A5017204235- Pancreatitis Pathology and Treatment
- Pancreatic function and diabetes
- Liver Disease Diagnosis and Treatment
- Pancreatic and Hepatic Oncology Research
- Ion Channels and Receptors
- Neuroscience and Neuropharmacology Research
- Phagocytosis and Immune Regulation
- Neonatal Health and Biochemistry
- Ion channel regulation and function
- Neuroscience and Neural Engineering
- Lipid metabolism and disorders
- Neuropeptides and Animal Physiology
- Calcium signaling and nucleotide metabolism
- Neural dynamics and brain function
- Pediatric Hepatobiliary Diseases and Treatments
- Cell death mechanisms and regulation
- Cellular transport and secretion
- Adenosine and Purinergic Signaling
- Lipid Membrane Structure and Behavior
- Mitochondrial Function and Pathology
- Nitric Oxide and Endothelin Effects
- Pain Mechanisms and Treatments
- Erythrocyte Function and Pathophysiology
- Neuroendocrine Tumor Research Advances
- Caveolin-1 and cellular processes
University of Liverpool
2015-2024
NIHR Liverpool Pancreatic Biomedical Research Unit
2013-2018
Royal Liverpool University Hospital
2012-2017
Sichuan Provincial Hospital of Traditional Chinese Medicine
2016
Royal Liverpool and Broadgreen University Hospital NHS Trust
2013
Medical Research Council
2008
Physiological Society
2007
Bogomoletz Institute of Physiology
1997-2002
National Academy of Sciences of Ukraine
1997-2002
Oxidative stress may be an important determinant of the severity acute pancreatitis. One-electron reduction oxidants generates reactive oxygen species (ROS) via redox cycling, whereas two-electron detoxification, e.g. by NAD(P)H:quinone oxidoreductase, does not. The actions menadione on ROS production and cell fate were compared with those a non-cycling analogue (2,4-dimethoxy-2-methylnaphthalene (DMN)) using real-time confocal microscopy isolated perfused murine pancreatic acinar cells....
<h3>Objective</h3> Acute pancreatitis is caused by toxins that induce acinar cell calcium overload, zymogen activation, cytokine release and death, yet without specific drug therapy. Mitochondrial dysfunction has been implicated but the mechanism not established. <h3>Design</h3> We investigated of induction consequences mitochondrial permeability transition pore (MPTP) in pancreas using biological methods including confocal microscopy, patch clamp technology multiple clinically...
<h3>Objective</h3> Non-oxidative metabolism of ethanol (NOME) produces fatty acid ethyl esters (FAEEs) via carboxylester lipase (CEL) and other enzyme action implicated in mitochondrial injury acute pancreatitis (AP). This study investigated the relative importance oxidative non-oxidative pathways dysfunction, pancreatic damage development alcoholic AP, whether deleterious effects NOME are preventable. <h3>Design</h3> Intracellular calcium ([Ca<sup>2+</sup>]<sub>C</sub>), NAD(P)H, membrane...
Ca2+ entry through store-operated channels involves the interaction at ER-PM (endoplasmic reticulum-plasma membrane) junctions of STIM (stromal molecule) and Orai. proteins are sensors luminal ER concentration and, following depletion Ca2+, they oligomerize translocate to where form puncta. Direct binding Orai activates their channel function. It has been suggested that an additional C-terminal polybasic domain STIM1 with PM phosphoinositides could contribute puncta formation prior In...
Caffeine reduces toxic Ca2+ signals in pancreatic acinar cells via inhibition of inositol 1,4,5-trisphosphate receptor (IP3R)-mediated signalling, but effects other xanthines have not been evaluated, nor on experimental acute pancreatitis (AP). We determined caffeine and its xanthine metabolites IP3R-mediated signalling AP.Isolated were exposed to secretagogues, uncaged IP3 or toxins that induce AP xanthines, non-xanthine phosphodiesterase (PDE) inhibitors cyclic adenosine monophosphate...
Mitochondrial dysfunction lies at the core of acute pancreatitis (AP). Diverse AP stimuli induce Ca2+-dependent formation mitochondrial permeability transition pore (MPTP), a solute channel modulated by cyclophilin D (CypD), which causes ATP depletion and necrosis. Oxidative stress reportedly triggers MPTP is elevated in clinical AP, but how reactive oxygen species influence cell death unclear. Here, we assessed potential involvement oxidant-induced effects on pancreatic acinar bioenergetics...
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...
Hereditary pancreatitis (HP) is an autosomal dominant disease that displays the features of both acute and chronic pancreatitis. Mutations in human cationic trypsinogen (PRSS1) are associated with HP have provided some insight into pathogenesis pancreatitis, but mechanisms responsible for initiation not been elucidated role apoptosis necrosis has much debated. However, it generally accepted trypsinogen, prematurely activated within pancreatic acinar cell, a major process. Functional studies...
The inducers of acute pancreatitis trigger a prolonged increase in the cytosolic Ca2+ concentration ([Ca2+]c), which is responsible for damage to and eventual death pancreatic acinar cells. Vacuolization an important indicator cell damage. Furthermore, activation trypsinogen occurs endocytic vacuoles; therefore vacuoles can be considered as ‘initiating’ organelles development injury. In present study, we investigated relationship between formation influx developed response [bile acid...
Although oxidative stress has been strongly implicated in the development of acute pancreatitis (AP), antioxidant therapy patients so far discouraging. The aim this study was to assess potential protective effects a mitochondria-targeted antioxidant, MitoQ, experimental AP using vitro and vivo approaches. MitoQ blocked H 2 O -induced intracellular ROS responses murine pancreatic acinar cells, an action not shared by control analogue dTPP. did reduce mitochondrial depolarisation induced...
Pancreatic acinar cells require high rates of amino acid uptake for digestive enzyme synthesis, but excessive concentrations can trigger acute pancreatitis (AP) by mechanisms that are not well understood. We have used three basic natural acids L-arginine, L-ornithine and L-histidine to determine acid-induced pancreatic injury whether these common all acids. Caffeine markedly inhibited necrotic cell death pathway activation in isolated induced L-ornithine, whereas caffeine accelerated...
Mitochondrial permeability transition pore inhibition is a promising approach to treat acute pancreatitis (AP). We sought determine (i) the effects of mitochondrial inhibitor 3,5-seco-4-nor-cholestan-5-one oxime-3-ol (TRO40303) on murine and human pancreatic acinar cell (PAC) injury induced by fatty acid ethyl esters (FAEEs) or taurolithocholic acid-3-sulfate (ii) TRO40303 pharmacokinetics efficacy in experimental alcoholic AP (FAEE-AP).Changes membrane potential (Δψm), cytosolic Ca ([Ca]c),...
Depletion of the endoplasmic reticulum (ER) calcium store triggers translocation stromal interacting molecule one (STIM1) to sub-plasmalemmal region and formation puncta-structures in which STIM1 interacts activates channels. ATP depletion induced puncta PANC1, RAMA37, HeLa cells. The sequence events triggered by inhibition production included a rapid decline ATP, phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) slow leak from ER followed puncta. were co-localized with clusters ORAI1...
Giant trypsin-containing endocytic vacuoles are formed in pancreatic acinar cells stimulated with inducers of acute pancreatitis. F-actin envelops and regulates their properties. Endocytic can rupture release content into the cytosol cells. fuse plasma membrane exocytose content.Intrapancreatic activation trypsinogen is an early event hallmark development vacuoles, which form by disconnection transport large post-exocytic structures, only resolvable sites trypsin activity live In present...
The WD40 domain (WDD) of ATG16L1 plays a pivotal role in non-canonical autophagy. This study examined the recently identified LAP-like autophagy (LNCA) acute pancreatitis. LNCA involves rapid single-membrane LC3 conjugation to endocytic vacuoles pancreatic acinar cells. rationale for this was previously observed presence trypsin organelles undergoing LNCA; aberrant formation is an important factor pancreatitis development. Here we report that deletion WDD (attained ATG16L1[E230] mice)...
The aim of this study was to develop a fluorescent reactive oxygen species (ROS) probe, which is preferentially localized in cellular membranes and displays strong change fluorescence upon oxidation. We also aimed test the performance probe for detecting pathophysiologically relevant ROS responses isolated cells.We introduced novel lipophilic dihydrorhodamine B octadecyl ester (H2RB-C18). then applied new characterize changes triggered by inducers acute pancreatitis pancreatic acinar cells....
Activation of trypsinogen (formation trypsin) inside the pancreas is an early pathological event in development acute pancreatitis. In our previous studies we identified activation within endocytic vacuoles (EVs), cellular organelles that appear pancreatic acinar cells treated with inducers EVs are formed as a result aberrant compound exocytosis and subsequent internalization post-exocytic structures. These can be up to 12 μm diameter actinated (i.e. coated F-actin). Notably, undergo...