Modulatory role of green tea extract on antinociceptive effect of morphine in diabetic mice

Diabetic neuropathic pain is an important microvascular complication, and morphine has been demonstrated to be ineffective in this condition. Therefore the present study was designed to investigate the modulatory effect of green tea extract (GTE) on the decreased antinociceptive effect of morphine in diabetic mice. The tail withdrawal test was performed for measurement of the nociceptive threshold in both streptozotocin (STZ)-injected and control mice. Four weeks after administration of STZ, antinociception of morphine (5 mg/kg, s.c.) alone or in combination with GTE (25, 50, and 100 mg/kg, i.p.) was measured. Experimental diabetes markedly decreased the antinociceptive effect of morphine. The decrement in morphine response was significantly attenuated by GTE administration. When GTE (25 mg/kg) and a nitric oxide (NO) inhibitor, L-N(G)-nitroarginine methyl ester (L-NAME) (10 mg/kg, i.p), were co-administered along with morphine (5 mg/kg, s.c) in diabetic mice, the antinociceptive action of morphine was significantly increased as compared with the GTE + morphine-treated diabetic group, but the increased antinociceptive action was significantly attenuated by administration of an NO precursor, L-arginine (100 mg/kg, i.p), instead of L-NAME. Plasma nitrite concentrations were estimated using the Griess reagent. Diabetes significantly increased the plasma nitrite levels that were attenuated by GTE administration. When GTE (25 mg/kg) and L-NAME (10 mg/kg, i.p) were co-administered along with morphine (5 mg/kg, s.c) in diabetic mice, the plasma nitrite levels were significantly decreased as compared with the GTE + morphine alone-treated diabetic group, but the decreased plasma nitrite levels were significantly reversed by administration of L-arginine (100 mg/kg) instead of L-NAME. It may be concluded that increased NO formation may be responsible for the decreased antinociceptive effect of morphine in diabetic mice and that GTE restored the antinociceptive effect of morphine by inhibition of NO production. The results of the present study indicate the possibility of adding GTE as an adjuvant in the treatment of diabetic neuropathic pain.     

Heterotopic neuroglial tissue in hard palate

Heterotopic neuroglial condition is a rare congenital anomaly in children. Most of the reported cases have been located in nose. To date, there was no recorded case of heterotopic neuroglial tissue in hard palate without any other congenital anomaly. The purpose of this report is to present a rare case of heterotopic neuroglial tissue in hard palate to add to literature we reviewed.     

Diabetes-induced mitochondrial dysfunction in the retina

PURPOSE: Oxidative stress is increased in the retina in diabetes, and antioxidants inhibit activation of caspase-3 and the development of retinopathy. The purpose of this study was to investigate the effect of diabetes on the release of cytochrome c from mitochondria and translocation of Bax into mitochondria in the rat retina and in the isolated retinal capillary cells. METHODS: Mitochondria and cytosol fractions were prepared from retina of rats with streptozotocin-induced diabetes and from the isolated retinal endothelial cells and pericytes incubated in 5 or 20 mM glucose medium for up to 10 days in the presence of superoxide dismutase (SOD) or a synthetic mimetic of SOD (MnTBAP). The release of cytochrome c into the cytosol and translocation of the proapoptotic protein Bax into the mitochondria were determined by the Western blot technique and cell death by caspase-3 activity and ELISA assay. RESULTS: Diabetes of 8 months' duration in rats increased the release of cytochrome c into the cytosol and Bax into the mitochondria prepared from the retina, and this phenomenon was not observed at 2 months of diabetes. Incubation of isolated retinal capillary cells with 20 mM glucose increased cytochrome c content in the cytosol and Bax in the mitochondria, and these abnormalities were accompanied by increased cell apoptosis. Inclusion of SOD or its mimetic inhibited glucose-induced release of cytochrome c, translocation of Bax, and apoptosis. CONCLUSIONS: Retinal mitochondria become leaky when the duration of diabetes is such that capillary cell apoptosis can be observed; cytochrome c starts to accumulate in the cytosol and Bax into the mitochondria. Inhibition of superoxides inhibits glucose-induced release of cytochrome c and Bax and inhibits apoptosis in both endothelial cells and pericytes. Identifying the mechanism by which retinal capillary cells undergo apoptosis may reveal novel therapies to inhibit the development of retinopathy in diabetes.     

Confirmation of structures of semecarpus biflavanones A1 and A2.

The biflavanone mixture from SEMECARPUS ANACARDIUM L. was reisolated and dehydrogenated with I (2)/KOAc in AcOH to yield the corresponding, relatively more stable, biflavone mixture which was methylated using diazomethane. Two biflavone methyl ethers SA1 and SA2 were obtained which confirmed the structures proposed for the parent biflavanones A1 and A2 respectively.     

Idiopathic hypereosinophilic syndrome presenting as childhood hemiplegia.

A case of childhood hemiplegia due to idiopathic hypereosinophilic syndrome is reported. There was no cardiac lesion. The neurological complications associated with hypereosinophilic syndrome and the pathophysiological mechanism of neurotoxicity of human eosinophils are discussed. It is likely that the neurological deficit was due to eosinophilic neurotoxicity.     

Positive modulation by Ras of interleukin-1beta-mediated nitric oxide generation in insulin-secreting clonal beta (HIT-T15) cells.

In the present study, we have shown that exposure of insulin-secreting clonal beta (HIT-T15) cells to interleukin-1beta (IL-1beta) results in a time- and concentration-dependent increase in nitric oxide (NO) release. These effects by IL-1beta on NO release were mediated by induction of inducible nitric oxide synthase (iNOS) from the cells. Preincubation of HIT cells with Clostridium sordellii lethal toxin-82, which irreversibly glucosylates and inactivates small G-proteins, such as Ras, Rap, Ral, and Rac, but not Cdc42, completely abolished IL-1beta-induced NO release. Pre-exposure of HIT cells to C. sordellii lethal toxin-9048, which monoglucosylates and inhibits Ras, Cdc42, Rac, and Rap, but not Ral, also attenuated IL-1beta-mediated NO release. These data indicate that activation of Ras and/or Rac may be necessary for IL-1beta-mediated NO release. Preincubation of HIT cells with C. difficile toxin-B, which monoglucosylates Rac, Cdc42, and Rho, had no demonstrable effects on IL-mediated NO release, ruling out the possibility that Rac may be involved in this signaling step. Further, two structurally dissimilar inhibitors of Ras function, namely manumycin A and damnacanthal, inhibited, in a concentration-dependent manner, the IL-1beta-mediated NO release from these cells. Together, our data provide evidence, for the first time, that Ras activation is an obligatory step in IL-1beta-mediated NO release and, presumably, the subsequent dysfunction of the pancreatic beta cell. Our data also provide a basis for future investigations to understand the mechanism of cytokine-induced beta cell death leading to the onset of insulin-dependent diabetes mellitus.     

A farnesylated G-protein suppresses Akt phosphorylation in INS 832/13 cells and normal rat islets: Regulation by pertussis toxin and PGE2

Protein isoprenylation constitutes incorporation of either 15-carbon farnesyl or 20-carbon geranylgeranyl derivative of mevalonic acid onto the C-terminal cysteine, culminating in increased hydrophobicity of the modified proteins for optimal membrane anchoring and interaction with their respective effectors. Emerging evidence confirms the participatory role of prenylated proteins in pancreatic β-cell function including insulin secretion. Herein, we investigated the putative regulatory roles of protein farnesylation in cell survival signaling pathways in insulin-secreting INS 832/13 cells and normal rodent islets, specifically at the level of protein kinase-B/Akt phosphorylation induced by insulin-like growth factor [IGF-1]. Selective inhibitors of farnesylation [e.g., FTI-277 or FTI-2628] or knockdown of the β-subunit of farnesyl transferase by siRNA significantly increased Akt activation under basal and IGF-1-stimulated conditions. Consequentially, the relative abundance of phosphorylated FoxO1 and Bad were increased implicating inactivation of critical components of the cell death machinery. In addition, FTI-induced Akt activation was attenuated by the PI3-kinase inhibitor, LY294002. Exposure of INS 832/13 cells to pertussis toxin [PTx] markedly potentiated Akt phosphorylation suggesting involvement of a PTx-sensitive G-protein in this signaling axis. Furthermore, prostaglandin E₂, a known agonist of inhibitory G-proteins, significantly attenuated FTI-induced Akt phosphorylation. Taken together, our findings suggest expression of a farnesylated G-protein in INS 832/13 cells and normal rat islets, which appear to suppress Akt activation and subsequent cell survival signaling steps. Potential regulatory roles of the islet endogenous protein kinase-B inhibitory protein [Probin] in islet function are discussed.