Silymarin Decreases Connective Tissue Growth Factor to Improve Liver Fibrosis in Rats Treated with Carbon Tetrachloride

Tzeng, Jann-Inn; Chen, Mei-Fen; Chung, Hsien-Hui

doi:10.1002/ptr.4829

Cited by 42 publications

(31 citation statements)

References 39 publications

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“…34 Smad3 signaling has been identified as the responsible pathway inducing CTGF expression in hepatocytes of CCl 4 -treated mice, 35 and knockdown of CTGF by injection of small interfering RNA into the portal veins of rat livers prevents CCl 4 -induced fibrosis by inhibiting TGF-b induction and HSC activation. 36 It has been reported that in rats treated with CCl 4 silymarin decreases CTGF to improve liver fibrosis 37 and curcumin significantly attenuates the severity of liver damage through inhibition of CTGF expression. 30 Our findings confirmed that chronic CCl 4 administration markedly enhanced the intrahepatic expression of CTGF mRNA and protein, and that melatonin significantly reduced these CCl 4 -induced increases.…”

Section: Discussionmentioning

confidence: 99%

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

Crespo

San‐Miguel

Fernández

et al. 2015

Translational Research

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We investigated whether melatonin ameliorates fibrosis and limits the expression of fibrogenic genes in mice treated with carbon tetrachloride (CCl 4 ). Mice in treatment groups received CCl 4 5 mL/g body weight intraperitoneally twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg/kg/d intraperitoneally, beginning 2 weeks after the start of CCl 4 administration. Treatment with CCl 4 resulted in fibrosis evidenced by the staining of Van Gieson and a-smooth muscle actin (a-SMA) positive cells in the liver. At both 4 and 6 weeks, CCl 4 induced an increase in the messenger RNA levels of collagens I and III, transforming growth factor (TGF)-b, platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), amphiregulin, matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1. Protein concentrations of CTGF, amphiregulin, MMP-9, TIMP-1, and phospho-Smad3 were also significantly augmented in fibrotic mice. Melatonin successfully attenuated liver injury, as shown by histopathology and decreased levels of serum transaminases. Immunohistochemical staining of a-SMA indicated an abrogation of hepatic stellate cell activation by the indol. Furthermore, melatonin treatment resulted in significant inhibition of the expression of collagens I and III, TGF-b, PDGF, CTGF, amphiregulin, and phospho-Smad3. The MMP-9 activity decreased and the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) increased in mice receiving melatonin. Data obtained suggest that attenuation of multiple profibrogenic gene pathways contributes to the beneficial effects of melatonin in mice with CCl 4 -induced liver fibrosis. (Translational Research 2015;165:346-357) Abbreviations: a-SMA ¼ a-smooth muscle actin; CCl 4 ¼ carbon tetrachloride; CTGF ¼ connective tissue growth factor; HSC ¼ hepatic stellate cell; MMP-9 ¼ matrix metalloproteinase 9; Nrf2 ¼ nuclear factor erythroid 2-related factor 2; PDGF ¼ platelet-derived growth factor; TGF-b ¼ transforming growth factor b; TIMP-1 ¼ tissue inhibitor of metalloproteinase 1 H epatic fibrosis is a reversible wound-healing response to either acute or chronic cellular injury from a wide variety of etiologies, characterized by an excessive deposition of extracellular matrix (ECM) resulting in liver dysfunction and irreversible cirrhosis. During liver fibrogenesis, hepatic stellate cells (HSCs) undergo activation to a a-smooth muscle actin (SMA)-positive myofibroblastic phenotype and synthesize excess ECM components, particularly collagen. 1 Among the numerous From the

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Section: Discussionmentioning

confidence: 99%

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

Crespo

San‐Miguel

Fernández

et al. 2015

Translational Research

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“…The dependence of CCl 4 toxicity on P450-mediated metabolism means that, similar to APAP, interventions which inhibit metabolism will likely protect against injury. Unfortunately, many studies showing protection against CCl 4 hepatotoxicity by herbal therapeutics have relied on either pretreatment or cotreatment (Kang et al, 2008; Dhanasekaran et al, 2009; Risal et al, 2012; Tzeng et al, 2012). Thus, any conclusions regarding an anti-inflammatory, antioxidant, or anti-fibrotic effect in these and similar studies are questionable at best.…”

Section: Non-acetaminophen Models Of Hepatotoxicitymentioning

confidence: 99%

Models of drug-induced liver injury for evaluation of phytotherapeutics and other natural products

Jaeschke

Williams

McGill

et al. 2013

Food and Chemical Toxicology

106

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Extracts from medicinal plants, many of which have been used for centuries, are increasingly tested in models of hepatotoxicity. One of the most popular models to evaluate the hepatoprotective potential of natural products is acetaminophen (APAP)-induced liver injury, although other hepatotoxicity models such as carbon tetrachloride, thioacetamide, ethanol and endotoxin are occasionally used. APAP overdose is a clinically relevant model of drug-induced liver injury. Critical mechanisms and signaling pathways, which trigger necrotic cell death and sterile inflammation, are discussed. Although there is increasing understanding of the pathophysiology of APAP-induced liver injury, the mechanism is complex and prone to misinterpretation, especially when unknown chemicals such as plant extracts are tested. This review discusses the fundamental aspects that need to be considered when using this model, such as selection of the animal species or in vitro system, timing and dose-responses of signaling events, metabolic activation and protein adduct formation, the role of lipid peroxidation and apoptotic versus necrotic cell death, and the impact of the ensuing sterile inflammatory response. The goal is to enable researchers to select the appropriate model and experimental conditions for testing of natural products that will yield clinically relevant results and allow valid interpretations of the pharmacological mechanisms.

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“…The whole extract, known as silymarin, as well as silybin, has been found to protect the liver from both acute and chronic toxicity and injury (17–20). Previous studies have demonstrated that silybin inhibits various inflammatory responses by suppressing the NF-κB pathway.…”

Section: Introductionmentioning

confidence: 99%

Silybin attenuates LPS-induced lung injury in mice by inhibiting NF-κB signaling and NLRP3 activation

Zhang

Wang

Cao

et al. 2017

International Journal of Molecular Medicine

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Silybin is one of the main flavonoids produced by milk thistle, which has been used in the treatment of liver diseases. In this study, we examined the protective effects and possible mechanisms of action of silybin in lipopolysaccharide (LPS)-induced lung injury and inflammation. Pre-treatment of mice with silybin significantly inhibited LPS-induced airway inflammatory cell recruitment, including macrophages, T cells and neutrophils. The production of cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in bronchoalveolar fluid and serum was also decreased following treatment with silybin. Elevated cytokine mRNA levels induced by LPS in lung tissue were all suppressed by silybin and lung histological alterations were also improved. In addition, experiments using cells indicated that silybin significantly decreased the mRNA levels and secretion of IL-1β and TNF-α in THP-1 cells. Moreover, the mechanisms responsible for these effects were attributed to the inhibitory effect of silybin on nuclear factor-κB (NF-κB) signaling and NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. The data form our study thus support the utility of silybin as a potential medicine for the treatment of acute lung injury-associated inflammation and pathological changes. Silybin exerts protective effects against lung injury by regulating NF-κB signaling and the NLRP3 inflammasome activation.

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Silymarin Decreases Connective Tissue Growth Factor to Improve Liver Fibrosis in Rats Treated with Carbon Tetrachloride

Cited by 42 publications

References 39 publications

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

Models of drug-induced liver injury for evaluation of phytotherapeutics and other natural products

Silybin attenuates LPS-induced lung injury in mice by inhibiting NF-κB signaling and NLRP3 activation

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