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Background And Aims: Apoptosis Signal-regulating Kinase 1 (ASK1) is activated by various pathological stimuli and induces cell apoptosis through downstream p38 activation. We studied the effect of pharmacological ASK1 inhibition on cirrhosis and its sequelae using comprehensive preclinical in vivo and in vitro systems.
Approach And Results: Short-term (4-6 wk) and long-term (24-44 wk) ASK1 inhibition using small molecule GS-444217 was tested in thioacetamide-induced and BALB/c. Mdr2-/- murine models of cirrhosis and HCC, and in vitro using primary hepatocyte cell death assays. Short-term GS-444217 therapy in both models strongly reduced phosphorylated p38, hepatocyte death, and fibrosis by up to 50%. Profibrogenic release of mitochondrial DAMP mitochondrial deoxyribonucleic acid from dying hepatocytes was blocked by ASK1 or p38 inhibition. Long-term (24 wk) therapy in BALBc.Mdr2 - / - model resulted in a moderate 25% reduction in bridging fibrosis, but not in net collagen deposition. Despite this, the development of cirrhosis was effectively prevented, with strongly reduced p21 + hepatocyte staining (by 72%), serum ammonia levels (by 46%), and portal pressure (average 6.07 vs. 8.53 mm Hg in controls). Extended ASK1 inhibition for 44 wk in aged BALB/c. Mdr2-/- mice resulted in markedly reduced tumor number and size by ~50% compared to the control group.
Conclusions: ASK1 inhibition suppresses the profibrogenic release of mitochondrial deoxyribonucleic acid from dying hepatocytes in a p38-dependent manner and protects from liver fibrosis. Long-term ASK1 targeting resulted in diminished net antifibrotic effect, but the progression to liver cirrhosis and cancer in BALBc/ Mdr2- / - mice was effectively inhibited. These data support the clinical evaluation of ASK1 inhibitors in fibrotic liver diseases.
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http://dx.doi.org/10.1097/HEP.0000000000000801 | DOI Listing |
Nat Prod Res
December 2024
State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Fermentation Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China.
T-cell acute lymphoblastic leukaemia (T-ALL) is a common childhood malignant tumour, which has poor prognosis and high recurrence rate. Ginsenoside Rh2 (GRh2), a bioactive ingredient of has significant anti-tumour effect. In this study, we found that gene expressions of Jurkat cells were significantly changed in the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) signalling pathways after 35 µm GRh2 treatment, involving in JUN, PIEN, AKT3 and MAPK8IP2.
View Article and Find Full Text PDFZhongguo Zhong Yao Za Zhi
October 2024
School of Pharmaceutical Sciences, Zhejiang Chinese Medical University Hangzhou 310053, China.
This study aims to investigate the effect and potential mechanism of Polygonati Rhizoma aqueous extract in protecting mice from gastric mucosal injury(stomach Yin deficiency). ICR mice were administrated with the mixture of pungent substance extract and alcohol by gavage once a day for 6 weeks to establish the mouse model of gastric mucosal injury with gastric Yin deficiency. The modeled mice were randomized into three groups of model and Polygonati Rhizoma aqueous extract administrated at 0.
View Article and Find Full Text PDFFASEB J
December 2024
Department of Nephrology, Hunan Clinical Research Center for Chronic Kidney Disease, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, People's Republic of China.
Tubulointerstitial injury has been increasingly recognized as an important component in lupus nephritis (LN) pathology over the last decades. However, current clinical treatment options for this process remain limited. In this study, we aimed to investigate the potential benefits of GS-4997, a selective inhibitor of ASK1, in tubulointerstitial injury of LN.
View Article and Find Full Text PDFPhytomedicine
December 2024
Engineering Research Center of Western Resource Innovation Medicine Green Manufacturing, Ministry of Education, School of Chemical Engineering, Northwest University, Xi'an 710127, China; Biotech. & Biomed. Research Institute, Northwest University, Xi'an 710127, China. Electronic address:
Background: Aging of the brain is a major contributor to the onset and progression of neurodegenerative diseases. Conventional treatments for these diseases are often limited by significant side effects and a lack of efficacy in halting disease progression. Ginsenoside compound K (CK), a bioactive secondary metabolite derived from ginseng, has shown promise because of its potent antioxidant properties.
View Article and Find Full Text PDFAdv Sci (Weinh)
December 2024
Shenzhen Eye Hospital, Shenzhen Key Laboratory of Ophthalmology, Jinan University, Shenzhen, Guangdong, 518043, China.
Pathological ocular angiogenesis is a significant cause of irreversible vision loss and blindness worldwide. Currently, most studies have focused on the angiogenesis factors in ocular vascular diseases, and very few endogenous anti-angiogenic compounds have been found. Moreover, although inflammation is closely related to the predominant processes involved in angiogenesis, the mechanisms by which inflammation regulates pathological ocular angiogenesis remain obscure.
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