Apoptosis induced by endoplasmic reticulum(ER)stress plays a crucial role in mediating brain damage after ischemic stroke.Recently,Hes1(hairy and enhancer of split 1)has been implicated in the regulation of ER stress,...Apoptosis induced by endoplasmic reticulum(ER)stress plays a crucial role in mediating brain damage after ischemic stroke.Recently,Hes1(hairy and enhancer of split 1)has been implicated in the regulation of ER stress,but whether it plays a functional role after ischemic stroke and the underlying mechanism remain unclear.In this study,using a mouse model of ischemic stroke via transient middle cerebral artery occlusion(tMCAO),we found that Hes1 was induced following brain injury,and that siRNA-mediated knockdown of Hes1 increased the cerebral infarction and worsened the neurological outcome,suggesting that Hes1 knockdown exacerbates ischemic stroke.In addition,mechanistically,Hes1 knockdown promoted apoptosis and activated the PERK/eIF2a/ATF4/CHOP signaling pathway after tMCAO.These results suggest that Hes1 knockdown promotes ER stress-induced apoptosis.Furthermore,inhibition of PERK with the specific inhibitor GSK2606414 markedly attenuated the Hes1 knockdown-induced apoptosis and the increased cerebral infarction as well as the worsened neurological outcome following tMCAO,implying that the protection of Hes1 against ischemic stroke is associated with the amelioration of ER stress via modulating the PERK/eIF2a/ATF4/CHOP signaling pathway.Taken together,these results unveil the detrimental role of Hes1 knockdown after ischemic stroke and further relate it to the regulation of ER stress-induced apoptosis,thus highlighting the importance of targeting ER stress in the treatment of ischemic stroke.展开更多
Aim Idiopathic pulmonary arterial hypertension(IPAH) and pulmonary veno-occlusive disease (PVOD) are undistinguished on clinical practice. We proposed that gene test might be a promising and feasible method in the fut...Aim Idiopathic pulmonary arterial hypertension(IPAH) and pulmonary veno-occlusive disease (PVOD) are undistinguished on clinical practice. We proposed that gene test might be a promising and feasible method in the future.Methods A 20-year-old woman was diagnosed as IPAH in 2013while a diagnosis of PVOD was also suspected. The genomic DNA was extracted from peripheral blood and gene panel testing was performed.展开更多
Using chemoproteomic techniques,we first identified EIF2AK2,eEF1A1,PRDX3 and VPS4B as direct targets of berberine(BBR)for its synergistically anti-inflammatory effects.Of them,BBR has the strongest affinity with EIF2A...Using chemoproteomic techniques,we first identified EIF2AK2,eEF1A1,PRDX3 and VPS4B as direct targets of berberine(BBR)for its synergistically anti-inflammatory effects.Of them,BBR has the strongest affinity with EIF2AK2 via two ionic bonds,and regulates several key inflammatory pathways through EIF2AK2,indicating the dominant role of EIF2AK2.Also,BBR could subtly inhibit the dimerization of EIF2AK2,rather than its enzyme activity,to selectively modulate its downstream pathways including JNK,NF-κB,AKT and NLRP3,with an advantage of good safety profile.In EIF2AK2 gene knockdown mice,the inhibitory IL-1β,IL-6,IL-18 and TNF-a secretion of BBR was obviously attenuated,confirming an EIF2AK2-dependent anti-inflammatory efficacy.The results highlight the BBR's network mechanism on anti-inflammatory effects in which EIF2AK2 is a key target,and inhibition of EIF2AK2 dimerization has a potential to be a therapeutic strategy against inflammationrelated disorders.展开更多
Stem cell fate decisions are increasingly understood through the dynamic interplay of two fundamental stress-adaptive programs:the integrated stress response(ISR)and the senescence-associated secretory phenotype(SASP)...Stem cell fate decisions are increasingly understood through the dynamic interplay of two fundamental stress-adaptive programs:the integrated stress response(ISR)and the senescence-associated secretory phenotype(SASP).These pathways act as a Yin-Yang system,balancing beneficial and detrimental outcomes across development,tissue homeostasis,and disease.On the yin(protective)side,transient ISR activation and acute SASP signaling foster adaptation,embryonic patterning,wound healing,and regeneration.On the yang(maladaptive)side,chronic ISR signaling and unresolved SASP output drive stem cell exhaustion,fibrosis,inflammation,and tumorigenesis.This duality highlights their roles as both guardians and disruptors of stem cell integrity.Mechanistically,ISR regulates translational control via eukaryotic initiation factor 2 alpha(eIF2α)phosphorylation and activating transcription factor 4(ATF4)-dependent transcription,while SASP reprograms the extracellular milieu through cytokines,growth factors,and proteases.Their crosstalk creates feedback loops that shape tissue niches and long-termstemcell potential.Framing ISR-SASP interactions through a Yin-Yang lens underscores the balance between resilience and decline,to offer new insights into regenerative medicine,anti-aging interventions,and cancer therapeutics.展开更多
基金supported by grants from the Guangxi Zhuang Autonomous Region Health and Family Planning Commission Science and Technology Project(Z2016419)Guangxi Natural Science Foundation Project(No.:2018JJA140853)the Science and Technology Project of Hunan Province,China(2014FJ4233).
文摘Apoptosis induced by endoplasmic reticulum(ER)stress plays a crucial role in mediating brain damage after ischemic stroke.Recently,Hes1(hairy and enhancer of split 1)has been implicated in the regulation of ER stress,but whether it plays a functional role after ischemic stroke and the underlying mechanism remain unclear.In this study,using a mouse model of ischemic stroke via transient middle cerebral artery occlusion(tMCAO),we found that Hes1 was induced following brain injury,and that siRNA-mediated knockdown of Hes1 increased the cerebral infarction and worsened the neurological outcome,suggesting that Hes1 knockdown exacerbates ischemic stroke.In addition,mechanistically,Hes1 knockdown promoted apoptosis and activated the PERK/eIF2a/ATF4/CHOP signaling pathway after tMCAO.These results suggest that Hes1 knockdown promotes ER stress-induced apoptosis.Furthermore,inhibition of PERK with the specific inhibitor GSK2606414 markedly attenuated the Hes1 knockdown-induced apoptosis and the increased cerebral infarction as well as the worsened neurological outcome following tMCAO,implying that the protection of Hes1 against ischemic stroke is associated with the amelioration of ER stress via modulating the PERK/eIF2a/ATF4/CHOP signaling pathway.Taken together,these results unveil the detrimental role of Hes1 knockdown after ischemic stroke and further relate it to the regulation of ER stress-induced apoptosis,thus highlighting the importance of targeting ER stress in the treatment of ischemic stroke.
文摘Aim Idiopathic pulmonary arterial hypertension(IPAH) and pulmonary veno-occlusive disease (PVOD) are undistinguished on clinical practice. We proposed that gene test might be a promising and feasible method in the future.Methods A 20-year-old woman was diagnosed as IPAH in 2013while a diagnosis of PVOD was also suspected. The genomic DNA was extracted from peripheral blood and gene panel testing was performed.
基金the CAMS initiative for innovative medicine(2022-I2M-2-002,China)National Natural Science Foundation of China(32141003)。
文摘Using chemoproteomic techniques,we first identified EIF2AK2,eEF1A1,PRDX3 and VPS4B as direct targets of berberine(BBR)for its synergistically anti-inflammatory effects.Of them,BBR has the strongest affinity with EIF2AK2 via two ionic bonds,and regulates several key inflammatory pathways through EIF2AK2,indicating the dominant role of EIF2AK2.Also,BBR could subtly inhibit the dimerization of EIF2AK2,rather than its enzyme activity,to selectively modulate its downstream pathways including JNK,NF-κB,AKT and NLRP3,with an advantage of good safety profile.In EIF2AK2 gene knockdown mice,the inhibitory IL-1β,IL-6,IL-18 and TNF-a secretion of BBR was obviously attenuated,confirming an EIF2AK2-dependent anti-inflammatory efficacy.The results highlight the BBR's network mechanism on anti-inflammatory effects in which EIF2AK2 is a key target,and inhibition of EIF2AK2 dimerization has a potential to be a therapeutic strategy against inflammationrelated disorders.
基金funded by the National Institutes of Health,grant numbers UG3OD023285,P42ES030991,and P30ES036084.
文摘Stem cell fate decisions are increasingly understood through the dynamic interplay of two fundamental stress-adaptive programs:the integrated stress response(ISR)and the senescence-associated secretory phenotype(SASP).These pathways act as a Yin-Yang system,balancing beneficial and detrimental outcomes across development,tissue homeostasis,and disease.On the yin(protective)side,transient ISR activation and acute SASP signaling foster adaptation,embryonic patterning,wound healing,and regeneration.On the yang(maladaptive)side,chronic ISR signaling and unresolved SASP output drive stem cell exhaustion,fibrosis,inflammation,and tumorigenesis.This duality highlights their roles as both guardians and disruptors of stem cell integrity.Mechanistically,ISR regulates translational control via eukaryotic initiation factor 2 alpha(eIF2α)phosphorylation and activating transcription factor 4(ATF4)-dependent transcription,while SASP reprograms the extracellular milieu through cytokines,growth factors,and proteases.Their crosstalk creates feedback loops that shape tissue niches and long-termstemcell potential.Framing ISR-SASP interactions through a Yin-Yang lens underscores the balance between resilience and decline,to offer new insights into regenerative medicine,anti-aging interventions,and cancer therapeutics.
