Effect of curcumin on ethanol-induced stress on mononuclear cells

Blood cells in circulation are exposed to a wide variety of stress-causing agents, causing a number of changes including interactions with other cells and the extracellular matrix of the endothelial wall. In order to understand the role of curcumin, an antioxidant principle from Curcuma longa Linn., on blood mononuclear cells from rabbits given ethanol for 30 days and ethanol with curcumin, cells were isolated and an attachment assay was carried out. The monocytes from ethanol-treated rabbits showed a lesser attachment to collagen, the major component of the vessel wall subendothelium, and those from curcumin treated animals along with ethanol showed a higher affinity to collagen, causing an alteration in the attachment of monocyte to collagen due to ethanol-induced stress.     

Depletion of the catalytic subunit of protein phosphatase-2A (PP2Ac) markedly attenuates glucose-stimulated insulin secretion in pancreatic beta-cells

Among various phosphatases, the protein phosphatase 2A (PP2A) is relatively well studied in the islet. Previously, we have demonstrated that the catalytic subunit of PP2A (PP2Ac) undergoes okadaic acid (OKA)-sensitive, reversible carboxylmethylation (CML), which appears to be requisite for glucose-stimulated insulin secretion (GSIS). Using the siRNA approach, we examined, herein, the contributory roles of PP2Ac in GSIS from insulin-secreting pancreatic β-(INS-1 832/13) cells. Immunologically, PP2Ac was detectable in all the subcellular fractions studied in rank order of: cytosol > microsomes > secretory granules = nucleus > mitochondria. Transfection of PP2Ac-specific, but not scrambled-siRNA, markedly attenuated PP2A activity and GSIS in these cells. Together, our findings provide a direct evidence for a positive modulatory role for PP2Ac in signaling steps leading to GSIS.     

Protective role of curcumin in ethanol toxicity

The effect of curcumin on ethanol induced liver toxicity was evaluated. The increased levels of aspartate transaminase and alkaline phosphatase induced by ethanol were significantly lowered by curcumin. Elevated serum cholesterol, phospholipids and free fatty acids were observed in ethanol fed rats, but on curcumin treatment they decreased. We have also observed a marked decrease in the levels of thiobarbituric acid reactive substances in serum of alcoholic rats fed curcumin. Thus this study shows that curcumin offers protection against ethanol induced toxicity. © 1998 John Wiley & Sons, Ltd.     

Neuroprotective role of curcumin from curcuma longa on ethanol-induced brain damage.

In the present study, curcumin from Curcuma longa was screened for neuroprotective activity using ethanol as a model of brain injury. Oral administration of curcumin to rats caused a significant reversal in lipid peroxidation, brain lipids and produced enhancement of glutathione, a non-enzymic antioxidant in ethanol intoxicated rats, revealing that the antioxidative and hypolipidaemic action of curcumin is-responsible for its protective role against ethanol induced brain injury.     

Structure‐Based Design of a Novel Class of Potent Inhibitors of InhA,the Enoyl Acyl Carrier Protein Reductase from Mycobacterium Tuberculosis: A Computer Modelling Approach

The NADH‐dependent Enoyl‐ACP reductase (InhA) of Mycobacterium tuberculosis has been shown to be the primary target of the frontline drug isoniazid (INH). However, INH must be first activated by katG gene, mutations in which have mediated resistance to INH. Recently, direct inhibitors of InhA have been reported. Using a structure‐based approach, we have identified a tripeptide inhibitor with the sequence WYW, which is 100 times more potent than the existing inhibitors. It is therefore, a potential lead compound for the development of new anti‐TB drugs.     

Usefulness of diastolic time measured on electrocardiogram to improve sensitivity and specificity of exercise tolerance tests

The current exercise tolerance test (ETT) criteria predominantly assess changes in ST-segment deviation (i.e., a systolic component of the cardiac cycle). Because diastolic dysfunction precedes that of systolic dysfunction during myocardial ischemia and most coronary flow is diastolic, the addition of electrocardiographic markers of diastolic time might improve the ETT sensitivity and specificity for detecting significant coronary artery disease. Among consecutive patients who had an ETT and subsequently underwent coronary angiography, we evaluated the diastolic time by assessing the TP and TQ segments and TP/RR and TQ/RR ratios in each ETT stage. Coronary artery disease was defined angiographically as significant (≥70% lumen occlusion), intermediate (>50% but <70% lumen occlusion), or nonsignificant (≤50% lumen occlusion). Of the 48 study patients, hypertension and hyperlipidemia appeared highly prevalent. TP, TQ, TP/RR, and TQ/RR correlated significantly with RR and changed with each ETT stage. Although TP and TQ were not significantly associated with significant coronary artery disease, TP/RR and TQ/RR proved to be, particularly beyond stage 2. When TQ/RR of ≤0.39 and TP/RR of ≤0.13 were used, their individual sensitivities and specificities were reasonably comparable to that of traditional ETT criteria (79% sensitivity and 44% specificity at our institution). Adding TQ/RR of ≤0.39 and/or TP/RR of ≤0.13 to existing ETT criteria improved its sensitivity to 100% and specificity to 86%. In conclusion, the addition of diastolic time indexes of TP/RR and TQ/RR significantly improved the overall ETT diagnostic value above the guideline-oriented, perhaps "traditional," criteria for the diagnosis of myocardial ischemia. Such parameters should be widely investigated further for clinical accuracy and compatibility.     

Effect of chronic ethanol ingestion on biochemical circadian rhythms in Wistar rats.

Chronic ingestion of ethanol for 60 days was known to alter the characteristics of biochemical circadian rhythms in Wistar rats. Peak times of glucose, potassium and lactic acid rhythms were delayed by 18 h, 3 h, and 3 h respectively, whereas peak times of cholesterol and malondialdehyde rhythms were advanced by 3 h and 9 h respectively during ethanol treatment. Significant changes in range (p < 0.001 expect in calcium) and 24 h mean (p < 0.001) of all the biochemical circadian rhythms studied were observed during ethanol treatment. The alterations in the characteristics of these biochemical circadian rhythms could be principally due to the alterations on the hepatic cellular architecture; other plausible underlying reasons are also discussed.     

Regulatory roles for Tiam1, a guanine nucleotide exchange factor for Rac1, in glucose-stimulated insulin secretion in pancreatic β-cells

Using various biochemical, pharmacological and molecular biological approaches, we have recently reported regulatory roles for Rac1, a small G-protein, in glucose-stimulated insulin secretion (GSIS). However, little is understood with respect to localization of, and regulation by, specific regulatory factors of Rac1 in GSIS. Herein, we investigated regulatory roles for Tiam1, a specific nucleotide exchange factor (GEF) for Rac1, in GSIS in pancreatic β-cells. Western blot analysis indicated that Tiam1 is predominantly cytosolic in distribution. NSC23766, a specific inhibitor of Tiam1-mediated activation of Rac1, markedly attenuated glucose-induced, but not KCl-induced insulin secretion in INS 832/13 cells and normal rat islets. Further, NSC23766 significantly reduced glucose-induced activation (i.e. GTP-bound form) and membrane association of Rac1 in INS 832/13 cells and rat islets. Moreover, siRNA-mediated knock-down of Tiam1 markedly inhibited glucose-induced membrane trafficking and activation of Rac1 in INS 832/13 cells. Interestingly, however, in contrast to the inhibitory effects of NSC23766, Tiam1 gene depletion potentiated GSIS in these cells; such a potentiation of GSIS was sensitive to extracellular calcium. Together, our studies present the first evidence for a regulatory role for Tiam1/Rac1-sensitive signaling step in GSIS. They also provide evidence for the existence of a potential Rac1/Tiam1-independent, but calcium-sensitive component for GSIS in these cells.