A5073234813- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Asthma and respiratory diseases
- Allergic Rhinitis and Sensitization
- Diabetes Treatment and Management
- Chemical Synthesis and Analysis
- Renin-Angiotensin System Studies
- Biochemical Analysis and Sensing Techniques
- Monoclonal and Polyclonal Antibodies Research
- Infrastructure Resilience and Vulnerability Analysis
- Disaster Management and Resilience
- Respiratory and Cough-Related Research
- Cardiac Fibrosis and Remodeling
- Cholesterol and Lipid Metabolism
- Inhalation and Respiratory Drug Delivery
- Ion channel regulation and function
- Signaling Pathways in Disease
- Cardiomyopathy and Myosin Studies
- Global Energy and Sustainability Research
- Anesthesia and Sedative Agents
- Immune Cell Function and Interaction
- Congenital heart defects research
- Neurotransmitter Receptor Influence on Behavior
- Adipose Tissue and Metabolism
- Computational Drug Discovery Methods
UNSW Sydney
2015-2024
Oxford University Hospitals NHS Trust
2024
Newcastle University
2017-2023
Manchester University NHS Foundation Trust
2023
St Vincent's Clinic
2012-2022
Victor Chang Cardiac Research Institute
2012-2022
Guy's and St Thomas' NHS Foundation Trust
2022
Evelina London Children's Healthcare
2022
University of Tennessee Medical Center
2021
University of Tennessee at Knoxville
2021
The physician's global evaluation of treatment effectiveness (GETE) at 16 weeks has been shown to be the most effective assessment response omalizumab (XOLAIR®). This randomized, open-label, parallel-group study evaluated persistency responder classification in patients receiving added optimized asthma therapy (OAT).Patients (12-75 years, n = 400) with severe allergic asthma, uncontrolled despite Global Initiative for Asthma 2004 Step 4 therapy, received OAT and (n 272) or 128) 32 weeks....
The discovery that a number of metabolites and metabolic intermediates can act through G protein-coupled receptors has attracted great interest in the field led to new therapeutic targets for diseases such as hypertension, type 2 diabetes, inflammation, syndrome. However, low apparent affinity these ligands their cognate poses challenges pharmacologists interested investigating receptor structure, function or physiology. Furthermore, endogenous matched have other, well established roles thus...
Free fatty acid receptor 2 (FFA2; GPR43) is a G protein-coupled seven-transmembrane for short-chain acids (SCFAs) that implicated in inflammatory and metabolic disorders. The SCFA propionate has close to optimal ligand efficiency FFA2 can hence be considered as highly potent given its size. Propionate, however, does not discriminate between the closely related FFA3 (GPR41). To identify FFA2-selective ligands understand molecular basis selectivity, targeted library of small carboxylic was...
Abstract Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of range metabolites and drugs. Genetic variations can alter efficacy safety compounds transported OCT1, such as those used for cardiovascular, oncological, psychological indications. Despite its importance drug pharmacokinetics, substrate selectivity underlying structural mechanisms OCT1 remain poorly understood. Here, we present cryo-EM structures full-length human inward-open...
FFA2 and FFA3 are closely related G protein-coupled receptors that bind respond to short chain fatty acids. (FFA2 the provisional International Union of Pharmacology designations for previously called GPR43 GPR41, respectively.) Sequence comparisons between these two alignments with receptor FFA1, linked homology modeling based on atomic level structure bovine rhodopsin, indicated potential polar residues within transmembrane helix bundle play important roles in ligand recognition function....
The renin–angiotensin system (RAS) regulates blood pressure mainly via the actions of angiotensin (Ang)II, generated converting enzyme (ACE). ACE homologue ACE2 metabolises AngII to Ang1-7, decreasing and increasing which counteracts activity Mas receptor. However, also converts AngI Ang1-9, a poorly characterised peptide can be further converted Ang1-7 ACE. Ang1-9 stimulates bradykinin release in endothelium has antihypertrophic heart, attributed its being competitive inhibitor ACE, leading...
The poorly characterized G-protein-coupled receptor GPR35 has been suggested as a potential exploratory target for the treatment of both metabolic disorders and hypertension. It also indicated to play an important role in immune modulation. A major impediment validation these concepts further study this paucity pharmacological tools that interact with GPR35. Using receptor-β-arrestin-2 interaction assay human rat orthologues GPR35, we identified number compounds possessing agonist activity....
ATP synthase produces the majority of cellular energy in most cells. We have previously reported cryo-EM maps autoinhibited E. coli imaged without addition nucleotide (Sobti et al. 2016), indicating that subunit ε engages α, β and γ subunits to lock enzyme prevent functional rotation. Here we present multiple reconstructions frozen after MgATP identify changes occur when this inhibition is removed. The generated show that, exposure MgATP, adopts a different conformation with catalytic...
Phosphodiesterase (PDE)-5 degrades guanosine 3',5'cyclic monophosphate (cGMP) and its inhibitor sildenafil citrate (Viagra) treats erectile dysfunction by smooth muscle relaxation through elevated cGMP. Sildenafil was examined in two guinea pig models of airways disease: pigs exposed to LPS or sensitized with atopy ovalbumen. Ovalbumen exposure caused early- late-phase bronchoconstrictor responses, measured conscious animals whole-body plethysmography. Twenty-four hours after ovalbumen there...
The endogenous ligands for free fatty acid receptor 1 (FFA1) are medium and longer chain acids. However, a range of selective, small molecule have recently been developed as tool compounds to explore the therapeutic potential this receptor, whereas clinically employed thiazolidinedione "glitazone" drugs also agonists at FFA1. Each these classes agonist was able promote phosphorylation ERK1/2 mitogen-activated protein (MAP) kinases in cells express human FFA1 on demand. although both lauric...
Background:Long-term oral corticosteroid (OCS) therapy and related adverse events are associated with a significant burden on patients healthcare resources.Methods:This subgroup analysis of randomized, open-label, parallel-group study evaluated the OCS-sparing effect omalizumab (OMA) added to optimized asthma (OAT), compared OAT alone. Patients (12–75 years) severe allergic asthma, uncontrolled despite GINA 2004 Step 4 therapy, received OMA or for 32 weeks. The change from baseline in OCS...
Allosteric agonists are powerful tools for exploring the pharmacology of closely related G protein-coupled receptors that have nonselective endogenous ligands, such as short chain fatty acids at free acid 2 and 3 (FFA2/GPR43 FFA3/GPR41, respectively). We explored molecular mechanisms mediating activity 4-chloro-α-(1-methylethyl)-N-2-thiazolylbenzeneacetamide (4-CMTB), a recently described phenylacetamide allosteric agonist modulator ligand function human FFA2, by combining our previous...
Fatty acid receptors have been recognized as important players in glycaemic control. This study is the first to describe a role for medium‐chain fatty (MCFA) receptor G‐protein‐coupled (Gpr) 84 skeletal muscle mitochondrial function and insulin secretion. We are able show that Gpr84 highly expressed adipose tissue. Mice with global deletion of [ knockout (KO)] exhibit mild impairment glucose tolerance when fed MCFA‐enriched diet. Studies mice pancreatic islets suggest intolerance accompanied...