Oxyresveratrol-ß-cyclodextrin mitigates streptozotocin-induced Alzheimer's model cognitive impairment, histone deacetylase activity in rats: in silico & in vivo studies.

Alzheimer's disease (AD) is associated with cognitive deficits and epigenetic deacetylation that can be modulated by natural products. The role of natural oxyresveratrol-ß-cyclodextrin (ORV) on cognition and histone deacetylase activity in AD is unclear. Herein, in-silico docking and molecular dynamics simulation analysis determined that oxyresveratrol potentially targets histone deacetylase-2 (HDAC2). We therefore evaluated the in vivo ameliorative effect of ORV against cognitive deficit, cerebral and hippocampal expression of HDAC in experimental AD rats. Intracerebroventricular injection of STZ (3 mg/kg) induced experimental AD and the rats were treated with low dose (200 mg/kg), high dose (400 mg/kg) of ORV and donepezil (10 mg/kg) for 21 days. The STZ-induced AD caused cognitive and behavioural deficits demonstrated by considerable increases in acetylcholinesterase activity and escape latency compared to sham control. The levels of malondialdehyde (MDA) and HDAC activity were significantly increased in AD disease group comparison to the sham. Interestingly, the ORV reversed the cognitive-behavioural deficit and prominently reduced the MDA and HDAC levels comparable to the effect of the standard drug, donepezil. The findings suggest anti-AD role of ORV via antioxidant effect and inhibition of HDAC in the hippocampal and frontal cortical area of rats for AD.

Anticancer therapeutic potential of phosphorylated galactosylated chitosan against N-nitrosodiethyl amine-induced hepatocarcinogenesis.

Chitosan is a natural polyfunctional polymer that can be modified to achieve compounds with tailored properties for targeting and treating different cancers. In this study, we report the development and anticancer potential of phosphorylated galactosylated chitosan (PGC). The synthesized compound was characterized by FT-IR, NMR, and mass spectroscopy. The interaction of PGC with asialoglycoprotein receptors (ASGPR) and cellular internalization in HepG2 cells was studied using in silico and uptake studies respectively. PGC was evaluated for its metal chelating, ferric ion reducing, superoxide, and lipid peroxide (LPO) inhibiting potential. Further, anticancer therapeutic potential of PGC was evaluated against N-nitrosodiethylamine (NDEA)-induced hepatocellular carcinoma in a mice model. After development of cancer, PGC was administered to the treatment group (0.5 mg/kg bw, intravenously), once a week for 4 weeks. Characterization studies of PGC revealed successful phosphorylation and galactosylation of chitosan. A strong interaction of PGC with ASGP-receptors was predicted by computational studies and cellular internalization studies demonstrated 98.76 ± 0.53% uptake of PGC in the HepG2 cells. A good metal chelating, ferric ion reducing, and free radical scavenging activity was demonstrated by PGC. The anticancer therapeutic potential of PGC was evident from the observation that PGC treatment increased number of tumor free animals (50%) (6/12) and significantly (p ≤ 0.05) lowered tumor multiplicity as compared to untreated tumor group.

An in-silico approach: identification of PPAR-γ agonists from seaweeds for the management of Alzheimer's Disease.

Alzheimer's Disease is a complex progressive neurodegenerative disorder characterized by neurofibrillary tangles and senile plaques in various parts of the brain particularly cerebral cortex affecting memory and cognition. Nuclear receptors such as Peroxisome proliferator-activated receptor γ [PPAR-γ] is reported to have a role in lipid and glucose homeostasis in the brain, reduces the synthesis of Aß (beta-amyloid plaques) and also regulates mitochondrial biogenesis and inhibit the neuro-inflammation, which contributes for the improvement in the cognitive function in AD. Hence PPAR-γ is one of the newer targets for the researchers to understand the pathology of AD and to evolve the novel strategy to retard/reverse the progression of AD. PPAR-γ agonists such as Rosiglitazone and Pioglitazone have shown promising results in AD by decreasing neuro-inflammation and restoring glucose dysmetabolism leading to a reduction in neuronal deterioration. These agonists possess poor blood-brain permeability and are poor candidates for clinical use in AD. Therefore, search, design, and development for new PPAR- γ agonists with improved BBB penetration ability are imperative. The present work deals with the use of computational tools and techniques such as molecular docking, molecular dynamics to discover PPAR-γ agonists from the unexplored Seaweed Metabolite Database and predicts it's toxicological and physiochemical profile, thereby saving time and resources. Out of 1,110 seaweed compounds, the hit molecule BS052 displayed a strong binding affinity towards PPAR-γ, which possessed better lipid solubility indicating the potential to be considered as a PPAR-γ agonist, which may be useful in the management of AD.Communicated by Ramaswamy H. Sarma.