A Herbal Formula, CGXII, Exerts Antihepatofibrotic Effect in Dimethylnitrosamine-Induced SD Rat Model

We aimed to evaluate the antihepatofibrotic effects of CGXII, an aqueous extract which is composed of A. iwayomogi, A. xanthioides, and S. miltiorrhiza, against dimethylnitrosamine- (DMN-) induced hepatofibrosis. Male Sprague Dawley rats were intraperitoneally injected with 10 mg/kg of DMN for 4 weeks (three consecutive days weekly). Rats were orally given distilled water, CGXII (50 or 100 mg/kg), or dimethyl dimethoxy biphenyl dicarboxylate (50 mg/kg) daily. DMN injection caused substantial alteration of total body weight and liver and spleen mass, whereas they were notably normalized by CGXII. CGXII treatment also markedly attenuated the elevation of serum aspartate aminotransferase and alanine aminotransferase levels, hepatic lipid peroxidation, and protein carbonyl contents. Collagen accumulation in hepatic tissue evidenced by histopathological analysis and quantitative assessment of hepatic hydroxyproline was ameliorated by CGXII. Immunohistochemistry analysis revealed decreased α-smooth muscle actin supporting the antihepatofibrotic effect of CGXII. The profibrogenic cytokines transforming growth factor-β, platelet-derived growth factor-β, and connective tissue growth factor were increased by DMN injection. Administration of CGXII normalized the protein and gene expression levels of these cytokines. Our findings suggest that CGXII lowers the levels of profibrogenic cytokines and thereby exerts antifibrotic effects.

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Regulation of Cellular Senescence Is Independent from Profibrotic Fibroblast-Deposited ECM

Cells ◽

10.3390/cells10071628 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1628

Author(s):

Kaj E. C. Blokland ◽

Habibie Habibie ◽

Theo Borghuis ◽

Greta J. Teitsma ◽

Michael Schuliga ◽

...

Keyword(s):

Growth Factor ◽

Cellular Senescence ◽

Transforming Growth Factor ◽

Cell Function ◽

Smooth Muscle Actin ◽

Transforming Growth Factor Β1 ◽

Tissue Growth ◽

Alveolar Epithelial Cells ◽

Lung Fibroblasts ◽

Alpha Smooth Muscle Actin

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with poor survival. Age is a major risk factor, and both alveolar epithelial cells and lung fibroblasts in this disease exhibit features of cellular senescence, a hallmark of ageing. Accumulation of fibrotic extracellular matrix (ECM) is a core feature of IPF and is likely to affect cell function. We hypothesize that aberrant ECM deposition augments fibroblast senescence, creating a perpetuating cycle favouring disease progression. In this study, primary lung fibroblasts were cultured on control and IPF-derived ECM from fibroblasts pretreated with or without profibrotic and prosenescent stimuli, and markers of senescence, fibrosis-associated gene expression and secretion of cytokines were measured. Untreated ECM derived from control or IPF fibroblasts had no effect on the main marker of senescence p16Ink4a and p21Waf1/Cip1. However, the expression of alpha smooth muscle actin (ACTA2) and proteoglycan decorin (DCN) increased in response to IPF-derived ECM. Production of the proinflammatory cytokines C-X-C Motif Chemokine Ligand 8 (CXCL8) by lung fibroblasts was upregulated in response to senescent and profibrotic-derived ECM. Finally, the profibrotic cytokines transforming growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF) were upregulated in response to both senescent- and profibrotic-derived ECM. In summary, ECM deposited by IPF fibroblasts does not induce cellular senescence, while there is upregulation of proinflammatory and profibrotic cytokines and differentiation into a myofibroblast phenotype in response to senescent- and profibrotic-derived ECM, which may contribute to progression of fibrosis in IPF.

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Hepatoprotective Effect of the Fruits of Polygonum orientale L. Against Carbon Tetrachloride-Induced Liver Fibrosis in Mice

Natural Product Communications ◽

10.1177/1934578x20971501 ◽

2020 ◽

Vol 15 (11) ◽

pp. 1934578X2097150

Author(s):

Yung-Jia Chiu ◽

Kun-Chang Wu ◽

Jen-Chieh Tsai ◽

Chun-Pin Kao ◽

Jung Chao ◽

...

Keyword(s):

Carbon Tetrachloride ◽

Growth Factor ◽

Liver Injury ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Transforming Growth Factor Β ◽

Serum Levels ◽

Hepatoprotective Activity ◽

Tissue Growth ◽

Factor Α

The aim of this study was to evaluate the hepatoprotective effects of the fruits of Polygonum orientale L. (POE) against fibrosis in carbon tetrachloride (CCl4)-induced liver injury. Bioactive components of POE were identified using liquid chromatography (LC)-mass spectrometry (MS)/MS by comparison with standards. Treatment with either silymarin (200 mg/kg) or POE (0.5 and 1.0 g/kg) caused significant decreases in the serum levels of enzymes and reduced the extent of liver lesions and fibrosis in histological analysis. POE (0.5 and 1.0 g/kg) decreased the levels of malondialdehyde, nitric oxide, proinflammatory cytokines (ie, tumor necrosis factor-α, interleukin [IL]-1β, and IL-6), an inflammatory cytokine (ie, cyclooxygenase-2), a profibrotic cytokine (ie, transforming growth factor-β), and fibrosis-related proteins (ie, connective tissue growth factor and α-smooth muscle actin) in the liver and enhanced the activities of the antioxidative enzymes superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. Quantitative analysis of the active constituents in POE revealed an extract composition of 3.4 mg/g of protocatechuic acid, 20.8 mg/g of taxifolin, and 5.6 mg/g of quercetin. We have demonstrated that the hepatoprotective mechanisms of POE are likely to be associated with the decrease in inflammatory cytokines by increasing the activities of antioxidant enzymes. Our findings provide evidence that POE possesses a hepatoprotective activity to ameliorate chronic liver injury.

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Role of the cytoskeleton in the development of a hypofibrotic cardiac fibroblast phenotype in volume overload heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00095.2018 ◽

2019 ◽

Vol 316 (3) ◽

pp. H596-H608 ◽

Cited By ~ 4

Author(s):

Rachel C. Childers ◽

Ian Sunyecz ◽

T. Aaron West ◽

Mary J. Cismowski ◽

Pamela A. Lucchesi ◽

...

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Cardiac Fibroblasts ◽

Smooth Muscle Actin ◽

Pressure Overload ◽

Volume Overload ◽

Transforming Growth Factor Β ◽

Collagen Type I ◽

Tissue Growth ◽

Type I

Hemodynamic load regulates cardiac remodeling. In contrast to pressure overload (increased afterload), hearts subjected to volume overload (VO; preload) undergo a distinct pattern of eccentric remodeling, chamber dilation, and decreased extracellular matrix content. Critical profibrotic roles of cardiac fibroblasts (CFs) in postinfarct remodeling and in response to pressure overload have been well established. Little is known about the CF phenotype in response to VO. The present study characterized the phenotype of primary cultures of CFs isolated from hearts subjected to 4 wk of VO induced by an aortocaval fistula. Compared with CFs isolated from sham hearts, VO CFs displayed a “hypofibrotic” phenotype, characterized by a ~50% decrease in the profibrotic phenotypic markers α-smooth muscle actin, connective tissue growth factor, and collagen type I, despite increased levels of profibrotic transforming growth factor-β1 and an intact canonical transforming growth factor-β signaling pathway. Actin filament dynamics were characterized, which regulate the CF phenotype in response to biomechanical signals. Actin polymerization was determined by the relative amounts of G-actin monomers versus F-actin. Compared with sham CFs, VO CFs displayed ~78% less F-actin and an increased G-actin-to-F-actin ratio (G/F ratio). In sham CFs, treatment with the Rho kinase inhibitor Y-27632 to increase the G/F ratio resulted in recapitulation of the hypofibrotic CF phenotype observed in VO CFs. Conversely, treatment of VO CFs with jasplakinolide to decrease the G/F ratio restored a more profibrotic response (>2.5-fold increase in α-smooth muscle actin, connective tissue growth factor, and collagen type I). NEW & NOTEWORTHY The present study is the first to describe a “hypofibrotic” phenotype of cardiac fibroblasts isolated from a volume overload model. Our results suggest that biomechanical regulation of actin microfilament stability and assembly is a critical mediator of cardiac fibroblast phenotypic modulation.

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Latent adenoviral infection induces production of growth factors relevant to airway remodeling in COPD

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00315.2002 ◽

2004 ◽

Vol 286 (1) ◽

pp. L189-L197 ◽

Cited By ~ 22

Author(s):

Emiko Ogawa ◽

W. Mark Elliott ◽

Fiona Hughes ◽

Thomas J. Eichholtz ◽

James C. Hogg ◽

...

Keyword(s):

Growth Factors ◽

Growth Factor ◽

Transforming Growth Factor ◽

Airway Remodeling ◽

Smooth Muscle Actin ◽

Tissue Growth ◽

Chronic Obstructive ◽

Adenoviral Infection ◽

E1a Gene ◽

Tgf Β1

Previous studies showed an association between latent adenoviral infection with expression of the adenoviral E1A gene and chronic obstructive pulmonary disease (COPD). The present study focuses on how the adenoviral E1A gene could alter expression of growth factors by human bronchial epithelial (HBE) cells. The data show that connective tissue growth factor (CTGF) and transforming growth factor (TGF)-β1 mRNA and protein expression were upregulated in E1A-positive HBE cells. Upregulation of CTGF in this in vitro model was independent of TGF-β secreted into the growth medium. Comparison of E1A-positive with E1A-negative HBE cells showed that both expressed cytokeratin but only E1A-positive cells expressed the mesenchymal markers vimentin and α-smooth muscle actin. We conclude that latent infection of epithelial cells by adenovirus E1A could contribute to airway remodeling in COPD by the viral E1A gene, inducing TGF-β1 and CTGF expression and shifting cells to a more mesenchymal phenotype.

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Effects of Allicin on Pathophysiological Mechanisms during the Progression of Nephropathy Associated to Diabetes

Antioxidants ◽

10.3390/antiox9111134 ◽

2020 ◽

Vol 9 (11) ◽

pp. 1134

Author(s):

Abraham Said Arellano-Buendía ◽

Luis Gerardo Castañeda-Lara ◽

María L. Loredo-Mendoza ◽

Fernando E. García-Arroyo ◽

Pedro Rojas-Morales ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Growth Factor ◽

Glucose Transporter ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Tissue Growth ◽

Kidney Cortex ◽

Mesangial Matrix ◽

Insulin Levels ◽

The Impact

This study aimed to assess the impact of allicin on the course of diabetic nephropathy. Study groups included control, diabetes, and diabetes-treated rats. Allicin treatment (16 mg/kg day/p.o.) started after 1 month of diabetes onset and was administered for 30 days. In the diabetes group, the systolic blood pressure (SBP) increased, also, the oxidative stress and hypoxia in the kidney cortex were evidenced by alterations in the total antioxidant capacity as well as the expression of nuclear factor (erythroid-derived 2)-like 2/Kelch ECH associating protein 1 (Nrf2/Keap1), hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor (VEGF), erythropoietin (Epo) and its receptor (Epo-R). Moreover, diabetes increased nephrin, and kidney injury molecule-1 (KIM-1) expression that correlated with mesangial matrix, the fibrosis index and with the expression of connective tissue growth factor (CTGF), transforming growth factor-β1 (TGF-β1), and α-smooth muscle actin (α-SMA). The insulin levels and glucose transporter protein type-4 (GLUT4) expression were decreased; otherwise, insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) expression was increased. Allicin increased Nrf2 expression and decreased SBP, Keap1, HIF-1α, and VEGF expression. Concurrently, nephrin, KIM-1, the mesangial matrix, fibrosis index, and the fibrotic proteins were decreased. Additionally, allicin decreased hyperglycemia, improved insulin levels, and prevented changes in (GLUT4) and IRSs expression induced by diabetes. In conclusion, our results demonstrate that allicin has the potential to help in the treatment of diabetic nephropathy. The cellular mechanisms underlying its effects mainly rely on the regulation of antioxidant, antifibrotic, and antidiabetic mechanisms, which can contribute towards delay in the progression of renal disease.

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Glucocorticoid-induced cell-derived matrix modulates transforming growth factor β2 signaling in human trabecular meshwork cells

Scientific Reports ◽

10.1038/s41598-020-72779-w ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Felix Yemanyi ◽

Janice Vranka ◽

Vijay Krishna Raghunathan

Keyword(s):

Growth Factor ◽

Trabecular Meshwork ◽

Transforming Growth Factor ◽

Lysyl Oxidase ◽

Tissue Transglutaminase ◽

Smooth Muscle Actin ◽

Plasminogen Activator Inhibitor ◽

Transglutaminase 2 ◽

Tissue Growth ◽

Type I

Abstract Aberrant remodeling of trabecular meshwork (TM) extracellular matrix (ECM) may induce ocular hypertensive phenotypes in human TM (hTM) cells to cause ocular hypertension, via a yet unknown mechanism. Here, we show that, in the absence of exogenous transforming growth factor-beta2 (TGFβ2), compared with control matrices (VehMs), glucocorticoid-induced cell-derived matrices (GIMs) trigger non-Smad TGFβ2 signaling in hTM cells, correlated with overexpression/activity of structural ECM genes (fibronectin, collagen IV, collagen VI, myocilin), matricellular genes (connective tissue growth factor [CTGF], secreted protein, acidic and rich in cysteine), crosslinking genes/enzymes (lysyl oxidase, lysyl oxidase-like 2–4, tissue transglutaminase-2), and ECM turnover genes/enzymes (matrix metalloproteinases-MMP2,14 and their inhibitors-TIMP2). However, in the presence of exogenous TGFβ2, VehMs and GIMs activate Smad and non-Smad TGFβ2 signaling in hTM cells, associated with overexpression of α-smooth muscle actin (α-SMA), and differential upregulation of aforementioned ECM genes/proteins with new ones emerging (collagen-I, thrombospondin-I, plasminogen activator inhibitor, MMP1, 9, ADAMTS4, TIMP1); with GIM-TGFβ2-induced changes being mostly more pronounced. This suggests dual glaucomatous insults potentiate profibrotic signaling/phenotypes. Lastly, we demonstrate type I TGFβ receptor kinase inhibition abrogates VehM-/GIM- and/or TGFβ2-induced upregulation of α-SMA and CTGF. Collectively, pathological TM microenvironments are sufficient to elicit adverse cellular responses that may be ameliorated by targeting TGFβ2 pathway.

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Ketamine-induced bladder fibrosis involves epithelial-to-mesenchymal transition mediated by transforming growth factor-β1

AJP Renal Physiology ◽

10.1152/ajprenal.00686.2016 ◽

2017 ◽

Vol 313 (4) ◽

pp. F961-F972 ◽

Cited By ~ 9

Author(s):

Junpeng Wang ◽

Yang Chen ◽

Di Gu ◽

Guihao Zhang ◽

Jiawei Chen ◽

...

Keyword(s):

Growth Factor ◽

Epithelial To Mesenchymal Transition ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Bladder Wall ◽

Transforming Growth Factor Β1 ◽

Sprague Dawley ◽

Mesenchymal Transition ◽

Tgf Β1

Bladder wall fibrosis is a major complication of ketamine-induced cystitis (KC), but the underlying pathogenesis is poorly understood. The aim of the present study was to elucidate the mechanism of ketamine-induced fibrosis in association with epithelial-to-mesenchymal transition (EMT) mediated by transforming growth factor-β1 (TGF-β1). Sprague-Dawley rats were randomly distributed into four groups, which received saline, ketamine, ketamine combined with a TGF-β receptor inhibitor (SB-505124) for 16 wk, or 12 wk of ketamine and 4 wk of abstinence. In addition, the profibrotic effect of ketamine was confirmed in SV-40 immortalized human uroepithelial (SV-HUC-1) cells. The ketamine-treated rats displayed voiding dysfunction and decreased bladder compliance. Bladder fibrosis was accompanied by the appearance of a certain number of cells expressing both epithelial and mesenchymal markers, indicating that epithelial cells might undergo EMT upon ketamine administration. Meanwhile, the expression level of TGF-β1 was significantly upregulated in the urothelium of bladders in ketamine-treated rats. Treatment of SV-HUC-1 cells with ketamine increased the expression of TGF-β1 and EMT-inducing transcription factors, resulting in the downregulation of E-cadherin and upregulation of fibronectin and α-smooth muscle actin. Administration of SB-505124 inhibited EMT and fibrosis both in vitro and vivo. In addition, withdrawal from ketamine did not lead to recovery of bladder urinary function or decreased fibrosis. Taken together, our study shows for the first time that EMT might contribute to bladder fibrosis in KC. TGF-β1 may have an important role in bladder fibrogenesis via an EMT mechanism.

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Reversine and herbal Xiang–Sha–Liu–Jun–Zi decoction ameliorate thioacetamide-induced hepatic injury by regulating the RelA/NF-κB/caspase signaling pathway

Open Life Sciences ◽

10.1515/biol-2020-0059 ◽

2020 ◽

Vol 15 (1) ◽

pp. 696-710

Author(s):

Zhen-Hao Mai ◽

Yu Huang ◽

Di Huang ◽

Zi-Sheng Huang ◽

Zhi-Xiang He ◽

...

Keyword(s):

Growth Factor ◽

Liver Injury ◽

Inflammatory Cytokines ◽

Hepatic Injury ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Transforming Growth Factor Β1 ◽

Mrna Levels ◽

Sprague Dawley ◽

Liver Index

AbstractThis study investigated the anti-fibrotic effects of reversine and Chinese medicine Xiang–Sha–Liu–Jun–Zi decoction (XSLJZD) on thioacetamide (TAA)-induced hepatic injury. Sprague-Dawley rats were intraperitoneally administered with TAA, then injected with reversine intraperitoneally, and/or orally provided with XSLJZD. TAA resulted in liver injury with increases in the liver index and levels of serum aspartate aminotransferase (AST) and alanine aminotransferase. Reversine alleviated the liver index and AST level and improved TAA-induced pathological changes but decreased TAA-induced collagen deposition, and α-smooth muscle actin and transforming growth factor-β1 expression. Reversine also modulated the mRNA levels of inflammatory cytokines, such as RelA, interleukin (IL)-17A, IL-22, IL-1β, IL-6, NLR family pyrin domain containing 3, platelet-derived growth factor, and monocyte chemoattractant protein, and suppressed nuclear factor (NF)-κB (p65) phosphorylation and caspase 1 activation. Meanwhile, XSLJZD protected TAA-injured liver without increasing fibrosis and enhanced the regulating effect of reversine on RelA, IL-17A, IL-1β, and MCP-1 cytokines. In conclusion, reversine ameliorates liver injury and inhibits inflammation reaction by regulating NF-κB, and XSLJZD protects the liver through its synergistic effect with reversine on regulating inflammatory cytokines.

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Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease

International Journal of Molecular Sciences ◽

10.3390/ijms222312963 ◽

2021 ◽

Vol 22 (23) ◽

pp. 12963

Author(s):

Mónika Gabriella Kovács ◽

Zsuzsanna Z. A. Kovács ◽

Zoltán Varga ◽

Gergő Szűcs ◽

Marah Freiwan ◽

...

Keyword(s):

Heart Failure ◽

Heart Disease ◽

Growth Factor ◽

Rat Model ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Left Ventricular ◽

Tissue Growth ◽

Sprague Dawley ◽

Radiation Induced

Radiation-induced heart disease (RIHD) is a potential late side-effect of thoracic radiotherapy resulting in left ventricular hypertrophy (LVH) and fibrosis due to a complex pathomechanism leading to heart failure. Angiotensin-II receptor blockers (ARBs), including losartan, are frequently used to control heart failure of various etiologies. Preclinical evidence is lacking on the anti-remodeling effects of ARBs in RIHD, while the results of clinical studies are controversial. We aimed at investigating the effects of losartan in a rat model of RIHD. Male Sprague-Dawley rats were studied in three groups: (1) control, (2) radiotherapy (RT) only, (3) RT treated with losartan (per os 10 mg/kg/day), and were followed for 1, 3, or 15 weeks. At 15 weeks post-irradiation, losartan alleviated the echocardiographic and histological signs of LVH and fibrosis and reduced the overexpression of chymase, connective tissue growth factor, and transforming growth factor-beta in the myocardium measured by qPCR; likewise, the level of the SMAD2/3 protein determined by Western blot decreased. In both RT groups, the pro-survival phospho-AKT/AKT and the phospho-ERK1,2/ERK1,2 ratios were increased at week 15. The antiremodeling effects of losartan seem to be associated with the repression of chymase and several elements of the TGF-β/SMAD signaling pathway in our RIHD model.

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Administration of Steamed and Freeze-Dried Mature Silkworm Larval Powder Prevents Hepatic Fibrosis and Hepatocellular Carcinogenesis by Blocking TGF-β/STAT3 Signaling Cascades in Rats

Cells ◽

10.3390/cells9030568 ◽

2020 ◽

Vol 9 (3) ◽

pp. 568 ◽

Cited By ~ 1

Author(s):

Da-Young Lee ◽

Sun-Mi Yun ◽

Moon-Young Song ◽

Sang-Deok Ji ◽

Jong-Gon Son ◽

...

Keyword(s):

Growth Factor ◽

Hepatic Fibrosis ◽

Target Genes ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Tissue Growth ◽

Signaling Cascades ◽

Type I ◽

Freeze Dried ◽

Hepatocellular Carcinogenesis

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide and the majority of HCC patients occur with a background of hepatic fibrosis and cirrhosis. We have previously reported the hepatoprotective effects of steamed and freeze-dried mature silkworm larval powder (SMSP) in a chronic ethanol-treated rat model. Here, we assessed the anti-fibrotic and anti-carcinogenic effects of SMSP on diethylnitrosamine (DEN)-treated rats. Wistar rats were intraperitoneally injected with DEN once a week for 12 or 16 weeks with or without SMSP administration (0.1 and 1 g/kg). SMSP administration significantly attenuated tumor foci formation and proliferation in the livers of the rats treated with DEN for 16 weeks. SMSP administration also inhibited hepatic fibrosis by decreasing the levels of collagen fiber and the expression of pro-collagen I and alpha-smooth muscle actin (α-SMA). Moreover, SMSP supplementation improved the major parameters of fibrosis such as transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor-1 (PAI-1), and collagen type I (Col1A1) in the livers from the rats treated with DEN for 16 weeks. As s possible mechanisms, we investigated the effects of SMSP on the TGF-β and signal transducer and activator of transcription 3 (STAT3)-mediated signaling cascades, which are known to promote hepatic fibrosis. We found that SMSP treatment inhibited the activation of TGF-β and the phosphorylation of STAT3 pathway in DEN-treated rats. Moreover, SMSP administration suppressed the expressions of the target genes of TGF-β and STAT3 induced by DEN treatment. Our findings provide experimental evidences that SMSP administration has inhibitory effects of hepatic fibrosis and HCC induced by DEN In Vivo and could be a promising strategy for the prevention or treatment of hepatic fibrosis and hepatocellular carcinogenesis.

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