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https://www.readbyqxmd.com/read/28518143/calcium-sensing-receptor-protects-high-glucose-induced-energy-metabolism-disorder-via-blocking-gp78-ubiquitin-proteasome-pathway
#1
Yuehong Wang, Ping Gao, Can Wei, Hongzhu Li, Li Zhang, Yajun Zhao, Bo Wu, Ye Tian, Weihua Zhang, Lingyun Wu, Rui Wang, Changqing Xu
Diabetic cardiomyopathy (DCM) is a major complication and fatal cause of the patients with diabetes. The calcium sensing receptor (CaSR) is a G protein-coupled receptor, which is involved in maintaining calcium homeostasis, regulating cell proliferation and apoptosis, and so on. In our previous study, we found that CaSR expression, intracellular calcium levels and cardiac function were all significantly decreased in DCM rats; however, the exact mechanism are not clear yet. The present study revealed the protective role of CaSR in myocardial energy metabolism disorder induced by high glucose (HG) as well as the underlying mechanism...
May 18, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28515208/glucocorticoid-responsive-lymphocytic-parathyroiditis-and-hypocalciuric-hypercalcemia-due-to-autoantibodies-against-the-calcium-sensing-receptor-a-case-report-and-literature-review
#2
Li Song, Liping Liu, R Tyler Miller, Shirley X Yan, Nancy Jackson, Shelby A Holt, Naim M Maalouf
OBJECTIVE: Autoimmune lymphocytic parathyroiditis and acquired hypocalciuric hypercalcemia associated with autoantibodies against the calcium-sensing receptor (anti-CaSR) are rare and poorly understood conditions. Here, we describe a patient with acquired parathyroid hormone (PTH)-dependent hypercalcemia with associated hypocalciuria, found to have true lymphocytic parathyroiditis on histopathology, and circulating anti-CaSR antibodies in serum. DESIGN AND METHODS: A 64-year-old woman was referred to our clinic for persistent hypercalcemia after a subtotal parathyroidectomy...
July 2017: European Journal of Endocrinology
https://www.readbyqxmd.com/read/28508378/population-pharmacokinetic-and-pharmacodynamic-modeling-of-etelcalcetide-in-patients-with-chronic-kidney-disease-and-secondary-hyperparathyroidism-receiving-hemodialysis
#3
Ping Chen, Adimoolam Narayanan, Benjamin Wu, Per Olsson Gisleskog, John P Gibbs, Andrew T Chow, Murad Melhem
INTRODUCTION: Etelcalcetide is a novel calcimimetic that binds and activates calcium-sensing receptors (CaSRs) for the treatment of secondary hyperparathyroidism (SHPT). METHODS: To assess titrated dosing regimens, population pharmacokinetic (PK) and PK/pharmacodynamic (PKPD) modeling of etelcalcetide was performed using NONMEM 7.2. In this analysis, plasma etelcalcetide, serum parathyroid hormone (PTH) and calcium (Ca) concentration-time data were collected from five phase I, II, and III clinical trials following single or multiple intravenous doses of etelcalcetide ranging from 2...
May 15, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28506888/calcium-sensing-receptor-erk-signaling-promotes-odontoblastic-differentiation-of-human-dental-pulp-cells
#4
Hiroyuki Mizumachi, Shinichiro Yoshida, Atsushi Tomokiyo, Daigaku Hasegawa, Sayuri Hamano, Asuka Yuda, Hideki Sugii, Suguru Serita, Hiromi Mitarai, Katsuaki Koori, Naohisa Wada, Hidefumi Maeda
Activation of the G protein-coupled calcium-sensing receptor (CaSR) has crucial roles in skeletal development and bone turnover. Our recent study has identified a role for activated CaSR in the osteogenic differentiation of human periodontal ligament stem cells. Furthermore, odontoblasts residing inside the tooth pulp chamber play a central role in dentin formation. However, it remains unclear how CaSR activation affects the odontoblastic differentiation of human dental pulp cells (HDPCs). We have investigated the odontoblastic differentiation of HDPCs exposed to elevated levels of extracellular calcium (Ca) and strontium (Sr), and the contribution of CaSR and the L-type voltage-dependent calcium channel (L-VDCC) to this process...
May 12, 2017: Bone
https://www.readbyqxmd.com/read/28498361/rectal-cancer-in-a-patient-with-bartter-syndrome-a-case-report
#5
Shiki Fujino, Norikatsu Miyoshi, Masayuki Ohue, Mikio Mukai, Yoji Kukita, Taishi Hata, Chu Matsuda, Tsunekazu Mizushima, Yuichiro Doki, Masaki Mori
A woman with rectal cancer was scheduled for surgery. However, she also had hypokalemia, hyperreninemia, and hyperaldosteronism in the absence of any known predisposing factors or endocrine tumors. She was given intravenous potassium, and her blood abnormalities stabilized after tumor resection. Genetic analysis revealed mutations in several genes associated with Bartter syndrome (BS) and Gitelman syndrome, including SLC12A1, CLCNKB, CASR, SLC26A3, and SLC12A3. Prostaglandin E2 (PGE2) plays an important role in BS and worsens electrolyte abnormalities...
May 12, 2017: Genes
https://www.readbyqxmd.com/read/28473749/amyloid-%C3%AE-exposed-human-astrocytes-overproduce-phospho-tau-and-overrelease-it-within-exosomes-effects-suppressed-by-calcilytic-nps-2143-further-implications-for-alzheimer-s-therapy
#6
Anna Chiarini, Ubaldo Armato, Emanuela Gardenal, Li Gui, Ilaria Dal Prà
The two main drivers of Alzheimer's disease (AD), amyloid-β (Aβ) and hyperphosphorylated Tau (p-Tau) oligomers, cooperatively accelerate AD progression, but a hot debate is still ongoing about which of the two appears first. Here we present preliminary evidence showing that Tau and p-Tau are expressed by untransformed cortical adult human astrocytes in culture and that exposure of such cells to an Aβ42 proxy, Aβ25-35, which binds the calcium-sensing receptor (CaSR) and activates its signaling, significantly increases intracellular p-Tau levels, an effect CaSR antagonist (calcilytic) NPS 2143 wholly hinders...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28460682/role-of-the-calcium-sensing-receptor-casr-in-bovine-gametes-and-during-in%C3%A2-vitro-fertilization
#7
Beatriz Macías-García, Graça Lopes, Antonio Rocha, Lauro González-Fernández
Calcium Sensing Receptor (CaSR) is a G-protein coupled receptor which senses extracellular calcium and activates diverse intracellular pathways. The objective of our work was to demonstrate the presence of CaSR in bovine gametes and its possible role in fertilization and embryo development. The location of CaSR was demonstrated by immunofluorescence in bovine gametes; additionally bovine sperm were incubated with 5, 10 and 15 μM of the specific CaSR inhibitor NPS2143 in a Tyrode's Albumin Lactate Pyruvate medium (4 h)...
June 2017: Theriogenology
https://www.readbyqxmd.com/read/28455519/calcium-sensing-receptor-antagonist-nps-2143-restores-amyloid-precursor-protein-physiological-non-amyloidogenic-processing-in-a%C3%AE-exposed-adult-human-astrocytes
#8
Anna Chiarini, Ubaldo Armato, Daisong Liu, Ilaria Dal Prà
Physiological non-amyloidogenic processing (NAP) of amyloid precursor holoprotein (hAPP) by α-secretases (e.g., ADAM10) extracellularly sheds neurotrophic/neuroprotective soluble (s)APPα and precludes amyloid-β peptides (Aβs) production via β-secretase amyloidogenic processing (AP). Evidence exists that Aβs interact with calcium-sensing receptors (CaSRs) in human astrocytes and neurons, driving the overrelease of toxic Aβ42/Aβ42-os (oligomers), which is completely blocked by CaSR antagonist (calcilytic) NPS 2143...
April 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28454088/overexpression-of-a-functional-calcium-sensing-receptor-dramatically-increases-osteolytic-potential-of-mda-mb-231-cells-in-a-mouse-model-of-bone-metastasis-through-epiregulin-mediated-osteoprotegerin-downregulation
#9
Boudot Cédric, Hénaut Lucie, Thiem Ursula, Geraci Sandra, Galante Mariangela, Saldanha Paulo, Saidak Zuzana, Six Isabelle, Clézardin Philippe, Kamel Said, Mentaverri Romuald
INTRODUCTION AND AIMS: Osteolytic bone metastases are observed in advanced cases of breast cancer. In vitro data suggest that the activity of the calcium-sensing receptor (CaSR) expressed by metastatic cells could potentiate their osteolytic potential. This study aimed to demonstrate in vivo the involvement of the CaSR in breast cancer cells osteolytic potential and to identify potential targets linked to CaSR activity. METHODS AND RESULTS: MDA-MB-231 stably transfected with plasmids containing either a full-length wild-type CaSR (CaSR-WT), or a functionally inactive dominant negative mutant (CaSR-DN) or an empty vector (EV) were intratibially injected into Balb/c-Nude mice...
April 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28450119/role-of-the-calcium-sensing-receptor-in-cardiomyocyte-apoptosis-via-mitochondrial-dynamics-in-compensatory-hypertrophied-myocardium-of-spontaneously-hypertensive-rat
#10
Siting Hong, Xin Zhang, Xiaohui Zhang, Wenxiu Liu, Yu Fu, Yue Liu, Zhiyu Shi, Jinyu Chi, Meng Zhao, Xinhua Yin
Calcium sensing receptor (CaSR) mediates pathological cardiac hypertrophy. Mitochondria maintain their function through fission and fusion and disruption of mitochondrial dynamic is linked to various cardiac diseases. This study examined how inhibition of CaSR by the inhibitor Calhex231 affected the mitochondrial dynamics in a hypertensive model in rats. Spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) rats were used in this study. Cardiac function and blood pressure was evaluated at the end of the study...
April 24, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28444561/a-rare-variant-in-the-fhl1-gene-associated-with-x-linked-recessive-hypoparathyroidism
#11
Nir Pillar, Oren Pleniceanu, Mingyan Fang, Limor Ziv, Einat Lahav, Shay Botchan, Le Cheng, Benjamin Dekel, Noam Shomron
Isolated familial hypoparathyroidism is an extremely rare disorder, which to date has been linked to several loci including mutations in CASR, GCM2, and PTH, as well as a rare condition defined as X-linked recessive hypoparathyroidism, previously associated with a 1.5 Mb region on Xq26-q27. Here, we report a patient with hypocalcemia-induced seizures leading to the diagnosis of primary hypoparathyroidism. Mutations in CASR, GCM2, and PTH were ruled out, while whole exome sequencing of the family suggested FHL1, located on chromosome Xq26, as the most likely causative gene variant (FHL1, exon 4, c...
April 25, 2017: Human Genetics
https://www.readbyqxmd.com/read/28422826/idiopathic-hypoparathyroidism-with-extensive-intracranial-calcification-in-children-first-report-from-saudi-arabia
#12
Naglaa M Kamal, Hamed A Alghamdi, Abdulrahman A Halabi, Ayman A Bakkar, Ali Algarni, Abdullah Alharbi, Abdulla A Alharthi, Rawan A Alharbi, Laila M Sherief
RATIONALE: Pediatric idiopathic hypoparathyroidism with extensive intracranial calcifications outside the basal ganglia (BG) is extremely rare with less than 10 cases worldwide. PATIENT CONCERNS: An 11-year-old Saudi male child presented with tetany with otherwise normal neurological and other body system examination diagnoses severe hypocalcemia for differential diagnosis. INTERVENTIONS: Further investigations revealed hyperphosphatemia and undetectable serum intact parathyroid hormone...
April 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28419469/the-endoplasmic-reticulum-associated-protein-os-9-behaves-as-a-lectin-in-targeting-the-immature-calcium-sensing-receptor
#13
Bryan K Ward, Sarah L Rea, Aaron L Magno, Bernadette Pedersen, Suzanne J Brown, Shelby Mullin, Ajanthy Arulpragasam, Evan Ingley, Arthur D Conigrave, Thomas Ratajczak
The mechanisms responsible for the processing and quality control of the calcium-sensing receptor (CaSR) in the endoplasmic reticulum (ER) are largely unknown. In a yeast two-hybrid screen of the CaSR C-terminal tail (residues 865 -1078), we identified osteosarcoma-9 (OS-9) protein as a binding partner. OS-9 is an ER-resident lectin that targets misfolded glycoproteins to the ER-associated degradation (ERAD) pathway through recognition of specific N-glycans by its mannose-6-phosphate receptor homology (MRH) domain...
April 17, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28417952/investigating-the-molecular-mechanism-of-positive-and-negative-allosteric-modulators-in-the-calcium-sensing-receptor-dimer
#14
Stine Engesgaard Jacobsen, Ulrik Gether, Hans Bräuner-Osborne
Allosteric modulators that are targeting the calcium-sensing receptor (CaSR) hold great therapeutic potential, and elucidating the molecular basis for modulation would thus benefit the development of novel therapeutics. In the present study, we aimed at investigating the mechanism of allosteric modulation in CaSR by testing dimers carrying mutations in the allosteric site of one or both of the subunits. To ensure measurements on a well-defined dimer composition, we applied a trans-activation system in which only the specific heterodimer of two loss-of-function mutants responded to agonist...
April 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28368538/combined-deletion-of-the-vitamin-d-receptor-and-calcium-sensing-receptor-delays-wound-re-epithelialization
#15
Yuko Oda, Lizhi Hu, Thai Nguyen, Chak Fong, Chia-Ling Tu, Daniel D Bikle
When the skin is injured, keratinocytes proliferate, migrate, and differentiate to regenerate the epidermis. We recently showed that ablation of the vitamin D receptor (Vdr) in keratinocytes delays wound re-epithelialization in mice also fed a low calcium diet, implicating a cooperative role of Vdr and calcium signaling in this process. In this study we examined the role of vitamin D and calcium signaling in wound healing by deleting their receptors, Vdr and the calcium sensing receptor (Casr). Gene expression profiling of neonatal epidermis lacking both Vdr and Casr (DKO) specifically in keratinocytes revealed that DKO affects a number of pathways relevant to wound healing including Vdr, β-catenin and adherens junction signaling...
March 22, 2017: Endocrinology
https://www.readbyqxmd.com/read/28348014/hypoxia-induced-mitogenic-factor-acts-as-a-nonclassical-ligand-of-calcium-sensing-receptor-therapeutically-exploitable-for-intermittent-hypoxia-induced-pulmonary-hypertension
#16
Xianqin Zeng, Liping Zhu, Rui Xiao, Bingxun Liu, Mengxiang Sun, Fangbo Liu, Qiang Hao, Yankai Lu, Jiwei Zhang, Jiansha Li, Tao Wang, Xiang Wei, Qinghua Hu
Hypoxia-induced mitogenic factor (HIMF) is an inflammatory cytokine playing important role(s) in the development of hypoxic pulmonary hypertension. The molecular target mediating HIMF-stimulated downstream events remains unclear. The coimmunoprecipitation screen identified extracellular calcium-sensing receptor (CaSR) as the binding partner for HIMF in pulmonary artery smooth muscle cells. The yeast 2-hybrid assay then revealed the binding of HIMF to the intracellular, not the extracellular, domain of extracellular CaSR...
May 2017: Hypertension
https://www.readbyqxmd.com/read/28336831/-calcilytic-drugs-feature-and-future
#17
Itsuro Endo
Calcium-sensing receptor(CaSR)is highly expressed in parathyroid, kidney, bone, and small and large intestines to regulate Ca homeostasis. Calcilytics are allosteric antagonists of CaSR, and stimulate endogenous PTH release. Several calcilytics have been evaluated as anabolic therapies for postmenopausal osteoporosis but clinical development of all of them has been abandoned because the lacked clinical efficacy. Calcilytics might be repurposed for new indications like autosomal dominant hypocalcemia or other disorders...
2017: Clinical Calcium
https://www.readbyqxmd.com/read/28336830/-the-discovery-research-and-development-of-etelcalcetide-hydrochloride-the-world-1st-intravenous-calcimimetics
#18
Atsuto Inoue, Kazutsune Harada
Etelcalcetide hydrochloride is the first intravenous calcimimetics agent for secondary hyperparathyroidism (SHPT). Etelcalcetide hydrochloride is to be administered through dialysis circuit by physician or medical staff upon completion of dialysis and such administration is expected to reduce the burden of medication in patients. From the nonclinical study results, etelcalcetide functions as an allosteric activator of calcium-sensing receptor(CaSR). Etelcalcetide suppressed PTH secretion both in vitro and in vivo...
2017: Clinical Calcium
https://www.readbyqxmd.com/read/28336828/-disorders-caused-by-mutations-in-calcium-sensing-receptor-and-related-diseases
#19
Toshimi Michigami
Sensing of extracellular calcium(Ca2+)levels involves the Ca-sensing receptor(CaSR), its downstream signaling molecule Gα11, and the adaptor-related protein complex 2(AP2)that plays a role in clathrin-dependent endocytosis of CaSR. Inactivating mutations in CaSR cause familial hypocalciuric hypercalcemia type 1(FHH1)and neonatal severe hyperparathyroidism(NSHPT), while activating mutations lead to autosomal dominant hypocalcemia type 1(ADH1)and Bartter syndrome type Ⅴ. Recent studies have identified that inactivating mutations in Gα11 and σ-subunit of AP2(AP2σ)also cause FHH, and these conditions have been classified as FHH2 and FHH3, respectively...
2017: Clinical Calcium
https://www.readbyqxmd.com/read/28336826/-etiology-and-pathogenesis-of-primary-hyperparathyroidism
#20
Mika Yamauchi, Toshitsugu Sugimoto
Primary hyperparathyroidism(pHPT)is a frequent endocrine disease in which abnormal calcium(Ca)regulation leads to hypercalcemia. The most frequent cause of pHPT in more than 80% of patients is an adenoma, followed by hyperplasia in about 15%, and cancer in 1~5%. Although most cases of pHPT are sporadic, a few are familial(hereditary), and this is known as familial hyperparathyroidism(FHPT). Gene abnormalities that affect cyclin D1 signaling(CCND1, CDC73, CDKN1B), Wnt/β-catenin signaling(MEN1), and calcium-sensing receptor signaling(CaSR, GNA11, AP2S1)play a role in the etiology and pathogenesis of pHPT...
2017: Clinical Calcium
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