Butyrate-induced phosphatase regulates VEGF and angiogenesis via Sp1.

Sp1 is a ubiquitous transcription factor and master regulator of various eukaryotic gene expression. Better understanding of the role of increased Sp1 levels on angiogenic regulation and the regulatory regions of that transcription factor may act as a useful target in 'transcriptional therapy'. At the molecular level, butyrate inhibits Sp1-DNA binding activity by promoting Sp1 protein dephosphorylation in EAT cells. It also inhibits Sp1 binding activity and reduces expression of VEGF gene, thereby inhibiting angiogenesis. It was confirmed that butyrate induces expression of a tyrosine phosphatase by RT-PCR, cDNA sequence analysis, protein ESI-MS analysis and protein sequence homology comparison. Thus our result strongly suggests that inhibition of angiogenesis by butyrate involves Sp1 dephosphorylation and down-regulation of VEGF gene expression. Further, butyrate inhibits neoangiogenesis induced by tumor cells and VEGF in peritoneum of EAT bearing mice and rat cornea.

Octacosanol isolated from Tinospora cordifolia downregulates VEGF gene expression by inhibiting nuclear translocation of NF-B and its DNA binding activity.

Octacosanol is a long-chain aliphatic alcohol, which is the main component of policosanol used as a normolipidemic agent. It is known that angiogenesis is involved in tumor growth and metastasis. The present study identified octacosanol isolated from the plant Tinospora cordifolia as a new antiangiogenic compound with inhibitory effects on in vivo angiogenesis assays. Our results showed that octacosanol (i) inhibits proliferation of endothelial cells and Ehrlich ascites tumor cells, (ii) inhibits neovascularization induced by angiogenic factors in chick chorioallantoic membrane and rat cornea in vivo angiogenesis assays, (iii) inhibits secretion of ascites fluid in the growing tumor cells in vivo. Concerning the mechanism of action, octacosanol inhibited secretion of vascular endothelial growth factor into ascites fluid by the tumor cells. At the molecular level octacosanol markedly inhibits activity of matrix metalloproteinases (MMPs) and translocation of transcription factor nuclear factor-B to nucleus. The mechanism of inhibition of angiogenesis by octacosanol reflects on its effect on tumor angiogenesis and metastasis.

Angiogenic and proliferative effects of the cytokine VEGF in Ehrlich ascites tumor cells is inhibited by Glycyrrhiza glabra.

Blood vessel plays a crucial role in solid tumor development. It has been suggested that blocking of angiogenesis and the action of the cytokine VEGF could be possible in cancer therapy. In a screen for naturally occurring angiogenic inhibitors, we have identified an extract from the roots of Glycyrrhiza glabra, which has potent antiangiogenic and antitumor activity. The aqueous extract inhibits the in vivo and in vitro proliferation of Ehrlich ascites tumor cells. The angioinhibitory activity of G. glabra was confirmed by its inhibition of angiogenesis in in vivo assays, peritoneal and chorioallantoic membrane assay. Reduction in the levels of the cytokine VEGF and microvessel density count in the peritoneum of mice treated with G. glabra indicated that the plant extract decreased VEGF production and the cytokine induced neovascularization. Our results suggest that the extract from the roots of G. glabra may be a potential supplemental source for cancer therapy.

The influence of different methods on basal metabolic rate measurements in human subjects.

While collating basal metabolic rate (BMR) measurements made worldwide it becomes important to know how different instruments compare with each other and whether errors in methodology could account for the differences in BMRs measured. BMRs of 34 healthy individuals were measured by using five different instruments in various combinations. Results show that energy outputs were comparable between the oxylog. Hartmann and Braun Metabolator, ventilated tent and hood, and whole-body indirect calorimeter: small differences, if any, were not statistically significant. However, significant interactions existed between subjects with the ventilated tent and hood and calorimeter when measurements were taken in subjects who were unaccustomed to the apparatus. When converting O2-consumption measurements to energy output, some instruments make assumptions that introduce a variable error in the final result, which may lead to systematic errors during the compilation of large databases of human BMRs.

Thermogenic responses to graded doses of noradrenaline in undernourished Indian male subjects.

1. Seventeen male subjects with an energy intake of 10.6 (SD 1.7) MJ/d and ten male undernourished labourers with an energy intake of 8.0 (SD 1.2) MJ/d were studied. The controls were subdivided into ten underweight controls with a body mass index (weight/height2; BMI) less than 18 (17.2 (SD 0.9)) and seven normal-weight controls with a BMI greater than 20 (21.3 (SD 1.6)), while the undernourished labourers had a BMI less than 18 (16.8 (SD 1.2)). 2. Comparison of thermogenic responses to increasing doses of noradrenaline showed no overall significant inter-group differences when subjected to a nested analysis of variance (ANOVA). For the initial doses of 0.05 and 0.1 micrograms noradrenaline, significantly lower responses were seen in the undernourished subjects, while the highest dose showed comparable responses in all three groups. Thermogenic responses to the initial two doses, when corrected for fat-free mass (FFM) differences, were 40% lower in the undernourished group when compared with the underweight group with similar BMI and FFM values. However, this finding was not statistically significant. 3. The basal oxygen consumption of the undernourished group, expressed per unit FFM, was significantly higher than that of the controls.

Prediction of steady-state oxygen consumption during norepinephrine infusions in humans.

A method for predicting maximal oxygen consumption during norepinephrine infusion is described. Using the initial response and enzyme kinetics, predicted values of maximal oxygen consumption were compared with observed values and a coefficient of variation of 1.4% was obtained. This method is of use in situations where it may not be possible to achieve steady-state conditions, especially with high doses of norepinephrine, and it permits comparison of maximal oxygen consumption between groups.