ABSTRACT
Alzheimer's disease (AD), a common chronic neurodegenerative disease, has become a major public health concern. Despite years of research, therapeutics for AD are limited. Overexpression of secretory glutaminyl cyclase (sQC) in AD brain leads to the formation of a highly neurotoxic pyroglutamate variant of amyloid beta, pGlu-Aß, which acts as a potential seed for the aggregation of full length Aß. Preventing the formation of pGlu-Aß through inhibition of sQC has become an attractive disease-modifying therapy in AD. In this current study, through a pharmacophore assisted high throughput virtual screening, we report a novel sQC inhibitor (Cpd-41) with a piperidine-4-carboxamide moiety (IC50 = 34 µM). Systematic molecular docking, MD simulations and X-ray crystallographic analysis provided atomistic details of the binding of Cpd-41 in the active site of sQC. The unique mode of binding and moderate toxicity of Cpd-41 make this molecule an attractive candidate for designing high affinity sQC inhibitors.
Subject(s)
Aminoacyltransferases/antagonists & inhibitors , Piperidines/pharmacology , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Brain/drug effects , Brain/metabolism , Cell Line, Tumor , Humans , Molecular Docking Simulation , Pyrrolidonecarboxylic Acid/metabolismABSTRACT
The purpose of this study was to assess the antioxidant and anti-inflammatory potential of liposomal formulations enriched with Hypericum hookerianum (Hyp) aqueous extracts. Cotyledon segments derived from protocorms of H. hookerianum were cultured on Murashige and Skoog (MS) media supplemented with Kinetin (KN, 1 mgl-1) and Naphthalene acetic acid (NAA, 0.1 mgl-1) to induce hypericin-rich red shoots (HypR, 0.87 mg/G DW). Highly stable liposomes (-29.4 mV) were successfully developed which encapsulated 63 ± 0.8% Hyp extracts, respectively. MTT assay subsequently confirmed the biocompatibility of liposome compositions using fibroblast cell lines. This work also evaluated acute toxicity of L-HypR and L-HypG formulations using Danio rerio (Zebrafish) embryos for 96 hpf. The expression of antioxidant and anti-inflammatory genes were found to be upregulated for L-HypR than L-HypG (green shoots without hypericin) formulations. These properties of L-HypR may be extremely useful for incorporating lipophilic substances into the food or pharmaceutical industry.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Hypericum/chemistry , Perylene/analogs & derivatives , Plant Extracts/pharmacology , Animals , Anthracenes , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/chemistry , Antioxidants/administration & dosage , Antioxidants/chemistry , Cell Line , Humans , Hypericum/growth & development , Liposomes/chemistry , Perylene/administration & dosage , Perylene/chemistry , Perylene/pharmacology , Plant Extracts/administration & dosage , Plant Extracts/chemistry , Zebrafish/embryologyABSTRACT
D-Galactosamine (GalN)-induced liver injury is associated with reactive oxygen species and oxidative stress. In the present study, we evaluated the effect of alpha lipoic acid (ALA) supplementation on acute GalN-induced oxidative liver injury. Hepatotoxicity induced by single intraperitoneal injection of GalN (500 mg/kg body wt) was evident from increase in lipid peroxidation and serum marker enzymes (asparate transaminase, alanine transaminase, alkaline phosphatase, and lactate dehydrogenase). The decreased activities of enzymic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase) as well as glutathione levels were the salient features observed in GalN-induced hepatotoxicity. Pretreatment with ALA (50 mg/kg body weight for 7 days) significantly precluded these changes and prevents the hepatic injury. Hence, this study clearly exemplified that ALA might be a suitable candidate against GalN-induced cellular abnormalities.
