Posts Tagged ‘study’

Administration of a low dose of sildenafil for one week decreases intrahepatic resistance in rats with biliary cirrhosis: The role of NO…

February 5th, 2010

Background/Aim: Increasing nitric oxide (NO) bioavailability improves hepatic endothelial dysfunction, which ameliorates intrahepatic resistance and portal hypertension. Acute administration of sildenafil increases hepatic production of nitric oxide (NO) with reduction of hepatic sinusoid resistance in cirrhotic patients and enhances the vasorelaxation response to nitric oxide in cirrhotic rat livers. However, the mechanisms were still unclear. Therefore, our study aims to evaluate the effects and mechanisms of administration of sildenafil for one week in the hepatic microcirculation of cirrhotic rats. Methods: Cirrhosis was induced by bile duct ligation. Sham-operated rats served as normal controls. Intrahepatic resistance was evaluated by in situ liver perfusion. Expression of phosphorylated endothelial nitric oxide synthase (p-eNOS), inducible nitric oxide synthase (iNOS), phosphorylated Akt (p-Akt), phosphodiesterase-5 (PDE-5), and soluble guanylyl cyclase (sGC) were determined by Western blot analysis. Biosynthesis of tetrahydrobiopterin (BH4) and GTP cyclohydrolase I (GTPCH-I) activity were examined by HPLC. Intravital microscopy was used to observe the direct change in hepatic microcirculation. Results: In cirrhotic rat livers, sildenafil treatment increased hepatic sinusoid volumetric flow, NO bioavailability, BH4, GTPCH-I activity, protein expression of p-Akt, p-eNOS and sGC. These events were associated with reduced protein expression of PDE-5, portal perfusion pressure, and portal vein pressure. In contrast, sham rats did not produce significant change in these measurements. Conclusions: Sildenafil treatment improves endothelial dysfunction by augmenting NO bioavailability in hepatic microcirculation.

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Administration of a low dose of sildenafil for one week decreases intrahepatic resistance in rats with biliary cirrhosis: The role of NO…

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{beta}-arrestin 1 contributes to primary biliary cirrhosis

December 21st, 2009

Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by anti-mitochondrial antibodies and autoreactive T cells that cause destruction of small primary bile ducts. The molecular mechanisms regulating the autoreactive T cells remain elusive. β-arrestins (βarr) are multifunctional signaling molecules essential for T cell survival. We hypothesized that βarr plays a critical regulatory function in the autoreactive T cells of PBC patients. Here, our studies showed that βarr1 expression was elevated significantly in T lymphocytes from PBC patients. Moreover, the level of βarr1 mRNA positively correlated with Mayo risk score in PBC patients. Based on modulation of βarr in autoreactive T cell lines, overexpression of βarr1 increased T cell proliferation, augmented interferon production, downregulated activities of NF–κB and AP–1, promoted acetylation of histone H4 in the promoter regions of CD40L, LIGHT, IL-17 and Interferon–γ, but downregulated acetylation of histone H4 in the promoter regions of TRAIL, Apo2 and HDAC7A, and suppressed their expression. Our findings suggest that overexpression of βarr1 contributes to the pathogenesis of PBC. This study broadens the correlation of barr1 overexpression in experimental allergic encephalomyelitis and multiple sclerosis to a third autoimmune disease, PBC. Further investigations on barr1 modulation in autoimmune disease are warranted.

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{beta}-arrestin 1 contributes to primary biliary cirrhosis

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Statins have beneficial effects on platelet free radical activity and intracellular distribution of GTPases in hyperlipidaemia

September 9th, 2009

Aims: In addition to lowering cholesterol, statins may alter endothelial release of the vasodilator nitric oxide and harmful superoxide free radical. Statins also reduce cholesterol intermediates including isoprenoids. These are important for post-translational modification of substances including the GTPases Rho and Rac. By altering membrane association of these molecules, statins affect intra-cellular positioning and hence activity of a multitude of substances. These include endothelial nitric oxide synthase which produces nitric oxide (inhibited by Rho) and the nicotinamide dinucleotide (phosphate) oxidase which produces superoxide (dependent on Rac). Statins may improve endothelial function by enhancing production of nitric oxide while decreasing superoxide production.

Methods: 40 hypercholesterolaemic patients were randomised to treatment with atorvastatin or placebo. 20 normolipidaemic patients were also studied. Platelet nitrite, nitric oxide and superoxide were examined as was cellular distribution of the GTPases Rho and Rac at baseline and after eight weeks of treatment.

Results: Following atorvastatin therapy platelet nitric oxide was increased (3.2 pmol/ 108 platelets) and superoxide output attenuated (-3.4pmol/min/108 platelets) when compared with placebo. The detection of both Rho and Rac was significantly reduced in the membranes of platelets implying reduced activity.

Conclusion: This study shows altered nitric oxide/superoxide production following statin therapy. A potential mechanism for this is the change in distribution of intracellular GTPases which was felt to be secondary to decreases in isoprenoid intermediates, suggesting that activity of the former had been affected by atorvastatin.

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Statins have beneficial effects on platelet free radical activity and intracellular distribution of GTPases in hyperlipidaemia

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Reduction in renal ACE2 expression in subtotal nephrectomy is ameliorated with ACE inhibition

August 21st, 2009

Alterations within the renin-angiotensin system (RAS) are pivotal for the development of renal disease. Angiotensin-converting enzyme (ACE) 2 is expressed in the kidney, and converts the vasoconstrictor angiotensin (Ang) II to Ang 1-7, a peptide with vasodilatory and anti-fibrotic actions. Whilst the expression of ACE2 in the diabetic kidney has been well studied, little is known about its expression in non-diabetic renal disease. We assessed ACE2 in rats with acute kidney injury induced by subtotal nephrectomy (STNx). STNx and Control rats received vehicle or ramipril (1 mg/kg/d), and measured renal ACE, ACE2 and mas receptor gene and protein expression 10 days later. STNx rats were characterised by polyuria, proteinuria, hypertension and elevated plasma ACE2 activity (all P<0.01), and plasma Ang 1-7 (P<0.05) compared to Control. There was increased cortical ACE binding and medullary mas receptor expression (P<0.05), but reduced cortical and medullary ACE2 activity in the remnant kidney (P<0.05, P<0.001) compared to Control. In STNx, ramipril reduced blood pressure (P<0.01), polyuria (P<0.05) and plasma ACE2 (P<0.01), increased plasma Ang 1-7 (P<0.001), and inhibited renal ACE (P<0.001). Ramipril increased both cortical and medullary ACE2 activity (P<0.01) but reduced medullary mas receptor expression (P<0.05). Our results show that ACE2 activity is reduced in kidney injury, and that ACE inhibition produced beneficial effects in association with increased renal ACE2 activity. As ACE2 both degrades Ang II and generates the vasodilator, Ang 1-7, a decrease in renal ACE2 activity as observed in this study has the potential to contribute to the progression of kidney disease.

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Reduction in renal ACE2 expression in subtotal nephrectomy is ameliorated with ACE inhibition

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Enhanced circulating retinol and nonesterified fatty acids in pregnancies complicated with intrauterine growth restriction

August 6th, 2009

Intrauterine growth restriction (IUGR) increases the incidence of perinatal complications, and although several placental transport functions have been shown to be altered in pregnancies complicated by IUGR, the mechanism behind it is not well understood. This study investigated factors in maternal and cord blood plasma from normal and IUGR complicated pregnancies associated with newborns’ body weight. At the time of caesarean section, twenty-four women with IUGR pregnancies were compared to a group of thirty normal controls with appropriate gestation age (AGA) fetuses that were studied at caesarean, which took place 5 weeks earlier than IUGRs and also to a group of twenty-five nondelivered gestational age-matched control pregnant women (AGA-35 wks). Maternal plasma retinol, γ- and α-tocopherol, non-esterified fatty acids (NEFA), palmitic-, palmitoleic-, γ-linolenic- and arachidonic-acid were higher in women with IUGR pregnancies than in AGA-35 wks controls, whereas stearic- and α-linolenic-acid were lower. Smaller differences were found when comparing these variables for IUGR and AGA women. However, umbilical vein plasma γ-tocopherol, cholesterol, triacylglycerols and NEFA were higher in the IUGR group than in AGA, whereas arachidonic acid was lower. Maternal plasma retinol and NEFA were the only variables negatively correlated with birth weight when multiple linear regressions were analyzed. In conclusion, the increased circulating retinol and NEFA in maternal plasma are negatively associated with birth and placental weights, which may reflect an impaired placental transfer in IUGR pregnancies. Since retinoids have been involved in the control of gene transcription, it is proposed that a decreased placental transfer of retinol could underlie the metabolic dysfunction of IUGR pregnancies.

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Enhanced circulating retinol and nonesterified fatty acids in pregnancies complicated with intrauterine growth restriction

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