Cellular senescence,an irreversible state of cell cycle arrest characterized by phenotypic changes and a specific secretory profile,plays a dual role in liver health and disease.Under physiological conditions,senescen...Cellular senescence,an irreversible state of cell cycle arrest characterized by phenotypic changes and a specific secretory profile,plays a dual role in liver health and disease.Under physiological conditions,senescence aids organ repair and regeneration,but its accumulation due to aging or pathological stress significantly contributes to chronic liver diseases,including alcoholic liver disease,metabolic dysfunction-associated steatohepatitis,liver fibrosis,and hepatocellular carcinoma.Senescence is identified by a range of cellular and molecular changes,such as morphological alterations,expression of cell cycle inhibitors,senescence-associated β-galactosidase activity,and nuclear membrane changes.The onset of senescence in organ cells can affect the entire organism,primarily through the senescence-associated secretory phenotype,which has autocrine,paracrine,and endocrine effects on tissue microenvironments.The objective of this review is to offer a contemporary overview of the pathophysiological events involving hepatic senescent cells and to elucidate their role in the onset and progression of liver diseases,particularly through mechanisms like telomere shortening,genomic and mitochondrial DNA damage,and inflammation.Additionally,this review discusses the emerging senolytic therapies aimed at targeting senescent cells to delay or mitigate liver disease progression.The therapeutic potential of these interventions,alongside their safety and effectiveness,highlights the need for further research to refine these approaches and address unresolved problems in the field of hepatic cellular senescence.展开更多
Currently,there is no effective drugs for treating clinically COVID-19 except dexamethasone.We previously revealed that human identical sequences of SARS-CoV-2 promote the COVID-19 progression by upregulating hyaluron...Currently,there is no effective drugs for treating clinically COVID-19 except dexamethasone.We previously revealed that human identical sequences of SARS-CoV-2 promote the COVID-19 progression by upregulating hyaluronic acid(HA).As the inhibitor of HA synthesis,hymecromone is an approved prescription drug used for treating biliary spasm.Here,we aimed to investigate the relation between HA and COVID-19,and evaluate the therapeutic effects of hymecromone on COVID-19.Firstly,HA was closely relevant to clinical parameters,including lymphocytes(n=158;r=−0.50;P<0.0001),C-reactive protein(n=156;r=0.55;P<0.0001),D-dimer(n=154;r=0.38;P<0.0001),and fibrinogen(n=152;r=0.37;P<0.0001),as well as the mass(n=78;r=0.43;P<0.0001)and volume(n=78;r=0.41;P=0.0002)of ground-glass opacity,the mass(n=78;r=0.48;P<0.0001)and volume(n=78;r=0.47;P<0.0001)of consolidation in patient with low level of hyaluronan(HA<48.43 ng/mL).Furthermore,hyaluronan could directly cause mouse pulmonary lesions.Besides,hymecromone remarkably reduced HA via downregulating HAS2/HAS3 expression.Moreover,89%patients with hymecromone treatment had pulmonary lesion absorption while only 42%patients in control group had pulmonary lesion absorption(P<0.0001).In addition,lymphocytes recovered more quickly in hymecromone-treated patients(n=8)than control group(n=5)(P<0.05).These findings suggest that hymecromone is a promising drug for COVID-19 and deserves our further efforts to determine its effect in a larger cohort.展开更多
基金funded by grants from the National Nat-ural Science Foundation of China(Nos.82325007 and 82370620)the National Key Research and Develop-ment Program of China(No.2021YFA1100502).
文摘Cellular senescence,an irreversible state of cell cycle arrest characterized by phenotypic changes and a specific secretory profile,plays a dual role in liver health and disease.Under physiological conditions,senescence aids organ repair and regeneration,but its accumulation due to aging or pathological stress significantly contributes to chronic liver diseases,including alcoholic liver disease,metabolic dysfunction-associated steatohepatitis,liver fibrosis,and hepatocellular carcinoma.Senescence is identified by a range of cellular and molecular changes,such as morphological alterations,expression of cell cycle inhibitors,senescence-associated β-galactosidase activity,and nuclear membrane changes.The onset of senescence in organ cells can affect the entire organism,primarily through the senescence-associated secretory phenotype,which has autocrine,paracrine,and endocrine effects on tissue microenvironments.The objective of this review is to offer a contemporary overview of the pathophysiological events involving hepatic senescent cells and to elucidate their role in the onset and progression of liver diseases,particularly through mechanisms like telomere shortening,genomic and mitochondrial DNA damage,and inflammation.Additionally,this review discusses the emerging senolytic therapies aimed at targeting senescent cells to delay or mitigate liver disease progression.The therapeutic potential of these interventions,alongside their safety and effectiveness,highlights the need for further research to refine these approaches and address unresolved problems in the field of hepatic cellular senescence.
基金the National Key R&D Program of China(2018YFC1005004)Major Special Projects of Basic Research of Shanghai Science and Technology Commission(18JC1411101)+1 种基金National Natural Science Foundation of China(31872814,32000505)Shanghai Science and Technology Innovation Action Plan,Medical Innovation Research Special Project(20Z11900900).
文摘Currently,there is no effective drugs for treating clinically COVID-19 except dexamethasone.We previously revealed that human identical sequences of SARS-CoV-2 promote the COVID-19 progression by upregulating hyaluronic acid(HA).As the inhibitor of HA synthesis,hymecromone is an approved prescription drug used for treating biliary spasm.Here,we aimed to investigate the relation between HA and COVID-19,and evaluate the therapeutic effects of hymecromone on COVID-19.Firstly,HA was closely relevant to clinical parameters,including lymphocytes(n=158;r=−0.50;P<0.0001),C-reactive protein(n=156;r=0.55;P<0.0001),D-dimer(n=154;r=0.38;P<0.0001),and fibrinogen(n=152;r=0.37;P<0.0001),as well as the mass(n=78;r=0.43;P<0.0001)and volume(n=78;r=0.41;P=0.0002)of ground-glass opacity,the mass(n=78;r=0.48;P<0.0001)and volume(n=78;r=0.47;P<0.0001)of consolidation in patient with low level of hyaluronan(HA<48.43 ng/mL).Furthermore,hyaluronan could directly cause mouse pulmonary lesions.Besides,hymecromone remarkably reduced HA via downregulating HAS2/HAS3 expression.Moreover,89%patients with hymecromone treatment had pulmonary lesion absorption while only 42%patients in control group had pulmonary lesion absorption(P<0.0001).In addition,lymphocytes recovered more quickly in hymecromone-treated patients(n=8)than control group(n=5)(P<0.05).These findings suggest that hymecromone is a promising drug for COVID-19 and deserves our further efforts to determine its effect in a larger cohort.
