Oxymatrine attenuates CCl 4 -induced hepatic fibrosis via modulation of TLR4-dependent inflammatory and TGF-β1 signaling pathways

Zhao, Hongwei; Zhang, Zhenfang; Chai, Xuan; Li, Guang-quan; Cui, Herong; Wang, Hongbo; Meng, Yan; Liu, Huimin; Wang, Jiabo; Li, Ruisheng; Bai, Zhaofang; Xiao, Xiaohe

doi:10.1016/j.intimp.2016.04.040

Cited by 49 publications

(32 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Oxymatrine (OMT) is an alkaloid derived from extract of Sophora flavescens and Sophora alopecuroides, which is a traditional Chinese medicine with anti-tumor [ 8 , 9 ], anti-inflammatory [ 10 ], and attenuating heart failure properties [ 11 ]. OMT is widely applied for various human diseases such as hepatitis B infection and liver fibrosis [ 12 ], and provides protection from damage to the liver, intestines, and heart [ 13 – 15 ]. Previous studies have shown that OMT can improve myocardial infarction induced by acute myocardial infarction [ 16 ] by attenuating myocardial hypertrophy, left ventricular dysfunction, and heart failure [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Oxymatrine Inhibits Transforming Growth Factor β1 (TGF-β1)-Induced Cardiac Fibroblast-to-Myofibroblast Transformation (FMT) by Mediating the Notch Signaling Pathway In Vitro

Zhao

Tao

et al. 2018

Med Sci Monit

View full text Add to dashboard Cite

BackgroundOxymatrine, a component extracted from the traditional Chinese herb Sophora japonica (Sophora flavescens Ait.), has various pharmacological effects, especially on the cardiovascular system. However, its cardiac protection effects and the underlying mechanism are still poorly understood. In the present study, we investigated the inhibitory effect and mechanism of oxymatrine on cardiac fibrosis induced by TGF-β1.Material/MethodsCardiac fibroblasts were isolated and purified from neonatal rats. Immunocytochemical staining was used to identify the cells. MTT assay and immunofluorescence staining were used to assess cardiac fibroblasts proliferation and myofibroblasts transformation. Hematoxylin-eosin staining was performed to evaluate morphological changes of cardiac fibroblasts. The secretion of type I and III collagen was assessed by staining with picrosirius red and the hydroxyproline content was determined by colorimetric assay. Cardiac fibroblast migration was examined by scratch assay and DNA content was detected to analyze cell cycle distribution using flow cytometry. Western blot analysis was used to detect the protein expressions of Notch pathway-associated protein in cardiac fibroblasts.ResultsOxymatrine and Notch signaling pathway inhibitor DAPT could attenuated TGF-β1 induced the capacity of proliferation and migration increased in cardiac fibroblasts, as well as the secretion of collagen and hydroxyproline colorimetric content in medium. TGF-β1 induced the biomarker α-SMA of fibroblast-to-myofibroblast transformation (FMT), which was inhibited by oxymatrine and DAPT. Western blotting confirmed that oxymatrine blocked the activation of Notch induced by TGF-β1.ConclusionsOxymatrine is a potential inhibitor FMT induced by TGF-β1, which is at least in part mediated via inhibition of Notch signaling.

show abstract

Section: Introductionmentioning

confidence: 99%

Oxymatrine Inhibits Transforming Growth Factor β1 (TGF-β1)-Induced Cardiac Fibroblast-to-Myofibroblast Transformation (FMT) by Mediating the Notch Signaling Pathway In Vitro

Zhao

Tao

et al. 2018

Med Sci Monit

View full text Add to dashboard Cite

show abstract

“…Oxymatrine (Fig. 1), additionally termed matrine, is an alkaloid with a tetracyclicquinolizidine structure extracted from Sophora alopecuroides L. (11), which belongs to the Ningxia herbal medicine Sophora. With anti-inflammatory, hepatoprotective and anti-neoplastic functions, Oxymatrine is effective in the treatment of cardiovascular disease (12).…”

Section: Introductionmentioning

confidence: 99%

“…With anti-inflammatory, hepatoprotective and anti-neoplastic functions, Oxymatrine is effective in the treatment of cardiovascular disease (12). As a drug with various pharmacological effects, Oxymatrine has been applied to the treatment of hepatitis B and liver fibrosis, in addition to preventing chronic kidney disease development into renal interstitial fibrosis in patients, with low rates of adverse reaction (11,13). Therefore, the specific purpose of the present study was to investigate the protective effects of oxymatrine against LPS/D-GalN-induced acute liver failure and potential mechanisms in the mouse model.…”

Section: Introductionmentioning

confidence: 99%

Protective effects of oxymatrine against lipopolysaccharide/D‑galactosamine‑induced acute liver failure through oxidative damage, via activation of Nrf2/HO‑1 and modulation of inflammatory TLR4‑signaling pathways

Yang

et al. 2017

Mol Med Report

View full text Add to dashboard Cite

Oxymatrine has a variety of pharmacological functions, including anti-viral, anti-liver fibrotic, anti-cancer, anti‑bacterial, anti‑epidemic, analgesic, anti‑allergy and anti‑inflammatory properties. The present study aimed to investigate the protective effects of oxymatrine against lipopolysaccharide (LPS)/D‑galactosamine (D‑GalN)‑induced acute liver failure and the associated underlying mechanisms. Mice were administrated 4 mg/kg LPS and 600 mg/kg D‑GalN. Then, mice in the Oxymatrine group were treated with 120 mg/kg of oxymatrine for 4 weeks. Oxymatrine treatment increased survival rate, decreased plasma aspartate transaminase and alanine aminotransferase activity, increased superoxide dismutase and glutathione peroxidase and decreased malondialdehyde, tumor necrosis factor‑ and myeloperoxidase activities in mice with LPS/D‑GalN‑induced liver failure. Furthermore, Oxymatrine activated nuclear factor erythroid 2‑related factor (Nrf) 2 and heme oxygenase (HO)‑1 protein expression, and suppressed Toll like receptor (TLR)4, myeloid differentiation primary response 88 and nuclear factor‑κB protein expression in mice LPS/D‑GalN mice. Overall, the present study suggests that oxymatrine effectively attenuates LPS/D‑GalN‑induced acute liver failure by oxidative damage via activation of Nrf2/HO‑1 and modulation of TLR4‑dependent inflammatory signaling pathways.

show abstract

“…TLR4 activates expression of several pro-inflammatory genes, chemokines, and cell surface molecules, and has many functions in various pathological conditions, including inflammatory bowel diseases, autoimmune disorders, infectious diseases, cardiovascular disease, neuronal degeneration, allergic diseases, or obesity-associated metabolic diseases ( 22 ). In previous studies, it has been suggested that there are close relationships between TLR4 and the fibrosis of organs, including liver ( 23 ), heart ( 24 ), kidney ( 25 ), and lung ( 26 ). In the present study, EPO was demonstrated to serve an antimyocardial fibrosis effect by downregulating the expression of TLR4.…”

Section: Discussionmentioning

confidence: 99%

Regulation of TLR4 expression mediates the attenuating effect of erythropoietin on inflammation and myocardial fibrosis in rat heart

et al. 2018

View full text Add to dashboard Cite

The mechanism underlying the anti-inflammatory or antifibrotic activity of erythropoietin (EPO) in myocardial fibrosis (MF) remains elusive. In the current study, abdominal aortic constriction (AAC) was performed on rats and EPO and/or Toll-like receptor (TLR)4 were overexpressed in rat hearts through intramyocardial administration of lentivirus expressing the EPO and TLR4 genes. Hematoxylin and eosin staining and Masson's trichrome staining were performed on tissue sections from rat hearts for histopathological examination. ELISA was used to determine the levels of inflammatory mediators in serum. Gene expression levels were determined by quantitative polymerase chain reaction analysis and protein expression levels were determined by western blot analysis and immunofluorescence staining. The results indicated that EPO overexpression improved MF in rat hearts, by inhibiting the release of transforming growth factor (TGF)-β1, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, IL-17A, matrix metalloproteinase (MMP)-9 and MMP-2. Moreover, EPO overexpression suppressed the expression of TLR4, while promoting phosphoinositide 3-kinase (PI3K) and phosphorylated AKT serine/threonine kinase 1 (Akt) expression levels. However, the beneficial effects of EPO were attenuated by overexpression of TLR4. In addition, inhibition of PI3K/Akt signaling activity by treatment with LY294002 markedly reversed the protective effect of EPO on the AAC-induced MF. Taken together, the present study demonstrated that EPO may have a critical role against MF by activating PI3K/Akt signaling and by down-regulating TLR4 expression, thereby inhibiting the release of TGF-β1, TNF-α, IL-6, IL-1β, IL-17A, MMP-9 and MMP-2. These findings suggest that the PI3K/Akt/TLR4 signaling pathway is associated with the anti-inflammatory effects of EPO and may play a role in attenuating AAC-induced MF.

show abstract

Oxymatrine attenuates CCl 4 -induced hepatic fibrosis via modulation of TLR4-dependent inflammatory and TGF-β1 signaling pathways

Cited by 49 publications

References 28 publications

Oxymatrine Inhibits Transforming Growth Factor β1 (TGF-β1)-Induced Cardiac Fibroblast-to-Myofibroblast Transformation (FMT) by Mediating the Notch Signaling Pathway In Vitro

Oxymatrine Inhibits Transforming Growth Factor β1 (TGF-β1)-Induced Cardiac Fibroblast-to-Myofibroblast Transformation (FMT) by Mediating the Notch Signaling Pathway In Vitro

Protective effects of oxymatrine against lipopolysaccharide/D‑galactosamine‑induced acute liver failure through oxidative damage, via activation of Nrf2/HO‑1 and modulation of inflammatory TLR4‑signaling pathways

Regulation of TLR4 expression mediates the attenuating effect of erythropoietin on inflammation and myocardial fibrosis in rat heart

Contact Info

Product

Resources

About