The liver injury leads to an inflammatory response, which causes the activation of hepatic stellate cells (HSCs) that further secrete ECM proteins and play an important role in liver fibrosis. Moreover, the inflammato...The liver injury leads to an inflammatory response, which causes the activation of hepatic stellate cells (HSCs) that further secrete ECM proteins and play an important role in liver fibrosis. Moreover, the inflammatory response is a driving force for fibrogenesis, which is triggered by many types of injuries. Exaggerated inflammatory immune responses are mediated by cytoplasmic protein complexes known as inflammasomes, which are involved in many chronic liver diseases. Inflammasomes are pattern recognition receptors (PRRs) that can sense any microbial motifs known as pathogen-associated molecular patterns (PAMPs), and host- or environmental-derived stress signals known as damage-associated molecular patterns (DAMPs). The inflammasomes cause caspase-mediated proteolytic cleavage of pro-IL-1β and pro-IL-18 into active IL-1β and IL-18. In this review, we provide a comprehensive summary of the important roles of NLRP3 inflammasome in the pathogenesis of liver fibrosis with an emphasis on several direct and indirect pathways responsible for the NLRP3 inflammasome-mediated HSCs activation and fibrogenesis. In addition, we discuss the general pharmacological and genetics strategies for the inhibition of NLRP3 inflammasome activation and its downstream signaling with examples of emerging pharmacotherapeutics, targeting the NLRP3 inflammasome signaling as well as a possible way to develop effective and safer NLRP3 inflammasome inhibitors.展开更多
The prevalence of diabetes and its complications is increasing at an alarming rate in both developed and deve1oping nations.The emerging evidences highlighted that both genetic and epigenetic mechanisms including hist...The prevalence of diabetes and its complications is increasing at an alarming rate in both developed and deve1oping nations.The emerging evidences highlighted that both genetic and epigenetic mechanisms including histone modifications play a significant role in the pathogenesis of diabetic nephropathy(DN).Histone deacetylases(HDACs)and acetylation are involved in the regulation of autophagy as well as pathogenesis of DN.Both HDACs and histone acetyltransferases(HATs)play a key role in chromatin remodeling and affect the transcription of various genes involved in the cellular homeostasis,apoptosis,immunity and angiogenesis.Further,HDAC inhibitors are exert the renoprotective effects in DN and other diabetic complications.Thus,the cellular acetylation plays a crucial role in the regulation of autophagy and can be explored as a new therapeutic target for the treatment of DN.This review aimed to delineate the role of HDACs and associated molecular signaling/pathways in the regulation of autophagy with an emphasis on promising targets for the treatment of DN.展开更多
文摘The liver injury leads to an inflammatory response, which causes the activation of hepatic stellate cells (HSCs) that further secrete ECM proteins and play an important role in liver fibrosis. Moreover, the inflammatory response is a driving force for fibrogenesis, which is triggered by many types of injuries. Exaggerated inflammatory immune responses are mediated by cytoplasmic protein complexes known as inflammasomes, which are involved in many chronic liver diseases. Inflammasomes are pattern recognition receptors (PRRs) that can sense any microbial motifs known as pathogen-associated molecular patterns (PAMPs), and host- or environmental-derived stress signals known as damage-associated molecular patterns (DAMPs). The inflammasomes cause caspase-mediated proteolytic cleavage of pro-IL-1β and pro-IL-18 into active IL-1β and IL-18. In this review, we provide a comprehensive summary of the important roles of NLRP3 inflammasome in the pathogenesis of liver fibrosis with an emphasis on several direct and indirect pathways responsible for the NLRP3 inflammasome-mediated HSCs activation and fibrogenesis. In addition, we discuss the general pharmacological and genetics strategies for the inhibition of NLRP3 inflammasome activation and its downstream signaling with examples of emerging pharmacotherapeutics, targeting the NLRP3 inflammasome signaling as well as a possible way to develop effective and safer NLRP3 inflammasome inhibitors.
基金This work has been funded by National Institute of Pharmaceutical Education and Research,SAS Nagar,Punjab,India.
文摘The prevalence of diabetes and its complications is increasing at an alarming rate in both developed and deve1oping nations.The emerging evidences highlighted that both genetic and epigenetic mechanisms including histone modifications play a significant role in the pathogenesis of diabetic nephropathy(DN).Histone deacetylases(HDACs)and acetylation are involved in the regulation of autophagy as well as pathogenesis of DN.Both HDACs and histone acetyltransferases(HATs)play a key role in chromatin remodeling and affect the transcription of various genes involved in the cellular homeostasis,apoptosis,immunity and angiogenesis.Further,HDAC inhibitors are exert the renoprotective effects in DN and other diabetic complications.Thus,the cellular acetylation plays a crucial role in the regulation of autophagy and can be explored as a new therapeutic target for the treatment of DN.This review aimed to delineate the role of HDACs and associated molecular signaling/pathways in the regulation of autophagy with an emphasis on promising targets for the treatment of DN.
