Objective: To imastigate the effects of anisodamine on pulmonary α1- adrenergic receptor andphospholipase A, in acute lung injurg. Methods: Change of α1--adrenergic receptor (al AR ) in lung tissllesduring endotoxin...Objective: To imastigate the effects of anisodamine on pulmonary α1- adrenergic receptor andphospholipase A, in acute lung injurg. Methods: Change of α1--adrenergic receptor (al AR ) in lung tissllesduring endotoxin--induced rat acute lung injury was measured with radioligand biding assay. The effects ofanisodamine on pulmonary α1--AR and phospholipase A2 (PLA2 ) were observed. Results: 1. 4 h after theendotoxin injection, there was a significant decrease in the maximal binding capacity of α1--AR by 34% ascompared with the control group. meanwhile elevated activity of PLA2 in rat lung and reduction of thephospholipids content of cell membrane was found. 2. Anisodamine could attenuate endotoxin--induced acutelung injury in rats. Conclusion: This effect might be related to anisodamine’s blockage of α1--AR andsuppression of PLA2, prevention of membranous phospholipids from degradation. and the reduction ofarachidonic acid release.展开更多
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
Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has b...Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.展开更多
Intracerebral hemorrhage(ICH)is a common severe emergency in neurosurgery,causing tremendous economic pressure on families and society and devastating effects on patients both physically and psychologically,especially...Intracerebral hemorrhage(ICH)is a common severe emergency in neurosurgery,causing tremendous economic pressure on families and society and devastating effects on patients both physically and psychologically,especially among patients with poor functional outcomes.ICH is often accompanied by decreased consciousness and limb dysfunction.This seriously affects patients’ability to live independently.Although rapid advances in neurosurgery have greatly improved patient survival,there remains insufficient evidence that surgical treatment significantly improves long-term outcomes.With in-depth pathophysiological studies after ICH,increasing evidence has shown that secondary injury after ICH is related to long-term prognosis and that the key to secondary injury is various immune-mediated neuroinflammatory reactions after ICH.In basic and clinical studies of various systemic inflammatory diseases,triggering receptor expressed on myeloid cells 1/2(TREM-1/2),and the TREM receptor family is closely related to the inflammatory response.Various inflammatory diseases can be upregulated and downregulated through receptor intervention.How the TREM receptor functions after ICH,the types of results from intervention,and whether the outcomes can improve secondary brain injury and the long-term prognosis of patients are unknown.An analysis of relevant research results from basic and clinical trials revealed that the inhibition of TREM-1 and the activation of TREM-2 can alleviate the neuroinflammatory immune response,significantly improve the long-term prognosis of neurological function in patients with cerebral hemorrhage,and thus improve the ability of patients to live independently.展开更多
BACKGROUND Transforming growth factor-β(TGF-β)superfamily plays an important role in tumor progression and metastasis.Activin A receptor type 1C(ACVR1C)is a TGF-βtype I receptor that is involved in tumorigenesis th...BACKGROUND Transforming growth factor-β(TGF-β)superfamily plays an important role in tumor progression and metastasis.Activin A receptor type 1C(ACVR1C)is a TGF-βtype I receptor that is involved in tumorigenesis through binding to dif-ferent ligands.AIM To evaluate the correlation between single nucleotide polymorphisms(SNPs)of ACVR1C and susceptibility to esophageal squamous cell carcinoma(ESCC)in Chinese Han population.METHODS In this hospital-based cohort study,1043 ESCC patients and 1143 healthy controls were enrolled.Five SNPs(rs4664229,rs4556933,rs77886248,rs77263459,rs6734630)of ACVR1C were assessed by the ligation detection reaction method.Hardy-Weinberg equilibrium test,genetic model analysis,stratified analysis,linkage disequi-librium test,and haplotype analysis were conducted.RESULTS Participants carrying ACVR1C rs4556933 GA mutant had significantly decreased risk of ESCC,and those with rs77886248 TA mutant were related with higher risk,especially in older male smokers.In the haplotype analysis,ACVR1C Trs4664229Ars4556933Trs77886248Crs77263459Ars6734630 increased risk of ESCC,while Trs4664229Grs4556933Trs77886248Crs77263459Ars6734630 was associated with lower susceptibility to ESCC.CONCLUSION ACVR1C rs4556933 and rs77886248 SNPs were associated with the susceptibility to ESCC,which could provide a potential target for early diagnosis and treatment of ESCC in Chinese Han population.展开更多
The macrophage-mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia.Therefore,macrophage-based therapeutic targets need to be explored for ischemic disease.In the current st...The macrophage-mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia.Therefore,macrophage-based therapeutic targets need to be explored for ischemic disease.In the current study,we found that the mRNA levels of scavenger receptor A1(Sr-a1)were elevated in patients with critical limb ischemia,based on an analysis of the Gene Expression Omnibus data.We then investigated the role and underlying mechanisms of macrophage SR-A1 in a mouse hindlimb ischemia(HLI)model.Compared with the Sr-a1^(fl/fl)mice,the Lyz^(Cre+)/Sr-a1^(flox/flox)(Sr-a1~(ΔMΦ))mice showed significantly reduced laser Doppler blood flow in the ischemic limb on day seven after HLI.Consistently,histological analysis revealed that the ischemic limb of the Sr-a1~(ΔMΦ)mice exhibited more severe and prolonged necrotic morphology,inflammation,fibrosis,decreased vessel density,and delayed regeneration than that of the control Sr-a1~(fl/fl)mice.Furthermore,restoring wild-type myeloid cells to the Sr-a1 knockout mice effectively improved the Doppler perfusion in the ischemic limb and mitigated skeletal muscle damage seven days after HLI.Consistent with these in vivo findings,co-cultivating macrophages with the mouse myoblast cell line C2C12 revealed that the Sr-a1^(-/-)bone marrow macrophages significantly inhibited myoblast differentiation in vitro.Mechanistically,SR-A1 enhanced the skeletal muscle regeneration in response to HLI by inhibiting oncostatin M production via suppression of the NF-κB signaling activation.These findings indicate that SR-A1 may be a promising candidate protein to improve tissue repair and regeneration in peripheral ischemic arterial disease.展开更多
Recent studies have shown that stress can substantially facilitate breast cancer metastasis,which can be reduced by nonselective β1/β2-adrenergic receptor(β1/β2-AR)blocker.However,several side effects were identif...Recent studies have shown that stress can substantially facilitate breast cancer metastasis,which can be reduced by nonselective β1/β2-adrenergic receptor(β1/β2-AR)blocker.However,several side effects were identified.Thus,it is extremely warranted to explore more effective and better-tolerated β2-AR blocker.Currently,we demonstrated that baicalin(BA),a major bioactive component of Scutellaria baicalensis Georgi,could significantly attenuate stress hormones especially epinephrine(Epi)-induced breast cancer cell migration and invasion in vitro.Mechanistically,we identified that β2-AR was a direct target of BA via the drug affinity responsive target stability(DARTS)combined with mass spectrum assay,and BA photoaffinity probe with pull-down assay,which was further confirmed by a couple of biophysical and biochemical assays.Furthermore,we demonstrated that BA could directly bind to the Phe193 and Phe-289 of β2-AR,subsequently inhibit cyclic adenosine monophosphate-protein kinase A-focal adhesion kinase(cAMP-PKA-FAK)pathway,and thus impede epithelial-mesenchymal transition(EMT),thereby hindering the metastatic progression of the chronic stress coupled with syngeneic and xenograft in vivo orthotopic and tail vein mouse model.These findings firstly identify BA as a potential b2-AR inhibitor in the treatment of stress-induced breast cancer metastasis.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
Objective: To scan single nucleotide polymorphism ( SNP ) in Chinese alpha-2Aadrenergic receptor (α_(2A)-AR) gene and study the effects of the SNP on the gene expression.Methods: The complete sequence of α_(2A)-AR g...Objective: To scan single nucleotide polymorphism ( SNP ) in Chinese alpha-2Aadrenergic receptor (α_(2A)-AR) gene and study the effects of the SNP on the gene expression.Methods: The complete sequence of α_(2A)-AR gene was analyzed with automated DNA sequencer to scanSNPs. Genomic DNA was extracted from whole blood and a 239 bp fragment containing the G/Cpolymorphism was amplified with PCR using a pair of. specific primers. PCR-RFLP was used to performthe genotyping of the SNP at the site-1 296 bp of the people in the North of China. Electrophoresismobility shift assay ( EMSA ) was used to study the binding of the 390 bp fragments (- 1 414-1 025bp) with G or C at the site-1 296 bp and nuclear extracts . Results: In our study, two SNPs werefound in α_(2A)-AR gene. Allele frequencies of the SNP at the site-1 296 bp were 0.61 and 0.39 forG and C , and the genotype frequencies were 0.34 , 0.54 and 0.13 for GG, GC and CC respectively fromthe people in the North of China. In the EMSA, a specific binding appeared in the complex ofnuclear extracts and DNA with C at-1 296 bp . Conclusion: Two SNPs exist in α_(2A)-AR gene from thepeople in the North of China , and DNA fragment with allele C of the SNP at the site-1 296 bp couldbind with a specific protein, which could influence the gene expression.展开更多
文摘Objective: To imastigate the effects of anisodamine on pulmonary α1- adrenergic receptor andphospholipase A, in acute lung injurg. Methods: Change of α1--adrenergic receptor (al AR ) in lung tissllesduring endotoxin--induced rat acute lung injury was measured with radioligand biding assay. The effects ofanisodamine on pulmonary α1--AR and phospholipase A2 (PLA2 ) were observed. Results: 1. 4 h after theendotoxin injection, there was a significant decrease in the maximal binding capacity of α1--AR by 34% ascompared with the control group. meanwhile elevated activity of PLA2 in rat lung and reduction of thephospholipids content of cell membrane was found. 2. Anisodamine could attenuate endotoxin--induced acutelung injury in rats. Conclusion: This effect might be related to anisodamine’s blockage of α1--AR andsuppression of PLA2, prevention of membranous phospholipids from degradation. and the reduction ofarachidonic acid release.
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.
文摘Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.
基金Supported by Shanxi Provincial Key Research and Development Plan Project,No.2020ZDLSF01-02Doctor Foundation of the Second Affiliated Hospital of Xi’an Medical University,No.X2Y-R11.
文摘Intracerebral hemorrhage(ICH)is a common severe emergency in neurosurgery,causing tremendous economic pressure on families and society and devastating effects on patients both physically and psychologically,especially among patients with poor functional outcomes.ICH is often accompanied by decreased consciousness and limb dysfunction.This seriously affects patients’ability to live independently.Although rapid advances in neurosurgery have greatly improved patient survival,there remains insufficient evidence that surgical treatment significantly improves long-term outcomes.With in-depth pathophysiological studies after ICH,increasing evidence has shown that secondary injury after ICH is related to long-term prognosis and that the key to secondary injury is various immune-mediated neuroinflammatory reactions after ICH.In basic and clinical studies of various systemic inflammatory diseases,triggering receptor expressed on myeloid cells 1/2(TREM-1/2),and the TREM receptor family is closely related to the inflammatory response.Various inflammatory diseases can be upregulated and downregulated through receptor intervention.How the TREM receptor functions after ICH,the types of results from intervention,and whether the outcomes can improve secondary brain injury and the long-term prognosis of patients are unknown.An analysis of relevant research results from basic and clinical trials revealed that the inhibition of TREM-1 and the activation of TREM-2 can alleviate the neuroinflammatory immune response,significantly improve the long-term prognosis of neurological function in patients with cerebral hemorrhage,and thus improve the ability of patients to live independently.
基金Supported by The National Natural Science Foundation of China,No.82350127 and No.82241013the Shanghai Natural Science Foundation,No.20ZR1411600+2 种基金the Shanghai Shenkang Hospital Development Center,No.SHDC2020CR4039the Bethune Ethicon Excellent Surgery Foundation,No.CESS2021TC04Xuhui District Medical Research Project of Shanghai,No.SHXH201805.
文摘BACKGROUND Transforming growth factor-β(TGF-β)superfamily plays an important role in tumor progression and metastasis.Activin A receptor type 1C(ACVR1C)is a TGF-βtype I receptor that is involved in tumorigenesis through binding to dif-ferent ligands.AIM To evaluate the correlation between single nucleotide polymorphisms(SNPs)of ACVR1C and susceptibility to esophageal squamous cell carcinoma(ESCC)in Chinese Han population.METHODS In this hospital-based cohort study,1043 ESCC patients and 1143 healthy controls were enrolled.Five SNPs(rs4664229,rs4556933,rs77886248,rs77263459,rs6734630)of ACVR1C were assessed by the ligation detection reaction method.Hardy-Weinberg equilibrium test,genetic model analysis,stratified analysis,linkage disequi-librium test,and haplotype analysis were conducted.RESULTS Participants carrying ACVR1C rs4556933 GA mutant had significantly decreased risk of ESCC,and those with rs77886248 TA mutant were related with higher risk,especially in older male smokers.In the haplotype analysis,ACVR1C Trs4664229Ars4556933Trs77886248Crs77263459Ars6734630 increased risk of ESCC,while Trs4664229Grs4556933Trs77886248Crs77263459Ars6734630 was associated with lower susceptibility to ESCC.CONCLUSION ACVR1C rs4556933 and rs77886248 SNPs were associated with the susceptibility to ESCC,which could provide a potential target for early diagnosis and treatment of ESCC in Chinese Han population.
基金supported by the National Natural Science Foundation of China(Grant Nos.82030012,81670263,82170444,82270476,82270361,and 82100433)the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(Grant No.24KJA310003)。
文摘The macrophage-mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia.Therefore,macrophage-based therapeutic targets need to be explored for ischemic disease.In the current study,we found that the mRNA levels of scavenger receptor A1(Sr-a1)were elevated in patients with critical limb ischemia,based on an analysis of the Gene Expression Omnibus data.We then investigated the role and underlying mechanisms of macrophage SR-A1 in a mouse hindlimb ischemia(HLI)model.Compared with the Sr-a1^(fl/fl)mice,the Lyz^(Cre+)/Sr-a1^(flox/flox)(Sr-a1~(ΔMΦ))mice showed significantly reduced laser Doppler blood flow in the ischemic limb on day seven after HLI.Consistently,histological analysis revealed that the ischemic limb of the Sr-a1~(ΔMΦ)mice exhibited more severe and prolonged necrotic morphology,inflammation,fibrosis,decreased vessel density,and delayed regeneration than that of the control Sr-a1~(fl/fl)mice.Furthermore,restoring wild-type myeloid cells to the Sr-a1 knockout mice effectively improved the Doppler perfusion in the ischemic limb and mitigated skeletal muscle damage seven days after HLI.Consistent with these in vivo findings,co-cultivating macrophages with the mouse myoblast cell line C2C12 revealed that the Sr-a1^(-/-)bone marrow macrophages significantly inhibited myoblast differentiation in vitro.Mechanistically,SR-A1 enhanced the skeletal muscle regeneration in response to HLI by inhibiting oncostatin M production via suppression of the NF-κB signaling activation.These findings indicate that SR-A1 may be a promising candidate protein to improve tissue repair and regeneration in peripheral ischemic arterial disease.
基金supported by the Matching Grant of National Natural Science Foundation of China from Nanjing University of Chinese Medicine(Grant Nos.:NZY81903857,and NZY81703765)the National Natural Science Foundation of China(Grant No.:21877062)+1 种基金the Opening Project of Chinese Materia Medica FirstClass Discipline of Nanjing University of Chinese Medicine(Grant No.:2020YLXK020)Postgraduate Research&Practice Innovation Program of Jiangsu Province(Grant Nos.:SJCX21_0707,KYCX21_1772,and KYCX22_2039).
文摘Recent studies have shown that stress can substantially facilitate breast cancer metastasis,which can be reduced by nonselective β1/β2-adrenergic receptor(β1/β2-AR)blocker.However,several side effects were identified.Thus,it is extremely warranted to explore more effective and better-tolerated β2-AR blocker.Currently,we demonstrated that baicalin(BA),a major bioactive component of Scutellaria baicalensis Georgi,could significantly attenuate stress hormones especially epinephrine(Epi)-induced breast cancer cell migration and invasion in vitro.Mechanistically,we identified that β2-AR was a direct target of BA via the drug affinity responsive target stability(DARTS)combined with mass spectrum assay,and BA photoaffinity probe with pull-down assay,which was further confirmed by a couple of biophysical and biochemical assays.Furthermore,we demonstrated that BA could directly bind to the Phe193 and Phe-289 of β2-AR,subsequently inhibit cyclic adenosine monophosphate-protein kinase A-focal adhesion kinase(cAMP-PKA-FAK)pathway,and thus impede epithelial-mesenchymal transition(EMT),thereby hindering the metastatic progression of the chronic stress coupled with syngeneic and xenograft in vivo orthotopic and tail vein mouse model.These findings firstly identify BA as a potential b2-AR inhibitor in the treatment of stress-induced breast cancer metastasis.
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.
文摘Objective: To scan single nucleotide polymorphism ( SNP ) in Chinese alpha-2Aadrenergic receptor (α_(2A)-AR) gene and study the effects of the SNP on the gene expression.Methods: The complete sequence of α_(2A)-AR gene was analyzed with automated DNA sequencer to scanSNPs. Genomic DNA was extracted from whole blood and a 239 bp fragment containing the G/Cpolymorphism was amplified with PCR using a pair of. specific primers. PCR-RFLP was used to performthe genotyping of the SNP at the site-1 296 bp of the people in the North of China. Electrophoresismobility shift assay ( EMSA ) was used to study the binding of the 390 bp fragments (- 1 414-1 025bp) with G or C at the site-1 296 bp and nuclear extracts . Results: In our study, two SNPs werefound in α_(2A)-AR gene. Allele frequencies of the SNP at the site-1 296 bp were 0.61 and 0.39 forG and C , and the genotype frequencies were 0.34 , 0.54 and 0.13 for GG, GC and CC respectively fromthe people in the North of China. In the EMSA, a specific binding appeared in the complex ofnuclear extracts and DNA with C at-1 296 bp . Conclusion: Two SNPs exist in α_(2A)-AR gene from thepeople in the North of China , and DNA fragment with allele C of the SNP at the site-1 296 bp couldbind with a specific protein, which could influence the gene expression.
