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Christopher J Berg, Jonathan D Kaunitz
The ability of humans to sense chemical signals in ingested substances is implicit in the ability to detect the five basic tastes; sweet, sour, bitter, salty, and umami. Of these, sweet, bitter, and umami tastes are detected by lingual G-protein-coupled receptors (GPCRs). Recently, these receptors were also localized to the gut mucosa. In this review, we will emphasize recent advances in the understanding of the mechanisms and consequences of foregut luminal chemosensing, with special emphasis on cell surface GPCRs such as the sweet and proteinaceous taste receptors (TASRs), short- and long-chain fatty acid (FA) receptors, and bile acid receptors...
2016: F1000Research
István Kenessey, Krisztina Kói, Orsolya Horváth, Mihály Cserepes, Dávid Molnár, Vera Izsák, Judit Dobos, Balázs HegedÅ S, József Tóvári, József Tímár
BACKGROUND: In non-small cell lung cancer (NSCLC) KRAS-mutant status is a negative prognostic and predictive factor. Nitrogen-containing bisphosphonates inhibit prenylation of small G-proteins (e.g. Ras, Rac, Rho) and thus may affect proliferation and migration. In our preclinical work, we investigated the effect of an aminobisphosphonate compound (zoledronic acid) on mutant and wild type KRAS-expressing human NSCLC cell lines. RESULTS: We confirmed that zoledronic acid was unable to inhibit the prenylation of mutant K-Ras unlike in the case of wild type K-Ras...
October 21, 2016: Oncotarget
Benjamin T Wall, Nicholas A Burd, Rinske Franssen, Stefan Hm Gorissen, Tim Snijders, Joan M Senden, Annemie P Gijsen, Luc J C van Loon
: Protein ingestion before sleep augments post-exercise muscle protein synthesis during overnight recovery. PURPOSE: It is unknown whether post-exercise and pre-sleep protein consumption modulates post-prandial protein handling and myofibrillar protein synthetic responses the following morning. Sixteen healthy young (24±1 y) men performed unilateral resistance-type exercise (contralateral leg acting as a resting control) at 20:00 h. Participants ingested 20 g protein immediately after exercise plus 60 g protein pre-sleep (PRO group; n=8) or equivalent boluses of carbohydrate (CON; n=8)...
October 25, 2016: American Journal of Physiology. Endocrinology and Metabolism
Federica Ferrari, Maria Camilla Cerlesi, Davide Malfacini, Laila Asth, Elaine C Gavioli, Velvet B Journigan, Uma G Kamakolanu, Michael E Meyer, Dennis Yasuda, Willma E Polgar, Anna Rizzi, Remo Guerrini, Chiara Ruzza, Nurulain T Zaveri, Girolamo Calo
Nociceptin/Orphanin FQ (N/OFQ) regulates several biological functions via selective activation of the N/OFQ receptor (NOP). In this study novel nonpeptide NOP ligands were characterized in vitro in receptor binding and [(35)S]GTPγS stimulated binding in membranes of cells expressing human NOP and classical opioid receptors, calcium mobilization assay in cells coexpressing the receptors and chimeric G proteins, bioluminescence resonance energy transfer (BRET) based assay for studying NOP receptor interaction with G protein and arrestin, the electrically stimulated mouse vas deferens and the mouse colon bioassays...
October 22, 2016: European Journal of Pharmacology
Robert I Menzies, Frederick W Tam, Robert J Unwin, Matthew A Bailey
Nucleotides are key subunits for nucleic acids and provide energy for intracellular metabolism. They can also be released from cells to act physiologically as extracellular messengers or pathologically as danger signals. Extracellular nucleotides stimulate membrane receptors in the P2 and P1 family. P2X are ATP-activated cation channels; P2Y and P1 are G-protein coupled receptors activated by ATP, ADP, UTP, and UDP in the case of P2 or adenosine for P1. Renal P2 receptors influence both vascular contractility and tubular function...
October 22, 2016: Kidney International
Joel T Cramer, Alfonso J Cruz-Jentoft, Francesco Landi, Mary Hickson, Mauro Zamboni, Suzette L Pereira, Deborah S Hustead, Vikkie A Mustad
BACKGROUND: Recent evidence suggests that nutritional interventions may improve muscle outcomes in malnutrition and sarcopenia. OBJECTIVES: We evaluated the effects of 2 high-quality oral nutritional supplements (ONS) differing in amount and type of key nutrients in older adult men and women. DESIGN: A multicenter, randomized, double-blinded, controlled clinical trial. PARTICIPANTS: Malnourished and sarcopenic men and women, 65 years and older (n = 330)...
November 1, 2016: Journal of the American Medical Directors Association
R Dorajoo, R T-H Ong, X Sim, L Wang, W Liu, E S Tai, J Liu, S-M Saw
INTRODUCTION: Recent genome-wide association studies have identified 103 adult obesity risk loci; however, it is unclear if these findings are relevant to East-Asian childhood body mass index (BMI) levels. METHODS AND RESULTS: We evaluated for paediatric obesity associations at these risk loci utilizing genome-wide data from Chinese childhood subjects in the Singapore Cohort study Of the Risk factors for Myopia study (N = 1006). A weighted gene-risk score of all adult obesity risk loci in the Singapore Cohort study Of the Risk factors for Myopia study showed strong associations with BMI at age 9 (p-value = 3...
October 25, 2016: Pediatric Obesity
I Lengyel, F Toth, D Biyashev, I Szatmari, K Monory, C Tomboly, G Toth, S Benyhe, A Borsodi
Endomorphins are natural amidated opioid tetrapeptides with the following structure: Tyr-Pro-Trp-Phe-NH2 (endomorphin-1), and Tyr-Pro-Phe-Phe-NH2 (endomorphin-2). Endomorphins interact selectively with the μ-opioid or MOP receptors and exhibit nanomolar or sub-nanomolar receptor binding affinities, therefore they suggested to be endogenous agonists for the μ-opioid receptors. Endomorphins mediate a number of characteristic opioid effects, such as antinociception, however there are several physiological functions in which endomorphins appear to act in a fashion that does not involve binding to and activation of the μ-opioid receptor...
August 2016: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
Annelies Cannaert, Jolien Storme, Florian Franz, Volker Auwärter, Christophe P Stove
Synthetic cannabinoids (SCs) are the largest group of compounds currently monitored in Europe by the EU Early Warning System on new psychoactive substances. Emerging recreational use of these products has led to multiple cases of adverse health effects and even death. In contrast to marijuana, where Δ9-tetrahydrocannabinol (Δ9THC) is metabolized to only one major active metabolite, it has been reported that several major phase I metabolites of SCs remain biologically active, exerting cannabinoid (CB) receptor affinity, potency and efficacy greater than Δ9THC...
October 25, 2016: Analytical Chemistry
Kanishka Senarath, Kasun Ratnayake, Praneeth Siripurapu, John L Payton, Ajith Karunarathne
Current assays to measure the activation of G protein coupled receptors (GPCRs) and G proteins are time consuming, indirect and expensive. Therefore, an efficient method which directly measures the ability of a ligand to govern GPCR-G protein interactions can help understand the molecular underpinnings of the associated signaling. A live cell imaging based approach is presented here to directly measure ligand-induced GPCR and G protein activity in real time. The number of active GPCRs governs G protein heterotrimer (αβγ) dissociation, thereby controlling the concentration of free βγ subunits...
October 25, 2016: Analytical Chemistry
Sebastian Schneider, Davide Provasi, Marta Filizola
Substantial attention has recently been devoted to G protein-biased agonism of the µ-opioid receptor (MOR) as an ideal new mechanism for the design of analgesics devoid of serious side effects. However, designing opioids with appropriate efficacy and bias is challenging because it requires an understanding of the ligand binding process and of the allosteric modulation of the receptor. Here, we investigated these phenomena for TRV-130, a G protein-biased MOR small-molecule agonist that has been shown to exert analgesia with less respiratory depression and constipation than morphine, and that it is currently being evaluated in human clinical trials for acute pain management...
October 25, 2016: Biochemistry
Leonid E Fridlyand, Natalia A Tamarina, Andrew V Schally, Louis H Philipson
Growth hormone-releasing hormone (GHRH) is produced by the hypothalamus and stimulates growth hormone synthesis and release in the anterior pituitary gland. In addition, GHRH is an important regulator of cellular functions in many cells and organs. Expression of GHRH G-Protein Coupled Receptor (GHRHR) has been demonstrated in different peripheral tissues and cell types, including pancreatic islets. Among the peripheral activities, recent studies demonstrate a novel ability of GHRH analogs to increase and preserve insulin secretion by beta-cells in isolated pancreatic islets, which makes them potentially useful for diabetes treatment...
2016: Frontiers in Endocrinology
N S Bayin, J D Frenster, J R Kane, J Rubenstein, A S Modrek, R Baitalmal, I Dolgalev, K Rudzenski, L Scarabottolo, D Crespi, L Redaelli, M Snuderl, J G Golfinos, W Doyle, D Pacione, E C Parker, A S Chi, A Heguy, D J MacNeil, N Shohdy, D Zagzag, D G Placantonakis
Glioblastoma (GBM) is a deadly primary brain malignancy with extensive intratumoral hypoxia. Hypoxic regions of GBM contain stem-like cells and are associated with tumor growth and angiogenesis. The molecular mechanisms that regulate tumor growth in hypoxic conditions are incompletely understood. Here, we use primary human tumor biospecimens and cultures to identify GPR133 (ADGRD1), an orphan member of the adhesion family of G-protein-coupled receptors, as a critical regulator of the response to hypoxia and tumor growth in GBM...
October 24, 2016: Oncogenesis
Shiho Fujisaka, Siegfried Ussar, Clary Clish, Suzanne Devkota, Jonathan M Dreyfuss, Masaji Sakaguchi, Marion Soto, Masahiro Konishi, Samir Softic, Emrah Altindis, Ning Li, Georg Gerber, Lynn Bry, C Ronald Kahn
Interactions of diet, gut microbiota, and host genetics play important roles in the development of obesity and insulin resistance. Here, we have investigated the molecular links between gut microbiota, insulin resistance, and glucose metabolism in 3 inbred mouse strains with differing susceptibilities to metabolic syndrome using diet and antibiotic treatment. Antibiotic treatment altered intestinal microbiota, decreased tissue inflammation, improved insulin signaling in basal and stimulated states, and improved glucose metabolism in obesity- and diabetes-prone C57BL/6J mice on a high-fat diet (HFD)...
October 24, 2016: Journal of Clinical Investigation
Andreas Link, Christa E Müller
Together forever? Functional selection was applied to finally achieve separation of the analgesic properties of opiods from serious side effects such as potentially lethal respiratory depression. A Gi-biased μ-opioid-receptor agonist (PZM21) was identified that stabilizes previously unexplored receptor conformations. This compound relieves pain in mice without causing hypoventilation or addiction.
October 24, 2016: Angewandte Chemie
S Schäfer-Somi, S S Ay, D Kaya, M Sözmen, H B Beceriklisoy, A R Ağaoğlu, M Fındık, T van Haeften, S Aslan
Uterine tissue was collected from bitches after ovariohysterectomy at different times after ovulation. Samples were assigned to four groups: metestrous non-pregnant, day 10-12, n = 4; pre-implantation, day 10-12, n = 9; post-implantation, day 18-25, n = 13; mid-gestation, day 30-40, n = 7. RT-qPCR detection was performed for kiss1 and the G protein-coupled receptor 54 (GPR54, specific receptor for kisspeptin). In addition, immunohistochemistry was performed for detection of kisspeptin-10 (KP-10), GPR54, as well as pan-cytokeratin and vimentin...
October 23, 2016: Reproduction in Domestic Animals, Zuchthygiene
Zhao Ma, Zhenzhen Liu, Tianyu Jiang, Tianchao Zhang, Huateng Zhang, Lupei Du, Minyong Li
High-throughput screening (HTS) of ligand library to find new active molecules for G protein-coupled receptors is still a major interest, as well as an actual challenge. Fluorescence polarization (FP) assay portrays an essential role in HTS; however, in many cases, it was restricted by the absence of FP probes, the narrow measurement window, and low signal-to-noise (S/N) ratio. Herein, based on the modification of our previous probe 1 (QFL), we discovered an FP probe 3 (QGGFL) for α1-adrenergic receptors (α1-ARs), which has satisfactory fluorescence intensity, specific binding ability to receptors, and suitable fluorescence properties that were compatible with the filters in the FP system...
October 13, 2016: ACS Medicinal Chemistry Letters
Masahiko Terakado, Hidehiro Suzuki, Kazuya Hashimura, Motoyuki Tanaka, Hideyuki Ueda, Hiroshi Kohno, Taku Fujimoto, Hiroshi Saga, Shinji Nakade, Hiromu Habashita, Yoshikazu Takaoka, Takuya Seko
Lysophosphatidic acid (LPA) evokes various physiological responses through a series of G protein-coupled receptors known as LPA1-6. A high throughput screen against LPA1 gave compound 7a as a hit. The subsequent optimization of 7a led to ONO-7300243 (17a) as a novel, potent LPA1 antagonist, which showed good efficacy in vivo. The oral dosing of 17a at 30 mg/kg led to reduced intraurethral pressure in rats. Notably, this compound was equal in potency to the α1 adrenoceptor antagonist tamsulosin, which is used in clinical practice to treat dysuria with benign prostatic hyperplasia (BPH)...
October 13, 2016: ACS Medicinal Chemistry Letters
Csaba Vastagh, Annie Rodolosse, Norbert Solymosi, Zsolt Liposits
Gonadotropin-releasing hormone (GnRH) neurons play a key role in the central regulation of reproduction. In proestrous female mice, estradiol triggers the pre-ovulatory GnRH surge, however, its impact on the expression of neurotransmitter receptor genes in GnRH neurons has not been explored yet. We hypothesized that proestrus is accompanied by substantial changes in the expression profile of genes coding for neurotransmitter receptors in GnRH neurons. We compared the transcriptome of GnRH neurons obtained from intact, proestrous, and metestrous female GnRH-GFP transgenic mice, respectively...
2016: Frontiers in Cellular Neuroscience
Yan-Qiang Zhang, Peng Li, Feng-Qin Zhang, Shao-Jun Sun, Yin-Guang Cao
Nasal respiratory epithelium is a ciliated pseudostratified columnar epithelium. The cellular components of nasal respiratory epithelium include ciliated cells, goblet cells, and basal cells. Until now, our knowledge in the development of nasal respiratory epithelium is still limited and the cellular mechanism of regeneration is still elusive. In this study, we found that adult stem cell marker leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) is expressed in the mice nasal respiratory epithelium...
October 20, 2016: Biochemical and Biophysical Research Communications
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