2D-QSAR, molecular docking and MD simulation based virtual screening of the herbal molecules against Alzheimer's disorder: an approach to predict CNS activity.

Acetylcholinesterase (AChE) is one of the key enzyme targets that have been used clinically for the management of Alzheimer's Disorder (AD). Numerous reports in the literature predict and demonstrate in-vitro, and in-silico anticholinergic activity of herbal molecules, however, majority of them failed to find clinical application. To address these issues, we developed a 2D-QSAR model that could efficiently predict the AChE inhibitory activity of herbal molecules along with predicting their potential to cross the blood-brain-barrier (BBB) to exert their beneficial effects during AD. Virtual screening of the herbal molecules was performed and amentoflavone, asiaticoside, astaxanthin, bahouside, biapigenin, glycyrrhizin, hyperforin, hypericin, and tocopherol were predicted as the most promising herbal molecules for inhibiting AChE. Results were validated through molecular docking, atomistic molecular dynamics simulations and Molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) studies against human AChE (PDB ID: 4EY7). To determine whether or not these molecules can cross BBB to inhibit AChE within the central nervous system (CNS) for being beneficial for the management of AD, we determined a CNS Multi-parameter Optimization (MPO) score, which was found in the range of 1 to 3.76. Overall, the best results were observed for amentoflavone and our results demonstrated a PIC50 value of 7.377 nM, molecular docking score of -11.5 kcal/mol, and CNS MPO score of 3.76. In conclusion, we successfully developed a reliable and efficient 2D-QSAR model and predicted amentoflavone to be the most promising molecule that could inhibit human AChE enzyme within the CNS and could prove beneficial for the management of AD.Communicated by Ramaswamy H. Sarma.

Essential oil and nanocarrier-based formulations approaches for vaginal candidiasis.

An exclusive site for local drug delivery is the vagina, especially for vaginal infections. The fungus Candida albicans causes vaginal infection known as vulvovaginal candidiasis, a highly prevalent and recurrent gynaecological disease among women. Vaginal candidiasis affects over 75% of women at a certain point in their life and has a recurrence rate of 40-50%. Medicinal plants provide some very effective phytoconstituents which when delivered as nanosystems have enhanced therapeutic action and efficacy by alteration in their characteristics. Antifungal drugs are used to treat these conditions, alternative medicine is required for prophylaxis and improved prognosis. The current review focuses on the research carried out on various nanocarrier-based approaches and essential oil-based formulations for vaginal candidiasis.

The vagina is a part of a woman's body that can sometimes get sick from a fungus called Candida albicans. This sickness is called thrush, and it's very common. More than 75% of women will get it at some point, and it might come back again after it's gone. There are medicines that can help, but some plants can also be used to make powerful medicine that can heal the sickness from tiny particles called 'nanosized carriers'. Scientists are studying different ways to give the medicine to the sick area from these plants.

Reckoning γ-Glutamyl-S-allylcysteine as a potential main protease (mpro) inhibitor of novel SARS-CoV-2 virus identified using docking and molecular dynamics simulation.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2 or COVID-19), outbreak was first reported in December 2019 in the Wuhan, China. COVID-19 managed to spread worldwide and so far more than 9.1 million cases and more than 4.7 lakh death has been reported globally. Children, pregnant women, elderly population, immunocompromised patients, and patients with conditions like asthma, diabetes, etc. are highly vulnerable to COVID infection. Currently, there is no treatment available for COVID-19 infection. Traditional medicinal plants have provided bioactive molecules in the past that are efficiently used during conditions like cancer, malaria, microbial infections, immune-compromised states, etc. AYUSH India has recommended the use of Curcuma longa, Allium sativum, Ocimum tenuiflorum, and Withania somnifera for immune-boosting during SARS-CoV-2 infection. In the present study, we investigated the potential of 63-major bioactive molecules of these plants against SARS-CoV-2 main protease (Mpro) through docking studies and compared the results with known inhibitor 11a. Our results proposed cuscohygrine, γ-Glutamyl-S-allylcysteine, anahygrine, and S-allylcystein as the potent inhibitors against Mpro identified using molecular docking and molecular simulation dynamics. Interestingly, these molecules are from A. sativum, and W. somnifera, which are known for their antimicrobial and immunomodulatory potential. None of the proposed molecules have earlier been reported as antiviral molecules. Our results predict very strong potential of these four-molecules against SARS-CoV-2 Mpro, especially γ-glutamyl-S-allylcysteine, as all four form hydrogen bonding with Glu166 that is a crucial residue for the formation of the biologically active dimeric form of Mpro. Therefore, we strongly recommend further research on these biomolecules against SARS-CoV-2.

Rutin alleviates chronic unpredictable stress-induced behavioral alterations and hippocampal damage in mice.

Chronic stress results in neurological complications like depression, cognitive dysfunction, and anxiety disorders. In our previous study, we observed that Urtica dioica leaf extract attenuated chronic stress-induced complications. Further, we observed that Urtica dioica contained a great amount of the flavonoid rutin in it. Hence, we aimed to evaluate the effect of rutin on 21days chronic unpredictable stress (CUS) mouse model. CUS led to a decline in locomotion & muscle coordination abilities, cognitive deficits, anxiety, and depression. These neurobehavioral outcomes were associated with neurodegeneration in the CA3 region of the hippocampus as found by H&E staining. Rutin efficiently rescued the CUS-induced behavioral deficits by reducing depression, anxiety, improving cognition, and locomotor & muscle coordination skills. Further, rutin treatment protected the CUS-induced hippocampal neuronal loss. This study establishes the neuroprotective effect of rutin in chronic stress.

Quercetin prevents chronic unpredictable stress induced behavioral dysfunction in mice by alleviating hippocampal oxidative and inflammatory stress.

It is now evident that chronic stress is associated with anxiety, depression and cognitive dysfunction and very few studies have focused on identifying possible methods to prevent these stress-induced disorders. Previously, we identified abundance of quercetin in Urtica dioica extract, which efficiently attenuated stress related complications. Therefore, current study was designed to investigate the effect of quercetin on chronic unpredicted stress (CUS) induced behavioral dysfunction, oxidative stress and neuroinflammation in the mouse hippocampus. Animals were subjected to unpredicted stress for 21days, during which 30mg/kg quercetin was orally administered to them. Effect of CUS and quercetin treatment on animal behavior was assessed between day 22-26. Afterward, the hippocampus was processed to evaluate neuronal damage, oxidative and inflammatory stress. Results revealed that stressed animals were highly anxious (Elevated Plus Maze and Open Field), showed depressive-like behavior (sucrose preference task), performed poorly in short-term and long-term associative memory task (passive avoidance step-through task) and displayed reduced locomotion (open field). Quercetin alleviated behavioral dysfunction in chronically stressed animals. Compared to CUS, quercetin treatment significantly reduced anxiety, attenuated depression, improved cognitive dysfunction and normalized locomotor activity. Further, CUS elevated the levels of oxidative stress markers (TBARS, nitric oxide), lowered antioxidants (total thiol, catalase), enhanced expression of pro-inflammatory cytokines (IL-6, TNF-α, IL-1ß and COX-2) in the hippocampus and damaged hippocampal neurons. Quercetin treatment significantly lowered oxidative and inflammatory stress and prevented neural damage. In conclusion, quercetin can efficiently prevent stress induced neurological complications by rescuing brain from oxidative and inflammatory stress.

Pharmacological screening of glycine amino acid prodrug of acetaminophen.

OBJECTIVE: To develop an amino acid prodrug of acetaminophen with comparable therapeutic profile and less hepatotoxicity than acetaminophen. MATERIALS AND METHODS: Acetaminophen prodrug was synthesized by esterification between the carboxyl group of amino acid glycine and hydroxyl group of acetaminophen. Analgesic, antipyretic, ulcer healing, and hepatotoxic activities were performed on Wistar rats in this study. RESULTS: Prodrug showed a 44% inhibition in writhings as compared to 53.3% of acetaminophen. Acetaminophen also offered highest antipyretic activity. Prodrug showed gastroprotective and hepatoprotective effects as it reduced the gastric lesions by 32.1% (P < 0.01) and significantly prevented the rise in liver enzymes (serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase and bilirubin). The most notable effect of prodrug was in preventing the depletion of hepatic glutathione (GSH), which is reduced by acetaminophen. CONCLUSION: Prodrug showed hepatoprotective and gastroprotective effects, although the therapeutic efficacy was compromised. Prodrug was successful in preventing a decrease in GSH, thereby exhibiting promising results in the field of prodrug designing to avoid the toxic effects of acetaminophen.

Urtica dioica leaves modulates muscarinic cholinergic system in the hippocampus of streptozotocin-induced diabetic mice.

Diabetes mellitus is a chronic metabolic disorder and has been associated with cognitive dysfunction. In our earlier study, chronic Urtica dioica (UD) treatment significantly ameliorated diabetes induced associative and spatial memory deficit in mice. The present study was designed to explore the effect of UD leaves extract on muscarinic cholinergic system, which has long been known to be involved in cognition. Streptozotocin (STZ) (50 mg/kg, i.p., consecutively for 5 days) was used to induce diabetes followed by treatment with UD extract (50 mg/kg, oral) or rosiglitazone (5 mg/kg, oral) for 8 weeks. STZ-induced diabetic mice showed significant reduction in hippocampal muscarinic acetylcholine receptor-1 and choline acetyltransferase expressions. Chronic diabetes significantly up-regulated the protein expression of acetylcholinesterase associated with oxidative stress in hippocampus. Besides, STZ-induced diabetic mice showed hypolocomotion with up-regulation of muscarinic acetylcholine receptor-4 expression in striatum. Chronic UD treatment significantly attenuated the cholinergic dysfunction and oxidative stress in the hippocampus of diabetic mice. UD had no effect on locomotor activity and muscarinic acetylcholine receptor-4 expression in striatum. In conclusion, UD leaves extract has potential to reverse diabetes mediated alteration in muscarinic cholinergic system in hippocampus and thereby improve memory functions.