sodium-taurodeoxycholate and Inflammation

Many enzymes are involved in numerous pathologies which are related to metabolic reactions and inflammatory diseases such as pancreatic lipase, α-amylase, α-glucosidase and xanthine oxidase and secreted phospholipases A2 (Group IIA, V and X), respectively. Therefore, inhibiting these enzymes offer the potential to block production of more inflammatory substances and decrease the risk factors for cardiovascular diseases. The purpose of this study was to investigate some potent, bioavailable and selective inhibitors of some catalytic proteins implicated to metabolic syndrome and their antioxidant effects from various solvent extracts of R. frangula leaves. The anti-inflammatory, obesity, diabete and XO potentials were evaluated through analyses of inhibition activities of corresponding metabolites.The water extract exhibited an important inhibitory effect on human, dromedary and stingray sPLA2-G IIA achieved an IC50 of 0.16±0.06, 0.19±0.05 and 0.07±0.01 mg/mL, respectively. Likewise, the same fraction demonstrated the highest pancreatic lipase inhibitory activity using two different substrates. Indeed, 50% of dromedary pancreatic lipase inhibition was demonstrated for 5 min and 15 min using olive oil and TC4 substrates, respectively. Besides, it was established that methanolic extract had more effective inhibitory lipase activity than ORLISTAT used as a specific inhibitor of gastric, pancreatic and carboxyl ester lipase for treating obesity, with an IC50 of 5.51±0.27 and 91.46±2.3 µg/mL, respectively. In the case of α-amylase, α-glucosidase and xanthine oxidase, the crude methanolic extract showed a potential inhibitory effect with an IC50 of 45±3.45, 3±0.15 and 27±1.71 µg/mL, respectively. Conclusively, R. frangula leaves extracts showed a potential value of some sPLA2, some metabolic enzymes and XO inhibitors as anti-inflammatory and metabolic syndrome drugs.

Topics: Animals; Enzyme Inhibitors; Enzymes; Humans; Inflammation; Inhibitory Concentration 50; Methanol; Plant Extracts; Plant Leaves; Rhamnus; Solvents; Taurodeoxycholic Acid

Acute pancreatitis (AP) is still one of the severe diseases, that cause the development of multiple organ dysfunction with a high mortality. Effective therapies for AP are still limited, mainly due to unclear mechanisms by which AP initiates both pancreatic and extrapancreatic organ injury.. Protease inhibitors (aprotinin, pefabloc, trypsin inhibitor) and PKC inhibitors (polymyxin B, staurosporine) were administrated 30 min before induction of AP in rats. To investigate the pancreatic, systemic and lung inflammatory response and injury, plasma IL-6 and IL-10, pancreatic and pulmonary myeloperoxidase (MPO) levels, pancreatic protease activity and phospholipase A(2) (PLA(2)) activity in ascites were measured 3 and 6 h after AP induction.. Pretreatment with protease inhibitors significantly prevented from AP-increased plasma levels of IL-10, pancreatic and pulmonary levels of MPO, pancreatic protease activity and the catalytic activity of PLA(2) in ascites. PKC inhibitors significantly reduced pancreatic and pulmonary levels of MPO and pancreatic protease activity.. Inhibition of proteases in AP may be helpful in ameliorating the inflammatory reaction in both pancreatic and extrapancreatic tissues, where neutrophil involvement may be regulated by PKC and proteases.

Topics: Animals; Aprotinin; Ascitic Fluid; Disease Models, Animal; Inflammation; Interleukin-10; Lung; Male; Neutrophils; Pancreas; Pancreatitis; Peptide Hydrolases; Peroxidase; Phospholipases A; Polymyxin B; Protease Inhibitors; Protein Kinase C; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Staurosporine; Sulfones; Taurodeoxycholic Acid; Time Factors; Trypsin Inhibitors

Endotoxin-mediated cholestasis stems from impaired hepatobiliary transport of bile acids and organic anions due to altered expression and activity of transporters, including Oatp, Mrp, Ntcp, and Bsep. However, the mechanisms by which the Oatp and Mrp genes are down-regulated are largely unknown. Using in vivo and in vitro murine models of inflammation, we examined the role of cytokines and bile acids in regulating Oatp and Mrp. Endotoxin (lipopolysaccharide, LPS), interleukin (IL)-6, IL-1beta, tumor necrosis factor (TNF)-alpha, cholic acid, taurocholate, or taurodeoxycholate was administered in vivo to mice or in vitro to Hepa 1-6 mouse hepatoma cells. Mrp, Oatp, and Bsep mRNA levels were measured by reverse transcription-polymerase chain reaction. Mrp efflux activity was measured using 5-carboxyfluorescein. In vivo, LPS treatment profoundly suppressed hepatic mRNA levels of Mrp2, Mrp3, Oatp1, Oatp2, and Bsep to 15, 60, 44, 30, and 32% of controls, respectively (p < 0.05), but did not significantly alter Mrp1 expression. IL-6 or IL-1beta administration suppressed Mrp2, Oatp1, Oatp2, and Bsep mRNA levels to 20 to 60% controls (p < 0.05). TNF-alpha administration affected mRNA levels of Mrp2, Mrp3, and Oatp2 but not Oatp1 or Bsep. Bile acid treatment increased the in vivo expression of Bsep but not Mrp or Oatp. Likewise, significantly lower mRNA levels of Mrp2 with a corresponding decrease in cellular efflux of 5-carboxyfluorescein was seen in vitro in IL-6- and IL-1beta-treated Hepa 1-6 cells, whereas bile acids did not have significant effects. In conclusion, cytokines are key mediators in regulating hepatic expression of anion transporters in inflammatory cholestasis, whereas bile acids likely play a minor role.

Topics: Animals; Anion Transport Proteins; Bile Acids and Salts; Cytokines; Endotoxemia; Endotoxins; Gene Expression Regulation; Inflammation; Interleukin-1; Interleukin-6; Lipopolysaccharides; Liver; Male; Mice; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Taurocholic Acid; Taurodeoxycholic Acid; Tumor Necrosis Factor-alpha