Synthesis and antitumour evaluation of 4-bromophenyl semicarbazones

4-Bromophenyl semicarbazone derivatives have been synthesized and their chemical structures have been confirmed by means of their IR, 1H-NMR data and by elemental analyses. The in vitro evaluation in the 3-cell line, one dose primary anticancer assay is described. The 4-bromo substituted p-nitrobenzylidene phenyl semicarbazone (5) showed significant activity against breast MCF7 cell line and was further evaluated for potential anticancer activity in an in vitro human disease-oriented tumour cell line screening panel that consisted of 59 human tumour cell lines arranged in nine subpanels, representing diverse histologies. Melanoma UACC-62 cell line was relatively more sensitive to compounds 5 (growth inhibitions: GI50 = 15.3 mumol/l).     

Radiation exposure impairs luteinizing hormone signal transduction and steroidogenesis in cultured human leydig cells.

Therapeutic, accidental, and experimental radiation exposures decreased serum testosterone in males, leading to various sexual problems. Since testicular Leydig cells are the predominant source of circulating testosterone, findings on the direct effects of radiation on Leydig cell steroidogenesis and the mechanism behind such effects would be of greater importance to the use of safer radiation doses in cancer therapy and to adopt preventive or therapeutic measures to alleviate postirradiation lesions, respectively. Therefore, this study was undertaken to explore the same using cultured human Leydig cells. Testicles removed from advanced prostatic carcinoma patients were used for isolation and purification of Leydig cells. Purified Leydig cells were cultured and then exposed to different doses (2, 4, 6, 8, and 10 Gy) of fractioned gamma radiation. Normal and irradiated cells were used for luteinizing hormone (LH) receptor quantification or total RNA isolation to study LH receptor mRNA expression or LH/cyclic AMP (cAMP) stimulation test. While LH-stimulated cells were used for cAMP assay, LH- and cAMP-stimulated cells were used for the estimation of steroidogenic enzymes, testosterone and estradiol production. Radiation exposure caused adverse effects on Leydig cell steroidogenesis in a dose-dependent manner. While lower doses (2 and 4 Gy) were ineffective, higher doses (6 Gy and above) drastically decreased LH receptor, basal and LH-stimulated cAMP generation, and basal, LH-, and cAMP-stimulated steroidogenesis. While 2 Gy of radiation exposure increased the LH receptor mRNA level, other doses did not induce any significant change. Therefore, it is concluded that higher doses of radiation impair Leydig cell steroidogenesis by affecting LH signal transduction at the level of both pre- and post-cAMP generation. Decreased level of LH receptors following higher doses of radiation exposure is not coupled with impaired expression of its mRNA.     

GABA binding in the brains of aggressive and non-aggressive female hamsters

Ovariectomized female hamsters were selected for agrressiveness of non-aggressiveness toward a drug-treated target hamster. Animals in the aggressive group were found to have significantly higher levels of GABA binding in their brain ‘midregions’ (including limbic, striatal and diencephalic structures). There were no between-group GABA binding differences in cortex or pons/medulla and no differences in dihydroalprenolol (DHA) binding in any of these three regions. The groups did not differ on a variety of other behavioral tests including measures of activity, emotionality, feeding, and hormonally primed sexual behavior. The differences in ‘midregion’ GABA binding therefore may relate to levels of aggressiveness specifically.     

Drug-induced differentiation of a rat glioma in vitro: II. The expression of S-100, a glial specific protein and steroid sulfatase

Amethopterin and 5-bromodeoxyuridine (BUdR) were used to induce morphological changes in cloned rat glioma (C6). The expression of S-100 protein, an acidic protein localized in glial cells, and steroid sulfatase, an ubiquitously distributed enzyme found in high concentration in glial cells, were followed during cell growth, from subculture to well into the stationary phase of control and drug-treated cultures. Amethopterin and BUdR differed in their effects on glioma morphology and in the expression of the biochemical parameters. Amethopterin coordinately stimualted both the production of S-100 protein and steroid sulfatase activity when cell division was inhibited during early logarithmic growth phase. BUdR stimulated steroid sulfatase activity but repressed production of S-100 protein. The results are discussed with respect to the mechanism of regulation of the differentiated state of tumor cells.     

Monosodium glutamate affects the temporal characteristics of biochemical variables in Wistar rats

Monosodium glutamate (MSG) was administrated chronically for 60 days to Wistar rats and 24 h rhythms of glucose, cholesterol, total protein and alkaline phosphatase were studied. MSG treatment was found to cause acrophase delays in the glucose and alkaline phosphatase rhythms and advances in acrophases of cholesterol and total protein levels. Amplitude and mesor values of these rhythms were found to be altered during MSG treatment. Glutamate levels in the brain were found to be significantly increased, which could alter these biochemical rhythms by modulating the transmission in retinohypothalamic tract and in the hypothalamic nuclei, probably including suprachiasmatic nuclei.     

Evaluation of analgesic, antipyretic activity and toxicity study of Bryonia laciniosa in mice and rats

Analgesic, antipyretic activity and toxicity study of the leaves of Bryonia laciniosa Linn. (Family: Cucurbitaceae) was evaluated in the standard animal models. The methanol extract of Bryonia laciniosa (MEBL) was evaluated by hot plate and acetic acid-induced writhing methods to assess analgesic activity. The antipyretic activity of the extract was also evaluated by normal body temperature and yeast-induced hyperpyrexia. The extract showed significant analgesic and antipyretic activity. The MEBL was further evaluated for toxicity at the doses of 125 and 250 mg/kg administered orally for 14 days in rats. At the end of experiments, the blood, liver function and kidney metabolism were observed. The hematological profile and different biochemical parameters such as SGOT, SGPT and ALP were estimated. The present study revealed that MEBL exhibited significant analgesic and antipyretic activity in the tested experimental animal models. The toxicity study indicates that the extract is not toxic at the tested doses.     

Grape seed extract inhibits advanced human prostate tumor growth and angiogenesis and upregulates insulin-like growth factor binding protein-3

Dietary intake of many fruits and vegetables has been shown to be associated with reduced risk of cancer. We investigated the in vivo efficacy of grape seed extract (GSE, patented as Traconol) against prostate cancer (PCA) and associated molecular events. Athymic nude mice were implanted with hormone-refractory human prostate carcinoma DU145 cells and fed with 100 and 200 mg/kg/day (5 days/week) doses of GSE for 7 weeks. At the end of experiment, tumors were immunohistochemically analyzed for cell proliferation, apoptosis and angiogenesis. Our data show that GSE feeding strongly inhibited tumor growth that accounted for 59-73% (p < 0.001) inhibition in tumor volume and 37-47% (p < 0.05) decrease in tumor weight at the end of the experiment. It did not show any significant change in body weight gain profile and diet consumption. Immunohistochemical analysis of tumors showed that GSE decreases proliferation index by 51-66% (p < 0.001) and increases apoptotic index by 3-4-fold (p < 0.001). CD31 staining for endothelial cells, showed decrease in intratumoral microvasculature in GSE-fed group of mice. Control tumors showed 64.0 +/- 1.6 CD31 positive cells/400x field compared to 23.2 +/- 0.9 and 15.7 +/- 0.08 (p < 0.001) CD31 positive cells in 100 and 200 mg/kg doses of GSE-treated tumors, respectively. GSE strongly inhibited (47-70%, p < 0.05) vascular endothelial growth factor (VEGF) secretion in conditioned medium by DU145 cells. Recently, the circulating level of insulin-like growth factor binding protein (IGFBP)-3 is shown to inversely related with PCA risk, growth and prognosis. Consistent with this, we observed 6-7-fold (p < 0.001) increase in tumor-secreted levels of IGFBP-3 after GSE feeding. In other immunohistochemical studies, compared to controls, tumor xenografts from GSE-fed groups of mice showed a moderate decrease in VEGF but an increase in IGFBP-3 levels. These findings suggest that GSE possesses in vivo anticancer efficacy against hormone-refractory human PCA, which is associated with its antiproliferative, proapoptotic and antiangiogenic activities together with upregulation of IGFBP-3.     

Enhancement of circulatory antioxidants by alpha-ketoglutarate during sodium valproate treatment in Wistar rats

The effects of alpha-ketoglutarate (alpha-KG) on sodium valproate-induced hyperammonemia and hepatotoxicity were studied in biochemical experiments in rats. The levels of ammonia, urea, serum transaminases, hydroperoxides and thiobarbituric acid reactive substances were significantly increased in sodium valproate-treated rats. These levels were significantly decreased in alpha-KG- and sodium valproate-treated rats. Further, non-enzymatic (vitamins C and E) and enzymatic (superoxide dismutase and catalase) antioxidants were significantly decreased in sodium valproate-treated rats and were increased in alpha-KG- and sodium valproate-treated rats. These biochemical alterations during alpha-KG treatment could be due to (i) its ability to act as an ubiquitous collector of amino groups in body tissues, (ii) the participation of alpha-KG in the non-enzymatic oxidative decarboxylation in the hydrogen peroxide decomposition process and (iii) enhancing the proper metabolism of fats which could suppress oxygen radical generation and, thus, prevent the lipid peroxidative damages in rats.