Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

G-protein-coupled receptors (GPCRs) are an important source of drug targets with diverse therapeutic applications. However, there are still more than one hundred orphan GPCRs, whose ligands and functions remain unidentified. The suprachiasmatic nucleus (SCN) is the central circadian clock of the brain, directing daily rhythms in activity-rest behavior and physiology. Malfunction of the circadian clock has been linked to a wide variety of diseases, including sleep-wake disorders, obesity, diabetes, cancer, and hypertension, making the circadian clock an intriguing target for drug development. The orphan receptor GPR176 is an SCN-enriched orphan GPCR that sets the pace of the circadian clock. GPR176 undergoes asparagine (N)-linked glycosylation, a post-translational modification required for its proper cell-surface expression. Although its ligand remains unknown, this orphan receptor shows agonist-independent basal activity. GPR176 couples to the unique G-protein subclass Gz (or Gx) and participates in reducing cAMP production during the night. The regulator of G-protein signaling 16 (RGS16) is equally important for the regulation of circadian cAMP synthesis in the SCN. Genome-wide association studies, employing questionnaire-based evaluations of individual chronotypes, revealed loci near clock genes and in the regions containing RGS16 and ALG10B, a gene encoding an enzyme involved in protein N-glycosylation. Therefore, increasing evidence suggests that N-glycosylation of GPR176 and its downstream G-protein signal regulation may be involved in pathways characterizing human chronotypes. This review argues for the potential impact of focusing on GPCR signaling in the SCN for the purpose of fine-tuning the entire body clock.
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PMID:Time-Restricted G-Protein Signaling Pathways via GPR176, Gz, and RGS16 Set the Pace of the Master Circadian Clock in the Suprachiasmatic Nucleus. 3270 14

: Although considerable success has been shown for antihypertensive medications, the resistant hypertension and hypertension-related organ damages are still the important clinical issues and pose as high health and economic pressure. Therefore, novel therapeutic techniques and antihypertensive drugs are needed to advance more effective therapy of hypertension and hypertension-related disease to ameliorate mortality and healthcare costs worldwide. In this review, we highlight the latest progress in supporting the therapeutic potential of Elabela (ELA), a recently discovered early endogenous ligand for G-protein-coupled receptor apelin peptide jejunum, apelin receptor. Systemic administration of ELA exerts vasodilatory, antihypertensive, cardioprotective, and renoprotective effects, whereas central application of ELA increases blood pressure and causes cardiovascular remodeling primarily secondary to the hypertension. In addition, ELA drives extravillous trophoblast differentiation and prevents the pathogenesis of preeclampsia (a gestational hypertensive syndrome) by promoting placental angiogenesis. These findings strongly suggest peripheral ELA's therapeutic potential in preventing and treating hypertension and hypertension-related diseases including cardiovascular disease, kidney disease, and preeclampsia. Since therapeutic use of ELA is mainly limited by its short half-life and parenteral administration, it may be a clinical application candidate for the therapy of hypertension and its complications when fused with a large inert chemicals (e.g. polyethylene glycol, termed polyethylene glycol-ELA-21) or other proteins (e.g. the Fc fragment of IgG and albumin, termed Fc-ELA-21 or albumin-ELA-21), and new delivery methods are encouraged to develop to improve the efficacy of ELA fragments on apelin peptide jejunum or alternative unknown receptors.
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PMID:The Elabela in hypertension, cardiovascular disease, renal disease, and preeclampsia: an update. 3274 Apr 7

Although new drug discoveries are revolutionizing cancer treatments, repurposing existing drugs would accelerate the timeline and lower the cost for bringing treatments to cancer patients. Our goal was to repurpose CPI211, a potent and selective antagonist of the thromboxane A2-prostanoid receptor (TPr), a G-protein-coupled receptor that regulates coagulation, blood pressure, and cardiovascular homeostasis. To identify potential new clinical indications for CPI211, we performed a phenome-wide association study (PheWAS) of the gene encoding TPr, TBXA2R, using robust deidentified health records and matched genomic data from more than 29,000 patients. Specifically, PheWAS was used to identify clinical manifestations correlating with a TBXA2R single-nucleotide polymorphism (rs200445019), which generates a T399A substitution within TPr that enhances TPr signaling. Previous studies have correlated 200445019 with chronic venous hypertension, which was recapitulated by this PheWAS analysis. Unexpectedly, PheWAS uncovered an rs200445019 correlation with cancer metastasis across several cancer types. When tested in several mouse models of metastasis, TPr inhibition using CPI211 potently blocked spontaneous metastasis from primary tumors, without affecting tumor cell proliferation, motility, or tumor growth. Further, metastasis following intravenous tumor cell delivery was blocked in mice treated with CPI211. Interestingly, TPr signaling in vascular endothelial cells induced VE-cadherin internalization, diminished endothelial barrier function, and enhanced transendothelial migration by tumor cells, phenotypes that were decreased by CPI211. These studies provide evidence that TPr signaling promotes cancer metastasis, supporting the study of TPr inhibitors as antimetastatic agents and highlighting the use of PheWAS as an approach to accelerate drug repurposing.
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PMID:Repurposing of a Thromboxane Receptor Inhibitor Based on a Novel Role in Metastasis Identified by Phenome-Wide Association Study. 3303 74


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