Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 16, Issue 1, 2016

Primary membranous nephropathy (also known as idiopathic membranous nephropathy, IMN) is an organ specific autoimmune kidney disease characterized by the development of immune complex deposits in the sub-epithelial spaces, podocyte effacement and glomerular capillary wall thickening in the later stages. Clinical studies have demonstrated that over 70% of patients with IMN possess circulating autoimmune antibodies specifically targeting the phospholipase A2 receptor (PLA2R) on the surface of podocytes. The autoantibodies only bind to the extracellular portion of PLA2R under the non-reducing condition, indicating that the epitope in PLA2R is conformational requiring specific disulfide bonds to maintain its structure. We recently have successfully located the dominant epitope in PLA2R to the extreme N-terminus of the receptor. This finding has opened a new direction for understanding the pathogenesis of anti-PLA2R autoantibody induced IMN and offered a strong basis for developing sensitive clinical assays for IMN diagnosis and prognosis, and potentially, new therapeutic approaches for IMN treatment.

A number of conventional therapeutic targets are available for treatment of Type 2 diabetes mellitus (T2DM) but due to development of resistance by using conventional drug as monotherapy, there is a need to identify novel therapeutic targets and/or use combination of conventional and novel drugs for diabetes therapy. In this review we have highlighted some of the novel approaches like inhibitors of (11β- Hydroxysteroid dehydrogenase type-1, Sodium-glucose linked cotransporter-2, Acyl-CoA Diacylglycerol Acyl Transferase-1, Glycogen phosphorylase-A, Pyruvate Dehydrogenase Kinase, Protein tyrosine phosphate 1B, Kappa kinase-B, Stearoyl-coA desaturase-1), antagonists of (Fatty acid binding proteins, Fibroblast growth factors-21 receptor, Glucagon receptor, Glucocorticoid receptors), Glucokinase and Sirtuin activators, Cannabinoid receptor blockers, Incretin-mimetics, agonists of (Adenosine monophosphate activated protein kinase, Augmenting GLP-1 secretion GPR40, GPR120, GPR 146 and TGR 5, GPCR 119, liver x receptors, Serotonin 2c receptor) and Rexinoids x receptor modulators developed for the treatment of diabetes.

Obesity is a worldwide problem that adversely affects human health. Genetic factors have been suggested to play role in the development of obesity. SNPs on proteins involved in de novo lipogenesis had been proposed to affect individual susceptibility for obesogenic environment. De novo lipogenesis is the process of converting carbohydrate absorbed from dietary intake into fat and this process usually occurs after a high carbohydrate intake. In modern society, where foods and beverages with highly processed carbohydrates are getting affordable, understanding the role of genetic factors has become more crucial. In this review, several genes that were previously reported to influence the risk of obesity has been pointed out. This observation was supported by previous findings in animal model which showed that genetic knock-out of genes involved in de novo lipogenesis (FASN and SCD-1) was found to be related to changes in obesity phenotype. Those genes not only produce enzymes which directly convert carbohydrate metabolite into fatty acid, but also influence the production of lipogenic enzymes.

Luk (Laccifer lacca Kerr) is an animal origin drug with possible contraceptive properties. Objective: Antiovulatory activity was performed on mature female Wistar rats by cyclic administration of Luk (Lac). The animals were divided into 4 groups of six each, one control group and three test groups (A, B and C). Control group received 1 ml 0.5% carboxy methyl cellulose. Test groups A and B were treated with Luk maghsool with water (LMW) in the dose of 470 mg/kg and 800 mg/kg, respectively. Test group C was treated with 800 mg/kg Luk maghsool with Izkhar Rewand (LMIR), and vaginal smear and histological and biochemical studies were performed for 15 days. The results displayed a remarkable increase in the duration of estrus cycle and diestrus phase. In test groups treated with LMIR, a decrease in estrus and proestrus phase was observed. An increase in uterine weight was observed in treated groups. Estrogenic nature of the test drug was assessed by noting the times taken for vagina to completely open after 7 days of treatment in immature rats. For this the animals were dividing into four groups i.e. Plain Control receiving CMC (0.5%), Test Group A and B receiving LMW (800 mg/kg) and LMIR (800 mg/kg) respectively where as standard group was given Ethinyl estradiol (0.02mg/kg). A significant Luk mediated estrogenic activity was exhibited by immature vaginal opening when compared to control, suggesting Lac as an antifertility agent due to its estrogenic nature. The findings of the present study may suggest Luk as effective antifertility agent devoid of side effects associated with other contraceptive pills.

In the present day scenario, even if many advances in diabetic therapy have been sought, but it is still in its formative years. Nanotechnology has brought a range of novel promises into biological discovery and medical practice. Nanoparticulate drug delivers have revolutionized drug delivery, allowing therapeutic agents to be selectively targeted for organs, tissues and cell specific levels, minimizing exposure of healthy tissues to drugs. Keeping all the views in mind, Glimepiride loaded PLGA nanoparticles (NPs) were prepared by the solvent evaporation method. Physicochemical characterization of NPs included dynamic laser spectroscopy and atomic force microscopy confirmed the mean particle diameter of NPs was ~300 nm with spherical morphology. Fourier transform infrared spectroscopy and differential scanning calorimetry analysis depicted no interaction between the drug and polymer in formulation. Drug encapsulation efficiency was found to be ~55 % and it released from NPs in a sustained manner. Blood glucose level of glimepiride loaded NPs treated to diabetic rats was reduced significantly to normal level compared with native drug treated group. Thus, this system could facilitate to achieve a sustained formulation resulting in reduced dose frequency and improved patient compliance for type-2 diabetes mellitus management.

Lactate receptor HCA1 (aka GPR81) is primarily expressed in adipose tissues and play roles in regulating fat metabolism. Hamsters have been often used as models for metabolic disorders such as dyslipidemia, obesity, and diabetes. In this report, we described the molecular characterization of hamster HCA1 and niacin receptor HCA2 using HCA1 ligands such as lactate, 3-hydroxybenzoic acid; 3,5-dihydroxybenzoic acid; 3-bromo-5-hydroxybenzoic acid; 3-chloro-5-hydroxybenzoic acid; 3-fluoro-5-hydroxybenzoic acid; and HCA2 ligands such as niacin, acifran, β-hydroxybutyrate; as well as HCA3 ligand 3-hydroxyoctanoic acid. Our results showed that 3,5-dihydroxybenzoic acid, 3-bromo-5-hydroxybenzoic acid; 3-chloro-5- hydroxybenzoic acid; 3-fluoro-5-hydroxybenzoic acid are specific ligands for hamster HCA1 and could be useful the hamster HCA1 in vivo activation.

A new series of triazole containing thiadiazine moiety have been synthesized and characterized. All the new compounds were assayed for their in vitro antioxidant activity by DPPH free radical scavenging method and in vivo anti-diabetic activity by streptozotocin-induced model in albino rat. Anticancer activity of synthesized compounds was performed at the National Cancer Institute (NCI) on NCI 60 cell lines panel. Among the synthesized compounds, 2d exhibited more prominent antioxidant activity with IC50 value 16.97 μg/ml, 59.15% blood glucose lowering activity and moderate anticancer activity with 44.59% growth inhibition against CCRF-CEM (Leukemia) cell lines. Compounds 2e and 2j showed good antioxidant activity with IC50 value 21.40 and 18.78 μg/ml. Compounds 2b and 2e showed significant 59.98 and 48.44% blood glucose lowering activity.