Effect of a Selective Cyclooxygenase Type 2 Inhibitor Celecoxib on Depression Associated with Obesity in Mice: An Approach Using Behavioral Tests

The biological mechanisms that link the development of depression to metabolic disorders such as obesity and diabetes remain ambiguous. In the present study the potential of a selective cyclooxygenase inhibitor celecoxib (15 mg/kg p.o.) was investigated in depression associated with obesity in mice. Behavioral tests used to assess depressive-like behavior were sucrose preference test, forced swim test (FST), tail suspension test (TST) and elevated plus maze (EPM). The basal locomotor score in obese mice was not altered. Furthermore, estimation of biochemical parameters was performed for plasma glucose, total cholesterol, triglycerides and total proteins. Escitalopram (10 mg/kg p.o.) served as reference standard drug. In the results, chronic treatment with celecoxib for 28 days significantly attenuated the behavioral alterations as indicated by increased the sucrose consumption, reduced the immobility time in FST and TST, increased the percent open arm time and entries in EPM in obese mice. In the biochemical parameters celecoxib significantly reversed the increased plasma glucose, total cholesterol, triglycerides and total proteins in obese mice. In conclusion, celecoxib exhibited potential antidepressant-like effect in depression associated with obesity, which to some extent is mediated by reversing the altered plasma glucose in obese mice.     

Initial studies of a phytoestrogen-deoxyribonucleic acid interaction

Molecular modeling studies show that estrogens such as estradiol complement the topography of spaces between base pairs in unwound DNA and simultaneously hydrogen bond phosphate moieties on opposite strands. We demonstrate here that the phytoestrogen coumestrol has this capability, in addition to its documented properties of UV absorbance at lambda greater than 300 nm and fluorescence. The latter properties enable spectroscopic examination of interactions with DNA by methods not possible with estrogenic steroids. On exposure to calf thymus DNA, the UV spectrum of coumestrol displays a bathochromic shift and simultaneous hypochromic effect with an isosbestic point at 370 nm, suggesting a shift between coexisting free and bound states. Similar results are observed with the intercalating agents adriamycin, ethidium bromide, and acridine. The fluorescence spectrum of coumestrol is quenched on exposure to DNA as are those of adriamycin and acridine. Coumestrol differs from the intercalators in that denatured DNA does not affect its UV spectrum or alter its relative fluorescence yield. Unlike classical intercalators, coumestrol has no influence on the thermal stability of calf thymus DNA. Preliminary electrophoretic analysis of DNA plasmid conformers indicates that coumestrol is incapable of significantly altering DNA superhelical density, in contrast to ethidium bromide. These initial physicochemical data provide evidence for the DNA base-estrogen electronic and/or hydrophobic interactions suggested by modeling studies, yet tend to rule out classical intercalation as an explanation for these phenomena.     

Estimation of mass transport parameters in a column packed with BioSep beads

An approach to estimate the parameters needed to describe the performance of a column packed with BioSepTM beads is presented. These parameters, which characterize the transport of materials through the column, have been estimated from experimental residence time distribution (RTD) data using both porous and non-porous beads. A laboratory-scale column was used to obtain the experimental data using several ionic species. © Rapid Science Ltd. 1998     

Design, synthesis and initial biological evaluation of a novel pladienolide analog scaffold

A novel and simplified synthetic scaffold based on pladienolide was designed using a consensus pharmacophore hypothesis. An initial target was synthesized and evaluated to examine the role of the 3-hydroxy group and the methyl groups present at positions 10, 16, 20, 22 in 1, on biological activity. We report the first totally synthetic analog of this macrolide that shows biological activity. Our novel synthetic strategy enables the rapid synthesis of other new analogs of pladienolide in order to develop selective anticancer lead compounds.     

Aqueous extract of Terminalia arjuna attenuates tert‐butyl hydroperoxide–induced oxidative stress in HepG2 cell model

Arjuna (Terminalia arjuna) is a medicinal plant used in many polyherbal hepatoprotective formulations. Although widely claimed to be antioxidant, data supporting such actions of Arjuna are limited. In the present study, we have investigated the efficacy of the aqueous extract of T. arjuna (AETA) using a standard pro‐oxidant [tertiary butyl hydroperoxide (TBHP)] in HepG2 cells. Cells were incubated with AETA (5–100 µg/ml) for a range of time points (4–24 h) with or without TBHP (500 μM), and biochemical markers of oxidative stress (OS) were determined. Cells incubated with TBHP showed the significant induction of OS response in cytosol manifested as lipid hydroperoxide (76%–198%) and the generation of reactive oxygen species (60%–127%). Diminished levels of reduced glutathione (35%–60%) and total antioxidant capacity (20%–61%) suggested an altered redox state. Significant perturbations in the activities of antioxidant enzymes such as catalase (30%–56%), superoxide dismutase (25%–68%), glutathione S‐transferase (29%–67%), glutathione peroxidase (24%–68%) and glutathione reductase (38%–49%) were discernible suggesting the ongoing OS in the cells. However, cells treated with AETA (100 µg/ml) along with TBHP offered significant protection by reducing levels of lipid hydroperoxide (33%–62%) and ROS (69%) and by increasing antioxidant capacity (54%–81%) and levels of reduced glutathione (49%–82%). Further, it also enhanced the activities of endogenous antioxidant enzymes (superoxide dismutase, 60%; catalase, 35%–82%; glutathione peroxidase, 42–65 %; glutathione reductase, 48%–62%; and glutathione S‐transferase, 22%–100%). Taken together, these data suggest that Arjuna can protect against the oxidative damage induced by TBHP and may be effectively used as a hepatoprotective adjuvant to abrogate OS in vivo. Copyright © 2012 John Wiley & Sons, Ltd.     

Role of 5α-reduction in progesterone's ability to release FSH in estrogen-primed ovariectomized rats

In ovariectomized estrogen-primed rats, progesterone as well as 5α-dihydroprogesterone (5α-DHP) are capable of inducing the release of gonadotropins. This study examined the need of 5α-reduction as a prerequisite for the action of progesterone. The 5α-reductase inhibitor, N,N-diethyl-4-methyl-3-oxo-4-aza-5α-androstane-17β-carboxamide was injected at a 1 or 2 mg dose/rat 2 h prior to an injection of 0.4 or 0.8 mg progesterone/kg body weight at 0900 h to immature ovariectomized, estrogen-primed rats and serum was analyzed for LH and FSH at 1500 h. Pituitary and hypothalamic 5α-reductase activity was measured at the time of progesterone administration and at the time of the surge by incubating tissue homogenates with [³H]progesterone. Substrate, ([³H]progesterone) and product ([³H]5α-DHP), were separated by reverse phase HPLC. The pituitary 5α-reductase activity was not blocked at 1500 h. However, both pituitary and hypothalamic 5α-reductase was blocked at the time of progesterone administration. No effect was seen by acute administration of the 5α-reductase inhibitor upon either the 0.4 or 0.8 mg progesterone/kg-induced release of LH and FSH. There was, however, a specific, significant inhibition of progesterone-induced FSH but not LH release when the 5α-reductase inhibition was sustained throughout the afternoon of the gonadotropin surge. These results indicate a biologically significant role for the irreversible 5α-reduction of progesterone in the modulation of the release of FSH.     

Activation of the kinin system in the ovary during ovulation: Role of endogenous progesterone

Background  

Previous work by our group and others has implicated a role for kinins in the ovulatory process. The purpose of the present study was to elucidate whether endogenous progesterone, which is an intraovarian regulator of ovulation, might be responsible for induction of the kinin system in the ovary during ovulation. The gonadotropin-primed immature rat was used as the experimental model, and the role of endogenous progesterone was explored using the antiprogestin, RU486.