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Lu L, Ma Y, Tao Q, Xie J, Liu X, Wu Y, Zhang Y, Xie X, Liu M, Jin Y. Hypoxia-inducible factor-1 alpha (HIF-1α) inhibitor AMSP-30 m attenuates CCl 4-induced liver fibrosis in mice by inhibiting the sonic hedgehog pathway. Chem Biol Interact 2025; 413:111480. [PMID: 40113123 DOI: 10.1016/j.cbi.2025.111480] [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: 06/25/2024] [Revised: 03/10/2025] [Accepted: 03/17/2025] [Indexed: 03/22/2025]
Abstract
Liver fibrosis is a passive and irreversible wound healing process caused by chronic liver injury. Research has shown that the upregulation of hypoxia inducible factor-1 alpha (HIF-1α) is closely related to the occurrence and development of liver fibrosis and HIF-1 α may be a promising target for the treatment of liver fibrosis. AMSP-30 m is a newly developed novel HIF-1α inhibitor by our group, which has strong anti-tumor and anti-inflammatory effects. In this study, we described the therapeutic effect and specific mechanism of AMSP-30 m on carbon tetrachloride (CCl4) induced liver fibrosis in mice. Liver fibrosis induced by CCl4 in mice and liver fibrosis induced by cobalt dichloride (CoCl2) in LX-2 cells (human hepatic stellate cell (HSC) line) were studied. Hematoxylin & eosin (H&E)and Masson's trichrome staining were used to observe pathological conditions. Western Blot, immunofluorescence and immunohistochemistry were used to detect protein expression and localization in cells, and quantitative real-time PCR analysis (qRT-PCR) was used to detect mRNA expression. Biochemical detection kits were used to detect alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. The results demonstrated that AMSP-30 m significantly alleviated pathological symptoms, reduced ALT and AST levels, and inhibited the expression of alpha-smooth muscle actin (α-SMA) and collagen type I (COL1α1) in CCl4-induced liver fibrosis in mice. AMSP-30 m could significantly reduce the expression of HIF-1α and sonic hedgehog (Shh) pathway related proteins (Smoothened (Smo), Shh, and glioma-associated oncogene-1 (Gli-1)) in CCl4 induced liver fibrosis mice. AMSP-30 m also played a similar role in the CoCl2-induced anoxic liver fibrosis model of LX-2 cells. Further experiments showed that Cyclopamine (a Shh inhibitor) could significantly inhibit the increase of α-SMA and COL1α1 resulting from HIF-1α but not significantly inhibit HIF-1α induced by CoCl2 in LX-2 cells. And the combination of Cyclopamine and AMSP-30 m further reduced the expression of α-SMA and COL1α1 induced by HIF-1α. In summary, this study demonstrates that the HIF-1α inhibitor AMSP-30 m exerts a robust anti-fibrotic effect by inhibiting the Shh pathway, which is identified as a critical underlying mechanism. These findings suggest a promising therapeutic strategy for the treatment of liver fibrosis.
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Affiliation(s)
- Lili Lu
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Yuchen Ma
- Pharmacy Department, Fuyang Cancer Hospital, Fuyang, Anhui, China
| | - Qing Tao
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Jing Xie
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Xiao Liu
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Yongkang Wu
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Yang Zhang
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Xiuli Xie
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Mingming Liu
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
| | - Yong Jin
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
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Xin W, Yang H, Heng X, Xu T, Zhang K, Zhao Y, Liu Y, Han D, Wu Y, Zhang W, He M, Pu L, Shen Y, Qu X, Sun N, Ye C. Sauchinone preserves cardiac function in doxorubicin-induced cardiomyopathy by inhibiting the NLRP3 inflammasome. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 140:156624. [PMID: 40068294 DOI: 10.1016/j.phymed.2025.156624] [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: 10/19/2024] [Revised: 03/02/2025] [Accepted: 03/06/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUND Doxorubicin (Dox)-induced cardiomyopathy (DIC) is characterized by severe myocardial damage that can progress to dilated cardiomyopathy and potentially lead to heart failure. No effective prevention or treatment strategies are available for DIC. Sauchinone, a diastereomeric lignan isolated from Saururus chinensis, is known for its notable anti-inflammatory effects. However, a paucity of research on sauchinone in relation to heart disease exists, particularly regarding its role in DIC, which remains unclear. PURPOSE This study aimed to assess the therapeutic potential of sauchinone in alleviating cardiac injury and elucidate its potential molecular mechanism in DIC. METHODS Male C57BL/6J mice were used to construct chronic and acute DIC models in vivo. The mice were administered sauchinone intragastrically concurrently with the first injection of Dox to evaluate the therapeutic effect of sauchinone on DIC. H9c2, a rat cardiomyocyte cell line, was treated with various concentrations of sauchinone in conjunction with Dox to assess the protective effects of sauchinone on cardiomyocyte injury in vitro. RESULTS Supplementation with exogenous sauchinone mitigated Dox-induced cardiac atrophy, cardiac fibrosis, and ventricular remodeling, while preserving cardiac function. Sauchinone reduced Dox-induced abnormal apoptosis both in vitro and in vivo. Additionally, sauchinone restored mitochondrial function and decreased reactive oxygen species levels, which may be attributed to its activation of nuclear factor erythroid 2-related factor 2 (NRF2) signaling, thereby attenuating Dox-induced oxidative damage. Furthermore, sauchinone significantly inhibited the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and reduced the cardiac infiltration of inflammatory factors, thereby alleviating oxidative stress and inhibiting the progression of DIC. The NLRP3 agonist nigericin abolished DIC progression, while the NLRP3 antagonist MCC950 further enhanced the beneficial effects of sauchinone on DIC progression both in vivo and in vitro. CONCLUSIONS The key novel finding of the present study is that the use of sauchinone, a diastereomeric lignan isolated from Saururus chinensis, effectively limits the progression of DIC. Specifically, sauchinone not only alleviates Dox-induced chronic cardiac injury but also significantly delays the progression of acute DIC. Mechanistically, inactivation of the NLRP3 inflammasome and NRF2-mediated antioxidant pathways have been identified as two critical signaling pathways regulated by sauchinone, which plays a vital role in blocking the progression of DIC. Sauchinone holds promise as a potential therapeutic approach for DIC or dilated cardiomyopathy.
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Affiliation(s)
- Wenxu Xin
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan university, Wuxi, Jiangsu 214122, China
| | - Hai Yang
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan university, Wuxi, Jiangsu 214122, China
| | - Xinyu Heng
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan university, Wuxi, Jiangsu 214122, China
| | - Tao Xu
- Department of Geriatrics, Sir Run Hospital, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Ke Zhang
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan university, Wuxi, Jiangsu 214122, China
| | - Yining Zhao
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan university, Wuxi, Jiangsu 214122, China
| | - Yankui Liu
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, Jiangsu 214122, China; Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Deshen Han
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, Jiangsu 214122, China
| | - Yueyue Wu
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, Jiangsu 214122, China
| | - Wei Zhang
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, Jiangsu 214122, China
| | - Meiqi He
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, Jiangsu 214122, China
| | - Lin Pu
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, Jiangsu 214122, China
| | - Yicong Shen
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan university, Wuxi, Jiangsu 214122, China
| | - Xiuxia Qu
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan university, Wuxi, Jiangsu 214122, China.
| | - Ning Sun
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan university, Wuxi, Jiangsu 214122, China.
| | - Chao Ye
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, Jiangsu 214122, China; Department of Cardiology, Affiliated Children's Hospital of Jiangnan University (Wuxi Children's Hospital), Jiangnan University, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan university, Wuxi, Jiangsu 214122, China.
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Bailly C. Benzoxanthenone Lignans Related to Carpanone, Polemanone, and Sauchinone: Natural Origin, Chemical Syntheses, and Pharmacological Properties. Molecules 2025; 30:1696. [PMID: 40333626 PMCID: PMC12029563 DOI: 10.3390/molecules30081696] [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: 03/18/2025] [Revised: 04/07/2025] [Accepted: 04/08/2025] [Indexed: 05/09/2025] Open
Abstract
Medicinal plants from the genus Saururus are commonly used to treat inflammatory pathologies. They contain numerous bioactive compounds, notably the polycyclic lignan sauchinone from the species Saururus chinensis. An in-depth analysis of benzoxanthenone lignans related to sauchinone, and the analogous products carpanone and polemannones, has been carried out. The review reports the product's isolation, biosynthetic pathway, and chemical strategies to synthesize benzoxanthenones via liquid- and solid-phase syntheses. The metabolic and pharmacokinetic properties of sauchinone are discussed. At the pharmacological level, sauchinone is a potent blocker of the production of pro-inflammatory mediators, such as nitric oxide and prostaglandin E2, and an efficient antioxidant agent. The properties of sauchinone can be exploited to combat multiple pathologies, such as liver injuries, renal dysfunction, osteoarthritis, inflammatory bowel disease, ulcerative colitis, and cancers. The capacity of the natural product to inhibit tumor cell proliferation and to reduce migration/invasion of cancer cells and the development of metastases is underlined, together with the regulation of the epithelial-mesenchymal transition and immune checkpoints. Altogether, the review offers a complete survey of the chemical and biochemical properties of sauchinone-type benzoxanthenones.
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Affiliation(s)
- Christian Bailly
- UMR9020-U1277-CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, CHU Lille, CNRS, Inserm, OncoLille Institut, University of Lille, 59000 Lille, France;
- Institute of Pharmaceutical Chemistry Albert Lespagnol (ICPAL), Faculty of Pharmacy, University of Lille, 59006 Lille, France
- OncoWitan, Scientific Consulting Office, 59290 Lille, France
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Chen M, Song L, Zeng A. Harnessing nature's arsenal: Targeting the TGF-β/Smad Cascade with novel natural anti-fibrotic agents. Fitoterapia 2025; 181:106372. [PMID: 39778722 DOI: 10.1016/j.fitote.2024.106372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 12/24/2024] [Accepted: 12/26/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND Hepatic fibrosis is a wound healing response that leads to excessive deposition of extracellular matrix (ECM) due to sustained liver injury. Hepatic stellate cells (HSCs) are key players in ECM synthesis, with the TGF-β/Smad signaling pathway being central to their activation. Despite advances in understanding the pathogenesis of hepatic fibrosis, effective anti-fibrotic therapies are still lacking. METHODS This treatise conducts a comprehensive review of the literature on the hepatoprotective effects of natural products, including natural medicine compounds, herbal extracts, and polysaccharides. The focus is on their ability to modulate the TGF-β pathway, which is critical in the activation of HSCs and ECM synthesis in hepatic fibrosis. RESULTS The review identifies a variety of natural products that have shown promise in inhibiting the TGF-β/Smad signaling cascade, thereby reducing the activation of HSCs and ECM accumulation. These findings highlight the potential of these natural products as therapeutic agents in the treatment of hepatic fibrosis. CONCLUSIONS The exploration of natural products as modulators of the TGF-β pathway presents a novel avenue for both clinical and preclinical research into hepatic fibrosis. Further investigation is warranted to fully understand the mechanisms of action and to develop these compounds into effective anti-fibrotic pharmaceuticals.
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Affiliation(s)
- Maohua Chen
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine,Chengdu, Sichuan 610041, PR China; Department of Plastic Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China. Chengdu, Sichuan 610072, PR China
| | - Linjiang Song
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, PR China.
| | - Anqi Zeng
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine,Chengdu, Sichuan 610041, PR China.
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Zhang Y, Zhu M, Dai Y, Gao L, Cheng L. Research Progress in Ulcerative Colitis: The Role of Traditional Chinese Medicine on Gut Microbiota and Signaling Pathways. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2024; 52:2277-2336. [PMID: 39756829 DOI: 10.1142/s0192415x24500885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2025]
Abstract
Ulcerative colitis (UC), one among other refractory diseases worldwide, has shown an increasing trend of progression to colorectal cancer in recent years. In the treatment of UC, traditional Chinese medicine has demonstrated good efficacy, with a high cure rate, fewer adverse effects, great improvement in the quality of patient survival, and reduction in the tendency of cancerous transformation. It shows promise as a complementary and alternative therapy. This review aims to evaluate and discuss the current research on UC, signaling pathways, and gut microbiota. We also summarized the mechanisms of action of various Chinese medicines (active ingredients or extracts) and herbal formulas, through signaling pathways and gut microbiota, with the expectation that they can provide references and evidence for treating UC and preventing inflammation-associated colorectal cancer by traditional Chinese medicine. We illustrate that multiple signaling pathways, such as TLR4, STAT3, PI3K/Akt, NF-[Formula: see text]B, and Keap1/Nrf2, can be inhibited by Chinese herbal treatments through the combined regulation of signaling pathways and gut microbiota, which can act individually or synergistically to inhibit intestinal inflammatory cell infiltration, attenuate gut oxidative responses, and repair the intestinal barrier.
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Affiliation(s)
- Yuyi Zhang
- Graduate School, Heilongjiang University of Chinese Medicine, Harbin, P. R. China
| | - Mingfang Zhu
- Graduate School, Zunyi Medical University Zunyi, P. R. China
| | - Yueying Dai
- Graduate School, Heilongjiang University of Chinese Medicine, Harbin, P. R. China
| | - Longying Gao
- Department of Anorectal, The First Affiliated Hospital of Heilongjiang, University of Chinese Medicine Harbin, P. R. China
| | - Limin Cheng
- Department of Anorectal, The First Affiliated Hospital of Heilongjiang, University of Chinese Medicine Harbin, P. R. China
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Liu XY, Zhang W, Ma BF, Sun MM, Shang QH. Advances in Research on the Effectiveness and Mechanism of Active Ingredients from Traditional Chinese Medicine in Regulating Hepatic Stellate Cells Autophagy Against Hepatic Fibrosis. Drug Des Devel Ther 2024; 18:2715-2727. [PMID: 38974122 PMCID: PMC11227309 DOI: 10.2147/dddt.s467480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 06/10/2024] [Indexed: 07/09/2024] Open
Abstract
Hepatic fibrosis (HF) is a pathological process of structural and functional impairment of the liver and is a key component in the progression of chronic liver disease. There are no specific anti-hepatic fibrosis (anti-HF) drugs, and HF can only be improved or prevented by alleviating the cause. Autophagy of hepatic stellate cells (HSCs) is closely related to the development of HF. In recent years, traditional Chinese medicine (TCM) has achieved good therapeutic effects in the prevention and treatment of HF. Several active ingredients from TCM (AITCM) can regulate autophagy in HSCs to exert anti-HF effects through different pathways, but relevant reviews are lacking. This paper reviewed the research progress of AITCM regulating HSCs autophagy against HF, and also discussed the relationship between HSCs autophagy and HF, pointing out the problems and limitations of the current study, in order to provide references for the development of anti-HF drugs targeting HSCs autophagy in TCM. By reviewing the literature in PubMed, Web of Science, Embase, CNKI and other databases, we found that the relationship between autophagy of HSCs and HF is currently controversial. HSCs autophagy may promote HF by consuming lipid droplets (LDs) to provide energy for their activation. However, in contrast, inducing autophagy in HSCs can exert the anti-HF effect by stimulating their apoptosis or senescence, reducing type I collagen accumulation, inhibiting the extracellular vesicles release, degrading pro-fibrotic factors and other mechanisms. Some AITCM inhibit HSCs autophagy to resist HF, with the most promising direction being to target LDs. While, others induce HSCs autophagy to resist HF, with the most promising direction being to target HSCs apoptosis. Future research needs to focus on cell targeting research, autophagy targeting research and in vivo verification research, and to explore the reasons for the contradictory effects of HSCs autophagy on HF.
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Affiliation(s)
- Xin-Yu Liu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250000, People’s Republic of China
| | - Wei Zhang
- Department of Liver Disease, The 960th Hospital of the PLA Joint Logistics Support Force, Jinan, Shandong, 250000, People’s Republic of China
| | - Bao-Feng Ma
- The third department of encephalopathy, Jinan Integrated Traditional Chinese and Western Medicine Hospital, Jinan, Shandong, 271100, People’s Republic of China
| | - Mi-Mi Sun
- Diagnosis and Treatment Center for Liver Diseases, Tai’an 88 Hospital, Tai’an, Shandong, 271000, People’s Republic of China
| | - Qing-Hua Shang
- Department of Liver Disease, The 960th Hospital of the PLA Joint Logistics Support Force, Jinan, Shandong, 250000, People’s Republic of China
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Kim YW, Bak SB, Song YR, Kim CE, Lee WY. Systematic exploration of therapeutic effects and key mechanisms of Panax ginseng using network-based approaches. J Ginseng Res 2024; 48:373-383. [PMID: 39036729 PMCID: PMC11258513 DOI: 10.1016/j.jgr.2024.01.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 11/30/2023] [Accepted: 01/19/2024] [Indexed: 07/23/2024] Open
Abstract
Background Network pharmacology has emerged as a powerful tool to understand the therapeutic effects and mechanisms of natural products. However, there is a lack of comprehensive evaluations of network-based approaches for natural products on identifying therapeutic effects and key mechanisms. Purpose We systematically explore the capabilities of network-based approaches on natural products, using Panax ginseng as a case study. P. ginseng is a widely used herb with a variety of therapeutic benefits, but its active ingredients and mechanisms of action on chronic diseases are not yet fully understood. Methods Our study compiled and constructed a network focusing on P. ginseng by collecting and integrating data on ingredients, protein targets, and known indications. We then evaluated the performance of different network-based methods for summarizing known and unknown disease associations. The predicted results were validated in the hepatic stellate cell model. Results We find that our multiscale interaction-based approach achieved an AUROC of 0.697 and an AUPR of 0.026, which outperforms other network-based approaches. As a case study, we further tested the ability of multiscale interactome-based approaches to identify active ingredients and their plausible mechanisms for breast cancer and liver cirrhosis. We also validated the beneficial effects of unreported and top-predicted ingredients, in cases of liver cirrhosis and gastrointestinal neoplasms. Conclusion our study provides a promising framework to systematically explore the therapeutic effects and key mechanisms of natural products, and highlights the potential of network-based approaches in natural product research.
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Affiliation(s)
- Young Woo Kim
- School of Korean Medicine, Dongguk University, Gyeongju, Republic of Korea
- Department of Computer Science, Kyungpook National University, Daegu, Republic of Korea
| | - Seon Been Bak
- School of Korean Medicine, Dongguk University, Gyeongju, Republic of Korea
| | - Yu Rim Song
- School of Korean Medicine, Dongguk University, Gyeongju, Republic of Korea
| | - Chang-Eop Kim
- School of Korean Medicine, Gachon University, Seongnam, Republic of Korea
| | - Won-Yung Lee
- School of Korean Medicine, Dongguk University, Gyeongju, Republic of Korea
- School of Korean Medicine, Wonkwang University, Iksan, Republic of Korea
- Research Center of Traditional Korean Medicine, Wonkwang University, Republic of Korea
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Gulzar N, Andleeb S, Raza A, Ali S, Liaqat I, Raja SA, Ali NM, Khan R, Awan UA. Acute Toxicity, Anti-diabetic, and Anti-cancerous Potential of Trillium Govanianum-conjugated Silver Nanoparticles in Balb/c Mice. Curr Pharm Biotechnol 2024; 25:1304-1320. [PMID: 37594092 DOI: 10.2174/1389201024666230818124025] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 06/26/2023] [Accepted: 07/20/2023] [Indexed: 08/19/2023]
Abstract
BACKGROUND The current study aimed to develop an economic plant-based therapeutic agent to improve the treatment strategies for diseases at the nano-scale because Cancer and Diabetes mellitus are major concerns in developing countries. Therefore, in vitro and in vivo antidiabetic and anti-cancerous activities of Trillium govanianum conjugated silver nanoparticles were assessed. METHODS In the current study synthesis of silver nanoparticles using Trillium govanianum and characterization were done using a scanning electron microscope, UV-visible spectrophotometer, and FTIR analysis. The in vitro and in vivo anti-diabetic and anti-cancerous potential (200 mg/kg and 400 mg/kg) were carried out. RESULTS It was discovered that Balb/c mice did not show any major alterations during observation of acute oral toxicity when administered orally both TGaqu (1000 mg/kg) and TGAgNPs (1000 mg/kg), and results revealed that 1000 mg/kg is not lethal dose as did not find any abnormalities in epidermal and dermal layers when exposed to TGAgNPs. In vitro studies showed that TGAgNPs could not only inhibit alpha-glucosidase and protein kinases but were also potent against the brine shrimp. Though, a significant reduction in blood glucose levels and significant anti-cancerous effects was recorded when alloxan-treated and CCl4-induced mice were treated with TGAgNPs and TGaqu. CONCLUSION Both in vivo and in vitro studies revealed that TGaqu and TGAgNPs are not toxic at 200 mg/kg, 400 mg/kg, and 1000 mg/kg doses and possess strong anti-diabetic and anti-cancerous effects due to the presence of phyto-constituents. Further, suggesting that green synthesized silver nanoparticles could be used in pharmaceutical industries to develop potent therapeutic agents.
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Affiliation(s)
- Nazia Gulzar
- Department of Zoology, Microbial Biotechnology Laboratory, University of Azad Jammu and Kashmir, Muzaffarabad, 13100, Pakistan
| | - Saiqa Andleeb
- Department of Zoology, Microbial Biotechnology Laboratory, University of Azad Jammu and Kashmir, Muzaffarabad, 13100, Pakistan
| | - Abida Raza
- PMAS-arid Agriculture University Rawalpindi, Pakistan
| | - Shaukat Ali
- Department of Zoology, Government College University, Lahore, Pakistan
| | - Iram Liaqat
- Department of Zoology, Government College University, Lahore, Pakistan
| | - Sadaf Azad Raja
- Bioscience Department, COMSATS University, Park Road, Chak Shahzad, Islamabad, 44000, Pakistan
| | - Nazish Mazhar Ali
- Department of Zoology, Government College University, Lahore, Pakistan
| | - Rida Khan
- Department of Zoology, Microbial Biotechnology Laboratory, University of Azad Jammu and Kashmir, Muzaffarabad, 13100, Pakistan
| | - Uzma Azeem Awan
- Department of Biological Sciences, National University of Medical Sciences (NUMS), Rawalpindi, Pakistan
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Sahu R, Goswami S, Narahari Sastry G, Rawal RK. The Preventive and Therapeutic Potential of the Flavonoids in Liver Cirrhosis: Current and Future Perspectives. Chem Biodivers 2023; 20:e202201029. [PMID: 36703592 DOI: 10.1002/cbdv.202201029] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 01/12/2023] [Indexed: 01/28/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) may vary from moderately mild non-alcohol fatty liver (NAFL) towards the malignant variant known as non-alcoholic steatohepatitis (NASH), which is marked by fatty liver inflammation and may progress to liver cirrhosis (LC), liver cancer, fibrosis, or liver failure. Flavonoids can protect the liver from toxins through their anti-inflammatory, antioxidant, anti-cancer, and antifibrogenic pharmacological activities. Furthermore, flavonoids protect against LC by regulation of hepatic stellate cells (HSCs) trans-differentiation, inhibiting growth factors like TGF-β and platelets-derived growth factor (PDGF), vascular epithelial growth factor (VEGF), viral infections like hepatitis-B, C and D viruses (HBV, HCV & HDV), autoimmune-induced, alcohol-induced, metabolic disorder-induced, causing by apoptosis, and regulating MAPK pathways. These flavonoids may be explored in the future as a therapeutic solution for hepatic diseases.
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Affiliation(s)
- Rakesh Sahu
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India
| | - Sourav Goswami
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India
| | - G Narahari Sastry
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, Uttar Pradesh, India
| | - Ravindra K Rawal
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, Uttar Pradesh, India
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Wu K, Liu X, Meng X, Cao L, Li H, Bi Y, Wang M, Wang M, Jiang Y. Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota. Front Microbiol 2023; 13:1084257. [PMID: 36699607 PMCID: PMC9868758 DOI: 10.3389/fmicb.2022.1084257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 12/09/2022] [Indexed: 01/11/2023] Open
Abstract
OBJECTIVE This study evaluated the effects of sauchinone on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice model and investigated the underlying mechanisms of the downstream pathway and gut microbiota. METHODS The UC mice model was induced by DSS. The disease phenotypes were determined through pathological symptoms (body weight and disease activity index score), inflammation markers (histological and inflammatory factor detections), and colonic mucosal barrier damage (detection of tight junction proteins). The level of the NF-κB pathway was detected through marker proteins. Database and bioinformatics analyses were used to predict sauchinone-mediated downstream molecules that were previously identified by expression analysis. Mouse feces were collected to detect the V3-V4 region of the 16S rRNA gene. RESULTS In DSS-induced UC mice, sauchinone alleviated pathological symptoms, inhibited inflammation, and prevented mucosal barrier damage. Sauchinone further inhibited the NF-κB pathway by upregulating NAD (P) H dehydrogenase [quinone] 1 (NQO1) in DSS-induced UC mice. Moreover, sauchinone regulated the diversity and composition of the gut microbiota in mice, stimulating the growth of Firmicutes and inhibiting the growth of Proteobacteria and Bacteroidetes. CONCLUSION Therefore, sauchinone exerted therapeutic effects on UC in mice by regulating the NQO1/NF-κB pathway and altering the gut microbiota. This provides a theoretical basis for developing sauchinone as a therapeutic agent and extends our understanding of its bioactivity.
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Affiliation(s)
- Kun Wu
- Department of Gastrointestinal Colorectal and Anal Surgery, The China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xianjun Liu
- College of Biological and Food Engineering, Jilin Engineering Normal University, Changchun, China
| | - Xianglong Meng
- Department of Burns Surgery, The First Hospital of Jilin University, Changchun, China
| | - Lingling Cao
- School of Clinical Medical, Changchun University of Chinese Medicine, Changchun, China
| | - Hao Li
- College of Biological and Food Engineering, Jilin Engineering Normal University, Changchun, China
| | - Yingxin Bi
- College of Biological and Food Engineering, Jilin Engineering Normal University, Changchun, China
| | - Mengyuan Wang
- College of Biological and Food Engineering, Jilin Engineering Normal University, Changchun, China
| | - Mingchuan Wang
- Department of Gastrointestinal Colorectal and Anal Surgery, The China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yang Jiang
- Department of Gastrointestinal Colorectal and Anal Surgery, The China-Japan Union Hospital of Jilin University, Changchun, China
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11
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Vijayan N, Perumal MK. A critical review on anti-fibrotic phytochemicals targeting activated hepatic stellate cells. J Food Biochem 2022; 46:e14438. [PMID: 36209494 DOI: 10.1111/jfbc.14438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/29/2022] [Accepted: 09/16/2022] [Indexed: 01/18/2023]
Abstract
Liver fibrosis is a major health concern occurring worldwide. It arises due to prolonged wound healing response of various insults like viral, autoimmune, cholestatic, drug-induced, and metabolic diseases. Currently, there is no clinically approved drug for liver fibrosis treatment. Hepatic stellate cells are the principal liver cells that are activated during liver fibrosis, and targeting these activated cells is an ideal therapeutic strategy. Numerous phytochemicals have been demonstrated in vitro and in vivo treating experimental liver fibrosis; however, none of them have been clinically approved for therapeutic use. This review mainly focuses on such hepatoprotective phytochemicals reported inhibiting major signaling pathways that are dysregulated in activated hepatic stellate cells. PRACTICAL APPLICATIONS: Liver fibrosis is a global health concern and there is no FDA approved drug to treat liver fibrosis. Although notable pharmacological agents like pentoxifylline, gliotoxin, imatinibmesylate, Gleevec, and so on are reported to exhibit anti-fibrotic effect, the major concern is their side effect. Hence, phytochemicals are promising candidates that could be employed against liver fibrosis. In this review, the anti-fibrotic potential of phytochemicals targeting activated HSCs are summarized. Understanding these phytochemicals will further help in the development of agents that are more effective against liver fibrosis.
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Affiliation(s)
- Nivya Vijayan
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Madan Kumar Perumal
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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12
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Xie Y, Du D, Zhang L, Yang Y, Zou Z, Li Z, Zhou L, Shang R, Zhou P. TJ-M2010-5, A self-developed MyD88 inhibitor, attenuates liver fibrosis by inhibiting the NF-κB pathway. Chem Biol Interact 2022; 354:109839. [PMID: 35101388 DOI: 10.1016/j.cbi.2022.109839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 01/17/2022] [Accepted: 01/26/2022] [Indexed: 02/09/2023]
Abstract
Liver fibrosis is the result of most chronic inflammatory liver damage and seriously endangers human health. However, no drugs have been approved to treat this disease. Previous studies showed that the Toll-like receptors (TLRs)/myeloid differentiation factor-88 (MyD88)/nuclear factor-κB (NF-κB) pathway plays a key role in liver fibrosis. TJ-M2010-5 is a self-developed small molecule MyD88 inhibitor, which has been proven to have a good protective effect in a variety of inflammatory disease models. In the present study, to investigate the anti-fibrotic effect of TJ-M2010-5, mice were injected with carbon tetrachloride (CCl4) in vivo and LX2 cells (a human hepatic stellate cell line) were treated with TGF-β1 in vitro to induce liver fibrosis. In vivo studies showed that TJ-M2010-5 attenuated the CCl4-induced liver damage, collagen accumulation, and the activation of hepatic stellate cells by inhibiting the nuclear transfer of NF-κB. Moreover, in vitro experiments of LX2 cells stimulated with TGF-β1 further indicated that the NF-κB pathway is involved in the development of liver fibrosis. TJ-M2010-5 significantly inhibited the proliferation and activation of LX2 cells. In addition, TJ-M2010-5 upregulated the expression of bone morphogenetic protein and membrane-bound inhibitor (BAMBI) in LX2 cells by blocking the activation of MyD88/NF-κB, thereby inhibiting the phosphorylation of Smad2/3 and the expression of collagen I (COL1A1) induced by TGF-β1. In conclusion, this study illustrates the anti-hepatic fibrosis effect of TJ-M2010-5 and provides a new treatment method for liver fibrosis.
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Affiliation(s)
- Yalong Xie
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Dunfeng Du
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Limin Zhang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Yang Yang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zhimiao Zou
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zeyang Li
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Liang Zhou
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Runshi Shang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Ping Zhou
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
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Tadijan A, Humphries JD, Samaržija I, Stojanović N, Zha J, Čuljak K, Tomić M, Paradžik M, Nestić D, Kang H, Humphries MJ, Ambriović-Ristov A. The Tongue Squamous Carcinoma Cell Line Cal27 Primarily Employs Integrin α6β4-Containing Type II Hemidesmosomes for Adhesion Which Contribute to Anticancer Drug Sensitivity. Front Cell Dev Biol 2021; 9:786758. [PMID: 34977030 PMCID: PMC8716755 DOI: 10.3389/fcell.2021.786758] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/18/2021] [Indexed: 12/12/2022] Open
Abstract
Integrins are heterodimeric cell surface glycoproteins used by cells to bind to the extracellular matrix (ECM) and regulate tumor cell proliferation, migration and survival. A causative relationship between integrin expression and resistance to anticancer drugs has been demonstrated in different tumors, including head and neck squamous cell carcinoma. Using a Cal27 tongue squamous cell carcinoma model, we have previously demonstrated that de novo expression of integrin αVβ3 confers resistance to several anticancer drugs (cisplatin, mitomycin C and doxorubicin) through a mechanism involving downregulation of active Src, increased cell migration and invasion. In the integrin αVβ3 expressing Cal27-derived cell clone 2B1, αVβ5 expression was also increased, but unrelated to drug resistance. To identify the integrin adhesion complex (IAC) components that contribute to the changes in Cal27 and 2B1 cell adhesion and anticancer drug resistance, we isolated IACs from both cell lines. Mass spectrometry (MS)-based proteomics analysis indicated that both cell lines preferentially, but not exclusively, use integrin α6β4, which is classically found in hemidesmosomes. The anticancer drug resistant cell clone 2B1 demonstrated an increased level of α6β4 accompanied with increased deposition of a laminin-332-containing ECM. Immunofluorescence and electron microscopy demonstrated the formation of type II hemidesmosomes by both cell types. Furthermore, suppression of α6β4 expression in both lines conferred resistance to anticancer drugs through a mechanism independent of αVβ3, which implies that the cell clone 2B1 would have been even more resistant had the upregulation of α6β4 not occurred. Taken together, our results identify a key role for α6β4-containing type II hemidesmosomes in regulating anticancer drug sensitivity.
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Affiliation(s)
- Ana Tadijan
- Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
- Laboratory for Protein Dynamics, Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia
| | - Jonathan D. Humphries
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
- Department of Life Sciences, Manchester Metropolitan University, Manchester, United Kingdom
| | - Ivana Samaržija
- Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
- Laboratory for Epigenomics, Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia
| | - Nikolina Stojanović
- Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
| | - Junzhe Zha
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
| | - Kristina Čuljak
- Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
| | - Marija Tomić
- Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
| | - Mladen Paradžik
- Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
| | - Davor Nestić
- Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
| | - Heemin Kang
- Department of Materials Science and Engineering, Korea University, Seoul, South Korea
| | - Martin J. Humphries
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
| | - Andreja Ambriović-Ristov
- Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
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Antifibrotic Effects of Kangxian Ruangan Capsule on Rats with Nonalcoholic Fatty Liver Fibrosis and Hepatic Stellate Cells through Regulation of TGF- β and TLR4 Signaling Pathways. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5649575. [PMID: 34422075 PMCID: PMC8371615 DOI: 10.1155/2021/5649575] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 05/07/2021] [Accepted: 07/22/2021] [Indexed: 01/18/2023]
Abstract
Kangxian ruangan (KXRG) is a traditional Chinese medicine (TCM) formula consisting of 12 herbs. TCM syndrome differentiation proposes that KXRG exerts pharmacological effects against nonalcoholic fatty liver disease (NAFLD) fibrosis. This work investigates the effect of KXRG on NAFLD fibrosis in vivo and in vitro. In vivo, the NAFLD fibrosis model was constructed in Wistar rats using methionine- and choline-deficient (MCD) diet, followed by KXRG (0.92 g/kg/d) treatment for 8 weeks. In vitro, primary hepatic stellate cells (HSCs) were activated using platelet-derived growth factor (PDGF) and treated with KXRG. Molecular mechanisms underlying fibrosis were investigated. After 8 weeks, compared with the control groups, the histological lesions, degree of fibrosis, and inflammatory reaction increased with the MCD diet as demonstrated by histological changes and increased fibrosis-related (α-SMA, TGF-β, COL1A1, and desmin, P < 0.01) and inflammation-related factors (TNF-α, MCP-1, and F4/80, P < 0.01), whereas they decreased with KXRG treatment (P < 0.01). KXRG not only inhibited the proliferation of activated HSCs and promoted their apoptosis but also resulted in G0-G1 arrest. Furthermore, KXRG suppressed HSC activation (P < 0.01), collagen synthesis (P < 0.01), and α-SMA expression (P < 0.01) with PDGF stimulation. In both the MCD diet-induced animal model and PDGF-induced cell model, KXRG inhibited TGF-β and TLR4 signaling (P < 0.01), similar to corresponding small-molecule inhibitors. These results demonstrated that KXRG might exert suppressive effects against NAFLD fibrosis via regulating TGF-β and TLR4 signaling. KXRG may act as a natural and potent therapeutic agent against NAFLD.
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15
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Plasminogen Activator Inhibitor-1 Secretion by Autophagy Contributes to Melanoma Resistance to Chemotherapy through Tumor Microenvironment Modulation. Cancers (Basel) 2021; 13:cancers13061253. [PMID: 33809137 PMCID: PMC7999393 DOI: 10.3390/cancers13061253] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 03/11/2021] [Indexed: 12/23/2022] Open
Abstract
Simple Summary Dysregulation of tumor autophagy is implicated in cancer progression and chemotherapeutic response. It is unclear how tumor autophagy modulates tumor microenvironment and thereby contributes to chemoresistance. In this study, we found that autophagy-dependent plasminogen activator inhibitor (PAI)-1 secretion contributed to melanoma resistance to mitoxantrone (MitoX), a chemotherapeutic agent clinically used for treating various types of cancers (but not melanoma), by shaping a pro-tumoral microenvironment. Disruption of autophagy activity or targeting PAI-1 pharmacologically reshaped a tumor-suppressive immune microenvironment and enhanced the susceptibility of melanoma to MitoX in vivo. Overall, the results show that targeting autophagy/PAI-1 axis can serve as a novel strategy to repurpose MitoX-based chemotherapy. Abstract Autophagy plays a crucial role in maintenance of cellular homeostasis via intracellular signaling pathways, lysosomal degradation of selective cargo and mediating protein secretion. Dysregulation of autophagy has been implicated in tumorigenesis, tumor progression, and resistance to therapy. However, the mechanism of autophagy-dependent secretion involved in the responsiveness to chemotherapy is poorly understood. In this study, we showed that mitoxantrone (MitoX), a chemotherapeutic agent used for treating various cancers but not melanoma, induced autophagy in melanoma cells in vitro and in vivo. We also found that plasminogen activator inhibitor (PAI)-1 secretion by MitoX-induced autophagy modulated the pro-tumoral microenvironment. Attenuation of PAI-1 activity using a specific inhibitor, tiplaxtinin (TPX), or by targeting the autophagy gene, Becn1, induced efficient antitumor immunity, thereby overcoming the resistance to MitoX in vivo. Of note, the therapeutic efficacy of TPX was abolished in MitoX-treated Becn1-defective tumors. Collectively, our results demonstrate that tumor autophagy-dependent PAI-1 secretion impairs the therapeutic efficacy of MitoX and highlight targeting of tumor autophagy or its secretory cargo, PAI-1, as a novel strategy to repurpose MitoX-based chemotherapy for melanoma treatment.
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16
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A Comprehensive Review of Natural Products against Liver Fibrosis: Flavonoids, Quinones, Lignans, Phenols, and Acids. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:7171498. [PMID: 33082829 PMCID: PMC7556091 DOI: 10.1155/2020/7171498] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/23/2020] [Accepted: 07/25/2020] [Indexed: 12/18/2022]
Abstract
Liver fibrosis resulting from continuous long-term hepatic damage represents a heavy burden worldwide. Liver fibrosis is recognized as a complicated pathogenic mechanism with extracellular matrix (ECM) accumulation and hepatic stellate cell (HSC) activation. A series of drugs demonstrate significant antifibrotic activity in vitro and in vivo. No specific agents with ideally clinical efficacy for liver fibrosis treatment have been developed. In this review, we summarized the antifibrotic effects and molecular mechanisms of 29 kinds of common natural products. The mechanism of these compounds is correlated with anti-inflammatory, antiapoptotic, and antifibrotic activities. Moreover, parenchymal hepatic cell survival, HSC deactivation, and ECM degradation by interfering with multiple targets and signaling pathways are also involved in the antifibrotic effects of these compounds. However, there remain two bottlenecks for clinical breakthroughs. The low bioavailability of natural products should be improved, and the combined application of two or more compounds should be investigated for more prominent pharmacological effects. In summary, exploration on natural products against liver fibrosis is becoming increasingly extensive. Therefore, natural products are potential resources for the development of agents to treat liver fibrosis.
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Xiao W, Lu MH, Rong PF, Zhang HY, Gong J, Peng YQ, Gong HY, Liu ZG. 11β‑hydroxysteroid dehydrogenase‑1 is associated with the activation of hepatic stellate cells in the development of hepatic fibrosis. Mol Med Rep 2020; 22:3191-3200. [PMID: 32945429 PMCID: PMC7453648 DOI: 10.3892/mmr.2020.11423] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 06/19/2020] [Indexed: 01/21/2023] Open
Abstract
Hepatic fibrosis (HF) is a common complication of numerous chronic liver diseases, but predominantly results from persistent liver inflammation or injury. If left untreated, HF can progress and develop into liver cirrhosis and even hepatocellular carcinoma. However, the underlying molecular mechanisms of HF remain unknown. The present study aimed to investigate the role of 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) during the development of hepatic fibrosis. An experimental rat model of liver fibrosis was induced using porcine serum. 11β-HSD1 gene expression levels and enzyme activity during hepatic fibrogenesis were assessed. 11β-HSD1 gene knockdown using small interfering RNA and overexpression were performed in LX2-human hepatic stellate cells (HSCs). HSCs were stimulated with transforming growth factor-β1 (TGF-β1). Cell cycle distribution, proliferation, collagen secretion and 11β-HSD1 gene activity in HSCs were compared before and after stimulation. As hepatic fibrosis progressed, 11β-HSD1 gene expression and activity increased, indicating a positive correlation with typical markers of liver fibrosis. 11β-HSD1 inhibition markedly reduced the degree of fibrosis. The cell proliferation was increased, the number of cells in the G0/G1 phase decreased and the number of cells in the S and G2/M phases increased in the pSuper transfected group compared with the N group. In addition, the overexpression of 11β-HSD1 enhanced the TGF-β1-induced activation of LX2-HSCs and enzyme activity of connective tissue growth factor. 11β-HSD1 knockdown suppressed cell proliferation by blocking the G0/G1 phase of the cell cycle, which was associated with HSC stimulation and inhibition of 11β-HSD1 enzyme activity. In conclusion, increased 11β-HSD1 expression in the liver may be partially responsible for hepatic fibrogenesis, which is potentially associated with HSC activation and proliferation.
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Affiliation(s)
- Wei Xiao
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Meng-Hou Lu
- Department of Infectious Disease, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Peng-Fei Rong
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Hao-Ye Zhang
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Jian Gong
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Ying-Qiong Peng
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Huan-Yu Gong
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Zhen-Guo Liu
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
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Hepatoprotective Effect of Pericarpium zanthoxyli Extract Is Mediated via Antagonism of Oxidative Stress. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:6761842. [PMID: 32695211 PMCID: PMC7368226 DOI: 10.1155/2020/6761842] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 06/03/2020] [Accepted: 06/12/2020] [Indexed: 02/06/2023]
Abstract
Pericarpium zanthoxyli has been extensively used in traditional Oriental medicine to treat gastric disorders and has anti-inflammatory and antioxidative activities. Therefore, the present study examined a possible hepatoprotective effect of a P. zanthoxyli extract (PZE) and investigated the underlying molecular mechanisms. We employed an in vitro model of arachidonic acid (AA) + iron-induced hepatocyte damage and an in vivo model of CCl4-induced liver injury to assess the effects of PZE and evaluated the relevant molecular targets using biochemical assays, flow cytometry analysis, Western blot, and histopathological analysis. The PZE inhibited AA + iron-induced hepatotoxicity in HepG2 cells, improved mitochondrial dysfunction, and reversed an increase in the cellular H2O2 production and a decrease in the reduced GSH levels induced by AA + iron. Treatment with either 30 or 100 μg/ml PZE significantly increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) protein, and the latter dose also increased the antioxidant response element- (ARE-) driven luciferase activity and enhanced the protein expressions of glutamate-cysteine ligase catalytic subunit and NAD(P)H:quinone oxidoreductase 1. In addition, treatment with 100 μg/ml PZE for 3 or 6 h increased the phosphorylation rates of Nrf2 and the extracellular signal-regulated kinase. In the in vivo experiment, oral treatment with both 100 and 300 mg/kg PZE inhibited the plasma aspartate aminotransferase activity, and the latter also inhibited the plasma alanine aminotransferase activity. In addition, both doses of PZE ameliorated the parenchymal degeneration and necrosis in the liver induced by CCl4 administration, which was associated with reduced expressions of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase, nitrotyrosine, and 4-hydroxynonenal by PZE. These findings suggest that PZE has protective effects against hepatotoxicity both in vitro and in vivo, which are mainly mediated via its antioxidant activity.
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Gong Y, Yang Y. Activation of Nrf2/AREs-mediated antioxidant signalling, and suppression of profibrotic TGF-β1/Smad3 pathway: a promising therapeutic strategy for hepatic fibrosis - A review. Life Sci 2020; 256:117909. [PMID: 32512009 DOI: 10.1016/j.lfs.2020.117909] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 05/19/2020] [Accepted: 06/01/2020] [Indexed: 02/07/2023]
Abstract
Hepatic fibrosis (HF) is a wound-healing response that occurs during chronic liver injury and features by an excessive accumulation of extracellular matrix (ECM) components. Activation of hepatic stellate cell (HSC), the leading effector in HF, is responsible for overproduction of ECM. It has been documented that transforming growth factor-β1 (TGF-β1) stimulates superfluous accumulation of ECM and triggers HSCs activation mainly via canonical Smad-dependent pathway. Also, the pro-fibrogenic TGF-β1 is correlated with generation of reactive oxygen species (ROS) and inhibition of antioxidant mechanisms. Moreover, involvement of oxidative stress (OS) can be clearly elucidated as a fundamental event in liver fibrogenesis. Nuclear factor erythroid 2-related factor 2-antioxidant response elements (Nrf2-AREs) pathway, a group of OS-mediated transcription factors with diverse downstream targets, is associated with the induction of diverse detoxifying enzymes and the most pivotal endogenous antioxidative system. More specifically, Nrf2-AREs pathway has recently assigned as a new therapeutic target for cure of HF. The overall goal of this review will focus on recent findings about activation of Nrf2-AREs-mediated antioxidant and suppression of profibrotic TGF-β1/Smad3 pathway in the liver, providing an overview of recent advances in transcriptional repressors that dislocated during HF formation, and highlighting possible novel therapeutic targets for liver fibrosis.
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Affiliation(s)
- Yongfang Gong
- Department of Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Hefei 230032, China
| | - Yan Yang
- Department of Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Hefei 230032, China.
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He X, Chen J, Mu Y, Zhang H, Chen G, Liu P, Liu W. The effects of inhibiting the activation of hepatic stellate cells by lignan components from the fruits of Schisandra chinensis and the mechanism of schisanhenol. J Nat Med 2020; 74:513-524. [PMID: 32193805 DOI: 10.1007/s11418-020-01394-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 03/06/2020] [Indexed: 12/15/2022]
Abstract
Liver fibrosis is a pathological manifestation induced by chronic liver injury and may cause cirrhosis and liver cancer with the chronic progression of fibrosis. During the onset and progression of liver fibrosis, the activation of hepatic stellate cells (HSCs) is the core mechanism for the secretion of many extracellular matrices to induce fibrosis. Lignans are reportedly the main effective components of Schisandra chinensis with good anti-fibrosis effects. In this study, we compared the inhibiting effects of the seven lignan components from S. chinensis on HSC activation. We found that the seven lignans inhibited the activation of human HSCs (LX-2) in various degrees. Among all lignans, schisanhenol showed the best effect in inhibiting the activation of LX-2 with a dose-effect relationship. Sal also inhibited the phosphorylations of Smad1, Smad2, Smad3, extracellular regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), p38, and nuclear transcription factor-κB (NF-κB), as well as downregulated Smad4. All these findings suggested that schisanhenol may ameliorate liver fibrosis by inhibiting the transforming growth factor β (TGF-β)/Smad and mitogen-activated protein kinase (MAPK) signaling pathways. Remarkably, schisanhenol may be a potential anti-liver fibrosis drug and warrants further research.
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Affiliation(s)
- Xiaoli He
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, China
- TCM Department, Ningbo Huamei Hospital Affiliated to Chinese Academy of Sciences, 41 Xibei Road, Ningbo, 315010, China
| | - Jiamei Chen
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Yongping Mu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Hua Zhang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Gaofeng Chen
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Ping Liu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China.
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, China.
| | - Wei Liu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China.
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, China.
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Xu S, Mao Y, Wu J, Feng J, Li J, Wu L, Yu Q, Zhou Y, Zhang J, Chen J, Ji J, Chen K, Wang F, Dai W, Fan X, Guo C. TGF-β/Smad and JAK/STAT pathways are involved in the anti-fibrotic effects of propylene glycol alginate sodium sulphate on hepatic fibrosis. J Cell Mol Med 2020; 24:5224-5237. [PMID: 32233073 PMCID: PMC7205790 DOI: 10.1111/jcmm.15175] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 01/14/2020] [Accepted: 03/01/2020] [Indexed: 12/25/2022] Open
Abstract
Liver fibrosis, a consequence of unhealthy modern lifestyles, has a growing impact on human health, particularly in developed countries. Here, we have explored the anti-fibrotic effects of propylene glycol alginate sodium sulphate (PSS), a natural extract from brown algae, in fibrotic mice and cell models. Thus, we established bile duct ligature and carbon tetrachloride mouse models and LX-2 cell models with or without PSS treatment. Liver pathological sections and the relevant indicators in serum and liver tissues were examined. PSS prevented hepatic injury and fibrosis to a significant extent, and induced up-regulation of matrix metalloproteinase-2 and down-regulation of tissue inhibitor of metalloproteinase-1 through suppressing the transforming growth factor β1 (TGF-β1)/Smad pathway. PSS additionally exerted an anti-autophagy effect through suppressing the Janus kinase (JAK) 2/transducer and activator of transcription 3 (STAT3) pathway. In conclusion, PSS prevents hepatic fibrosis by suppressing inflammation, promoting extracellular matrix (ECM) decomposition and inactivating hepatic stellate cells through mechanisms involving the TGF-β1/Smad2/3 and JAK2/STAT3 pathways in vivo and in vitro.
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Affiliation(s)
- Shizan Xu
- Department of GastroenterologyPutuo People's HospitalTongji University School of MedicineShanghaiChina
- Department of GastroenterologyJinshan Hospital of Fudan UniversityShanghaiChina
- Department of GastroenterologyShanghai Tenth People’s HospitalTongji University School of MedicineShanghaiChina
- Shanghai Tenth HospitalSchool of Clinical Medicine of Nanjing Medical UniversityShanghaiChina
| | - Yuqing Mao
- Department of GerontologyShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jianye Wu
- Department of GastroenterologyPutuo People's HospitalTongji University School of MedicineShanghaiChina
| | - Jiao Feng
- Department of GastroenterologyShanghai Tenth People’s HospitalTongji University School of MedicineShanghaiChina
| | - Jingjing Li
- Department of GastroenterologyPutuo People's HospitalTongji University School of MedicineShanghaiChina
| | - Liwei Wu
- Department of GastroenterologyShanghai Tenth People’s HospitalTongji University School of MedicineShanghaiChina
| | - Qiang Yu
- Department of GastroenterologyShanghai Tenth People’s HospitalTongji University School of MedicineShanghaiChina
- Shanghai Tenth HospitalSchool of Clinical Medicine of Nanjing Medical UniversityShanghaiChina
| | - Yuting Zhou
- Department of GastroenterologyShanghai Tenth People’s HospitalTongji University School of MedicineShanghaiChina
- Shanghai Tenth HospitalSchool of Clinical Medicine of Nanjing Medical UniversityShanghaiChina
| | - Jie Zhang
- Department of GastroenterologyShanghai Tenth People’s HospitalTongji University School of MedicineShanghaiChina
- Shanghai Tenth HospitalSchool of Clinical Medicine of Nanjing Medical UniversityShanghaiChina
| | - Jiaojiao Chen
- Department of GastroenterologyShanghai Tenth People’s HospitalTongji University School of MedicineShanghaiChina
- Shanghai Tenth HospitalSchool of Clinical Medicine of Nanjing Medical UniversityShanghaiChina
| | - Jie Ji
- Department of GastroenterologyShanghai Tenth People’s HospitalTongji University School of MedicineShanghaiChina
| | - Kan Chen
- Department of GastroenterologyShanghai Tenth People’s HospitalTongji University School of MedicineShanghaiChina
| | - Fan Wang
- Department of OncologyShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Weiqi Dai
- Department of GastroenterologyPutuo People's HospitalTongji University School of MedicineShanghaiChina
- Department of GastroenterologyShanghai Tenth People’s HospitalTongji University School of MedicineShanghaiChina
- Department of GastroenterologyZhongshan Hospital of Fudan UniversityShanghaiChina
- Shanghai Institute of Liver DiseasesZhongshan Hospital of Fudan UniversityShanghaiChina
- Shanghai Tongren HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xiaoming Fan
- Department of GastroenterologyJinshan Hospital of Fudan UniversityShanghaiChina
| | - Chuanyong Guo
- Department of GastroenterologyPutuo People's HospitalTongji University School of MedicineShanghaiChina
- Department of GastroenterologyShanghai Tenth People’s HospitalTongji University School of MedicineShanghaiChina
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Liu G, Zhao Z, Shen M, Zhao X, Xie J, He X, Li C. A Review of Traditional Uses, Phytochemistry, and Pharmacological Properties of the Genus Saururus. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2020; 48:47-76. [PMID: 31964158 DOI: 10.1142/s0192415x20500032] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The genus Saururus, belonging to Saururaceae, contains two species, S. cernuus L. and S. chinensis (Lour) Baill. with common utilization in traditional medicine from Asia to North America for the treatment of edema, beriberi, jaundice, leucorrhea, urinary tract infections, hypertension, hepatitis diseases, and tumors. An extensive review of literature was made on traditional uses, phytochemistry, and ethnopharmacology of Saururus using ethno-botanical books, published articles, and electronic databases. The 147 of chemical constituents have been isolated and identified from S. cernuus and S. chinensis, and lignans, flavonoids, alkaloids, anthraquinones, saponins, and phenols are the major constituents. Various pharmacological investigations in many in vitro and in vivo models have revealed the potential of the genus Saururus with anti-inflammatory, antitumor, anti-oxidant, hepatoprotective, antimelanogenic, lipid-lowering, and bone protective activities, supporting the rationale behind numerous of its traditional uses. Due to the noteworthy pharmacological properties, Saururus can be a better option for new drug discovery. Data regarding many aspects of this plant such as toxicology, pharmacokinetics, quality-control measures, and the clinical value of the active compounds is still limited which call for additional studies.
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Affiliation(s)
- Guangxin Liu
- Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource, Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710062, P. R. China
| | - Zefeng Zhao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, 229 Taibai Road, Xi'an, Shaanxi 710069, P. R. China
| | - Meilun Shen
- Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource, Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710062, P. R. China
| | - Xue Zhao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, 229 Taibai Road, Xi'an, Shaanxi 710069, P. R. China
| | - Jing Xie
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, 229 Taibai Road, Xi'an, Shaanxi 710069, P. R. China
| | - Xirui He
- Honghui Hospital, Xi'an Jiaotong University, 76 Nanguo Road, Xi'an, Shaanxi 710054, P. R. China
| | - Cuiqin Li
- Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource, Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710062, P. R. China
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TGF-β1/Smad7 signaling pathway and cell apoptosis: Two key aspects of Selenium-biofortified soybean peptide attenuating liver fibrosis. J Funct Foods 2019. [DOI: 10.1016/j.jff.2019.103583] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Cao G, Zhu R, Jiang T, Tang D, Kwan HY, Su T. Danshensu, a novel indoleamine 2,3-dioxygenase1 inhibitor, exerts anti-hepatic fibrosis effects via inhibition of JAK2-STAT3 signaling. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 63:153055. [PMID: 31377585 DOI: 10.1016/j.phymed.2019.153055] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 07/03/2019] [Accepted: 07/26/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND Indoleamine 2,3-dioxygenase 1 (IDO1), an important intracellular rate-limiting enzyme in the development of Hepatic fibrosis (HF), and has been proposed as a hallmark of HF. Danshensu (DSS) is a major bioactive component that isolated from a edible traditional Chinese medicinal herb Salviae Miltiorrhizae Radix et Rhizoma (Danshen), while, the anti-HF mode and mechanism of action of DSS have not been fully elucidated. METHODS Carbon tetrachloride (CCl4)-induced rat HF model and TGF-β1-induced hepatic stellate cell (HSC) model were employed to assess the in vivo and in vitro anti-HF effects of DSS. HSC-T6 cells stably expressing IDO1, a constitutively active IDO1 mutant, was used to determine the role of JAK2-STAT3 signaling in the DSS's anti-HF effects. RESULTS We found that intragastric administration of DSS potently reduced fibrosis, inhibited IDO1 expression and STAT3 activity both in vitro and in vivo. Using molecular docking and molecular dynamics analysis, DSS was identified as a novel IDO1 inhibitor. Mechanistic studies indicated that DSS inhibited JAK2-STAT3 signaling, it reduced IDO1 expression, STAT3 phosphorylation and STAT3 nuclear localization. More importantly, overexpression of IDO1 diminished DSS's anti-HF effects. CONCLUSION Our findings provide a pharmacological justification for the clinical use of DSS in treating HF, and suggest that DSS has the potential to be developed as a modern alternative and/or complimentary agent for HF treatment and prevention.
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Affiliation(s)
- Gang Cao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Ruyi Zhu
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Ting Jiang
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Dongxin Tang
- First Affiliated Hospital of Guiyang College of Traditional Chinese Medicine, Guiyang, China
| | - Hiu Yee Kwan
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Tao Su
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.
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Zhangdi HJ, Su SB, Wang F, Liang ZY, Yan YD, Qin SY, Jiang HX. Crosstalk network among multiple inflammatory mediators in liver fibrosis. World J Gastroenterol 2019; 25:4835-4849. [PMID: 31543677 PMCID: PMC6737310 DOI: 10.3748/wjg.v25.i33.4835] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 07/24/2019] [Accepted: 08/07/2019] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is the common pathological basis of all chronic liver diseases, and is the necessary stage for the progression of chronic liver disease to cirrhosis. As one of pathogenic factors, inflammation plays a predominant role in liver fibrosis via communication and interaction between inflammatory cells, cytokines, and the related signaling pathways. Damaged hepatocytes induce an increase in pro-inflammatory factors, thereby inducing the development of inflammation. In addition, it has been reported that inflammatory response related signaling pathway is the main signal transduction pathway for the development of liver fibrosis. The crosstalk regulatory network leads to hepatic stellate cell activation and proinflammatory cytokine production, which in turn initiate the fibrotic response. Compared with the past, the research on the pathogenesis of liver fibrosis has been greatly developed. However, the liver fibrosis mechanism is complex and many pathways involved need to be further studied. This review mainly focuses on the crosstalk regulatory network among inflammatory cells, cytokines, and the related signaling pathways in the pathogenesis of chronic inflammatory liver diseases. Moreover, we also summarize the recent studies on the mechanisms underlying liver fibrosis and clinical efforts on the targeted therapies against the fibrotic response.
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Affiliation(s)
- Han-Jing Zhangdi
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Si-Biao Su
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Fei Wang
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zi-Yu Liang
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yu-Dong Yan
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Shan-Yu Qin
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Hai-Xing Jiang
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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Lee EH, Park KI, Kim KY, Lee JH, Jang EJ, Ku SK, Kim SC, Suk HY, Park JY, Baek SY, Kim YW. Liquiritigenin inhibits hepatic fibrogenesis and TGF-β1/Smad with Hippo/YAP signal. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 62:152780. [PMID: 31121384 DOI: 10.1016/j.phymed.2018.12.003] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 11/23/2018] [Accepted: 12/09/2018] [Indexed: 06/09/2023]
Abstract
BACKGROUND Recent reports highlighted the possibility that Yes-associated protein (YAP) and transforming growth factor-β1 (TGF-β1) can act as critical regulators of hepatic stellate cells (HSCs) activation; therefore, it is natural for compounds targeting Hippo/YAP and TGF-β1/Smad signaling pathways to be identified as potential anti-fibrotic candidates. PURPOSE Liquiritigenin (LQ) is an aglycone of liquiritin and has been reported to protect the liver from injury. However, its effects on the Hippo/YAP and TGF-β1/Smad pathways have not been identified to date. METHODS We conducted a series of experiments using CCl4-induced fibrotic mice and cultured LX-2 cells. RESULT LQ significantly inhibited liver fibrosis, as indicated by decreases in regions of hepatic degeneration, inflammatory cell infiltration, and the intensity of α-smooth muscle actin (α-SMA) staining in mice. Moreover, LQ blocked the TGF-β1-induced phosphorylation of Smad 3, and the transcript levels of plasminogen activator inhibitor-1 (PAI-1) and matrix metalloproteinase-2 (MMP-2) in LX-2 cells, which is similar with resveratrol and oxyresveratrol (positive controls). Furthermore, LQ increased activation of large tumor suppressor kinase 1 (LATS1) with the induction of YAP phosphorylation, thereby preventing YAP transcriptional activity and suppressing the expression of exacerbated TGF-β1/Smad signaling molecules. CONCLUSION These results clearly show that LQ ameliorated experimental liver fibrosis by acting on the TGF-β1/Smad and Hippo/YAP pathways, indicating that LQ has the potential for effective treatment of liver fibrosis.
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Affiliation(s)
- Eun Hye Lee
- Department of Pathology, School of Medical Science, Kyungpook National University, Daegu 41566, South Korea
| | - Kwang-Il Park
- Korea Institute of Oriental Medicine, Daegu 41062, South Korea
| | - Kwang-Youn Kim
- Korea Institute of Oriental Medicine, Daegu 41062, South Korea
| | - Ju-Hee Lee
- College of Korean Medicine, Dongguk University, Gyeongju 38066, South Korea
| | - Eun Jeong Jang
- College of Oriental Medicine, Daegu Haany University, Gyeongsan 38610, South Korea
| | - Sae Kwang Ku
- College of Oriental Medicine, Daegu Haany University, Gyeongsan 38610, South Korea
| | - Sang Chan Kim
- College of Oriental Medicine, Daegu Haany University, Gyeongsan 38610, South Korea
| | - Ho Young Suk
- Yeungnam University, Gyeongsan 38541, South Korea
| | - Ji Young Park
- Department of Pathology, School of Medical Science, Kyungpook National University, Daegu 41566, South Korea
| | - Su Youn Baek
- College of Oriental Medicine, Daegu Haany University, Gyeongsan 38610, South Korea.
| | - Young Woo Kim
- College of Korean Medicine, Dongguk University, Gyeongju 38066, South Korea; College of Oriental Medicine, Daegu Haany University, Gyeongsan 38610, South Korea.
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Feng MH, Li JW, Sun HT, He SQ, Pang J. Sulforaphane inhibits the activation of hepatic stellate cell by miRNA-423-5p targeting suppressor of fused. Hum Cell 2019; 32:403-410. [PMID: 31278688 DOI: 10.1007/s13577-019-00264-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Accepted: 06/25/2019] [Indexed: 02/07/2023]
Abstract
Liver fibrosis, a common pathological process in chronic liver diseases, is characterized by excessive accumulation of extracellular matrix proteins and considered as a wound healing response to chronic liver injury. Hepatic stellate cell (HSC) activation plays a key role in liver fibrosis development. Previous studies showed that sulforaphane (SFN) has wide protective effects against tissue injury and inflammation. Accumulating evidence has shown that microRNAs play important roles in the development of hepatic fibrosis, some of which have been identified as potential therapeutic targets. This study was conducted to explore the role of SFN in the suppression of HSC activation. Quantitative real-time PCR showed that HSC miR-423-5p levels were up-regulated during HSC activation and down-regulated after SFN administration. Further, transfection of a miR-423-5p mimic demonstrated that inhibition of HSC activation by SFN required down-regulation of miR-423-5p. We showed that suppressor of fused is the direct target of miR-423-5p. SFN may play a role in inhibiting hepatic fibrosis by downregulating miRNA-423-5p. MiRNA-423-5p may be useful as a therapeutic target for treating hepatic fibrosis.
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Affiliation(s)
- Ming-Hui Feng
- The Third Affiliated Hospital Of Guangzhou University of Chinese Medicine, Guangzhou, 510515, China
| | - Jian-Wei Li
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Hai-Tao Sun
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Song-Qi He
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Jie Pang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.
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28
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Kim MB, Bae M, Hu S, Kang H, Park YK, Lee JY. Fucoxanthin exerts anti-fibrogenic effects in hepatic stellate cells. Biochem Biophys Res Commun 2019; 513:657-662. [DOI: 10.1016/j.bbrc.2019.04.052] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 04/07/2019] [Indexed: 01/24/2023]
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Deng M, Xu L, Xie X, Sheng X, Zou Z, Yao M. Downregulation of syndecan‑1 expression induces activation of hepatic stellate cells via the TGF‑β1/Smad3 signaling pathway. Mol Med Rep 2019; 20:368-374. [PMID: 31115505 DOI: 10.3892/mmr.2019.10221] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 04/26/2019] [Indexed: 11/06/2022] Open
Abstract
The activation of hepatic stellate cells (HSCs) is considered associated with liver fibrosis. However, the exact role of syndecan‑1 (SDC1), a protein that regulates the interaction between cells and the microenvironment, in the activation of HSCs resulting in liver fibrosis remains elusive. The objective of the present study was to explore the effects and mechanism of action of SDC1 in the activation of HSCs. HSCs were isolated from mouse liver and cultured to detect the expression of SDC1, transforming growth factor (TGF)‑β1, Smad3 and α‑smooth muscle actin (α‑SMA; a marker of HSC activation) by western blotting and reverse transcription‑quantitative PCR. The expression of SDC1 was found to be downregulated, while the expression of TGF‑β1, Smad3 and α‑SMA was upregulated in HSCs during cell culture. In addition, following stimulation of HSCs with recombinant SDC1, the expression of TGF‑β1, Smad3 and α‑SMA in HSCs was downregulated, whereas small interfering RNA targeting Smad3 antagonized the effects of recombinant SDC1 on α‑SMA. Taken together, these data suggest that SDC1 plays a key role in the development of liver fibrosis.
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Affiliation(s)
- Min Deng
- Department of Infectious Diseases, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China
| | - Longsheng Xu
- Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China
| | - Xinsheng Xie
- Department of Infectious Diseases, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China
| | - Xiong Sheng
- Department of Infectious Diseases, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China
| | - Zhuolin Zou
- Department of Infectious Diseases, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China
| | - Ming Yao
- Institute of Hepatology, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China
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30
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Lee Y, Cho IJ, Kim JW, Lee M, Ku SK, Choi J, Lee H. Hepatoprotective effects of blue honeysuckle on CCl 4-induced acute liver damaged mice. Food Sci Nutr 2019; 7:322-338. [PMID: 30680187 PMCID: PMC6341158 DOI: 10.1002/fsn3.893] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 10/23/2018] [Accepted: 11/03/2018] [Indexed: 12/20/2022] Open
Abstract
The objective of this study was to evaluate the hepatoprotective effects of blue honeysuckle (BH) on carbon tetrachloride (CCl4)-induced acute hepatic damage in mice. The experiment used a total of 60 ICR mice, which were divided into six groups. Except for the intact control groups, all groups received a single intraperitoneal injection of CCl4 after a 7 day pre-treatment period with distilled water, BH extracts, or silymarin. Twenty-four hours after the CCl4 injection, the following observations, representative of classical oxidative stress-mediated centrolobular necrotic acute liver injuries, were observed: decreased body weight; small nodule formation and enlargement on the gross inspections with related liver weight increase; elevation of serum AST and ALT, increases in hepatic lipid peroxidation and related depletion of endogenous antioxidants and antioxidative enzymes; centrolobular necrosis; increases in apoptotic markers, lipid peroxidation markers, and oxidative stress markers. However, liver damage was significantly inhibited by the pre-treatment with BH extracts. The present study demonstrated that oral administration of BH extracts prior to exposure to CCl4 conferred favorable hepatoprotective effects. These results demonstrated that BHe possessed suitable properties for use as a potent hepatoprotective medicinal food.
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Affiliation(s)
- You‐Suk Lee
- Department of Food and NutritionCollege of BioNano TechnologyGachon UniversitySeongnam‐siGyeonggi‐doKorea
| | - Il Je Cho
- The Medical Research Center for Globalization of Herbal FormulationDepartment of Herbal FormulationCollege of Oriental MedicineDaegu Haany UniversityGyeongsan‐siGyeongdanuk‐doKorea
| | | | - Min‐Ki Lee
- Department of Physical EducationKongju National UniversityKongju‐siChngcheongnam‐doKorea
| | - Sae Kwang Ku
- Department of Anatomy and HistologyCollege of Korean MedicineDaegu Haany UniversityGyeongsan‐siGyeongdanuk‐doKorea
| | - Jae‐Suk Choi
- Division of BioindustryCollege of Medical and Life SciencesSilla UniversityBusanKorea
| | - Hae‐Jeung Lee
- Department of Food and NutritionCollege of BioNano TechnologyGachon UniversitySeongnam‐siGyeonggi‐doKorea
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Cheng Q, Li C, Yang CF, Zhong YJ, Wu D, Shi L, Chen L, Li YW, Li L. Methyl ferulic acid attenuates liver fibrosis and hepatic stellate cell activation through the TGF-β1/Smad and NOX4/ROS pathways. Chem Biol Interact 2018; 299:131-139. [PMID: 30543783 DOI: 10.1016/j.cbi.2018.12.006] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 11/24/2018] [Accepted: 12/10/2018] [Indexed: 02/06/2023]
Abstract
Liver fibrosis is a pathological wound-healing response caused by chronic liver damage due to a virus, autoimmune disorder, or drugs. Hepatic stellate cells (HSCs) play an essential role in the pathogenesis of liver fibrosis. Methyl ferulic acid (MFA), a biologically active monomer, has a protective effect on liver injury. However, the effects and roles of MFA in liver fibrosis remain unknown. The purpose of the current study was to investigate the effect of MFA on hepatic fibrosis and the underlying mechanisms. Human hepatic stellate LX-2 cells were exposed to 5 μg/L TGF-β1 for 48 h to stimulate liver fibrosis in vitro. Using MTT, RT-PCR and Western blot analysis, we revealed that MFA significantly inhibited the proliferation of LX-2 cells as well as decreased the expressions of α-SMA and type I collagen in LX-2 cells. SD rats were fed with ethanol, and this combined with the intraperitoneal injection of CCl4 induced liver fibrosis in vivo. We found that the administration of MFA markedly decreased the levels of hyaluronic acid (HA), procollagen type III (PC-III), type IV collagen (CIV) and laminin (LN) in the serum, inhibited the expression of α-smooth muscle actin (α-SMA) as well as type I and type III collagen, and up-regulated the ratio of MMP-2/TIMP-1 in rats. The antifibrotic effects of MFA were also evaluated by H&E staining and Masson's trichrome staining. In addition, further studies suggested that this protection by MFA from liver fibrosis was possibly related to the inhibition of TGF-β1/Smad and NOX4/ROS signalling. In conclusion, our results demonstrate that MFA attenuated liver fibrosis and hepatic stellate cell activation by inhibiting the TGF-β1/Smad and NOX4/ROS signalling pathways.
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Affiliation(s)
- Qi Cheng
- College of Pharmacy, Guilin Medical University, Guilin, 541004, PR China
| | - Chen Li
- College of Pharmacy, Guilin Medical University, Guilin, 541004, PR China
| | - Cheng-Fang Yang
- College of Pharmacy, Guilin Medical University, Guilin, 541004, PR China
| | - Yu-Juan Zhong
- College of Pharmacy, Guilin Medical University, Guilin, 541004, PR China
| | - Dan Wu
- College of Pharmacy, Guilin Medical University, Guilin, 541004, PR China
| | - Lin Shi
- College of Pharmacy, Guilin Medical University, Guilin, 541004, PR China
| | - Li Chen
- College of Pharmacy, Guilin Medical University, Guilin, 541004, PR China
| | - Yong-Wen Li
- College of Pharmacy, Guilin Medical University, Guilin, 541004, PR China.
| | - Li Li
- College of Pharmacy, Guilin Medical University, Guilin, 541004, PR China.
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Amiri Dehkharghani R, Zandi Doust M, Tavassoti Kheiri M, Hossein Shahi H. Impacts of Chemical Variables on the Encapsulated Corticoids in Poly-ε-caprolactone Nanoparticles and Statistical Biological Analysis. RUSS J APPL CHEM+ 2018. [DOI: 10.1134/s1070427218070157] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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A combination of astragaloside I, levistilide A and calycosin exerts anti-liver fibrosis effects in vitro and in vivo. Acta Pharmacol Sin 2018; 39:1483-1492. [PMID: 29849130 DOI: 10.1038/aps.2017.175] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 11/18/2017] [Indexed: 12/11/2022]
Abstract
Liver fibrosis is excessive accumulation of extracellular matrix proteins that results from various chronic liver diseases. Hepatic stellate cells (HSCs) play an essential role in the pathogenesis of liver fibrosis. Danggui Buxue Tang (DBT) is a classic formula of Chinese traditional medicine. We previously showed that DBT could ameliorate liver fibrosis in rats. However, the bioactive components of DBT in the treatment of liver fibrosis remain unknown. In this study we evaluated 14 ingredients from DBT in human hepatic stellate cell line LX-2, and found that astragaloside I (A), levistilide A (L) and calycosin (C) produced synergistic proliferation inhibition on LX-2 cells and TGF-β1-activated LX-2 cells. Thus, we prepared a mixture of them, and named this combination as ALC formula. Using high-content screening and Western blot assay we revealed that the ALC formula significantly reduced the expression of α-SMA and collagen I in LX-2 cells. The in vivo anti-fibrosis effects of ALC formula were evaluated in a liver fibrosis model in C57BL/6 mice established through injection of dimethylnitrosamine (DMN 2 mg/kg, ip) for 4 weeks. In the third week, the nice were injected with ALC formula (astragaloside I 44.21 mg/kg per day, levistilide A 6 mg/kg per day and calycosin 3.45 mg/kg per day; ip) or sorafenib, a positive control drug (6 mg/kg per day, ip) for 2 weeks. We found that administration of the ALC formula markedly decreased collagen deposition, hydroxyproline (Hyp) content and α-SMA expression levels in the liver tissues compared to the model mice. In conclusion, the present study demonstrates for the first time that astragaloside I, levistilide A and calycosin may be the 3 main bioactive components in DBT; their combination exerts anti-liver fibrosis effects in vitro and in vivo.
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Pan H, Li Y, Qian H, Qi X, Wu G, Zhang H, Xu M, Rao Z, Li JL, Wang L, Ying H. Effects of Geniposide from Gardenia Fruit Pomace on Skeletal-Muscle Fibrosis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:5802-5811. [PMID: 29771121 DOI: 10.1021/acs.jafc.8b00739] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Geniposide is the main bioactive constituent of gardenia fruit. Skeletal-muscle fibrosis is a common and irreversibly damaging process. Numerous studies have shown that geniposide could improve many chronic diseases, including metabolic syndrome and tumors. However, the effects of geniposide on skeletal-muscle fibrosis are still poorly understood. Here, we found that crude extracts of gardenia fruit pomace could significantly decrease the expression of profibrotic genes in vitro. Moreover, geniposide could also reverse profibrotic-gene expression induced by TGF-β and Smad4, a regulator of skeletal-muscle fibrosis. In addition, geniposide treatment could significantly downregulate profibrotic-gene expression and improve skeletal-muscle injuries in a mouse model of contusion. These results together suggest that geniposide has an antifibrotic effect on skeletal muscle through the suppression of the TGF-β-Smad4 signaling pathway.
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Affiliation(s)
- Haiou Pan
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology , Jiangnan University , Lihu Avenue 1800 , Wuxi 214122 , China
| | - Yan Li
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology , Jiangnan University , Lihu Avenue 1800 , Wuxi 214122 , China
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , University of Chinese Academy of Sciences , 320 Yueyang Road , Shanghai 200031 , China
| | - Haifeng Qian
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology , Jiangnan University , Lihu Avenue 1800 , Wuxi 214122 , China
| | - Xiguang Qi
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology , Jiangnan University , Lihu Avenue 1800 , Wuxi 214122 , China
| | - Gangcheng Wu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology , Jiangnan University , Lihu Avenue 1800 , Wuxi 214122 , China
| | - Hui Zhang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology , Jiangnan University , Lihu Avenue 1800 , Wuxi 214122 , China
| | - Meijuan Xu
- Key Laboratory of Industrial Biotechnology, Ministry of Education, Laboratory of Applied Microorganisms and Metabolic Engineering, School of Biotechnology , Jiangnan University , Wuxi 214122 , China
| | - Zhiming Rao
- Key Laboratory of Industrial Biotechnology, Ministry of Education, Laboratory of Applied Microorganisms and Metabolic Engineering, School of Biotechnology , Jiangnan University , Wuxi 214122 , China
| | - Jin-Long Li
- School of Pharmacy , Nantong University , Nantong 226001 , China
| | - Li Wang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology , Jiangnan University , Lihu Avenue 1800 , Wuxi 214122 , China
| | - Hao Ying
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , University of Chinese Academy of Sciences , 320 Yueyang Road , Shanghai 200031 , China
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Chae HS, You BH, Kim DY, Lee H, Ko HW, Ko HJ, Choi YH, Choi SS, Chin YW. Sauchinone controls hepatic cholesterol homeostasis by the negative regulation of PCSK9 transcriptional network. Sci Rep 2018; 8:6737. [PMID: 29712938 PMCID: PMC5928089 DOI: 10.1038/s41598-018-24935-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 04/12/2018] [Indexed: 12/15/2022] Open
Abstract
Whole-transcriptome analysis and western blotting of sauchinone-treated HepG2 cells demonstrated that sauchinone regulated genes relevant to cholesterol metabolism and synthesis. In particular, it was found that the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) was downregulated, and the expression of low density lipoprotein receptor (LDLR) was upregulated in sauchinone-treated HepG2 cells. Consequently, LDL-cholesterol (LDL-C) uptake was increased. As a transcriptional regulator of PCSK9 expression, sterol regulatory elements binding protein-2 (SREBP-2) was proposed by transcriptome analysis and western blotting. Oral administration of sauchinone increased hepatic LDLR through PCSK9 inhibition in obese mice and showed the reduced serum LDL-C levels and downstream targets of SREBP-2. Thus, it is evident that sauchinone reduces hepatic steatosis by downregulating the expression of hepatic PCSK9 via SREBP-2.
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Affiliation(s)
- Hee-Sung Chae
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang, Gyeonggi-do, 10326, Republic of Korea
| | - Byoung Hoon You
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang, Gyeonggi-do, 10326, Republic of Korea
| | - Dong-Yeop Kim
- Division of Biomedical Convergence, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon, Gangwon, 24341, Republic of Korea
| | - Hankyu Lee
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang, Gyeonggi-do, 10326, Republic of Korea
| | - Hyuk Wan Ko
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang, Gyeonggi-do, 10326, Republic of Korea
| | - Hyun-Jeong Ko
- Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, Gangwon, 24341, Republic of Korea
| | - Young Hee Choi
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang, Gyeonggi-do, 10326, Republic of Korea
| | - Sun Shim Choi
- Division of Biomedical Convergence, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon, Gangwon, 24341, Republic of Korea
| | - Young-Won Chin
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang, Gyeonggi-do, 10326, Republic of Korea.
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Wang YR, Hong RT, Xie YY, Xu JM. Melatonin Ameliorates Liver Fibrosis Induced by Carbon Tetrachloride in Rats via Inhibiting TGF-β1/Smad Signaling Pathway. Curr Med Sci 2018; 38:236-244. [DOI: 10.1007/s11596-018-1871-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 12/28/2017] [Indexed: 12/18/2022]
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Gong QZ, Xiao D, Feng F, Wen XD, Qu W. ent-Sauchinone as Potential Anticancer Agent Inhibiting Migration and Invasion of Human Liver Cancer CellsviaSuppressing the STAT3 Signaling Pathway. Chem Biodivers 2018; 15:e1800024. [DOI: 10.1002/cbdv.201800024] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Accepted: 02/27/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Qi-Zhe Gong
- State Key Laboratory Natural Medicines; China Pharmaceutical University; Nanjing 210009 P. R. China
| | - Di Xiao
- Department of Natural Medicinal Chemistry; China Pharmaceutical University; Nanjing 210009 P. R. China
| | - Feng Feng
- Department of Natural Medicinal Chemistry; China Pharmaceutical University; Nanjing 210009 P. R. China
- Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University); Ministry of Education; China Pharmaceutical University; Nanjing 210009 P. R. China
| | - Xiao-Dong Wen
- State Key Laboratory Natural Medicines; China Pharmaceutical University; Nanjing 210009 P. R. China
| | - Wei Qu
- Department of Natural Medicinal Chemistry; China Pharmaceutical University; Nanjing 210009 P. R. China
- Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University); Ministry of Education; China Pharmaceutical University; Nanjing 210009 P. R. China
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Xie ZY, Xiao ZH, Wang FF. Inhibition of autophagy reverses alcohol-induced hepatic stellate cells activation through activation of Nrf2-Keap1-ARE signaling pathway. Biochimie 2018; 147:55-62. [PMID: 29305174 DOI: 10.1016/j.biochi.2017.12.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 12/28/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Numerous documents have indicated a critical role of autophagy in alcoholic liver fibrosis (ALF), but few papers have reported its function in hepatic stellate cells (HSCs) activation. The current study aimed to investigate the regulation effect of autophagy in HSCs activation, in further to explore the underlying mechanism involved. METHODS HSC-T6 cells were treated with ethanol, 3-MA (autophagy inhibitor) or rapamycin (autophagy inducer), and cells were also transfected with si-Nrf2 or si-Keap1. Moreover, ALF animal model was established and Nrf-2(-/-), Keap1 (-/-) mice were purchased. The level of autophagy, the expression of α-SMA and CoL1A1, and Nrf2 antioxidant response were evaluated in stellate cells and livers. RESULTS Ethanol treatment in cultured cells increased autophagy, oxidative stress level and promoted HSCs activation. Inhibition of autophagy reversed alcohol-induced HSCs activation and suppressed HSCs oxidative stress. Nrf2-Keap1-ARE pathway was involved in HSCs activation and oxidative stress regulated by autophagy. In addition, through in vivo study, we found that inhibition of autophagy could alleviate alcoholic fatty liver injury in ALF model mice and Nrf2 signaling was involved in autophagy regulated HSCs activation. CONCLUSION These data implicated mechanisms underlying autophagy in regulating the fibrogenic response in HSCs activation.
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Affiliation(s)
- Zheng-Yuan Xie
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
| | - Zhi-Hua Xiao
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Fen-Fen Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
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Vescarelli E, Pilloni A, Dominici F, Pontecorvi P, Angeloni A, Polimeni A, Ceccarelli S, Marchese C. Autophagy activation is required for myofibroblast differentiation during healing of oral mucosa. J Clin Periodontol 2017. [PMID: 28646601 DOI: 10.1111/jcpe.12767] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
AIM It is known that periodontal tissues heal faster that skin, and gingiva in particular heal without scar formation. The mechanisms regulating this behaviour are still unclear. The aim of our work was to compare wound healing in oral mucosa and gingiva, investigating the role of α-smooth muscle actin (αSMA)-expressing myofibroblasts and autophagy. MATERIALS AND METHODS Biopsies were obtained from seven patients immediately before and 24 hr after vertical releasing incision in oral mucosa and attached gingiva. Both whole biopsies and primary cultures of fibroblasts derived from the same tissues were subjected to immunofluorescence, Western blot and quantitative real-time PCR analyses. RESULTS We demonstrated that in oral mucosa, characterized by partially fibrotic outcome during repair, the activation of autophagy determined an increase in αSMA and collagen 1a1 production. Conversely, wound healing did not stimulate autophagy in attached gingiva, and subsequently, no increase in myofibroblast differentiation and collagen deposition could be seen, thus justifying its scarless outcome. CONCLUSIONS The elucidation of the differential regulation of autophagy in periodontal tissues and its correlation with myofibroblast differentiation and fibrotic outcome could allow the identification of new molecules involved in periodontal healing and the development of new surgical approaches for periodontal treatment that could improve the outcome of postoperative wounds.
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Affiliation(s)
- Enrica Vescarelli
- Department of Experimental Medicine, Sapienza University of Rome, Roma, Italy
| | - Andrea Pilloni
- Section of Periodontology, Sapienza University of Rome, Roma, Italy
| | | | - Paola Pontecorvi
- Department of Experimental Medicine, Sapienza University of Rome, Roma, Italy
| | - Antonio Angeloni
- Department of Molecular Medicine, Sapienza University of Rome, Roma, Italy
| | | | - Simona Ceccarelli
- Department of Experimental Medicine, Sapienza University of Rome, Roma, Italy
| | - Cinzia Marchese
- Department of Experimental Medicine, Sapienza University of Rome, Roma, Italy
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Activation of AMPK by Buddleja officinalis Maxim. Flower Extract Contributes to Protecting Hepatocytes from Oxidative Stress. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 2017:9253462. [PMID: 28473864 PMCID: PMC5394415 DOI: 10.1155/2017/9253462] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Accepted: 03/06/2017] [Indexed: 12/16/2022]
Abstract
The Buddleja officinalis Maxim. flower is used in traditional Chinese and Korean medicine to treat inflammation, vascular diseases, headache, and stroke, as well as enhance liver function. This research investigated the effects of B. officinalis Maxim. flower extract (BFE) on hepatotoxicity. The cytoprotective effects and mechanism of BFE against severe mitochondrial dysfunction and H2O2 production in hepatotoxicity induced by coadministration of arachidonic acid (AA) and iron were observed in the HepG2 cell line. In addition, we performed blood biochemical, histopathological, and histomorphometric analyses of mice with carbon tetrachloride- (CCl4-) induced acute liver damage. BFE inhibited the AA + iron-mediated hepatotoxicity of HepG2 cells. Moreover, it inhibited mitochondrial dysfunction, H2O2 production, and glutathione depletion mediated by AA + iron in the same cells. Meanwhile, the cytoprotective effects of BFE against oxidative stress were associated with the activation of AMP-activated protein kinase (AMPK). In particular, based on the histopathological observations, BFE (30 and 100 mg/kg) showed clear hepatoprotective effects against CCl4-induced acute hepatic damage. Furthermore, it inhibited 4-hydroxynonenal and nitrotyrosine immunoreactivity in hepatocytes. These results provide evidence that BFE has beneficial hepatoprotective effects against hepatic damage via the activation of AMPK pathway. Accordingly, BFE may have therapeutic potential for diverse liver disorders.
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Ge MX, He HW, Shao RG, Liu H. Recent progression in the utilization of autophagy-regulating nature compound as anti-liver fibrosis agents. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2017; 19:109-113. [PMID: 28133978 DOI: 10.1080/10286020.2016.1276168] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 12/20/2016] [Indexed: 06/06/2023]
Abstract
Hepatic fibrosis is a wound-healing response to chronic liver injury caused by various pathogenesis, such as hepatitis virus infection, drugs toxicity and autoimmune imbalances. Autophagy, a cellular process degrading damaged organelles or aggregative proteins, participates in multiple human diseases including hepatic fibrosis. However, the precise role of autophagy in the pathogenesis of hepatic fibrosis is yet to be elucidated. Accumulated evidences indicate that several nature compounds exhibit anti-fibrotic potential through modulating autophagy activity. For a better understanding of the relationships among autophagy, hepatic fibrosis, and autophagy-regulating nature compounds, this review highlights the recent advancement of nature compounds treating hepatic fibrosis through regulating autophagy.
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Affiliation(s)
- Mao-Xu Ge
- a Key Laboratory of Biotechnology of Antibiotics of NHFPC , Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences , Beijing 100050 , China
| | - Hong-Wei He
- a Key Laboratory of Biotechnology of Antibiotics of NHFPC , Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences , Beijing 100050 , China
| | - Rong-Guang Shao
- a Key Laboratory of Biotechnology of Antibiotics of NHFPC , Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences , Beijing 100050 , China
| | - Hong Liu
- a Key Laboratory of Biotechnology of Antibiotics of NHFPC , Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences , Beijing 100050 , China
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Liqustri lucidi Fructus inhibits hepatic injury and functions as an antioxidant by activation of AMP-activated protein kinase in vivo and in vitro. Chem Biol Interact 2017; 262:57-68. [DOI: 10.1016/j.cbi.2016.11.031] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 11/14/2016] [Accepted: 11/30/2016] [Indexed: 12/27/2022]
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Sauchinone exerts anticancer effects by targeting AMPK signaling in hepatocellular carcinoma cells. Chem Biol Interact 2017; 261:108-117. [DOI: 10.1016/j.cbi.2016.11.016] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 11/08/2016] [Accepted: 11/16/2016] [Indexed: 02/07/2023]
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Zhang CY, Yuan WG, He P, Lei JH, Wang CX. Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets. World J Gastroenterol 2016; 22:10512-10522. [PMID: 28082803 PMCID: PMC5192262 DOI: 10.3748/wjg.v22.i48.10512] [Citation(s) in RCA: 435] [Impact Index Per Article: 48.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 10/12/2016] [Accepted: 11/15/2016] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the absence of liver transplantation. Fibrosis generally results from chronic hepatic injury caused by various factors, mainly viral infection, schistosomiasis, and alcoholism; however, the exact pathological mechanisms are still unknown. Although numerous drugs have been shown to have antifibrotic activity in vitro and in animal models, none of these drugs have been shown to be efficacious in the clinic. Importantly, hepatic stellate cells (HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis. These cells are subject to intricate cross-talk with adjacent cells, resulting in scarring and subsequent liver damage. Thus, an understanding of the molecular mechanisms of liver fibrosis and their relationships with HSCs is essential for the discovery of new therapeutic targets. This comprehensive review outlines the role of HSCs in liver fibrosis and details novel strategies to suppress HSC activity, thereby providing new insights into potential treatments for liver fibrosis.
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Zhang CY, Yuan WG, He P, Lei JH, Wang CX. Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets. World J Gastroenterol 2016. [PMID: 28082803 DOI: 10.3748/wjg.v22.i48.10512.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/29/2022] Open
Abstract
Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the absence of liver transplantation. Fibrosis generally results from chronic hepatic injury caused by various factors, mainly viral infection, schistosomiasis, and alcoholism; however, the exact pathological mechanisms are still unknown. Although numerous drugs have been shown to have antifibrotic activity in vitro and in animal models, none of these drugs have been shown to be efficacious in the clinic. Importantly, hepatic stellate cells (HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis. These cells are subject to intricate cross-talk with adjacent cells, resulting in scarring and subsequent liver damage. Thus, an understanding of the molecular mechanisms of liver fibrosis and their relationships with HSCs is essential for the discovery of new therapeutic targets. This comprehensive review outlines the role of HSCs in liver fibrosis and details novel strategies to suppress HSC activity, thereby providing new insights into potential treatments for liver fibrosis.
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Affiliation(s)
- Chong-Yang Zhang
- Chong-Yang Zhang, Jia-Hui Lei, Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Wei-Gang Yuan
- Chong-Yang Zhang, Jia-Hui Lei, Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Pei He
- Chong-Yang Zhang, Jia-Hui Lei, Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Jia-Hui Lei
- Chong-Yang Zhang, Jia-Hui Lei, Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Chun-Xu Wang
- Chong-Yang Zhang, Jia-Hui Lei, Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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Li J, Zhao TT, Zhang P, Xu CJ, Rong ZX, Yan ZY, Fang CY. Autophagy mediates oral submucous fibrosis. Exp Ther Med 2016; 11:1859-1864. [PMID: 27168817 DOI: 10.3892/etm.2016.3145] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 01/15/2016] [Indexed: 12/16/2022] Open
Abstract
Oral submucous fibrosis (OSF) is a chronic insidious disease of the oral mucosa, well-recognized as a premalignant condition and commonly found in Southern China. It is primarily caused by the habit of areca nut or gutkha chewing. OSF is believed to be a homeostatic disorder of the extracellular matrix and fibroblast proliferation. The present study demonstrated a novel link between autophagy and OSF. Tissue samples from human OSF showed an overexpression of the autophagy marker microtubule-associated protein 1 light chain 3 using immunohistochemistry and quantitative polymerase chain reaction. With regard to the crucial role of transforming growth factor (TGF)-β in OSF disease, western blot analysis demonstrated that TGF-β signaling was shown to contribute to the activation of autophagy in fibroblasts in vitro; however, a cell apoptosis and MTS assay demonstrated that the suppression of autophagy ameliorated the fibrosis induced by active TGF-β receptor type I signaling, as well as promoted fibroblast apoptosis and suppressed proliferation. Therefore, the present results suggest that autophagy serves a crucial function in OSF.
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Affiliation(s)
- Jiang Li
- Oral Medical Center, Xiangya Hospital, Central South University, Changsha, Hunan 410000, P.R. China
| | - Ting-Ting Zhao
- Oral Medical Center, Xiangya Hospital, Central South University, Changsha, Hunan 410000, P.R. China
| | - Peng Zhang
- Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Chao-Jin Xu
- Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Zhuo-Xiang Rong
- Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410000, P.R. China
| | - Zi-Yi Yan
- Oral Medical Center, Xiangya Hospital, Central South University, Changsha, Hunan 410000, P.R. China
| | - Chang-Yun Fang
- Oral Medical Center, Xiangya Hospital, Central South University, Changsha, Hunan 410000, P.R. China
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Ko HL, Jung EH, Jung DH, Kim JK, Ku SK, Kim YW, Kim SC, Zhao R, Lee CW, Cho IJ. Paeonia japonica root extract protects hepatocytes against oxidative stress through inhibition of AMPK-mediated GSK3β. J Funct Foods 2016. [DOI: 10.1016/j.jff.2015.11.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Pasta L, Pasta F. PAI-1 4G-4G and MTHFR 677TT in non-hepatitis C virus/hepatitis B virus-related liver cirrhosis. World J Hepatol 2015; 7:2920-2926. [PMID: 26689658 PMCID: PMC4678379 DOI: 10.4254/wjh.v7.i29.2920] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 09/04/2015] [Accepted: 11/25/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the different roles of thrombophilia in patients with and without viral etiology. The thrombophilic genetic factors (THRGFs), PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q and prothrombin 20210A, were studied as risk factors in 1079 patients with liver cirrhosis (LC), enrolled from January 2000 to January 2014.
METHODS: All Caucasian LC patients consecutively observed in a fourteen-year period were included; the presence of portal vein thrombosis (PVT) and Budd Chiari syndrome (BCS) was registered. The differences between the proportions of each THRGF with regard to the presence or absence of viral etiology and the frequencies of the THRGF genotypes with those predicted in a population by the Hardy-Weinberg equilibrium were registered.
RESULTS: Four hundred and seventeen/one thousand and seventy-six patients (38.6%) showed thrombophilia: 217 PAI-1 4G-4G, 176 MTHFR C677TT, 71 V Leiden factor and 41 prothrombin G20210 A, 84 with more than 1 THRGF; 350 presented with no viral liver cirrhosis (NVLC) and 729 with, called viral liver cirrhosis (VLC), of whom 56 patients were hepatitis C virus + hepatitis B virus. PAI-1 4G-4G, MTHFR C677TT, the presence of at least one TRHGF and the presence of > 1 THRGF, were statistically more frequent in patients with NVLC vs patients with VLC: All χ2 > 3.85 and P < 0.05. Patients with PVT and/or BCS with at least one TRHGF were 189/352 (53.7%). The Hardy-Weinberg of PAI-1 and MTHFR 677 genotypes deviated from that expected from a population in equilibrium in patients with NVLC (respectively χ2 = 39.3; P < 0.000 and χ2 = 27.94; P < 0.05), whereas the equilibrium was respected in VLC.
CONCLUSION: MTHFR 677TT was nearly twofold and PAI-1 4G-4G more than threefold more frequently found in NVLC vs patients with VLC; the Hardy-Weinberg equilibrium of these two polymorphisms confirms this data in NVLC. We suggest that PAI-1 4G-4G and MTHFR 677TT could be considered as factors of fibrosis and thrombosis mechanisms, increasing the inflammation response, and causing the hepatic fibrosis and augmented intrahepatic vascular resistance typical of LC. PAI-1 4G-4G and MTHFR 677TT screening of LC patients could be useful, mainly in those with NVLC, to identify patients in which new drug therapies based on the attenuation of the hepatic stellate cells activation or other mechanisms could be more easily evaluated.
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