Altered Trace Mineral Milieu Might Play An Aetiological Role in the Pathogenesis of Polycystic Ovary Syndrome

Insulin resistance is a very common associate of polycystic ovary syndrome (PCOS). Pathophysiology in relation with the essential elements including copper, magnesium, zinc, manganese, chromium, and calcium has been reported in women with insulin resistance. This prospective study was designed to explore whether the women with PCOS do exhibit altered serum element levels in association with/without insulin resistance. One hundred and thirty-two women with PCOS and forty-six control women were studied. Women with PCOS were further divided based on the presence of insulin resistance (insulin resistant: n?=?50; non-insulin resistant: n?=?82). In all women, basal levels of gonadotropins, prolactin, testosterone, insulin, glucose, and the six different elements were measured. Serum levels of testosterone (p?<?0.001), luteinizing hormone (p?<?0.05), and fasting insulin (p?<?0.004) were significantly higher in the PCOS population compared to controls as well as PCOS women without insulin resistance. Women with PCOS exhibited a significantly high calcium (p?<?0.04) and lower manganese levels (p?<?0.002) when compared to controls. However, the PCOS women with insulin resistance exhibited significantly lower serum levels of magnesium and chromium (p?<?0.04), in addition to higher levels of zinc and copper (p?<?0.04). The differences in calcium (p?<?0.03) and manganese levels (p?<?0.0001) became aggravated with the presence of insulin resistance when compared to control as well as PCOS women without insulin resistance. In PCOS-associated insulin resistance, circulating serum magnesium (r?=??0.31; p?<?0.03) and chromium (r?=??0.38; p?<?0.006) status significantly correlated with fasting insulin levels. We conclude that imbalanced element status may be a key foundation for insulin resistance in PCOS. The findings in this study should be investigated with further trials in order to obtain new insights into PCOS.     

Discovery of a potent and selective small molecule hGPR91 antagonist

GPR91, a 7TM G-Protein-Coupled Receptor, has been recently deorphanized with succinic acid as its endogenous ligand. Current literature indicates that GPR91 plays role in various pathophysiology including renal hypertension, autoimmune disease and retinal angiogenesis. Starting from a small molecule high-throughput screening hit 1 (hGPR91 IC₅₀: 0.8 μM)—originally synthesized in Merck for Bradykinin B₁ Receptor (BK₁R) program, systematic structure-activity relationship study led us to discover potent and selective hGPR91 antagonists e.g. 2c, 4c, and 5g (IC₅₀: 7-35 nM; >1000 fold selective against hGPR99, a closest related GPCR; >100 fold selective in Drug Matrix screening). This initial work also led to identification of two structurally distinct and orally bio-available lead compounds: 5g (%F: 26) and 7e (IC₅₀: 180 nM; >100 fold selective against hGPR99; %F: 87). A rat pharmacodynamic assay was developed to characterize the antagonists in vivo using succinate induced increase in blood pressure. Using two representative antagonists, 2c and 4c, the GPR91 target engagement was subsequently demonstrated using the designed pharmacodynamic assay.     

HIV Treatments Reduce Malaria Liver Stage Burden in a Non-Human Primate Model of Malaria Infection at Clinically Relevant Concentrations In Vivo

We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV) and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX) inhibit Plasmodium liver stages in rodent malarias and in vitro in P. falciparum. Since clinically relevant levels are better achieved in the non-human-primate model, and since Plasmodium knowlesi is an accepted animal model for the study of liver stages of malaria as a surrogate for P. falciparum infection, we investigated the antimalarial activity of these drugs on Plasmodium knowlesi liver stages in rhesus macaques. We demonstrate that TMP-SMX and TMP-SMX+LPV-RTV (in combination), but not LPV-RTV alone, inhibit liver stage parasite development. Because drugs that inhibit the clinically silent liver stages target parasites when they are present in lower numbers, these results may have implications for eradication efforts.     

Structural motifs in protein cores and at protein–protein interfaces are different

Structures of proteins and protein–protein complexes are determined by the same physical principles and thus share a number of similarities. At the same time, there could be differences because in order to function, proteins interact with other molecules, undergo conformations changes, and so forth, which might impose different restraints on the tertiary versus quaternary structures. This study focuses on structural properties of protein–protein interfaces in comparison with the protein core, based on the wealth of currently available structural data and new structure‐based approaches. The results showed that physicochemical characteristics, such as amino acid composition, residue–residue contact preferences, and hydrophilicity/hydrophobicity distributions, are similar in protein core and protein–protein interfaces. On the other hand, characteristics that reflect the evolutionary pressure, such as structural composition and packing, are largely different. The results provide important insight into fundamental properties of protein structure and function. At the same time, the results contribute to better understanding of the ways to dock proteins. Recent progress in predicting structures of individual proteins follows the advancement of deep learning techniques and new approaches to residue coevolution data. Protein core could potentially provide large amounts of data for application of the deep learning to docking. However, our results showed that the core motifs are significantly different from those at protein–protein interfaces, and thus may not be directly useful for docking. At the same time, such difference may help to overcome a major obstacle in application of the coevolutionary data to docking—discrimination of the intramolecular information not directly relevant to docking.     

Effect of green tea extract (catechins) in reducing oxidative stress seen in patients of pulmonary tuberculosis on DOTS Cat I regimen

Background and AimThe role played by free radicals in pathogenesis of pulmonary tuberculosis and treatment mediated toxicity is well established. Hence, the present study was undertaken to assess the effect of crude green tea catechin in reducing the oxidative stress seen in patients of AFB positive pulmonary tuberculosis.MethodsA total of 200 newly diagnosed cases of AFB positive pulmonary tuberculosis, who received CAT I regimen were enrolled consecutively from DOTS center. Out of 200 patients, 100 randomly selected patients received catechin (500 μg) with antitubercular treatment (ATT) (cases) and 100 received starch (500 μg) with ATT (control). Oxidative stress level in blood samples of cases and controls as compared at the time of enrollment and after one and four months of treatment. Oxidative stress was measured in terms of free radicals (lipid peroxidation, nitric oxide), enzymatic antioxidant (catalase, superoxide dismutase, glutathione peroxidase) and non enzymatic antioxidant (total thiol, reduced glutathione) levels.ResultsThe results showed significant difference in all the parameters among cases and controls. A significant decrease (p≤0.001) in LPO level was observed in cases as compare to controls during the follow up while the level of NO was significantly increased (p≤0.001) in cases as compare to controls. Significant decrease (p≤0.001) in catalase and GPx level was observed in cases as compare to controls while SOD levels significantly rose (p≤0.001) in cases as compared to controls. Significant decrease (p≤0.001) in SH level was observed in cases as compared to controls while the level of GSH was significantly increased (p≤0.001) .ConclusionThese findings suggest that crude catechin extract can play a definite role as adjuvant therapy in management of oxidative stress seen in pulmonary tuberculosis patients. More detailed studies are needed to document use of catechin in reducing the frequency and severity of side effects of treatment.     

Effect of Arbuscular Mycorrhizal Inoculations on Seedling Growth and Biomass Productivity of Two Bamboo Species

A study was conducted to identify suitable arbuscular mycorrhizal (AM) fungi for inoculation of Bambusa bambos and Dendrocalamus strictus at nursery stage for increasing growth and productivity. Twelve AM species, isolated from bamboo and other common trees of Bundelkhand were used for inoculations. In B. bambos, total dry weight and phosphorus (P) uptake were significantly increased by all studied fungi and shoot length was increased by eight AM inoculants. Maximum mycorrhizal dependency (MD) was recorded for Acaulospora scrobiculata (44.2%), followed by Glomus cerebriforme (41.6%) and G. intraradix (41.0%). In D. strictus, all tested AM inoculants significantly increased shoot length, dry shoot weight and P uptake, except Glomus 1. Dry root weight was significantly increased by only two inoculants namely, G. cerebriforme and G. etunicatum. Total dry weight was significantly increased by eight AM fungi. Maximum MD was recorded for G. cerebriforme (62.9%), followed by G. diaphanum (55.0%) and G. etunicatum (51.3%). Thus, the results showed that utilization of effective AM fungi can enhance the productivity of bamboo in the region.