Synthesis and electronic properties of ester substituted 1,4-dicyanodibenzodioxins and evaluation of anti-proliferative activity of all isomeric 1,2-, 2,3- and 1,4-dicyanodibenzodioxins against HeLa cell line.

1,4-Dicyanodibenzodioxins bearing carboxy methyl ester groups were synthesized using our established one-step SNAr coupling reaction between ortho- and meta-ester substituted catechols and perfluorinated terephthalonitrile. These are the first examples of 1,4-dicyanodibenzodioxins substituted at both the benzene moieties. Optical spectra were similar to the earlier examples reported, with a marginal blue shift for the ester dibenzodioxins. Theoretical analysis of the molecular orbitals reveals modest destabilization of the frontier molecular orbitals of one carboxy methyl ester isomer over the other and overall higher HOMO-LUMO gap for both isomers when compared to the earlier published 1,4-dicyanodibenzodioxins. In vitro cytotoxicity against human cervical cancer HeLa cell line was evaluated for these two compounds and all other previously published dibenzodioxins from our laboratory (1,4-dicyano, 1,2-dicyano and 2,3-dicyano variants). A number of derivatives showed anti-tumor activity in µM ranges and also exhibited no cytotoxicity against normal HEK 293 cell line. Mechanistic investigation of cell death pathways indicated high levels of reactive oxygen species (ROS) in the dibenzodioxin treated tumor cell lines along with cellular nuclear fragmentation, both of which are markers of the apoptotic cell death pathway.

Expression of ODC1, SPD, SPM and AZIN1 in the hypothalamus, ovary and uterus during rat estrous cycle.

The aim of the present study was to investigate variation in the expression pattern of ornithine decarboxylase (ODC1), spermine (SPM), spermidine (SPD) and antizyme inhibitor (AZIN1) in hypothalamus, ovary and uterus during the estrous cycle of rats. Further, to understand any correlation between polyamines and GnRH I expression in hypothalamus; effect of putrescine treatment on GnRH I expression in hypothalamus and progesterone and estradiol levels in serum were investigated. The study also aims in quantifying all the immunohistochemistry images obtained based on pixel counting algorithm to yield the relative pixel count. This algorithm uses a red green blue (RGB) colour thresholding approach to quantify the intensity of the chromogen present. The result of the present study demonstrates almost similar expression pattern of polyamine and polyamine related factors, ODC1, SPD, SPM and AZIN1, with that of hypothalamic GnRH I, all of which mainly localized in the medial preoptic area (MPA) of the hypothalamus, during the proestrus, estrus and diestrus. This suggest that hypothalamic GnRH I expression is under regulation of polyamines. The study showed significant increase in hypothalamic GnRH I expression for both the doses of putrescine treatment to adult female rats. Further, it was shown that in ovary expression pattern of ODC1, SPM, SPD and AZIN1 were similar with that of steroidogenic factor, StAR during the estrous cycle, and putrescine supplementation increased significantly estradiol and progesterone levels in serum, all suggesting ovarian polyamines are involved in regulation of ovarian steroidogenesis. Localization of these factors in the theca and granulosa cells suggest involvement of polyamines in the process of folliculogenesis and luteinization; and ODC1, SPD, SPM and AZIN1 in oocyte further suggests polyamine role in maintenance of oocyte physiology. Finally, in uterus SPM and AZIN1 were localized throughout the estrous cycle, being comparatively more during the metestrus phase. There was intense immunostaining of SPD in the luminal and glandular epithelium during the metestrus and diestrus phases of the estrous cycle suggesting these all the three polyamines as such play important role in regulation of uterine physiology.

Regulation of the hypothalamic GnRH-GnIH system by putrescine in adult female rats and GT1-7 neuronal cell line.

The gonadotropin-releasing hormone-gonadotropin inhibitor (GnRH-GnIH) system in the hypothalamus of mammals is the key factor that controls the entire reproductive system. The aim of this study was to immunolocalize GnIH (RFRP-3) in the hypothalamus during the estrous cycle and to study the effect of putrescine on the expression of GnRH-I and GnIH through both in vivo and in vitro (GT1-7 cells) approach and the circulatory levels of GnRH-I, GnIH, and gonadotropins were also investigated. The study also aims in analyzing all the immunofluorescence images by measuring the relative pixel count of an image. This study showed the effect of putrescine on the morphology of ovary, uterus, and the expression of the steroidogenic acute regulatory protein in the ovary. This study showed GnIH expression was intense during the diestrus and moderate during proestrus and estrus, whereas mild staining during the metestrus. The study further showed that putrescine supplementation to adult female rats increased both GnRH-I expression in the hypothalamus as well as the GnRH-I levels in circulation. The study, for the first time, also showed that putrescine supplementation decreased the expression and release of GnIH. These effects of upregulating GnRH-I expression and downregulating GnIH expression were confirmed by in vitro experiments using GT1-7 cells. Putrescine supplementation also increased the gonadotropin levels in the serum. To summarize, putrescine can regulate the hypothalamic-pituitary-gonadal axis by increasing the GnRH-I, luteinizing hormone, and follicle-stimulating hormone levels and suppressing GnIH levels. This is the first report showing the simultaneous effects of putrescine on the regulation of both GnRH-I and GnIH in the hypothalamus.

Liraglutide modulates adipokine expression during adipogenesis, ameliorating obesity, and polycystic ovary syndrome in mice.

PURPOSE: The incidence of obesity is increasing among all age groups throughout the world and it is highly associated with numerous other metabolic disorders, such as insulin resistance, polycystic ovarian syndrome (PCOS) etc. METHODS AND RESULTS: Using in vitro and in vivo approach, this study investigated the adipokine profile after liraglutide on differentiated murine 3T3-L1 pre-adipocytes. Effect of liraglutide on DHEA-induced PCOS mice were investigated. This study showed Liraglutide treatment resulted in up-regulation of adiponectin and IL-6 along with down-regulation of ICAM 1 in differentiated 3T3-L1 cells. Liraglutide in absence of other differentiating factors, significantly increased glucose, lipid uptake and PPARγ, C/EBPα expression in the adipocytes suggesting its ability to solely promote pre-adipocyte differentiation into mature adipocyte. Liraglutide treatment showed increased adiponectin expression and decreased number of cystic follicles, body weight, circulating glucose, triglyceride and testosterone levels in comparison to the PCOS induced mice. CONCLUSION: This study suggests that adiponectin may act as a link between metabolic disorders and PCOS and that liraglutide might be a promising therapeutic agent for the treatment of PCOS in addition to obesity and insulin resistance.

Imaging Jupiter's aurorae from H3+ emissions in the 3-4 micrometers band.

Since H3+ was first spectroscopically detected on Jupiter, there has been considerable interest in using this simple molecular ion to probe conditions existing in the planet's auroral regions. Here we present a series of images of Jupiter recorded at wavelengths sensitive to emission by H3+, which reveal the spatial distribution of excited H3+ molecular ions in the jovian ionosphere, as seen from Earth. We believe that they provide high-spatial-resolution images of polar aurorae on Jupiter. They suggest that the intensity of the auroral emission can vary on a timescale of an hour, a shorter period than had previously been noted. We also find that the spatial distribution of H3+ emissions correlates only partially with the loci of auroral activity inferred from ultraviolet and longer-wavelength infrared observations. The H3+ emission may therefore be controlled by auroral processes that are different from those responsible for the ultraviolet and infrared emissions.