A5005851612- Cancer Cells and Metastasis
- Pulmonary Hypertension Research and Treatments
- Immune cells in cancer
- Gut microbiota and health
- Liver physiology and pathology
- Microscopic Colitis
- Cancer, Hypoxia, and Metabolism
- Gastrointestinal motility and disorders
- Caveolin-1 and cellular processes
- Immune Response and Inflammation
- Inflammatory Bowel Disease
- Nitric Oxide and Endothelin Effects
- Asthma and respiratory diseases
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Peptidase Inhibition and Analysis
- Eosinophilic Esophagitis
- Eosinophilic Disorders and Syndromes
- Wnt/β-catenin signaling in development and cancer
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Electron Spin Resonance Studies
- Protease and Inhibitor Mechanisms
- Tissue Engineering and Regenerative Medicine
- Circadian rhythm and melatonin
- Cytokine Signaling Pathways and Interactions
- Digestive system and related health
University of East Anglia
2017-2024
Norwich Research Park
2013-2023
Quadram Institute
2013-2017
Addenbrooke's Hospital
2004-2012
University of Cambridge
2004-2012
Cambridge School
2007-2012
Papworth Hospital
2004-2011
King's College London
2008
Neutrophils are key effector cells of the innate immune response and required to migrate function within adverse microenvironmental conditions. These inflammatory sites characterized by low levels oxygen glucose high reductive metabolites. A major regulator neutrophil functional longevity is ability these undergo apoptosis. We examined mechanism which hypoxia causes an inhibition apoptosis in human murine neutrophils. show that neutrophils possess hypoxia-inducible factor (HIF)-1α inhibiting...
Dendritic cells' (DCs) ability to present antigens and initiate the adaptive immune response confers them a pivotal role in immunological defense against hostile infection and, at same time, tolerance towards harmless components of microbiota. Food products can modulate inflammatory status intestinal DCs. Among nutritionally-derived products, we investigated quercetin suppress cytokines secretion, antigen presentation, DCs migration draining lymph nodes. We recently identified Slpi...
Abstract Gut homeostasis is a tightly regulated process requiring finely tuned complex interactions between different cell types, growth factors, or cytokines and their receptors. Previous work has implicated role for IL-6 mucosal immune cells in intestinal regeneration following injury promoting inflammation cancer. We hypothesized that signaling could also modulate crypt homeostasis. Using mouse vitro organoid vivo models, this study first demonstrated exogenous promoted proliferation...
Heterozygous germ line mutations in the gene encoding bone morphogenetic protein (BMP) type II receptor occur more than 80% of patients with familial pulmonary arterial hypertension. Because inhibitors DNA binding (Id) genes are major targets BMP/Smad signaling, we studied regulation these transcription factors artery smooth muscle cells harboring BMP and control cells. Mutant demonstrated a marked deficiency BMP4-stimulated Id1 Id2 expression compared were deficient Smad1/5 signaling...
<h3>Background</h3> A defining characteristic of the human intestinal epithelium is that it most rapidly renewing tissue in body. However, processes underlying renewal and mechanisms govern their coordination have proved difficult to study gut. <h3>Objective</h3> To investigate regulation stem cell-driven by canonical Wnt TGFβ/bone morphogenetic protein (BMP) pathways native colonic epithelium. <h3>Design</h3> Intact crypts were isolated from mucosal samples placed into 3D culture conditions...
Heterozygous germline mutations in the gene encoding bone morphogenetic protein type II receptor cause familial pulmonary arterial hypertension (PAH). We previously demonstrated that substitution of cysteine residues ligand-binding domain this prevents trafficking to cell membrane. Here we demonstrate potential for chemical chaperones rescue cell-surface expression mutant BMPR-II and restore function. HeLa cells were transiently transfected with wild or (C118W) constructs. Immunolocalization...
Inflammatory bowel diseases (IBDs) are chronic and relapsing immune disorders that result, or possibly originate, from epithelial barrier defects. Intestinal organoids a new reliable tool to investigate response in models of inflammation. We produced the ulcerative colitis murine model Winnie explore if inflammatory features observed parental intestine were preserved by organoids. Furthermore, we investigated quercetin administration vitro cultured could suppress LPS-induced inflammation...
Inflammatory bowel diseases (IBD) are debilitating chronic inflammatory disorders that develop as a result of defective immune response toward intestinal bacteria. Intestinal dysbiosis is associated with the onset IBD and has been reported to persist even in patients deep remission. We investigated possibility dietary-induced switch gut microbiota composition using Winnie mice model spontaneous ulcerative colitis chow enriched 1% Bronze tomato. used near isogenic tomato line strategy...
Abstract Background Inflammatory bowel disease (IBD), including Crohn (CD) and ulcerative colitis (UC), is a multifactorial disorder characterized by chronic inflammation altered gut barrier function. Dysbiosis, condition defined dysregulation of the microbiome, has been reported in patients with IBD experimental models colitis. Although several factors have implicated directly affecting microbial composition, genetic determinants impacting intestinal dysbiosis remain relatively unknown....
Abstract The intestinal epithelium forms a vital barrier between luminal microbes and the underlying mucosal immune system. Epithelial function is maintained by continuous renewal of pivotal for gut homeostasis. Breaching causes mobilization cells to promote epithelial restitution. However, it not known whether at surface healthy influence cell modulate tissue Using mouse colonic explant model, we demonstrate that close proximity healthy, intact results in rapid mucus secretion movement...
Neutrophil apoptosis plays a central role in the resolution of granulocytic inflammation. We have shown previously that tumor necrosis factor-alpha (TNFalpha) enhances rate neutrophil at early time points via mechanism involving both TNF receptor (TNFR) I and TNFRII. Here we reveal marked but consistent variation magnitude pro-apoptotic effect TNFalpha neutrophils isolated from healthy donors, show inhibition cell surface aminopeptidase N (APN) using actinonin, bestatin, or inhibitory...
Summary Background Eosinophils are pro‐inflammatory cells implicated in the pathogenesis of asthma and atopy. Apoptosis has been proposed as a potential mechanism underlying resolution eosinophilic inflammation studies have indicated ability interventions that induce human eosinophil apoptosis to promote inflammation. Recently, cyclin‐dependent kinase (CDK) inhibitor R‐roscovitine was shown enhance neutrophil neutrophilic Objective The purpose this study examine expression CDKs blood...
Abstract Airway eosinophilia plays a major role in the pathogenesis of asthma with inhibition apoptosis by GM-CSF and IL-5 proposed as mechanism underlying prolonged eosinophil survival. In vivo ex studies have indicated capacity interventions that drive human to promote resolution inflammation. Far less is known about impact transendothelial migration on survival, particular, endothelial cell-derived factors contribute toward apoptosis-resistant phenotype characteristic airway-resident...
Nitric oxide (NO) is involved in many biological processes affecting the cardiovascular, nervous and immune systems. Intracellular NO can be monitored using fluorescent probes combination with fluorescence imaging techniques. Most of currently available molecular are excited via one-photon excitation UV or Vis light, which results poor penetration high photodamage to living tissues. Here, we report a two-photon probe, DANPY-NO, able detect live cells. The probe consists an o-phenylenediamine...
Long-term infusion of prostacyclin, or its analogs, is an effective treatment for severe pulmonary arterial hypertension. However, dose escalation often required to maintain efficacy. The aim this study was investigate the mechanisms prostacyclin receptor desensitization using analog cicaprost in rat artery smooth muscle cells (PASMCs). Desensitization cAMP response occurred 63 nM after a 6-h preincubation with agonist. This reversed 12 h agonist removal, and resensitization inhibited by 10...
Tunneling nanotubes (TNTs) are thin cytoplasmic extensions involved in long-distance intercellular communication and can transport intracellular organelles signalling molecules. In cancer cells, TNT formation contributes to cell survival, chemoresistance, malignancy. However, the molecular mechanisms underlying not well defined, especially different cancers. TNTs present non-small lung (NSCLC) patients with adenocarcinoma. NSCLC, hepatocyte growth factor (HGF) its receptor, c-Met,...
Granulocyte apoptosis has been proposed as a fundamental, injury-limiting granulocyte-clearance mechanism. As such, inhibition of this process may prevent the resolution inflammation. Our previous studies have shown that TNFα (tumour necrosis factor-α) bi-modal influence on rate constitutive neutrophil in vitro, causing early acceleration and late process. The pro-apoptotic effect is uniquely TNFR1 (TNF receptor 1) TNFR2-dependent latter survival mediated via phosphoinositide 3-kinase NF-κB...
We have shown previously that hypoxia inhibits the growth of distal human pulmonary artery smooth muscle cells (PASMC) isolated under standard normoxic conditions (PASMC norm ). By contrast, a subpopulation PASMC, through survival selection was found to proliferate in response hyp sought investigate role hypoxia‐inducible factor (HIF) these differential responses and assess relationship between HIF, proliferation, apoptosis, vascular remodeling emphysema. PASMC were derived from lobar...
A library of ferrocenyl β-diketonate compounds with varying degrees aromatic functionality have been synthesized and fully characterized. This includes cyclic voltammetry the analysis four new structures by single crystal X-ray diffraction. The cytotoxic potential has determined MTT screening against pancreatic carcinoma (MIA PaCa-2), ovarian adenocarcinoma (A2780), breast adenocarcinomas (MDA-MB-231 MCF-7) normal epithelial retinal (ARPE-19). show a general trend, where increasing number...
<h3></h3> Non-small cell lung cancer(NSCLC) accounts for 85% of all cancer cases and is often associated with mutations in hepatocyte growth factor(HGF) epidermal factor(EGF) expression. Tunneling nanotubes(TNTs) are thin cytoplasmic connections shown to be involved long-distance intercellular communication have an important role progression. We investigated the EGF/HGF signalling pathway crosstalk TNT formation, addition defining key characteristics TNTs A549 cells. For quantification,...
<h3>Background</h3> Eosinophils are pro-inflammatory cells implicated in the pathogenesis of asthma and atopy. Apoptosis has been proposed as a potential mechanism underlying resolution eosinophilic inflammation studies have indicated ability interventions that induce human eosinophil apoptosis to promote inflammation. Recently, cyclin-dependent kinase (CDK) inhibitor R-roscovitine was shown enhance neutrophil neutrophilic <h3>Aim</h3> The purpose this study examine expression CDKs blood...
The colonic epithelium is the most rapidly renewing tissue in body and organized into a single cell layer of invaginations called crypts. Crypt renewal occurs through Lgr5 + gut stem cells situated at crypt base, which divide, produce daughter that proliferate, migrate, differentiate all required for normal function, are finally shed lumen. In health, this rapid helps maintain barrier function next to hostile microbial luminal environment. Inflammation results an influx immune including...