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Localization and role of metabotropic glutamate receptors subtype 5 in the gastrointestinal tract

World Journal of gastroenterology 2017年第25期23卷 4500-4507页

作者： Andrea Ferrigno Clarissa Berardo laura g di pasqua Veronica Siciliano Plinio Richelmi Mariapia Vairetti Department of Internal Medicine and Therapeutics (Cellular and Molecular Pharmacology and Toxicology) University of Pavia

Metabotropic glutamate receptor subtype 5 (mgluR5) is a group I mglu subfamily of receptors coupled to the inositol trisphosphate/diacylglycerol pathway. Like other mgluR subtypes, mgluR5s contain a phylogenetically conserved, extracellular orthosteric binding site and a more variable allosteric binding site, located on the heptahelical transmembrane domain. The mgluR5 receptor has proved to be a key pharmacological target in conditions affecting the central nervous system (CNS) but its presence outside the CNS underscores its potential role in pathologies affecting peripheral organs such as the gastrointestinal (gI) tract and accessory digestive organs such as the tongue, liver and pancreas. Following identification of mgluR5s in the mouth, various studies have subsequently demonstrated its involvement in mechanical allodynia, inflammation, pain and oral cancer. mgluR5 expression has also been identified in gastroesophageal vagal pathways. Indeed, experimental and human studies have demonstrated that mgluR5 blockade reduces transient lower sphincter relaxation and reflux episodes. In the intestine, mgluR5s have been shown to be involved in the control of intestinal inﬂammation, visceral pain and the epithelial barrier function. In the liver, mgluR5s have a permissive role in the onset of ischemic injury in rat and mice hepatocytes. Conversely, livers from mice treated with selective negative allosteric modulators and mgluR5 knockout mice are protected against ischemic injury. Similar results have been observed in experimental models of free-radical injury and in vivo mouse models of acetaminophen intoxication. Finally, mgluR5s in the pancreas are associated with insulin secretion control. The picture is, however, far from complete as the review attempts to establish in particular as regards identifying specific targets and innovative therapeutic approaches for the treatment of gI disorders.

关键词： Metabotropic glutamate receptor subtype 5 Esophagus Intestine Liver Pancreas

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Liver plays a central role in asymmetric dimethylargininemediated organ injury

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World Journal of gastroenterology 2015年第17期21卷 5131-5137页

作者： Andrea Ferrigno laura g di pasqua Clarissa Berardo Plinio Richelmi Mariapia Vairetti Department of Internal Medicine and Therapeutics University of Pavia27100 PaviaItaly

Asymmetric-dimethylarginine(ADMA) competes with L-arginine for each of the three isoforms of nitric oxide synthase:endothelial;neuronal;*** is synthesized by protein methyltransferases followed by proteolytic *** is metabolized to citrulline and dimethylamine,by dimethylarginine dimethylaminohydrolase(DDAH) and enters cells through cationic amino-acid transporters extensively expressed in the *** liver plays a crucial role in ADMA metabolism by DDAH-1 and,as has been recently demonstrated,it is also responsible for ADMA biliary excretion.A correlation has been demonstrated between plasma ADMA levels and the degree of hepatic dysfunction in patients suffering from liver diseases with varying aetiologies:plasma ADMA levels are increased in patients with liver cirrhosis,alcoholic hepatitis and acute liver *** mechanism by which liver dysfunction results in raised ADMA concentrations is probably due to impaired activity of DDAH due to severe inflammation,oxidative stress,and direct damage to *** plasma ADMA levels are also relevant as they are associated with the onset of multiorgan failure(MOF).Increased plasma concentration of ADMA was identified as an independent risk factor for MOF in critically-ill patients causing enhanced Intensive Care Unit mortality:a significant reduction in nitric oxide synthesis,leading to malperfusion in various organs,eventually culminating in multi organs dysfunction.

关键词： Liver Asymmetric dimethylarginine Nitricoxide Nitric oxide-synthase Multiple organ failure

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Metabolic shift in liver: Correlation between perfusion temperature and hypoxia inducible factor-1α

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World Journal of gastroenterology 2015年第4期21卷 1108-1116页

作者： Andrea Ferrigno laura giuseppina di pasqua Alberto Bianchi Plinio Richelmi Mariapia VairettiAndrea Ferrigno Unit of Cellular and Molecular Pharmacology and Toxicology Department of Interna Medicine and TherapeuticsUniversity of PaviaPavia 27100 Italy

AIM: To study at what temperature the oxygen carried by the perfusate meets liver requirements in a model of organ perfusion. METHODS: in this study, we correlated hypoxia induciblefactor(Hi F)-1α expression to the perfusion temperature and the hepatic oxygen uptake in a model of isolated perfused rat liver. Livers from Wistar rats were perfused for 6 h with an oxygenated medium at 10, 20, 30 and 37 ℃. Oxygen uptake was measured by an oxygen probe; lactate dehydrogenase activity, lactate release and glycogen were measured spectrophotometrically; bile flow was gravitationally determined; p H of the perfusate was also evaluated; Hi F-1α m RNA and protein expression were analyzed by real time-polymerase chain reaction and ELi SA, respectively. RESULTS: Livers perfused at 10 and 20 ℃ showed no difference in lactate dehydrogenase release after 6 h of perfusion(0.96 ± 0.23 vs 0.93 ± 0.09 m U/min per g) and had lower hepatic damage as compared to 30 and 37 ℃(5.63 ± 0.76 vs 527.69 ± 45.27 m U/min per g, respectively, P s gnificantly higher in livers perfused at 10 and 20 ℃than in livers perfused at 30 and 37 ℃(0.89 ± 0.06 and 1.16 ± 0.05 vs 0.57 ± 0.09 and 0.33 ± 0.08 nmol/mg, respectively, P s gn of hypoxia was observed at 10 and 20 ℃, as highlighted by low lactate release respect to livers perfused at 30 and 37 ℃(121.4 ± 12.6 and 146.3 ± 7.3 vs 281.8 ± 45.3 and 1094.5 ± 71.7 nmol/m L, respectively, P s gn of liver injury or anaerobiosis, in contrast to livers perfused at 30 and 37 ℃.

关键词： Anaerobiosis Hypoxia inducible factor-1 α ischemia

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