A5051150938- Liver physiology and pathology
- Metal complexes synthesis and properties
- X-ray Diffraction in Crystallography
- Organ Transplantation Techniques and Outcomes
- Crystallization and Solubility Studies
- Liver Disease Diagnosis and Treatment
- Drug Transport and Resistance Mechanisms
- Drug-Induced Hepatotoxicity and Protection
- Liver Disease and Transplantation
- Immune cells in cancer
- Ferrocene Chemistry and Applications
- Adipose Tissue and Metabolism
- Metal-Catalyzed Oxygenation Mechanisms
- Clinical Nutrition and Gastroenterology
- Lanthanide and Transition Metal Complexes
- Pediatric Hepatobiliary Diseases and Treatments
- Organometallic Complex Synthesis and Catalysis
- Genetic and Kidney Cyst Diseases
- Trace Elements in Health
- Apelin-related biomedical research
- Advanced Glycation End Products research
- Microscopic Colitis
- Synthesis and pharmacology of benzodiazepine derivatives
- Cannabis and Cannabinoid Research
- Cancer, Lipids, and Metabolism
MRC Centre for Regenerative Medicine
2020-2025
University of Edinburgh
2001-2025
Medical Research Council
2021
Centre for Inflammation Research
2017
British Heart Foundation
2016
Queen's Medical Centre
2016
Edinburgh Cancer Research
2002-2007
Western General Hospital
2001-2006
University of Warwick
2005
Inhibition of the growth human ovarian cancer cell line A2780 by organometallic ruthenium(II) complexes type [(eta(6)-arene)Ru(X)(Y)(Z)], where arene is benzene or substituted benzene, X, Y, and Z are halide, acetonitrile, isonicotinamide, X,Y ethylenediamine (en) N-ethylethylenediamine, has been investigated. The X-ray crystal structures [(eta(6)-p-cymene)Ru(en)Cl]PF(6) (5), [(eta(6)-p-cymene)RuCl(2)(isonicotinamide)] (7), [(eta(6)-biphenyl)Ru(en)Cl]PF(6) (9) reported. They have "piano...
Ruthenium complexes offer the potential of reduced toxicity, a novel mechanism action, non-cross resistance and different spectrum activity compared to platinum containing compounds. Thirteen ruthenium(II) organometallic arene have been evaluated for (in vitro in vivo) models human ovarian cancer, cross-resistance profiles established cisplatin multi-drug-resistant variants. A broad range IC50 values was obtained (0.5 >100 μM) A2780 parental cells with two compounds (RM175 HC29) equipotent...
We report structure−activity relationships for organometallic RuII complexes of the type [(η6-arene)Ru(XY)Cl]Z, where XY is an N,N- (diamine), N,O- (e.g., amino acidate), or O,O- β-diketonate) chelating ligand, arene ranges from benzene derivatives to fused polycyclic hydrocarbons, and Z usually PF6. The X-ray structures 13 are reported. All have characteristic “piano-stool” geometry. most active toward A2780 human ovarian cancer cells contained = ethylenediamine (en) extended arenes....
•Primary BMDMs localised to liver and spleen within hours following intravenous injection in mice.•AAMs were highly phagocytic i.v. transfer elicited reductions necrotic area, HMGB1 translocation, hepatic neutrophil infiltration.•AAM reduced inflammatory mediators stimulated hepatocyte/endothelium proliferation injured liver.•Injection of clinical-grade human AAMs could partially recapitulate the efficacy murine immunocompetent mice. Background & AimFollowing acetaminophen (APAP) overdose,...
Abstract Cirrhosis is a major cause of morbidity and mortality; however, there are no approved therapies except orthotopic liver transplantation. Preclinical studies showed that bone-marrow-derived macrophage injections reduce inflammation, resolve fibrosis stimulate regeneration. In multicenter, open-label, parallel-group, phase 2 randomized controlled trial ( ISRCTN10368050 ) in n = 51 adult patients with compensated cirrhosis Model for End-Stage Liver Disease (MELD) score ≥10 ≤17, we...
Hepatocyte transplantation has shown promise for genetic diseases of the hepatocytes but to date limited efficacy non-genetic forms severe liver injury. Limited cell engraftment and poor function donor in recipient livers impacts clinical utility hepatocyte therapy. The mechanisms underpinning this are poorly understood. We explored a injury model, where predictable levels senescence was induced AhCreMdm2
Organometallic compounds offer broad scope for the design of therapeutic agents, but this avenue has yet to be widely explored. A key concept in anticancer complexes is optimization chemical reactivity allow facile attack on target site (e.g., DNA) avoid other sites associated with unwanted side effects. Here, we consider how result can achieved monofunctional “piano-stool” ruthenium(II) arene type [(η 6 -arene)Ru(ethylenediamine)(X)] n + . potentially important activation mechanism...
The Os(II) arene ethylenediamine (en) complexes [(eta(6)-biphenyl)Os(en)Cl][Z], Z = BPh(4) (4) and BF(4) (5), are inactive toward A2780 ovarian cancer cells despite 4 being isostructural with an active Ru(II) analogue, 4R. Hydrolysis of 5 occurred 40 times more slowly than aqua adduct 5A has a low pK(a) (6.3) compared to that [(eta(6)-biphenyl)Ru(en)(OH(2))](2+) (7.7) is therefore largely in the hydroxo form at physiological pH. rate extent reaction 9-ethylguanine were also less those We...
Biliary diseases can cause inflammation, fibrosis, bile duct destruction, and eventually liver failure. There are no curative treatments for biliary disease except transplantation. New therapies urgently required. We have therefore purified human epithelial cells (hBECs) from livers that were not used hBECs tested as a cell therapy in mouse model of which the conditional deletion Mdm2 cholangiocytes causes senescence, strictures, fibrosis. expandable phenotypically stable help restore...
Abstract Acute liver failure is a rapidly progressing, life-threatening condition most commonly caused by an overdose of acetaminophen (paracetamol). The antidote, N-acetylcysteine (NAC), has limited efficacy when injury established. If acute damage severe, can develop with associated high mortality rates. We have previously demonstrated that alternatively, activated macrophages are potential therapeutic option to reverse in pre-clinical models. In this paper, we present data using...
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...
Biliary complications are a major cause of morbidity and mortality in liver transplantation. Up to 25% patients that develop biliary require additional surgical procedures, re-transplantation or die the absence suitable regraft. Here, we investigate role primary cilium, highly-specialised sensory organelle, injury leading post-transplant complications. Human biopsies were used study structure function cilia transplant recipients (N=7) comparison with without (N=12). To biological effects...
Liver transplantation is the only curative option for patients with end-stage liver disease. Despite improvements in surgical techniques, nonanastomotic strictures (characterized by progressive loss of biliary tract architecture) continue to occur after transplantation, negatively affecting function and frequently leading graft retransplantation. To study biological effects organ preservation before we generated murine models that recapitulate procurement static cold storage. In these...
Abstract Background and Aim Acetaminophen (APAP) induced acute liver injury (ALI), the leading cause failure in western world, has limited treatment options. APAP toxicity results massive hepatic necrosis secondary infiltrating monocytes neutrophils, which contribute to pathogenesis. Semaphorin 7a (Sema7a), a chemoattractant modulator of is potential therapeutic target other conditions, but its role APAP-ALI unexplored. Methods Wild-type (WT) Sema7a knockout (KO) mice were examined during...
Background and aims Alcohol-associated hepatitis (AH) is an acute form of alcohol-related liver disease (ALD) with high mortality rate. AH histologically characterised by cellular processes, including steatosis, inflammation cell death. Apoptosis the most studied death in AH; however, role senescence, another response to injury, unknown. Here, we explore mechanisms ALD pathophysiology describe senescence AH. Methods We performed RNA sequencing bioinformatics analysis 0- 28-day transjugular...
PVI 5FU gives increased response rates and reduced toxicity when compared to bolus (J Clin Oncol 1989, 425–432). administration was reported give highly variable (>1000-fold) plasma concentrations at steady state (FU Css) which correlated with (Ann 1996, 47–53); but only 19 patients were studied. Therefore, we performed a study of in 61 advanced colorectal cancer assess the variability (inter- intra-subject) Css associated (300 mg m−2 day−1) attempt correlate pharmacodynamic end-points...
Abstract Currently liver transplantation is the only treatment option for disease, but organ availability cannot meet demand and transplant recipients require lifelong immunosuppression. The identification of alternative treatments, e.g. cell therapies, able to tip resolution injury from inflammation regeneration requires an understanding host response degree injury. We adopt a combined in vivo-in silico approach develop mathematical model acute disease predict utilise Mdm2 fl/fl mouse...