Recent studies have shown that fibrotic scar formation following cerebral ischemic injury has varying effects depending on the microenvironment.However,little is known about how fibrosis is induced and regulated after...Recent studies have shown that fibrotic scar formation following cerebral ischemic injury has varying effects depending on the microenvironment.However,little is known about how fibrosis is induced and regulated after cerebral ischemic injury.Sonic hedgehog signaling participates in fibrosis in the heart,liver,lung,and kidney.Whether Shh signaling modulates fibrotic scar formation after cerebral ischemic stroke and the underlying mechanisms are unclear.In this study,we found that Sonic Hedgehog expression was upregulated in patients with acute ischemic stroke and in a middle cerebral artery occlusion/reperfusion injury rat model.Both Sonic hedgehog and Mitofusin 2 showed increased expression in the middle cerebral artery occlusion rat model and in vitro fibrosis cell model induced by transforming growth factor-beta 1.Activation of the Sonic hedgehog signaling pathway enhanced the expression of phosphorylated Smad 3 and Mitofusin 2 proteins,promoted the formation of fibrotic scars,protected synapses or promoted synaptogenesis,alleviated neurological deficits following middle cerebral artery occlusion/reperfusion injury,reduced cell apoptosis,facilitated the transformation of meninges fibroblasts into myofibroblasts,and enhanced the proliferation and migration of meninges fibroblasts.The Smad3 phosphorylation inhibitor SIS3 reversed the effects induced by Sonic hedgehog signaling pathway activation.Bioinformatics analysis revealed significant correlations between Sonic hedgehog and Smad3,between Sonic hedgehog and Mitofusin 2,and between Smad3 and Mitofusin 2.These findings suggest that Sonic hedgehog signaling may influence Mitofusin 2 expression by regulating Smad3 phosphorylation,thereby modulating the formation of early fibrotic scars following cerebral ischemic stroke and affecting prognosis.The Sonic Hedgehog signaling pathway may serve as a new therapeutic target for stroke treatment.展开更多
Primary cilia function as critical sensory organelles that mediate multiple signaling pathways,including the Hedgehog(Hh)pathway,which is essential for organ patterning and morphogenesis.Disruptions in Hh signaling ha...Primary cilia function as critical sensory organelles that mediate multiple signaling pathways,including the Hedgehog(Hh)pathway,which is essential for organ patterning and morphogenesis.Disruptions in Hh signaling have been implicated in supernumerary tooth formation and molar fusion in mutant mice.Cilk1,a highly conserved serine/threonine-protein kinase localized within primary cilia,plays a critical role in ciliary transport.Loss of Cilk1 results in severe ciliopathy phenotypes,including polydactyly,edema,and cleft palate.However,the role of Cilk1 in tooth development remains unexplored.In this study,we investigated the role of Cilk1 in tooth development.Cilk1 was found to be expressed in both the epithelial and mesenchymal compartments of developing molars.Cilk1 deficiency resulted in altered ciliary dynamics,characterized by reduced frequency and increased length,accompanied by downregulation of Hh target genes,such as Ptch1 and Sostdc1,leading to the formation of diastemal supernumerary teeth.Furthermore,in Cilk1^(-/-);PCS1–MRCS1^(△/△)mice,which exhibit a compounded suppression of Hh signaling,we uncovered a novel phenomenon:diastemal supernumerary teeth can be larger than first molars.Based on these findings,we propose a progressive model linking Hh signaling levels to sequential changes in tooth patterning:initially inducing diastemal supernumerary teeth,then enlarging them,and ultimately leading to molar fusion.This study reveals a previously unrecognized role of Cilk1 in controlling tooth morphology via Hh signaling and highlights how Hh signaling levels shape tooth patterning in a gradient-dependent manner.展开更多
激素性股骨头坏死(steroid-induced osteonecrosis of the femoral head,SONFH)是一种严重的髋关节疾病,其发病机制仍完全不清楚,治疗难度大,给患者和社会带来了沉重的负担。随着SONFH研究深入,Hedgehog信号通路因调控骨形成、脂肪分化...激素性股骨头坏死(steroid-induced osteonecrosis of the femoral head,SONFH)是一种严重的髋关节疾病,其发病机制仍完全不清楚,治疗难度大,给患者和社会带来了沉重的负担。随着SONFH研究深入,Hedgehog信号通路因调控骨形成、脂肪分化及细胞增殖等功能备受关注,其通过多靶点调控对骨骼稳态维持具有关键作用。中医药作为传统医学的重要组成部分,具有辨证论治、整体调节和不良反应小的特点,在SONFH的治疗中展现出独特的优势。本文查阅了近年来国内外通过中医药调控Hedgehog信号通路治疗SONFH的研究进展,综述了信号通路的调控机制,通过影响Hedgehog信号的转导和表达,同时总结了祖国医学对SONFH的认识,中药单体和中药复方在Hedgehog信号通路中的干预作用,为临床SONFH的治疗提供新的思路和方法。展开更多
基金supported by the National Natural Science Foundation of China,Nos.82171456(to QY)and 81971229(to QY)the Natural Science Foundation of Chongqing,Nos.CSTC2021JCYJ-MSXMX0263(to QY)and CSTB2023NSCQ-MSX1015(to XL)Doctoral Innovation Project of The First Affiliated Hospital of Chongqing Medical University,Nos.CYYY-BSYJSCXXM-202318(to JW)and CYYY-BSYJSCXXM-202327(to HT).
文摘Recent studies have shown that fibrotic scar formation following cerebral ischemic injury has varying effects depending on the microenvironment.However,little is known about how fibrosis is induced and regulated after cerebral ischemic injury.Sonic hedgehog signaling participates in fibrosis in the heart,liver,lung,and kidney.Whether Shh signaling modulates fibrotic scar formation after cerebral ischemic stroke and the underlying mechanisms are unclear.In this study,we found that Sonic Hedgehog expression was upregulated in patients with acute ischemic stroke and in a middle cerebral artery occlusion/reperfusion injury rat model.Both Sonic hedgehog and Mitofusin 2 showed increased expression in the middle cerebral artery occlusion rat model and in vitro fibrosis cell model induced by transforming growth factor-beta 1.Activation of the Sonic hedgehog signaling pathway enhanced the expression of phosphorylated Smad 3 and Mitofusin 2 proteins,promoted the formation of fibrotic scars,protected synapses or promoted synaptogenesis,alleviated neurological deficits following middle cerebral artery occlusion/reperfusion injury,reduced cell apoptosis,facilitated the transformation of meninges fibroblasts into myofibroblasts,and enhanced the proliferation and migration of meninges fibroblasts.The Smad3 phosphorylation inhibitor SIS3 reversed the effects induced by Sonic hedgehog signaling pathway activation.Bioinformatics analysis revealed significant correlations between Sonic hedgehog and Smad3,between Sonic hedgehog and Mitofusin 2,and between Smad3 and Mitofusin 2.These findings suggest that Sonic hedgehog signaling may influence Mitofusin 2 expression by regulating Smad3 phosphorylation,thereby modulating the formation of early fibrotic scars following cerebral ischemic stroke and affecting prognosis.The Sonic Hedgehog signaling pathway may serve as a new therapeutic target for stroke treatment.
基金supported by the National Research Foundation of Korea(NRF)grants funded by the Korean government(MSIT)(NRF-2020R1A2C2005790,NRF2023R1A2C1007510,RS-2023-00269830,RS-2024-00438542)。
文摘Primary cilia function as critical sensory organelles that mediate multiple signaling pathways,including the Hedgehog(Hh)pathway,which is essential for organ patterning and morphogenesis.Disruptions in Hh signaling have been implicated in supernumerary tooth formation and molar fusion in mutant mice.Cilk1,a highly conserved serine/threonine-protein kinase localized within primary cilia,plays a critical role in ciliary transport.Loss of Cilk1 results in severe ciliopathy phenotypes,including polydactyly,edema,and cleft palate.However,the role of Cilk1 in tooth development remains unexplored.In this study,we investigated the role of Cilk1 in tooth development.Cilk1 was found to be expressed in both the epithelial and mesenchymal compartments of developing molars.Cilk1 deficiency resulted in altered ciliary dynamics,characterized by reduced frequency and increased length,accompanied by downregulation of Hh target genes,such as Ptch1 and Sostdc1,leading to the formation of diastemal supernumerary teeth.Furthermore,in Cilk1^(-/-);PCS1–MRCS1^(△/△)mice,which exhibit a compounded suppression of Hh signaling,we uncovered a novel phenomenon:diastemal supernumerary teeth can be larger than first molars.Based on these findings,we propose a progressive model linking Hh signaling levels to sequential changes in tooth patterning:initially inducing diastemal supernumerary teeth,then enlarging them,and ultimately leading to molar fusion.This study reveals a previously unrecognized role of Cilk1 in controlling tooth morphology via Hh signaling and highlights how Hh signaling levels shape tooth patterning in a gradient-dependent manner.
文摘激素性股骨头坏死(steroid-induced osteonecrosis of the femoral head,SONFH)是一种严重的髋关节疾病,其发病机制仍完全不清楚,治疗难度大,给患者和社会带来了沉重的负担。随着SONFH研究深入,Hedgehog信号通路因调控骨形成、脂肪分化及细胞增殖等功能备受关注,其通过多靶点调控对骨骼稳态维持具有关键作用。中医药作为传统医学的重要组成部分,具有辨证论治、整体调节和不良反应小的特点,在SONFH的治疗中展现出独特的优势。本文查阅了近年来国内外通过中医药调控Hedgehog信号通路治疗SONFH的研究进展,综述了信号通路的调控机制,通过影响Hedgehog信号的转导和表达,同时总结了祖国医学对SONFH的认识,中药单体和中药复方在Hedgehog信号通路中的干预作用,为临床SONFH的治疗提供新的思路和方法。
