Efficacy of a Non-Hypercalcemic Vitamin-D2 Derived Anti-Cancer Agent (MT19c) and Inhibition of Fatty Acid Synthesis in an Ovarian Cancer Xenograft Model

BACKGROUND:Numerous vitamin-D analogs exhibited poor response rates, high systemic toxicities and hypercalcemia in human trials to treat cancer. We identified the first non-hypercalcemic anti-cancer vitamin D analog MT19c by altering the A-ring of ergocalciferol. This study describes the therapeutic efficacy and mechanism of action of MT19c in both in vitro and in vivo models. METHODOLOGY/PRINCIPAL FINDING:Antitumor efficacy of MT19c was evaluated in ovarian cancer cell (SKOV-3) xenografts in nude mice and a syngenic rat ovarian cancer model. Serum calcium levels of MT19c or calcitriol treated animals were measured. In-silico molecular docking simulation and a cell based VDR reporter assay revealed MT19c-VDR interaction. Genomewide mRNA analysis of MT19c treated tumors identified drug targets which were verified by immunoblotting and microscopy. Quantification of cellular malonyl CoA was carried out by HPLC-MS. A binding study with PPAR-Y receptor was performed. MT19c reduced ovarian cancer growth in xenograft and syngeneic animal models without causing hypercalcemia or acute toxicity. MT19c is a weak vitamin-D receptor (VDR) antagonist that disrupted the interaction between VDR and coactivator SRC2-3. Genome-wide mRNA analysis and western blot and microscopy of MT19c treated xenograft tumors showed inhibition of fatty acid synthase (FASN) activity. MT19c reduced cellular levels of malonyl CoA in SKOV-3 cells and inhibited EGFR/phosphoinositol-3kinase (PI-3K) activity independently of PPAR-gamma protein. SIGNIFICANCE:Antitumor effects of non-hypercalcemic agent MT19c provide a new approach to the design of vitamin-D based anticancer molecules and a rationale for developing MT19c as a therapeutic agent for malignant ovarian tumors by targeting oncogenic de novo lipogenesis

Tuning the Gas Separation Performance of CuBTC by Ionic Liquid Incorporation

The efficient separation of gases has industrial, economic, and environmental importance. Here, the gas separation performance of a metal organic framework (MOF) is enhanced by ionic liquid (IL) incorporation. One of the most commonly used ILs, 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM]­[BF₄]), was incorporated into a commercially available MOF, CuBTC. Detailed characterization by combining spectroscopy with diffraction, electron microscopy, and thermal analysis confirmed that the structures were intact after incorporation. Adsorption isotherms of CH₄, H₂, N₂, and CO₂ in IL-incorporated CuBTC were experimentally measured and compared with those of pristine CuBTC. Consequently, ideal selectivities for CO₂/CH₄, CO₂/N₂, CO₂/H₂, CH₄/N₂, CH₄/H₂, and N₂/H₂ separations were calculated. The results showed that the CH₄ selectivity of CuBTC over CO₂, H₂, and N₂ gases becomes at least 1.5 times higher than that of pristine CuBTC upon the incorporation of IL. For example, the CH₄/H₂ selectivity of CuBTC increased from 26 to 56 at 0.2 bar when the IL loading was 30 wt %. These results show that the incorporation of ILs into MOFs can lead to unprecedented improvements in the gas separation performance of MOFs. The tunable physicochemical properties of ILs combined with a large number of possible MOF structures open up opportunities for the rational design of novel materials for meeting future energy challenges

The effect of repeated administration of methotrexate (MTX) on rat ovary: measurement of serum antimullerian hormone (AMH) levels

Objective: To evaluate the possible effect of methotrexate (MTX) on rat ovaries by measuring serum antimullerian hormone (AMH), the novel marker of the ovarian reserve. Methods: Pretreatment serum AMH levels were measured in 15 Wistar albino rats. MTX was given in 1 mg/kg dose in days 1, 3, 5, and 7. Serum AMH levels were measured twenty-four hours after each MTX administration. Pre- and post-treatment serum AMH levels were compared. Results: Pretreatment median serum AMH was 102.4 ng/mL (25%: 41.9; 75%: 179.8). The median serum AMH levels were 70.6 ng/mL (25%: 54.08; 75%: 125.5); 136.1 ng/mL (25%: 57.3; 75%: 223.09); 121.2 ng/mL (25%: 52.5; 75%: 151.5); and 104.7 ng/mL (25%: 65.8; 75%: 265.5) after the first, second, third, and fourth methotrexate administrations, respectively. The ratio of the final (eighth day) median serum AMH level to the pretreatment median AMH level was 1.27 (25%: 0.84 and 75%: 2.57). Wilcoxon related samples test showed that final AMH was significantly higher as compared to the second day AMH measurement (p = 0.041). Conclusion: MTX administration did not cause a statistically significant change between pretreatment and final serum AMH levels in rats. There was no decrease in AMH levels indicating a decrease in ovarian reserve

Biomarkers of lipid peroxidation related to hypertension in aging

The aim of this clinical study was to evaluate the influence of aging on the levels of lipid peroxidation (quantified as thiobarbituric acid-reactive substances (TBARS) content), lipid hydroperoxide (LOOH), hexanoyl lysine (HEL), 8-iso-prostaglandin F2 alpha (8-iso-PGF2 alpha) and total antioxidant capacity (TAC), and determine their relationships to the demographic and cardiovascular risk factors in elderly hypertensive (HT) patients. This study consisted of four groups: two elderly groups with 30 HT patients (11 males, 19 females) and 30 normotensive healthy volunteers (15 males, 15 females), and two young groups with 30 HT patients (13 males, 17 females) and 30 normotensive healthy volunteers (12 males, 18 females). In the elderly control group, the TBARS, LOOH, HEL and 8-iso-PGF2 alpha levels, and the carotid intima media thickness (CIMT) were significantly higher than in the young control group. The TBARS, LOOH, HEL and 8-iso-PGF2 alpha levels and the CIMT measurements were significantly higher in the elderly HT group than in the young HT group. In addition, the TAC levels were significantly lower in the elderly and young HT groups than in the elderly and young control groups. The CIMT was significantly positively correlated with TBARS (r=0.40, P<0.001), HEL (r= 0.30, P=0.001), LOOH (r= 0.44, P<0.001) and 8-iso-PGF2 alpha (r=0.32, P<0.001) in all of the HT groups. It seems that in elderly patients, the LOOH and TBARS are better biomarkers of lipid peroxidation in hypertension in terms of sensitivity. In all of the HT groups, 8-iso-PGF2 alpha had the highest sensitivity. Hypertension is associated with lipid peroxidation due to an impaired oxidant/antioxidant status. Increased lipid peroxidation and decreased antioxidants with aging indicate that peroxidative damage further increases with higher blood pressure and the aging process