A5040881753- Genomics, phytochemicals, and oxidative stress
- Glutathione Transferases and Polymorphisms
- Drug-Induced Adverse Reactions
- Pharmacogenetics and Drug Metabolism
- Hormonal Regulation and Hypertension
- COVID-19 diagnosis using AI
- Congenital heart defects research
- Antifungal resistance and susceptibility
- T-cell and B-cell Immunology
- Insect and Pesticide Research
- S100 Proteins and Annexins
- Immune Cell Function and Interaction
- Hepatitis B Virus Studies
- Estrogen and related hormone effects
- Hepatitis C virus research
- Computational Drug Discovery Methods
- COVID-19 Clinical Research Studies
- Single-cell and spatial transcriptomics
- Antimicrobial Resistance in Staphylococcus
- Botany and Geology in Latin America and Caribbean
- Healthcare and Venom Research
- Ion Transport and Channel Regulation
- Dialysis and Renal Disease Management
- Drug-Induced Hepatotoxicity and Protection
- Environmental Toxicology and Ecotoxicology
University of Liverpool
2010-2025
Earlham Institute
2024
Medical Research Council
2010-2021
Liverpool School of Tropical Medicine
2021
University of Basel
2012-2018
Angelina College
2010
University of Mississippi Medical Center
2003
Jackson Memorial Hospital
2003
Nrf2 regulates the expression of numerous cytoprotective genes in mammalian cells. The activity is regulated by Cul3 adaptor Keap1, yet little known regarding mechanisms regulation Keap1 itself. Here, we have used immunopurification and mass spectrometry, addition to immunoblotting, identify sequestosome 1 (SQSTM1) as a cellular binding partner Keap1. SQSTM1 serves scaffold various signaling pathways shuttles polyubiquitinated proteins proteasomal lysosomal degradation machineries. Ectopic...
Background Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key transcription regulating plethora of detoxifying enzymes and antioxidant genes involved in drug metabolism defence against oxidative stress. The glucocorticoid receptor (GR) ligand-induced the regulation energy supply for metabolic needs to cope with various stressors. GR activity controlled by glucocorticoids, which are synthesized adrenal glands regenerated mainly liver from inactive cortisone 11β-hydroxysteroid...
Background and Aims The transcription factor nuclear erythroid 2‐related 2 (Nrf2) regulates an array of cytoprotective genes, yet studies in transgenic mice have led to conflicting reports on its role liver regeneration. We aimed test the hypothesis that pharmacological activation Nrf2 would enhance Approach Results Wild‐type null were administered bardoxolone methyl (CDDO‐Me), a potent activator has entered clinical development, then subjected two‐thirds partial hepatectomy. Using...
Synthetic triterpenoids including CDDO, its methyl ester (CDDO-Me, bardoxolone methyl), and imidazolide (CDDO-Im) enhance Nrf2-mediated antioxidant anti-inflammatory activity in many diseases by reacting with thiols on the adaptor protein, Keap1. Unlike monofunctional CDDO-Me, bifunctional analog, CDDO-Im, has a second reactive site (imidazolide) can covalently bind to amino acids other than cysteine target proteins such as glutathione S-transferase pi (GSTP), serum albumin, or Here we show...
Exposure to atabecestat is associated with liver injury, which subsequently led its withdrawal from development. Previous studies of patients induced injury identified T cells responsive and metabolites, indicating that immune-mediated mechanisms are involved. As irreversible protein modification suspected drive immunogenicity, this study aimed characterize potential adducts using HSA, GSTA1, GSTP as model proteins. We have shown only formed a cysteine adduct on in the presence metabolic...
Massive, multiple fire ant, Solenopsis invicta, stings are often treated aggressively, particularly in the elderly, despite limited evidence of systemic toxicity due to venom. Over 95% S. invicta venom is composed piperidine alkaloid components, whose toxicity, if any, unknown. To assess a possible pharmacological basis for an alkaloid-rich, protein-free methanol extract from whole ants was assayed inhibitory activity on following nitric oxide synthase (NOS) isoforms, rat cerebellar neuronal...
Activation of metabotropic glutamate receptor 5 (mGluR5) by (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) was shown to suppress microglia activation and decrease the release associated pro-inflammatory mediators. In contrast, consequences mGluR5 inhibition are less well understood. Here, we used BV-2 cells, retaining key characteristics primary mouse microglia, examine whether 2-methyl-6-(phenylethynyl)-pyridine (MPEP) enhances cellular stress production inflammatory cells were treated with...
Expression of the glutamine transporter SNAT3 increases in kidney during metabolic acidosis, suggesting a role ammoniagenesis. Microarray analysis Nrf2 knock-out (KO) mouse identified Snat3 as most significantly down-regulated transcript compared to wild-type (WT). We hypothesized that absence NRF2 would be unable induce under conditions acidosis and therefore reduce availability for Metabolic was induced 7 days WT KO mice. mice failed mRNA protein expression acidosis. However, there were no...
The transcription factor Nrf2 protects against a number of experimental pathologies, and is promising therapeutic target. clinical investigation potent Nrf2-inducing agent, the triterpenoid (TP) bardoxolone methyl (BARD), was recently halted due to adverse cardiovascular events in chronic kidney disease patients, although underlying mechanisms are yet be resolved. majority small molecule inducers electrophilic trigger accumulation via chemical modification its redox-sensitive repressor...
Abstract Background SARS-CoV-2 is frequently shed in the stool of patients hospitalised with COVID-19. The extent faecal shedding among individuals community, and its potential to contribute spread disease, unknown. Methods In this prospective, observational cohort study households Liverpool, UK, participants underwent weekly nasal/throat swabbing detect virus, over a 12-week period from enrolment starting July 2020. Participants that tested positive for were asked provide sample three 14...
Flucloxacillin is a β-lactam antibiotic associated with high incidence of drug-induced liver injury. Although expression HLA-B*57:01 increased susceptibility, little known the pathological mechanisms involved in induction clinical phenotype. Irreversible protein modification suspected to drive reaction through provision flucloxacillin-modified peptides that are presented T-cells by encoded risk allele. In this study, we have shown flucloxacillin binds multiple proteins within human primary...
Abstract Previous studies have shown that cysteine-reactive drug metabolites bind covalently with protein to activate patient T cells. However, the nature of antigenic determinants interact HLA and whether cell stimulatory peptides contain bound metabolite has not been defined. Because susceptibility dapsone hypersensitivity is associated expression HLA-B*13:01, we designed synthesized nitroso dapsone–modified, HLA-B*13:01 binding explored their immunogenicity using cells from hypersensitive...
Drug rash with eosinophilia systemic symptoms (DRESS) is a serious adverse event associated use of the glycopeptide antibiotic vancomycin. Vancomycin-induced drug expression human leukocyte antigen (HLA)-A*32:01, suggesting that interacts this HLA to activate CD8+ T cells. The purpose study was utilize peripheral blood mononuclear cell from healthy donors to: (1) investigate whether HLA-A*32:01 critical for priming naïve cells vancomycin and (2) generate T-cell clones (TCC) determine...
Abstract Use of the atypical antipsychotic clozapine is associated with life-threatening agranulocytosis. The delayed onset and association HLA variants are characteristic an immunological mechanism. objective this study was to generate clozapine-specific T cell clones (TCC) characterize pathways activation cross-reactivity metabolites olanzapine. TCC were established characterized by culturing PBMCs from healthy donors patients a history clozapine-induced Modeling used explore drug–HLA...
Introduction: Vertebrate body axis formation initiates during gastrulation and continues within the tail bud at posterior end of embryo. Major structures in trunk are paired somites, which generate musculoskeletal system, spinal cord—forming part central nervous notochord, with important patterning functions. The specification these different cell lineages by key signalling pathways transcription factors is essential, however, a global map types expressed genes avian missing. Methods: Here...
Abstract In vitro preclinical drug-induced liver injury (DILI) risk assessment relies largely on the use of hepatocytes to measure drug-specific changes in cell function or viability. Unfortunately, this does not provide indications toward immunogenicity drugs and/or likelihood idiosyncratic reactions clinic. This is because molecular initiating event immune DILI an interaction drug-derived antigen with MHC proteins and T-cell receptor. study utilized cells from drug-naïve donors, recently...