Light deprivation is known to induce a significant decrease in the percentage of N-methyi-D- aspartate receptor 2A subunit （NR2A）-expressing neurons during development. The purpose of this study was to investigate t...Light deprivation is known to induce a significant decrease in the percentage of N-methyi-D- aspartate receptor 2A subunit （NR2A）-expressing neurons during development. The purpose of this study was to investigate the effects of binocular form deprivation （BFD） and chondroitin sulfate proteoglycan （CSPG） degradation on NR2A expression via an immunohistochemical study, around the end of a critical developmental period. The results show that the positive staining of NR2A in the normal rat visual cortex increases gradually from postnatal 3-5 weeks （P 〈 0.05）, but the changes from 5 weeks to 7 weeks were not significant. The positive staining of NR2A following BFD in the rat visual cortex slightly increased from postnatal 3-7 weeks （P 〉 0.05）. The positive staining of NR2A in the CSPG-treated group was insignificant compared with the BFD group at the same time point from 4 weeks to 7 weeks （P 〉 0.05）. Thus, the effect of BFD on NR2A expression in the rat visual cortex was similar to that of CSPG degradation around the end of the critical developmental period.展开更多
Chronic visceral pain is a persistent and debilitating condition arising from dysfunction or sensitization of the visceral organs and their associated nervous pathways.Increasing evidence suggests that imbalances in c...Chronic visceral pain is a persistent and debilitating condition arising from dysfunction or sensitization of the visceral organs and their associated nervous pathways.Increasing evidence suggests that imbalances in central nervous system function play an essential role in the progression of visceral pain,but the exact mechanisms underlying the neural circuitry and molecular targets remain largely unexplored.In the present study,the ventral tegmental area(VTA)was shown to mediate visceral pain in mice.Visceral pain stimulation increased c-Fos expression and Ca2+activity of glutamatergic VTA neurons,and optogenetic modulation of glutamatergic VTA neurons altered visceral pain.In particular,the upregulation of NMDA receptor 2A(NR2A)subunits within the VTA resulted in visceral pain in mice.Administration of a selective NR2A inhibitor decreased the number of visceral pain-induced c-Fos positive neurons and attenuated visceral pain.Pharmacology combined with chemogenetics further demonstrated that glutamatergic VTA neurons regulated visceral pain behaviors based on NR2A.In summary,our findings demonstrated that the upregulation of NR2A in glutamatergic VTA neurons plays a critical role in visceral pain.These insights provide a foundation for further comprehension of the neural circuits and molecular targets involved in chronic visceral pain and may pave the way for targeted therapies in chronic visceral pain.展开更多
Background:VPS37A(VPS37A subunit of ESCRT-I),a component of the ESCRT-I(endosomal sorting complex required for transport I)complex,mediates vesicular trafficking through sorting endocytic ubiquitinated cargos into mul...Background:VPS37A(VPS37A subunit of ESCRT-I),a component of the ESCRT-I(endosomal sorting complex required for transport I)complex,mediates vesicular trafficking through sorting endocytic ubiquitinated cargos into multivesicular bodies(MVBs).Although accumulating evidence indicates that VPS37A deficiency occurs in numerous malignancies and exerts tumor-suppressive effects during cancer progression,its functional significance in colorectal cancer(CRC)pathogenesis remains poorly characterized.Therefore,this study aims to further investigate the functional and molecular mechanisms by which VPS37A downregulation contributes to malignant biological phenotypes in CRC,with a specific focus on how its dysregulation affects cell death pathways.Methods:Multi-omics analysis of TCGA,GEO,and CPTAC cohorts identified VPS37A as a downregulated tumor suppressor gene in CRC.The prognostic relevance of VPS37A was validated in two clinical cohorts(Cohorts 1 and 2)using immunohistochemistry.Functional assays in VPS37A-overexpressing CRC cells and xenografts assessed proliferation,cell cycle progression,and stress-induced cell death.RNA sequencing,nuclear factor kappa-B(NF-κB)luciferase reporter assays,and lysosomal inhibition experiments elucidated the mechanisms underlying tumor necrosis factor receptor 1(TNFR1)degradation.Results:VPS37A is significantly downregulated in advanced-stage CRC and independently predicts poor survival.Functionally,VPS37A overexpression suppresses proliferation and induces G2/M arrest in vitro,while reducing xenograft growth.Under metabolic stress(glucose deprivation/galactose adaptation),VPS37A triggers cell death via apoptosis,necroptosis,and ferroptosis.Mechanistically,VPS37A redirects TNFR1 to lysosomal degradation,suppressing NF-κB nuclear translocation and transcriptional activity.Conclusion:VPS37A deficiency drives CRC progression by sustaining TNFR1/NF-κB signaling under metabolic stress.Restoring VPS37A activity promotes TNFR1 degradation,offering a therapeutic strategy to counteract NF-κB-mediated treatment resistance in CRC.展开更多
The role of B7-1 in podocyte injury has received increasing attention.The aim of this study was to investigate whether losartan protects podocytes of patients with diabetic kidney disease(DKD)by regulating B7-1 and th...The role of B7-1 in podocyte injury has received increasing attention.The aim of this study was to investigate whether losartan protects podocytes of patients with diabetic kidney disease(DKD)by regulating B7-1 and the underlying mechanisms.Rats with streptozotocin-induced DKD were treated with losartan for 8 weeks.Biochemical changes in blood and urine were analyzed.Kidneys were isolated for electron microscopy,immunofluorescence,real-time quantitative PCR(RT-PCR),and Western blot analysis.Immortalized mouse podocyte cells were cultured in normal or high glucose medium in the presence or absence of losartan for 48 h,and then the cells were collected for immunofluorescence,PCR,Western blotting and monolayer permeability detection.The phosphatidylinositol 3-kinase(PI3K)110a subunit and angiotensin II type 1 receptor(AT1R)plasmids were transfected into podocytes,respectively,and then Western blotting was performed to assess the expression of B7-1 protein.The results showed that losartan ameliorated podocyte structure and function in the rat model of DKD,and reduced the expression of B7-1 protein.Overexpression of PI3K 110a subunit in podocytes attenuated the inhibitory effect of losartan on B7-1 expression in high glucose-stimulated podocytes.The expression of B7-1 was significantly increased by overexpression of ATI R and significantly reduced by blocking PI3K 110a subunit.We conclude that losartan protects podocytes against high glucose-induced injury by inhibiting AT1R-mediated B7-1 expression.This effect is dependent on the AT1R-PI3K 110a subunit pathway.展开更多
基金the National Natural Science Foundation of China,No.30772350
文摘Light deprivation is known to induce a significant decrease in the percentage of N-methyi-D- aspartate receptor 2A subunit （NR2A）-expressing neurons during development. The purpose of this study was to investigate the effects of binocular form deprivation （BFD） and chondroitin sulfate proteoglycan （CSPG） degradation on NR2A expression via an immunohistochemical study, around the end of a critical developmental period. The results show that the positive staining of NR2A in the normal rat visual cortex increases gradually from postnatal 3-5 weeks （P 〈 0.05）, but the changes from 5 weeks to 7 weeks were not significant. The positive staining of NR2A following BFD in the rat visual cortex slightly increased from postnatal 3-7 weeks （P 〉 0.05）. The positive staining of NR2A in the CSPG-treated group was insignificant compared with the BFD group at the same time point from 4 weeks to 7 weeks （P 〉 0.05）. Thus, the effect of BFD on NR2A expression in the rat visual cortex was similar to that of CSPG degradation around the end of the critical developmental period.
基金supported by grants from the National Natural Science Foundation of China(82401454 and 32230041)the Postdoctoral Fellowship Program of CPSF(GZC20231890)+1 种基金Zhangjiagang Technology Project for Youth(ZJGQNKJ202424)the Priority Academic Program Development of Jiangsu Higher Education Institutions of China.
文摘Chronic visceral pain is a persistent and debilitating condition arising from dysfunction or sensitization of the visceral organs and their associated nervous pathways.Increasing evidence suggests that imbalances in central nervous system function play an essential role in the progression of visceral pain,but the exact mechanisms underlying the neural circuitry and molecular targets remain largely unexplored.In the present study,the ventral tegmental area(VTA)was shown to mediate visceral pain in mice.Visceral pain stimulation increased c-Fos expression and Ca2+activity of glutamatergic VTA neurons,and optogenetic modulation of glutamatergic VTA neurons altered visceral pain.In particular,the upregulation of NMDA receptor 2A(NR2A)subunits within the VTA resulted in visceral pain in mice.Administration of a selective NR2A inhibitor decreased the number of visceral pain-induced c-Fos positive neurons and attenuated visceral pain.Pharmacology combined with chemogenetics further demonstrated that glutamatergic VTA neurons regulated visceral pain behaviors based on NR2A.In summary,our findings demonstrated that the upregulation of NR2A in glutamatergic VTA neurons plays a critical role in visceral pain.These insights provide a foundation for further comprehension of the neural circuits and molecular targets involved in chronic visceral pain and may pave the way for targeted therapies in chronic visceral pain.
基金funded by the National Natural Science Foundation of China(81902815,81802786)the Natural Science Foundation of Shandong Province(ZR2023MH011,ZR2019BH044,ZR2018BH025).
文摘Background:VPS37A(VPS37A subunit of ESCRT-I),a component of the ESCRT-I(endosomal sorting complex required for transport I)complex,mediates vesicular trafficking through sorting endocytic ubiquitinated cargos into multivesicular bodies(MVBs).Although accumulating evidence indicates that VPS37A deficiency occurs in numerous malignancies and exerts tumor-suppressive effects during cancer progression,its functional significance in colorectal cancer(CRC)pathogenesis remains poorly characterized.Therefore,this study aims to further investigate the functional and molecular mechanisms by which VPS37A downregulation contributes to malignant biological phenotypes in CRC,with a specific focus on how its dysregulation affects cell death pathways.Methods:Multi-omics analysis of TCGA,GEO,and CPTAC cohorts identified VPS37A as a downregulated tumor suppressor gene in CRC.The prognostic relevance of VPS37A was validated in two clinical cohorts(Cohorts 1 and 2)using immunohistochemistry.Functional assays in VPS37A-overexpressing CRC cells and xenografts assessed proliferation,cell cycle progression,and stress-induced cell death.RNA sequencing,nuclear factor kappa-B(NF-κB)luciferase reporter assays,and lysosomal inhibition experiments elucidated the mechanisms underlying tumor necrosis factor receptor 1(TNFR1)degradation.Results:VPS37A is significantly downregulated in advanced-stage CRC and independently predicts poor survival.Functionally,VPS37A overexpression suppresses proliferation and induces G2/M arrest in vitro,while reducing xenograft growth.Under metabolic stress(glucose deprivation/galactose adaptation),VPS37A triggers cell death via apoptosis,necroptosis,and ferroptosis.Mechanistically,VPS37A redirects TNFR1 to lysosomal degradation,suppressing NF-κB nuclear translocation and transcriptional activity.Conclusion:VPS37A deficiency drives CRC progression by sustaining TNFR1/NF-κB signaling under metabolic stress.Restoring VPS37A activity promotes TNFR1 degradation,offering a therapeutic strategy to counteract NF-κB-mediated treatment resistance in CRC.
基金the National Natural Science Foundation of China(No.81400333).
文摘The role of B7-1 in podocyte injury has received increasing attention.The aim of this study was to investigate whether losartan protects podocytes of patients with diabetic kidney disease(DKD)by regulating B7-1 and the underlying mechanisms.Rats with streptozotocin-induced DKD were treated with losartan for 8 weeks.Biochemical changes in blood and urine were analyzed.Kidneys were isolated for electron microscopy,immunofluorescence,real-time quantitative PCR(RT-PCR),and Western blot analysis.Immortalized mouse podocyte cells were cultured in normal or high glucose medium in the presence or absence of losartan for 48 h,and then the cells were collected for immunofluorescence,PCR,Western blotting and monolayer permeability detection.The phosphatidylinositol 3-kinase(PI3K)110a subunit and angiotensin II type 1 receptor(AT1R)plasmids were transfected into podocytes,respectively,and then Western blotting was performed to assess the expression of B7-1 protein.The results showed that losartan ameliorated podocyte structure and function in the rat model of DKD,and reduced the expression of B7-1 protein.Overexpression of PI3K 110a subunit in podocytes attenuated the inhibitory effect of losartan on B7-1 expression in high glucose-stimulated podocytes.The expression of B7-1 was significantly increased by overexpression of ATI R and significantly reduced by blocking PI3K 110a subunit.We conclude that losartan protects podocytes against high glucose-induced injury by inhibiting AT1R-mediated B7-1 expression.This effect is dependent on the AT1R-PI3K 110a subunit pathway.
