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https://www.readbyqxmd.com/read/29675711/%C3%AE-2-adrenoceptor-signaling-reduction-is-involved-in-the-inflammatory-response-of-fibroblast-like-synoviocytes-from-adjuvant-induced-arthritic-rats
#1
Huaxun Wu, Jingyu Chen, Chun Wang, Lihua Liu, Yujing Wu, Yunfang Zhang, Aiwu Zhou, Lingling Zhang, Wei Wei
OBJECTIVE: To investigate the effects of β-AR signaling on fibroblast-like synoviocytes (FLS) from adjuvant-induced arthritis (AA) rats and the partial mechanisms focused on β-AR desensitization mediated by GRK2 and β-arrestin2. METHODS: Animals were divided into a control group and an AA model group, and FLSs were cultured. Arthritis index, histopathology of joints, epinephrine (Epi) and norepinephrine (NE) were detected in vivo. The effect of the β-AR agonist isoprenaline (ISO) and the β2 -AR agonist salbutamol on FLS cell viability were detected by CCK8...
April 19, 2018: Inflammopharmacology
https://www.readbyqxmd.com/read/29673115/the-nuclear-retinoid-related-orphan-receptor-ror%C3%AE-controls-circadian-thermogenic-programming-in-white-fat-depots
#2
Chloé Monnier, Martine Auclair, Gala Le Cam, Marie-Pauline Garcia, Bénédicte Antoine
The RORα-deficient staggerer (sg/sg) mouse is lean and resistant to diet-induced obesity. Its thermogenic activity was shown to be increased not only in brown adipose tissue (BAT), but also in subcutaneous white adipose tissue (WAT) where UCP1 content was enhanced, however, without Prdm16 coexpression. Our observation of partial multilocular lipid morphology of WAT in sg/sg mice both in the inguinal and perigonadal sites led us to focus on the phenotype of both fat depots. Because RORα is a nuclear factor acting in the clock machinery, we looked at the circadian expression profile of genes involved in thermogenesis and browning in WAT and BAT depots of sg/sg and WT mice, through real-time quantitative PCR and western blotting...
April 2018: Physiological Reports
https://www.readbyqxmd.com/read/29673037/sphingosine-1-phosphate-selectively-activates-vagal-afferent-c-fiber-subtype-in-guinea-pig-esophagus
#3
X Yu, M J Patil, M Yu, Y Liu, J Wang, B J Undem, S Yu
BACKGROUND: Activation and sensitization of visceral afferent nerves by inflammatory mediators play important roles in visceral nociception. Sphingosine-1-phosphate (S1P) is a lipid with intracellular and extracellular functions. Extracellularly, it can act as an autacoid via interactions with S1P receptors. The present study aims to determine the effect of S1P on esophageal vagal afferent nerve functions. METHODS: Extracellular single-unit recordings were performed in ex vivo guinea pig esophageal-vagal preparations...
April 19, 2018: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
https://www.readbyqxmd.com/read/29671814/sex-specific-alterations-in-%C3%AE-4-nicotinic-receptor-expression-in-the-nucleus-accumbens
#4
Joan Y Holgate, Josephine R Tarren, Selena E Bartlett
Background : The mechanisms leading from traumatic stress to social, emotional and cognitive impairment and the development of mental illnesses are still undetermined and consequently there remains a critical need to develop therapies for preventing the adverse consequences of traumatic stress. Research indicates nicotinic acetylcholine receptors containing α4 subunits (α4*nAChRs) are both impacted by stress and capable of modulating the stress response. In this study, we investigated whether varenicline, a partial α4β2*nAChR agonist which reduces nicotine, alcohol and sucrose consumption, can reduce stress, a driving factor in substance use disorders...
April 19, 2018: Brain Sciences
https://www.readbyqxmd.com/read/29671504/buprenorphine-therapy-for-opioid-use-disorder
#5
Roger Zoorob, Alicia Kowalchuk, Maria Mejia de Grubb
Opioid misuse, including the use of heroin and the overprescribing, misuse, and diversion of opioid pain medications, has reached epidemic proportions in the United States. As a result, there has been a dramatic increase in opioid use disorder and associated overdoses and deaths. Addiction is a chronic brain disease with a genetic component that affects motivation, inhibition, and cognition. Patient characteristics associated with successful buprenorphine maintenance treatment include stable or controlled medical or psychiatric comorbidities and a safe, substance-free environment...
March 1, 2018: American Family Physician
https://www.readbyqxmd.com/read/29670396/sustained-analgesic-effect-of-clonidine-co-polymer-depot-in-a-porcine-incisional-pain-model
#6
Jared T Wilsey, Julie H Block
Background: Previous research suggests that the α2 adrenergic agonist clonidine, a centrally acting analgesic and antihypertensive, may also have direct effects on peripheral pain generators. However, aqueous injections are limited by rapid systemic absorption leading to off target effects and a brief analgesic duration of action. Purpose: The aim of this study was to examine the efficacy of a sustained-release clonidine depot, placed in the wound bed, in a pig incisional pain model...
2018: Journal of Pain Research
https://www.readbyqxmd.com/read/29669060/plasticizer-di-2-ethylhexyl-phthalate-induces-epithelial-to-mesenchymal-transition-and-renal-fibrosis-in-vitro-and-in-vivo
#7
Cheng-Tien Wu, Ching-Chia Wang, Li-Chen Huang, Shing-Hwa Liu, Chih-Kang Chiang
Plasticizer di-(2-ethylhexyl)phthalate (DEHP) is known as an endocrine disruptor and a peroxisome proliferator. A currently epidemiological study has suggested that daily high di-(2-ethylhexyl)phthalate (DEHP) intake from phthalate-tainted foods in children may be a risk factor for renal dysfunction. DEHP can leach from medical devices such as blood storage bags and the tubing. Long-term exposure to DEHP is associated with nephropathy and exacerbates chronic kidney diseases (CKD) progression. However, the detailed effects and molecular mechanisms remain unclear...
April 14, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29660434/the-beclomethasone-anti-inflammatory-effect-occurs-in-cell-mediator-dependent-manner-and-is-additively-enhanced-by-formoterol-nfkb-p38-pka-analysis
#8
Silvana Cianchetti, Cristina Cardini, Alessandro Corti, Marta Menegazzi, Elena Darra, Eleonora Ingrassia, Alfonso Pompella, Pierluigi Paggiaro
AIMS: Beclomethasone/formoterol (BDP/FOR) has been reported to be more effective than its separate components in airway disease control and in airway inflammation improvement. However, BDP/FOR effects on cytokine-induced inflammation in structural cells have not been described and whether these effects occur in a cell- and mediator-dependent manner has not been fully elucidated. We sought to evaluate BDP and/or FOR effects on endothelial ICAM-1, E-selectin, IL-8 and on bronchial epithelial ICAM-1 and IL-8...
April 13, 2018: Life Sciences
https://www.readbyqxmd.com/read/29660376/new-insight-into-isobolographic-analysis-for-combinations-of-a-full-and-partial-agonist-curved-isoboles
#9
Martin Ezechiáš, Tomáš Cajthaml
Receptor ligands in mixtures may produce effects that are greater than the effect predicted from their individual dose-response curves. The historical basis for predicting the mixture effect is based on Loewés concept and its mathematical formulation. This concept considers compounds with constant relative potencies (parallel dose-response curves) and leads to linear additive isoboles. These lines serve as references for distinguishing additive from nonadditive interactions according to the positions of the experimental data on or outside of the lines...
April 13, 2018: Toxicology
https://www.readbyqxmd.com/read/29653218/comparing-ran-out-status-of-inhaled-short-acting-beta-agonists-in-emergency-department-patients-with-acute-asthma-1996-1998-versus-2015-2017
#10
Tadahiro Goto, Carlos A Camargo, Catalina Gimenez-Zapiola, Daniel J Pallin, Nathan I Shapiro, Thomas J Ferro, Carolyn Rainville, Stanislav Stoyanov, Kohei Hasegawa
BACKGROUND: Medication non-adherence including running out of inhaled asthma medications, is an important problem. OBJECTIVE: To examine the changes in the proportion of adults with acute asthma who ran out of their short-acting beta-agonist (SABA) inhalers before presenting to the emergency department (ED) between 1996-1998 and 2015-2017. METHODS: We analyzed data from prospective multicenter observational cohort studies of ED adult patients (aged 18-54 years) with acute asthma...
April 10, 2018: Journal of Allergy and Clinical Immunology in Practice
https://www.readbyqxmd.com/read/29649502/a-behavioral-mechanistic-investigation-of-the-role-of-5-ht-1a-receptors-in-the-mediation-of-rat-maternal-behavior
#11
Xiaonan Li, Xiaojing Ding, Ruiyong Wu, Leilei Chen, Jun Gao, Gang Hu, Ming Li
Previous work suggests that 5-HT1A receptors play a special role in rodent maternal aggression, but not in other aspects of maternal care (e.g. pup retrieval and nest building). The present study re-assessed the basic effects of 5-HT1A activation or blockade on various maternal responses in postpartum female rats. We also examined the possible behavioral mechanisms underlying the maternal effects of 5-HT1A . Sprague-Dawley mother rats were injected with a 5-HT1A agonist 8-OH-DPAT (0.1, 0.5 or 1.0 mg/kg, sc), a 5-HT1A antagonist WAY-101405 (0...
April 9, 2018: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/29643252/-in-vitro-pharmacological-characterization-and-in-vivo-validation-of-lsn3172176-a-novel-m1-selective-muscarinic-receptor-agonist-tracer-molecule-for-positron-emission-tomography-pet
#12
Adrian J Mogg, Thomas Eessalu, Megan Johnson, Rebecca Wright, Helen E Sanger, Hongling Xiou, Michael Crabtree, Alex Smith, Ellen Colvin, Douglas Schober, Donald Gehlert, Cynthia Jesudason, Paul Goldsmith, Michael P Johnson, Christian C Felder, Vanessa N Barth, Lisa M Broad
In the search for improved symptomatic treatment options for neurodegenerative and neuropsychiatric diseases, muscarinic acetylcholine M1 receptors (M1 mAChRs) have received significant attention. Drug development efforts have identified a number of novel ligands, some of which have advanced to the clinic. However, a significant issue for progressing these therapeutics is the lack of robust, translatable and validated biomarkers. One valuable approach to assessing target engagement is to utilize PET tracers...
April 11, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29643189/elevated-hepatic-cd1d-levels-coincide-with-invariant-nkt-cell-defects-in-chronic-hepatitis-b-virus-infection
#13
Xiaosheng Tan, Yajie Ding, Peng Zhu, Rui Dou, Zhihui Liang, Daofeng Yang, Zhiyong Huang, Wei Wang, Xiongwen Wu, Xiufang Weng
Activation of invariant NKT (iNKT) cells manifests antiviral immune responses in vivo. However, clinical trials have failed to show consistent hepatitis B virus (HBV) DNA reduction postadministration of iNKT cell-specific agonist α-galactosylceramide (α-GalCer). In this study, we aimed to investigate HBV infection-related iNKT cell defects and explore iNKT cell-based therapeutic potential for chronic hepatitis B (CHB). Liver specimens from 30 HBV-infected hepatocellular carcinoma patients were collected for CD1d/hepatitis B surface Ag (HBsAg) staining and/or intrahepatic iNKT cell assay...
April 11, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29626056/methylindoles-and-methoxyindoles-are-agonists-and-antagonists-of-human-aryl-hydrocarbon-receptor-ahr
#14
Martina Stepankova, Iveta Bartonkova, Eva Jiskrova, Radim Vrzal, Sridhar Mani, Sandhya Kortagere, Zdenek Dvorak
Novel methyl-indoles were identified as endobiotic and xenobiotic ligands of human aryl hydrocarbon receptor (AhR). We examined the effects of 22 methylated and methoxylated indoles on the transcriptional activity of AhR. Employing reporter gene assays in AZ-AHR transgenic cells, we determined full agonist, partial agonist or antagonist activities of tested compounds, having substantially variable EC50 , IC50 and relative efficacies. The most effective agonists (EMAX relative to 5 nM dioxin) of AhR were 4-Me-indole (134%), 6-Me-indole (91%) and 7-MeO-indole (80%), respectively...
April 6, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29625570/the-inhibition-of-human-lung-fibroblast-proliferation-and-differentiation-by-gs-coupled-receptors-is-not-predicted-by-the-magnitude-of-camp-response
#15
Maxine J Roberts, Rebecca E Broome, Toby C Kent, Steven J Charlton, Elizabeth M Rosethorne
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic lung disease for which there is no cure. Current therapeutics are only able to slow disease progression, therefore there is a need to explore alternative, novel treatment options. There is increasing evidence that the 3', 5' cyclic adenosine monophosphate (cAMP) pathway is an important modulator in the development of fibrosis, with increasing levels of cAMP able to inhibit cellular processes associated with IPF...
April 7, 2018: Respiratory Research
https://www.readbyqxmd.com/read/29625294/overexpressing-human-gpr109a-leads-to-pronounced-reduction-in-plasma-triglyceride-levels-in-bac-transgenic-rats
#16
Yusuke Masuda, Nobuya Kurikawa, Tomohiro Nishizawa
BACKGROUND AND AIMS: Nicotinic acid administration causes plasma non-esterified fatty acid (NEFA) reduction and plasma lipid changes, including reduced triglyceride levels. GPR109A, which is expressed mainly in adipose tissue and has anti-lipolytic activity, was reported to be a molecular target for nicotinic acid. However, recent clinical reports have shown that most GPR109A agonists failed to induce clinically meaningful plasma lipid changes. In addition, a recent study has shown that the TG lowering effect of nicotinic acid was not diminished in Gpr109a deficient mice, which is different from the original finding...
March 24, 2018: Atherosclerosis
https://www.readbyqxmd.com/read/29622583/a-pharmacogenetic-approach-to-the-treatment-of-patients-with-pparg-mutations
#17
Maura Agostini, Erik Schoenmakers, Junaid Beig, Louise Fairall, Istvan Szatmari, Odelia Rajanayagam, Frederick W Muskett, Claire Adams, A David Marais, Stephen O'Rahilly, Robert K Semple, Laszlo Nagy, Amit R Majithia, John W R Schwabe, Dirk J Blom, Rinki Murphy, Krishna Chatterjee, David B Savage
Loss-of-function mutations in PPARG cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many cases. Missense mutations in PPARG are present in ∼1:500 people. Whilst mutations are often binarily classified as 'benign' or 'deleterious', prospective functional classification of all missense PPARG variants suggests that their impact is graded. Furthermore, in testing novel mutations with both prototypic 'endogenous' (e.g. prostaglandin J2 (PGJ2)) and synthetic ligands (thiazolidinediones, tyrosine agonists), we observed that synthetic agonists selectively rescue function of some PPARγ mutants...
April 5, 2018: Diabetes
https://www.readbyqxmd.com/read/29620897/design-synthesis-and-characterization-of-4-undecylpiperidine-2-carboxamides-as-positive-allosteric-modulators-of-the-serotonin-5-ht-5-ht2c-receptor
#18
Christopher T Wild, Joanna M Miszkiel, Eric A Wold, Claudia A Soto, Chunyong Ding, Rachel M Hartley, Mark Andrew White, Noelle C Anastasio, Kathryn A Cunningham, Jia Zhou
An impaired signaling capacity of the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) has been implicated in the neurobehavioral processes that promote relapse vulnerability in cocaine use disorder (CUD). Restoration of the diminished 5-HT2CR signaling through positive allosteric modulation presents a novel therapeutic approach. Various new molecules with the 4-alkylpiperidine-2-carboxamide scaffold were designed, synthesized, and pharmacologically evaluated, leading to the discovery of several 5-HT2CR positive allosteric modulators (PAMs)...
April 5, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29619682/a-population-pharmacokinetic-and-pharmacodynamic-analysis-of-rp5063-phase-2-study-data-in-patients-with-schizophrenia-or-schizoaffective-disorder
#19
Marc Cantillon, Robert Ings, Arul Prakash, Laxminarayan Bhat
BACKGROUND AND OBJECTIVE: RP5063 is a novel multimodal dopamine (D)-serotonin (5-HT) stabilizer possessing partial agonist activity for D2/3/4 and 5-HT1A/2A , antagonist activity for 5-HT2B/2C/7, and moderate affinity for the serotonin transporter. Phase 2 trial data analysis of RP5063 involving patients with schizophrenia and schizoaffective disorder defined: (1) the pharmacokinetic profile; and (2) the pharmacokinetic/pharmacodynamic relationships. METHODS: Pharmacokinetic sample data (175 patients on RP5063; 28 doses/patient) were analyzed, utilized one- and two-compartment models, and evaluated the impact of covariates...
April 4, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29618597/regulation-of-vascular-calcification-by-growth-hormone-releasing-hormone-and-its-agonists
#20
Jian Shen, Ning Zhang, Yi-Nuo Lin, PingPing Xiang, Xian-Bao Liu, Peng-Fei Shan, Xin-Yang Hu, Wei Zhu, Yao-Liang Tang, Keith A Webster, Ren-Zhi Cai, Andrew Schally, Jian'an Wang, Hong Yu
<u>Rationale:</u> Vascular calcification (VC) is a marker of the severity of atherosclerotic disease. Hormones play important roles in regulating calcification; estrogen and parathyroid hormones exert opposing effects, the former alleviating VC and the latter exacerbating it. So far no treatment strategies have been developed to regulate clinical VC. <u>Objective:</u> To investigate the effect of growth hormone-releasing hormone (GHRH) and its agonist (GHRH-A) on the blocking of VC in a mouse model...
April 4, 2018: Circulation Research
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