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BACKGROUND Ursodeoxycholic acid (UDCA) is a secondary hydrophilic bile acid, metabolised in the gut, by microbiota. UDCA is currently prescribed for primary biliary cirrhosis, and of recently has shown β-cell protective effects, which suggests potential antidiabetic effects. Thus, this study aimed to design targeted-delivery microcapsules for oral uptake of UDCA and test its effects in type 1 diabetes (T1D). METHODS UDCA microcapsules were produced using alginate-NM30 matrix. Three equal groups of mice (6-7 mice per group) were gavaged daily UDCA powder, empty microcapsules and UDCA microcapsules for 7 days, then T1D was induced by alloxan injection and treatments continued until mice had to be euthanised due to weight loss > 10% or severe symptoms develop. Plasma, tissues, and faeces were collected and analysed for bile acids' concentrations. RESULTS UDCA microcapsules brought about reduction in elevated blood glucose, reduced inflammation and altered concentrations of the primary bile acid chenodeoxycholic acid and the secondary bile acid lithocholic acid, without affecting survival rate of mice. Bezafibrate manufacturer CONCLUSION The findings suggest that UDCA exerted direct protective effects on pancreatic β-cells and this is likely to be associated with alterations of concentrations of primary and secondary bile acids in plasma and tissues. Three equal groups of mice were gavaged daily UDCA (ursodeoxycholic acid) powder, empty microcapsules and UDCA microcapsules for 7 days, then T1D was induced and treatments continued until mice had to be euthanised. UDCA microcapsules brought about reduction in elevated blood glucose, reduced inflammation and altered concentrations of the primary bile acid chenodeoxycholic acid and the secondary bile acid lithocholic acid, without affecting survival rate of mice. The findings suggest that UDCA exerted direct protective effects on pancreatic β-cells and this is likely to be associated with alterations of concentrations of primary and secondary bile acids in plasma and tissues.BACKGROUND Hexahydrocurcumin (HHC), a major metabolite of curcumin, has been reported to have protective effects against ischemic and reperfusion damage. The goal of the present research was to examine whether HHC could alleviate brain damage and ameliorate functional outcomes by diminishing the blood-brain barrier (BBB) damage that follows cerebral ischemia/reperfusion. METHODS Middle cerebral artery occlusion was induced for 2 h in rats followed by reperfusion. The rats were divided into three groups sham-operated, vehicle-treated, and HHC-treated groups. At the onset of reperfusion, the rats were immediately intraperitoneally injected with 40 mg/kg HHC. At 48 h after reperfusion, the rats were evaluated for neurological deficits and TTC staining. At 24 h and 48 h after reperfusion, animals were sacrificed, and their brains were extracted. RESULTS Treatment with HHC reduced neurological scores, infarct volume, morphological changes, Evans blue leakage and immunoglobulin G extravasation. Moreover, HHC treatment reduced BBB damage and neutrophil infiltration, downregulated myeloperoxidase, ICAM-1, and VCAM-1, upregulated tight junction proteins (TJPs), and reduced aquaporin 4 expression and brain water content. CONCLUSION These results revealed that HHC treatment preserved the BBB from cerebral ischemia/reperfusion injury by regulating TJPs, attenuating neutrophil infiltration, and reducing brain edema formation.OBJECTIVE The effects of prasugrel, a third-generation thienopyridine, on myocardial infarction, and ischemia-induced ventricular arrhythmias was evaluated in open-chest anesthetized rats. The role of protein kinase C and phosphoinositide 3-kinase pathways in these effects was also examined. METHODS The effect of P2Y12 receptor inhibition by prasugrel (3-10 mg/kg, po) on infarct size after 30-min coronary artery occlusion and 120-min reperfusion or on arrhythmias after 7-min coronary occlusion and 7-min reperfusion was evaluated. RESULTS In the control group, 31.25 ± 3.01% of the risk zone infarcted. At both prasugrel doses, infarct size was significantly smaller than that in the control group 5.03 ± 0.81% for 3 mg/kg (p  less then  0.0001), and 8.78 ± 2.04% for 10 mg/kg (p  less then  0.0001). The protein kinase C antagonist chelerythrine abolished the anti-infarct effect of prasugrel at 24.77 ± 1.73% as did the phosphoinositide 3-kinase antagonist wortmannin abolished the anti-infarct effect of prasugrel at 27.45 ± 2.74%. Ten mg/kg prasugrel reduced the duration of VT (p = 0.0152 vs control), and wortmannin, but not chelerythrine, reversed the effect of prasugrel on arrhythmias (p = 0.0295). CONCLUSION The selective P2Y12 inhibitor prasugrel provides effective protection against myocardial infarction and ischemia-induced ventricular arrhythmias in rats. As in ischemic postconditioning, protein kinase C and phosphoinositide 3-kinase signaling pathways play a role in this protection.BACKGROUND Fenofibrate was reported to be beneficial for cholestasis in combination with ursodeoxycholic acid. However, its therapeutic action as single therapy for chronic cholestasis and the underlying mechanism are not known. METHODS In the present study, wild-type (WT) mice were administered a 0.05% ANIT diet to mimic chronic cholestatic liver injury. Mice were dosed fenofibrate 25 mg/kg twice every day for 10 days to investigate the therapeutic action of fenofibrate on chronic cholestatic liver injury. Ppara-null (KO) mice were used to explore PPARα's role in the therapeutic outcome. RESULTS Fenofibrate, administered at 25 mg/kg twice daily, substantially reversed ANIT-induced chronic cholestatic liver injury shown by biochemical and pathological end points. The modifications of bile acid metabolism were found to be adaptive responses. The JNK-AP1-CCL2/CXCL2 axis was activated in all the mice administered ANIT which developed chronic cholestatic liver injury. But it was substantially decreased by fenofibrate in WT mice rather than that in KO mice. CONCLUSIONS Low-dose fenofibrate reversed chronic cholestatic liver injury in mice. The therapeutic action was dependent on PPARα activation and occurred by inhibiting chemotaxis via the JNK-AP1-CCL2/CXCL2 signaling. These data provided an exciting basis for optimization of therapeutic fenofibrate regimen in the clinic. Additionally, they suggested anti-chemotaxis of low-dose fenofibrate in single therapy to treat cholestatic liver diseases.
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