Acacia nilotica L., also known as babul, belonging to the Fabaceae family and the Acacia genus, is typically used for ornamental purposes and also as a medicinal plant found in tropical and subtropical areas. This plant is a rich source of bioactive compounds. The current study aimed to elucidate the hypoglycemic, anti-inflammatory, and neuroprotective potential of A. nilotica\'s crude methanolic extract. The results of the in vitro antidiabetic assay revealed that methanolic extract of A. nilotica inhibited the enzyme α-glucosidase (IC50: 33 μg mL-1) and α-amylase (IC50: 17 μg mL-1) in a dose-dependent manner. While in the anticholinesterase enzyme inhibitory assay, maximum inhibition was shown by the extract against acetylcholinesterase (AChE) (637.01 μg mL-1) and butyrylcholinesterase (BChE) (491.98 μg mL-1), with the highest percent inhibition of 67.54% and 71.50% at 1000 μg mL-1, respectively. This inhibitory potential was lower as compared to the standard drug Galantamine that exhibited 82.43 and 89.50% inhibition at the same concentration, respectively. Moreover, the methanolic extract of A. nilotica also significantly inhibited the activities of cyclooxygenase 2 (COX-2) and 5-lipoxygenase (5-LOX) in a concentration-dependent manner. The percent inhibitory activity of 5-LOX and COX-2 ranged from 42.47% to 71.53% and 43.48% to 75.22%, respectively. Furthermore, in silico, in vivo, and clinical investigations must be planned to validate the above-stated bioactivities of A. nilotica.

Tris (2-chloroethyl) phosphate (TCEP) is a crucial organophosphorus flame retardant widely used in many industrial and commercial products. Available reports reported that TCEP could cause various toxicological effects on organisms, including humans. Unfortunately, toxicity data for TCEP (particularly on neurotoxicity) on aquatic organisms are lacking. In the present study, Danio rerio were exposed to different concentrations of TCEP for 42 days (chronic exposure), and oxidative stress, neurotoxicity, sodium, potassium-adenosine triphosphatase (Na+, K+-ATPase) activity, and histopathological changes were evaluated in the brain. The results showed that TCEP (100 and 1500 µg L-1) induced oxidative stress and significantly decreased the activities of antioxidant enzymes (SOD, CAT and GR) in the brain tissue of zebrafish. In contrast, the lipid peroxidation (LPO) level was increased compared to the control group. Exposure to TCEP inhibited the acetylcholinesterase (AChE) and Na+,K+-ATPase activities in the brain tissue. Brain histopathology after 42 days of exposure to TCEP showed cytoplasmic vacuolation, inflammatory cell infiltration, degenerated neurons, degenerated purkinje cells and binucleate. Furthermore, TCEP exposure leads to significant changes in dopamine and 5-HT levels in the brain of zebrafish. The data in the present study suggest that high concentrations of TCEP might affect the fish by altering oxidative balance and inducing marked pathological changes in the brain of zebrafish. These findings indicate that chronic exposure to TCEP may cause a neurotoxic effect in zebrafish.

In silico studies were performed to assess the binding affinity of selected organophosphorus compounds toward the acetylcholinesterase enzyme (AChE). Quantum mechanical calculations, molecular docking, and molecular dynamics (MD) with molecular mechanics Generalized-Born surface area (MM/GBSA) were applied to assess quantitatively differences between the binding energies of acetylcholine (ACh; the natural agonist of AChE) and neurotoxic, synthetic correlatives (so-called \"Novichoks\", and selected compounds from the G- and V-series). Several additional quantitative descriptors like root-mean-square fluctuation (RMSF) and the solvent accessible surface area (SASA) were briefly discussed to give-to the best of our knowledge-the first quantitative in silico description of AChE-Novichok non-covalent binding process and thus facilitate the search for an efficient and effective treatment for Novichok intoxication and in a broader sense-intoxication with other warfare nerve agents as well.

BACKGROUND: Belamcanda chinensis (L.) DC. (BC) and Iris tectorum Maxim. (ITM) have been widely used in recent years due to their remarkable curative effects on sore throat, cough and asthma. but they are often misused due to their similar appearance. A comprehensive comparison of the chemical composition, biological activity, pharmacokinetics and tissue distribution between the two active differential components has not been performed. Differences in their specific effects have not been fully elucidated.
OBJECTIVE: This work aims at differentiating between BC and ITM in terms of appearance, chemical composition, biological activity, pharmacokinetics and tissue distribution.
METHODS: In this study, the HPLC-FP method was used to find the differences between the chemical components of BC and ITM. The pharmacological experiments were used to compare the differences in activity, including in vitro anti-inflammatory activity with LPS-induced inflammation model of RAW 264.7 cells, inhibition of AChE activity, and the regulation of isolated small intestinal smooth muscle in mice. The pharmacokinetic and tissue distribution profiles were used to analyze the differences between the two in rats.
RESULTS: The types of isoflavones in BC and ITM are basically the same, but their contents in ITM is much higher than that in BC. At the same doses, the release of TNF-α, NO, IL-1β and IL-6 from RAW 264.7 cells in the ITM group was lower than that of the BC group, and the in vitro anti-inflammatory activity of ITM was stronger than that of BC. Meanwhile, ITM had stronger inhibition ability to inhibit AChE activity than BC. The BC extract exhibited an inhibitory effect on the isolated small intestinal smooth muscle of mice, and the ITM extract showed stimulatory effect at low concentration and inhibitory effect at high concentration. There were significant differences in drug-time profiles, kinetic parameters and tissue distribution.
CONCLUSIONS: There are significant differences in the multidimensional aspects of appearance, chemical composition, biological activity, pharmacokinetics, and tissue distribution between BC and ITM. This study provides a theoretical basis for the quality control, pharmacological efficacy and clinical application of the two herbs.

Alzheimer\'s disease (AD) is a chronic neurodegenerative condition characterized by progressive cognitive impairment. While the formation of β-amyloid plaques and neurofibrillary tangles are the hallmarks features of AD, the downstream consequence of these byproducts is the disruption of the cholinergic and glutamatergic neural systems. Growing evidence for the existence of interplay between AChE and NMDARs has opened up new venues for the discovery of novel ligands endowed with anticholinesterase and NMDAR-blocking activity. Plants belonging to the stachys genus have been extensively explored for having a broad range of therapeutic applications and have been used traditionally for millennia, to treat various CNS-related disorders, which makes them the ideal source of novel therapeutics. The present study was designed to identify natural dual-target inhibitors for AChE and NMDAR deriving from stachys genus for their potential use in AD. Using molecular docking, drug-likeness-profiling, MD simulation and MMGBSA calculations, an in-house database of biomolecules pertaining to the stachys genus was shortlisted based on their binding affinity, overall stability and critical ADMET parameters. Pre- and post-MD analysis revealed that Isoorientin effectively binds to AChE and NMDAR with various vital interactions, exhibits a stable behavior with minor fluctuations relative to two clinical drugs used as positive control, and displays strong and consistent interactions that lasted for the majority of the simulation. Findings from this study have elucidated the rationale behind the traditional use of Stachys plants for the treatment of AD and could provide new impetus for the development of novel dual-target therapeutics for AD treatment.Communicated by Ramaswamy H. Sarma.

Cannabis sativa is a medicinal plant that has been known for years and is used as an Ayurvedic medicine. This plant has great potential in treating various types of brain diseases. Phytochemicals present in this plant act as antioxidants by maintaining synaptic plasticity and preventing neuronal loss. Cannabidiol (CBD) and Tetrahydrocannabinol (THC) are both beneficial in treating Alzheimer\'s disease by increasing the solubility of Aβ42 amyloid and Tau aggregation. Apart from these therapeutic effects, there are certain unknown functions of these phytochemicals in Alzheimer\'s disease that we want to elucidate through this study. In this research, our approach is to analyze the effect of phytochemicals in Cannabis sativa on multiple culprit enzymes in Alzheimer\'s disease, such as AChE (Acetylcholinesterase), BChE (Butyrylcholinesterase), γ-secretase, and BACE-1. In this study, the compounds were selected by Lipinski\'s rule, ADMET, and ProTox based on toxicity. Molecular docking between the selected compounds (THCV, Cannabinol C2, and Cannabidiorcol) and enzymes mentioned above was obtained by various software programs including AutoDock Vina 4.2, AutoDock, and iGEMDOCK. In comparison to Donepezil (BA = -8.4 kcal/mol, Ki = 1.46 mM), Rivastigmine (BA = -7.0 kcal/mol, Ki = 0.02 mM), and Galantamine (BA = -7.1, Ki = 2.1 mM), Cannabidiorcol (BA = -9.4 kcal/mol, Ki = 4.61 mM) shows significant inhibition of AChE. On the other hand, Cannabinol C2 (BA = -9.2 kcal/mol, Ki = 4.32 mM) significantly inhibits Butyrylcholinesterase (BuChE) in comparison to Memantine (BA = -6.8 kcal/mol, Ki = 0.54 mM). This study sheds new light and opens new avenues for elucidating the role of bioactive compounds present in Cannabis sativa in treating Alzheimer\'s disease.

LC-HRESIMS metabolomic profiling of Olea europaea L. cv. Picual (OEP) (Saudi Arabian olive cultivar, F. Oleacea) revealed 18 compounds. Using pharmacology networking to specify the targets of the identified compounds with a relationship to Alzheimer\'s disease, it was possible to identify the VEGFA, AChE, and DRD2 genes as the top correlated genes to Alzheimer\'s disease with 8, 8, and 6 interactions in the same order. The mechanism of action on cellular components, biological processes, and molecular functions was determined by gene enrichment analysis. A biological pathway comparison revealed 13 shared pathways between the identified genes and Alzheimer protein genes (beta-amyloid band tau proteins). The suggested extract\'s anti-Alzheimer potential in silico screening was confirmed through in vivo investigation in regressing the neurodegenerative features of Alzheimer\'s dementia in an aluminum-intoxicated rat model (protective and therapeutic effects, 100 mg/kg b.w.). In vivo results suggested that OEP extract significantly improved Alzheimer\'s rats, which was indicated by the crude extract\'s ability to improve T-maze performance; lower elevated serum levels of AChE, AB peptide, and Ph/T ratio; and normalize the reduced level of TAC during the study. The results presented in this study may provide potential dietary supplements for the management of Alzheimer\'s disease.

Galantamine is one of the approved drugs based on the cholinergic hypothesis for the symptomatic treatment of mild to moderate Alzheimer\'s disease (AD). The etiology of AD is not fully known; however, the reported cholinergic hypothesis suggests the inadequate synthesis of the neurotransmitter acetylcholine (ACh) is responsible for this disease. The crystal structure of galantamine bound human acetylcholinesterase (hAChE) has been reported; however, the inhibition mechanism of hAChE by galantamine is not well understood. A Well-tempered metadynamics (WTMtD) simulation study has been performed with the crystal structure of galantamine bound hAChE. The reported mechanism for the degradation of ACh is suggested through a proton transfer process from a carboxylic group of Glu334 to the hydroxyl group of Ser203, which attacks ACh for the degradation to acetic acid and choline. Such proton transfer process is lowered in the presence of galantamine due to the separation of catalytic triad inside the gorge of AChE as observed with WTMtD. A docking study has been performed to examine the ACh\'s binding with the catalytic triad of galantamine bound hAChE. The docking results reveal that the approach of ACh to the catalytic triad is interrupted due to the galantamine\'s presence in the gorge of the enzyme.

The lack of effective treatment for chronic discomfort without negative side effects highlights the need for alternative treatments. Pain Bloc-R is a natural health product composed of vitamins B6, B12, D, white willow bark extract, Angelica root extract, acetyl L-carnitine HCl, caffeine, L-theanine, Benfotiamine, and L-tetrahydropalmatine. The objective of this study was to compare the effects of Pain Bloc-R, acetaminophen, and placebo on unresolved aches and discomfort as assessed by the brief pain inventory (BPI) and modified Cornell musculoskeletal discomfort questionnaires. This randomized, double-blind, placebo-controlled, crossover study consisted of three 7-day periods with Pain Bloc-R, acetaminophen, or placebo, each separated by a 7-day washout. Twenty-seven healthy adults (ages 22-63 years) were randomized to receive the three interventions in different sequences. The BPI \"pain at its worst\" scores were significantly lower when participants took Pain Bloc-R than when they took acetaminophen (21.8% vs. 9.8% decrease, p = 0.026) after seven days of supplementation. Pain Bloc-R achieved a significant improvement in the \"pain at its least\" score, significantly decreased the interference of discomfort in walking, and significantly decreased musculoskeletal discomfort total scores (34%, p = 0.040) after seven days. In a post hoc subgroup analysis based on age and gender, male participants ≤45 years taking Pain Bloc-R reported significant reductions in pain severity and pain interference vs. acetaminophen. Pain Bloc-R performed as well as acetaminophen in managing unresolved non-pathological pain in otherwise healthy individuals.

Alzheimer\'s disease (AD) is the most well-known reason for disability in persons aged greater than 65 years worldwide. AD influences the part of the brain that controls cognitive and non-cognitive functions.
The study focuses on the screening of natural compounds for the inhibition of AChE and BuChE using a computational methodology.
We performed a docking-based virtual screening utilizing the 3D structure of AChE and BuChE to search for potential inhibitors for AD. In this work, a screened inhibitor Ajmalicine similarity search was carried out against a natural products database (Super Natural II). Lipinski rule of five was carried out and docking studies were performed between ligands and enzyme using \'Autodock4.2\'.
Two phytochemical compounds SN00288228 and SN00226692 were predicted for the inhibition of AChE and BuChE, respectively. The docking results revealed Ajmalicine, a prominent natural alkaloid, showing promising inhibitory potential against AChE and BuChE with the binding energy of -9.02 and -8.89 kcal/mole, respectively. However, SN00288228- AChE, and SN00226692-BuChE were found to have binding energy -9.88 and -9.54 kcal/mole, respectively. These selected phytochemical compounds showed better interactions in comparison to Ajmalicine with the target molecule.
The current study verifies that SN00288228 and SN00226692 are more capable inhibitors of human AChE and BuChE as compared to Ajmalicine with reference to ΔG values.