BACKGROUND:While theα7 nicotinic acetylcholine receptor(α7 nAChR)is implicated in sepsis-associated encephalopathy(SAE),its pathophysiological contributions require further investigation.METHODS:SAE was induced in m...BACKGROUND:While theα7 nicotinic acetylcholine receptor(α7 nAChR)is implicated in sepsis-associated encephalopathy(SAE),its pathophysiological contributions require further investigation.METHODS:SAE was induced in mice via cecal ligation and puncture(CLP),and microglia were treated with lipopolysaccharide(LPS).PHA-543613(anα7 nAChR agonist)was used to activateα7 nAChR.To study the role ofα7 nAChR in mitophagy and pyroptosis,caspase-1-deficient mice and PTEN-induced kinase 1(PINK1)small interfering RNA(siRNA)were used.Cognitive function,cerebral oxygen extraction ratio(CERO2),and brain tissue oxygen pressure(PbtO2)were measured.Blood-brain barrier(BBB)integrity was evaluated via Evan’s blue staining.Mitophagy,pyroptosis,and cytokine levels were analyzed via Western blotting and immunofl uorescence.RESULTS:CLP or LPS treatment signifi cantly down-regulatedα7 nAChR protein expression in microglia.The administration of PHA-543613 to activateα7 nAChR not only restored its expression post-sepsis,but also notably decreased BBB permeability and mitigated cognitive deficits.Bothα7 nAChR activation and caspase-1 knockout effectively suppressed microglial pyroptosis.The activation ofα7 nAChR also promoted mitophagy in microglia.This led to an amelioration of brain tissue hypoxia,as shown by elevated PbtO2 and reduced CERO2 levels.The suppression of microglial pyroptosis byα7 nAChR was counteracted when mitophagy was inhibited through the siRNA-mediated silencing of PINK1.CONCLUSION:The activation ofα7 nAChR reduces pyroptosis by enhancing microglial mitophagy,thereby mitigating SAE.展开更多
OBJECTIVE:to investigate the anti-arthritic effects of lappaconitine(LA)on adjuvant-induced arthritis in Sprague-Dawley rats and its possible involvement in the regulation of M1/M2 macrophage balance through the P2X7 ...OBJECTIVE:to investigate the anti-arthritic effects of lappaconitine(LA)on adjuvant-induced arthritis in Sprague-Dawley rats and its possible involvement in the regulation of M1/M2 macrophage balance through the P2X7 receptor(P2X7r).METHODS:Rats were immunized with complete Freund's adjuvant and then intraperitoneally administered LA(2,4,or 8 mg·kg^(-1)·d^(-1))or methotrexate(0.5 mg/kg per 3 d)for 14 d.The anti-arthritic effects of LA were evaluated through arthritis index(AI)assessment,ankle diameter measurement,and histopathological staining analysis.The analgesic effect of LA on arthritis was measured using mechanical withdrawal threshold testing and gait scoring.The impacts of LA on macrophage polarization,the expression of pro-/anti-inflammatory cytokines and P2X7r were analyzed using quantitative real-time polymerase chain reaction,enzyme-linked immunosorbent assay,and Western blotting.RESULTS:LA treatment significantly reduced AI scores,paw swelling,joint destruction,and inflammatory cell infiltration,and alleviated arthritis pain.Additionally,LA promoted a balanced M1/M2 ratio by increasing the m RNA expression level of M2 marker arginase 1 and decreasing those of M1 markers inducible nitric oxide synthase and interleukin(IL)-1βin synovial tissues.Furthermore,LA lowered the levels of three M1-related cytokines,namely tumor necrosis factor-α,IL-1βand IL-18,and raised the level of the M2-related cytokine IL-10.Further research showed that treatment with LA inhibited the expression of P2X7r.CONCLUSION:Our findings indicate that the notable therapeutic and analgesic effects of LA on AIA rats are exerted through balancing the M1/M2 ratio,probably via P2X7r.展开更多
A deficiency ofγδT cells has been described in Crohn's disease(CD).AIM To analyze the gene expression of interleukin 7(IL-7)and its receptors in the tissues of patients with CD.METHODS We studied the peripheral ...A deficiency ofγδT cells has been described in Crohn's disease(CD).AIM To analyze the gene expression of interleukin 7(IL-7)and its receptors in the tissues of patients with CD.METHODS We studied the peripheral blood of 80 patients with CD,comparing them with a group of 80 healthy subjects.The number and apoptosis ofαβandγδT cells in peripheral blood and the proportion ofαβandγδT cells in the intestinal tissues of patients with CD(n=25)were studied.The gene and protein expression of IL-7,IL-2 receptor subunitγ[cluster of differentiation 132(CD132)],receptorα(CD127),and caspase-3 in tissues was analyzed by quantitative PCR.Serum IL-7 levels were also analyzed.RESULTS In patients with CD,a decreased number ofγδT cells and an increase in the apoptosis of CD56+αβandγδT cells in peripheral blood was observed(P<0.0001 and P<0.01)respectively,and there was an inverse correlation among T subsets and their apoptosis.In addition,IL-7 gene expression and IL-7 protein in the tissues of these patients were increased.The titers of caspase-3 in tissues were low vs control group(P>0.01).The percentage of CD8+γδT cells decreased in tissues(P<0.01),and was directly related to IL-7 levels in peripheral blood.The expression of IL-2 receptor subunitγ(CD132)was greatly decreased in the tissues of patients with CD(P<0.05).CONCLUSION There may be a cause-effect relationship between the lower gene expression of the IL-2 receptor subunitγ(CD132)in tissues of patients with CD andγδT cells immunodeficiency.展开更多
BACKGROUND Diabetic cognitive dysfunction(DCD)is one of the chronic complications of diabetes,but its mechanism is currently unknown.Studies have shown that mitochondrial fission mediated by calcium overload is an imp...BACKGROUND Diabetic cognitive dysfunction(DCD)is one of the chronic complications of diabetes,but its mechanism is currently unknown.Studies have shown that mitochondrial fission mediated by calcium overload is an important mechanism of DCD.Blocking calcium overload and restoring calcium homeostasis are key steps in treatment.Transient receptor potential melastatin 7(TRPM7)is a novel player in causing calcium overload.Our previous studies have shown that genetic silencing of TRPM7 in type 1 diabetic rats leads to significant improvements in cognitive function,but the specific mechanism remains unclear.Troxerutin,extracted from the flowers of Sophora japonica,is one of the derivatives of rutin and has been shown to have neuroprotective effects.However,its association with TRPM7 remains unclear.AIM To use animal and cellular models,we investigated whether TRPM7 mediated mitochondrial fission by upregulation of calcineurin(CaN)/dynamin-related protein 1(Drp1)ser637 in DCD,and whether Troxerutin improved DCD by inhibiting TRPM7-mediated mitochondrial division.METHODS In this study,we used db/db mice and hippocampal neuronal cell lines(HT22)treated with high-concentration glucose as our study subjects.We evaluated cognitive function using Morris water maze,novel object recognition tasks,and Nesting tests.We observed mitochondrial morphology using transmission electron microscopy and measured mitochondrial energy metabolism indicators using a spectrophotometer.We also detected mRNA and protein expression of TRPM7,CaN,p-Drp1^(ser637),caspase-3,B-cell lymphoma 2 associated X protein,and B-cell lymphoma 2 using quantitative real-time polymerase chain reaction,western blotting,and immunofluorescence.RESULTS In the db/db diabetic mice with cognitive dysfunction,as well as in hippocampal neurons exposed to high-concentration glucose,TRPM7 and CaN expression were upregulated,phosphorylated Drp1^(ser637)expression was downregulated,and mitochondrial fission was increased.By modulating(inhibiting or overexpressing)TRPM7,it was further validated that TRPM7 activates the CaN/Drp1^(ser637)pathway,resulting in an increase in mitochondrial fission and neuronal cell apoptosis.Troxerutin downregulated TRPM7/CaN/Drp1^(ser637),reduced mitochondrial fission,and improved DCD.CONCLUSION TRPM7 promotes mitochondrial fission via the CaN/Drp1^(ser637)pathway.Troxerutin improves mitochondrial function and reduces neuronal damage by inhibiting this pathway,suggesting TRPM7 as a potential therapeutic target for DCD.展开更多
Crohn’s disease(CD)is a chronic inflammatory disorder characterized by dysregulated immune responses and significant disruption of intestinal immunity.A recent case-control study by Andreu-Ballester et al revealed de...Crohn’s disease(CD)is a chronic inflammatory disorder characterized by dysregulated immune responses and significant disruption of intestinal immunity.A recent case-control study by Andreu-Ballester et al revealed decreased expression of interleukin(IL)-2 receptor subunitγ(CD132)in CD tissues,a finding that has profound implications for understanding immune dysregulation in CD.CD132,an essential component of the IL-7/IL-2 signaling axis,is critical forγδT cell survival and function,which are pivotal for maintaining gut integrity and modulating inflammation.Here,we propose that reduced CD132 expression represents a key mechanism underlyingγδT cell deficiencies in CD,contributing to impaired immune surveillance and exacerbated inflammation.This hypothesis integrates emerging evidence from cytokine signaling and immunopathology in CD,offering new insights into its pathogenesis.These findings highlight the therapeutic potential of targeting the IL-7/IL-2 axis to restore immune homeostasis in CD,presenting a novel avenue for future research and intervention.展开更多
The P2X7 receptor mRNA and proteins in guinea-pig dorsal root ganglia （DRG） were studied by using RT-PCR and immunohistochemistry. The co-localization of P2X7 receptor with four cytochemical markers, the neurofilame...The P2X7 receptor mRNA and proteins in guinea-pig dorsal root ganglia （DRG） were studied by using RT-PCR and immunohistochemistry. The co-localization of P2X7 receptor with four cytochemical markers, the neurofilament protein NF200, S100, substance P and isolectin t34 （IB4） binding glyco-conjugates, were also examined. It was found that P2X7 receptor immunoreactivity （P2X7 R-IR） was present mostly in large-and medium-sized DRG neurons （62%±9% and 36%±6% respectively in all P2X7 R-IR neurons）. All the P2X7 R-IR neurons were also NF200 and S100 immunopositive. However, in a small number of NF200 or S100 immunopositive neurons no P2XTR-IR was detectable. All the IB4-positive or substance P-immunopositive neurons had no P2X7 R-IR. These results demonstrate that P2X7 receptors are expressed in a large subpopulation of DRG neurons and they may play a role in the transduction of specific peripheral sensory signals.展开更多
AIM To determine if activation of the ATP-gated P2X7 receptor channel induces phosphatidylserine(PS)exposure in erythrocytes from multiple dog breeds.METHODS Peripheral blood was collected from 25 dogs representing 13...AIM To determine if activation of the ATP-gated P2X7 receptor channel induces phosphatidylserine(PS)exposure in erythrocytes from multiple dog breeds.METHODS Peripheral blood was collected from 25 dogs representing 13 pedigrees and seven crossbreeds.ATP-induced PS exposure on canine erythrocytes in vitro was assessed using a flow cytometric Annexin V binding assay.RESULTS ATP induced PS exposure in erythrocytes from all dogs studied.ATP caused PS exposure in a concentrationdependent manner with an EC50 value of 395μmol/L.The non-P2X7 agonists,ADP or AMP,did not cause PS exposure.The P2X7 antagonist,AZ10606120,but not the P2X1 antagonist,NF449,blocked ATP-induced PS exposure.CONCLUSION The results indicate that ATP induces PS exposure in erythrocytes from various dog breeds and that this process is mediated by P2X7 activation.展开更多
目的从结直肠癌症患者血浆中分离微量来源于肿瘤细胞的游离DNA,检测甲基化EphA7作为肿瘤标志。方法提取血浆中微量游离DNA,并以亚硫酸氢钠修饰DNA。根据修饰后的DNA序列,设计EphA7甲基化特异性引物和探针,利用Real Time PCR仪扩增甲基化...目的从结直肠癌症患者血浆中分离微量来源于肿瘤细胞的游离DNA,检测甲基化EphA7作为肿瘤标志。方法提取血浆中微量游离DNA,并以亚硫酸氢钠修饰DNA。根据修饰后的DNA序列,设计EphA7甲基化特异性引物和探针,利用Real Time PCR仪扩增甲基化EphA7基因。结果从大肠癌患者血浆中检出微量甲基化EphA7基因。结论应用荧光标记TaqMan探针RealTime PCR可以检测出结直肠癌患者血浆中微量游离DNA中甲基化EphA7基因,血浆甲基化EphA7可能作为一种新的肿瘤标志物。展开更多
Chronic loss of sleep damages health and disturbs the quality of life.Long-lasting sleep deprivation(SD)as well as sleep abnormalities are substantial risk factors for major depressive disorder,although the underlying...Chronic loss of sleep damages health and disturbs the quality of life.Long-lasting sleep deprivation(SD)as well as sleep abnormalities are substantial risk factors for major depressive disorder,although the underlying mechanisms are not clear.Here,we showed that chronic SD in mice promotes a gradual elevation of extracellular ATP,which activates astroglial P2X7 receptors(P2X7Rs).Activated P2X7Rs,in turn,selectively down-regulated the expression of 5-HT2B receptors(5-HT2BRs)in astrocytes.Stimulation of P2X7Rs induced by SD selectively suppressed the phosphorylation of AKT and FoxO3 a in astrocytes,but not in neurons.The overexpression of FoxO3a in astrocytes inhibited the expression of 5-HT2BRs.Down-regulation of 5-HT2BsRs instigated by SD suppressed the activation of STAT3 and relieved the inhibition of Ca2+-dependent phospholipase A2.This latter cascade promoted the release of arachidonic acid and prostaglandin E2.The depression-like behaviors induced by SD were alleviated in P2X7R-KO mice.Our study reveals the mechanism underlying chronic SD-induced depression-like behaviors and suggests 5-HT2BRs as a key target for exploring therapeutic strategies aimed at the depression evoked by sleep disorders.展开更多
Cerebral ischemia is one of the most common diseases resulting in death and disability in aged people. It leads immediately to rapid energy failure, ATP depletion, and ionic imbalance, which increase extracellular ATP...Cerebral ischemia is one of the most common diseases resulting in death and disability in aged people. It leads immediately to rapid energy failure, ATP depletion, and ionic imbalance, which increase extracellular ATP levels and accordingly activate P2X7 receptors. These receptors are ATP-gated cation channels and widely distributed in nerve cells, especially in the immunocompetent cells of the brain. Currently, interest in the roles of P2Xz receptors in ischemic brain injury is growing. In this review, we discuss recent research progress on the actions of P2X7 receptors, their possible mechanisms in cerebral ischemia, and the potential therapeutic value of P2X7 receptor antagonists which may provide a new target both for clinical and for research purposes.展开更多
To date there is no treatment able to stop or slow down the loss of dopaminergic neurons that characterizes Parkinson’s disease.It was recently observed in a rodent model of Alzheimer’s disease that the interaction ...To date there is no treatment able to stop or slow down the loss of dopaminergic neurons that characterizes Parkinson’s disease.It was recently observed in a rodent model of Alzheimer’s disease that the interaction between the α7 subtype of nicotinic acetylcholine receptor(α7-nAChR)and sigma-1 receptor(σ1-R)could exert neuroprotective effects through the modulation of neuroinflammation which is one of the key components of the pathophysiology of Parkinson’s disease.In this context,the aim of the present study was to assess the effects of the concomitant administration of N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-furo[2,3-c]pyridine-5-carboxamide(PHA)543613 as an α7-nAChR agonist and 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate(PRE)-084 as aσ1-R agonist in a well-characterized 6-hydroxydopamine rat model of Parkinson’s disease.The animals received either vehicle separately or the dual therapy PHA/PRE once a day until day 14 postlesion.Although no effect was noticed in the amphetamine-induced rotation test,our data has shown that the PHA/PRE treatment induced partial protection of the dopaminergic neurons(15-20%),assessed by the dopamine transporter density in the striatum and immunoreactive tyrosine hydroxylase in the substantia nigra.Furthermore,this dual therapy reduced the degree of glial activation consecutive to the 6-hydroxydopamine lesion,i.e,the 18 kDa translocation protein density and glial fibrillary acidic protein staining in the striatum,and the CD11b and glial fibrillary acidic protein staining in the substantia nigra.Hence,this study reports for the first time that concomitant activation of α7-nAChR andσ1-R can provide a partial recovery of the nigro-striatal dopaminergic neurons through the modulation of microglial activation.The study was approved by the Regional Ethics Committee(CEEA Val de Loire n°19)validated this protocol(Authorization N°00434.02)on May 15,2014.展开更多
基金supported by grants from the Natural Science Foundation of Hunan Province(2022JJ70037 and 2022JJ40402)the National Natural Science Foundation of China(82472220 and 82002074)+1 种基金the Natural Science Foundation of Guangdong Province(2023A1515010267,2023A1515012665 and 2024A1515010073)the China International Medical Foundation Cerebrovascular Disease Youth Innovation Fund(Z-2016-20-2201).
文摘BACKGROUND:While theα7 nicotinic acetylcholine receptor(α7 nAChR)is implicated in sepsis-associated encephalopathy(SAE),its pathophysiological contributions require further investigation.METHODS:SAE was induced in mice via cecal ligation and puncture(CLP),and microglia were treated with lipopolysaccharide(LPS).PHA-543613(anα7 nAChR agonist)was used to activateα7 nAChR.To study the role ofα7 nAChR in mitophagy and pyroptosis,caspase-1-deficient mice and PTEN-induced kinase 1(PINK1)small interfering RNA(siRNA)were used.Cognitive function,cerebral oxygen extraction ratio(CERO2),and brain tissue oxygen pressure(PbtO2)were measured.Blood-brain barrier(BBB)integrity was evaluated via Evan’s blue staining.Mitophagy,pyroptosis,and cytokine levels were analyzed via Western blotting and immunofl uorescence.RESULTS:CLP or LPS treatment signifi cantly down-regulatedα7 nAChR protein expression in microglia.The administration of PHA-543613 to activateα7 nAChR not only restored its expression post-sepsis,but also notably decreased BBB permeability and mitigated cognitive deficits.Bothα7 nAChR activation and caspase-1 knockout effectively suppressed microglial pyroptosis.The activation ofα7 nAChR also promoted mitophagy in microglia.This led to an amelioration of brain tissue hypoxia,as shown by elevated PbtO2 and reduced CERO2 levels.The suppression of microglial pyroptosis byα7 nAChR was counteracted when mitophagy was inhibited through the siRNA-mediated silencing of PINK1.CONCLUSION:The activation ofα7 nAChR reduces pyroptosis by enhancing microglial mitophagy,thereby mitigating SAE.
文摘OBJECTIVE:to investigate the anti-arthritic effects of lappaconitine(LA)on adjuvant-induced arthritis in Sprague-Dawley rats and its possible involvement in the regulation of M1/M2 macrophage balance through the P2X7 receptor(P2X7r).METHODS:Rats were immunized with complete Freund's adjuvant and then intraperitoneally administered LA(2,4,or 8 mg·kg^(-1)·d^(-1))or methotrexate(0.5 mg/kg per 3 d)for 14 d.The anti-arthritic effects of LA were evaluated through arthritis index(AI)assessment,ankle diameter measurement,and histopathological staining analysis.The analgesic effect of LA on arthritis was measured using mechanical withdrawal threshold testing and gait scoring.The impacts of LA on macrophage polarization,the expression of pro-/anti-inflammatory cytokines and P2X7r were analyzed using quantitative real-time polymerase chain reaction,enzyme-linked immunosorbent assay,and Western blotting.RESULTS:LA treatment significantly reduced AI scores,paw swelling,joint destruction,and inflammatory cell infiltration,and alleviated arthritis pain.Additionally,LA promoted a balanced M1/M2 ratio by increasing the m RNA expression level of M2 marker arginase 1 and decreasing those of M1 markers inducible nitric oxide synthase and interleukin(IL)-1βin synovial tissues.Furthermore,LA lowered the levels of three M1-related cytokines,namely tumor necrosis factor-α,IL-1βand IL-18,and raised the level of the M2-related cytokine IL-10.Further research showed that treatment with LA inhibited the expression of P2X7r.CONCLUSION:Our findings indicate that the notable therapeutic and analgesic effects of LA on AIA rats are exerted through balancing the M1/M2 ratio,probably via P2X7r.
文摘A deficiency ofγδT cells has been described in Crohn's disease(CD).AIM To analyze the gene expression of interleukin 7(IL-7)and its receptors in the tissues of patients with CD.METHODS We studied the peripheral blood of 80 patients with CD,comparing them with a group of 80 healthy subjects.The number and apoptosis ofαβandγδT cells in peripheral blood and the proportion ofαβandγδT cells in the intestinal tissues of patients with CD(n=25)were studied.The gene and protein expression of IL-7,IL-2 receptor subunitγ[cluster of differentiation 132(CD132)],receptorα(CD127),and caspase-3 in tissues was analyzed by quantitative PCR.Serum IL-7 levels were also analyzed.RESULTS In patients with CD,a decreased number ofγδT cells and an increase in the apoptosis of CD56+αβandγδT cells in peripheral blood was observed(P<0.0001 and P<0.01)respectively,and there was an inverse correlation among T subsets and their apoptosis.In addition,IL-7 gene expression and IL-7 protein in the tissues of these patients were increased.The titers of caspase-3 in tissues were low vs control group(P>0.01).The percentage of CD8+γδT cells decreased in tissues(P<0.01),and was directly related to IL-7 levels in peripheral blood.The expression of IL-2 receptor subunitγ(CD132)was greatly decreased in the tissues of patients with CD(P<0.05).CONCLUSION There may be a cause-effect relationship between the lower gene expression of the IL-2 receptor subunitγ(CD132)in tissues of patients with CD andγδT cells immunodeficiency.
基金Supported by the Natural Science Foundation of Hebei Province,No.H2021206187 and No.H2021206452.
文摘BACKGROUND Diabetic cognitive dysfunction(DCD)is one of the chronic complications of diabetes,but its mechanism is currently unknown.Studies have shown that mitochondrial fission mediated by calcium overload is an important mechanism of DCD.Blocking calcium overload and restoring calcium homeostasis are key steps in treatment.Transient receptor potential melastatin 7(TRPM7)is a novel player in causing calcium overload.Our previous studies have shown that genetic silencing of TRPM7 in type 1 diabetic rats leads to significant improvements in cognitive function,but the specific mechanism remains unclear.Troxerutin,extracted from the flowers of Sophora japonica,is one of the derivatives of rutin and has been shown to have neuroprotective effects.However,its association with TRPM7 remains unclear.AIM To use animal and cellular models,we investigated whether TRPM7 mediated mitochondrial fission by upregulation of calcineurin(CaN)/dynamin-related protein 1(Drp1)ser637 in DCD,and whether Troxerutin improved DCD by inhibiting TRPM7-mediated mitochondrial division.METHODS In this study,we used db/db mice and hippocampal neuronal cell lines(HT22)treated with high-concentration glucose as our study subjects.We evaluated cognitive function using Morris water maze,novel object recognition tasks,and Nesting tests.We observed mitochondrial morphology using transmission electron microscopy and measured mitochondrial energy metabolism indicators using a spectrophotometer.We also detected mRNA and protein expression of TRPM7,CaN,p-Drp1^(ser637),caspase-3,B-cell lymphoma 2 associated X protein,and B-cell lymphoma 2 using quantitative real-time polymerase chain reaction,western blotting,and immunofluorescence.RESULTS In the db/db diabetic mice with cognitive dysfunction,as well as in hippocampal neurons exposed to high-concentration glucose,TRPM7 and CaN expression were upregulated,phosphorylated Drp1^(ser637)expression was downregulated,and mitochondrial fission was increased.By modulating(inhibiting or overexpressing)TRPM7,it was further validated that TRPM7 activates the CaN/Drp1^(ser637)pathway,resulting in an increase in mitochondrial fission and neuronal cell apoptosis.Troxerutin downregulated TRPM7/CaN/Drp1^(ser637),reduced mitochondrial fission,and improved DCD.CONCLUSION TRPM7 promotes mitochondrial fission via the CaN/Drp1^(ser637)pathway.Troxerutin improves mitochondrial function and reduces neuronal damage by inhibiting this pathway,suggesting TRPM7 as a potential therapeutic target for DCD.
文摘Crohn’s disease(CD)is a chronic inflammatory disorder characterized by dysregulated immune responses and significant disruption of intestinal immunity.A recent case-control study by Andreu-Ballester et al revealed decreased expression of interleukin(IL)-2 receptor subunitγ(CD132)in CD tissues,a finding that has profound implications for understanding immune dysregulation in CD.CD132,an essential component of the IL-7/IL-2 signaling axis,is critical forγδT cell survival and function,which are pivotal for maintaining gut integrity and modulating inflammation.Here,we propose that reduced CD132 expression represents a key mechanism underlyingγδT cell deficiencies in CD,contributing to impaired immune surveillance and exacerbated inflammation.This hypothesis integrates emerging evidence from cytokine signaling and immunopathology in CD,offering new insights into its pathogenesis.These findings highlight the therapeutic potential of targeting the IL-7/IL-2 axis to restore immune homeostasis in CD,presenting a novel avenue for future research and intervention.
文摘The P2X7 receptor mRNA and proteins in guinea-pig dorsal root ganglia （DRG） were studied by using RT-PCR and immunohistochemistry. The co-localization of P2X7 receptor with four cytochemical markers, the neurofilament protein NF200, S100, substance P and isolectin t34 （IB4） binding glyco-conjugates, were also examined. It was found that P2X7 receptor immunoreactivity （P2X7 R-IR） was present mostly in large-and medium-sized DRG neurons （62%±9% and 36%±6% respectively in all P2X7 R-IR neurons）. All the P2X7 R-IR neurons were also NF200 and S100 immunopositive. However, in a small number of NF200 or S100 immunopositive neurons no P2XTR-IR was detectable. All the IB4-positive or substance P-immunopositive neurons had no P2X7 R-IR. These results demonstrate that P2X7 receptors are expressed in a large subpopulation of DRG neurons and they may play a role in the transduction of specific peripheral sensory signals.
基金The Centre for Medical and Molecular Bioscience(University of Wollongong)the American Kennel Club Canine Health Foundation
文摘AIM To determine if activation of the ATP-gated P2X7 receptor channel induces phosphatidylserine(PS)exposure in erythrocytes from multiple dog breeds.METHODS Peripheral blood was collected from 25 dogs representing 13 pedigrees and seven crossbreeds.ATP-induced PS exposure on canine erythrocytes in vitro was assessed using a flow cytometric Annexin V binding assay.RESULTS ATP induced PS exposure in erythrocytes from all dogs studied.ATP caused PS exposure in a concentrationdependent manner with an EC50 value of 395μmol/L.The non-P2X7 agonists,ADP or AMP,did not cause PS exposure.The P2X7 antagonist,AZ10606120,but not the P2X1 antagonist,NF449,blocked ATP-induced PS exposure.CONCLUSION The results indicate that ATP induces PS exposure in erythrocytes from various dog breeds and that this process is mediated by P2X7 activation.
文摘目的从结直肠癌症患者血浆中分离微量来源于肿瘤细胞的游离DNA,检测甲基化EphA7作为肿瘤标志。方法提取血浆中微量游离DNA,并以亚硫酸氢钠修饰DNA。根据修饰后的DNA序列,设计EphA7甲基化特异性引物和探针,利用Real Time PCR仪扩增甲基化EphA7基因。结果从大肠癌患者血浆中检出微量甲基化EphA7基因。结论应用荧光标记TaqMan探针RealTime PCR可以检测出结直肠癌患者血浆中微量游离DNA中甲基化EphA7基因,血浆甲基化EphA7可能作为一种新的肿瘤标志物。
基金the National Natural Science Foundation of China(81871852,81200935,81671862,and 81871529)Liaoning Revitalization Talents Program(XLYC1807137)+1 种基金the Scientific Research Foundation for Overseas Scholars of the Education Ministry of China(20151098)the Natural Science Foundation of Liaoning Province,China(20170541030)。
文摘Chronic loss of sleep damages health and disturbs the quality of life.Long-lasting sleep deprivation(SD)as well as sleep abnormalities are substantial risk factors for major depressive disorder,although the underlying mechanisms are not clear.Here,we showed that chronic SD in mice promotes a gradual elevation of extracellular ATP,which activates astroglial P2X7 receptors(P2X7Rs).Activated P2X7Rs,in turn,selectively down-regulated the expression of 5-HT2B receptors(5-HT2BRs)in astrocytes.Stimulation of P2X7Rs induced by SD selectively suppressed the phosphorylation of AKT and FoxO3 a in astrocytes,but not in neurons.The overexpression of FoxO3a in astrocytes inhibited the expression of 5-HT2BRs.Down-regulation of 5-HT2BsRs instigated by SD suppressed the activation of STAT3 and relieved the inhibition of Ca2+-dependent phospholipase A2.This latter cascade promoted the release of arachidonic acid and prostaglandin E2.The depression-like behaviors induced by SD were alleviated in P2X7R-KO mice.Our study reveals the mechanism underlying chronic SD-induced depression-like behaviors and suggests 5-HT2BRs as a key target for exploring therapeutic strategies aimed at the depression evoked by sleep disorders.
基金supported by a grant from the Natural Science Foundation of Liaoning Province, China (201202050)
文摘Cerebral ischemia is one of the most common diseases resulting in death and disability in aged people. It leads immediately to rapid energy failure, ATP depletion, and ionic imbalance, which increase extracellular ATP levels and accordingly activate P2X7 receptors. These receptors are ATP-gated cation channels and widely distributed in nerve cells, especially in the immunocompetent cells of the brain. Currently, interest in the roles of P2Xz receptors in ischemic brain injury is growing. In this review, we discuss recent research progress on the actions of P2X7 receptors, their possible mechanisms in cerebral ischemia, and the potential therapeutic value of P2X7 receptor antagonists which may provide a new target both for clinical and for research purposes.
基金supported by Inserm(to SV,LFF,CT,JV,SB,SS,SC)by the Labex IRON(ANR-11-LABX-18-01:to all authors).
文摘To date there is no treatment able to stop or slow down the loss of dopaminergic neurons that characterizes Parkinson’s disease.It was recently observed in a rodent model of Alzheimer’s disease that the interaction between the α7 subtype of nicotinic acetylcholine receptor(α7-nAChR)and sigma-1 receptor(σ1-R)could exert neuroprotective effects through the modulation of neuroinflammation which is one of the key components of the pathophysiology of Parkinson’s disease.In this context,the aim of the present study was to assess the effects of the concomitant administration of N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-furo[2,3-c]pyridine-5-carboxamide(PHA)543613 as an α7-nAChR agonist and 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate(PRE)-084 as aσ1-R agonist in a well-characterized 6-hydroxydopamine rat model of Parkinson’s disease.The animals received either vehicle separately or the dual therapy PHA/PRE once a day until day 14 postlesion.Although no effect was noticed in the amphetamine-induced rotation test,our data has shown that the PHA/PRE treatment induced partial protection of the dopaminergic neurons(15-20%),assessed by the dopamine transporter density in the striatum and immunoreactive tyrosine hydroxylase in the substantia nigra.Furthermore,this dual therapy reduced the degree of glial activation consecutive to the 6-hydroxydopamine lesion,i.e,the 18 kDa translocation protein density and glial fibrillary acidic protein staining in the striatum,and the CD11b and glial fibrillary acidic protein staining in the substantia nigra.Hence,this study reports for the first time that concomitant activation of α7-nAChR andσ1-R can provide a partial recovery of the nigro-striatal dopaminergic neurons through the modulation of microglial activation.The study was approved by the Regional Ethics Committee(CEEA Val de Loire n°19)validated this protocol(Authorization N°00434.02)on May 15,2014.
