Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0...Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.展开更多
Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and ...Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and sigma-1 receptor(Sig-1R)-mediated mitochondrial apoptosis in human proximal tubule epithelial-originated kidney-2(HK-2)cells.However,the involvement of Sig-1R in OTA-induced nephrotoxicity,encompassing other forms of regulated cell death like ferroptosis,remains unexplored.In this research,cell viability,apoptotic rate,cholesterol levels,mitochondrial glutathione(mGSH)levels,reactive oxygen species(ROS)levels,and protein expressions in HK-2 cells treated with OTA and/or blarcamesine hydrochloride(Anavex 2-73)were evaluated.The results suggest that OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,subsequently promoting sterol regulatory element-binding protein 2,3-hydroxy-3-methylglutaryl-CoA reductase,GRAM domain-containing protein 1B,steroidogenic acute regulatory protein,mitochondrial,78 kDa glucose-regulated protein,CCAAT/enhancer-binding protein homologous protein,cyclophilin D,cleaved-caspase-3,B-cell lymphoma-2-associated X protein,and long-chain fatty acid-CoA ligase 4,inhibiting tumor necrosis factor receptor-associated protein 1,mitochondrial 2-oxoglutarate/malate carrier protein,B-cell lymphoma-2-like protein 1,and glutathione peroxidase 4,reducing mGSH levels,and increasing total cholesterol,mitochondrial cholesterol,and ROS levels.In conclusion,OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,thereby disrupting redox and cholesterol homeostasis in vitro.The regulation of cholesterol homeostasis by Sig-1R and its involvement in OTA-induced mitochondrial apoptosis and ferroptosis are reported here for the first time.展开更多
Background:Therapy in the latent period is favorable for retarding the process of epileptogenesis.Recently,we have discovered that the activated sigma-1 receptor(Sig-1R)attenuates the hippocampus pathological injury a...Background:Therapy in the latent period is favorable for retarding the process of epileptogenesis.Recently,we have discovered that the activated sigma-1 receptor(Sig-1R)attenuates the hippocampus pathological injury and memory impairment in the latent period of epileptogenesis.But the molecular mechanism needs further investigation.Methods:PRE-084 was utilized as a research tool to highly selectively activate Sig-1R in epileptic mice.After the treatment of PRE-084,the pro-inflammatory cytokines,neuropathological traits,and the level of mitochondrial translocator assembly and maintenance 41 homolog(TAMM41)in the hippocampus were examined.The mode in which the Sig-1R interacts with TAMM41 was explored.The role of TAMM41 in the protecting effect of PRE-084 was established.Results:PRE-084 inhibited the growth of pro-inflammatory cytokines,reduced the formation of gliosis,alleviated neuronal damage in the hippocampus,and attenu-ated memory impairment in the latent period of epileptogenesis.The protein level of TAMM41 decreased in the hippocampi of epileptic mice and increased in the PRE-084-treated mice.The Sig-1R bound with TAMM41 directly,maintaining the stability of TAMM41.Knockdown of TAMM41 reversed the protective effect of PRE-084,and overexpression of TAMM41 exhibited a similar protective action to that of PRE-084.Conclusion:We presented the concept of the“sigma-1 receptor–TAMM41 axis”and proposed that augmenting this axis can attenuate neuroinflammation and memory impairment in the process of epileptogenesis.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82204360(to HM)and 82270411(to GW)National Science and Technology Innovation 2030 Major Program,No.2021ZD0200900(to YL)。
文摘Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.
基金financially supported by the National Natural Science Foundation of China(3226058782060598)+4 种基金the Scientific Research Program of Guizhou Provincial Department of Education(QJJ[2023]019)the Science&Technology Program of Guizhou Province(QKHPTRC-CXTD[2022]014)the Excellent Youth Talents of Zunyi Medical University(17zy-006)the Innovation and Entrepreneurship Training Program for College Students of China(202210661140)the Innovation and Entrepreneurship Training Program for College Students of Zunyi Medical University(ZYDC2021110).
文摘Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and sigma-1 receptor(Sig-1R)-mediated mitochondrial apoptosis in human proximal tubule epithelial-originated kidney-2(HK-2)cells.However,the involvement of Sig-1R in OTA-induced nephrotoxicity,encompassing other forms of regulated cell death like ferroptosis,remains unexplored.In this research,cell viability,apoptotic rate,cholesterol levels,mitochondrial glutathione(mGSH)levels,reactive oxygen species(ROS)levels,and protein expressions in HK-2 cells treated with OTA and/or blarcamesine hydrochloride(Anavex 2-73)were evaluated.The results suggest that OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,subsequently promoting sterol regulatory element-binding protein 2,3-hydroxy-3-methylglutaryl-CoA reductase,GRAM domain-containing protein 1B,steroidogenic acute regulatory protein,mitochondrial,78 kDa glucose-regulated protein,CCAAT/enhancer-binding protein homologous protein,cyclophilin D,cleaved-caspase-3,B-cell lymphoma-2-associated X protein,and long-chain fatty acid-CoA ligase 4,inhibiting tumor necrosis factor receptor-associated protein 1,mitochondrial 2-oxoglutarate/malate carrier protein,B-cell lymphoma-2-like protein 1,and glutathione peroxidase 4,reducing mGSH levels,and increasing total cholesterol,mitochondrial cholesterol,and ROS levels.In conclusion,OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,thereby disrupting redox and cholesterol homeostasis in vitro.The regulation of cholesterol homeostasis by Sig-1R and its involvement in OTA-induced mitochondrial apoptosis and ferroptosis are reported here for the first time.
基金This project was supported by grants from the National Natural Science Foundation of China(Grant Nos.81872847 and 82173803)the Science and Technology Planning Project of Xuzhou(Grant No.KC22256)the Science and Technology Developing Fund of The Affiliated Hospital of Xuzhou Medical University(Grant No.2021ZA14)。
文摘Background:Therapy in the latent period is favorable for retarding the process of epileptogenesis.Recently,we have discovered that the activated sigma-1 receptor(Sig-1R)attenuates the hippocampus pathological injury and memory impairment in the latent period of epileptogenesis.But the molecular mechanism needs further investigation.Methods:PRE-084 was utilized as a research tool to highly selectively activate Sig-1R in epileptic mice.After the treatment of PRE-084,the pro-inflammatory cytokines,neuropathological traits,and the level of mitochondrial translocator assembly and maintenance 41 homolog(TAMM41)in the hippocampus were examined.The mode in which the Sig-1R interacts with TAMM41 was explored.The role of TAMM41 in the protecting effect of PRE-084 was established.Results:PRE-084 inhibited the growth of pro-inflammatory cytokines,reduced the formation of gliosis,alleviated neuronal damage in the hippocampus,and attenu-ated memory impairment in the latent period of epileptogenesis.The protein level of TAMM41 decreased in the hippocampi of epileptic mice and increased in the PRE-084-treated mice.The Sig-1R bound with TAMM41 directly,maintaining the stability of TAMM41.Knockdown of TAMM41 reversed the protective effect of PRE-084,and overexpression of TAMM41 exhibited a similar protective action to that of PRE-084.Conclusion:We presented the concept of the“sigma-1 receptor–TAMM41 axis”and proposed that augmenting this axis can attenuate neuroinflammation and memory impairment in the process of epileptogenesis.
