitochondrial respiration. Highlights: Gentiopicroside may minimise lipotoxicity leading to apoptosis and necrosis in hepatocytes in the presence of arachidonic acid. A pre-treatment of hepatocytes with phytochemicals, namely gentiopicroside, sweroside, and silymarin provides a degree of protection which may be attributed to the enhancement of mitochondrial function. Sweroside, silymarin, and swertiamarin may protect HepG2 and THLE-2 cells by scavenging ROS produced by arachidonic acid and the mitochondrial electron transport chain.
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Affiliation(s)
- Anthony O. Boateng
- School of Science, Faculty of Engineering & Science, University of Greenwich, Central Avenue, Chatham, Kent ME4 4TB, UK
| | - Vinood B. Patel
- School of Life Science, College of Liberal Arts and Science, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK
| | - S. W. Annie Bligh
- S. K. Yee School of Health Sciences, Saint Francis University, Hong Kong, China
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Park YS, Kang SM, Kim YJ, Lee IJ. Exploring the dietary and therapeutic potential of licorice (Glycyrrhiza uralensis Fisch.) sprouts. JOURNAL OF ETHNOPHARMACOLOGY 2024; 328:118101. [PMID: 38527575 DOI: 10.1016/j.jep.2024.118101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 03/11/2024] [Accepted: 03/21/2024] [Indexed: 03/27/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE This research substantiates the traditional use of Glycyrrhiza uralensis Fisch. for liver health, with scientific evidence of the non-toxic and lipid-lowering properties of licorice sprout extracts. The sprouts' rich mineral and amino acid content, along with their strong antioxidant activity, reinforce their value in traditional medicine. These findings bridge ancient herbal practices with modern science, highlighting licorice's potential in contemporary therapeutic applications. AIM OF THE STUDY The study aimed to investigate the dietary and medicinal potential of G. uralensis sprouts by assessing their safety, nutritional content, and antioxidant properties using both plant and animal models. Specifically, the study sought to determine the effects of different sizes of licorice sprouts on lipid metabolism in human liver cancer cells and their overall impact on rat health indicators. MATERIALS AND METHODS The study examined the effects of aqueous and organic extracts from G. uralensis sprouts of varying lengths on the cytotoxicity, lipid metabolism, and antioxidant activity in HepG2 cells, alongside in vivo impacts on Sprague-Dawley rats, using MTT, ICP, and HPLC. It aimed to assess the potential health benefits of licorice sprouts by analyzing their protective effects against oxidative stress and their nutritional content. RESULTS Licorice sprout extracts from G. uralensis demonstrated no cytotoxicity in HepG2 cells, significantly reduced lipid levels, and enhanced antioxidant activities, with the longest sprouts (7 cm) showing higher mineral, sugar, and arginine content as well as increased glycyrrhizin and liquiritigenin. In vivo studies with Sprague-Dawley rats revealed weight gain and improved antioxidant enzyme activities in blood plasma and liver tissues after consuming the extracts, highlighting the sprouts' dietary and therapeutic potential. CONCLUSIONS This study is the first to demonstrate that G. uralensis sprouts, particularly those 7 cm in length, have no cytotoxic effects, reduce lipids, and have high mineral and antioxidant contents, offering promising dietary and therapeutic benefits.
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Affiliation(s)
- Yong-Sung Park
- Department of Applied Biosciences, Kyungpook National University, 80 Daehakro, Buk-gu, Daegu, 41566, South Korea
| | - Sang-Mo Kang
- Department of Applied Biosciences, Kyungpook National University, 80 Daehakro, Buk-gu, Daegu, 41566, South Korea
| | - Yeon-Ji Kim
- Korean Medicine-Application Center, Korea Institute of Oriental Medicine, 70 Cheomdanro, Dong-gu, Daegu, 41062, South Korea
| | - In-Jung Lee
- Department of Applied Biosciences, Kyungpook National University, 80 Daehakro, Buk-gu, Daegu, 41566, South Korea.
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Tyczyńska M, Hunek G, Szczasny M, Brachet A, Januszewski J, Forma A, Portincasa P, Flieger J, Baj J. Supplementation of Micro- and Macronutrients-A Role of Nutritional Status in Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2024; 25:4916. [PMID: 38732128 PMCID: PMC11085010 DOI: 10.3390/ijms25094916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 04/28/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a condition in which the pathological cumulation of fat with coexisting inflammation and damage of hepatic cells leads to progressive dysfunctions of the liver. Except for the commonly well-known major causes of NAFLD such as obesity, dyslipidemia, insulin resistance, or diabetes, an unbalanced diet and imbalanced nutritional status should also be taken into consideration. In this narrative review, we summarized the current knowledge regarding the micro- and macronutrient status of patients suffering from NAFLD considering various diets and supplementation of chosen supplements. We aimed to summarize the knowledge indicating which nutritional impairments may be associated with the onset and progression of NAFLD at the same time evaluating the potential therapy targets that could facilitate the healing process. Except for the above-mentioned objectives, one of the most important aspects of this review was to highlight the possible strategies for taking care of NAFLD patients taking into account the challenges and opportunities associated with the micronutrient status of the patients. The current research indicates that a supplementation of chosen vitamins (e.g., vitamin A, B complex, C, or D) as well as chosen elements such as zinc may alleviate the symptoms of NAFLD. However, there is still a lack of sufficient data regarding healthy ranges of dosages; thus, further research is of high importance in this matter.
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Affiliation(s)
- Magdalena Tyczyńska
- Department of Correct, Clinical and Imaging Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland;
| | - Gabriela Hunek
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (G.H.); (A.B.)
| | - Martyna Szczasny
- Chair and Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (M.S.); (J.J.)
| | - Adam Brachet
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (G.H.); (A.B.)
| | - Jacek Januszewski
- Chair and Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (M.S.); (J.J.)
| | - Alicja Forma
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (G.H.); (A.B.)
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy;
| | - Jolanta Flieger
- Department of Analytical Chemistry, Medical University of Lublin, Chodźki 4A, 20-093 Lublin, Poland;
| | - Jacek Baj
- Chair and Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (M.S.); (J.J.)
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Lai X, Zhou H, Wan Y, Kuang J, Yang Y, Mai L, Chen Y, Liu B. Magnesium isoglycyrrhizinate attenuates nonalcoholic fatty liver disease by strengthening intestinal mucosal barrier. Int Immunopharmacol 2024; 128:111429. [PMID: 38171057 DOI: 10.1016/j.intimp.2023.111429] [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: 07/19/2023] [Revised: 12/11/2023] [Accepted: 12/19/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) has recently risen to the top spot among chronic liver diseases in the world. However, there are no recognized treatments for it. Magnesium isoglycyrrhizate (MgIG) has potential as a NAFLD/NASH therapy. AIMS To investigate the efficacy of MgIG in improving NAFLD/NASH and the possible pathways and mechanisms. METHODS C57bl/6 mice were fed a high-fat diet (HFD) and 1 % dextran sulfate sodium (DSS) for 12 weeks to establish the NAFLD/NASH model. MgIG was administered by gavage during the last 7 weeks. First, the therapeutic effects of MgIG on hepatic steatosis and fibrosis, liver injury, and inflammation in the NAFLD/NASH mice were evaluated. Second, liver oxidative stress and hepatocyte apoptosis were detected. Finally, the effect of MgIG on intestinal permeability and short-chain fatty acid (SCFA) levels in mice's intestinal contents were examined. RESULTS MgIG administration attenuated HFD-induced hepatic steatosis and fibrosis, improved serum biochemical and NAFLD/NASH mice, reduced liver oxidative stress and hepatocyte apoptosis, improved intestinal permeability, and increased fecal SCFA levels in NAFLD/NASH mice. CONCLUSION MgIG protects against HFD-induced NAFLD/NASH through multiple pathways as well as mechanisms and holds promise as a potentially effective treatment for NAFLD/NASH.
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Affiliation(s)
- Xueying Lai
- Department of Gastroenterology, Panyu Central Hospital, Guangzhou, 511400, China
| | - Hong Zhou
- National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yu Wan
- Department of Gastroenterology, Panyu Central Hospital, Guangzhou, 511400, China
| | - Jiesi Kuang
- Department of Gastroenterology, Panyu Central Hospital, Guangzhou, 511400, China
| | - Yuhui Yang
- Department of Gastroenterology, Panyu Central Hospital, Guangzhou, 511400, China
| | - Limei Mai
- Department of Gastroenterology, Panyu Central Hospital, Guangzhou, 511400, China
| | - Yumei Chen
- Department of Infectious Diseases, Panyu Central Hospital, Guangzhou, 511400, China
| | - Bin Liu
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
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Gao W, Zhao Y, Guo L, Wang Y, Gong H, Zhang B, Yan M. Comparative effectiveness of glycyrrhizic acid preparations aimed at improving liver function of patients with chronic hepatitis B: A network meta-analysis of 53 randomized controlled trials. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 116:154883. [PMID: 37224775 DOI: 10.1016/j.phymed.2023.154883] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 04/27/2023] [Accepted: 05/15/2023] [Indexed: 05/26/2023]
Abstract
BACKGROUND AND OBJECTIVES Entecavir (ETV) has disadvantages, such as poor improvement in liver function, during the treatment of Chronic hepatitis B (CHB). Thus ETV is often used in clinical therapy with glycyrrhizic acid (GA) preparations. However, due to the lack of reliable and direct clinical studies, it remains controversial whether glycyrrhizic acid preparations have the best efficacy in CHB. Therefore, we aimed to compare and rank the different GA preparations in the treatment of CHB using network meta-analysis (NMA). METHODS We systematically searched MEDLINE, EMBASE, Cochrane Library, Web of Science, China national knowledge internet (CNKI), Wanfang, VIP, and SinoMed databases as of August 4, 2022. Literature was screened according to predefined inclusion and exclusion criteria to extract meaningful information. A Bayesian approach was used for random effects model network meta-analysis, and Stata 17 software was used for data analysis. RESULTS From 1074 papers, we included 53 relevant randomized clinical trials (RCTs). For the primary outcome, we used the overall effective rate in assessing the effectiveness of treatment for CHB (31 RCTs including 3007 patients): CGI, CGT, DGC and MgIGI significantly reduced the incidence of overall response compared to controls (RRs range from 1.16 to 1.24); SUCRA results showed that MgIGI was the best (SUCRA 0.923). In terms of secondary outcomes, we assessed the effect of treatment for CHB according to the level of reduction in ALT and AST: for ALT (37 RCTs including 3752 patients), CGI, CGT, DGC, DGI and MgIGI significantly improved liver function index compared to controls (MD range from 14.65 to 20.41); SUCRA results showed that CGI was the best (SUCRA 0.87); for AST, GI, CGT, DGC, DGI and MgIGI significantly improved liver function index compared to the control group (MD range from 17.46 to 24.42); SUCRA results showed that MgIGI was the best (SUCRA 0.871). CONCLUSION In this study, we verified that the combination of GA and Entecavir is more effective than entecavir monotherapy in the treatment of hepatitis B. MgIGI and CGI showed clinically significant effects on liver function recovery compared with other GA preparations. MgIGI appeared to be the best choice among all GA preparations for the treatment of CHB. Our study provides some references for the treatment of CHB.
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Affiliation(s)
- Wen Gao
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China; Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Yichang Zhao
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Lin Guo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Yikun Wang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Hui Gong
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Bikui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Miao Yan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China.
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Vijayan N, Perumal MK. A critical review on anti-fibrotic phytochemicals targeting activated hepatic stellate cells. J Food Biochem 2022; 46:e14438. [PMID: 36209494 DOI: 10.1111/jfbc.14438] [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: 07/13/2022] [Revised: 08/29/2022] [Accepted: 09/16/2022] [Indexed: 01/18/2023]
Abstract
Liver fibrosis is a major health concern occurring worldwide. It arises due to prolonged wound healing response of various insults like viral, autoimmune, cholestatic, drug-induced, and metabolic diseases. Currently, there is no clinically approved drug for liver fibrosis treatment. Hepatic stellate cells are the principal liver cells that are activated during liver fibrosis, and targeting these activated cells is an ideal therapeutic strategy. Numerous phytochemicals have been demonstrated in vitro and in vivo treating experimental liver fibrosis; however, none of them have been clinically approved for therapeutic use. This review mainly focuses on such hepatoprotective phytochemicals reported inhibiting major signaling pathways that are dysregulated in activated hepatic stellate cells. PRACTICAL APPLICATIONS: Liver fibrosis is a global health concern and there is no FDA approved drug to treat liver fibrosis. Although notable pharmacological agents like pentoxifylline, gliotoxin, imatinibmesylate, Gleevec, and so on are reported to exhibit anti-fibrotic effect, the major concern is their side effect. Hence, phytochemicals are promising candidates that could be employed against liver fibrosis. In this review, the anti-fibrotic potential of phytochemicals targeting activated HSCs are summarized. Understanding these phytochemicals will further help in the development of agents that are more effective against liver fibrosis.
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Affiliation(s)
- Nivya Vijayan
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Madan Kumar Perumal
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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Cao X, Du X, Jiao H, An Q, Chen R, Fang P, Wang J, Yu B. Carbohydrate-based drugs launched during 2000 -2021. Acta Pharm Sin B 2022; 12:3783-3821. [PMID: 36213536 PMCID: PMC9532563 DOI: 10.1016/j.apsb.2022.05.020] [Citation(s) in RCA: 111] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/18/2022] [Accepted: 05/12/2022] [Indexed: 01/09/2023] Open
Abstract
Carbohydrates are fundamental molecules involved in nearly all aspects of lives, such as being involved in formating the genetic and energy materials, supporting the structure of organisms, constituting invasion and host defense systems, and forming antibiotics secondary metabolites. The naturally occurring carbohydrates and their derivatives have been extensively studied as therapeutic agents for the treatment of various diseases. During 2000 to 2021, totally 54 carbohydrate-based drugs which contain carbohydrate moities as the major structural units have been approved as drugs or diagnostic agents. Here we provide a comprehensive review on the chemical structures, activities, and clinical trial results of these carbohydrate-based drugs, which are categorized by their indications into antiviral drugs, antibacterial/antiparasitic drugs, anticancer drugs, antidiabetics drugs, cardiovascular drugs, nervous system drugs, and other agents.
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Affiliation(s)
- Xin Cao
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Xiaojing Du
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Heng Jiao
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Quanlin An
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Ruoxue Chen
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Pengfei Fang
- State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
| | - Jing Wang
- State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
| | - Biao Yu
- State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
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Gong JY, Ren H, Peng SY, Xing K, Fan L, Liu MZ, Luo ZY, Luo JQ. Comparative effectiveness of glycyrrhizic acid preparations aimed at preventing and treating anti-tuberculosis drug-induced liver injury: A network meta-analysis of 97 randomized controlled trials. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 98:153942. [PMID: 35093672 DOI: 10.1016/j.phymed.2022.153942] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 12/24/2021] [Accepted: 01/12/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND AND OBJECTIVES Clinical guidelines and expert consensus do not yet recommend glycyrrhizic acid (GA) preparations, such as compound glycyrrhizin, diammonium glycyrrhizin, magnesium isoglycyrrhizinate (MGIG), et al., for the prevention of anti-tuberculosis(anti-TB) drug-induced liver injury (DILI) due to insufficient evidence. Although these GA preparations are recommended for the treatment of anti-TB DILI, which one performs best is unclear. Previous conventional meta-analyses did not summarize the results of simultaneous comparisons of different glycyrrhizinate preparations. Therefore, we aimed to compare and rank different GA preparations on preventing and treating the anti-TB DILI by network meta-analysis (NMA). METHODS A systematic search on PubMed, Web of Science, Embase, the Cochrane Library, China National Knowledge Infrastructure, SinoMed, Chongqing VIP and, the Wanfang Database was performed up to December 19, 2020. The literature was screened according to predefined inclusion and exclusion criteria to extract important information. The outcomes were the incidence of liver injury (prevention section) and treatment response rate (treatment section). The NMA was conducted with a random-effects model under the Bayesian framework to calculate risk ratios (RRs) with 95% credible intervals (95% CrIs) using R software (version 3.6.1). RESULTS From 1,411 publications, we included 97 relevant randomized clinical trials (RCTs) (10,923 participants). In terms of preventing anti-TB DILI (33 RCTs, comprising 5,762 patients), CGC, DGC, DGEC, and DGI, but not CGI, significantly reduced the incidence of liver injury than control group (RRs ranged from 0.26 to 0.58); CGC and DGEC were superior to DGC (RRs = 0.50 and 0.58, respectively). In terms of treating anti-TB DILI (64 RCTs, comprising 5,161 patients), MGIG was most effective among all regimens (RRs ranged from 1.15 to 1.72) while DGC ranked last (RRs ranged from 0.58 to 0.83). CONCLUSIONS All GA preparations except for CGI were effective in preventing the incidence of anti-TB DILI and CGC was superior to DGC. MGIG seems to be the best choice among all GA preparations for the treatment of anti-TB DILI. Future clinical practice guidelines should factor in these novel findings to improve patient outcomes; however, further high-quality trials are needed to validate these results.
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Affiliation(s)
- Jin-Yu Gong
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Huan Ren
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
| | - Si-Yin Peng
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Kai Xing
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Li Fan
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Mou-Ze Liu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Zhi-Ying Luo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Jian-Quan Luo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China.
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Dai W, Wang K, Zhen X, Huang Z, Liu L. Magnesium isoglycyrrhizinate attenuates acute alcohol-induced hepatic steatosis in a zebrafish model by regulating lipid metabolism and ER stress. Nutr Metab (Lond) 2022; 19:23. [PMID: 35331265 PMCID: PMC8944020 DOI: 10.1186/s12986-022-00655-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 03/01/2022] [Indexed: 12/15/2022] Open
Abstract
Background Alcoholism is a well-known risk factor for liver injury and is one of the major causes of hepatic steatosis worldwide. Although many drugs have been reported to have protective effects against acute alcohol-induced hepatotoxicity, there is limited available treatment for alcoholic liver disease (ALD), indicating an urgent need for effective therapeutic options. Herein, we first reported the protective effects of magnesium isoglycyrrhizinate (MgIG) on acute alcohol-induced hepatic steatosis and its related mechanisms in a zebrafish model. Methods Alcohol was administered directly to embryo medium at 5 days post-fertilization (dpf) for up to 32 h. MgIG was given to the larvae 2 h before the administration of alcohol and then cotreated with alcohol starting at 5 dpf. Oil red O staining was used to determine the incidence of steatosis, and pathological features of the liver were assessed by hematoxylin–eosin staining. Biological indexes, total cholesterol (TC) and triacylglycerol (TG) were detected in the livers of zebrafish larvae. Morphological changes in the livers of zebrafish larvae were observed using liver-specific EGFP transgenic zebrafish (Tg(lfabp10a:eGFP)). The expression levels of critical molecules related to endoplasmic reticulum (ER) stress and lipid metabolism were detected by qRT–PCR, whole-mount in situ hybridization and western blotting. Results Alcohol-treated larvae developed hepatomegaly and steatosis after 32 h of exposure. We found that MgIG improved hepatomegaly and reduced the incidence of steatosis in a dose-dependent manner by oil red O staining and diminished deposits of alcohol-induced fat droplets by histologic analysis. Moreover, MgIG significantly decreased the levels of TC and TG in the livers of zebrafish larvae. Furthermore, the expression levels of critical genes involved in ER stress (atf6, irela, bip, chop) and the key enzymes regulating lipid metabolism (acc1, fasn, hmgcs1 and hmgcra) were significantly higher in the alcohol-treated group than in the control group. However, in the MgIG plus alcohol-treated group, the expression of these genes was markedly decreased compared with that in the alcohol-treated group. Whole-mount in situ hybridization and western blotting also showed that MgIG had an effect on the expression levels of critical genes and proteins involved in lipid metabolism and ER stress. Our results revealed that MgIG could markedly regulate these genes and protect the liver from ER stress and lipid metabolism disorders. Conclusions Our study is the first to demonstrate that MgIG could protect the liver from acute alcohol stimulation by ameliorating the disorder of lipid metabolism and regulating ER stress in zebrafish larvae. Supplementary Information The online version contains supplementary material available at 10.1186/s12986-022-00655-7.
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Affiliation(s)
- Wencong Dai
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Kunyuan Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Xinchun Zhen
- Department of Infectious Diseases, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China
| | - Zhibin Huang
- Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China
| | - Li Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
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Benić MS, Nežić L, Vujić-Aleksić V, Mititelu-Tartau L. Novel Therapies for the Treatment of Drug-Induced Liver Injury: A Systematic Review. Front Pharmacol 2022; 12:785790. [PMID: 35185538 PMCID: PMC8847672 DOI: 10.3389/fphar.2021.785790] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 12/30/2021] [Indexed: 12/15/2022] Open
Abstract
Many drugs with different mechanisms of action and indications available on the market today are capable of inducing hepatotoxicity. Drug-induced liver injury (DILI) has been a treatment challenge nowadays as it was in the past. We searched Medline (via PubMed), CENTRAL, Science Citation Index Expanded, clinical trials registries and databases of DILI and hepatotoxicity up to 2021 for novel therapies for the management of adult patients with DILI based on the combination of three main search terms: 1) treatment, 2) novel, and 3) drug-induced liver injury. The mechanism of action of novel therapies, the potential of their benefit in clinical settings, and adverse drug reactions related to novel therapies were extracted. Cochrane Risk of bias tool and Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment approach was involved in the assessment of the certainty of the evidence for primary outcomes of included studies. One thousand three hundred seventy-two articles were identified. Twenty-eight articles were included in the final analysis. Eight randomized controlled trials (RCTs) were detected and for six the available data were sufficient for analysis. In abstract form only we found six studies which were also anaylzed. Investigated agents included: bicyclol, calmangafodipir, cytisin amidophospate, fomepizole, livina-polyherbal preparation, magnesium isoglycyrrhizinate (MgIG), picroliv, plasma exchange, radix Paeoniae Rubra, and S-adenosylmethionine. The primary outcomes of included trials mainly included laboratory markers improvement. Based on the moderate-certainty evidence, more patients treated with MgIG experienced alanine aminotransferase (ALT) normalization compared to placebo. Low-certainty evidence suggests that bicyclol treatment leads to a reduction of ALT levels compared to phosphatidylcholine. For the remaining eight interventions, the certainty of the evidence for primary outcomes was assessed as very low and we are very uncertain in any estimate of effect. More effort should be involved to investigate the novel treatment of DILI. Well-designed RCTs with appropriate sample sizes, comparable groups and precise, not only surrogate outcomes are urgently welcome.
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Affiliation(s)
- Mirjana Stanić Benić
- Department of Clinical Pharmacology, Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Lana Nežić
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Banja Luka, Banja Luka, Bosnia and Herzegovina
| | - Vesna Vujić-Aleksić
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Banja Luka, Banja Luka, Bosnia and Herzegovina
- The Republic of Srpska Agency for Certification, Accreditation and Quality Improvement in Health Care, Banja Luka, Bosnia and Herzegovina
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11
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Arora M, Kutinová Canová N, Farghali H. mTOR as an eligible molecular target for possible pharmacological treatment of nonalcoholic steatohepatitis. Eur J Pharmacol 2022; 921:174857. [PMID: 35219732 DOI: 10.1016/j.ejphar.2022.174857] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 02/07/2022] [Accepted: 02/22/2022] [Indexed: 12/14/2022]
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Chen X, Wang X, Yang L, Xu H, Wu Y, Wu J, Chen L, Xu C. Magnesium isoglycyrrhizinate prevents cadmium-induced activation of JNK and apoptotic hepatocyte death by reversing ROS-inactivated PP2A. J Pharm Pharmacol 2021; 73:1663-1674. [PMID: 34468764 DOI: 10.1093/jpp/rgab125] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 08/05/2021] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Cadmium (Cd) induces reactive oxygen species (ROS)-mediated hepatocyte apoptosis and consequential liver disorders. This study aimed to investigate the effect of magnesium isoglycyrrhizinate (MgIG) on Cd-induced hepatotoxicity. METHODS L02 and AML-12 cells were used to study MgIG hepatoprotective effects. Cd-evoked apoptosis, ROS and protein phosphatase 2A (PP2A)/c-Jun N-terminal kinase (JNK) cascade disruption were analysed by cell viability assay, 6-diamidino-2-phenylindole (DAPI) and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, ROS imaging and Western blotting. Pharmacological and genetic approaches were used to explore the mechanisms. KEY FINDINGS We show that MgIG attenuated Cd-evoked hepatocyte apoptosis by blocking JNK pathway. Pre-treatment with SP600125 or ectopic expression of dominant-negative c-Jun enhanced MgIG's anti-apoptotic effects. Further investigation found that MgIG rescued Cd-inactivated PP2A. Inhibition of PP2A activity by okadaic acid attenuated the MgIG's inhibition of the Cd-stimulated JNK pathway and apoptosis; in contrast, overexpression of PP2A strengthened the MgIG effects. In addition, MgIG blocked Cd-induced ROS generation. Eliminating ROS by N-acetyl-l-cysteine abrogated Cd-induced PP2A-JNK pathway disruption and concurrently reinforced MgIG-conferred protective effects, which could be further slightly strengthened by PP2A overexpression. CONCLUSIONS Our findings indicate that MgIG is a promising hepatoprotective agent for the prevention of Cd-induced hepatic injury by mitigating ROS-inactivated PP2A, thus preventing JNK activation and hepatocyte apoptosis.
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Affiliation(s)
- Xiaoling Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, P. R. China.,School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China
| | - Xiaoxue Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, P. R. China.,School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China
| | - Liu Yang
- School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China
| | - Hongjiang Xu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, P. R. China
| | - Yiqun Wu
- Institute for Pharmacology & Toxicology, Chia Tai Tianqing Pharmaceutical Group Co., LTD, Nanjing, P. R. China
| | - Jialin Wu
- Institute for Pharmacology & Toxicology, Chia Tai Tianqing Pharmaceutical Group Co., LTD, Nanjing, P. R. China
| | - Long Chen
- School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China
| | - Chong Xu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, P. R. China.,School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China.,Institute for Pharmacology & Toxicology, Chia Tai Tianqing Pharmaceutical Group Co., LTD, Nanjing, P. R. China
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13
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Lu L, Hao K, Hong Y, Liu J, Zhu J, Jiang W, Zhu Z, Wang G, Peng Y. Magnesium Isoglycyrrhizinate Reduces Hepatic Lipotoxicity through Regulating Metabolic Abnormalities. Int J Mol Sci 2021; 22:ijms22115884. [PMID: 34070938 PMCID: PMC8198484 DOI: 10.3390/ijms22115884] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/27/2021] [Accepted: 05/27/2021] [Indexed: 01/22/2023] Open
Abstract
The excessive accumulation of lipids in hepatocytes induces a type of cytotoxicity called hepatic lipotoxicity, which is a fundamental contributor to liver metabolic diseases (such as NAFLD). Magnesium isoglycyrrhizinate (MGIG), a magnesium salt of the stereoisomer of natural glycyrrhizic acid, is widely used as a safe and effective liver protectant. However, the mechanism by which MGIG protects against NAFLD remains unknown. Based on the significant correlation between NAFLD and the reprogramming of liver metabolism, we aimed to explore the beneficial effects of MGIG from a metabolic viewpoint in this paper. We treated HepaRG cells with palmitic acid (PA, a saturated fatty acid of C16:0) to induce lipotoxicity and then evaluated the antagonistic effect of MGIG on lipotoxicity by investigating the cell survival rate, DNA proliferation rate, organelle damage, and endoplasmic reticulum stress (ERS). Metabolomics, lipidomics, and isotope tracing were used to investigate changes in the metabolite profile, lipid profile, and lipid flux in HepaRG cells under different intervention conditions. The results showed that MGIG can indeed protect hepatocytes against PA-induced cytotoxicity and ERS. In response to the metabolic abnormality of lipotoxicity, MGIG curtailed the metabolic activation of lipids induced by PA. The content of total lipids and saturated lipids containing C16:0 chains increased significantly after PA stimulation and then decreased significantly or even returned to normal levels after MGIG intervention. Lipidomic data show that glycerides and glycerophospholipids were the two most affected lipids. For excessive lipid accumulation in hepatocytes, MGIG can downregulate the expression of the metabolic enzymes (GPATs and DAGTs) involved in triglyceride biosynthesis. In conclusion, MGIG has a positive regulatory effect on the metabolic disorders that occur in hepatocytes under lipotoxicity, and the main mechanisms of this effect are in lipid metabolism, including reducing the total lipid content, reducing lipid saturation, inhibiting glyceride and glycerophospholipid metabolism, and downregulating the expression of metabolic enzymes in lipid synthesis.
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Affiliation(s)
- Li Lu
- Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China; (L.L.); (K.H.); (Y.H.); (J.L.); (J.Z.); (W.J.)
| | - Kun Hao
- Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China; (L.L.); (K.H.); (Y.H.); (J.L.); (J.Z.); (W.J.)
| | - Yu Hong
- Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China; (L.L.); (K.H.); (Y.H.); (J.L.); (J.Z.); (W.J.)
| | - Jie Liu
- Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China; (L.L.); (K.H.); (Y.H.); (J.L.); (J.Z.); (W.J.)
| | - Jinwei Zhu
- Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China; (L.L.); (K.H.); (Y.H.); (J.L.); (J.Z.); (W.J.)
| | - Wenjiao Jiang
- Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China; (L.L.); (K.H.); (Y.H.); (J.L.); (J.Z.); (W.J.)
| | - Zheying Zhu
- Division of Molecular Therapeutics & Formulation, School of Pharmacy, University Park Campus, The University of Nottingham, Nottingham NG7 2RD, UK;
| | - Guangji Wang
- Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China; (L.L.); (K.H.); (Y.H.); (J.L.); (J.Z.); (W.J.)
- Correspondence: (G.W.); (Y.P.); Tel.: +86-25-83271128 (G.W.); +86-25-83271176 (Y.P.); Fax: +86-25-83271060 (G.W. & Y.P.)
| | - Ying Peng
- Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China; (L.L.); (K.H.); (Y.H.); (J.L.); (J.Z.); (W.J.)
- Correspondence: (G.W.); (Y.P.); Tel.: +86-25-83271128 (G.W.); +86-25-83271176 (Y.P.); Fax: +86-25-83271060 (G.W. & Y.P.)
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14
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Bagherieh M, Kheirollahi A, Zamani-Garmsiri F, Emamgholipour S, Meshkani R. Folic acid ameliorates palmitate-induced inflammation through decreasing homocysteine and inhibiting NF-κB pathway in HepG2 cells. Arch Physiol Biochem 2021:1-8. [PMID: 33596128 DOI: 10.1080/13813455.2021.1878539] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Prevention of inflammation is one of the possible remedy procedure for steatohepatitis during NAFLD. In this study, we researched the folic acid (FA) potency to attenuate the inflammation of palmitate-treated HepG2 cells and the related signalling pathways. METHODS The molecular mechanisms related to FA anti-inflammatory effect in palmitate and Hcy-treated HepG2 cell line were assessed. RESULTS The results indicated that while palmitate enhances the expression and secretion of TNF-α, IL-6, and IL-1β, and also intracellular ROS level, FA at concentrations of 25, 50, and 75 µg/mL significantly reversed these effects in HepG2 cells. In addition, FA could ameliorate inflammation and decrease ROS production induced by Hcy. Furthermore, FA pre-treatment suppress palmitate -induced (NF-κB) p65 level in palmitate or Hcy stimulated cells. CONCLUSIONS Overall, these results suggest that FA reduces inflammation in HepG2 cells through decreasing ROS and Hcy concentration level resulting in inhibiting the NF-κB pathway.
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Affiliation(s)
- Molood Bagherieh
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Asma Kheirollahi
- Department of Comparative Biosciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Fahimeh Zamani-Garmsiri
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Solaleh Emamgholipour
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Meshkani
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Gao Y, Tian Y, Zhang X, Zhang X, Duan Z, Ren F, Chen Y. Magnesium isoglycyrrhizinate ameliorates concanavalin A-induced liver injury via the p38 and JNK MAPK pathway. Immunopharmacol Immunotoxicol 2020; 42:445-455. [PMID: 32787473 DOI: 10.1080/08923973.2020.1808984] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 08/06/2020] [Indexed: 12/11/2022]
Abstract
CONTEXT Acute liver failure is a serious disease caused by a variety of factors, and immunological injury is an important pathological process. Comprehensive liver treatment efficacy is poor, and the mortality rate is high. Magnesium isoglycyrrhizinate (MgIG) is a new glycyrrhizin drug extracted from the traditional Chinese medicine licorice. The mechanism by which MgIG regulates ConcanavalinA (ConA)-induced immunological liver injury in mice is not completely clear. MATERIALS AND METHODS Immunological liver injury was induced in mice by ConA injection, and the inflammatory macrophages model was induced by lipopolysaccharide (LPS). MgIG was administered 30 min prior to ConA and LPS treatment. The mice in the different groups were sacrificed 12 h after treatment, and macrophages were measured at 30 min, 1 h, and 2 h after induction. Macrophages, liver, and blood samples were then collected for analysis. RESULTS After drug administration, the MgIG group showed a marked decrease in serum transaminase levels, reduced apoptosis and hepatic inflammatory responses compared to the ConA group. Furthermore, there was a significant reduction in inflammatory cytokine levels in the serum and liver tissue. In vitro, the expression of inflammatory cytokines was distinctly reduced after MgIG administration. In addition, MgIG pretreatment reduced the expression of inflammatory cytokines and regulated the phosphorylation of p38 and JNK proteins in the MAPK pathway. CONCLUSION These findings demonstrated that MgIG protects against ConA-induced immunological liver injury by markedly alleviating liver inflammation, and this provides guidance for the clinical amelioration of liver inflammation induced by immunological factors.
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Affiliation(s)
- Yudi Gao
- Difficult and Complicated Liver Diseases and Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Yuan Tian
- Difficult and Complicated Liver Diseases and Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xiangying Zhang
- Difficult and Complicated Liver Diseases and Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xiaohui Zhang
- Difficult and Complicated Liver Diseases and Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Zhongping Duan
- Difficult and Complicated Liver Diseases and Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Feng Ren
- Difficult and Complicated Liver Diseases and Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yu Chen
- Difficult and Complicated Liver Diseases and Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
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16
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Jiang W, Xu S, Guo H, Lu L, Liu J, Wang G, Hao K. Magnesium isoglycyrrhizinate prevents the nonalcoholic hepatic steatosis via regulating energy homeostasis. J Cell Mol Med 2020; 24:7201-7213. [PMID: 32410294 PMCID: PMC7339216 DOI: 10.1111/jcmm.15230] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 01/22/2020] [Accepted: 03/06/2020] [Indexed: 12/21/2022] Open
Abstract
Non-alcoholic fatty liver disease is a public health problem worldwide associated with high morbidity and hepatic steatosis, but no effective therapeutic interventions. Magnesium isoglycyrrhizinate (MGIG), a derivative of an active component of Glycyrrhiza glabra, is widely used for the treatment of inflammatory liver diseases due to its potent anti-inflammatory and hepatoprotective activities. Hence, this study aimed to study the effects of MGIG on hepatic steatosis in mice fed a high-fat diet (HFD). Oil Red O staining and transmission electron microscopy revealed a decrease in lipid accumulation in the liver after MGIG treatment along with improved mitochondrial ultramicrostructures. Metabonomic analysis demonstrated that MGIG intervention increased glutamate utilization in mitochondria by promoting the uptake of glutamate into the tricarboxylic acid (TCA) cycle. The NAD+ /NADH ratio and the expression of other lipid-metabolism-related genes were increased in MGIG-treated livers. Transcriptome sequencing showed that the expression of TLR4, an isoform of the innate immunity Toll-like receptors (TLRs), was significantly decreased after MGIG treatment, suggesting a link between the anti-inflammatory effects of MGIG and its suppression of lipidation. Our results reveal the potent effects of MGIG on lipid metabolism and suggest that hepatic TLR4 might be a crucial therapeutic target to regulate energy homeostasis in hepatic steatosis.
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Affiliation(s)
- Wenjiao Jiang
- Key Laboratory of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjingChina
| | - Shiyu Xu
- Key Laboratory of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjingChina
| | - Huijie Guo
- Key Laboratory of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjingChina
| | - Li Lu
- Key Laboratory of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjingChina
| | - Jie Liu
- Key Laboratory of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjingChina
| | - Guangji Wang
- Key Laboratory of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjingChina
| | - Kun Hao
- Key Laboratory of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjingChina
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Zhang Q, Mohammed EAH, Wang Y, Bai Z, Zhao Q, He D, Wang Z. Synthesis and anti-hepaticfibrosis of glycyrrhetinic acid derivatives with inhibiting COX-2. Bioorg Chem 2020; 99:103804. [PMID: 32272365 DOI: 10.1016/j.bioorg.2020.103804] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 02/24/2020] [Accepted: 03/27/2020] [Indexed: 02/08/2023]
Abstract
Many tests have shown cyclooxygenase-2 (COX-2) was closely related to the activation of hepatic stellate cells (HSCs), which further promoting the onset and development of hepatic fibrosis. According to these research findings, a series of glycyrrhetinic acid derivatives were designed and synthesized. Meanwhile, their anti-hepaticfibrotic activities were evaluated in vitro and in vivo. Firstly, in the tests of the cell models, all the compounds displayed anti-proliferative effect on the HSC-T6 activated by (transforming growth factor beta) TGF-β1 (10 ng/mL). Among them, compounds 2 and 16 exhibited a stronger activity than the others, and their IC50 values were 17.6 µM and 30.3 µM, respectively; both of them were low toxicity to normal HSC-T6 cells and WI38 cells, and they inhibited the activated HSC-T6 cells proliferation by promoting apoptosis and resting them at the G0/G1 phase. Secondly, compounds 2 and 16 displayed strong inhibitory effect on activation of HSCs; they not only inhibited the expression of α-SMA and Col1 in the activated HSC-T6 cells, but also decreased the levels of COX-2, TGF-β1 and (reactive oxygen species) ROS in a concentration-dependent manner; they down-regulated the levels of three biomarkers in the process of test, but this decrease did not change linearly with the action time of compound. Thirdly, for the rats which induced with (carbontetrachloride) CCl4, the symptoms of liver fibrosis in rats were significantly alleviated after successive administration the tested compound for 14d; the α-SMA level in liver tissue decreased in a concentration dependent manner; and the liver cell necrosis and the fat collagen fiber decreased significantly compared with the positive control group; furthermore, inflammatory infiltration was significantly lower than that of the control. This suggests the compounds possibly are candidates for hepatic fibrosis with promising application in clinic.
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Affiliation(s)
- Qiuping Zhang
- Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, Lanzhou 730000, China
| | | | - Yanni Wang
- Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, Lanzhou 730000, China
| | - Zhongjie Bai
- Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, Lanzhou 730000, China
| | - Quanyi Zhao
- Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, Lanzhou 730000, China.
| | - Dian He
- Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, Lanzhou 730000, China
| | - Zhen Wang
- Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, Lanzhou 730000, China
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18
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Ameliorative effect of Magnesium Isoglycyrrhizinate on hepatic encephalopathy by Epirubicin. Int Immunopharmacol 2019; 75:105774. [PMID: 31351363 DOI: 10.1016/j.intimp.2019.105774] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 06/27/2019] [Accepted: 07/18/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND The purpose of the present study was to evaluate the protective effect of Magnesium Isoglycyrrhizinate (MI) on Epirubicin (EPI)-induced hepatic encephalopathy (HE) and explore its underlying mechanism. METHODS Mice were divided randomly into groups for treatments as follows: control group, EPI group (Model group), EPI + MI (25, 50 mg/kg) group. Morris water maze test were conducted to evaluate the spatial learning and memory ability. The serum and hippocampus levels of oxidative stress or inflammation were uncovered with the detection of superoxide dismutase (SOD), malondialdehyde (MDA), and pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). RESULTS As a result, treatment with MI effectively ameliorated the EPI-induced decline in the ability of spatial learning and memory. MI also significantly relieved the severity of oxidative stress or inflammation in serum and hippocampus, which was accompanied with regulating liver functional parameters. Western blot data demonstrated that administration of MI could regulate the redox-related expressions of Txnip, Trx, Nrf2, HO-1, p-IκB-α, p-NF-κB, Caspase-3, Caspase-9, Bax and Bcl-2 in EPI-stimulated hepatic encephalopathy (HE). And the potency of MI treatments on Nrf2, NF-κB expression was also confirmed with immunohistochemical analysis. CONCLUSIONS Taken together, the protective effect of Magnesium Isoglycyrrhizinate on EPI-induced hepatic encephalopathy might be mediated via the Txnip/Nrf2/NF-κB signaling pathway.
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Cao Y, Shi H, Sun Z, Wu J, Xia Y, Wang Y, Wu Y, Li X, Chen W, Wang A, Lu Y. Protective Effects of Magnesium Glycyrrhizinate on Methotrexate-Induced Hepatotoxicity and Intestinal Toxicity May Be by Reducing COX-2. Front Pharmacol 2019; 10:119. [PMID: 30971913 PMCID: PMC6444054 DOI: 10.3389/fphar.2019.00119] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 01/31/2019] [Indexed: 12/18/2022] Open
Abstract
Magnesium isoglycyrrhizinate (MgIG), which has been widely employed to treat chronic hepatitis, is synthesized from 18-β glycyrrhizic acid, a main component of traditional Chinese medicine Glycyrrhiza uralensis Fisch. Although the protective effects of MgIG on methotrexate (MTX)-induced liver toxicity have been well-documented, the underlying mechanism remains elusive. MTX was initially used to treat pediatric acute leukemia, and has been widely applied to psoriasis therapy. However, its clinical applications are limited due to hepatotoxicity and intestinal toxicity. Herein, prophylactic administration of MgIG (9 and 18 mg/kg/day) significantly reduced the levels of aspartate aminotransferase and alanine aminotransferase in the serum of rats receiving intravenous injection of MTX (20 mg/kg body weight). MgIG also attenuated MTX-induced hepatic fibrosis. Moreover, it better protected against MTX-induced hepatocyte apoptosis and decreased the serum level of malondialdehyde than reduced glutathione (80 mg/kg/day) did. Interestingly, MTX-induced cyclooxygenase-2 (COX-2) expression, intestinal permeability and inflammation were attenuated after MgIG administration. In addition, MgIG (9 and 18 mg/kg) reduced MTX-induced colocalization of zonula occludens-1 (ZO-1) and connexin 43 (Cx43) in intestinal villi. In conclusion, MgIG exerted beneficial effects on MTX-induced hepatotoxicity and intestinal damage, as a potentially eligible drug for alleviating the hepatic and intestinal side effects of MTX during chemotherapy.
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Affiliation(s)
- Yuzhu Cao
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Hang Shi
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhiguang Sun
- Department of The First College, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiawei Wu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yawen Xia
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yufei Wang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuanyuan Wu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiaoman Li
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenxing Chen
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, China
| | - Aiyun Wang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yin Lu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, China
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20
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Xie C, Li X, Zhu J, Wu J, Geng S, Zhong C. Magnesium isoglycyrrhizinate suppresses LPS-induced inflammation and oxidative stress through inhibiting NF-κB and MAPK pathways in RAW264.7 cells. Bioorg Med Chem 2018; 27:516-524. [PMID: 30617018 DOI: 10.1016/j.bmc.2018.12.033] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 12/13/2018] [Accepted: 12/27/2018] [Indexed: 02/07/2023]
Abstract
Magnesium Isoglycyrrhizinate (MgIG), a novel molecular compound extracted from licorice root, has exhibited greater anti-inflammatory activity and hepatic protection than glycyrrhizin and β-glycyrrhizic acid. In this study, we investigated the anti-inflammatory effect and the potential mechanism of MgIG on Lipopolysaccharide (LPS)-treated RAW264.7 cells. MgIG down-regulated LPS-induced pro-inflammatory mediators and enzymes in LPS-treated RAW264.7 cells, including TNF-α, IL-6, IL-1β, IL-8, NO and iNOS. The generation of reactive oxygen species (ROS) in LPS-treated RAW264.7 cells was also reduced. MgIG attenuated NF-κB translocation by inhibiting IKK phosphorylation and IκB-α degradation. Simultaneously, MgIG also inhibited LPS-induced activation of MAPKs, including p38, JNK and ERK1/2. Taken together, these results suggest that MgIG suppresses inflammation by blocking NF-κB and MAPK signaling pathways, and down-regulates ROS generation and inflammatory mediators.
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Affiliation(s)
- Chunfeng Xie
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Xiaoting Li
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Jianyun Zhu
- Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215008, China
| | - Jieshu Wu
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Shanshan Geng
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Caiyun Zhong
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
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21
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Lin R, Liu Y, Piao M, Song Y. Magnesium isoglycyrrhizinate positively affects concanavalin A-induced liver damage by regulating macrophage polarization. FOOD AGR IMMUNOL 2018. [DOI: 10.1080/09540105.2018.1508424] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Affiliation(s)
- Rui Lin
- Department of Gastroenterology and Hepatology, Tianjin Medical University, General Hospital, Tianjin, People’s Republic of China
| | - Yun Liu
- Tianjin Bonagene Bio-Technology Co. Ltd., Tianjin, People’s Republic of China
- Academician Workstation of Hunan Baodong Farming Co. Ltd., Hunan, People’s Republic of China
| | - Meiyu Piao
- Department of Gastroenterology and Hepatology, Tianjin Medical University, General Hospital, Tianjin, People’s Republic of China
| | - Yan Song
- Department of Gastroenterology and Hepatology, Tianjin Medical University, General Hospital, Tianjin, People’s Republic of China
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22
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Tee JK, Peng F, Tan YL, Yu B, Ho HK. Magnesium Isoglycyrrhizinate Ameliorates Fibrosis and Disrupts TGF-β-Mediated SMAD Pathway in Activated Hepatic Stellate Cell Line LX2. Front Pharmacol 2018; 9:1018. [PMID: 30319402 PMCID: PMC6167412 DOI: 10.3389/fphar.2018.01018] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Accepted: 08/22/2018] [Indexed: 12/21/2022] Open
Abstract
Liver fibrosis is a histological change often attributed to the activation of hepatic stellate cells (HSCs) and the excessive formation of scar tissues in the liver. Advanced stages of the disease frequently lead to cirrhosis. Magnesium isoglycyrrhizinate (MgIG) has been accepted as a hepatoprotective drug with the potential of alleviating inflammatory conditions and thus promote liver recovery from viral- or drug-induced injury. While MgIG has been empirically integrated into the clinics to treat some liver diseases, its anti-fibrotic effect and the associated mechanisms remain poorly characterized. Herein, we demonstrated that 1 mg/ml MgIG attenuated the production of αSMA and collagen-1 in activated HSCs using TGF-β1-induced human HSCs LX2 as the fibrotic cell model. We found that MgIG exerts an inhibitory effect on the TGF-β-SMAD signaling pathway by arresting the binding of downstream transcription factors SMAD2/3 and SMAD4. Furthermore, MgIG was shown to suppress proliferation and induce senescence of activated LX2 cells. Protein expression of p27 and enzymatic activity of senescence-associated β-galactosidase were elevated upon exposure to MgIG. In addition, we observed that exposure of activated LX2 cells to MgIG reduces TGF-β-induced apoptosis. Interestingly, a lower toxicity profile was observed when human fetal hepatocytes LO2 were exposed to the same concentration and duration of the drug, suggesting the specificity of MgIG effect toward activated HSCs. Overall, hepatoprotective concentrations of MgIG is shown to exert a direct effect on liver fibrosis through inhibiting TGF-β-signaling, in which SMAD2/3 pathway could be one of the mechanisms responsible for the fibrotic response, thereby restoring the surviving cells toward a more quiescent phenotype. This provides critical mechanistic insights to support an otherwise empirical therapy.
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Affiliation(s)
- Jie Kai Tee
- NUS Graduate School for Integrative Sciences and Engineering, Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore
| | - Fei Peng
- Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore
| | - Yeong Lan Tan
- NUS Graduate School for Integrative Sciences and Engineering, Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore
| | - Bo Yu
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Han Kiat Ho
- NUS Graduate School for Integrative Sciences and Engineering, Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore
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23
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Zou X, Wang Y, Peng C, Wang B, Niu Z, Li Z, Niu J. Magnesium isoglycyrrhizinate has hepatoprotective effects in an oxaliplatin‑induced model of liver injury. Int J Mol Med 2018; 42:2020-2030. [PMID: 30066834 PMCID: PMC6108852 DOI: 10.3892/ijmm.2018.3787] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 07/05/2018] [Indexed: 12/24/2022] Open
Abstract
Oxaliplatin is a core chemotherapeutic agent used for the treatment of colorectal liver metastasis; however, liver injury caused by oxaliplatin increases the risk of peri‑operative morbidity and mortality. Magnesium isoglycyrrhizinate (MgiG) is a magnesium salt of 18‑α glycyrrhizic acid stereoisomer that has demonstrated liver‑protective effects against toxins and hepatitis. In the present study, the liver‑protective effect of MgiG against oxaliplatin‑induced hepatic injury was examined in vitro and in vivo. The results demonstrated that MgiG had a protective effect against oxaliplatin‑induced liver injury, as evidenced by the alleviation of hepatic pathological damage and transaminase levels. The protective effect of MgiG was demonstrated to be correlated with inhibition of oxidative stress, the interleukin‑6 pathway and the coagulation system. Altogether, the present findings suggested that MgiG may have potential value in the clinical prevention and treatment of oxaliplatin‑induced liver injury.
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Affiliation(s)
- Xueqing Zou
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Yongmei Wang
- Center of Diagnosis and Treatment of Breast Disease, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Cheng Peng
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Ben Wang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Zhengchuan Niu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Zequn Li
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Jun Niu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
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Magnesium isoglycyrrhizinate shows hepatoprotective effects in a cyclophosphamide-induced model of hepatic injury. Oncotarget 2018; 8:33252-33264. [PMID: 28402274 PMCID: PMC5464865 DOI: 10.18632/oncotarget.16629] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 03/04/2017] [Indexed: 12/19/2022] Open
Abstract
The purpose of the current study was to investigate the effect of Magnesium Isoglycyrrhizinate (GM) on cyclophosphamide (CP)-induced hepatic injury in vivo and in vitro. The results demonstrated that GM exerted a protective effect on CP-induced acute liver injury, as evidenced by the alleviations of hepatic pathological damage and serum transaminase activities. Meantime, GM attenuated serum and HepG2 cell supernatant levels of TNF-α, IL-6, IL-1β, SOD and MDA. Western blot results presented that GM down-regulated the expressions of the microtubule associated protein 1A/1B-light chain 3 (LC3), Lysosome associated membrane protein-1 (LAMP-1), p-phosphatidylinositol 3-kinase (PI3K), p-protein Kinase B(Akt), p-mechanistic target of rapamycin(mTOR), p-ribosomal protein S6 kinase 70 kDa (p70S6K), p-4E binding protein 1(4EBP1), p- inhibitor of NF-κB(IκB)α and p-nuclear factor kappa B(NF-κB)p65 in CP-stimulated hepatic tissue and HepG2 cells. Taken together, our results suggested that GM showed beneficial effect on CP-induced liver injury through NF-κB-mediated inflammation and PI3K/Akt/mTOR/p70S6K/4EBP1 axis-mediated autophagy in vivo and in vitro.
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25
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Wang W, Li X, Xu J. Magnesium isoglycyrrhizinate attenuates D-galactosamine/lipopolysaccharides induced acute liver injury of rat via regulation of the p38-MAPK and NF-κB signaling pathways. Immunopharmacol Immunotoxicol 2018; 40:262-267. [PMID: 29486613 DOI: 10.1080/08923973.2018.1441300] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
CONTEXT Acute hepatic failure involves in serious inflammatory responses and leads to a high mortality. Magnesium isoglycyrrhizinate (MgIG), a magnesium salt of 18-α glycyrrhizic acid (GA) stereoisomer, has been shown anti-inflammatory activity previously. OBJECTIVE This study aimed to investigate the protective effects of MgIG, a hepatocyte protective agent, on D-galactosamine and lipopolysaccharide (D-GaIN/LPS)-induced acute liver injury in rats, and meanwhile explore the molecular mechanism. MATERIALS AND METHODS Male Sprague-Dawley (SD) rats were injected with D-GaIN/LPS (800 mg/kgBW/10 μg/kgBW) with or without administration of MgIG (225 mg/kg once 6 h after D-GaIN/LPS injection and MgIG 45 mg/kg twice in another 12 h, intraperitoneal injection). Rats were sacrificed 24 h after D-GaIN/LPS injection, the blood and liver samples were collected for future inflammation and hepatotoxicity analyses. RESULTS MgIG significantly inhibited D-GaIN/LPS-induced inflammatory cytokines production and hepatotoxicity as indicated by both diagnostic indicators of liver damage [aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels] and histopathological analysis. Western blot analysis demonstrated that MgIG significantly decreased p38-mitogen activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) activation induced by D-GaIN/LPS. CONCLUSION The results indicated that the protective effects of MgIG on D-GaIN/LPS-induced acute liver injury might be correlated with its capacity to regulate the p38-MAPK and NF-κB signaling pathways.
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Affiliation(s)
- Wei Wang
- a Department of Infectious Diseases , Peking University Third Hospital , Beijing , P R China
| | - XiaoGuang Li
- a Department of Infectious Diseases , Peking University Third Hospital , Beijing , P R China
| | - Jie Xu
- a Department of Infectious Diseases , Peking University Third Hospital , Beijing , P R China
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Isoglycyrrhizinate Magnesium Enhances Hepatoprotective Effect of FK506 on Ischemia-Reperfusion Injury Through HMGB1 Inhibition in a Rat Model of Liver Transplantation. Transplantation 2017; 101:2862-2872. [PMID: 28885495 DOI: 10.1097/tp.0000000000001941] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Ischemia-reperfusion injury after liver transplantation (LT) impairs graft function and affects prognosis of recipients. Isoglycyrrhizinate magnesium (Iso) is a hepatoprotective drug usually used after liver injury. In this study, we intended to explore whether Iso alone have protective effect after ischemia-reperfusion injury in a rat model of liver transplantation. We also aimed to study whether Iso could enhance the hepatoprotective effect of FK506 (tacrolimus) and underlying mechanism. METHODS Rats after LT were treated with different concentration of FK506 with or without, Iso or lower-dose FK506 plus Iso. Alanine transaminase, aspartate transaminase, and albumin level were measured after 48 hours, 72 hours, and 7 days. A cell ischemic/reperfusion model was established to further study the mechanism of hepatoprotective effect of FK506 and Iso. RESULTS Iso treatment alone had no effect on liver grafts after LT, but lower-dose FK506 + Iso was better for maintenance of liver function than lower-dose FK506 alone at 48 hours, 72 hours, and 7 days after LT. In terms of mechanism, FK506 induced autophagy which resulted in significantly reduced apoptosis and maintained proliferative potential. However, autophagy induced by FK506 also lead to high-mobility group box (HMGB) 1 release from nuclei, resulting in hepatocyte injury through triggering of p38 phosphorylation and chemokine release. Iso effectively inhibited the release of HMGB1 and downstream inflammatory cytokines. CONCLUSIONS Iso could inhibit release of HMGB1 by FK506 and enhance the hepatoprotective effect of FK506 in rat LT. Combining Iso with FK506 would be promising for the patients after LT.
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27
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Wu Z, Zhang Y, Song T, Song Q, Zhang Y, Zhang X, Han X, Zhang J, Chu L. Magnesium isoglycyrrhizinate ameliorates doxorubicin-induced acute cardiac and hepatic toxicity via anti-oxidant and anti-apoptotic mechanisms in mice. Exp Ther Med 2017; 15:1005-1012. [PMID: 29399108 DOI: 10.3892/etm.2017.5470] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 09/19/2017] [Indexed: 12/27/2022] Open
Abstract
The present study investigated the effects and potential mechanisms of action of magnesium isoglycyrrhizinate (MgIG) in doxorubicin (DOX)-treated mice. Histopathological analysis and western blot analysis were conducted in the liver and heart tissues and biochemical analysis of the serum was performed. The results revealed that MgIG (10, 20 and 40 mg/kg/day) could protect the structure and functions of the liver and heart by inhibiting the activities of the myocardial enzymes creatine kinase (CK), CK-MB and lactate dehydrogenase and the hepatic-specific enzymes aspirate aminotransferase and alanine aminotransferase, increasing the activities of the antioxidants superoxide dismutase and glutathione peroxidase, and inhibiting cellular apoptosis induced by DOX (30 mg/kg). These results demonstrate that inhibiting lipid peroxidation and reducing myocardial and hepatocyte apoptosis may be one of the mechanisms by which MgIG exhibits hepatoprotective and cardioprotective effects in DOX-treated mice.
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Affiliation(s)
- Zhonglin Wu
- Department of Radiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Yuanyuan Zhang
- Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, P.R. China
| | - Tao Song
- Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Qiongtao Song
- Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Ying Zhang
- Department of Pathology, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, P.R. China
| | - Xuan Zhang
- Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, P.R. China
| | - Xue Han
- Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, P.R. China
| | - Jianping Zhang
- Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, P.R. China
| | - Li Chu
- Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, P.R. China.,Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
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28
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Improving the accumulation of 18 α -and 18 β -glycyrrhizins by over-expressing GuHMGR , GuSQS 1, and GuBAS genes in Glycyrrhiza uralensis. JOURNAL OF TRADITIONAL CHINESE MEDICAL SCIENCES 2017. [DOI: 10.1016/j.jtcms.2017.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Amelioration of Ethanol-Induced Hepatitis by Magnesium Isoglycyrrhizinate through Inhibition of Neutrophil Cell Infiltration and Oxidative Damage. Mediators Inflamm 2017; 2017:3526903. [PMID: 28951632 PMCID: PMC5603137 DOI: 10.1155/2017/3526903] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 08/13/2017] [Indexed: 12/15/2022] Open
Abstract
Alcoholic liver disease (ALD) is a leading cause of liver-related morbidity and mortality worldwide. There is no effective treatment to prevent the disease progression. Magnesium isoglycyrrhizinate (MgIG) showed potent anti-inflammatory, antioxidant, and hepatoprotective activities and was used for treating liver diseases in Asia. In this study, we examined whether MgIG could protect mice against alcohol-induced liver injury. The newly developed chronic plus binge ethanol feeding model was used to study the role of MgIG in ALD. Serum liver enzyme levels, H&E staining, immunohistochemical staining, flow cytometric analysis, and real-time PCR were used to evaluate the liver injury and inflammation. We showed that MgIG markedly ameliorated chronic plus binge ethanol feeding liver injury, as shown by decreased serum alanine transaminase and aspartate aminotransferase levels and reduced neutrophil infiltration. The reason may be attributed to the reduced expression of proinflammatory cytokines and chemokines with the treatment of MgIG. The hepatoprotective effect of MgIG was associated with suppression of neutrophil ROS production as well as hepatocellular oxidative stress. MgIG may play a critical role in protecting against chronic plus binge ethanol feeding-induced liver injury by regulating neutrophil activity and hepatic oxidative stress.
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30
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Zhao XJ, Yang YZ, Zheng YJ, Wang SC, Gu HM, Pan Y, Wang SJ, Xu HJ, Kong LD. Magnesium isoglycyrrhizinate blocks fructose-induced hepatic NF-κB/NLRP3 inflammasome activation and lipid metabolism disorder. Eur J Pharmacol 2017; 809:141-150. [DOI: 10.1016/j.ejphar.2017.05.032] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 05/14/2017] [Accepted: 05/15/2017] [Indexed: 12/31/2022]
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Lu C, Xu W, Shao J, Zhang F, Chen A, Zheng S. Blockade of hedgehog pathway is required for the protective effects of magnesium isoglycyrrhizinate against ethanol-induced hepatocyte steatosis and apoptosis. IUBMB Life 2017; 69:540-552. [DOI: 10.1002/iub.1639] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 04/24/2017] [Indexed: 12/17/2022]
Affiliation(s)
- Chunfeng Lu
- Department of Pharmacology, School of Pharmacy; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Functional Substance of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
| | - Wenxuan Xu
- Department of Pharmacology, School of Pharmacy; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Functional Substance of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
| | - Jiangjuan Shao
- Department of Pharmacology, School of Pharmacy; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Functional Substance of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
| | - Feng Zhang
- Department of Pharmacology, School of Pharmacy; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Functional Substance of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
| | - Anping Chen
- Department of Pathology, School of Medicine; Saint Louis University; St Louis MO USA
| | - Shizhong Zheng
- Department of Pharmacology, School of Pharmacy; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
- Jiangsu Key Laboratory for Functional Substance of Chinese Medicine; Nanjing University of Chinese Medicine; Nanjing Jiangsu China
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Jiang W, Chen Q, Li P, Lu Q, Pei X, Sun Y, Wang G, Hao K. Magnesium Isoglycyrrhizinate attenuates lipopolysaccharide-induced depressive-like behavior in mice. Biomed Pharmacother 2017; 86:177-184. [DOI: 10.1016/j.biopha.2016.12.033] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Revised: 12/02/2016] [Accepted: 12/05/2016] [Indexed: 02/07/2023] Open
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Xu Q, Wang J, Chen F, Lin K, Zhu M, Chen L, Zhou X, Li C, Zhu H. Protective role of magnesium isoglycyrrhizinate in non-alcoholic fatty liver disease and the associated molecular mechanisms. Int J Mol Med 2016; 38:275-82. [PMID: 27220460 DOI: 10.3892/ijmm.2016.2603] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 05/13/2016] [Indexed: 01/30/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide and there is an urgent need to identify effective pharmacological strategies to treat NAFLD. For this purpose, in the present study, we examined the the possible molecular mechanisms responsible for the effects of MgIG and the protective effects of MgIG in a model of NAFLD. The human hepatic L02 cell line and oleic acid were employed to establish an in vitro model of NAFLD. The CCK-8 assay, Hoechst 33258 staining and Annexin V-PI staining were performed in order to evaluate cell viability and apoptosis. Oil red O staining was used to detect lipid accumulation within the L02 cells. We found that MgIG significantly inhibited lipid accumulation and protected the L02 cells against lipid accumulation-induced apoptosis. Key molecules involved in unfolded protein response (UPR) signaling were upregulated in lipid-overloaded hepatic cells whereas MgIG suppressed the activation of the UPR. Furthermore, MgIG significantly inhibited the expression of the downstream inflammatory cytokines which had been induced by lipid accumulation. Taken together, these findings suggest that the activation of UPR signaling induces the expression of inflammatory cytokines through the activation of nuclear factor-κB (NF-κB) in lipid-overloaded hepatic cells. In addition, MgIG may suppress the activation of UPR signaling thereby protecting hepatic cells from NAFLD‑induced injury.
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Affiliation(s)
- Qian Xu
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Ji Wang
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Feifei Chen
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Kaisu Lin
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Mingao Zhu
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Lei Chen
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Xiumin Zhou
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Chong Li
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences (CAS), Beijing 100101, P.R. China
| | - Hong Zhu
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
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Yang Q, Wang J, Liu R, Wang Z, Li Y, Zhang Y, Hao X, Huang Y, Xie W, Wei H. Amelioration of concanavalin A-induced autoimmune hepatitis by magnesium isoglycyrrhizinate through inhibition of CD4(+)CD25(-)CD69(+) subset proliferation. DRUG DESIGN DEVELOPMENT AND THERAPY 2016; 10:443-53. [PMID: 26869766 PMCID: PMC4734720 DOI: 10.2147/dddt.s92440] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Magnesium isoglycyrrhizinate (MGL) is a new stereoisomer of glycyrrhizic acid, which is clinically used as a hepatoprotective medicine with more potent effects and less side effects than glycyrrhizic acid. This study was designed to evaluate the protective effects and possible mechanism of MGL against concanavalin A (Con A)-induced autoimmune hepatitis. Hepatitis was induced by Con A in C57/6J mice with or without MGL administration; injury score and serum ALT were evaluated. The CD4+ T-cells were isolated from splenocytes and challenged with Con A after coculturing with MGL. The injury score was significantly improved in MGL-treated mice after Con A challenging for 12 and 24 hours compared with those merely challenged with Con A. Similar trends were observed in the serum levels of ALT and AST. The most interesting result was that MGL administration significantly decreased the frequency of CD4+CD25−CD69+ T-cells rather than CD4+CD25+CD69+ T-cells in peripheral blood mononuclear cells, after Con A challenging 12 and 24 hours. Moreover, the serum ALT levels were markedly correlated with the frequency of CD4+CD25−CD69+ cells, but only weakly correlated with CD4+CD25+CD69+ cells in peripheral blood mononuclear cells. More importantly, MGL (5 mg/mL) almost completely eliminated the proliferation of the CD25−CD69+ subset in primary CD4+ T-cells after Con A challenge. Compared with merely Con A-challenged mice, those with MGL administration significantly demonstrated decreased NALP3, NLRP6, and caspase-3 expression, in which the NALP3 and caspase-3 downregulated in a dose-dependent manner. Our results indicate that MGL may have potential as a therapeutic agent in autoimmune hepatitis by ameliorating liver injury. Its molecular mechanism may be involved in inhibiting CD4+CD25−CD69+ subset proliferation and downregulating inflammasome expression in liver tissue.
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Affiliation(s)
- Qi Yang
- Beijing Ditan Teaching Hospital, Peking University Health Science Center, Beijing, People's Republic of China
| | - Jianwei Wang
- Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Ran Liu
- Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Zhiqiang Wang
- Beijing Ditan Teaching Hospital, Peking University Health Science Center, Beijing, People's Republic of China
| | - Yufeng Li
- Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Yifan Zhang
- Beijing Ditan Teaching Hospital, Peking University Health Science Center, Beijing, People's Republic of China
| | - Xiaohua Hao
- Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Yubo Huang
- Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Wen Xie
- Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Hongshan Wei
- Beijing Ditan Teaching Hospital, Peking University Health Science Center, Beijing, People's Republic of China; Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, People's Republic of China
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Tang GH, Yang HY, Zhang JC, Ren JJ, Sang XT, Lu X, Zhong SX, Mao YL. Magnesium isoglycyrrhizinate inhibits inflammatory response through STAT3 pathway to protect remnant liver function. World J Gastroenterol 2015; 21:12370-12380. [PMID: 26604644 PMCID: PMC4649120 DOI: 10.3748/wjg.v21.i43.12370] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Revised: 06/18/2015] [Accepted: 09/15/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the protective effect of magnesium isoglycyrrhizinate (MgIG) on excessive hepatectomy animal model and its possible mechanism.
METHODS: We used the standard 90% hepatectomy model in Sprague-Dawley rats developed using the modified Emond’s method, in which the left, middle, right upper, and right lower lobes of the liver were removed. Rats with 90% liver resection were divided into three groups, and were injected intraperitoneally with 3 mL saline (control group), 30 mg/kg (low-dose group) and 60 mg/kg (high-dose group) of MgIG, respectively. Animals were sacrificed at various time points and blood was drawn from the vena cava. Biochemical tests were performed with an automatic biochemical analyzer for the following items: serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamyl endopeptidase, total bilirubin (TBil), direct bilirubin (DBil), total protein, albumin, blood glucose (Glu), hyper-sensitivity C-reactive protein, prothrombin time (PT), and thrombin time (TT). Postoperative survival time was observed hourly until death. Hepatocyte regeneration was analyzed by immunohistochemistry. Serum inflammatory cytokines (IL-1, IL-6, IL-10, and iNOS) was analyzed by ELISA. STAT3 protein and mRNA were analyzed by Western blot and quantitative reverse-transcription PCR, respectively.
RESULTS: The high-dose group demonstrated a significantly prolonged survival time, compared with both the control and the low-dose groups (22.0 ± 4.7 h vs 8.9 ± 2.0 vs 10.3 ± 3.3 h, P = 0.018). There were significant differences among the groups in ALT, Glu and PT levels starting from 6 h after surgery. The ALT levels were significantly lower in the MgIG treated groups than in the control group. Both Glu and PT levels were significantly higher in the MgIG treated groups than in the control group. At 12 h, ALT, AST, TBil, DBil and TT levels showed significant differences between the MgIG treated groups and the control group. No significant differences in hepatocyte regeneration were found. Compared to the control group, the high-dose group showed a significantly increase in serum inflammatory cytokines IL-1 and IL-10, and a decrease in IL-6. Both STAT3 protein and mRNA levels were significantly lower in the MgIG treated groups than in the control group at 6 h, 12 h, and 18 h after surgery.
CONCLUSION: High-dose MgIG can extend survival time in rats after excessive hepatectomy. This hepatoprotective effect is mediated by inhibiting the inflammatory response through inhibition of the STAT3 pathway.
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Xie C, Li X, Wu J, Liang Z, Deng F, Xie W, Zhu M, Zhu J, Zhu W, Geng S, Zhong C. Anti-inflammatory Activity of Magnesium Isoglycyrrhizinate Through Inhibition of Phospholipase A2/Arachidonic Acid Pathway. Inflammation 2015; 38:1639-1648. [PMID: 25691139 DOI: 10.1007/s10753-015-0140-2] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Glycyrrhiza glabra (licorice) has been known to possess various pharmacological properties including anti-inflammatory, antioxidants, antiviral, and hepatoprotective activities. Magnesium isoglycyrrhizinate (MgIG), a magnesium salt of 18-α glycyrrhizic acid stereoisomer, is clinically used for the treatment of inflammatory liver diseases. However, the mechanism by which MgIG exerts its anti-inflammatory effects remains unknown. In the present study, we investigated the inhibitory potential of MgIG in phospholipase A2 (PLA2)/arachidonic acid (AA) pathway and release of the pathway-generated inflammatory lipid mediators in RAW264.7 macrophages. Results revealed that MgIG suppressed LPS-induced activation of PLA2 and production of AA metabolites such as prostaglandin E2 (PGE2), prostacyclin (PGI2), thromboxane 2 (TXB2), and leukotrienes (LTB4) in macrophages. Furthermore, LPS-induced AA-metabolizing enzymes including COX-2, COX-1, 5-LOX, TXB synthase, and PGI2 synthase were significantly inhibited by MgIG. Taken together, our data suggest that modulation of cyclooxygenase (COXs) and 5-lipoxygenase (LOX) pathways in AA metabolism could be a novel mechanism for the anti-inflammatory effects of MgIG.
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Affiliation(s)
- Chunfeng Xie
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, 818 East Tianyuan Rd, Jiangning, Nanjing, 211166, China
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Wang L, Yang R, Yuan B, Liu Y, Liu C. The antiviral and antimicrobial activities of licorice, a widely-used Chinese herb. Acta Pharm Sin B 2015; 5:310-5. [PMID: 26579460 PMCID: PMC4629407 DOI: 10.1016/j.apsb.2015.05.005] [Citation(s) in RCA: 333] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Revised: 02/02/2015] [Accepted: 02/05/2015] [Indexed: 12/17/2022] Open
Abstract
Licorice is a common herb which has been used in traditional Chinese medicine for centuries. More than 20 triterpenoids and nearly 300 flavonoids have been isolated from licorice. Recent studies have shown that these metabolites possess many pharmacological activities, such as antiviral, antimicrobial, anti-inflammatory, antitumor and other activities. This paper provides a summary of the antiviral and antimicrobial activities of licorice. The active components and the possible mechanisms for these activities are summarized in detail. This review will be helpful for the further studies of licorice for its potential therapeutic effects as an antiviral or an antimicrobial agent.
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Key Words
- Antimicrobial
- Antiviral
- CCEC, cerebral capillary vessel endothelial
- CCL5, chemokine (C-C motif) ligand 5
- CVA16, coxsackievirus A16
- CVB3, coxsackievirus B3
- CXCL10, chemokine, (C-X-C motif) ligand 10
- Chalcone
- DGC, dehydroglyasperin C
- DHV, duck hepatitis virus
- EV71, enterovirus 71
- GA, 18β-glycyrrhetinic acid
- GATS, glycyrrhizic acid trisodium salt
- GL, glycyrrhizin
- GLD, glabridin
- Glycyrrhetinic acid
- Glycyrrhizin
- HBV, hepatitis B virus
- HCV, hepatitis C virus
- HIV, human immunodeficiency virus
- HMGB1, high-mobility-group box1
- HRSV, human respiratory syncytial virus
- HSV, herpes simplex virus
- HSV1, herpes simplex virus type 1
- IFN, interferon
- IL-6, interleukin-6
- ISL, isoliquiritigenin
- LCA, licochalcone A
- LCE, licochalcone E
- LTG, liquiritigenin
- Licorice
- MRSA, methicillin-resistant Staphylococcus aureus
- MSSA, methicillin-sensitive Staphylococcus aureus
- MgIG, magnesium isoglycyrrhizinate
- PMN, polymorph nuclear
- PrV, pseudorabies virus
- TCM, traditional Chinese medicine
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Chen KJ, Chen WY, Chen X, Jia YM, Peng GQ, Chen L. Increased elimination of paclitaxel by magnesium isoglycyrrhizinate in epithelial ovarian cancer patients treated with paclitaxel plus cisplatin: a pilot clinical study. Eur J Drug Metab Pharmacokinet 2013; 39:25-31. [PMID: 23681836 DOI: 10.1007/s13318-013-0136-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Accepted: 05/03/2013] [Indexed: 01/20/2023]
Abstract
Magnesium isoglycyrrhizinate (MI) has been complementarily used for restoring the hepatic impairments caused by taxol plus platinum based chemotherapies in China. Due to the hepatic dependence of paclitaxel elimination, this pilot clinical study aimed to investigate the influence of MI on the pharmacokinetics of paclitaxel in epithelial ovarian cancer patients. During the standard chemotherapy of intravenous paclitaxel (125 mg/m(2) infused over a 3-h period) and intraperitoneal cisplatin (60 mg/m(2)) for patients with FIGO stage II epithelial ovarian cancer, 9 each of total 18 patients were respectively treated with intravenous MI (100 mg) or vehicle control for 4 days. Plasma paclitaxel was analyzed by HPLC and the pharmacokinetic parameters were calculated with non-compartmental analysis. The hematological, hepatic and renal status was monitored before and 3 days after paclitaxel administration. It was observed the terminal t 1/2 and MRT of paclitaxel were significantly (p = 0.002 and 0.001) reduced by MI, respectively, from 11.0 ± 2.2 and 5.6 ± 1.0 h to 7.7 ± 1.7 and 4.0 ± 0.3 h. Hematological toxicity indicated by platelet count and hepatic events marked with ALT, AST and γ-GT were significant in both groups. In spite of the insignificance of decreased system exposure of paclitaxel and recovered hepatic function by MI, they did correlate with each other. It was therefore deduced that the liver toxicities of paclitaxel plus cisplatin chemotherapy potentially decrease hepatic elimination and increase system exposure of paclitaxel, and the recovery of liver function by MI helps to restore hepatic clearance of paclitaxel. The clinical significance of this pharmacokinetic interaction requires further studies with larger population size.
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Affiliation(s)
- Kai Jie Chen
- Department of Pharmacy, West China Second University Hospital, Sichuan University, No. 20, Section 3, Renminnan Road, Chengdu, 610041, China
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Hepatic lipid composition differs between ob/ob and ob/+ control mice as determined by using in vivo localized proton magnetic resonance spectroscopy. MAGNETIC RESONANCE MATERIALS IN PHYSICS BIOLOGY AND MEDICINE 2012; 25:381-9. [PMID: 22441585 DOI: 10.1007/s10334-012-0310-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2011] [Revised: 02/24/2012] [Accepted: 02/24/2012] [Indexed: 12/21/2022]
Abstract
OBJECT Hepatic lipid accumulation is associated with nonalcoholic fatty liver disease, and the metabolic syndrome constitutes an increasing medical problem. In vivo proton magnetic resonance spectroscopy ((1)H MRS) allows the assessment of hepatic lipid levels noninvasively and also yields information on the fat composition due to its high spectral resolution. MATERIALS AND METHODS We applied (1)H MRS at 9.4T to study lipid content and composition in eight leptin-deficient ob/ob mice as a model of obesity and in four lean ob/+ control mice at 24 weeks of age. PRESS sequence was used. For accurate estimation of signal intensity, differences in relaxation behavior of individual signals were accounted for each mouse individually. Also, in order to minimize spectral degrading due to motion artifacts, respiration gating was applied. RESULTS Significant differences between ob/ob and ob/+ control mice were found in both lipid content and composition. The mean chain length was found to be significantly longer in ob/ob mice with a higher fraction of monounsaturated lipids. CONCLUSION (1)H MRS enables accurate assessment in hepatic lipids in mice, which is attractive for mechanistic studies of altered metabolism given the large number of genetically engineered mouse models available.
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Abstract
PURPOSE OF REVIEW This review focuses on recent advances in the study of the epidemiology, pathogenesis, natural history and treatment of nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS Study of hepatic lipid metabolism, insulin resistance, mitochondrial dysfunction and oxidative stress, genetic variants and predisposition to altered metabolism and cell injury have contributed to our current understanding of NAFLD. Differential expression of microRNA in fatty liver and its implication in disease pathogenesis and therapeutic potential have continued to advance over the year. The pathogenesis of hepatocellular carcinoma in steatohepatitis continues to be explored. The diagnostic utility of imaging and noninvasive markers seems promising in estimating the severity of steatosis and fibrosis. Liver biopsy remains the gold standard for accurately assessing NAFLD and steatohepatitis. Lifestyle modification and weight loss improve both metabolic profile and liver histology. Pharmacotherapy for the treatment of NAFLD remains lacking. SUMMARY The underlying mechanism and pathogenesis of NAFLD remain elusive despite ongoing researches to make significant advances in the understanding of its natural history, pathogenesis and management. Pharmacotherapy has yet to indicate a promising therapeutic intervention. Current treatment focuses on managing underlying cardio-metabolic risks.
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