Current Issue : October - December Volume : 2018 Issue Number : 4 Articles : 6 Articles
The realization of the therapeutic potential of targeting the M1\nmuscarinic acetylcholine receptor (mAChR) for the treatment\nof cognitive decline in Alzheimerââ?¬â?¢s disease has prompted the\ndiscovery of M1 mAChR ligands showing efficacy in alleviating\ncognitive dysfunction in both rodents and humans. Among these\nis GSK1034702 (7-fluoro-5-methyl-3-[1-(oxan-4-yl)piperidin-4-\nyl]-1H-benzimidazol-2-one), described previously as a potentM1\nreceptor allosteric agonist, which showed procognitive effects in\nrodents and improved immediate memory in a clinical nicotine\nwithdrawal test but induced significant side effects. Here we\nprovide evidence using ligand binding, chemical biology and\nfunctional assays to establish that rather than the allosteric\nmechanism claimed, GSK1034702 interacts in a bitopic manner\nat the M1 mAChR such that it can concomitantly span both\nthe orthosteric and an allosteric binding site. The bitopic\nnature of GSK1034702, together with the intrinsic agonist\nactivity and a lack of muscarinic receptor subtype selectivity\nreported here, all likely contribute to the adverse effects of\nthis molecule in clinical trials. Although they impart beneficial\neffects on learning and memory, we conclude that these\nproperties are undesirable in a clinical candidate due to the\nlikelihood of adverse side effects. Rather, our data support\nthe notion that ââ?¬Å?pureââ?¬Â positive allosteric modulators showing\nselectivity for the M1 mAChR with low levels of intrinsic\nactivity would be preferable to provide clinical efficacy with\nlow adverse responses....
The present study was performed to evaluate the antihyperglycemic effects of yesaka, an ayurvedic polyherbal formulation and metformin in high fat diet-streptozotocin induced diabetic rats. Diabetes was induced by feeding Sprague Dawley rats with high-fat diet (HFD) for two months followed by a single dose of streptozotocin (STZ, 30 mg/kg intraperitoneally). All the diabetic rats were orally treated with metformin as standard (300 mg/kg), yesaka (1.8 ml/kg and 3.6 ml/kg) and with combination of formulation and standard for 4 weeks. The results were evaluated by significant restoration of body weight, decreased levels of plasma glucose, total cholesterol (TC), triglycerides (TG), low density lipoprotein-cholesterol (LDL-C) while increased high density lipoprotein cholesterol (HDL-C) levels in all the treatment groups compared to diabetic. These results demonstrated the prominent antidiabetic effect of yesaka in HFD-fed STZ-treated diabetic rats along with metformin. Hence, may be a promising candidate in the treatment and management of diabetes....
The renin angiotensin system (RAS) participates in inflammatory processes,\nas either a pro-inflammatory or an anti-inflammatory mediator. Components\nof RAS, such as angiotensin-converting enzyme (ACE), have been detected\nlocally in the gut epithelium. In addition, the anti-inflammatory steroid, corticosterone,\nis produced in the gut. Hypertension and aging evoke a low-grade\ninflammatory process in the vascular endothelium. It is not known whether\nthey induce a similar low-grade inflammation in the intestine and if the\nlow-grade inflammation would evoke an activation of ACE and an elevation\nof corticosterone production. These two variables were measured in ileum and\ncolon of 9- and 26-week old spontaneously hypertensive rats (SHR) and their\nnormotensive Wistar-Kyoto (WK) controls. ACE-activity, measured via the\nformation of histidyl-leucine from hippuryl-histidyl-leucine in the tissue homogenate\nsamples, was similar in the ileum and colon of young animals although\nthe ileum of the young normotensive animals displayed the lowest\nlevel. In the old animals, the ACE activity was higher in the ileum than in the\ncolon, especially in normotensive rats. Corticosterone production was measured\nas corticosterone concentration in the supernatants of ileum or colon after\na 90-min ex vivo incubation. Corticosterone production was higher in ileum\nthan in colon in both SHR and WK. No clear evidence was seen for\nage-dependency or for an effect of hypertension in the measured variables in\nthe intestine. Thus, the putative low-grade inflammation in the intestine in\naging or hypertension is not a strong enough stimulus to elevate corticosterone\nproduction or activate ACE....
P2X7 receptor (P2X7R) activation requires âË?¼100-fold higher\nconcentrations of ATP than other P2X receptor (P2XR) subtypes.\nSuch high levels are found during cellular stress, and\nP2X7Rs consequently contribute to a range of pathophysiological\nconditions.We have used chimeric and mutant P2X7Rs,\ncoupled with molecular modeling, to produce a validated model\nof the binding mode of the subtype-selective antagonist\nA438079 at an intersubunit allosteric site. Within the allosteric\nsite large effects on antagonist action were found for point\nmutants of residues F88A, D92A, F95A, and F103A that were\nconserved or similar between sensitive/insensitive P2XR subtypes,\nsuggesting that these side-chain interactions were not\nsolely responsible for high-affinity antagonist binding. Antagonist\nsensitivity was increased with mutations that remove the\nbulk of side chains around the center of the binding pocket,\nsuggesting that the dimensions of the pocket make a significant\ncontribution to selectivity. Chimeric receptors swapping\nthe left flipper (around the orthosteric site) reduced both ATP\nand antagonist sensitivity. Point mutations within this region\nhighlighted the contribution of a P2X7R-specific aspartic acid\nresidue (D280) that modeling suggests forms a salt bridge with\nthe lower body region of the receptor. The D280A mutant\nremoving this charge increased ATP potency 15-fold providing\na new insight into the low ATP sensitivity of the P2X7R. The\northo- and allosteric binding sites form either side of the\nb-strand Y291-E301 adjacent to the left flipper. This structural\nlinking may explain the contribution of the left flipper to both\nagonist and antagonist action....
Despite the initial evidence on the role of zinc and zinc transporters in cancer prevention,\nlittle attention has been paid to the zinc-derived compounds. In the present work, we reported a\nstrategy to prepare a kind of zinc-releasing container with enhanced biocompatibility and release\ndynamics using ZIF-8 nanocrystals as the sacrificial templates. Transmission electron microscopy\n(TEM) analysis demonstrated that the ZIF-8 nanocrystals were gradually etched out in the aqueous\nmedia within 48 h, resulting in hollow nanocapsules. Notably, we found the self-polymerization of\ndopamine can form nanoshells around the ZIF-8 nanocrystals, which served as a type of functional\nmembranes during the release of zinc. More interestingly, PDA@ZIF-8ââ?¬â??based nanohybrids expressed\nstronger inhibition to the cancer cell growth, which implied that the nanohybrids could be a drug\ncarrier for chemotherapy. This study broadens the biomedical application of ZIF-8 and also provides\na versatile strategy toward the development of multifunctional delivery system....
The Kelch-like erythroid-associated protein 1 (Keap1)ââ?¬â??NF-E2-\nrelated factor 2 (Nrf2) signaling pathway is the subject of several\nclinical trials evaluating the effects of Nrf2 activation on the\nprevention of cancer and diabetes and the treatment of chronic\nkidney disease and multiple sclerosis. 3H-1,2-dithiole-3-thione\n(D3T) and 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-\nimidazole (CDDO-Im) are representative members of two distinct\nseries of Nrf2 chemical activators. Previous reports have described\nactivator-specific effects on Nrf2-dependent gene regulation\nand physiologic outcomes. Here we used a robust\nchemical genomics approach to characterize expression profiles\nbetween D3T and CDDO-Im in livers from wild-type and Nrf2-null\nmice. At equally efficacious doses in wild-type mice, 406 genes\nshow common RNA responses to both treatments. These genes\nenriched the Nrf2-regulated pathways of antioxidant defense\nand xenobiotic metabolism. In addition, 197 and 745 genes were\nrespectively. Functional analysis of the D3T-regulated set showed\na significant enrichment of Nrf2-regulated enzymes involved in\ncholesterol biosynthesis. This result was supported by Nrf2-\ndependent increases in lanosterol synthase and CYP51 protein\nexpression. CDDO-Im had no effect on cholesterol biosynthesis\nregardless of the dose tested. However, unlike D3T, CDDO-Im\nresulted in Nrf2-dependent elevation of peroxisome proliferator a\nand Kruppel-like factor 13, as well as the coactivator peroxisome\nproliferator Ãâ?? coactivator 1b, together indicating regulation of\nb-oxidation and lipid metabolic pathways. These findings provide\nnovel insights into the pharmacodynamic action of these two\nactivators of Keap1-Nrf2 signaling. Although both compounds\nmodify Keap1 to affect canonical cytoprotective gene expression,\nadditional unique sets of Nrf2-dependent genes were regulated by\neach agent with enrichment of selective metabolic pathways....
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