Effect of Solanum trilobatum on hepatic drug metabolising enzymes during diethylnitrosamine-induced hepatocarcinogenesis promoted by Phenobarbital in rat

The present study was aimed to investigate the chemopreventive effects of Solanum trilobatum (ST) extract against diethylnitrosamine (DEN)-induced hepatocarcinogenesis promoted by Phenobarbital (PB) in Wistar rats. Hepatocarcinogenesis was initiated by a single intraperitoneal injection of DEN (200 mg/kg b.w.) and promoted with PB (0.05%) in basal diet. The experimental study extended for periods of 13 and 26 weeks. Alcoholic extract of ST was orally administered for the entire experimental period after initiation along with commencement of promotion. The chemopreventive effect of ST was assessed from the incidence of nodules, drug metabolizing phase I components such as contents of cytochrome P450, cytochrome b(5), activities of NADPH cytochrome c reductase, NADH - cytochrome b(5) reductase and phase II components such as levels of glutathione, activities of UDP-glucuronyl transferase, glutathione S-transferase and gamma-glutamyl transpeptidase in the liver. Lipid peroxidation at basal and prooxidants-induced (NADPH + ADP + Fe and Ascorbate + Fe) states was assessed in the microsomes. Animals administered with ST extract evidenced significant inhibition of tumor nodular incidence in DEN + PB + ST animals compared to DEN + PB animals, with favorable alterations in the hepatic drug-metabolizing phase I and phase II components. Administration of ST inhibited basal and pro-oxidant-induced lipid peroxidation. The present result suggests the probable mediation of chemoprevention by ST against DEN-induced carcinogenesis by the modulation of drug metabolizing components in the liver of treated animals.     

Review analysis of medullary carcinoma of the thyroid: a 15-year Indian experience

The aim of this study was to emphasize the importance of adequate primary surgery in cases of medullary carcinoma of the thyroid. We retrospectively reviewed 44 cases of medullary carcinoma of the thyroid treated in Government General Hospital, Chennai between 1987 and 2002. Patients who underwent total thyroidectomy with only central compartment dissection were compared with those who had undergone total thyroidectomy with meticulous triple compartment (bilateral lateral and central groups) nodal dissection. The group of total thyroidectomy with only central compartment dissection had a high rate of lymph nodal recurrence and persistent hypercalcitoninemia compared with the group with total thyroidectomy with meticulous triple compartment nodal dissection. (chi square, 4.503; P > 0.05). Primary surgery with total thyroidectomy with meticulous triple compartment dissection is superior to total thyroidectomy with central compartment dissection alone in terms of preventing nodal and local recurrences and achieving normal (basal and stimulated) serum calcitonin levels postoperatively.     

Effect of green tea extract on advanced glycation and cross-linking of tail tendon collagen in streptozotocin induced diabetic rats.

Diabetes leads to modification of collagen such as advanced glycation and cross-linking which play an important role in the pathogenesis of diabetes mellitus. We have investigated the effect of green tea on modification of collagen in streptozotocin (60 mg/kg body weight) induced diabetic rats. To investigate the therapeutic effect of green tea, treatment was begun six weeks after the onset of diabetes and green tea extract (300 mg/kg body weight) was given orally for 4 weeks. The collagen content, extent of advanced glycation, advanced glycation end products (AGE) and cross-linking of tail tendon collagen were investigated. Green tea reduced the tail tendon collagen content which increased in diabetic rats. Accelerated advanced glycation and AGE in diabetic animals, as detected by Ehrlich's-positive material and collagen linked fluorescence respectively were reduced significantly by green tea. The solubility of tail tendon collagen decreased significantly in diabetic rats indicating a remarkable increase in the cross-linking, whereas green tea increases the solubility of collagen in diabetic rats. The present study reveals that green tea is effective in reducing the modification of tail tendon collagen in diabetic rats. Thus green tea may have a therapeutic effect in the treatment of glycation induced complications of diabetes.     

Green tea attenuates diabetes induced Maillard-type fluorescence and collagen cross-linking in the heart of streptozotocin diabetic rats.

The enhanced myocardial collagen content, collagen glycation and the resulting advanced glycation end products (AGE) which exhibit the characteristics of increased cross-linking are proposed for the stiffness of myocardium in diabetes. To explore the cardioprotective effect of green tea in diabetes, we study the effect of green tea extract on myocardial collagen characteristics in streptozotocin diabetic rats. The effect of green tea on marker enzymes in serum and cardiac tissues were also assayed to understand the extent of protection. Six weeks after the diabetes induction, diabetic rats were treated with green tea extract [300 mg (kg body weight)(-1)day(-1)] for 4 weeks. AGE were determined by fluorescence assay and cross-linking of collagen by solubility measurement while collagen content was measured by biochemical assay. The activities of aspartate transaminase (AST), lactate dehydrogenase (LDH) and creatine kinase (CPK) were measured by biochemical assay. The increase in blood glucose, glycated hemoglobin and systolic blood pressure in diabetic rats were reduced upon green tea treatment. The activities of AST, LDH and CPK were significantly increased in serum whereas decreased in cardiac tissues in diabetic rats representing the cardiac damage. Administration of green tea to diabetic rats significantly ameliorates these enzyme activities. There was no significant difference in the myocardial collagen content among the experimental rats. A significant (P<0.05) increase in collagen linked Maillard-type fluorescence and decrease in collagen solubility in the myocardium of diabetic rats as compared to control rats (0.955+/-0.02 versus 0.683+/-0.04 and 30+/-1.41 versus 45.17+/-1.17, respectively) indicates the increase in advanced glycation end products formation and degree of collagen cross-linking. Green tea administration to diabetic rats significantly (P<0.05) decreased the fluorescence (0.73+/-0.02) whereas increased the solubility of collagen (41.5+/-1.04) indicating the reduction in advanced glycation end products and collagen cross-linking. The present study reveals that green tea by ameliorating myocardial collagen characteristics may provide a therapeutic option in the treatment of cardiovascular complications of diabetes.     

Evidence that nitric oxide production increases gamma-amino butyric acid permeability of blood-brain barrier

Blood-brain barrier permeability (BBB) to the inhibitory neurotransmitter gamma-amino butyric acid (GABA) was studied in rats following intraperitoneal (i.p) injections of GABA alone and in combination with L-Arginine (L-Arg). Administration of GABA (600 mg/kg body weight [b. wt.]) alone increased brain GABA concentration (33%, p < 0.01), when compared to untreated rats and administration of L-Arg (2000 mg/kg b. wt.) alone also increased GABA concentration (65%, p < 0.01) in the brain. Moreover, GABA + L-Arg treated brains showed a fourfold increase in GABA level (383.3%, p < 0.01) when compared to controls. Dose-dependent increase in nitric oxide production was observed 10 min after i.p injections of L-Arg (400, 800, 1000, and 2000 mg/kg b. wt.) and a peak nitric oxide (NO) production was observed at the dose level of 2000 mg/kg b. wt. On the other hand, administration of GABA failed to increase NO production in the brain. Rats pretreated (10 min) with a nonspecific nitric oxide synthase (NOS) inhibitor N(omega)-nitro-L-Arginine methyl ester (L-NAME, 50 mg/kg b. wt.) completely blocked the production of NO induced by L-Arg. In addition, L-NAME attenuated GABA entry into the brain after the administration of GABA alone or in combination with L-Arg. We conclude that high NO concentrations in the brain following L-Arg administration may increase the permeability of BBB to peripheral GABA.     

Lactate dehydrogenase isoenzyme patterns upon chronic exposure to cigarette smoke: Protective effect of bacoside A

Despite a strong association between cigarette smoking and alarming increase in mortality rate from smoking-related diseases, around 35-40% of the world's population continues to smoke and many more are being exposed to environmental tobacco smoke. Since the role of free radicals and oxidative damage in the pathogenesis of smoking-related diseases has been suggested, bacoside A, a potent antioxidant was tested for its ability to protect against cigarette smoking-induced toxicity in terms of lactate dehydrogenase (LDH) and its isoenzymes. Rats were exposed to cigarette smoke and simultaneously administered with bacoside A, for a period of 12 weeks. Total LDH activity was assayed in serum, lung, heart, brain, liver and kidney, and serum LDH isoforms were separated electrophoretically. Cigarette smoke exposure resulted in significant increase in serum LDH and its isoenzymes with a concomitant decrease in these organs. These alterations were prevented by administration of bacoside A. Excessive oxidants from cigarette smoke is known to cause peroxidation of membrane lipids leading to cellular damage, thereby resulting in the leakage of LDH into the circulation. Bacoside A could have rendered protection to the organs by stabilizing their cell membranes and prevented the release of LDH, probably through its free radical scavenging and anti-lipid peroxidative effect.     

Attenuation of neutrophil infiltration and proinflammatory cytokines by Cissus quadrangularis: a possible prevention against gastric ulcerogenesis

Reactive oxygen species, neutrophil infiltration and proinflammatory cytokines play an important role in the pathogenesis of gastric ulcers caused by aspirin. The present study demonstrates the healing effect of Cissus quadrangularis extract (CQE) through inhibitory action on generation of lipid peroxidation, proinflammatory cytokines and neutrophil infiltration. The concentration ofmalondialdehye (MDA), protein carbonyl content, conjugated dienes, mucosal (SH) sulphydryls, uric acid, tumor necrosis factor-alpha (TNF-alpha), and activities of myeloperoxidase (MPO), xanthine oxidase (XO) and antioxidative enzymes were determined in the gastric mucosa. Administration of CQE significantly attenuated the gastric lesions induced by aspirin and this was accompanied by the rise in uric acid, antioxidative enzymes, SH groups, and a significant decrease in lipid peroxidase, TNF-alpha, MPO and XO activities. These findings suggest that the significant gastroprotective activity could be mediated by the antioxidant activity as well as by the attenuation of oxidative mechanism and proinflammatory cytokines.     

Inhibition of matrix metalloproteinase-9 reduces in vitro invasion and angiogenesis in human microvascular endothelial cells

The expression of matrix metalloproteinases (MMPs), particularly MMP-9, is significantly increased during tumor progression and is thought to play a major role in mediating angiogenic process. Since microvasculature plays an important role in controlling tumor growth, we investigated the effects of MMP-9 inhibition on endothelial cell migration and tube formation, two determinants of angiogenesis. Adenoviral-mediated MMP-9 downregulation inhibited endothelial cell migration in cell wounding and spheroid migration assays. To determine the effects of MMP-9 reduction in glioblastoma/endothelial co-cultures, we used a three-dimensional co-culture assay of glioblastoma spheroids and endothelial spheroids. Untreated controls showed invasion of both cell populations into each other whereas treatment of the co-cultures with adenoviral antisense MMP-9 particles resulted in reduced invasion. Next, inhibition of MMP-9 by adenoviral vectors in endothelial cells was assessed for in vitro capillary-like structure formation either by co-culture with glioblastoma cells or exposure to glioblastoma-conditioned medium. Addition of conditioned medium from human glioblastoma cells to endothelial cells treated with antisense MMP-9 adenoviral vectors or co-cultures of glioblastoma cell lines with MMP-9-reduced endothelial cells resulted in reduced capillary-like tube formation demonstrating the key role of MMP-9 in endothelial cell network organization. Examination of in vitro capillary-like tube structure formation using Matrigel showed a significant decrease in MMP-9 downregulated endothelial cells as compared to controls. In conclusion, the inhibition of MMP-9 is required for inhibition of endothelial cell migration and tube formation and is likely to be of importance in cerebral angiogenesis for therapeutic targets.