scholarly journals Estrogen Deficiency Potentiates Thioacetamide-Induced Hepatic Fibrosis in Sprague-Dawley Rats

2019 ◽  
Vol 20 (15) ◽  
pp. 3709 ◽  
Author(s):  
Yong Hee Lee ◽  
Ji Yeon Son ◽  
Kyeong Seok Kim ◽  
Yoo Jung Park ◽  
Hae Ri Kim ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Estrogen Deficiency ◽  
Male Rats ◽  
Sprague Dawley ◽  
Sod Activity ◽  
Ovx Rats ◽  
Glutamyl Transferase

Hepatic fibrosis is characterized by persistent deposition of extracellular matrix proteins and occurs in chronic liver diseases. The aim of the present study is to investigate whether estrogen deficiency (ED) potentiates hepatic fibrosis in a thioacetamide (TAA)-treated rat model. Fibrosis was induced via intraperitoneal injection (i.p.) of TAA (150 mg/kg/day) for four weeks in ovariectomized (OVX) female, sham-operated female, or male rats. In TAA-treated OVX rats, the activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and γ-glutamyl transferase (GGT) were significantly increased compared to those in TAA-treated sham-operated OVX rats or TAA-treated male rats. Furthermore, α-smooth muscle actin (α-SMA) expression was significantly increased compared to that in TAA-treated sham-operated rats. This was accompanied by the appearance of fibrosis biomarkers including vimentin, collagen-I, and hydroxyproline, in the liver of TAA-treated OVX rats. In addition, ED markedly reduced total glutathione (GSH) levels, as well as catalase (CAT) and superoxide dismutase (SOD) activity in TAA-treated OVX rats. In contrast, hepatic malondialdehyde (MDA) levels were elevated in TAA-treated OVX rats. Apoptosis significantly increased in TAA-treated OVX rats, as reflected by elevated p53, Bcl-2, and cleaved caspase 3 levels. Significant increases in interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) concentrations were exhibited in TAA-treated OVX rats, and this further aggravated fibrosis through the transforming growth factor-β (TGF-β)/Smad pathway. Our data suggest that ED potentiates TAA-induced oxidative damage in the liver, suggesting that ED may enhance the severity of hepatic fibrosis in menopausal women.

Acupuncture Combined with Curcumin Attenuates Carbon Tetrachloride-Induced Hepatic Fibrosis in Rats

2012 ◽  
Vol 30 (2) ◽  
pp. 132-138 ◽  
Author(s):  
Feng Zhang ◽  
Jin Ma ◽  
Yin Lu ◽  
Guang-Xia Ni ◽  
Chun-Yan Ni ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Fibrosis ◽  
Hepatic Fibrosis ◽  
Smooth Muscle Actin ◽  
Sham Acupuncture ◽  
Male Rats ◽  
Sprague Dawley ◽  
Combined Use ◽  
Serum Aspartate Aminotransferase

Background Increasingly, studies demonstrate the effectiveness of acupuncture therapy against liver fibrosis. Curcumin is a natural product with antifibrotic effects, but has poor pharmacokinetic profiles. This study aimed to evaluate whether acupuncture combined with curcumin could more potently attenuate liver fibrosis in chemical intoxicated rats. Methods 60 Sprague–Dawley male rats were randomly divided into control, model, sham, acupuncture, curcumin and combination therapy groups. During the establishment of fibrosis using carbon tetrachloride (CCl4), acupuncture at LR3, LR14, BL18 and ST36 and/or curcumin treatment by mouth were performed simultaneously. After treatment, pathological indexes and histology for hepatic injury and fibrogenesis were detected. The expression of extracellular matrix (ECM) components was also determined. Results Acupuncture combined with curcumin potently protected the liver from CCl4-induced injury and fibrogenesis, as indicated by reduced levels of serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, hyaluronic acid, laminin and procollagen III. Combined use also led to significant liver histological improvements. Furthermore, combined use effectively inhibited ECM expression such as α-smooth muscle actin, fibronectin and α1(1) collagen. Conclusions Acupuncture treatment could significantly enhance the antifibrotic efficacy of curcumin on CCl4-induced hepatic fibrosis in rats in vivo, suggesting that a combination of acupuncture with curcumin may be exploited for the prevention of hepatic fibrosis.

Overexpression of angiotensin type 2 receptor ameliorates glomerular injury in a mouse remnant kidney model

2004 ◽  
Vol 286 (3) ◽  
pp. F516-F525 ◽  
Author(s):  
Naoko Hashimoto ◽  
Yohei Maeshima ◽  
Minoru Satoh ◽  
Masahiro Odawara ◽  
Hitoshi Sugiyama ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Glomerular Injury ◽  
Wild Mice ◽  
Angiotensin Type 2 Receptor ◽  
Glomerular Size ◽  
Nitric Oxide Metabolites

Angiotensin II mediates the progression of renal disease through the type 1 receptor (AT1R). Recent studies have suggested that type 2 receptor (AT2R)-mediated signaling inhibits cell proliferation by counteracting the actions of AT1R. The aim of the present study was to determine the effect of AT2R overexpression on glomerular injury induced by ⅚ nephrectomy (⅚Nx). AT2R transgenic mice (AT2-Tg), overexpressing AT2R under the control of α-smooth muscle actin (α-SMA) promoter, and control wild-type mice (Wild) were subjected to ⅚Nx. In AT2-Tg mice, the glomerular expression of AT2R was upregulated after ⅚Nx. Urinary albumin excretion at 12 wk after ⅚Nx was decreased by 33.7% in AT2-Tg compared with Wild mice. Glomerular size in AT2-Tg mice was significantly smaller than in Wild mice after ⅚Nx (93.1 ± 3.0 vs. 103.3 ± 1.8 μm; P < 0.05). Immunohistochemistry revealed significant decreases in glomerular expression of platelet-derived growth factor-BB chain (PDGF-BB) and transforming growth factor-β1 (TGF-β1) in AT2-Tg with ⅚Nx compared with Wild mice. Urinary excretion of nitric oxide metabolites was increased 2.5-fold in AT2-Tg compared with Wild mice. EMSA showed that activation of early growth response gene-1, which induces the transcription of PDGF-BB and TGF-β1, was decreased in AT2-Tg mice. These changes in AT2-Tg mice at 12 wk after ⅚Nx were blocked by the AT2R antagonist PD-123319. Taken together, our findings suggest that AT2R-mediated signaling may protect from glomerular injuries induced by ⅚Nx and that overexpression of AT2R may serve as a potential therapeutic strategy for glomerular disorders.

scholarly journals Sestrin 2 Attenuates Rat Hepatic Stellate Cell (HSC) Activation and Liver Fibrosis via an mTOR/AMPK-Dependent Mechanism

2018 ◽  
Vol 51 (5) ◽  
pp. 2111-2122 ◽  
Author(s):  
Yi-Bing Hu ◽  
Xiao-Ting Ye ◽  
Qing-Qing Zhou ◽  
Rong-Quan Fu
Keyword(s):  
Liver Fibrosis ◽  
Protein Expression ◽  
Hepatic Fibrosis ◽  
Transforming Growth Factor ◽  
Histopathological Examination ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Mrna Levels ◽  
Alpha Smooth Muscle Actin

Background/Aims: Sestrin 2 is associated with the pathophysiology of several diseases. The aim of this study was to investigate the effects and potential mechanisms of Sestrin 2 in rat hepatic stellate cells (HSCs) during liver fibrogenesis. Methods: In this study, Sestrin 2 protein expression was detected in rat HSC-T6 cells challenged with transforming growth factor-β (TGF-β) and in mice treated with carbon tetrachloride (CCl4), a well-known model of hepatic fibrosis. Next, HSC-T6 cells and fibrotic mice were transfected with lentivirus. The mRNA expression levels of markers of liver fibrosis [alpha-smooth muscle actin (α-SMA) and collagen 1A1 (Col1A1)] were analyzed by quantitative reverse transcription–polymerase chain reaction (RT-PCR). Cell death and proliferation were evaluated by the MTT assay, and biochemical markers of liver damage in serum [alanine transaminase (ALT) and aspartate transaminase (AST)] were also measured using a biochemical analyzer. Histopathological examination was used to evaluate the degree of liver fibrosis, and protein expression [phospho-adenosine monophosphate-activated protein kinase (p-AMPK), AMPK, phospho-mammalian target of rapamycin (p-mTOR), and mTOR] was determined by western blotting. Results: We found that Sestrin 2 was elevated in both the HSC-T6 cell and hepatic fibrosis models. In vitro, overexpression of Sestrin 2 attenuated the mRNA levels of α-SMA and Col1A1, suppressed α-SMA protein expression, and modulated HSC-T6 cell proliferation. In vivo, overexpression of Sestrin 2 reduced the ALT and AST levels as well as the α-SMA and Col1A1 protein expression in the CCl4 model of liver fibrosis. Moreover, the degree of liver fibrosis was ameliorated. Interestingly, overexpression of Sestrin 2 increased p-AMPK but decreased p-mTOR protein expression. Conclusion: Our findings indicate that Sestrin 2 may attenuate the activation of HSCs and ameliorate liver fibrosis, most likely via upregulation of AMPK phosphorylation and suppression of the mTOR signaling pathway.

scholarly journals PASS-Predicted Hepatoprotective Activity ofCaesalpinia sappanin Thioacetamide-Induced Liver Fibrosis in Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Farkaad A. Kadir ◽  
Normadiah M. Kassim ◽  
Mahmood Ameen Abdulla ◽  
Behnam Kamalidehghan ◽  
Fatemeh Ahmadipour ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Transforming Growth Factor ◽  
Antioxidant Activities ◽  
Smooth Muscle Actin ◽  
Immunohistochemical Analysis ◽  
Hepatoprotective Activity ◽  
Nuclear Antigen ◽  
Sprague Dawley ◽  
Liver Fibrogenesis

The antifibrotic effects of traditional medicinal herbCaesalpinia sappan(CS) extract on liver fibrosis induced by thioacetamide (TAA) and the expression of transforming growth factorβ1 (TGF-β1),α-smooth muscle actin (αSMA), and proliferating cell nuclear antigen (PCNA) in rats were studied. A computer-aided prediction of antioxidant and hepatoprotective activities was primarily performed with the Prediction Activity Spectra of the Substance (PASS) Program. Liver fibrosis was induced in male Sprague Dawley rats by TAA administration (0.03% w/v) in drinking water for a period of 12 weeks. Rats were divided into seven groups: control, TAA, Silymarin (SY), and CS 300 mg/kg body weight and 100 mg/kg groups. The effect of CS on liver fibrogenesis was determined by Masson’s trichrome staining, immunohistochemical analysis, and western blotting.In vivodetermination of hepatic antioxidant activities, cytochrome P450 2E1 (CYP2E1), and matrix metalloproteinases (MPPS) was employed. CS treatment had significantly increased hepatic antioxidant enzymes activity in the TAA-treated rats. Liver fibrosis was greatly alleviated in rats when treated with CS extract. CS treatment was noted to normalize the expression of TGF-β1,αSMA, PCNA, MMPs, and TIMP1 proteins. PASS-predicted plant activity could efficiently guide in selecting a promising pharmaceutical lead with high accuracy and required antioxidant and hepatoprotective properties.

scholarly journals P1196AN INIHIBITOR OF KRUPPEL-LIKE FACTOR 5 SUPPRESSES PERITONEAL FIBROSIS IN MICE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Kumiko Muta ◽  
Yuka Nakazawa ◽  
Yoko Obata ◽  
Hiro Inoue ◽  
Kenta Torigoe ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Retinoic Acid Receptor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Treated Group ◽  
Peritoneal Fibrosis ◽  
Retinoic Acid Receptor Α ◽  
Klf5 Expression

Abstract Background and Aims We presented previously that Am80, a synthetic retinoic acid receptor α specific agonist, inhibited the expression of Krüppel-like transcription factor 5 (KLF5) and reduced peritoneal fibrosis in mice. Now, we examined further detail about the mechanism to inhibit peritoneal fibrosis. Method Peritoneal fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate (CG) into peritoneal cavity of ICR mice. Am80 was administered orally for every day from the start of CG injection. After 3 weeks of treatment, peritoneal tissues were examined using serial sections by immunohistochemistry to identify what kind of cells expressed KLF5. We also examined the effect of Am80 to inhibit peritoneal fibrosis in vitro. Results While KLF5 was expressed in the thickened submesothelial area of CG injected mice, Am80 treatment reduced KLF5 expression and remarkably attenuated peritoneal thickening. The numbers of transforming growth factor β positive cells, α-smooth muscle actin (αSMA) or F4/80 positive cells were significantly decreased in Am80 treated group. KLF5 was expressed in αSMA, F4/80 or CD31 positive cells. Conclusion These results indicate the KLF5 might not only associate phenotypical differentiation from fibroblasts to myofibroblasts but also regulate inflammatory responses and angiogenesis in peritoneal fibrosis model. Am80 can suppress peritoneal fibrosis through inhibiting these mechanisms. In vitro experiments are ongoing.

scholarly journals Sedum sarmentosum Total Flavonoids Alleviate Schistosomiasis-Induced Liver Fibrosis by Altering TGF-β1 and Smad7 Expression

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Peng-chun Yang ◽  
Wei-zhe Bai ◽  
Jing Wang ◽  
Cai-hua Yan ◽  
Wei-feng Huang ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Protein Expression ◽  
Hepatic Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Schistosomiasis Japonica ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Tgf Β1 ◽  
Liver Tissues

Objectives. Schistosomiasis is a parasitic disease that affects over 142 million people worldwide. The main causes of death of schistosomiasis include liver granuloma and secondary hepatic cirrhosis resulting from severe fibrosis. Despite intensive research, controlling liver fibrosis associated with schistosomiasis remains challenging. Sedum sarmentosum total flavonoid (SSTF) is a promising agent to reduce liver fibrosis with an unknown mechanism. Thus, the objectives of this study are to validate its effect on the liver fibrosis caused by schistosomiasis and to explore the underlying molecular mechanism. Methods. Sixty male Sprague-Dawley rats were randomly divided into six groups: one group of normal control and five groups of liver fibrosis induced by schistosomiasis japonica with or without SSTF or colchicine treatment, the latter serving as the positive control. Liver tissues from each animal were harvested to observe the degree and grade of hepatic fibrosis. We also measured the expression of transforming growth factor-beta 1 (TGF-β1) and Smad7 using RT-qPCR, Western blot, and immunohistochemistry. Results. Compared with the untreated model group, groups treated with SSTF at all three tested doses had significantly reduced hepatic fibrosis ( P < 0.05 ). Each dose of SSTF also significantly reduced TGF-β1 protein expression and mRNA levels in the liver tissues ( P < 0.05 ). In contrast, the middle and high doses of SSTF significantly increased Smad7 protein expression and mRNA levels ( P < 0.05 ). Immunohistochemistry showed that each dose of SSTF reduced TGF-β1 protein expression ( P < 0.05 ). Conclusion. Our results demonstrated that SSTF alleviated schistosomiasis japonica-induced hepatic fibrosis by inhibiting the TGF-β1/Smad7 pathway.

scholarly journals Oral Astaxanthin Supplementation Prevents Peritoneal Fibrosis in Rats

2015 ◽  
Vol 35 (5) ◽  
pp. 506-516 ◽  
Author(s):  
Keiichi Wakabayashi ◽  
Chieko Hamada ◽  
Reo Kanda ◽  
Takanori Nakano ◽  
Hiroaki Io ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Normal Diet ◽  
Vascular Density ◽  
Related Factor ◽  
Sprague Dawley ◽  
Peritoneal Fibrosis ◽  
Group 3 ◽  
Group 1

BackgroundPreventing peritoneal damage during peritoneal dialysis is critical. Reactive oxygen species (ROS) have an important role in peritoneal damage; however, few studies have investigated this. We aimed to determine the effects of oral astaxanthin (AST) supplementation in a peritoneal fibrosis (PF) rat model.MethodsThirty-seven Sprague-Dawley rats were divided into 5 groups: Control 1 (fed a normal diet without stimulation), Control 2 (fed an AST-supplemented diet without stimulation), Group 1 (fed a normal diet with 8% chlorhexidine gluconate [CG] stimulation for 3 weeks), Group 2 (fed a 0.06% AST-supplemented diet with CG stimulation), and Group 3 (fed a 0.06% AST-supplemented diet that was initiated 4 weeks before CG stimulation). Peritoneal fibrosis, vascular proliferation, and fibrosis-related factor expression were examined.ResultsPeritoneal thickness was significantly suppressed by AST supplementation. Astaxanthin diminished the number of CD68-, 8-hydroxy-2'–deoxyguanosine (8-OHdG)-, and monocyte chemoattractant protein-1 (MCP-1)-positive cells. Type 3 collagen, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and MCP-1 mRNA expression was significantly lower in Group 3 than in Group 1. Increased transforming growth factor-β (TGF-β) and Snail mRNA expression, vascular density, and the number of α–smooth muscle actin (α–SMA)-positive cells were also decreased in Group 3.ConclusionAstaxanthin suppressed PF development through the inhibition of inflammation and oxidation in PF rats. It appears that the anti-oxidative agent AST may be useful for the prevention of peritoneal damage.

scholarly journals Pioglitazone attenuates hepatic inflammation and fibrosis in phosphatidylethanolamine N-methyltransferase-deficient mice

2016 ◽  
Vol 310 (7) ◽  
pp. G526-G538 ◽  
Author(s):  
Jelske N. van der Veen ◽  
Susanne Lingrell ◽  
Xia Gao ◽  
Ariel D. Quiroga ◽  
Abhijit Takawale ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Transforming Growth Factor ◽  
Body Weight Gain ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Liver Weight ◽  
Mrna Levels ◽  
Nonalcoholic Fatty Liver ◽  
Diet Induced Obesity ◽  
Important Enzyme

Phosphatidylethanolamine N-methyltransferase (PEMT) is an important enzyme in hepatic phosphatidylcholine (PC) biosynthesis. Pemt−/− mice are protected against high-fat diet (HFD)-induced obesity and insulin resistance; however, these mice develop nonalcoholic fatty liver disease (NAFLD). We hypothesized that peroxisomal proliferator-activated receptor-γ (PPARγ) activation by pioglitazone might stimulate adipocyte proliferation, thereby directing lipids from the liver toward white adipose tissue. Pioglitazone might also act directly on PPARγ in the liver to improve NAFLD. Pemt+/+ and Pemt−/− mice were fed a HFD with or without pioglitazone (20 mg·kg−1·day−1) for 10 wk. Pemt−/− mice were protected from HFD-induced obesity but developed NAFLD. Treatment with pioglitazone caused an increase in body weight gain in Pemt−/− mice that was mainly due to increased adiposity. Moreover, pioglitazone improved NAFLD in Pemt−/− mice, as indicated by a 35% reduction in liver weight and a 57% decrease in plasma alanine transaminase levels. Livers from HFD-fed Pemt−/− mice were steatotic, inflamed, and fibrotic. Hepatic steatosis was still evident in pioglitazone-treated Pemt−/− mice; however, treatment with pioglitazone reduced hepatic fibrosis, as evidenced by reduced Sirius red staining and lowered mRNA levels of collagen type Iα1 ( Col1a1), tissue inhibitor of metalloproteinases 1 ( Timp1), α-smooth muscle actin ( Acta2), and transforming growth factor-β ( Tgf-β). Similarly, oxidative stress and inflammation were reduced in livers from Pemt−/− mice upon treatment with pioglitazone. Together, these data show that activation of PPARγ in HFD-fed Pemt −/− mice improved liver function, while these mice were still protected against diet-induced obesity and insulin resistance.

scholarly journals LTBP2 is secreted from lung myofibroblasts and is a potential biomarker for idiopathic pulmonary fibrosis

2018 ◽  
Vol 132 (14) ◽  
pp. 1565-1580 ◽  
Author(s):  
Yasunori Enomoto ◽  
Sayomi Matsushima ◽  
Kiyoshi Shibata ◽  
Yoichiro Aoshima ◽  
Haruna Yagi ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Bootstrap Method ◽  
Transforming Growth Factor Β ◽  
Lung Fibroblasts ◽  
Potential Biomarker ◽  
Fibrotic Process ◽  
Mouse Lungs

Although differentiation of lung fibroblasts into α-smooth muscle actin (αSMA)-positive myofibroblasts is important in the progression of idiopathic pulmonary fibrosis (IPF), few biomarkers reflecting the fibrotic process have been discovered. We performed microarray analyses between FACS-sorted steady-state fibroblasts (lineage (CD45, TER-119, CD324, CD31, LYVE-1, and CD146)-negative and PDGFRα-positive cells) from untreated mouse lungs and myofibroblasts (lineage-negative, Sca-1-negative, and CD49e-positive cells) from bleomycin-treated mouse lungs. Amongst several genes up-regulated in the FACS-sorted myofibroblasts, we focussed on Ltbp2, the gene encoding latent transforming growth factor-β (TGF-β) binding protein-2 (LTBP2), because of the signal similarity to Acta2, which encodes αSMA, in the clustering analysis. The up-regulation was reproduced at the mRNA and protein levels in human lung myofibroblasts induced by TGF-β1. LTBP2 staining in IPF lungs was broadly positive in the fibrotic interstitium, mainly as an extracellular matrix (ECM) protein; however, some of the αSMA-positive myofibroblasts were also stained. Serum LTBP2 concentrations, evaluated using ELISA, in IPF patients were significantly higher than those in healthy volunteers (mean: 21.4 compared with 12.4 ng/ml) and showed a negative correlation with % predicted forced vital capacity (r = −0.369). The Cox hazard model demonstrated that serum LTBP2 could predict the prognosis of IPF patients (hazard ratio for death by respiratory events: 1.040, 95% confidence interval: 1.026–1.054), which was validated using the bootstrap method with 1000-fold replication. LTBP2 is a potential prognostic blood biomarker that may reflect the level of differentiation of lung fibroblasts into myofibroblasts in IPF.

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