Hepatic fibrosis is a wound healing process which results in deposition of excessive abnormal extracellular matrix (ECM) in response to various liver injuries. Activated hepatic stellate cells (HSCs) are the major sources of ECM and induction of senescence of activated HSCs is an attractive therapeutic strategy for liver fibrosis. Our previous studies have shown that interleukin-10 (IL-10) attenuates the carbon tetrachloride (CCL) - and porcine serum-induced liver fibrosis in rats. However, little is known about the mechanisms of IL-10 regulating the senescence of activated HSCs. The aim of this study is to uncover the underlying pathway by which IL-10 mediates activated HSCs senescence to attenuate liver fibrosis. In vivo, we found that IL-10 gene by hydrodynamics-based transfection attenuated CCL-induced liver fibrosis associated with senescence of activated HSCs in rats. In vitro experiment confirmed that IL-10 could induce senescence of activated HSCs via inhibiting cell proliferation, inducing cell cycle arrest, increasing the SA-β-Gal activity and enhancing expression of senescence marker protein p53 and p21. Treatment with Pifithrin-α, a specific inhibitor of p53, could abrogate IL-10-increased SA-β-Gal activity and expression of P53 and P21in activated HSCs. Lastly, IL-10 also increased the expression of total and phosphorylated signal transducers and activators of transcription 3(STAT3) and promoted phosphorylated STAT3 translocation from cytoplasm to nucleus. Treatment with cryptotanshinone, a specific inhibitor of STAT3, could inhibit the phosphorylation of STAT3 and its downstream proteins p53 and p21 expression and decrease the activity of SA-β-Gal in activated HSCs induced by IL-10. Taken together, IL-10 induced senescence of activated HSCs via STAT3-p53 pathway to attenuate liver fibrosis in rats and present study will provide a new mechanism of antifibrotic effects of IL-10.
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http://dx.doi.org/10.1016/j.cellsig.2019.109445 | DOI Listing |
Biochem Pharmacol
December 2024
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; University of Chinese Academy of Sciences, Beijing, China. Electronic address:
With the recent approval of Resmetirom as the first drug targeting nuclear receptors for metabolic dysfunction-associated steatohepatitis (MASH), there is promising way to treat MASH-associated liver fibrosis. However, liver fibrosis can arise from various pathogenic factors, and effective treatments for fibrosis due to other causes remain elusive. The activation of hepatic stellate cells (HSCs) represents a central link in the pathogenesis of hepatic fibrosis.
View Article and Find Full Text PDFCell Biol Toxicol
December 2024
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 13850 E. Montview Blvd, Box C238/V20-3128, Aurora, CO, 80045, USA.
Toxicant exposure can lead to acute liver injury, characterized by hepatic reprogramming and wound healing. Hepatic stellate cells (HSC) play a key role in liver regeneration during wound healing by secreting fibrogenic factors and production of extracellular matrix (ECM). However, repetitive injury to the liver can lead to extensive scarring and liver fibrosis, indicating HSCs coordinate both regeneration and disease.
View Article and Find Full Text PDFBlood Res
December 2024
Department of Laboratory Hematology and Blood Bank, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Introduction: Despite advances in the treatment of acute myeloid leukemia (AML), refractory forms of this malignancy and relapse remain common. Therefore, development of novel, synergistic targeted therapies are needed urgently. Recently, mesenchymal stem cells (MSCs) have been shown to be effective in treating various diseases, with most of their therapeutic outcomes attributed to their exosomes.
View Article and Find Full Text PDFInt J Hematol Oncol Stem Cell Res
October 2024
Sri Sri Institute for Advanced Research (SSIAR), Ved Vignan Maha Vidhya Peeth (VVMVP), Bangalore, India.
: Human fetal liver hematopoietic stem cells have proven potential as therapeutics but lack extensive research due to their limited supply. Even expanded fetal liver hematopoietic stem cells enter senescence or lose their self-renewal capacity after a few days in culture. The present study aimed to obtain a homogeneous and persistent supply of hematopoietic stem cells from the fetal liver by establishing a cell line through immortalization of cells by enhancing telomerase activity.
View Article and Find Full Text PDFZhongguo Zhong Yao Za Zhi
October 2024
Chengdu University of Traditional Chinese Medicine Chengdu 610075, China.
This study aims to reveal the mechanism of Qijia Rougan Decoction(QJRG) and its disassembled formulas in mitigating hepatic fibrosis via the vascular endothelial growth factor(VEGF)/serum response factor(SRF)/c-FOS pathway and hepatic sinusoidal capillarization. Male Sprague-Dawley(SD) rats were randomized into a control group(n=6) and a modeling group(n=28). Hepatic fibrosis was induced by subcutaneous injection of 40% carbon tetrachloride(CCl_4) in olive oil.
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