Identification and design of a novel series of MGAT2 inhibitors

[Acyl CoA]monoacylglycerol acyltransferase 2 (MGAT2) is of interest as a target for therapeutic treatment of diabetes, obesity and other diseases which together constitute the metabolic syndrome. In this Letter we report our discovery and optimisation of a novel series of MGAT2 inhibitors. The development of the SAR of the series and a detailed discussion around some key parameters monitored and addressed during the lead generation phase will be given. The in vivo results from an oral lipid tolerance test (OLTT) using the MGAT2 inhibitor (S)-10, shows a significant reduction (68% inhibition relative to na?ve, p <0.01) in plasma triacylglycerol (TAG) concentration.     

Regulation of somatostatin-14 and gastrin I binding sites in rat gastrointestinal mucosa by ulcerogenic dose of cysteamine

A single duodenal ulcerogenic dose of cysteamine administered into rats induced time-dependent depletion of immunoreactive somatostatin in the gastric corporeal, antral, and duodenal mucosa with a parallel increase (up-regulation) of somatostatin binding sites. The concentration of somatostatin binding sites returned to the control level in the corporeal mucosa when measured at 24 hrs; however, in the duodenal mucosa there was only a partial return to the control level. Somatostatin binding sites in the antral mucosa did not return to control level even after 24 hrs. Except for the duodenum mucosal immunoreactive gastrin level was unaffected by cysteamine administration, but corporeal mucosal gastrin I binding sites were diminished (down-regulation) after 24 hrs.     

Somatostatin as a mediator of the effect of neurotensin on pentagastrin-stimulated acid secretion in rats

Neurotensin and somatostatin have both been shown to inhibit gastric acid secretion, but no interaction between these peptides has been demonstrated. To determine whether somatostatin might be a mediator of neurotensin's effect on pentagastrin-stimulated gastric acid secretion, we performed the following three experiments. First, we collected 0.2-ml samples of portal venous blood as frequently as every 5 min, and we confirmed a significant release of somatostatin-like immunoreactivity into portal venous blood during neurotensin-induced inhibition of acid secretion. This release of somatostatin-like immunoreactivity and inhibition of acid secretion were only seen in pentobarbital-anesthetized rats, but no sustained release of somatostatin-like immunoreactivity or inhibition of acid secretion occurred in urethane-anesthetized animals. In the second experiment, we analyzed portal plasma by high pressure liquid chromatography, and found that portal somatostatin-like immunoreactivity in blood collected during neurotensin infusion was composed of a single peak corresponding to somatostatin-14. In the third experiment, we found that infusion of antibody to somatostatin prevented neurotensin from inhibiting pentagastrin-stimulated acid secretion. Taken together, these data show that somatostatin, possibly from the stomach itself, is a necessary mediator of neurotensin's inhibitory effect in pentobarbital-anesthetized rats.     

Identification of miR-17, miR-21, miR-27a,miR-106b and miR-222 as endoplasmic reticulum stress-related potential biomarkers in circulation of patients with atherosclerosis

Molecular Biology Reports - Atherosclerosis and related cardiovascular diseases are among the most common&nbsp;causes of death worldwide. Unfolded protein response, also known as Endoplasmic...     

Development and verification of a three-dimensional (3D) breast cancer tumor model composed of circulating tumor cell (CTC) subsets

Molecular Biology Reports - Breast cancer is one of the most common cancer types among women in which early tumor invasion leads to metastases and death. EpCAM (epithelial cellular adhesion...     

N‐acetyl‐L‐cysteine inhibits bleomycin induced apoptosis in malignant testicular germ cell tumors

Antioxidants may prevent apoptosis of cancer cells via inhibiting reactive oxygen species (ROS). However, to date no study has been carried out to elucidate the effects of strong antioxidant N‐acetylcysteine (NAC) on Bleomycin induced apoptosis in human testicular cancer (NTERA‐2, NT2) cells. For this reason, we studied the effects of Bleomycin and NAC alone and in combination on apoptotic signaling pathways in NT2 cell line. We determined the cytotoxic effect of bleomycin on NT2 cells and measured apoptosis markers such as Caspase‐3, ‐8, ‐9 activities and Bcl‐2, Bax, Cyt‐c, Annexin V‐FTIC and PI levels in NT2 cells incubated with different agents for 24 h. Early apoptosis was determined using FACS assay. We found half of the lethal dose (LD₅₀) of Bleomycin on NT2 cell viability as 400, 100, and 20 µg/ml after incubations for 24, 48, and 72 h, respectively. Incubation with bleomycin (LD₅₀) and H₂O₂ for 24 h increased Caspase‐3, ‐8, ‐9 activities, Cyt‐c and Bax levels and decreased Bcl‐2 levels. The concurrent incubation of NT2 cells with bleomycin/H₂O₂ and NAC (5 mM) for 24 h abolished bleomycin/H₂O₂‐dependent increases in Caspase‐3, ‐8, ‐9 activities, Bax and Cyt‐c levels and bleomycin/H₂O₂‐dependent decrease in Bcl‐2 level. Our results indicate that bleomycin/H₂O₂ induce apoptosis in NT2 cells by activating mitochondrial pathway of apoptosis, while NAC diminishes bleomycin/H₂O₂ induced apoptosis. We conclude that NAC has antagonistic effects on Bleomycin‐induced apoptosis in NT2 cells and causes resistance to apoptosis which is not a desired effect in eliminating cancer cells. J. Cell. Biochem. 114: 1685–1694, 2013. © 2013 Wiley Periodicals, Inc.     

Tick survey and detection of Crimean-Congo hemorrhagic fever virus in tick species from a non-endemic area, South Marmara region, Turkey

Crimean-Congo hemorrhagic fever (CCHF) is an increasing health concern in Turkey since 2002. There were also some recent human cases from the South Marmara region of Turkey; thus, a tick survey was performed, and possible vector tick species for the CCHF virus were determined in the region. A total of 740 adult ticks were collected from infested livestock from five locations: Çanakkale-Biga, Bursa-Orhaneli, Bursa-Keles, Bal?kesir and Bilecik. Total of 11 tick species from the genera Hyalomma, Rhipicephalus, Dermacentor, Ixodes and Haemaphysalis were identified. Rhipicephalus ticks were dominant in the region; the most frequently observed tick species was R. turanicus, (53.1 %), and only 15.4 % of the identified ticks were H. marginatum. The occurrence of H. rufipes infestation in the region fort he first time. A total of 73 pools of adult ticks were tested with both an antigen-detecting ELISA and RT real-time PCR (RT rt PCR). The presence of the CCHF virus was demonstrated in 9 (12.3 %) of the tested tick pools. Although seven of the tick pools were positive for the CCHF virus with both of the methods, one pool was positive only with RT rt PCR and the other pool was only positive with the ELISA. Positive results were obtained from ticks collected from cattle, sheep and goats from two locations, Bursa-Orhaneli and Bilecik. The CCHF virus was detected in R. turanicus (n = 3), R. bursa (n = 2), H. marginatum (n = 2) and D. marginatus (n = 2) ticks. The results of this study confirm the presence of the CCHF virus and present preliminary data on the vector tick species in the southern Marmara region of Turkey.