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Liang C, Liu J, Jiang M, Zhu Y, Dong P. The advancement of targeted regulation of hepatic stellate cells using traditional Chinese medicine for the treatment of liver fibrosis. JOURNAL OF ETHNOPHARMACOLOGY 2025; 341:119298. [PMID: 39798676 DOI: 10.1016/j.jep.2024.119298] [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: 09/02/2024] [Revised: 12/19/2024] [Accepted: 12/27/2024] [Indexed: 01/15/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Liver fibrosis, which is a precursor to cirrhosis in chronic liver diseases, is driven by various factors. The activation and proliferation of hepatic stellate cells (HSCs) are recognized as a crucial phase in the progression of liver fibrosis. Compared with western drug therapy, Traditional Chinese medicine (TCM) and herbal medicine not only have the advantages of multi-target and multi-pathways in the treatment of liver fibrosis, but also have high safety without toxic side effects. AIM OF THE REVIEW This paper aims to compile and analyze the active ingredients in TCM and their corresponding signaling pathways that target and modulate the phenotype of hepatic stellate cells, offering a potential treatment for hepatic fibrosis. METHODS The Literature information was obtained from the scientific databases PubMed, Web of Science and CNKI from January 2010 to June 2020 with the aim of elucidating the intrinsic mechanisms and roles of TCM and natural medicine in the treatment of LF. The search terms included "liver fibrosis" or "hepatic fibrosis", "traditional Chinese medicine" or "Chinese herbal medicine", "medicinal plant", "natural plant", and "herb". RESULTS We described the antifibrosis activity of TCM and natural medicine in LF based on different signaling pathways. Plant medicine and herbal formulas regulated the related gene and protein expression via pathways such as TGF-β/Smad, PI3K/AKT/mTOR, MAPK and Wnt/β-catenin, which inhibit the proliferation, apoptosis, autophagy and activation of HSCs. CONCLUSION By reviewing both domestic and international literature on TCM interventions in liver fibrosis, this study presents a thorough evaluation of recent research progress and the challenges faced in the clinical application of TCM for this condition. The goal is to lay a solid foundation for further in-depth studies and to strengthen the theoretical framework in this field. The inhibitory effect of TCM and natural medicine on fibrosis was reflected in multiple levels and multiple pathways, providing reasonable evidence for new drug development. To make TCM and natural medicine widely and flexibly used in clinical practice, the efficacy, safety and mechanism of action need more in-depth experimental research. It also seeks to provide a theoretical foundation for future research on targeted therapies for liver fibrosis and related diseases.
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Affiliation(s)
- Chen Liang
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, PR China
| | - Jingjing Liu
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, PR China
| | - Meixiu Jiang
- The Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330031, PR China
| | - Yan Zhu
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, PR China
| | - Pengzhi Dong
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, PR China.
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Hu R, Wu F, Zheng YQ. Ivacaftor attenuates gentamicin-induced ototoxicity through the CFTR-Nrf2-HO1/NQO1 pathway. Redox Rep 2024; 29:2332038. [PMID: 38563333 PMCID: PMC10993751 DOI: 10.1080/13510002.2024.2332038] [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] [Indexed: 04/04/2024] Open
Abstract
OBJECTIVES Gentamicin is one of the most common ototoxic drugs that can lower patients' quality of life. Oxidative stress is a key factors inducing sensory hair cell death during gentamicin administration. So far, there are no effective drugs to prevent or treat gentamicin- induced hearing loss. A recent study found cystic fibrosis transmembrane conductance regulator (CFTR) as a new target to modulate cellular oxidative balance. The objective of this study was to estimate the effect of the CFTR activator ivacaftor on gentamicin-induced ototoxicity and determine its mechanism. METHODS The hair cell count was analyzed by Myosin 7a staining. Apoptosis was analyzed by TUNEL Apoptosis Kit. Cellular reactive oxygen species (ROS) level was detected by DCFH-DA probes. The Nrf2 related proteins expression levels were analyzed by western blot. RESULTS An in vitro cochlear explant model showed that gentamicin caused ROS accumulation in sensory hair cells and induced apoptosis, and this effect was alleviated by pretreatment with ivacaftor. Western blotting showed that ivacaftor administration markedly increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO1), and NAD(P)H:quinone oxidoreductase 1 (NQO1). The protective effect of ivacaftor was abolished by the Nrf2 inhibitor ML385. DISCUSSION Our results indicate the protective role of the CFTR-Nrf2-HO1/NQO1 pathway in gentamicin-induced ototoxicity. Ivacaftor may be repositioned or repurposed towards aminoglycosides-induced hearing loss.
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Affiliation(s)
- Rui Hu
- Shenshan Medical Center, Memorial Hospital of Sun Yat-Sen University, Shanwei, People’s Republic of China
- Department of Otolaryngology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China
| | - Fan Wu
- Department of Otolaryngology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
- Department of Pathology and Laboratory Medicine, The Medical University of South Carolina, Charleston, SC, USA
| | - Yi-Qing Zheng
- Shenshan Medical Center, Memorial Hospital of Sun Yat-Sen University, Shanwei, People’s Republic of China
- Department of Otolaryngology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
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Song X, Zhu J, Sun F, Wang N, Qiu X, Zhu Q, Qi J, Wang X. Target-centric analysis of hepatitis B: identifying key molecules and pathways for treatment. Sci Rep 2024; 14:26858. [PMID: 39500944 PMCID: PMC11538522 DOI: 10.1038/s41598-024-76567-8] [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: 08/22/2024] [Accepted: 10/15/2024] [Indexed: 11/08/2024] Open
Abstract
Hepatitis B virus (HBV) poses a significant global health challenge, potentially leading to severe liver conditions, with currently limited effective treatment options available. Xiao-Chai-Hu-Tang (XCHT), a well-known Traditional Chinese Medicine (TCM) prescription, shows promise in clinical trials for treating HBV. Therefore, screening the complex components of XCHT, identifying the active compounds, and closely exploring the targets associated with hepatitis B may constitute an effective strategy for the development of new therapeutic drugs for the treatment of this disease. A systematic pharmacology and GEO chip analysis identified key targets and pathways for hepatitis B treatment and effective ingredients. Molecular docking and molecular dynamics simulation techniques were used to explore the affinity and stability of active compounds with core targets, while assessing the druggability and safety of the active compounds. The therapeutic effect of the active compound protoporphyrin in XCHT on hepatitis B were mediated through key targets such as AKT1, MAPK1, and LCK, as well as key signaling pathways like PI3K-Akt signaling pathway and Ras signaling pathway. Protoporphyrin effectively bond to active pockets of core targets and demonstrated favorable druggability and a high safety threshold. The study provided valuable insights into the development of effective treatments for hepatitis B.
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Affiliation(s)
- Xinyu Song
- Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Jinlu Zhu
- Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Fengzhi Sun
- Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
| | - Nonghan Wang
- Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Xiao Qiu
- Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Qingjun Zhu
- Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
| | - Jianhong Qi
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 211198, China.
| | - Xiaolong Wang
- Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
- Key Laboratory of TCM Classical Theory, Ministry of Education, Shandong University of TCM, Jinan, 250355, China.
- Shandong Provincial Key Laboratory of TCM for Basic Research, Shandong University of TCM, Jinan, 250355, China.
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Dong Z, Wang Y, Jin W. Liver cirrhosis: molecular mechanisms and therapeutic interventions. MedComm (Beijing) 2024; 5:e721. [PMID: 39290252 PMCID: PMC11406049 DOI: 10.1002/mco2.721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 08/19/2024] [Accepted: 08/19/2024] [Indexed: 09/19/2024] Open
Abstract
Liver cirrhosis is the end-stage of chronic liver disease, characterized by inflammation, necrosis, advanced fibrosis, and regenerative nodule formation. Long-term inflammation can cause continuous damage to liver tissues and hepatocytes, along with increased vascular tone and portal hypertension. Among them, fibrosis is the necessary stage and essential feature of liver cirrhosis, and effective antifibrosis strategies are commonly considered the key to treating liver cirrhosis. Although different therapeutic strategies aimed at reversing or preventing fibrosis have been developed, the effects have not be more satisfactory. In this review, we discussed abnormal changes in the liver microenvironment that contribute to the progression of liver cirrhosis and highlighted the importance of recent therapeutic strategies, including lifestyle improvement, small molecular agents, traditional Chinese medicine, stem cells, extracellular vesicles, and gut remediation, that regulate liver fibrosis and liver cirrhosis. Meanwhile, therapeutic strategies for nanoparticles are discussed, as are their possible underlying broad application and prospects for ameliorating liver cirrhosis. Finally, we also reviewed the major challenges and opportunities of nanomedicine‒biological environment interactions. We hope this review will provide insights into the pathogenesis and molecular mechanisms of liver cirrhosis, thus facilitating new methods, drug discovery, and better treatment of liver cirrhosis.
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Affiliation(s)
- Zihe Dong
- The First School of Clinical Medicine Lanzhou University Lanzhou People's Republic of China
- Institute of Cancer Neuroscience Medical Frontier Innovation Research Center The First Hospital of Lanzhou University Lanzhou People's Republic of China
| | - Yeying Wang
- The First School of Clinical Medicine Lanzhou University Lanzhou People's Republic of China
- Institute of Cancer Neuroscience Medical Frontier Innovation Research Center The First Hospital of Lanzhou University Lanzhou People's Republic of China
| | - Weilin Jin
- The First School of Clinical Medicine Lanzhou University Lanzhou People's Republic of China
- Institute of Cancer Neuroscience Medical Frontier Innovation Research Center The First Hospital of Lanzhou University Lanzhou People's Republic of China
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Zhong Y, Li J, Zhu X, Huang N, Liu R, Sun R. A comprehensive review of bupleuri radix and its bioactive components： with a major focus on treating chronic liver diseases. JOURNAL OF ETHNOPHARMACOLOGY 2024; 330:118244. [PMID: 38663781 DOI: 10.1016/j.jep.2024.118244] [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: 12/02/2023] [Revised: 04/19/2024] [Accepted: 04/22/2024] [Indexed: 04/30/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Bupleuri Radix (BR) has been recognized as an essential herbal medicine for relieving liver depression for thousands of years. Contemporary research has provided compelling evidence of its pharmacological effects, including anti-inflammatory, immunomodulatory, metabolic regulation, and anticancer properties, positioning it as a promising treatment option for various liver diseases. Hepatitis, steatohepatitis, cirrhosis, and liver cancer are among the prevalent and impactful liver diseases worldwide. However, there remains a lack of comprehensive systematic reviews that explore the prescription, bio-active components, and underlying mechanisms of BR in treating liver diseases. AIM OF THE REVIEW To summarize the BR classical Chinese medical prescription and ingredients in treating liver diseases and their mechanisms to inform reference for further development and research. MATERIALS AND METHODS Literature in the last three decades of BR and its classical Chinese medical prescription and ingredients were collated and summarized by searching PubMed, Wiley, Springer, Google Scholar, Web of Science, CNKI, etc. RESULTS: BR and its classical prescriptions, such as Xiao Chai Hu decoction, Da Chai Hu decoction, Si Ni San, and Chai Hu Shu Gan San, have been utilized for centuries as effective therapies for liver diseases, including hepatitis, steatohepatitis, cirrhosis, and liver cancer. BR is a rich source of active ingredients, such as saikosaponins, polysaccharides, flavonoids, sterols, organic acids, and so on. These bioactive compounds exhibit a wide range of beneficial effects, including anti-inflammatory, antioxidant, immunomodulatory, and lipid metabolism regulation. However, it is important to acknowledge that BR and its constituents can also possess hepatotoxicity, which is associated with cytochrome P450 (CYP450) enzymes and oxidative stress. Therefore, caution should be exercised when using BR in therapeutic applications to ensure the safe and appropriate utilization of its potential benefits while minimizing any potential risks. CONCLUSIONS To sum up, BR, its compounds, and its based traditional Chinese medicine are effective in liver diseases through multiple targets, multiple pathways, and multiple effects. Advances in pharmacological and toxicological investigations of BR and its bio-active components in the future will provide further contributions to the discovery of novel therapeutics for liver diseases.
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Affiliation(s)
- Ying Zhong
- The Second Hospital of Shandong University, 247 Beiyuan Ave, Jinan, Shandong, 250033, China.
| | - Jianchao Li
- Shandong University of Traditional Chinese Medicine, 4655 Daxue Road, Jinan, Shandong, 250355, China.
| | - Xiaomin Zhu
- The Second Hospital of Shandong University, 247 Beiyuan Ave, Jinan, Shandong, 250033, China.
| | - Nana Huang
- The Second Hospital of Shandong University, 247 Beiyuan Ave, Jinan, Shandong, 250033, China; Shandong University of Traditional Chinese Medicine, 4655 Daxue Road, Jinan, Shandong, 250355, China.
| | - Runping Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Rong Sun
- The Second Hospital of Shandong University, 247 Beiyuan Ave, Jinan, Shandong, 250033, China; Advanced Medical Research Institute, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong, 250012, China.
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Liu H, Fan D, Wang J, Wang Y, Li A, Wu S, Zhang B, Liu J, Wang S. Lactobacillus rhamnosus NKU FL1-8 Isolated from Infant Feces Ameliorates the Alcoholic Liver Damage by Regulating the Gut Microbiota and Intestinal Barrier in C57BL/6J Mice. Nutrients 2024; 16:2139. [PMID: 38999886 PMCID: PMC11243132 DOI: 10.3390/nu16132139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 06/28/2024] [Accepted: 07/02/2024] [Indexed: 07/14/2024] Open
Abstract
Alcoholic liver damage is caused by long-term or heavy drinking, and it may further progress into alcoholic liver diseases (ALD). Probiotic supplements have been suggested for the prevention or improvement of liver damage. This study was designed to consider the ameliorative effects of Lactobacillus rhamnosus NKU FL1-8 isolated from infant feces against alcoholic liver damage. The mice were gavaged with a 50% ethanol solution and treated with 109 CFU of L. rhamnosus NKU FL1-8 suspension. The factors for liver function, oxidative stress, inflammation, gut microbiota composition, and intestinal barrier integrity were measured. The results showed that L. rhamnosus NKU FL1-8 could decrease the levels of aspartate aminotransferase (AST) to 61% and alanine aminotransferase (ALT) to 50% compared with ethanol given by gavage. It could inhibit the expression level of malondialdehyde (MDA), increase superoxide dismutase (SOD), glutathione (GSH) to relieve oxidative stress, and down-regulate the cytokines to decrease hepatic inflammation. After treatment, the level of triglycerides was reduced, and the expression levels of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and the peroxisome proliferators-activated receptor-α (PPAR-α) pathway were up-regulated. Additionally, the 16S rRNA sequencing analysis showed that L. rhamnosus NKU FL1-8 increased the relative abundance of Lactobacillus, Ruminococcaceae, etc. At the same time, L. rhamnosus NKU FL1-8 could significantly reduce lipopolysaccharides (LPS) and enhance intestinal tight junction proteins. These results demonstrated that L. rhamnosus NKU FL1-8 could reduce the level of oxidative stress, fat accumulation, and liver inflammation caused by alcohol in the host. The underlying mechanism could be that L. rhamnosus NKU FL1-8 inhibits LPS by regulating the gut microbiota and repairing the intestinal barrier. Thereby, these findings support L. rhamnosus NKU FL1-8 as a potential functional food for the relief of ALD.
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Affiliation(s)
- Haiwei Liu
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300350, China
| | - Dancai Fan
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300350, China
| | - Jin Wang
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300350, China
| | - Yuanyifei Wang
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300350, China
| | - Ang Li
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300350, China
| | - Sihao Wu
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300350, China
| | - Bowei Zhang
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300350, China
| | - Jingmin Liu
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300350, China
| | - Shuo Wang
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300350, China
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Ouyang H, Miao H, Li Z, Wu D, Gao SC, Dai YY, Gao XD, Chai HS, Hu WY, Zhu JF. Yinhuang granule alleviates carbon tetrachloride-induced liver fibrosis in mice and its mechanism. World J Hepatol 2024; 16:264-278. [PMID: 38495271 PMCID: PMC10941736 DOI: 10.4254/wjh.v16.i2.264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 01/09/2024] [Accepted: 02/01/2024] [Indexed: 02/27/2024] Open
Abstract
BACKGROUND Liver fibrosis is a formidable global medical challenge, with no effective clinical treatment currently available. Yinhuang granule (YHG) is a proprietary Chinese medicine comprising Scutellariae Radix and Lonicerae Japonicae Flos. It is frequently used for upper respiratory tract infections, pharyngitis, as well as acute and chronic tonsillitis. AIM To investigate the potential of YHG in alleviating carbon tetrachloride (CCl4)-induced liver fibrosis in mice. METHODS To induce a hepatic fibrosis model in mice, this study involved intraperitoneal injections of 2 mL/kg of CCl4 twice a week for 4 wk. Meanwhile, liver fibrosis mice in the low dose of YHG (0.4 g/kg) and high dose of YHG (0.8 g/kg) groups were orally administered YHG once a day for 4 wk. Serum alanine/aspartate aminotransferase (ALT/AST) activity and liver hydroxyproline content were detected. Sirius red and Masson's trichrome staining assay were conducted. Real-time polymerase chain reaction, western-blot and enzyme-linked immunosorbent assay were conducted. Liver glutathione content, superoxide dismutase activity level, reactive oxygen species and protein carbonylation amount were detected. RESULTS The administration of YHG ameliorated hepatocellular injury in CCl4-treated mice, as reflected by decreased serum ALT/AST activity and improved liver histological evaluation. YHG also attenuated liver fibrosis, evident through reduced liver hydroxyproline content, improvements in Sirius red and Masson's trichrome staining, and lowered serum hyaluronic acid levels. Furthermore, YHG hindered the activation of hepatic stellate cells (HSCs) and ameliorated oxidative stress injury and inflammation in liver from CCl4-treated mice. YHG prompted the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulated the expression of Nrf2-dependent downstream antioxidant genes. In addition, YHG promoted mitochondrial biogenesis in liver from CCl4-treated mice, as demonstrated by increased liver adenosine triphosphate content, mitochondrial DNA levels, and the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha and nuclear respiratory factor 1. CONCLUSION YHG effectively attenuates CCl4-induced liver fibrosis in mice by inhibiting the activation of HSCs, reducing inflammation, alleviating liver oxidative stress damage through Nrf2 activation, and promoting liver mitochondrial biogenesis.
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Affiliation(s)
- Hao Ouyang
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hui Miao
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 201203, China
| | - Zhen Li
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Duan Wu
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Si-Cheng Gao
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yao-Yao Dai
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiao-Di Gao
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hai-Sheng Chai
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wei-Ye Hu
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jun-Feng Zhu
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Wang X, Tian H, Chen J, Huang D, Ding F, Ma T, Xi J, Wu C, Zhang Y. Isobavachalcone attenuates liver fibrosis via activation of the Nrf2/HO-1 pathway in rats. Int Immunopharmacol 2024; 128:111398. [PMID: 38171054 DOI: 10.1016/j.intimp.2023.111398] [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: 10/27/2023] [Revised: 12/08/2023] [Accepted: 12/14/2023] [Indexed: 01/05/2024]
Abstract
Liver fibrosis, a progression of chronic liver disease, is a significant concern worldwide due to the lack of effective treatment modalities. Recent studies have shown that natural products play a crucial role in preventing and treating liver fibrosis. Isobavachalcone (IBC) is a chalcone compound with anti-inflammatory, antioxidant, and anti-cancer properties. However, its potential antifibrotic effects remain to be elucidated. This study aimed to investigate the antifibrotic effects of IBC on liver fibrosis and its underlying mechanisms in rats. The results showed that IBC significantly ameliorated the pathological damage and collagen deposition in liver tissues; it also reduced the levels of hydroxyproline (HYP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). In addition, IBC activated Nuclear factor E2-associated factor 2/Hemeoxygenase-1 (Nrf2/HO-1) signaling, leading to the nuclear translocation of Nrf2. This translocation subsequently increased the levels of superoxide dismutase (SOD) and glutathione (GSH) and decreased the levels of malondialdehyde (MDA) and reactive oxygen species (ROS), thereby alleviating oxidative stress-induced damage. Moreover, it inhibited the expression of nuclear factor kappa B (NF-κB), which further reduced the levels of downstream inflammatory factors, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1 beta (IL-1β), thereby suppressing the activation of HSCs and weakening liver fibrosis. In HSC-T6 cell experiments, changes observed in inflammatory responses, oxidative stress indicators, and protein expression were consistent with the in vivo results. Furthermore, the Nrf2 inhibitor (ML385) attenuated the effect of IBC on inhibiting the activation of quiescent HSCs. Consequently, IBC could alleviate liver fibrosis by activating Nrf2/ HO-1 signaling.
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Affiliation(s)
- Xiangshu Wang
- School of Laboratory Medicine, Bengbu Medical College, Bengbu, Anhui Province, China; Anhui Key Laboratory of Tissue Transplantation at Bengbu Medical College, Bengbu, Anhui Province, China
| | - Haozhe Tian
- School of Laboratory Medicine, Bengbu Medical College, Bengbu, Anhui Province, China; Anhui Key Laboratory of Tissue Transplantation at Bengbu Medical College, Bengbu, Anhui Province, China
| | - Jie Chen
- School of Pharmacy, Bengbu Medical College, Bengbu, Anhui Province, China
| | - Di Huang
- School of Pharmacy, Bengbu Medical College, Bengbu, Anhui Province, China
| | - Feng Ding
- School of Pharmacy, Bengbu Medical College, Bengbu, Anhui Province, China; Anhui Engineering Technology Research Center of Biochemical Pharmaceutical, Bengbu Medical College, Bengbu, Anhui Province, China
| | - Tao Ma
- School of Pharmacy, Bengbu Medical College, Bengbu, Anhui Province, China; Anhui Engineering Technology Research Center of Biochemical Pharmaceutical, Bengbu Medical College, Bengbu, Anhui Province, China
| | - Jin Xi
- Anhui Key Laboratory of Tissue Transplantation at Bengbu Medical College, Bengbu, Anhui Province, China
| | - Chengzhu Wu
- School of Pharmacy, Bengbu Medical College, Bengbu, Anhui Province, China; Anhui Engineering Technology Research Center of Biochemical Pharmaceutical, Bengbu Medical College, Bengbu, Anhui Province, China.
| | - Yuxin Zhang
- School of Laboratory Medicine, Bengbu Medical College, Bengbu, Anhui Province, China; Anhui Key Laboratory of Tissue Transplantation at Bengbu Medical College, Bengbu, Anhui Province, China.
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Li Z, Zhu JF, Ouyang H. Progress on traditional Chinese medicine in improving hepatic fibrosis through inhibiting oxidative stress. World J Hepatol 2023; 15:1091-1108. [PMID: 37970620 PMCID: PMC10642434 DOI: 10.4254/wjh.v15.i10.1091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 08/26/2023] [Accepted: 09/19/2023] [Indexed: 10/24/2023] Open
Abstract
Hepatic fibrosis is a common pathological process that occurs in the development of various chronic liver diseases into cirrhosis and liver cancer, characterized by excessive deposition of the extracellular matrix. In the past, hepatic fibrosis was thought to be a static and irreversible pathological process. In recent years, with the rapid development of molecular biology and the continuous in-depth study of the liver at the microscopic level, more and more evidence has shown that hepatic fibrosis is a dynamic and reversible process. Therefore, it is particularly important to find an effective, simple, and inexpensive method for its prevention and treatment. Traditional Chinese medicine (TCM) occupies an important position in the treatment of hepatic fibrosis due to its advantages of low adverse reactions, low cost, and multi-target effectiveness. A large number of research results have shown that TCM monomers, single herbal extracts, and TCM formulas play important roles in the prevention and treatment of hepatic fibrosis. Oxidative stress (OS) is one of the key factors in the occurrence and development of hepatic fibrosis. Therefore, this article reviews the progress in the understanding of the mechanisms of TCM monomers, single herbal extracts, and TCM formulas in preventing and treating hepatic fibrosis by inhibiting OS in recent years, in order to provide a reference and basis for drug therapy of hepatic fibrosis.
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Affiliation(s)
- Zhen Li
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jun-Feng Zhu
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Department of Liver, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Hao Ouyang
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Soliman MM, Elshehawei AM, Althobaiti S, Sayed SM. Protective impacts of Withania somnifera leaf extract from Taif area against diclofenac induced hepato-renal toxicity: role of antioxidants, inflammation, apoptosis, and anti-oxidative stress biomarkers. Toxicol Res (Camb) 2023; 12:685-692. [PMID: 37663806 PMCID: PMC10470349 DOI: 10.1093/toxres/tfad058] [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: 05/15/2023] [Revised: 06/24/2023] [Accepted: 07/05/2023] [Indexed: 09/05/2023] Open
Abstract
Current study examined the boosting impacts of Withania somnifera leaf extract from Taif area (high-altitude area) against hepatic and renal toxicity induced by diclofenac in experimental rats. Withania is highly grown on Taif area as environmental herb with multiple functions. Diclofenac is non-steroidal medication used for treatment of pain but over dose has severe side effects. Thirty-two adult Wistar rats of male type were subdivided into 4 groups. The control rats (group 1) received saline. Second group received diclofenac (50 mg/kg BW intraperitoneally) at days 4 and 5. Third group received W. somnifera leaf extract (250 mg /kg body weight) for 6 days. The fourth protective group, received W. somnifera leaf extract plus diclofenac for 6 days as shown in groups 2 and 3. Diclofenac significantly increased serum AST, ALT, and decreased albumin and total proteins levels. It also increased serum concentrations of uric acid and creatinine. In addition, it increased lipid peroxidation, and decreased reduced glutathione and superoxide dismutase levels. Diclofenac increased inflammatory cytokines secretion and up-regulated hepatic oxidative stress genes (HO-1; hemoxygenase-1 and Nrf2nuclear factor erythroid 2-related factor 2 (Nrf2) and renal inflammatory transcriptional markers (TGF-β1; transforming growth factor-beta1 and COX-2; cycloxygenas-2). In parallel, hepatic caspase-3 expression was up-regulated as an apoptotic marker, while Bcl2; (B-cell lymphoma 2) mRNA expression was down regulated as anti-apoptotic marker. W. somnifera pre-administration in the protective group ameliorated the altered parameters induced by diclofenac. In conclusion, W. somnifera leaf extract has the potential to antagonize side effects of diclofenac by regulating the pathways of oxidative stress, inflammation, and apoptosis/antiapoptosis.
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Affiliation(s)
- Mohamed Mohamed Soliman
- Clinical Laboratory Sciences Department, Turabah University College, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Ahmed M Elshehawei
- Department of Bitechnology, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Saed Althobaiti
- Biology Department, Turabah University College, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Samy M Sayed
- Department of Science and Technology, University College-Ranyah, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
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Duan J, Zhao Y, Pei F, Deng W, He L, Rao C, Zhai Y, Zhang C. Swietenine inhibited oxidative stress through AKT/Nrf2/HO-1 signal pathways and the liver-protective effect in T2DM mice: In vivo and in vitro study. ENVIRONMENTAL TOXICOLOGY 2023; 38:1292-1304. [PMID: 36880193 DOI: 10.1002/tox.23764] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 01/03/2023] [Accepted: 02/20/2023] [Indexed: 05/18/2023]
Abstract
Swietenia macrophylla King, belongs to the Meliaceae family, is a valuable medicinal plant and its fruits have been processed commercially to a variety of health foods. The seeds have long been known for their ethnomedicinal significance against these diseases. Swietenine (Swi) was isolated from S. macrophylla and could ameliorate inflammation and oxidative stress. In this study, HepG2 cells induced by H2 O2 were used to construct oxidative stress model in vitro. The aim of this study was to investigate the protective effect of Swi on H2 O2 induced oxidative injury in HepG2 cells and its molecular mechanism, and to explore the effect of Swi on liver injury in db/db mice and its possible mechanism. The results showed that Swi significantly inhibited HepG2 cells viability and reduced oxidative damage in a dose-dependent manner as evidenced by a range of biochemical analysis and immunoblotting study. Moreover, it induced the protein and mRNA expression of HO-1 together with its upstream mediator Nrf2 and activated the phosphorylation of AKT in HepG2 cells. LY294002, a PI3K/AKT inhibitor, significantly suppressed the Nrf2 nuclear translocation and HO-1 expression in H2 O2 induced HepG2 cells treated with Swi. In addition, RNA interference with Nrf2 significantly reduced the expression level of Nrf2 and HO-1 in the nucleus. Swi has a significant protective effect on cell damage in H2 O2 induced HepG2 cells by increasing the antioxidant capacity which is achieved through the AKT/Nrf2/HO-1 pathway. Additionally, in vivo, Swi could protect the liver of type 2 diabetic mice by improving lipid deposition in liver tissue and inhibiting oxidative stress. These findings indicated that Swi can be a promising dietary agent to improve type 2 diabetes.
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Affiliation(s)
- Jingyu Duan
- School of Pharmacy, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Yangqi Zhao
- School of Pharmacy, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Feilong Pei
- School of Pharmacy, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Wenhao Deng
- School of Pharmacy, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Liangliang He
- School of Pharmacy, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Chengdian Rao
- School of Pharmacy, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Yutong Zhai
- School of Pharmacy, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Chunping Zhang
- School of Pharmacy, Xuzhou Medical University, Xuzhou, People's Republic of China
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, People's Republic of China
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Melaibari M, Alkreathy HM, Esmat A, Rajeh NA, Shaik RA, Alghamdi AA, Ahmad A. Anti-Fibrotic Efficacy of Apigenin in a Mice Model of Carbon Tetrachloride-Induced Hepatic Fibrosis by Modulation of Oxidative Stress, Inflammation, and Fibrogenesis: A Preclinical Study. Biomedicines 2023; 11:biomedicines11051342. [PMID: 37239014 DOI: 10.3390/biomedicines11051342] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 04/27/2023] [Accepted: 04/28/2023] [Indexed: 05/28/2023] Open
Abstract
BACKGROUND Hepatic fibrosis is a major health problem all over the world, and there is no effective treatment to cure it. Hence, the current study sought to assess the anti-fibrotic efficacy of apigenin against CCl4-induced hepatic fibrosis in mice. METHODS Forty-eight mice were put into six groups. G1: Normal Control, G2: CCl4 Control, G3: Silymarin (100 mg/kg), G4 and G5: Apigenin (2 &20 mg/Kg), G6: Apigenin alone (20 mg/Kg). Groups 2, 3, 4, and 5 were given CCl4 (0.5 mL/kg. i.p.) twice/week for six weeks. The level of AST, ALT, TC, TG, and TB in serum and IL-1β, IL-6, and TNF-α in tissue homogenates were assessed. Histological studies by H&E staining and Immunostaining of liver tissues were also performed. RESULTS The CCl4-challenged group showed increased serum AST (4-fold), ALT (6-fold), and TB (5-fold). Both silymarin and apigenin treatments significantly improved these hepatic biomarkers. The CCl4-challenged group showed reduced levels of CAT (89%), GSH (53%), and increased MDA (3-fold). Both silymarin and apigenin treatments significantly altered these oxidative markers in tissue homogenates. The CCl4-treated group showed a two-fold increase in IL-1β, IL-6, and TNF-α levels. Silymarin and apigenin treatment considerably decreased the IL-1β, IL-6, and TNF-α levels. Apigenin treatment inhibited angiogenic activity, as evidenced by a decrease in VEGF (vascular endothelial growth factor) expression in liver tissues, and a decline in vascular endothelial cell antigen expression (CD34). CONCLUSIONS Finally, these data collectively imply that apigenin may have antifibrotic properties, which may be explained by its anti-inflammatory, antioxidant, and antiangiogenic activities.
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Affiliation(s)
- Maryam Melaibari
- Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Huda M Alkreathy
- Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Ahmed Esmat
- Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
| | - Nisreen A Rajeh
- Department of Clinical Anatomy, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Rasheed A Shaik
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Anwar A Alghamdi
- Health Information Technology Department, The Applied College, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Pharmacovigilance and Medication Safety Unit, Center of Research Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Aftab Ahmad
- Health Information Technology Department, The Applied College, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Pharmacovigilance and Medication Safety Unit, Center of Research Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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Wang SJ, Ye W, Li WY, Tian W, Zhang M, Sun Y, Feng YD, Liu CX, Liu SY, Cao W, Meng JR, Li XQ. Effects and mechanisms of Xiaochaihu Tang against liver fibrosis: An integration of network pharmacology, molecular docking and experimental validation. JOURNAL OF ETHNOPHARMACOLOGY 2023; 303:116053. [PMID: 36529247 DOI: 10.1016/j.jep.2022.116053] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 12/05/2022] [Accepted: 12/10/2022] [Indexed: 06/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Liver fibrosis is a potentially harmful chronic liver disease caused by various etiologies. There is currently no specific drug for liver fibrosis. Xiaochaihu Tang (XCHT) is a traditional formula combined of seven herbs, which was first recorded in the Treatise on Febrile Diseases in Han Dynasty of ancient China. It is widely used in clinic to hepatic protection, analgesic, antipyretic and anti-inflammatory treatment. And it has been recommended for treating chronic hepatitis and chronic cholecystitis in the latest guidelines for the diagnosis and treatment of liver fibrosis with integrated traditional and western medicine. However, the underlying regulatory mechanisms remain elusive. AIM OF THE STUDY This study aims to explore the therapeutic effects of XCHT on liver fibrosis and its underlying molecular mechanisms from the perspective of network pharmacology and experimental research. MATERIALS AND METHODS Carbon tetrachloride (CCl4) induced and bile duct ligation (BDL) induced liver fibrosis models in mice were established to evaluate the anti-fibrosis effects of XCHT in vivo. Potential anti-fibrosis targets of XCHT were screened via network establishment. The underlying mechanisms were uncovered through GO and pathway enrichment analysis. Then, the core targets were identified from protein-protein interaction network by means of the Cytohubba plug-in of Cytoscape. Furthermore, two effective monomer components of XCHT were recognized by molecular docking. Moreover, the predicted components and pathways were verified by in vitro experiments. RESULTS When treated with XCHT, liver fibrosis was alleviated in both mice models, showing as the improvement of liver function, the protection of hepatocytes, the inhibition of HSC activation and the reduction of hepatic collagen accumulation. 540 monomer components, 300 therapeutic targets, 109 signaling pathways, 246 GO biological processes, 77 GO cellular components, 107 GO molecular functions items and core targets were identified by network analysis. Then, 6-gingerol and baicalein were identified as the core components of anti-fibrosis effects of XCHT via leptin or Nrf2 signaling pathway. Furthermore, the experiment in vitro also validated the results. CONCLUSIONS Our study suggests XCHT could alleviate liver fibrosis through multi-targets and multi-pathways; 6-gingerol and baicalein are its core components which may play an important role via leptin or Nrf2 signaling pathway.
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Affiliation(s)
- Shou-Jia Wang
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Key Laboratory of Qin Medicine R&D of the Shaanxi Province Administration of Traditional Chinese Medicine, Xi'an, Shaanxi, 710032, China
| | - Wen Ye
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Key Laboratory of Qin Medicine R&D of the Shaanxi Province Administration of Traditional Chinese Medicine, Xi'an, Shaanxi, 710032, China
| | - Wan-Yi Li
- School of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, 150081, China
| | - Wen Tian
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Key Laboratory of Qin Medicine R&D of the Shaanxi Province Administration of Traditional Chinese Medicine, Xi'an, Shaanxi, 710032, China
| | - Meng Zhang
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Key Laboratory of Qin Medicine R&D of the Shaanxi Province Administration of Traditional Chinese Medicine, Xi'an, Shaanxi, 710032, China
| | - Yang Sun
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Key Laboratory of Qin Medicine R&D of the Shaanxi Province Administration of Traditional Chinese Medicine, Xi'an, Shaanxi, 710032, China
| | - Ying-Da Feng
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Key Laboratory of Qin Medicine R&D of the Shaanxi Province Administration of Traditional Chinese Medicine, Xi'an, Shaanxi, 710032, China
| | - Chen-Xu Liu
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Key Laboratory of Qin Medicine R&D of the Shaanxi Province Administration of Traditional Chinese Medicine, Xi'an, Shaanxi, 710032, China
| | - Shao-Yuan Liu
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Key Laboratory of Qin Medicine R&D of the Shaanxi Province Administration of Traditional Chinese Medicine, Xi'an, Shaanxi, 710032, China
| | - Wei Cao
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Department of Pharmacy, School of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Jing-Ru Meng
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Key Laboratory of Qin Medicine R&D of the Shaanxi Province Administration of Traditional Chinese Medicine, Xi'an, Shaanxi, 710032, China.
| | - Xiao-Qiang Li
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Key Laboratory of Qin Medicine R&D of the Shaanxi Province Administration of Traditional Chinese Medicine, Xi'an, Shaanxi, 710032, China.
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Zhang G, Zhao X, Cai J, Li S, Li X, Li W, Shi P, Liu D, Zheng D, Zhang T, Feng R, Liu H. XCHT alleviates the pancreatic fibrosis via VDR/NLRP3 signaling pathway in a mouse model of CP. JOURNAL OF ETHNOPHARMACOLOGY 2023; 300:115689. [PMID: 36096349 DOI: 10.1016/j.jep.2022.115689] [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: 04/19/2022] [Revised: 08/29/2022] [Accepted: 08/30/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Xiao Chai Hu Tang (XCHT) derived from the classic medical book Shang Han Lun (Treatise on Febrile Diseases) in the Eastern Han Dynasty, which has been widely used in China and other Asian countries for the treatment of inflammation and fibrosis of chronic pancreatitis (CP), but the therapeutic mechanism of XCHT in pancreatic fibrosis remains unclear. AIM OF THE STUDY This study aimed to evaluate the intervention effects and explore pharmacological mechanism of XCHT on inflammation and fibrosis in cerulein-induced CP model. MATERIALS AND METHODS Fifty male C57BL/6 mice were randomly divided into five main groups, 10 animals in each: Control, CP model (50 μg/kg cerulein), high dose XCHT-treated CP group (60 g/kg XCHT), medium dose XCHT-treated CP group (30 g/kg XCHT) and low dose XCHT-treated CP group (15 g/kg XCHT). Different doses of XCHT were given to mice by gavage twice a day for 2 weeks after the CP model induction. Pancreatic tissues were harvested and the pancreatic inflammation and fibrosis were evaluated by histological score, Sirius red staining, and alpha-smooth muscle actin (α-SMA) immunohistochemical staining. ELISA, IHC and RT-qPCR were performed to detect the expression of Vitamin D3 (VD3) and Vitamin D receptor (VDR) in serum and pancreatic tissues, respectively. The expressions of NLRP3 inflammasome related genes and molecules were assayed by WB, IHC and RT-qPCR. RESULTS The pathohistological results demonstrated that XCHT markedly inhibited the fibrosis and chronic inflammation of cerulein-induced CP, indicated by reduction of collagen I, collagen III, α-SMA, and NLRP3 expressions. XCHT significantly increased VD3 and VDR expression while reduced the pancreatic NLRP3 expression. Correspondingly, XCHT decreased the levels of NLRP3 downstream targets IL-1β, TNF-α and IL-6. CONCLUSIONS These results revealed that XCHT suppressed the pancreatic fibrosis and chronic inflammation in cerulein-induced CP model by enhancing the VD3/VDR expression and inhibiting the secretion of NLRP3-assoicated inflammatory factors.
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Affiliation(s)
- Guixian Zhang
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Xiumei Zhao
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Jun Cai
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Sainan Li
- Graduate School of Tianjin Medical University, Tianjin, 300070, China
| | - Xijing Li
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Wenchang Li
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Pengcheng Shi
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Dawei Liu
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Duo Zheng
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Ting Zhang
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Renrui Feng
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Hongbin Liu
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China.
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Xiaochaihu Decoction Treatment of Chicken Colibacillosis by Improving Pulmonary Inflammation and Systemic Inflammation. Pathogens 2022; 12:pathogens12010030. [PMID: 36678378 PMCID: PMC9862048 DOI: 10.3390/pathogens12010030] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/14/2022] [Accepted: 12/19/2022] [Indexed: 12/28/2022] Open
Abstract
Chicken colibacillosis-the most common disease of poultry, is caused mainly by avian pathogenic Escherichia coli (APEC). It has a major impact on the poultry industry worldwide. The present study was conducted to investigate the therapeutic effects of Xiaochaihu Decoction (XCHD) supplementation on clinical manifestation, organ index, bacterial load in organ and inflammatory mediators in a chicken model challenged with APEC. The results showed that all doses of XCHD significantly elevated the survival rate of infected chickens. XCHD improved the clinical signs of infected chickens, reduced the organ index, reduced the bacterial load of organs, and inhibited the secretion of serum and pulmonary inflammatory factors IL-1β, IL-6 and TNF- α. Taken together, this study demonstrates that XCHD had protective effects on APEC-infected chickens. Its mechanism includes anti-inflammatory and antibacterial effects. These findings may contribute to the further study of the mechanism of the formula and the prevention or treatment of colibacillosis in poultry. The significance of this study is that it provides a certain theoretical basis for the replacement of antibiotics by XCHD.
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Xu X, Liu S, Zhao Y, Wang M, Hu L, Li W, Xu H. Combination of Houttuynia cordata polysaccharide and Lactiplantibacillus plantarum P101 alleviates acute liver injury by regulating gut microbiota in mice. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2022; 102:6848-6857. [PMID: 35639719 DOI: 10.1002/jsfa.12046] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/16/2022] [Accepted: 05/31/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Polysaccharides and probiotics can play an outstanding role in the treatment of liver disease by regulating gut microbiota. Recently, the combined therapeutic effect of probiotics and polysaccharides has attracted the attention of researchers. Houttuynia cordata polysaccharide (HCP) combined with Lactiplantibacillus plantarum P101 was used to prevent carbon tetrachloride (CCl4 )-induced acute liver injury (ALI) in mice, and its effect on gut microbiota regulation was explored. RESULTS Results showed that, in mice, HCP combined with L. plantarum P101 significantly alleviated oxidative stress and inflammatory injury in the liver by activating Nrf2 signals and inhibiting NF-κB signals. The analysis of gut microbiota revealed that the combination of HCP and L. plantarum P101 increased the abundance of beneficial bacteria such as Alloprevotella, Roseburia, and Akkermansia, but reduced that of the pro-inflammatory bacteria Alistipes, Enterorhabdus, Anaerotruncus, and Escherichia-Shigella. Correlation analysis also indicated that the expression of Nrf2 and TLR4/NF-κB was connected to the changes in gut microbiota composition. Houttuynia cordata polysaccharide combined with L. plantarum P101 can regulate the gut microbiota and then mediate the gut-liver axis to activate the antioxidant pathway and inhibit inflammatory responses, thereby alleviating CCl4 -induced ALI. CONCLUSION Our study provided a new perspective on the use of polysaccharides combined with probiotics in the treatment of liver disease. © 2022 Society of Chemical Industry.
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Affiliation(s)
- Xiaowei Xu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
| | - Shanji Liu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
| | - Yu Zhao
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
| | - Mengqi Wang
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
| | - Liehai Hu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
| | - Wenjuan Li
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
| | - Hengyi Xu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
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Ameliorative Impacts of Wheat Germ Oil against Ethanol-Induced Hepatic and Renal Dysfunction in Rats: Involvement of Anti-Inflammatory, Anti-Apoptotic, and Antioxidant Signaling Pathways. LIFE (BASEL, SWITZERLAND) 2022; 12:life12101671. [PMID: 36295108 PMCID: PMC9605469 DOI: 10.3390/life12101671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 10/19/2022] [Accepted: 10/19/2022] [Indexed: 11/07/2022]
Abstract
Wheat germ oil (WGO) is a well-known product with anti-inflammatory and antioxidant properties. The current study aimed to investigate the impacts of WGO against ethanol-induced liver and kidney dysfunction at the serum, anti-inflammatory, antioxidants and anti-apoptotic signaling pathways. Rats received saline orally as a negative control or WGO in a dose of 1.5 mL/kg (1400 mg/kg body weight orally) for 15 days. The affected group received ethanol 50% v/v 10 mL/kg (5 g/kg) body weight orally once a day for consecutive 15 days to induce hepatorenal injuries in ethanolic non-treated group. The protective group received WGO daily 1 h before ethanol administration. Serum (1.5 mL) from blood was extracted and examined for the changes in biochemical assessments in serum alkaline phosphatase (ALP), alanine aminotransferase (ALT), bilirubin, serum γ-glutamyl transpeptidase (GGT), total protein, serum albumin, butyrylcholinesterase (BChE), total cholesterol (TC), total triglyceride (TG), urea, creatinine, uric acid, potassium (K+), Beta-2 microglobulin (β2M), malondialdehyde (MDA), catalase (CAT), reduced glutathione (GSH), superoxide dismutase (SOD) and aspartate aminotransferase (AST). Kidney and liver homogenate was used to measure MDA, GSH and catalase activities. Quantitative real time PCR (qRT-PCR) was used to express Nrf2 and HO-1 in liver, and NF-kB and kidney injury molecule (KIM-1) in kidneys, which are correlated with oxidative stress and inflammation. Capase-3 and Bcl2 genes were examined using immunohistochemical analysis in the kidney and liver. Ethanol administration induced significant alteration in examined liver and kidney markers (AST, ALT, GGT, ALP, total proteins, urea, creatinine and uric acid). Moreover, alcohol administration decreased antioxidant activities at serum and hepatorenal tissues (GSH, catalase and SOD), while MDA was increased as a tissue degradation marker. Inflammatory cytokines, together with genes of oxidative stress markers (Nrf2 and HO-1), were all affected. At cellular levels, apoptotic marker caspase-3 was upregulated, while antiapoptotic marker B-cell lymphoma 2 (Bcl2), was down regulated using immunohistochemical analysis. Of interest, pretreatment with WGO improved the side effects induced by ethanol on hepatic, renal biomarkers and reversed its impact on serum and tissue antioxidant parameters. Nrf2/HO-1 were upregulated, while NFk-B and KIM-1 were downregulated using real time PCR. Immune reactivities of caspase-3 and Bcl2 genes were restored in the protective group. In conclusion, WGO ameliorated ethanol-induced hepatic and renal dysfunction at the biochemical, molecular and cellular levels by regulating some mechanisms that controls oxidative stress, apoptosis, inflammation and anti-apoptotic pathways.
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Li WQ, Liu WH, Qian D, Liu J, Zhou SQ, Zhang L, Peng W, Su L, Zhang H. Traditional Chinese medicine: An important source for discovering candidate agents against hepatic fibrosis. Front Pharmacol 2022; 13:962525. [PMID: 36081936 PMCID: PMC9445813 DOI: 10.3389/fphar.2022.962525] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 07/28/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatic fibrosis (HF) refers to the pathophysiological process of connective tissue dysplasia in the liver caused by various pathogenic factors. Nowadays, HF is becoming a severe threat to the health of human being. However, the drugs available for treating HF are limited. Currently, increasing natural agents derived from traditional Chinese medicines (TCMs) have been found to be beneficial for HF. A systemic literature search was conducted from PubMed, GeenMedical, Sci-Hub, CNKI, Google Scholar and Baidu Scholar, with the keywords of "traditional Chinese medicine," "herbal medicine," "natural agents," "liver diseases," and "hepatic fibrosis." So far, more than 76 natural monomers have been isolated and identified from the TCMs with inhibitory effect on HF, including alkaloids, flavones, quinones, terpenoids, saponins, phenylpropanoids, and polysaccharides, etc. The anti-hepatic fibrosis effects of these compounds include hepatoprotection, inhibition of hepatic stellate cells (HSC) activation, regulation of extracellular matrix (ECM) synthesis & secretion, regulation of autophagy, and antioxidant & anti-inflammation, etc. Natural compounds and extracts from TCMs are promising agents for the prevention and treatment of HF, and this review would be of great significance to development of novel drugs for treating HF.
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Affiliation(s)
- Wen-Qing Li
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wen-Hao Liu
- Department of Pharmacy, Tenth People’s Hospital of Tongji University, Shanghai, China
| | - Die Qian
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jia Liu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shi-Qiong Zhou
- Hospital of Nursing, The Second Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Lei Zhang
- Department of Vascular Surgery, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wei Peng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Li Su
- Institute of Translational Medicine, Shanghai University, Shanghai, China
| | - Hong Zhang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Wang FD, Zhou J, Chen EQ. Molecular Mechanisms and Potential New Therapeutic Drugs for Liver Fibrosis. Front Pharmacol 2022; 13:787748. [PMID: 35222022 PMCID: PMC8874120 DOI: 10.3389/fphar.2022.787748] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 01/17/2022] [Indexed: 12/11/2022] Open
Abstract
Liver fibrosis is the pathological process of excessive extracellular matrix deposition after liver injury and is a precursor to cirrhosis, hepatocellular carcinoma (HCC). It is essentially a wound healing response to liver tissue damage. Numerous studies have shown that hepatic stellate cells play a critical role in this process, with various cells, cytokines, and signaling pathways engaged. Currently, the treatment targeting etiology is considered the most effective measure to prevent and treat liver fibrosis, but reversal fibrosis by elimination of the causative agent often occurs too slowly or too rarely to avoid life-threatening complications, especially in advanced fibrosis. Liver transplantation is the only treatment option in the end-stage, leaving us with an urgent need for new therapies. An in-depth understanding of the mechanisms of liver fibrosis could identify new targets for the treatment. Most of the drugs targeting critical cells and cytokines in the pathogenesis of liver fibrosis are still in pre-clinical trials and there are hardly any definitive anti-fibrotic chemical or biological drugs available for clinical use. In this review, we will summarize the pathogenesis of liver fibrosis, focusing on the role of key cells, associated mechanisms, and signaling pathways, and summarize various therapeutic measures or drugs that have been trialed in clinical practice or are in the research stage.
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Affiliation(s)
| | | | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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Soliman MM, Alotaibi SS, Sayed S, Hassan MM, Althobaiti F, Aldhahrani A, Youssef GBA, El-Shehawi AM. The Protective Impact of Salsola imbricata Leaf Extract From Taif Against Acrylamide-Induced Hepatic Inflammation and Oxidative Damage: The Role of Antioxidants, Cytokines, and Apoptosis-Associated Genes. Front Vet Sci 2022; 8:817183. [PMID: 35155650 PMCID: PMC8835116 DOI: 10.3389/fvets.2021.817183] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 12/21/2021] [Indexed: 12/22/2022] Open
Abstract
Salsola imbricata is a herbal plant native to Saudi Arabia, known for its antioxidative and anti-inflammatory properties. This study explored the protective effects of an ethanolic leaf extract of Salsola imbricata against the oxidative stress and hepatic injury caused by acrylamide. Rats received intragastric administrations of 20 mg/kg of body weight of acrylamide to induce hepatic injury, or 300 mg/kg of body weight of Salsola ethanolic extract orally for 7 days before acrylamide administration. The treatments were continued for 3 weeks. Blood and liver samples were collected from all the groups, and the following biochemical parameters were tested: serum ALT (alanine aminotransferase), AST (aspartate aminotransferase), GGT (gamma glutaryl transferase), urea, albumin, total proteins, catalase, SOD (superoxide dismutase), reduced glutathione (GSH), nitric oxide (NO), and MDA (malondialdehyde). Quantitative real-time PCR (qRT-PCR) was used to examine the expression of Nrf2 (Nuclear factor-erythroid factor 2-related factor 2), HO-1 (Hemoxygenase-1), COX-2 (Cyclooxgenase-2), TGF-β1 (transforming growth factor-beta1), Bax, and Bcl2 (B-cell lymphoma 2), which are associated with oxidative stress, fibrosis, apoptosis, and anti-apoptotic effects. The annexin and survivin immunoreactivity were examined at the immunohistochemical level. Pretreatment with the Salsola ethanolic extract reduced the negative impact of acrylamide on ALT, AST, GGT, urea, albumin, and total proteins. The Salsola ethanolic extract reversed acrylamide's effects on serum and tissue antioxidants. Nrf2/HO-1 expression was downregulated, while COX-2 and TGF-β1 were upregulated in the acrylamide-administered group and normalized by the pre-administration of Salsola ethanolic extract to the acrylamide experimental group. The immunoreactivity of annexin and survivin was restored in the experimental group administered Salsola ethanolic extract plus acrylamide. In conclusion, Salsola ethanolic extract inhibits and regulates the side effects induced in the liver by acrylamide. Salsola induced its impacts by regulating inflammation, oxidative stress, and apoptosis-/anti-apoptosis-associated genes at the biochemical, molecular, and cellular levels. Salsola is recommended as oxidative stress relievers against environmental toixicity at high altitude areas.
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Affiliation(s)
- Mohamed Mohamed Soliman
- Clinical Laboratory Sciences Department, Turabah University College, Taif University, Taif, Saudi Arabia
- *Correspondence: Mohamed Mohamed Soliman
| | - Saqer S. Alotaibi
- Department of Biotechnology, College of Science, Taif University, Taif, Saudi Arabia
| | - Samy Sayed
- Department of Science and Technology, University College-Ranyah, Taif University, Taif, Saudi Arabia
| | - Mohamed M. Hassan
- Department of Biology, College of Science, Taif University, Taif, Saudi Arabia
| | - Fayez Althobaiti
- Department of Biotechnology, College of Science, Taif University, Taif, Saudi Arabia
| | - Adil Aldhahrani
- Clinical Laboratory Sciences Department, Turabah University College, Taif University, Taif, Saudi Arabia
| | - Gehan B. A. Youssef
- Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, Benha University, Benha, Egypt
| | - Ahmed M. El-Shehawi
- Department of Biotechnology, College of Science, Taif University, Taif, Saudi Arabia
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21
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Chen HJ, Huang JY, Ko CY. Peach Kernel Extracts Inhibit Lipopolysaccharide-Induced Activation of HSC-T6 Hepatic Stellate Cells. Int J Clin Pract 2022; 2022:4869973. [PMID: 36105786 PMCID: PMC9444415 DOI: 10.1155/2022/4869973] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 08/06/2022] [Indexed: 11/21/2022] Open
Abstract
There is an important role for hepatic stellate cells (HSCs) in liver fibrosis. As it stands, many traditional Chinese medicine formulations can effectively improve liver fibrosis, whether it is clinically used or in animal studies; however, the efficacy and mechanism of the main formulations remain unclear, including the peach kernel, which contains numerous phytochemicals with a wide range of biological activities. The purpose of this study was to investigate peach kernel's anti-liver fibrosis effects. In this study, peach kernel extracts inhibited lipopolysaccharide (LPS) activation in HSC-T6 cells and the expression of α-smooth muscle actin and connective tissue growth factor induced by LPS in HSC-T6 cells. Furthermore, peach kernel extracts inhibited signal transducers involving protein kinase B and mitogen-activated protein kinase, which regulate downstream genes associated with inflammation. As a result, peach kernel extracts inhibited inflammatory responses and subsequently inhibited LPS-induced transformation of activated HSC-T6 cells.
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Affiliation(s)
- Hong-Jie Chen
- Department of Clinical Nutrition, People's Hospital of Leshan, Leshan 614000, China
| | - Jin-Yuan Huang
- Department of Clinical Nutrition, Suzhou Dushu Lake Hospital, Suzhou 215123, Jiangsu, China
| | - Chih-Yuan Ko
- Department of Clinical Nutrition, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, China
- School of Public Health, Fujian Medical University, Fuzhou 350122, Fujian, China
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22
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Jia Z, Yang F, Liu X, Zhang X, Hu W, Sheng Z. The n-butanol fraction of the Xiao-Chai-Hu decoction alleviates the endocrine disturbance in the liver of mice exposed to lead. JOURNAL OF ETHNOPHARMACOLOGY 2021; 279:114381. [PMID: 34197961 DOI: 10.1016/j.jep.2021.114381] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 06/26/2021] [Accepted: 06/26/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Lead is a toxic heavy metal that causes health risks globally. However, the mechanism of endocrine poisoning and detoxification of lead poisoning, especially in the liver, still needs to be studied. Xiao-Chai-Hu decoction (XCHD) is regarded as an antidote and an anti-hepatotoxic traditional prescription that has been recorded in the pharmacopeia of the People's Republic of China. AIM OF THE STUDY The study aimed to probe the hepatoprotective activity of XCHD in the regulation of endocrine dysfunction in the liver and its molecular mechanism. MATERIALS AND METHODS The mice from the Institute of Cancer Research (ICR) were exposed to different concentrations of XCHD and lead. Then, serum biochemical indices and liver pathology were analyzed. The key differential genes were detected by qRT-PCR and Western blot. RESULTS According to the biochemical and histopathological analysis, XCHD-NBA was the most effective in attenuating lead-induced hepatotoxicity. From the transcriptome, we analyzed the key genes of XCHD-NBA in the regulation of lead toxicity, including Tubb2a, Stip1, Cyp4a12a, Cyp2c50, Ugt1a1, Cyp3a11, Cyp4a12b, Ahsa1, Cyp2c54, Tubb4b, Esr1, Hsp90aa1, Tuba1a, Tuba1c, and Hsph1. We also analyzed the main components of XCHD-NBA by LC-MS. Because of their extensive role in regulating the endocrine function, baicalin and glycyrrhizin were identified as the main active components of XCHD in regulating endocrine disorders caused by lead. CONCLUSIONS Lead can disturb the endocrine regulatory process of the liver, while XCHD-NBA alleviates lead-induced liver injury by regulating the endocrine regulatory process.
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Affiliation(s)
- Zheng Jia
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, PR China
| | - Fan Yang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Xiaoqing Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Xiaomeng Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Wanjun Hu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Zunlai Sheng
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, PR China.
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23
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Systematic analysis of the mechanism of Xiaochaihu decoction in hepatitis B treatment via network pharmacology and molecular docking. Comput Biol Med 2021; 138:104894. [PMID: 34607274 DOI: 10.1016/j.compbiomed.2021.104894] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/18/2021] [Accepted: 09/22/2021] [Indexed: 12/18/2022]
Abstract
Hepatitis B (HB) is a globally prevalent infectious disease caused by the HB virus. Xiaochaihu decoction (XCHD) is a classic herbal formula with a long history of clinical application in treating HB. Although the anti-HB activity of XCHD has been reported, systematic research on the exact mechanism of action is lacking. Here, a network pharmacology-based approach was used to predict the active components, important targets, and potential mechanism of XCHD in HB treatment. Investigation included drug-likeness evaluation; absorption, distribution, metabolism, and elimination (ADME) screening; protein-protein interaction (PPI) network construction and cluster analysis; Gene Ontology (GO) analysis; and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation. Molecular docking was adopted to investigate the interaction between important target proteins and active components. Eighty-seven active components of XCHD and 155 anti-HB targets were selected for further analysis. The GO enrichment and similarity analysis results indicated that XCHD might perform similar or the same GO functions. Glycyrrhizae Radix (GR), one of the seven XCHD herbs, likely exerts some unique GO functions such as the regulation of interleukin-12 production, positive regulation of interleukin-1 beta secretion, and regulation of the I-kappaB/NF-kappaB complex. The PPI network and KEGG pathway analysis results showed that XCHD affects HB mainly through modulating pathways related to viral infection, immunity, cancer, signal transduction, and metabolism. Additionally, molecular docking verified that the active compounds (quercetin, chrysin, and capsaicin) could bind with the key targets. This work systematically explored the anti-HB mechanism of XCHD and provides a novel perspective for future pharmacological research.
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Huang K, Zhang P, Zhang Z, Youn JY, Wang C, Zhang H, Cai H. Traditional Chinese Medicine (TCM) in the treatment of COVID-19 and other viral infections: Efficacies and mechanisms. Pharmacol Ther 2021; 225:107843. [PMID: 33811957 PMCID: PMC8011334 DOI: 10.1016/j.pharmthera.2021.107843] [Citation(s) in RCA: 310] [Impact Index Per Article: 77.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 03/27/2021] [Accepted: 03/29/2021] [Indexed: 02/06/2023]
Abstract
COVID-19 has remained an uncontained, worldwide pandemic. While battling for the disease in China, six Traditional Chinese Medicine (TCM) recipes have been shown to be remarkably effective for treating patients with COVID-19. The present review discusses principles of TCM in curing infectious disease, and clinical evidence and mechanisms of the 6 most effective TCM recipes used in treating COVID-19 in 92% of all of the confirmed cases in China. Applications of TCM and specific recipes in the treatment of other viral infections, such as those caused by SARS-CoV, MERS-CoV, hepatitis B virus, hepatitis C virus, influenza A virus (including H1N1 and H7N9), influenza B, dengue virus as well as Ebola virus, are also discussed. Among the 6 TCM recipes, Jinhua Qinggan (JHQG) granules and Lianhua Qingwen (LHQW) capsules are recommended during medical observation; Lung Cleansing and Detoxifying Decoction (LCDD) is recommended for the treatment of both severe and non-severe patients; Xuanfeibaidu (XFBD) granules are recommended for treating moderate cases; while Huashibaidu (HSBD) and Xuebijing (XBJ) have been used in managing severe cases effectively. The common components and the active ingredients of the six TCM recipes have been summarized to reveal most promising drug candidates. The potential molecular mechanisms of the active ingredients in the six TCM recipes that target ACE2, 3CLpro and IL-6, revealed by molecular biological studies and/or network pharmacology prediction/molecular docking analysis/visualization analysis, are fully discussed. Therefore, further investigation of these TCM recipes may be of high translational value in enabling novel targeted therapies for COVID-19, potentially via purification and characterization of the active ingredients in the effective TCM recipes.
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Affiliation(s)
- Kai Huang
- Department of Anesthesiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, United States of America
| | - Pan Zhang
- Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Zhenghao Zhang
- Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Ji Youn Youn
- Department of Anesthesiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, United States of America
| | - Chen Wang
- Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China; Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China.
| | - Hongchun Zhang
- Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.
| | - Hua Cai
- Department of Anesthesiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, United States of America.
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Cai S, Wu L, Yuan S, Liu G, Wang Y, Fang L, Xu D. Carvacrol alleviates liver fibrosis by inhibiting TRPM7 and modulating the MAPK signaling pathway. Eur J Pharmacol 2021; 898:173982. [PMID: 33647257 DOI: 10.1016/j.ejphar.2021.173982] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/15/2021] [Accepted: 02/23/2021] [Indexed: 01/18/2023]
Abstract
Liver fibrosis is a compensatory response to the tissue repair process. The activation and proliferation of hepatic stellate cells (HSCs) are thought to be related to the occurrence of hepatic fibrosis. Therefore, inhibiting the activation and proliferation of HSCs is a key step in alleviating liver fibrosis. As a non-specific inhibitor of transient receptor potential melastatin 7 (TRPM7), carvacrol has anti-tumor, anti-inflammatory and anti-hepatic fibrosis activities. This study aimed to explore the protective effect of carvacrol on liver fibrosis and related molecular mechanisms. A CCl4-induced liver fibrosis mouse model and platelet-derived growth factor (PDGF-BB)-activated HSC-T6 cells (a rat hepatic stellate cell line) were employed for in vivo and in vitro experiments. C57BL/6J mice were orally administered different concentrations of carvacrol every day for 6 weeks during the development of CCl4-induced liver fibrosis. The results show that carvacrol could effectively reduce liver damage and the progression of liver fibrosis in mice, which are expressed as fibrotic markers levels were reduced and histopathological characteristics were improved. Moreover, carvacrol inhibited the proliferation and activation of HSC-T6 cells induced by PDGF-BB. In addition, it was found that carvacrol inhibits the expression of TRPM7 and mediated through mitogen-activated protein kinases (MAPK). Collectively, our study shows that carvacrol can reduce liver fibrosis by inhibiting the activation and proliferation of hepatic stellate cells, and the MAPK signaling pathway might be involved in this process.
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Affiliation(s)
- Shiyi Cai
- Inflammation and Immune Mediated Diseases Laboratory of Anhui, Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Lijun Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui, Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Siyu Yuan
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Guofang Liu
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yalu Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui, Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Ling Fang
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
| | - Dujuan Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui, Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China; Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
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Soliman MM, Aldhahrani A, Alghamdi YS, Said AM. Impact of Thymus vulgaris extract on sodium nitrite-induced alteration of renal redox and oxidative stress: Biochemical, molecular, and immunohistochemical study. J Food Biochem 2021; 46:e13630. [PMID: 33769578 DOI: 10.1111/jfbc.13630] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 01/09/2021] [Accepted: 01/12/2021] [Indexed: 01/22/2023]
Abstract
Thyme (Thymus vulgaris) is an herbal plant with pleiotropic medicinal properties. In this study, we examined the possible protective effect of an ethanolic extract of thyme leaves against the renal oxidative stress induced by sodium nitrite (NaNO2 ). Male Swiss mice received either saline or thyme extract for 15 days (0.5 g/kg body weight, orally). NaNO2 (60 mg/kg) was injected intraperitoneally at Day 14. The protective group received the thyme extract for 15 days and NaNO2 on Day 14. Blood and kidney samples were taken from all groups to measure serum urea, blood urea nitrogen (BUN), creatinine, serum, tissue antioxidant activity, and the inflammatory cytokines IL-1β and IL-6. Quantitative real-time PCR (qRT-PCR) was used to examine the expression of kidney injury marker-1 (Kim-1), TNF-α, nuclear factor erythroid-2 related factor 2 (Nrf2), and hemoxygenase-1 (HO-1), all of which are associated with kidney redox and oxidative stress. Pretreatment with thyme extract reduced the effects of NaNO2 on urea, BUN, and creatinine, and reversed its effect on tissue and serum antioxidants. NaNO2 -induced nephritis as demonstrated by the upregulation in mRNA expression of Kim-1 and TNF-α, which was, however, recovered and protected by pretreatment with thyme extract. Expression of Nrf2 and HO-1 was upregulated by treatment with thyme extract and downregulated by NaNO2 intoxication. NaNO2 -induced congestion in glomeruli and dilatation of the renal tubules, conditions that were restored in the group pretreated with thyme extract. NaNO2 upregulated Bax immunoreactivity and caused apoptosis in renal structures. Thus, thyme extract is effective in managing the renal toxicity associated with oxidative stress and renal redox. PRACTICAL APPLICATIONS: The results from this study have shown that use of thyme extract may promote better health due to its high antioxidant activity. For instance, it could be ingested to alleviate the symptoms of renal inflammation and oxidative stress associated with nitrite toxicity. Thyme extract regulated renal redox, oxidative stress, antioxidant levels, and inflammation-associated genes at the molecular, biochemical, and cellular immunohistochemical levels.
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Affiliation(s)
- Mohamed Mohamed Soliman
- Clinical Laboratory Sciences Department, Turabah University College, Taif University, Taif, Saudi Arabia.,Biochemistry Department, Faculty of Veterinary Medicine, Benha University, Benha, Egypt
| | - Adel Aldhahrani
- Clinical Laboratory Sciences Department, Turabah University College, Taif University, Taif, Saudi Arabia
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Soliman MM, Aldhahrani A, Metwally MMM. Hepatoprotective effect of Thymus vulgaris extract on sodium nitrite-induced changes in oxidative stress, antioxidant and inflammatory marker expression. Sci Rep 2021; 11:5747. [PMID: 33707592 PMCID: PMC7952422 DOI: 10.1038/s41598-021-85264-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 02/28/2021] [Indexed: 02/03/2023] Open
Abstract
The herb thyme (Thymus vulgaris) has multiple therapeutic uses. In this study, we explored how T. vulgaris leaf extract protects liver cells against sodium nitrite-(NaNO2) induced oxidative stress. Mice were divided into four groups; each group received one of the following treatments orally: saline; T. vulgaris extract alone; NaNO2 alone; or T. vulgaris extract + NaNO2. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), reduced glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), IL-1β, IL-6, TNF-α, and total proteins were measured in serum using standard methods. TNF-α, hemooxygenase-1 (HO-1), thioredoxin, SOD, and GSH synthase, all of which are linked to oxidative stress, were measured using quantitative real-time PCR (qRT-PCR). In mice treated with T. vulgaris extract, the effect of NaNO2 on ALT and AST levels and total proteins was reduced, and its effect on antioxidant levels was reversed. Normally, NaNO2 causes hepatocyte congestion and severe hepatic central vein congestion. Tissues in the mice treated with T. vulgaris were restored to normal conditions. Our results demonstrate that NaNO2-induced hepatic injury is significantly reduced by pretreatment with T. vulgaris extract, which protects against hepatic oxidative stress and its associated genes at the biochemical, molecular, and cellular levels.
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Affiliation(s)
- Mohamed Mohamed Soliman
- Clinical Laboratory Sciences Department, Turabah University College, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia. .,Biochemistry Department, Faculty of Veterinary Medicine, Benha University, Benha, 13736, Egypt.
| | - Adil Aldhahrani
- Clinical Laboratory Sciences Department, Turabah University College, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia
| | - Mohammed M M Metwally
- Department of Pathology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44519, Egypt
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The ameliorative impacts of Moringa oleifera leaf extract against oxidative stress and methotrexate-induced hepato-renal dysfunction. Biomed Pharmacother 2020; 128:110259. [DOI: 10.1016/j.biopha.2020.110259] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 05/03/2020] [Accepted: 05/10/2020] [Indexed: 12/25/2022] Open
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29
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Li X, Shao S, Li H, Bi Z, Zhang S, Wei Y, Bai J, Zhang R, Ma X, Ma B, Zhang L, Xie C, Ning W, Zhou H, Yang C. Byakangelicin protects against carbon tetrachloride-induced liver injury and fibrosis in mice. J Cell Mol Med 2020; 24:8623-8635. [PMID: 32643868 PMCID: PMC7412405 DOI: 10.1111/jcmm.15493] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 05/14/2020] [Accepted: 05/24/2020] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a disease caused by long-term damage that is related to a number of factors. The current research on the treatment of liver fibrosis mainly focuses on the activation of hepatic stellate cell, in addition to protecting liver cells. byakangelicin has certain anti-inflammatory ability, but its effect on liver fibrosis is unclear. This study aims to explore whether byakangelicin plays a role in the development of liver fibrosis and to explore its mechanism. We determined that byakangelicin has a certain ability to resist fibrosis and reduce liver cell damage in a model of carbon tetrachloride-induced liver fibrosis in mice. Thereafter, we performed further verification in vitro. The signalling pathways of two important pro-fibrotic cytokines, transforming growth factor-β and platelet-derived growth factor, were studied. Results showed that byakangelicin can inhibit related pathways. According to the hepatoprotective effect of byakangelicin observed in animal experiments, we studied the effect of byakangelicin on 4-HNE-induced hepatocyte (HepG2) apoptosis and explored its related pathways. The results showed that byakangelicin could attenuate 4-HNE-induced hepatocyte apoptosis via inhibiting ASK-1/JNK signalling. In conclusion, byakangelicin could improve carbon tetrachloride-induced liver fibrosis and liver injury by inhibiting hepatic stellate cell proliferation and activation and suppressing hepatocyte apoptosis.
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Affiliation(s)
- Xiaohe Li
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Shuaibo Shao
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Hailong Li
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China
| | - Zhun Bi
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China
| | - Shanshan Zhang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China
| | - Yiying Wei
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Jiakun Bai
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Ruotong Zhang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Xiaoyang Ma
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Bowei Ma
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Liang Zhang
- Department of Thoracic Surgery, Tian Jin First Central Hospital, Tianjin, China
| | - Chunfeng Xie
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Wen Ning
- College of Life Sciences, Nankai University, Tianjin, China
| | - Honggang Zhou
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Cheng Yang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
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30
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Jia W, Liu J, Hu R, Hu A, Tang W, Li L, Li J. Xiaochaihutang Improves the Cortical Astrocyte Edema in Thioacetamide-Induced Rat Acute Hepatic Encephalopathy by Activating NRF2 Pathway. Front Pharmacol 2020; 11:382. [PMID: 32372950 PMCID: PMC7179068 DOI: 10.3389/fphar.2020.00382] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Accepted: 03/12/2020] [Indexed: 12/15/2022] Open
Abstract
Oxidative stress induced by high ammonia, which leads to astrocyte edema, is the key to acute hepatic encephalopathy (AHE). Nuclear factor erythroid 2-related factor 2 (NRF2) has been implicated in oxidative stress, but the mechanism of NRF2 against ammonia-induced astrocytes edema has not been fully studied. We confirmed that the NRF2 pathway is related to brain edema caused by AHE and found that Xiaochaihutang (XCHT) could effectively activate the NRF2 pathway to treat AHE. The model of AHE was established with thioacetamide (TAA) in rats. Rat behaviors were observed, brain water content, blood ammonia levels, glutamine synthetase (GS), malondialdehyde (MDA), and total superoxide dismutase (T-SOD) were determined after XCHT treatment. Furthermore, the expression of NRF2 pathway proteins and mRNA, glial fibrillary acidic protein (GFAP) and aquaporins 4 (AQP4) were examined. In order to determine whether XCHT has a direct effect on cerebral edema caused by high ammonia, we examined the effect of XCHT compound serum on cortical astrocytes in the presence of ammonia, through microscopic observation and immunofluorescence (IF). Results showed that AHE induced by TAA changed the behavior of the rats, and increased brain water content, blood ammonia levels, GS and MDA content meanwhile decreasing T-SOD, but these symptoms were improved by treatment with XCHT. XCHT protected brain edema by activating the NRF2 pathway and increasing the expression of downstream proteins and genes. Astrocytes treated with 5 mM ammonia also showed an increase in the AQP4 protein expression but a decrease in XCHT compound serum and ammonia-induced cell edema groups. This study demonstrates that the NRF2 pathway is involved in the brain edema in AHE, and XCHT may represent a useful prescription for the treatment of AHE.
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Affiliation(s)
- Weiyi Jia
- Key Laboratory of Infectious Disease and Biosafety, and Provincial Department of Education, Zunyi Medical University, Zunyi, China.,Research Center for Medicine and Biology, Zunyi Medical University, Zunyi, China
| | - Jiajia Liu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, China
| | - Rui Hu
- Key Laboratory of Brain Science, Zunyi Medical University, Zunyi, China
| | - Anling Hu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, China
| | - Weiwei Tang
- Department of Pathophysiology, Basic Medical College, Zunyi Medical University, Zunyi, China
| | - Lijuan Li
- Department of Pathophysiology, Basic Medical College, Zunyi Medical University, Zunyi, China
| | - Jin Li
- Key Laboratory of Infectious Disease and Biosafety, and Provincial Department of Education, Zunyi Medical University, Zunyi, China.,Research Center for Medicine and Biology, Zunyi Medical University, Zunyi, China
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31
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Li H. Advances in anti hepatic fibrotic therapy with Traditional Chinese Medicine herbal formula. JOURNAL OF ETHNOPHARMACOLOGY 2020; 251:112442. [PMID: 31891799 DOI: 10.1016/j.jep.2019.112442] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 11/27/2019] [Accepted: 11/27/2019] [Indexed: 06/10/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The process of liver fibrogenesis includes a number of common and etiology-dependent or independent mechanisms and events. Up to now, there are still insufficient approved biological or chemical therapies directly targeting and reversing advanced fibrosis. The key is that once liver fibrosis is triggered, it presents a complex network control model with the activation of HSCs as the core, resulting in poor efficacy of treatment. Traditional Chinese medicine (TCM) has unique advantages in treating hepatic fibrosis because of its syndrome differentiation and treatment and comprehensive pharmacological effects of multi-channel, multi-level and multi-target. However, TCM's advantages were rarely discussed as previous reviews focused on the active ingredients of TCM and single Chinese Medicine. Therefore, this paper focuses on TCM herbal formulae's pharmacological role, target and related mechanisms in the treatment of liver fibrosis. AIM OF THE STUDY This paper will focus on the pharmacological role, target and related mechanisms of TCM herbal formulae in the treatment of liver fibrosis. MATERIALS AND METHODS We collect English literatures or Chinese literatures with English Abstract on the treatment of liver fibrosis with TCM herbal formulae from databases including PubMed, Wiley InterScience, Science Direct OnSite/Elsevier, Ovid, Excerpta Medica Database, SpringLink, CNKI and China Biomedical Literature Database. Based on previous literatures, we summarize the TCM herbal formulae with definite anti-hepatic fibrosis effects. RESULTS To some extent, classical or modern TCM herbal formulae including Yinchenhao Decoction (YCHD), Xiayuxue Decoction (XYXD), Xiaochaihutang (XCHT), Yiguanjian Decoction (YGJ), Huangqi Decoction (HQD), Dahuang Zhechong Pills (DHZC), Fuzheng Huayu Formula (FZHY), Fufang Biejia Ruangan Tablets (FFBJRG), Anluo Huaxian Pills (ALHX) and Compound 861 (Cpd861) have anti-hepatic fibrosis effect both on patients with liver fibrosis and animal models with liver fibrosis. CONCLUSION According to the principle of syndrome differentiation and treatment, Liver fibrosis patients with different syndromes are treated with different herbal formula, which increases the difficulty of clinical efficacy research. YCHD and XYXD research lack randomized and controlled clinical trials. XCHT, YGJ and HQD research has small sample sizes despite randomized and controlled clinical trials. In contrast, most modern herbal formulae have randomized and controlled clinical trials. For instance, FZHY and ALHX recently published the research results of the combination of entecavir in the treatment of patients with chronic hepatitis B liver fibrosis or cirrhosis. Compared to anti-viral treatment with entecavir alone, this method has improved the reversion rate of liver fibrosis but still needs syndrome classification therapy of TCM. TCM Herbal formulae have a good prospect in treating liver fibrosis, but its composition of multiple drugs and a wide range of targets intensify the difficulty of studying their anti-hepatic fibrosis mechanisms. Future research needs to further study the anti-hepatic fibrosis mechanisms and select corresponding TCM herbal formula to treat patients with different syndromes of liver fibrosis or the same patient with different syndromes at different stages to achieve better curative results.
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Affiliation(s)
- Hui Li
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, NO. 39 Shi-er-qiao Road, Chengdu, 610072, Sichuan Province, PR China.
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Li S, Zhou J, Xu S, Li J, Liu J, Lu Y, Shi J, Zhou S, Wu Q. Induction of Nrf2 pathway by Dendrobium nobile Lindl. alkaloids protects against carbon tetrachloride induced acute liver injury. Biomed Pharmacother 2019; 117:109073. [PMID: 31212129 DOI: 10.1016/j.biopha.2019.109073] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 05/25/2019] [Accepted: 06/02/2019] [Indexed: 12/18/2022] Open
Abstract
Dendrobium nobile Lindl. alkaloids (DNLA), the active ingredients of Dendrobium, has been shown to possess anti-oxidative effects. The nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant signaling pathway plays a critical role in the cellular response to oxidative stress. Oxidative damage has been implicated in the mechanism of various hepatotoxins induced liver injury. The present study aimed to examine the protective effects of DNLA on CCl4-induced acute liver injury, and to explore the role of the Nrf2 pathway in the protective action of DNLA. Wild-type (WT) and Nrf2-knockout (Nrf2-/-) mice were administrated with DNLA (20 mg/kg/day, ig) for 7 days, and then challenged with CCl4 (20 μL/kg, ip). In WT mice, DNLA reduced CCl4 induced liver injury, as evidenced by the reduction in the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), attenuation of malondialdehyde (MDA) production, and improved ultrastructural morphology in hepatocytes. However, the protective effect was diminished in Nrf2-/- mice, indicating an essential role of Nrf2 in DNLA-mediated protection over CCl4 liver injury. Furthermore, it was found that DNLA enhanced Nrf2 expression and nuclear accumulation and increased the expression of Nrf2 regulated downstream proteins. These results demonstrate that DNLA protects mice from CCl4 induced liver injury, probably through the activation of the Nrf2 signaling pathway.
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Affiliation(s)
- Shiyue Li
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563003, China
| | - Jinxin Zhou
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563003, China
| | - Shangfu Xu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563003, China
| | - Jin Li
- Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, Guizhou, 563003, China
| | - Jie Liu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563003, China
| | - Yuanfu Lu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563003, China
| | - Jingshan Shi
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563003, China
| | - Shaoyu Zhou
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563003, China.
| | - Qin Wu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563003, China.
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33
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Fang S, Cai Y, Li P, Wu C, Zou S, Zhang Y, Lin X, Guan M. [Exendin-4 alleviates oxidative stress and liver fibrosis by activating Nrf2/HO-1 in streptozotocin-induced diabetic mice]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2019; 39:464-470. [PMID: 31068291 DOI: 10.12122/j.issn.1673-4254.2019.04.13] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVE To investigate the effects of exendin-4 on hepatic lipid metabolism, fibrosis and oxidative stress in mice with streptozotocin (STZ)-induced diabetes and explore the underlying mechanisms. METHODS C57BL/6J mice were fed with high-fat diet (HFD) for 4 weeks and received intraperitoneal injections of 120 mg/kg STZ to induce diabetes. After successful modeling, the mice were randomized into diabetic control group and exendin-4 treatment group (DM+E4), and in the latter group, the mice were given a daily dose of 1 nmol/kg of exendin-4 for 8 weeks. The changes in the body weight (BW) and random blood glucose (RBG) in the mice were recorded. The mRNA expressions of the genes related with liver lipid metabolism, fibrosis and oxidative stress were analyzed using RT-PCR, and the structural changes of the liver tissues were observed with HE, Sirius red and oil red O staining; the expressions of TGF-β1, Nrf2 and HO-1 proteins in the liver tissues were detected using Western blotting. RESULTS The diabetic mice showed significantly higher RBG levels and BW with obvious lipid deposition, fibrosis and oxidative stress in the liver as compared with the normal control mice (P < 0.001). Exendin-4 treatment of the diabetic mice did not significantly lessened liver lipid deposition but obviously reduced the levels of RBG and TG (P < 0.05), lowered the expression levels of liver fibrosis-related genes TGF-β, α-SMA and Col-Ⅰ (P < 0.05), increased the expression levels of the antioxidant genes Nrf2, HO-1 and GPX4 (P < 0.01), and enhanced the protein expressions of Nrf2 and HO-1 in the liver tissues (P < 0.01). CONCLUSIONS Exendin-4 improves liver fibrosis and oxidative stress in diabetic mice by activating Nrf2/HO-1 pathway without significantly reducing liver lipid deposition.
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Affiliation(s)
- Shu Fang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yingying Cai
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Ping Li
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Chunyan Wu
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Shaozhou Zou
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yudan Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xiaochun Lin
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Meiping Guan
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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Miao H, Zhang Y, Huang Z, Lu B, Ji L. Lonicera japonica Attenuates Carbon Tetrachloride-Induced Liver Fibrosis in Mice: Molecular Mechanisms of Action. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2019; 47:351-367. [PMID: 30871359 DOI: 10.1142/s0192415x19500174] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Liver fibrosis is a worldwide clinical issue that generally causes hepatic cirrhosis. Lonicerae Japonicae Flos (dried flower buds of Lonicera japonica Thunb) is a traditional heat-clearing and detoxifying herbal medicine in China. This study aims to observe the protection of the water extract of Lonicerae Japonicae Flos (FL) from carbon tetrachloride (CCl4)-induced liver fibrosis in mice. Liver fibrosis was induced in mice by intraperitoneal injection of 2 ml/kg CCl4 twice a week for 4 weeks. FL's attenuation of CCl4-induced liver fibrosis in mice was evidenced by the results of Masson's trichrome and Sirius red staining, liver hydroxyproline content and serum amount of collagen IV. FL reduced hepatic stellate cells (HSCs) activation and reversed the epithelial-mesenchymal transition (EMT) process in mice treated with CCl4. FL also alleviated liver oxidative stress injury and enhanced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) anti-oxidant signaling pathway in mice treated with CCl4. Additionally, the main phenolic acids in FL including chlorogenic acid (CGA) and caffeic acid (CA) both reduced HSCs activation in vitro. In summary, FL attenuates CCl4-induced liver fibrosis in mice by inhibiting HSCs activation, reversing EMT and reducing liver oxidative stress injury via inducing Nrf2 activation. CGA may be the main active compound contributing to the antifibrotic activity of FL.
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Affiliation(s)
- Hui Miao
- 1 The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, P. R. China
| | - Yi Zhang
- 1 The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, P. R. China
| | - Zhenlin Huang
- 1 The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, P. R. China
| | - Bin Lu
- 1 The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, P. R. China
| | - Lili Ji
- 1 The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, P. R. China
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35
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Liu J, Lu YF, Wu Q, Xu SF, Shi FG, Klaassen CD. Oleanolic acid reprograms the liver to protect against hepatotoxicants, but is hepatotoxic at high doses. Liver Int 2019; 39:427-439. [PMID: 30079536 DOI: 10.1111/liv.13940] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 07/14/2018] [Accepted: 07/27/2018] [Indexed: 12/13/2022]
Abstract
Oleanolic acid (OA) is a triterpenoid that exists widely in fruits, vegetables and medicinal herbs. OA is included in some dietary supplements and is used as a complementary and alternative medicine (CAM) in China, India, Asia, the USA and European countries. OA is effective in protecting against various hepatotoxicants, and one of the protective mechanisms is reprogramming the liver to activate the nuclear factor erythroid 2-related factor 2 (Nrf2). OA derivatives, such as CDDO-Im and CDDO-Me, are even more potent Nrf2 activators. OA has recently been shown to also activate the Takeda G-protein-coupled receptor (TGR5). However, whereas a low dose of OA is hepatoprotective, higher doses and long-term use of OA can produce liver injury, characterized by cholestasis. This paradoxical hepatotoxic effect occurs not only for OA, but also for other OA-type triterpenoids. Dose and length of time of OA exposure differentiate the ability of OA to produce hepatoprotection vs hepatotoxicity. Hepatotoxicity produced by herbs is increasingly recognized and is of global concern. Given the appealing nature of OA in dietary supplements and its use as an alternative medicine around the world, as well as the development of OA derivatives (CDDO-Im and CDDO-Me) as therapeutics, it is important to understand not only that they program the liver to protect against hepatotoxic chemicals, but also how they produce hepatotoxicity.
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Affiliation(s)
- Jie Liu
- Key Laboratory for Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine, Zunyi Medical University, Zunyi, China.,Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas, Kansas City, Kansas
| | - Yuan-Fu Lu
- Key Laboratory for Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine, Zunyi Medical University, Zunyi, China
| | - Qin Wu
- Key Laboratory for Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine, Zunyi Medical University, Zunyi, China
| | - Shang-Fu Xu
- Key Laboratory for Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine, Zunyi Medical University, Zunyi, China
| | - Fu-Guo Shi
- Key Laboratory for Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine, Zunyi Medical University, Zunyi, China
| | - Curtis D Klaassen
- Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas, Kansas City, Kansas
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36
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Hu R, Jia WY, Xu SF, Zhu ZW, Xiao Z, Yu SY, Li J. Xiaochaihutang Inhibits the Activation of Hepatic Stellate Cell Line T6 Through the Nrf2 Pathway. Front Pharmacol 2019; 9:1516. [PMID: 30666206 PMCID: PMC6330344 DOI: 10.3389/fphar.2018.01516] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 12/11/2018] [Indexed: 12/20/2022] Open
Abstract
Xiaochaihutang (XCHT) is one of classic prescriptions in Treatise on Febrile Diseases in China which was reported to have the effect of anti-hepatic fibrosis in vivo. Activation of hepatic stellate cells (HSCs) is now well established as a central driver of fibrosis in liver injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important element for anti-oxidative damage which is one of the key factors responsible for occurrence. This study was to investigate the effect of XCHT compound serum on HSCs activation and focus on the Nrf2 pathway. Rats in treatment groups were given the appropriate doses of XCHT granules (5 g/kg) and Silybin (50 mg/kg) for 6 days, and the serum were obtained. The compound serum was used to intervene HSCs. The results found that XCHT compound serum significantly inhibited the proliferation of HSCT6 cells. The number of α-SMA positive stained cells in HSCT6 cells and the content of Collagen type I (collagen-I) in supernatant were significantly decreased indicating suppression of activated HSCs. Compared with the control group, the nuclear transcription of Nrf2 and the expressions of Nqo1, GCLC, and GCLM were significantly increased in XCHT group. However, the effects of XCHT were inhibited in Nrf2-siRNA transfected HSCT6 cells. These studies demonstrated that XCHT could inhibit HSCT6 cell proliferation and activation. The mechanism might be related to up-regulation of the Nrf2 pathway against oxidative stress.
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Affiliation(s)
- Rui Hu
- Research Center for Medicine and Biology, Zunyi Medical University, Zunyi, China.,Key Laboratory of Brain Science, Zunyi Medical University, Zunyi, China
| | - Wei-Yi Jia
- Research Center for Medicine and Biology, Zunyi Medical University, Zunyi, China
| | - Shang-Fu Xu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
| | - Zhi-Wei Zhu
- Research Center for Medicine and Biology, Zunyi Medical University, Zunyi, China
| | - Zhi Xiao
- Key Laboratory of Brain Science, Zunyi Medical University, Zunyi, China
| | - Shou-Yang Yu
- Key Laboratory of Brain Science, Zunyi Medical University, Zunyi, China
| | - Jin Li
- Research Center for Medicine and Biology, Zunyi Medical University, Zunyi, China
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Fayez AM, Zakaria S, Moustafa D. Alpha lipoic acid exerts antioxidant effect via Nrf2/HO-1 pathway activation and suppresses hepatic stellate cells activation induced by methotrexate in rats. Biomed Pharmacother 2018; 105:428-433. [PMID: 29879626 DOI: 10.1016/j.biopha.2018.05.145] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 05/26/2018] [Accepted: 05/28/2018] [Indexed: 12/14/2022] Open
Abstract
Hepatic injury is a major side effect associated with methotrexate (MTX) therapy resulting from inflammatory reactions and oxidative stress induction. Therefore, liver fibrosis incidence is augmented with long-term MTX therapy. Alpha lipoic acid (ALA) is a naturally occurring compound with potent antioxidant activity. This study explored the hepatoprotective mechanisms of ALA against MTX-induced hepatic injury in rats. Hepatic injury was induced in MTX group by 20 mg/kg body weight ip. injection of MTX. ALA group was pretreated with ALA 60 mmol/kg body weight ip. for five days followed by a single dose of MTX in the sixth day. Blood samples and liver tissues were then obtained to assess several biochemical parameters as serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), reduced glutathione (GSH), total antioxidant capacity (TAC) and lipid peroxidation. Nuclear factor E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway was studied by determining the extent of mRNA Nrf2 expression and the level of HO-1. Hepatic stellate cells (HSCs) activation was evaluated by estimating the expression of α-smooth muscle actin (α-SMA) and hydroxyproline content. Also, tumor necrosis factor alpha (TNF-α), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and caspase-3 were assessed by ELISA in addition to histopathological examination of liver samples. Results showed that ALA pretreatment improved liver function since serum ALT, AST and ALP levels were reduced. Additionally, ALA restored GSH and TAC levels when compared to MTX group and decreased lipid peroxidation. ALA exerted its antioxidant effect via Nrf2/HO-1 pathway as well as it showed anti-inflammatory and antiapoptotic effects by reducing TNF-α, iNOS, COX-2 and caspase-3 levels in liver tissue homogenate. Finally, ALA suppressed HSCs activation by decreasing α-SMA expression and hydroxyproline content in liver. It was concluded that ALA has hepatoprotective effects against MTX-induced hepatic injury mediated by Nrf2/HO-1 pathway as well as anti-inflammatory and antiapoptotic properties.
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Affiliation(s)
- Ahmed M Fayez
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, MSA University, 6 October City, Giza, Egypt
| | - Soad Zakaria
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, October 6 University, 6 October City, Giza, Egypt.
| | - Dina Moustafa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, October 6 University, 6 October City, Giza, Egypt
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