Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Cu...Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.展开更多
Objective To analyze the relationship between Chemokine IP10 and its receptor CXCR3 during prion infection.Methods We investigated the increases in IP10 signals,primarily localized in neurons within the brains of scra...Objective To analyze the relationship between Chemokine IP10 and its receptor CXCR3 during prion infection.Methods We investigated the increases in IP10 signals,primarily localized in neurons within the brains of scrapie-infected mice,using western blotting,ELISA,co-immunoprecipitation,immunohistochemistry,immunofluorescence assays,and RT-PCR.Results Both CXCR3 levels and activation were significantly higher in the brains of scrapie-infected mice and prion-infected SMB-S15 cells.Enhanced CXCR3 expression was predominantly observed in neurons and activated microglia.Morphological colocalization of PrPC/PrPSc with IP10/CXCR3 was observed in scrapie-infected mouse brains using immunohistochemistry and immunofluorescence.immunohistochemistry(IHC)analysis of whole brain sections further revealed increased accumulation of IP10/CXCR3 specifically in brain regions with higher levels of PrPSc deposits.Co-immunoprecipitation and biomolecular interaction assays revealed the molecular interactions between PrP and IP10/CXCR3.Notably,a significantly larger amount of IP10 accumulated within prion-infected SMB-S15 cells than in the normal partner cell line,SMB-PS.Importantly,resveratrol treatment effectively suppressed prion replication in SMB-S15 cells,thereby restoring the accumulation and secretion pattern of cellular IP10 similar to that observed in SMB-PS cells.Conclusion Our data demonstrate that the activation of IP10/CXCR3 signaling in prion-infected brain tissues coincides with PrPSc deposition.Modulation of IP10/CXCR3 signaling in the brain represents a potential therapeutic target for mitigating the progression of prion diseases.展开更多
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well ...Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease.展开更多
BACKGROUND Melanocortin 3 and 5 receptors(i.e.,MC3R and MC5R)belong to the melanocortin family.However,data regarding their role in inflammatory bowel diseases(IBD)are currently unavailable.AIM This study aims to asce...BACKGROUND Melanocortin 3 and 5 receptors(i.e.,MC3R and MC5R)belong to the melanocortin family.However,data regarding their role in inflammatory bowel diseases(IBD)are currently unavailable.AIM This study aims to ascertain their expression profiles in the colonic mucosa of Crohn’s disease(CD)and ulcerative colitis(UC),aligning them with IBD disease endoscopic and histologic activity.METHODS Colonic mucosal biopsies from CD/UC patients were sampled,and immunohisto-chemical analyses were conducted to evaluate the expression of MC3R and MC5R.Colonic sampling was performed on both traits with endoscopic scores(Mayo endoscopic score and CD endoscopic index of severity)consistent with inflamed mucosa and not consistent with disease activity(i.e.,normal appearing mucosa).RESULTS In both CD and UC inflamed mucosa,MC3R(CD:+7.7 fold vs normal mucosa,P<0.01;UC:+12 fold vs normal mucosa,P<0.01)and MC5R(CD:+5.5 fold vs normal mucosa,P<0.01;UC:+8.1 fold vs normal mucosa,P<0.01)were significantly more expressed compared to normal mucosa.CONCLUSION MC3R and MC5R are expressed in the colon of IBD patients.Furthermore,expression may differ according to disease endoscopic activity,with a higher degree of expression in the traits affected by disease activity in both CD and UC,suggesting a potential use of these receptors in IBD pharmacology.展开更多
目的:克隆人CXCR3B基因,并构建含有该目的基因的真核表达载体,获得稳定表达人CXCR3B分子的基因转染细胞株L929-huCXCR3B。方法:采用PCR方法从pMD19-T/huCXCR3A质粒中扩增人CXCR3B基因,通过双酶切装入真核表达载体pIRES2-EGFP中;脂质体...目的:克隆人CXCR3B基因,并构建含有该目的基因的真核表达载体,获得稳定表达人CXCR3B分子的基因转染细胞株L929-huCXCR3B。方法:采用PCR方法从pMD19-T/huCXCR3A质粒中扩增人CXCR3B基因,通过双酶切装入真核表达载体pIRES2-EGFP中;脂质体法转染L929细胞,G418加压筛选阳性克隆;分别用RT-PCR方法与免疫荧光技术分析阳性克隆中人CXCR3B在mRNA和蛋白水平的表达。MTT分析基因转染细胞株L929-huCXCR3B在Mig(monokineinduced by IFN-γ,IFN-γ诱导的单核因子)作用下的增殖能力。结果:成功克隆了人CXCR3B基因并构建了真核表达载体pIRES2-EGFP/huCXCR3B,转染该载体后获得了稳定表达人CXCR3B的基因转染细胞株L929-huCXCR3B,膜表面CX-CR3B分子的阳性表达率为93%。该基因转染细胞与其配体Mig共培养24、48及72 h,抑制率分别为41.44%、44.01%和24.80%。结论:L929-huCXCR3B细胞株的建立为研究CXCR3B信号转导及制备相应的单克隆抗体(mAb)奠定了基础。展开更多
基金supported by the National Natural Science Foundation of China,No.82071254(to WZ).
文摘Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.
基金supported by SKLID Development Grants(2021SKLID504,2019SKLID401,2019SKLID603,and 2016SKLID603)the National Natural Science Foundation of China(81772197,81401670,and 81630062)。
文摘Objective To analyze the relationship between Chemokine IP10 and its receptor CXCR3 during prion infection.Methods We investigated the increases in IP10 signals,primarily localized in neurons within the brains of scrapie-infected mice,using western blotting,ELISA,co-immunoprecipitation,immunohistochemistry,immunofluorescence assays,and RT-PCR.Results Both CXCR3 levels and activation were significantly higher in the brains of scrapie-infected mice and prion-infected SMB-S15 cells.Enhanced CXCR3 expression was predominantly observed in neurons and activated microglia.Morphological colocalization of PrPC/PrPSc with IP10/CXCR3 was observed in scrapie-infected mouse brains using immunohistochemistry and immunofluorescence.immunohistochemistry(IHC)analysis of whole brain sections further revealed increased accumulation of IP10/CXCR3 specifically in brain regions with higher levels of PrPSc deposits.Co-immunoprecipitation and biomolecular interaction assays revealed the molecular interactions between PrP and IP10/CXCR3.Notably,a significantly larger amount of IP10 accumulated within prion-infected SMB-S15 cells than in the normal partner cell line,SMB-PS.Importantly,resveratrol treatment effectively suppressed prion replication in SMB-S15 cells,thereby restoring the accumulation and secretion pattern of cellular IP10 similar to that observed in SMB-PS cells.Conclusion Our data demonstrate that the activation of IP10/CXCR3 signaling in prion-infected brain tissues coincides with PrPSc deposition.Modulation of IP10/CXCR3 signaling in the brain represents a potential therapeutic target for mitigating the progression of prion diseases.
基金Supported by Fondo per gli Investimenti della Ricerca di Base(FIRB)(RBAP10MY35_002)by Ente Cassa di Risparmio di Firenzeby FiorGen ONLUS to Galli A
文摘Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease.
基金The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of University of Campania Luigi Vanvitelli(Protocol code 795 on December 23,2019).
文摘BACKGROUND Melanocortin 3 and 5 receptors(i.e.,MC3R and MC5R)belong to the melanocortin family.However,data regarding their role in inflammatory bowel diseases(IBD)are currently unavailable.AIM This study aims to ascertain their expression profiles in the colonic mucosa of Crohn’s disease(CD)and ulcerative colitis(UC),aligning them with IBD disease endoscopic and histologic activity.METHODS Colonic mucosal biopsies from CD/UC patients were sampled,and immunohisto-chemical analyses were conducted to evaluate the expression of MC3R and MC5R.Colonic sampling was performed on both traits with endoscopic scores(Mayo endoscopic score and CD endoscopic index of severity)consistent with inflamed mucosa and not consistent with disease activity(i.e.,normal appearing mucosa).RESULTS In both CD and UC inflamed mucosa,MC3R(CD:+7.7 fold vs normal mucosa,P<0.01;UC:+12 fold vs normal mucosa,P<0.01)and MC5R(CD:+5.5 fold vs normal mucosa,P<0.01;UC:+8.1 fold vs normal mucosa,P<0.01)were significantly more expressed compared to normal mucosa.CONCLUSION MC3R and MC5R are expressed in the colon of IBD patients.Furthermore,expression may differ according to disease endoscopic activity,with a higher degree of expression in the traits affected by disease activity in both CD and UC,suggesting a potential use of these receptors in IBD pharmacology.
文摘目的:克隆人CXCR3B基因,并构建含有该目的基因的真核表达载体,获得稳定表达人CXCR3B分子的基因转染细胞株L929-huCXCR3B。方法:采用PCR方法从pMD19-T/huCXCR3A质粒中扩增人CXCR3B基因,通过双酶切装入真核表达载体pIRES2-EGFP中;脂质体法转染L929细胞,G418加压筛选阳性克隆;分别用RT-PCR方法与免疫荧光技术分析阳性克隆中人CXCR3B在mRNA和蛋白水平的表达。MTT分析基因转染细胞株L929-huCXCR3B在Mig(monokineinduced by IFN-γ,IFN-γ诱导的单核因子)作用下的增殖能力。结果:成功克隆了人CXCR3B基因并构建了真核表达载体pIRES2-EGFP/huCXCR3B,转染该载体后获得了稳定表达人CXCR3B的基因转染细胞株L929-huCXCR3B,膜表面CX-CR3B分子的阳性表达率为93%。该基因转染细胞与其配体Mig共培养24、48及72 h,抑制率分别为41.44%、44.01%和24.80%。结论:L929-huCXCR3B细胞株的建立为研究CXCR3B信号转导及制备相应的单克隆抗体(mAb)奠定了基础。
