A5064671004- Pancreatic function and diabetes
- Pancreatitis Pathology and Treatment
- Calcium signaling and nucleotide metabolism
- Adenosine and Purinergic Signaling
- Ion Channels and Receptors
- Cellular transport and secretion
- Ion channel regulation and function
- Cell death mechanisms and regulation
- Photoreceptor and optogenetics research
- Mitochondrial Function and Pathology
- Apelin-related biomedical research
- Ion Transport and Channel Regulation
- Erythrocyte Function and Pathophysiology
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Phagocytosis and Immune Regulation
- Diabetes Treatment and Management
- Diet, Metabolism, and Disease
- Pancreatic and Hepatic Oncology Research
- Endoplasmic Reticulum Stress and Disease
- Neonatal Health and Biochemistry
- Liver Disease Diagnosis and Treatment
- Lipid Membrane Structure and Behavior
- Toxin Mechanisms and Immunotoxins
- Signaling Pathways in Disease
- Neuroscience and Neuropharmacology Research
Cardiff University
2015-2024
Medical Research Council
1996-2018
University of Liverpool
2001-2010
Physiological Society
2007
We have investigated in detail the role of intra-organelle Ca2+ content during induction apoptosis by oxidant menadione while changing and monitoring load endoplasmic reticulum (ER), mitochondria, acidic organelles. Menadione causes production reactive oxygen species, oxidative stress, subsequently apoptosis. In both pancreatic acinar tumor AR42J cells, was found to induce repetitive cytosolic responses because release from ER stores. were accompanied elevation mitochondrial depolarization,...
Ca2+ release from the envelope of isolated pancreatic acinar nuclei could be activated by nicotinic acid adenine dinucleotide phosphate (NAADP) as well inositol 1,4,5-trisphosphate (IP3) and cyclic ADP-ribose (cADPR). Each these agents reduced concentration inside nuclear envelope, this was associated with a transient rise in nucleoplasmic concentration. NAADP released same thapsigargin-sensitive pool IP3. The action specific because, for example, nicotineamide ineffective. unaffected...
Alcohol-related acute pancreatitis can be mediated by a combination of alcohol and fatty acids (fatty acid ethyl esters) is initiated sustained elevation the Ca(2+) concentration inside pancreatic acinar cells ([Ca(2+)]i), due to excessive release stored followed entry from interstitial fluid. The [Ca(2+)]i activates intracellular digestive proenzymes resulting in necrosis inflammation. We tested hypothesis that pharmacological blockade store-operated or release-activated channels (CRAC)...
In normal pancreatic acinar cells, the oxidant menadione evokes repetitive cytosolic Ca2+ spikes, partial mitochondrial depolarisation,cytochrome c release and apoptosis. The physiological agonists acetylcholine cholecystokinin also evoke spikes but do not depolarise mitochondria fail to induce induced by low agonist concentrations are confined apical secretory pole of cell buffering action perigranular mitochondria. Menadione prevents uptake, which permits rapid spread throughout cell....
Inositol trisphosphate and cyclic ADP-ribose release Ca2+ from the endoplasmic reticulum via inositol ryanodine receptors, respectively. By contrast, nicotinic acid adenine dinucleotide phosphate may activate a novel channel in an compartment. We show, two-photon permeabilized pancreatic acinar cells, that three messengers tested could each also store granular region. The action on both types of store, like but unlike trisphosphate, depended operational since it was blocked by or ruthenium...
Gallstones can cause acute pancreatitis, an often fatal disease in which the pancreas digests itself. This is probably because of biliary reflux into pancreatic duct and subsequent bile acid action on acinar cells. Because Ca(2+) toxicity important for cellular damage we have studied mechanisms by taurolithocholic 3-sulfate (TLC-S) liberates Ca(2+). Using two-photon plasma membrane permeabilization measurement [Ca(2+)] inside intracellular stores at cell base (dominated ER) near apex...
Toxic alcohol effects on pancreatic acinar cells, causing the often fatal human disease acute pancreatitis, are principally mediated by fatty acid ethyl esters (non-oxidative products of and acids), emptying internal stores Ca(2+). This excessive Ca(2+) liberation induces Ca(2+)-dependent necrosis due to intracellular trypsin activation. Our aim was identify specific source release linked protease In 2-photon permeabilized mouse we monitored changes in concentration thapsigargin-sensitive...
Cell-death programs executed in the pancreas under pathological conditions remain largely undetermined, although severity of experimental pancreatitis has been found to depend on ratio apoptosis necrosis. We have defined mechanisms by which is induced pancreatic acinar cells oxidant stressor menadione. Real-time monitoring initiator caspase activity showed that caspase-9 (66% cells) and caspase-8 (15% were activated within 30 min menadione administration, but no activation caspase-2, -10, or...
Exocytotic secretion of digestive enzymes from pancreatic acinar cells is elicited by physiological cytosolic Ca 2+ signals, occurring as repetitive short-lasting spikes largely confined to the secretory granule region, that stimulate mitochondrial adenosine triphosphate (ATP) production. By contrast, sustained global elevations decrease ATP levels and cause necrosis, leading disease acute pancreatitis (AP). Toxic signals can be evoked products alcohol fatty acids well bile acids. Here, we...
Intracellular Ca(2+) release is mostly mediated by inositol trisphosphate, but intracellular cyclic-ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are important messengers in many systems. Whereas cADPR generally activates type 2 ryanodine receptors (RyR2s), the NAADP-activated mechanism less clear. Using knockouts antibodies against RyRs Two-Pore Channels (TPCs), we have compared their relative importance for NAADP-induced from two-photon permeabilized...
Key points Bradykinin may play a role in the autodigestive disease acute pancreatitis, but little is known about its pancreatic actions. In this study, we have investigated bradykinin‐elicited Ca 2+ signal generation normal mouse lobules. We found complete separation of signalling between acinar (PACs) and stellate cells (PSCs). Pathophysiologically relevant bradykinin concentrations consistently evoked signals, via B2 receptors, PSCs never neighbouring PACs, whereas cholecystokinin, evoking...