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.

Molecular Insights to the Wnt Signaling During Alzheimer's Disorder: a Potential Target for Therapeutic Interventions.

In the adult brain, Wnt signaling is crucial for neurogenesis, and it also regulates neuronal development, neuronal maturation, neuronal differential, and proliferation. Impaired Wnt signaling pathways are associated with enhanced levels of amyloid-ß, reduced ß-catenin levels, and increased expression of GSK-3ß enzyme, suggesting its direct association with the pathogenesis of Alzheimer's disorder (AD). These findings are consolidated by reports where activation of Wnt signaling by genetic factors and pharmacological intervention has improved the cognitive functions in animals and restored neurogenesis in the adult brain. Various natural and synthetic molecules have been identified that modulate Wnt signaling in the adult brain and promote neurogenesis and alleviate behavioral dysfunction. These molecules include lithium, valproic acid, ethosuximide, selenomethionine, curcumin, andrographolide, xanthoceraside, huperzine A, pyridostigmine, ginkgolide-B, ricinine, cannabidiol, and resveratrol. These molecules are associated with the DKK1 and GSK-3ß inhibition and ß-catenin stabilization along with their effects on neurogenesis, neuronal proliferation, and differentiation in the hippocampus through modulation of Wnt signaling and thereby could prove beneficial in the management of AD pathogenesis. Although modulation of the Wnt signaling seems to suggest to be promising in the management of AD, unfortunately, most of the literature available for the association of Wnt signaling and AD pathogenesis is either from preclinical studies or post-mortem brain. Therefore, it will be interesting to understand the role of Wnt signaling in AD patients, and a rigorous investigation could provide us with a better understanding of AD pathogenesis and the identification of novel targets for therapeutic interventions.

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.

Nutraceuticals in Neurological Disorders.

Neurological diseases are one of the major healthcare issues worldwide. Posed lifestyle changes are associated with drastically increased risk of chronic illness and diseases, posing a substantial healthcare and financial burden to society globally. Researchers aim to provide fine treatment for ailing disorders with minimal exposed side effects. In recent decades, several studies on functional foods have been initiated to obtain foods that have fewer side effects and increased therapeutic activity. Hence, an attempt has been made to unravel several extraction techniques to acquire essential bioactive compounds or phytochemicals from therapeutically active food products. This has led to the conception of the term functional foods being meddled with other similar terms like "pharmafoods," "medifoods", "vitafoods", or "medicinal foods". With a dire need to adhere towards healthy options, the demand of nutraceuticals is widely increasing to combat neurological interventions. An association between food habits and the individual lifestyle with neurodegeneration has been manifested, thereby proposing the role of nutraceuticals as prophylactic treatment for neurological interventions. The current review covers some of the major neurological disorders and nutraceutical therapy in the prevention of disease.

Antidepressant and anxiolytic like effects of Urtica dioica leaves in streptozotocin induced diabetic mice.

The present study was aimed to investigate the effect of Urtica dioica Linn. (UD) extract against chronic diabetes mediated anxiogenic and depressive like behavior in mice. Streptozotocin (STZ) (50 mg/kg, i.p.) for 5 consecutive days was used to induce diabetes followed by treatment with UD leaves extract (50 mg/kg, p.o.) and rosiglitazone (ROSI) (5 mg/kg, p.o.) for 8 weeks. STZ induced chronic diabetes significantly induced anxiety and depressive like behavior in mice. Chronic diabetes significantly downregulated BDNF (p < 0.001), TrKB (p < 0.001), Cyclin D1 (p < 0.001), Bcl2 (p < 0.05) and autophagy7 (p < 0.001), while upregulated iNOS (p < 0.05) mRNA expression in the hippocampus as compared to control mice. In addition, chronic diabetes significantly increased the expression of TNF-α in CA1 (p < 0.001), CA2 (p < 0.01), CA3 (p < 0.001) and DG (p < 0.001) regions of hippocampus as compared to control mice. Chronic diabetes mediated neuronal damage in the CA2, CA3 and DG regions of hippocampus. Chronic administration of UD leaves extract significantly reversed diabetes mediated anxiogenic and depressive like behavior in mice. Further, UD treatment significantly upregulated BDNF (p < 0.01), TrKB (p < 0.001), Cyclin D1 (p < 0.001), Bcl2 (p < 0.01), autophagy5 (p < 0.01) and autophagy7 (p < 0.001), while downregulated iNOS (p < 0.05) mRNA expression in the hippocampus of diabetic mice. Concomitantly, UD administration significantly decreased the expression of TNF-α in hippocampal CA1 (p < 0.001), CA2 (p < 0.01), CA3 (p < 0.001) and DG (p < 0.001) regions of diabetic mice. Diabetes mediated neuronal damage and DNA fragmentation in the hippocampus was substantially attenuated following UD treatment. UD leaves extract might prove to be effective for diabetes mediated anxiety and depressive like behavior.

Microbe-bio-Chemical Insight: Reviewing Interactions between Dietary Polyphenols and Gut Microbiota.

OBJECTIVE: Polyphenols are widespread constituents of different food commodities. These are regarded as essential micronutrients because of their well-documented health benefits. These health benefits depend on the amount of polyphenols consumed and their bioavailability in the gut. The microbial transformation of polyphenols in gut is poorly characterized, where, these polyphenols may act as promoting factors for proliferation of beneficial gut inhabitants and inhibiting the pathogenic species. CONCLUSION: The aim of this review is to present a holistic view on occurrence of polyphenols, their health benefits and influence of dietary polyphenols on gut microbiota.

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.

Antifertility effect of hydroalcoholic leaves extract of Michelia champaca L.: an ethnomedicine used by Bhatra women in Chhattisgarh state of India.

ETHNOPHARMACOLOGICAL RELEVANCE: Michelia champaca L. (family: Magnoliaceae), commonly known as Champa [Hindi], is traditionally used for fertility regulation by the women of Chhattisgarh state in India. No scientific evidence regarding the antifertility effect of this plant is available till date. AIM OF THE STUDY: To study the anti-fertility effect of hydroalcoholic leaf extract of Michelia champaca Linn. in female rats. MATERIALS AND METHODS: The antifertility activity of the extract (HAEMC) administered at dose levels (100 and 200mg/kg body weight, p.o.) was evaluated in two experimental animal models i.e. antiimplantation activity in female wistar rats and esterogenic/antiestrogenic activity in ovariectomized female rats. In anti-implantation activity, the extract (200 and 400mg/kg body weight, p.o.) was administered to female rats from 1 to 7 days of pregnancy and on 10th day, laprotomy was performed to count the no. of implants. For estrogenic/anti-estrogenic activity, ovariectomized female rats were administered with the extract at both the doses alone as well as along with 17α-ethinyl estradiol (1 µ/rat/day) for 7 consecutive days. On the 8th day, all animals were sacrificed and blood serum was further processed for the estimation of biochemical parameters such as estrogen level, alkaline phosphates, cholesterol, tryglycerides, total protein etc. RESULTS: The extract (HAEMC) showed significant (p<0.01) 49.95% and 71.03% antiimplantation activities at 100 and 200mg/kg doses respectively. The extract also exhibited significant (p<0.01) estrogenic activity as evidenced by increase in body weight, uterine weight, increased thickness and height of endometrium, vaginal cornification and significant (p<0.01) increase in estrogen, cholesterol, alkaline phosphate and triglycerides levels at higher dose when administered alone as well as along with ethinyl estradiol. Phytochemical screening showed the presence of steroids, flavonoids and alkaloids in the extract. CONCLUSIONS: Hydroalchoholic extract of Michelia champaca leaves possesses significant antifertility effect which might be due to the inhibition of implantation and estrogenic effect which in turn might be due to the presence of some phytoconstituents in the plant.