目的通过研究维生素D受体(vitamin D receptor,VDR)和钙敏感受体(calciumsensingreceptor,CaSR)在继发性甲状旁腺功能亢进症(Secondary hyperparathyroidism,SHPT)患者甲状旁腺组织中的表达,探讨VDR和CaSR与SHPT甲状旁腺组织病理改变的...目的通过研究维生素D受体(vitamin D receptor,VDR)和钙敏感受体(calciumsensingreceptor,CaSR)在继发性甲状旁腺功能亢进症(Secondary hyperparathyroidism,SHPT)患者甲状旁腺组织中的表达,探讨VDR和CaSR与SHPT甲状旁腺组织病理改变的关系。方法用免疫组化的方法计数CaSR和VDR阳性细胞,比较其在不同程度SHPT中甲状旁腺组织及正常甲状旁腺组织的阳性表达。结果 VDR阳性细胞表达几乎存在于所有主细胞的细胞核,呈黄褐色,胞膜和胞浆不着色。SHPT组较对照组明显下调,分别为(39.0±19.7)%和(78.0±2.5)%,差异有统计学意义(P<0.01)。SHPT弥漫性增生组、结节性增生组和腺瘤样增生组表达分别为57.1%、(31.0±6.7)%和(23.0±2.1)%,差异有统计学意义(P<0.01)。CaSR阳性细胞表达主要定位于主细胞的胞膜和胞浆,呈黄褐色。SHPT组较对照组明显下调,分别为(48.0±17.9)%和(79.0±1.0)%,差异有统计学意义(P<0.01)。弥漫性增生组、结节性增生组和腺瘤样增生组的CaSR表达分别为51.0%、(47.0±9.8)%和(29.0±10.1)%,差异有统计学意义(P<0.01)。结论 VDR和CaSR表达均随甲状旁腺组织增生的程度增高而下调。VDR和CaSR的表达下调可能是活性维生素D治疗无效的病理基础。上调VDR和CaSR表达水平以及进一步激活受体功能是内科治疗SHPT的研究方向。展开更多
The extracellular calcium-sensing receptor(CaSR) is best known for its action in the parathyroid gland and kidneys where it controls body calcium homeostasis. However, the CaSR has different roles in the gastrointesti...The extracellular calcium-sensing receptor(CaSR) is best known for its action in the parathyroid gland and kidneys where it controls body calcium homeostasis. However, the CaSR has different roles in the gastrointestinal tract, where it is ubiquitously expressed. In the colon, the CaSR is involved in controlling multiple mechanisms, including fluid transport, inflammation, cell proliferation and differentiation. Although the expression pattern and functions of the CaSR in the colonic microenvironment are far from being completely understood, evidence has been accumulating that the Ca SR might play a protective role against both colonic inflammation and colorectal cancer. For example, CaSR agonists such as dipeptides have been suggested to reduce colonic inflammation, while dietary calcium was shown to reduce the risk of colorectal cancer. CaSR expression is lost in colonic malignancies, indicating that the CaSR is a biomarker for colonic cancer progression. This dual anti-inflammatory and anti-tumourigenic role of the CaSR makes it especially interesting in colitisassociated colorectal cancer. In this review, we describe the clinical and experimental evidence for the role of the CaSR in colonic inflammation and colorectal cancer, the intracellular signalling pathways which are putatively involved in these actions, and the possibilities to exploit these actions of the CaSR for future therapies of colonic inflammation and cancer.展开更多
Astrocytes＇ roles in late-onset Alzheimer＇s disease （LOAD） promotion are important, since they survive soluble or fibrillar amyloid-β peptides （Aβs） neurotoxic effects, undergo alterations of intracellular and...Astrocytes＇ roles in late-onset Alzheimer＇s disease （LOAD） promotion are important, since they survive soluble or fibrillar amyloid-β peptides （Aβs） neurotoxic effects, undergo alterations of intracellular and intercellular Ca2＋ signaling and gliotransmitters release via the Aβ/a7-nAChR （αT-nicotinic acetylcholine receptor） signaling, and overproduce/oversecrete newly synthesized Aβ42 oligomers, NO, and VEGF-A via the Aβ/CaSR （calcium-sensing receptor） signaling. Recently, it was suggested that the NMDAR （N-methyl-D-aspartate receptor） inhibitor nitromemantine would block the synapse-destroying effects of Aβ/α7-nAChR signaling. Yet, this and the progressive extracellular accrual and spreading of Aβ42 oligomers would be stopped well upstream by NPS 2143, an allosteric CaSR antagonist （calcilytic）.展开更多
Calcium-sensing receptor(CaSR),a family C G-protein-coupled receptor,plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca^(2+),Mg^(2+),amino acids(e.g.,L-Tr...Calcium-sensing receptor(CaSR),a family C G-protein-coupled receptor,plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca^(2+),Mg^(2+),amino acids(e.g.,L-Trp and L-Phe),small peptides,anions(e.g.,HCO_(3)^(-)and PO_(4)^(3-)),and pH.CaSR-mediated intracellular Ca^(2+)signaling regulates a diverse set of cellular processes including gene transcription,cell proliferation,differentiation,apoptosis,muscle contraction,and neuronal transmission.Dysfunction of CaSR with mutations results in diseases such as autosomal dominant hypocalcemia,familial hypocalciuric hypercalcemia,and neonatal severe hyperparathyroidism.CaSR also influences calciotropic disorders,such as osteoporosis,and noncalciotropic disorders,such as cancer,Alzheimer's disease,and pulmonary arterial hypertension.This study first reviews recent advances in biochemical and structural determination of the framework of CaSR and its interaction sites with natural ligands,as well as exogenous positive allosteric modulators and negative allosteric modulators.The establishment of the first CaSR protein-protein interactome network revealed 94 novel players involved in protein processing in endoplasmic reticulum,trafficking,cell surface expression,endocytosis,degradation,and signaling pathways.The roles of these proteins in Ca^(2+)-dependent cellular physiological processes and in CaSR-dependent cellular signaling provide new insights into the molecular basis of diseases caused by CaSR mutations and dysregulated CaSR activity caused by its protein interactors and facilitate the design of therapeutic agents that target CaSR and other family C G-protein-coupled receptors.展开更多
目的探讨钙敏感受体(CaR)参与心肌缺血/再灌注损伤诱发细胞凋亡的机制。方法Langendorff 离体灌流的方法复制心脏缺血/再灌注模型。观察缺血/再灌注和加入 CaR 激动剂时 CaR的表达情况。TUNEL 染色观察不同组别细胞凋亡,应用激光扫描共...目的探讨钙敏感受体(CaR)参与心肌缺血/再灌注损伤诱发细胞凋亡的机制。方法Langendorff 离体灌流的方法复制心脏缺血/再灌注模型。观察缺血/再灌注和加入 CaR 激动剂时 CaR的表达情况。TUNEL 染色观察不同组别细胞凋亡,应用激光扫描共聚焦显微镜观察大鼠心肌细胞的线粒体膜电位的变化。Western blot 检测心肌组织线粒体中细胞色素 C 及 Bcl-2的表达。结果心肌缺血/再灌注和加入 CaR 激动剂时 CaR 的表达明显高于对照组(P 均<0.01)。TUNEL 染色发现缺血/再灌注组和激动剂组细胞凋亡率明显增加(P 均<0.05),同时此两组的线粒体膜电位下降明显(P 均<0.05),线粒体细胞色素 C 与 Bcl-2的表达也明显下降(P 均<0.05)。结论 CaR 激活在缺血/再灌注时通过诱发线粒体损伤,促进细胞凋亡。展开更多
基金Supported by the European Union’s Horizon 2020 research and innovation programme,No.675228the Austrian Science Fund(FWF),No.P 29948-B28
文摘The extracellular calcium-sensing receptor(CaSR) is best known for its action in the parathyroid gland and kidneys where it controls body calcium homeostasis. However, the CaSR has different roles in the gastrointestinal tract, where it is ubiquitously expressed. In the colon, the CaSR is involved in controlling multiple mechanisms, including fluid transport, inflammation, cell proliferation and differentiation. Although the expression pattern and functions of the CaSR in the colonic microenvironment are far from being completely understood, evidence has been accumulating that the Ca SR might play a protective role against both colonic inflammation and colorectal cancer. For example, CaSR agonists such as dipeptides have been suggested to reduce colonic inflammation, while dietary calcium was shown to reduce the risk of colorectal cancer. CaSR expression is lost in colonic malignancies, indicating that the CaSR is a biomarker for colonic cancer progression. This dual anti-inflammatory and anti-tumourigenic role of the CaSR makes it especially interesting in colitisassociated colorectal cancer. In this review, we describe the clinical and experimental evidence for the role of the CaSR in colonic inflammation and colorectal cancer, the intracellular signalling pathways which are putatively involved in these actions, and the possibilities to exploit these actions of the CaSR for future therapies of colonic inflammation and cancer.
文摘Astrocytes＇ roles in late-onset Alzheimer＇s disease （LOAD） promotion are important, since they survive soluble or fibrillar amyloid-β peptides （Aβs） neurotoxic effects, undergo alterations of intracellular and intercellular Ca2＋ signaling and gliotransmitters release via the Aβ/a7-nAChR （αT-nicotinic acetylcholine receptor） signaling, and overproduce/oversecrete newly synthesized Aβ42 oligomers, NO, and VEGF-A via the Aβ/CaSR （calcium-sensing receptor） signaling. Recently, it was suggested that the NMDAR （N-methyl-D-aspartate receptor） inhibitor nitromemantine would block the synapse-destroying effects of Aβ/α7-nAChR signaling. Yet, this and the progressive extracellular accrual and spreading of Aβ42 oligomers would be stopped well upstream by NPS 2143, an allosteric CaSR antagonist （calcilytic）.
文摘Calcium-sensing receptor(CaSR),a family C G-protein-coupled receptor,plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca^(2+),Mg^(2+),amino acids(e.g.,L-Trp and L-Phe),small peptides,anions(e.g.,HCO_(3)^(-)and PO_(4)^(3-)),and pH.CaSR-mediated intracellular Ca^(2+)signaling regulates a diverse set of cellular processes including gene transcription,cell proliferation,differentiation,apoptosis,muscle contraction,and neuronal transmission.Dysfunction of CaSR with mutations results in diseases such as autosomal dominant hypocalcemia,familial hypocalciuric hypercalcemia,and neonatal severe hyperparathyroidism.CaSR also influences calciotropic disorders,such as osteoporosis,and noncalciotropic disorders,such as cancer,Alzheimer's disease,and pulmonary arterial hypertension.This study first reviews recent advances in biochemical and structural determination of the framework of CaSR and its interaction sites with natural ligands,as well as exogenous positive allosteric modulators and negative allosteric modulators.The establishment of the first CaSR protein-protein interactome network revealed 94 novel players involved in protein processing in endoplasmic reticulum,trafficking,cell surface expression,endocytosis,degradation,and signaling pathways.The roles of these proteins in Ca^(2+)-dependent cellular physiological processes and in CaSR-dependent cellular signaling provide new insights into the molecular basis of diseases caused by CaSR mutations and dysregulated CaSR activity caused by its protein interactors and facilitate the design of therapeutic agents that target CaSR and other family C G-protein-coupled receptors.
文摘目的探讨钙敏感受体(CaR)参与心肌缺血/再灌注损伤诱发细胞凋亡的机制。方法Langendorff 离体灌流的方法复制心脏缺血/再灌注模型。观察缺血/再灌注和加入 CaR 激动剂时 CaR的表达情况。TUNEL 染色观察不同组别细胞凋亡,应用激光扫描共聚焦显微镜观察大鼠心肌细胞的线粒体膜电位的变化。Western blot 检测心肌组织线粒体中细胞色素 C 及 Bcl-2的表达。结果心肌缺血/再灌注和加入 CaR 激动剂时 CaR 的表达明显高于对照组(P 均<0.01)。TUNEL 染色发现缺血/再灌注组和激动剂组细胞凋亡率明显增加(P 均<0.05),同时此两组的线粒体膜电位下降明显(P 均<0.05),线粒体细胞色素 C 与 Bcl-2的表达也明显下降(P 均<0.05)。结论 CaR 激活在缺血/再灌注时通过诱发线粒体损伤,促进细胞凋亡。
