Deciphering the multi-functional role of Indian propolis for the management of Alzheimer's disease by integrating LC-MS/MS, network pharmacology, molecular docking, and in-vitro studies.

The conventional one-drug-one-disease theory has lost its sheen in multigenic diseases such as Alzheimer's disease (AD). Propolis, a honeybee-derived product has ethnopharmacological evidence of antioxidant, anti-inflammatory, antimicrobial and neuroprotective properties. However, the chemical composition is complex and highly variable geographically. So, to leverage the potential of propolis as an effective treatment modality, it is essential to understand the role of each phytochemical in the AD pathophysiology. Therefore, the present study was aimed at investigating the anti-Alzheimer effect of bioactive in Indian propolis (IP) by combining LC-MS/MS fingerprinting, with network-based analysis and experimental validation. First, phytoconstituents in IP extract were identified using an in-house LC-MS/MS method. The drug likeness and toxicity were assessed, followed by identification of AD targets. The constituent-target-gene network was then constructed along with protein-protein interactions, gene pathway, ontology, and enrichment analysis. LC-MS/MS analysis identified 16 known metabolites with druggable properties except for luteolin-5-methyl ether. The network pharmacology-based analysis revealed that the hit propolis constituents were majorly flavonoids, whereas the main AD-associated targets were MAOB, ESR1, BACE1, AChE, CDK5, GSK3ß, and PTGS2. A total of 18 gene pathways were identified to be associated, with the pathways related to AD among the topmost enriched. Molecular docking analysis against top AD targets resulted in suitable binding interactions at the active site of target proteins. Further, the protective role of IP in AD was confirmed with cell-line studies on PC-12, in situ AChE inhibition, and antioxidant assays.

Reoirt: Insight into the lipophilicity of selected monosubstituted chalcones.

This study represents our attempt to understand how the antimicrobial activity of chalcones is modulated by their lipophilicity. To achieve this overall objective, a library of monosubstituted chalcones was targeted after careful consideration of the stereo electronic properties of the substituents appended in each of its constituent members. The lipophilicities of these derivatives were determined experimentally as well as by means of different validated computational programs. The theoretical determination was necessitated by the long-winded and time-consuming experimental protocols involved. It was gratifying to note the good correlation between these determinations which indicated the suitability of using such theoretical descriptors not only for assessing the lipophilicity of putative lead molecules but also for evaluating their biological activity. Standard disc diffusion technique employed against gram positive & negative bacteria as well as fungi revealed some preliminary information about the antimicrobial activity of these analogues.

Nootropic effect of Indian Royal Jelly against okadaic acid induced rat model of Alzheimer's disease: Inhibition of neuroinflammation and acetylcholineesterase.

Background: Royal jelly is an anti-inflammatory, antioxidant, and neuroprotective bee product. There are several sources for royal jelly and one of them is Indian Royal Jelly (IRJ). However, the neuroprotective actions of IRJ and the underlying molecular mechanisms involved are not well known. Objective: To evaluate the neuroprotective effect of IRJ in the okadaic acid (OKA)-induced Alzheimer's disease (AD) model in rats. Methods: In male Wistar rats, OKA was intracerebroventricularly (ICV) administered, and from day 7, they were treated orally with IRJ or memantine for 21 days. Spatial and recognition learning and memory were evaluated from days 27-34; employing the Morris water maze (MWM) and the novel object recognition tests (NORT), respectively. In vitro biochemical measurements were taken of the cholinergic system and oxidative stress markers. In silico docking was used to find the role of tau protein kinase and phosphatase in the pharmacological action. Results: In OKA-induced rats, IRJ decreased the escape latency and path length in MWM and increased the exploration time for novel objects and the discrimination index in NORT. ICV-OKA rats had higher free radicals and cytokines that caused inflammation and their level of free radical scavengers was back to normal with IRJ treatment. IRJ increased the level of acetylcholine and inhibited acetylcholinesterase. Moreover, the in silico docking study revealed the strong binding affinity of 10-hydroxy-2-decenoic acid (10-HDA), a bioactive constituent of IR, to the tau protein kinases and phosphatases. Conclusion: IRJ may serve as a nootropic agent in the treatment of dementia, and owing to its capacity to prevent oxidative stress and neuroinflammation, and increase cholinergic tone; it has the potential to be explored as a novel strategy for the treatment of dementia and AD. More studies may be needed to develop 10-HDA as a novel drug entity for AD.