scholarly journals Role of Harmaline as Adiponectin Modulator in Defeating Liver Cirrhosis Induced By Thioacetamide in Mice

2021 ◽  
Vol 14 (1) ◽  
pp. 123-131
Author(s):  
Doha M. Beltagy ◽  
Khloud Gamal Abdelsalam ◽  
Tarek M Mohamed ◽  
Mai M. El-Keey
Keyword(s):  
Oxidative Stress ◽  
Liver Cirrhosis ◽  
Transforming Growth Factor Beta ◽  
Liver Tissue ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Matrix Deposition ◽  
Anti Inflammatory ◽  
Tgf Β1

Liver cirrhosis is currently the 11th most common cause of death which includes inflammatory, oxidative damage, and immune response. Harmaline has antioxidant and anti-inflammatory mechanisms which can defeat against hepatic cirrhosis pathways. The present work aimed to evaluate the ameliorating effect of harmaline against liver cirrhosis induced by thioacetamide in mice. The study was carried out on sixty male mice divided into three main groups. Control and harmaline groups (GIa and GIb), thioacetamide-group (GII) and harmaline co-treated and treated groups (GIIIa and GIIIb). By the end of the experiment, adiponectin concentrations were measured in serum and liver tissue. Gene expression of adiponectin, transforming growth factor beta-1 (TGF-β1), tissue inhibitor metalloprotease-1(TIMP-1) and peroxisome proliferator activated receptor-gamma (PPAR-γ) were assessed. Some oxidative stress biomarkers as malondialdehyde, reduced glutathione, catalase, superoxide dismutase and nitric oxide were determined. The results indicated that harmaline administration cause significant suppression of oxidative stress and inflammatory response.Inhibition of hepatic stellate cell activation and extracellular matrix deposition were also noticed with a significant decrease in the expression of the profibrotic markers(TGF-β1 and TIMP-1) which have direct effects on adiponectin activation. These results were confirmed by the histological studies in liver tissue. In Conclusion,Harmaline has excellent protective role against liver cirrhosis induced by thioacetamide in mice via its antioxidant and anti-inflammatory properties.It can be therapeutically used as a safe liver support by a dose of 10 mg/kg after furtherin vivo studies.

Effects of transforming growth factor-beta (TGF-β1) on satellite cell activation and survival during oxidative stress

2011 ◽  
Vol 32 (2) ◽  
pp. 99-109 ◽  
Author(s):  
Christopher R. Rathbone ◽  
Keitaro Yamanouchi ◽  
Xiaoyu K. Chen ◽  
Cedrine J. Nevoret-Bell ◽  
Robert P. Rhoads ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Growth Factor ◽  
Satellite Cell ◽  
Transforming Growth Factor Beta ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Satellite Cell Activation ◽  
Growth Factor Beta ◽  
Tgf Β1

Effects of Siniruangan Recipe on Proliferation, Apoptosis and Activation of Human Hepatic Stellate Cell Line LX-2

Pharmacology ◽  
2019 ◽  
Vol 104 (5-6) ◽  
pp. 342-351 ◽  
Author(s):  
Jinming Liu ◽  
Guorong Zhao ◽  
Bichen Ai ◽  
Yirong He ◽  
Ming Mei ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Liver Fibrosis ◽  
Cell Apoptosis ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Cell Activity ◽  
Relative Content ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Cell Counting ◽  
Tgf Β1

Background: Experimental and clinical evidence suggests that liver fibrosis is potentially reversible. Hepatic stellate cells (HSCs) play a key role in the development of hepatic fibrosis. Previous clinical applications and researches showed that Siniruangan recipe (SNRG) reversed liver fibrosis and even liver cirrhosis. This experimental study aimed to elucidate the effects of SNRG on the proliferation, apoptosis and activation of HSCs. Methods: The human HSCs line LX-2 was cultured with normal culture medium and multi-dose SNRG water decoction for 48 h. Cell Counting Kit-8 assay was used to detect the proliferation and cytotoxicity of LX-2 cells. Annexin V-FITC/PI double staining was performed to identify apoptotic cells. Immunofluorescence staining was used to determine the relative content of cleaved caspase-3, tissue inhibitor of metalloproteinase-1 (TIMP-1) and transforming growth factor-β1 (TGF-β1) in LX-2 cells. Western blot was used to detect the relative content of Bcl-2, Bax, α-smooth muscle actin, β-catenin and TIMP-1 protein expression in LX-2 cells. Results: The SNRG inhibited the proliferation of LX-2 and induced cell apoptosis through caspase-dependent and mitochondrial-dependent pathways. SNRG may inhibit the activation of LX-2 through the β-catenin pathway. The decrease in TIMP-1 and TGF-β1 protein induced by SNRG promoted the degradation of the extracellular matrix (ECM). Conclusions: SNRG induced LX-2 cell apoptosis, inhibited cell proliferation, decreased LX-2 cell activity and promoted the degradation of ECM in vitro, which may be important mechanisms for reversing liver fibrosis and liver cirrhosis.

scholarly journals TGF-β-induced α-SMA expression is mediated by C/EBPβ acetylation in human alveolar epithelial cells

2021 ◽  
Author(s):  
Hui Ding ◽  
Jinjun Chen ◽  
Jingping Qin ◽  
Ruhua Chen ◽  
Zili Yi
Keyword(s):  
Pulmonary Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
A549 Cells ◽  
Alveolar Epithelial Cells ◽  
Collagen I ◽  
Sirtuin 1 ◽  
Mesenchymal Transition ◽  
Matrix Deposition ◽  
Tgf Β1

Abstract Background: Although the morbidity and mortality rates associated with idiopathic pulmonary fibrosis (IPF) are high, there is still lack of powerful and precise therapeutic options for IPF. Object: Through in vitro model, this study sought to determine whether binding of acetylated CCAAT/enhancer binding protein β (C/EBPβ) to alpha-smooth muscle actin (α-SMA) promoter could affect the activity of the latter as well as assess if it is essential for epithelial-to-mesenchymal transition (EMT) and extracellular matrix deposition in IPF. Methods: The expression of EMT and C/EBPβ in A549 cells treated with transforming growth factor-beta (TGF-β) as pulmonary fibrotic model was detected by western blotting and qPCR. Collagen-I expression using ELISA was performed. The luciferase activity was used to examine the activity of C/EBPβ. Knockdown of C/EBPβ was performed by siRNA. We also investigated the effect of deacetylation of C/EBPβ on EMT using sirtuin 1 (SIRT1). The binding ability of C/EBPβ with α-SMA promoter was affirmed via chromatin immunoprecipitation (ChIP) and electrophoresis mobility shift assay (EMSA). The relationship between α-SMA and acetylated C/EBPβ was determined with co-immunoprecipitation (Co-IP). SiRNA-mediated knockdown of C/EBPβ in A549 cells attenuated TGF-β1-induced myofibroblast differentiation and ECM deposition. The extent of association between acetylated C/EBPβ and α-SMA promoter was dynamically monitored. Results: It was confirmed that deacetylation of C/EBPβ in A549 cells successfully ameliorated TGF-β1-induced EMT, as shown by reduction in α-SMA expression and excessive collagen-I accumulation. Conclusion: The EMT and fibrotic effect of TGF-β1 is dependent on acetylated C/EBPβ-mediated regulation of α-SMA gene activity. Thus, C/EBPβ acetylation may play a central role in pulmonary fibrosis.

scholarly journals Perilipin 5 Ameliorates Hepatic Stellate Cell Activation via SMAD2/3 and SNAIL Signaling Pathways and Suppresses STAT3 Activation

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2184
Author(s):  
Rafael Cierpka ◽  
Ralf Weiskirchen ◽  
Anastasia Asimakopoulos
Keyword(s):  
Signaling Pathways ◽  
Cell Lines ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Type I ◽  
Hepatic Fibrogenesis ◽  
Perilipin 5 ◽  
Tgf Β1

Comprehending the molecular mechanisms underlying hepatic fibrogenesis is essential to the development of treatment. The hallmark of hepatic fibrosis is the development and deposition of excess fibrous connective tissue forcing tissue remodeling. Hepatic stellate cells (HSC) play a major role in the pathogenesis of liver fibrosis. Their activation via the transforming growth factor-β1 (TGF-β1) as a key mediator is considered the crucial event in the pathophysiology of hepatic fibrogenesis. It has been shown that Perilipin 5 (PLIN5), known as a lipid droplet structural protein that is highly expressed in oxidative tissue, can inhibit such activation through various mechanisms associated with lipid metabolism. This study aimed to investigate the possible influence of PLIN5 on TGF-β1 signaling. Our findings confirm the importance of PLIN5 in maintaining HSC quiescence in vivo and in vitro. PLIN5 overexpression suppresses the TGF-β1-SMAD2/3 and SNAIL signaling pathways as well as the activation of the signal transducers and activators of transcription 3 (STAT3). These findings derived from experiments in hepatic cell lines LX-2 and Col-GFP, in which overexpression of PLIN5 was able to downregulate the signaling pathways SMAD2/3 and SNAIL activated previously by TGF-β1 treatment. Furthermore, TGF-β1-mediatedinduction of extracellular matrix proteins, such as collagen type I (COL1), Fibronectin, and α-smooth muscle actin (α-SMA), was suppressed by PLIN5. Moreover, STAT3, which is interrelated with TGF-β1 was already basally activated in the cell lines and inhibited by PLIN5 overexpression, leading to a further reduction in HSC activity shown by lowered α-SMA expression. This extension of the intervening mechanisms presents PLIN5 as a potent and pleiotropic target in HSC activation.

scholarly journals Targeting Follistatin like 1 ameliorates liver fibrosis induced by carbon tetrachloride through TGF-β1-miR29a in mice

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Xin-Yi Xu ◽  
Yan Du ◽  
Xue Liu ◽  
Yilin Ren ◽  
Yingying Dong ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Neutralizing Antibody ◽  
Transforming Growth Factor Β1 ◽  
Chemokine Ligand ◽  
Tgf Β1

Abstract Background Hepatic fibrosis is a pathological response of the liver to a variety of chronic stimuli. Hepatic stellate cells (HSCs) are the major source of myofibroblasts in the liver. Follistatin like 1 (Fstl1) is a secreted glycoprotein induced by transforming growth factor-β1 (TGF-β1). However, the precise functions and regulation mechanisms of Fstl1 in liver fibrogenesis remains unclear. Methods Hepatic stellate cell (HSC) line LX-2 stimulated by TGF-β1, primary culture of mouse HSCs and a model of liver fibrosis induced by CCl4 in mice was used to assess the effect of Fstl1 in vitro and in vivo. Results Here, we found that Fstl1 was significantly up regulated in human and mouse fibrotic livers, as well as activated HSCs. Haplodeficiency of Fstl1 or blockage of Fstl1 with a neutralizing antibody 22B6 attenuated CCl4-induced liver fibrosis in vivo. Fstl1 modulates TGF-β1 classic Samd2 and non-classic JNK signaling pathways. Knockdown of Fstl1 in HSCs significantly ameliorated cell activation, cell migration, chemokines C-C Motif Chemokine Ligand 2 (CCL2) and C-X-C Motif Chemokine Ligand 8 (CXCL8) secretion and extracellular matrix (ECM) production, and also modulated microRNA-29a (miR29a) expression. Furthermore, we identified that Fstl1 was a target gene of miR29a. And TGF-β1 induction of Fstl1 expression was partially through down regulation of miR29a in HSCs. Conclusions Our data suggests TGF-β1-miR29a-Fstl1 regulatory circuit plays a key role in regulation the HSC activation and ECM production, and targeting Fstl1 may be a strategy for the treatment of liver fibrosis. Graphical abstract

Increased Expression of Genes for Protooncoproteins SnoN and SnoA in Human Myeloblastic Leukemia ML2 Cells and Resistance of ML2 Cells to Transforming Growth Factor-beta-Induced Growth Arrest.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4347-4347
Author(s):  
Ota Fuchs ◽  
Gabriela Peslova ◽  
Dana Provaznikova ◽  
Iuri Marinov
Keyword(s):  
Growth Factor ◽  
Histone Deacetylase ◽  
Transforming Growth Factor Beta ◽  
Histone Deacetylase Inhibitors ◽  
Transforming Growth Factor ◽  
Growth Arrest ◽  
Matrix Deposition ◽  
Growth Factor Beta ◽  
P21 Waf1 ◽  
Tgf Β1

Abstract Transforming growth factor-beta 1 (TGF-β1) is a multifunctional cytokine involved in a variety of biological processes including development, cell growth, differentiation, apoptosis, cell adhesion, migration, extracellular matrix deposition, and the immune response. The loss of a growth inhibitory response to TGF-β1 is a common feature of many cancers. Human myeloblastic ML2 cells originally obtained from Dr. Minowada (Palumbo A. et al., Blood64, 1059–1063, 1984) were pre-incubated with or without TGF-β1 (5 or 10 ng/ml) or with TGF-β1 antibody for 24 h or 72h and then incubated for further 4 h in the presence of [6-3H] thymidine. TGF-β1 did not decreased the proliferation of ML2 cells measured by incorporation of [6-3H] thymidine into DNA in comparison with control without TGF-β1 or with ML2 cells icubated in the presence of inactivating TGF-β1antibody. The resistance of ML2 cells to TGF-β1-induced growth arrest is not caused by mutation in TGF-β1 receptors (TβRII and ALK5) or Smad4 as we verified by direct sequencing of exons of these genes. After 24 h incubation TGF-β1 increased the levels of mRNA for some target proteins of TGF-β1 -plasminogen activator inhibitor-1, Smad7, SnoN and SnoA (ski novel related gene products), inhibitors of cyclin-dependent kinases (p15/INK4b, p21/WAF1/CIP1) and decreased the levels of mRNA for c-myc, transferrin receptor 1 and inhibitor of differentiation/DNA binding Id1. TGF-β1 did not affect the levels of mRNA for CDC25 phosphatase and RhoA GTPase. The levels of these mRNA were determined by real-time PCR or semiquantitative PCR using specific oligonucleotide primers. The increased expression of SnoN and SnoA genes and the inability of TGF-β1 to cause SnoN degradation may be the cause of ML2 cells resistance to TGF-β1 -induced growth arrest. Antiproliferative genes coding for p15/INK4b, p21/WAF1/CIP1 are not under control of SnoN and SnoA. SnoN (684 aminoacids) and SnoA (415 aminoacids) are the alternatively spliced isoforms. Both these isoforms contain the N-terminal region that is similar to the ski (sloan kettering virus gene product) protooncoprotein. These oncoproteins are incorporated into the histone deacetylase-1 complex through binding to the nuclear corepressor and Smad (Smad2, Smad3 and Smad4) proteins and repress the activity of Smad proteins. The addition of histone deacetylase inhibitors (0.5μM MS-275 or 1mM sodium butyrate) in combination with TGF-β1 (5 ng/ml or 10 ng/ml) in pre-incubation of ML2 cells for 24 h before the incorporation of [6-3H] thymidine into DNA measurement decreased proliferation of ML2 cells in comparison with ML2 cells without additions (control) or ML2 cells with TGF-β1 or histone deacetylase inhibitors. These results support the role of Sno protooncoproteins in resistance of ML2 cells to TGF-β1-induced growth arrest. This study was financially supported by the Internal Grant Agency of the Ministry of Health, Czech Republic (NC/7605-3).

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