Development of phytosterol-loaded silver nanoparticles for ameliorating haemorrhoidal complications via the AMPK pathway-a mechanistic approach.

The aim of the current study was to synthesize silver nanoparticles (PLSNPs) using green technology by means of phytosterol-enriched fractions fromBlumea laceraextracts (EAF) and evaluate their toxicological and anti-haemorrhoidal potential. The average size of the synthesized particles was found to be 85.64 nm by scanning electron microscopy and transmission electron microscopy. Energy dispersive spectroscopy showed the elemental composition of PLSNPs to be 12.59% carbon and 87.41% silver, indicating the capping of phytochemicals on the PLSNPs. The PLSNPs were also standardized for total phytosterol content using chemical methods and high-perfromance liquid chromatography. The PLSNPs were found to be safe up to 1000 mg kg-1as no toxicity was observed in the acute and sub-acute toxicity studies performed as per OECD guidelines. After the induction of haemorrhoids, experimental animals were treated with different doses of EAF, PLSNPs and a standard drug (Pilex) for 7 d, and on the eighth day the ameliorative potential was assessed by evaluating the haemorrhoidal (inflammatory severity index, recto-anal coefficient) and biochemical (tumour necrosis factor-alpha and interleukin-6) parameters and histology of the recto-anal tissue. The results showed that treatment with PLSNPs and Pilex significantly (p< 0.05) reduced haemorrhoidal and biochemical parameters. This was further supported by restoration of altered antioxidant status. Further, a marked reduction in the inflammatory zones along with minimal dilated blood vessels was observed in the histopathological study. The results of molecular docking studies also confirmed the amelioration of haemorrhoids via AMP-activated protein kinase (AMPK)-mediated reduction of inflammation and endothelin B receptor modification by PLSNPs. In conclusion, PLSNPs could be a good alternative for the management of haemorrhoids.

Evaluation of anticancer activity of Gmelina asiatica leaves, in-vitro and in-silico studies.

Cervical cancer poses a major threat to women's health worldwide, constituting the fourth most prevalent cancer among the female population. High-risk variants of human papillomavirus (HPV) with its oncogenic proteins are a necessary cause of cervical cancer. Due to the resistance of cancer cells to the current treatment, there is a need for new medicines with new strategies to treat cervical cancer. Gmelina asiatica Linn. is a medicinal plant with various traditional uses and biological activities. Its anticancer potential against breast cancer and lymphoma has been demonstrated in the literature. In view of this, our study aims to investigate the anticancer activity of Gmelina asiatica leaves against cervical cancer. Various extracts of Gmelina asiatica leaves were prepared by soxhletation and maceration methods. The cytotoxic activity of the extracts was evaluated through in-vitro studies against SiHa cell line using MTT assay and fluorescence imaging. The most potent extract (GAME) phytochemical profile was analysed by UHPLC-HRMS. Further, in-silico studies were performed on its phytoconstituents against E6 oncoprotein, and the DFT studies were conducted on the active component to assess the physicochemical properties. In-vitro studies revealed that methanolic extract (GAME) showed the highest inhibition on the SiHa cell line compared to the other extracts and the control (p < 0.0001). In-silico studies indicated high affinity with stable interaction of the compound 5 (JC5ABDR) at E6 binding sites. This study revealed the importance of Gmelina asiatica plant as a potential source of anticancer molecules with a specific mode of action against cervical cancer.Communicated by Ramaswamy H. Sarma.

Discovery of Multitarget-Directed Ligands from Piperidine Alkaloid Piperine as a Cap Group for the Management of Alzheimer's Disease.

The naturally inspired multitarget-directed ligands (PC01-PC10 and PD01-PD26) were synthesized from piperine for the management of Alzheimer's disease (AD). The compound PD07 showed significant inhibitory activity on ChEs, BACE1, and Aß1-42 aggregation in in vitro studies. Further, compound PD07 effectively displaced the propidium iodide at the AChE PAS site. The compound PD07 exhibited significant lipophilicity in PAMPA studies. Additionally, PD07 demonstrated neuroprotective properties in the Aß1-42 induced SH-SY5Y cell line. Furthermore, DFT calculations were performed using B3LYP/6-311G(d,p) basis sets to explore the PD07 physical and chemical properties. The compound PD07 showed a similar binding interaction profile at active sites of AChE, BuChE, and BACE1 proteins as compared to reference ligands (donepezil, tacrine, and BSD) in molecular docking and dynamic simulation studies. In acute oral toxicity studies, compound PD07 exhibited no toxicity symptoms up to 300 mg/kg, po. The compound PD07 (10 mg/kg, po) improved memory and cognition in scopolamine-induced amnesia rats. Further, PD07 increased ACh levels in the brain by inhibiting the AChE activity. The results from in vitro, in silico, and in vivo studies suggested that compound PD07 is a potent multitarget-directed lead from piperine to overcome Alzheimer's disease.

Discovery of multi-target directed 3-OH pyrrolidine derivatives through a semisynthetic approach from alkaloid vasicine for the treatment of Alzheimer's disease.

Vasicine is a pyrroloquinazoline alkaloid, which has been isolated from the plant Adhatoda vasica. Naturally inspired semi-synthetic transformations were prepared using vasicine as a synthetic precursor to overcome Alzheimer's disease (AD). These semi-synthetic analogs exhibited stable interactions and were well resided at AChE and BChE active sites in in-silico studies. Further, in-vitro experiments were performed to assess the cholinesterase inhibitory activity and reduction of amyloid-beta (Aß1-42) plaques potency, PAMPA assay permeability, and antioxidant activity, these findings suggested that compound VA10 can be a lead molecule among all the synthesized analogs. The compound VA10 binds towards AChE peripheral anionic site (PAS) property was established through propidium iodide displacement assay. Moreover, VA10 showed no notable cytotoxicity and exhibited neuroprotective nature on Aß1-42 treated SH-SY5Y cell line. In addition, VA10 was found to be safe in rats, which was confirmed by acute oral toxicity studies. Furthermore, in-vivo studies suggested that compound VA10 (10 mg/kg, p.o) ameliorated the memory and cognition impairment in scopolamine-induced amnesia model and Aß1-42 induced Alzheimer rat model. Ex-vivo studies of compound VA10 demonstrate improved ACh levels by inhibiting AChE activity in rat brain. Moreover, histopathological observations on rats brain sections indicate VA10 (10 mg/kg, p.o) recovered the neuronal cells at hippocampus region (DG, CA3, and CA1). These positive experimental data from in-silico, in-vitro and in-vivo studies, suggested that compound VA10 can be a lead compound for further preclinical development studies as a naturally derived alkaloid for anti-AD.