Mark Shahmurov

Melatonin inhibits nuclear factor kappa B activation and oxidative stress and protects against thioacetamide induced liver damage in rats

BACKGROUND/AIMS Free radical-mediated oxidative stress has been implicated in the pathogenesis of acute liver injury. The aim of our study was to investigate whether melatonin, a potent free radical scavenger could prevent fulminant hepatic failure in rats. METHODS Liver damage was induced by two consecutive injections of thioacetamide (TAA, 300 mg/kg/i.p.) at 24 h intervals. Treatment with melatonin (3 mg/kg/daily, i.p) was initiated 24 h prior to TAA. RESULTS Twenty-four h after the second TAA injection, serum liver enzymes and blood ammonia were lower in rats treated with TAA+melatonin compared to TAA (P<0.001). Liver histology was significantly improved and the mortality in the melatonin-treated rats was decreased (P<0.001). The increased nuclear binding of nuclear factor kappa B in the livers of the TAA-treated rats, was inhibited by melatonin. The hepatic levels of thiobarbituric acid reactive substances, protein carbonyls and inducible nitric oxide synthase were lower in the TAA+melatonin-treated group (P<0.01), indicating decreased oxidative stress and inflammation. CONCLUSIONS In a rat model of TAA-induced fulminant hepatic failure, melatonin improves survival and reduces liver damage and oxidative stress. The results suggest a causative role of oxidative stress in TAA-induced hepatic damage and suggest that melatonin may be utilized to reduce liver injury associated with oxidative stress.

Curcumin ameliorates acute thioacetamide-induced hepatotoxicity.

Background and Aim:  Increased production of reactive oxygen species and nitric oxide and activation of nuclear factor κ B are implicated in the pathogenesis of various liver diseases, including fulminant hepatic failure. Curcumin is a naturally occurring anti‐oxidant that reduces oxidative stress and inhibits nuclear factor κ B and nitric oxide formation. The aim of the present study is to assess curcumins therapeutic potential in acute thioacetamide hepatotoxicity, a rat model of fulminant hepatic failure.

Glycine modulates cytokine secretion, inhibits hepatic damage and improves survival in a model of endotoxemia in mice.

Background and aim: There is substantial experimental evidence that the amino acid glycine may have a role in protecting tissues against insults such as ischemia, hypoxia and reperfusion. Our aim was to investigate the ability of the amino acid glycine to prevent hepatic damage induced by injection of lipopolysaccharide and d‐galactosamine (d‐Gal), to modulate pro‐ and anti‐inflammatory cytokine levels, and to improve survival.

Evaluation of a novel continuous real time 13C urea breath analyser for Helicobacter pylori

To evaluate the sensitivity and specificity of a new 13C urea breath test, Oridion BreathID, for the diagnosis of Helicobacter pylori.

Utility of a 13C-methacetin breath test in evaluating hepatic injury in rats

Background and Aim:  Methacetin is thought to be a good substrate for the evaluation of different cytochrome P450 enzymatic systems of liver microsomes because of its rapid metabolism and lack of toxicity in small doses. Recent studies indicate that a methacetin breath test may be a non‐invasive alternative for the evaluation of liver function since it correlates well with the severity of liver damage. It may also discriminate between different stages of liver cirrhosis and correlates with the Child–Pugh score. The application of this test in experimental liver damage in animal models has not yet been examined. This study aimed to evaluate the efficacy of the 13C‐methacetin breath test in assessing the extent of hepatic injury in models of acute liver failure, liver cirrhosis, and fatty liver in rats.

The Cyclin-Dependent Kinase Inhibitor, p27kip1, Has No Correlation with the Malignant Potential of GIST

Background: Tumor size and mitotic activity are characteristically associated with the malignant potential and prognosis of gastrointestinal stromal tumors (GIST). However, since neither small tumor size nor low mitotic activity can rule out malignancy, additional factors that may predict malignant behavior have been suggested. Aim: To evaluate the correlation between the cyclin-dependent kinase inhibitor (CDI), p27kip1, expression and the malignant potential of GIST. Methods: Serial sections were evaluated by immunohistochemistry after staining with antibodies against p27/Kip1 and Ki-67 in surgical material obtained from 36 patients with GIST. p27kip1 staining intensity and the percentage of positive cells were investigated for association with the malignancy risk, pathological features, overall survival, and disease-free survival. Histologic grade was assigned by spindle vs. epithelioid cell histology, mucosal invasion, tumor cell necrosis or atypia and the number of mitoses. Results: In the multivariate model, p27kip1 expression was not significantly associated with any of the variables examined except Kit protein-CD117 (r = 0.37, p = 0.03). Comparative evaluation of p27kip1 expression in GIST cells revealed higher levels of p27kip1 in patients who died compared to those who survived (2.04 ± 0.54 vs. 1.3 ± 0.99, p = 0.1). Conclusion: The CDI p27kip1 was not associated with malignancy of GISTs and did not serve as a predictor of survival.

Chronic Cholestasis Associated with Turner’s Syndrome: 12 Years of Clinical and Histopathological Follow-Up

Clinically significant liver disease is probably a rare condition in Turner’s syndrome and only a few cases of severe liver disease have been described. The natural history of patients with Turner’s syndrome and elevated cholestatic liver enzymes is unclear. We report a case with a long history of intrahepatic cholestasis and without clinical or histopathological progression in 12 years of follow-up. Like some other reports our case suggests, also histologically, that the liver disease in these patients runs a benign course.

Renoprotective Effect of Angiotensin II Receptor Antagonists in Experimental Chronic Renal Failure

We compared the antihypertensive and renoprotective effects of the angiotensin II receptor antagonist losartan and the calcium channel blocker verapamil in the rat with chronic renal failure. One month after five-sixths nephrectomy, male WKY rats were treated for 2 months with either losartan or verapamil. Both resulted in a similar reduction in blood pressure: from 147.1 to 112 mm Hg in losartan-treated and from 155 to 118 mm Hg (p = NS) in verapamil-treated rats. Losartan improved the creatinine clearance (difference +17.1% as compared with +6.6% for verapamil, p = 0.039) and prevented the increase in proteinuria: 12.26 ± (SE) 2.33 mg/day before and 18.48 ± 2.19 mg/day (p = NS) after therapy in the losartan-treated and 17.27 ± 2.73 mg/day before and 32.27 ± 10.29 mg/day after therapy (p = 0.0484) in the verapamil-treated group. In addition, losartan resulted in minimal mesangial proliferation and significantly less glomerular sclerosis and thickening of the small arterial and arteriolar walls. The changes in interstitial fibrosis and tubular hypertrophy, however, were similar in both the verapamil- and losartan-treated groups. Treatment with losartan 1 month after five-sixths nephrectomy in male WKY rats resulted in reduced blood pressure, similar to that of the verapamil-treated group. However, despite similar antihypertensive properties, losartan improved creatinine clearance and reduced proteinuria. The losartan-treated group also had a marked reduction in mesangial proliferation and less glomerular sclerosis and less reduced vascular wall thickness in renal small arteries and arterioles. However, losartan did not totally eliminate nephrosclerosis. The tubular and interstitial changes were fewer in the losartan-treated group. Thus losartan has an additional, although only partial, renoprotective effect when compared with verapamil.

p27kip1 expression is inversely related to the grade of gastric MALT lymphoma

AbstractBackground: Decreased or lost expression of the cyclin-dependent kinase inhibitor p27kip1 protein has been found to be a poor prognostic factor in many cancers, including gastric cancer. Aim: To evaluate p27kip1 expression in gastric mucosa-associated lymphoid tissue (MALT) and gastric B-cell lymphoma. Methods: Fifty-two cases of gastric lymphoma, mean age 68.7 yr (range 23–90 yr), 11 of chronic Helicobacter pylori-associated gastritis, and 5 of normal gastric mucosa were studied. Patients were classified into two groups. Stage IE gastric lymphomas were defined as local gastric lymphoma of MALT and more advanced stages as advanced gastric lymphoma. Twenty-three patients diagnosed as stage IE, 13 of these were low-grade and 10 diffuse large B-cell lymphoma (DLBL). Twenty-nine patients were at stage IIE or above, 18 with low-grade and 11 with DLBL. Serial sections were evaluated by immunohistochemistry after staining with antibodies against p27/Kip1 and Ki-67. Results: The proliferative index was higher in gastric DLBL than in low-grade MALT lymphomas, 57.1±31.2 vs 17.3±20.6 (p=0.0001). The mean p27kip1 expression score for high-grade patients was significantly lower compared with that of low-grade patients, 0.5 ± 0.4 and 1.6±0.8, respectively (p=0.001). Comparative evaluation of p27kip1 expression in malignant lymphoid cells revealed that B cells of the localized gastric DLBL patients expressed the least p27kip1, 0.36±0.32. This value was lower than that of malignant lymphoid cells of patients with advanced DLBL, 0.64±0.53, advanced low-grade MALT lymphoma, 1.59±0.79, and localized low-grade MALT lymphoma, 1.59±0.84. In the multivariate model in which all p27kip1 variables were entered, the expression of p27kip1 in malignant lymphoid cells was inversely correlated with the grade of the lymphoma irrespective of the stage of the disease (p=0.0001), and significantly predicted grade: OR:0.07, 95% CI 0.07–0.31, p=0.0001.Conclusion: p27kip1 may be a putative distinct molecular marker to differentiate between low-grade and high-grade gastric lymphoma.