Demethyleneberberine attenuates combined cognitive and metabolic dysfunctions in an insulin-resistance-induced Alzheimer's disease rat model: Synthesis, in-silico and in-vivo insights.

Design-led synthesis and multidimensional evaluation of novel thiadiazoles as multitarget anti-Alzheimer agents: kinetics, DFT and in silico mapping.

Discovery of undescribed PCSK9 inhibitory activities in Annonaceous acetogenins from Polyalthia evecta.

Tryptophan 2,3-dioxygenase (TDO) is a haem-containing enzyme of the kynurenine pathway, which is imperative for tryptophan metabolism. Primarily found in the liver, TDO facilitates the breakdown of TRP into N-formyl kynurenine. TDO is regarded as a promising target for antidepressant therapies. As an enzyme responsible for tryptophan degradation, its inhibition may enhance serotonin availability, which plays a key role in mood regulation. This study identifies TDO as a potential target for central nervous system drugs (acamprosate, roxindole, and L-ascorbic acid) that may alter brain activity and potentially impact mood and behavior. The study involved male Albino Wistar rats, each weighing between 150 and 200 grams. The rats were decapitated, the livers were promptly excised within 10 seconds, and perfused in situ with ice-cold saline. The perfused livers were then immediately frozen at -80°C for subsequent analysis. In vitro TDO enzyme activity was assessed in frozen liver homogenates. Enzymatic activity was measured for both the holoenzyme and total enzyme spectrophotometrically. Molecular docking of the selected compounds with TDO was conducted using AutoDock Vina. The crystal structure of TDO was retrieved from the Protein Data Bank (PDB), while ligand structures were obtained from PubChem. In vitro experiments revealed that these drugs inhibited apoenzyme activity by 68-85%, while total enzyme activity was reduced by 34%, 38% and 37% for acamprosate, roxindole, and L-ascorbic acid, respectively. Further validation through molecular docking analysis confirmed their strong binding affinity to the TDO active site, with l-ascorbic acid showing the highest binding energy (-7.2 kcal/mol), followed by acamprosate (-6.7 kcal/mol) and roxindole (-6.4 kcal/mol). These findings suggest that acamprosate, roxindole, and L-ascorbic acid act as competitive TDO inhibitors, potentially enhancing serotonin synthesis and mitigating depressive symptoms.

Evaluation of the efflux inhibitory potential of aminopyrazole derivative to restore azole sensitivity in Candida albicans.

Therapeutic potential of Oxalis corniculata in circumventing Alzheimer's disease through in vitro and in silico investigations.

Background: Nut protein is gaining recognition worldwide due to its encryptable amino acid sequences. This study investigates the inhibitory potential of Aduwa hydrolysates from Aduwa protein concentrate, produced by selected proteases or hypertensive-modulated activities with the aim of enriching the database of bioactive peptides that could serve as a potential ingredient in lowering hypertension. Objective: This study reports on the in vitro and in vivo ACE-inhibitory activity of Aduwa (Balanites aeqyptiaca del) protein hydrolysates to evaluate their potency as anti-hypertensive agents. Methods: Aduwa protein concentrate (APC) sample was digested with pancreatin-pepsin (PP) combined protease, Alcalase (Alca), and Flavourzyme (Flav) hydrolytic enzymes. Samples were subjected to hypertension-lowering ability in spontaneous hypertensive rats (SHRs). Results: The Alcalase hydrolysate had better angiotensin-converting enzyme in vitro and in vivo lowering activity than APC and Flav samples. The angiotensin converting enzyme in vitro and in vivo lowering activity at 200mg/kg and 500mg/kg revealed enhanced hypertension, lowering potentials by PP and Flavourzyme; SBP (maximum~ -9, ~ -7) mmHg, dystonic blood pressure; DBP (maximum~ -6.96, -4.3) mmHg and mean arterial blood pressure MAP (maximum ~ -9, ~ -6) mmHg, respectively in SHRs. This study provides the first report of the in vitro and in vivo antihypertensive potential of PP and Flav hydrolysates. These results suggest that Aduwa hydrolysates are effective functional ingredients or raw materials for the production of ACE inhibitors and antihypertensive agents. Practical Implication: Functional foods derived from nut proteins such as soybean and moringa oleifera can be successfully incorporated into various food matrices, including beverages, baked goods, dairy products, and dietary supplements, without a significant effect on palatability or nutritional quality. Plant peptides are adaptable to diverse climatic conditions and have the potential to support sustainable agricultural production, thereby enhancing their commercial viability as functional food ingredients. Conclusion: This is the first study to report the antihypertensive potential of Aduwa (Balanites aegyptiaca) protein hydrolysates as ACE inhibitors. The peptides from APC, PP, and Alcalase hydrolysates are capable of lowering SBP, DBP, and MAP to levels comparable to captopril. These peptides appear to resist gastrointestinal degradation, retaining ACE-inhibitory activity after oral gavage. Overall, PP and Alca peptides show strong potential for development into functional foods, nutraceuticals, and natural antihypertensive agents. APC and PP hydrolysates could serve as useful bioactive raw materials to promote human health as antihypertensive ingredients in functional food formulations, helping manage high blood pressure. Keyword: Balanites aegyptiaca (Aduwa), protein hydrolysates, ACE-inhibitory peptides, antihypertensive peptides, spontaneously hypertensive rats (SHR), blood pressure reduction, enzymatic hydrolysis, functional food ingredients

With increasing anthropogenic activities, man is faced with carcinogenic substances like arsenate, which according to the Agency for Toxic Substances and Diseases Registry, is top on the list of twenty most toxic substances of public health concern. Therefore, this research investigated the effects of P. amarus leaf fraction on arsenate toxicity on key cell lines, with focus on addressing the challenge of arsenic poison in food and the environment. Various assays such as free radical scavenging assays and in-vitro cell lines assays on Human hepatic (HepG2), Kidney epithelial (LLCPK1), fibroblast and clonal pancreatic cells were employed using crude and pure fractions of the leaf. Data obtained were subjected to analytical tools such as SPSS, and Mnova software. From five solvent extracts screened, ethyl acetate extract had strongest antioxidant activity against in-vitro radicals. In-vivo LD50 of sub-acute toxicity on Wistar rats is 707.11mg/Kg. The cell line study revealed that 10μg/mL and above of crude leaf fraction protected pancreatic cells from cytotoxic effect of sodium arsenate (about 33% cells are viable against 50mg/mL arsenate), while on normal cells, 1.0-100μg/mL of the fraction showed improved cell viability. The fraction is less toxic on kidney epithelial cells and no effect on kidney fibroblast compared to Doxorubicin drug. Moreso, the fraction activated Pregnane X Receptor (PXR) which is responsible for CYPs mRNA genes expression for enzymes involve in xenobiotic metabolism, in concentration-dependent manner. Pure compounds isolated also showed same activation on PXR. In Conclusion, P. amarus leaf fraction act as ameliorative agent against arsenic toxicity as demonstrated through rejuvenation of cell growth due to its polyphenols, known for their membrane stabilizing activity by inhibiting ROS. It also acts as molecular ligand that activates PXR receptor. Although, it contains niranthin and cubebin dimethyl ether with same inhibitory potential as Ketoconazole which has been verified to have side effects.

Urease increases the stomach's pH by hydrolyzing urea and fostering the growth of Helicobacter pylori, linked to a variety of gastrointestinal issues, including peptic ulcers. Despite the availability of conventional therapies, the development of safe and effective, nontoxic urease inhibitors with better pharmacological profiles remains an unmet need. Novel 2-cyclopentylidenehydr azinyl thiazole derivatives were first time synthesized by first reacting cyclopentanone with thiosemicarbazide to afford thiosemicarbazone which then treated with different phenacyl bromides to afford products. All compounds exhibited outstanding urease inhibitory activity (IC50 = 0.14 to 6.39 µM) than the standard inhibitors thiourea and acetohydroxamic acid (AHA), with IC50 values of 19.43 and 41.3 µM, respectively. In fact, CH3 bearing compound 10 (IC50 = 0.04 ± 0.008 µM) exhibited the highest inhibitory potential against urease. Structure-activity relationship (SAR) indicated that the inhibitory potential is strongly influenced by the electronic and steric factors. Furthermore, molecular docking experiments also revealed various interactions between the ligands (compounds) and the enzyme's active site. Detailed pharmacokinetics, drug-likeness, and absorption, distribution, metabolism, and excretion (ADME) properties were also assessed. This study demonstrates that these newly synthesized thiazole derivatives may serve as potential lead candidates for the discovery of antiulcer agents.

In this work, a series of 2H-benzoxaborinines was synthesized via an "aromatic metamorphosis" strategy based on the nickel-catalyzed insertion of boron into benzofuran scaffolds and were evaluated as novel carbonic anhydrase (CA) inhibitors. All compounds were evaluated in vitro against seven human CA isoforms (I, II, IV, VA, VII, IX, and XII), with several derivatives displaying low-nanomolar inhibitory activity. X-ray crystallographic analysis of the complexes of 2H-benzoxaborinine 2a with hCA I and hCA II revealed significant differences compared with the 1H-benzoxaborinine analogue, which can be attributed to the increased structural rigidity of the scaffold. Finally, the selected compounds (2a, 3d, 5c, and 9c) were further evaluated for their in vitro antiproliferative activity against human triple-negative breast cancer (MDA-MB-231) and glioblastoma (U87MG) cancer cell lines, with derivative 5c demonstrating superior antiproliferative activity compared with the antitumor CA inhibitor SLC-0111.

Objective: This study seeks to investigate 4-hydroxy-3-methoxycinnamic acid (Ferulic acid) derivatives using computational approaches—specifically Lipinski’s Rule of Five, ADMET profiling, Mol-Inspiration analysis, and molecular docking—in order to evaluate their drug-likeness, pharmacokinetic properties, and therapeutic potential, with a particular focus on lung cancer treatment. Methodology: The study examined the physicochemical, pharmacokinetic, and pharmacodynamic properties of 4-hydroxy-3-methoxycinnamic acid derivatives substituted with aromatic amines through in-silico approaches. Computational analyses were performed using web-based tools and specialized programs, including Pre-ADMET, Mol-Inspiration, and Molegro Virtual Docker 6.0. Result and Discussion: Computational evaluation of 15 aromatic amine–substituted 4-hydroxy-3-methoxycinnamic acid (Ferulic acid) derivatives demonstrated favourable drug-likeness, as confirmed by Mol-Inspiration analysis and compliance with Lipinski’s Rule of Five. ADMET predictions indicated promising pharmacokinetic behaviour with minimal toxicity risks. Molecular docking against tyrosine kinase targets (PDB IDs: 4ZSE, 8A27, 5T4B, 6CU6) revealed strong binding affinities, with 6CU6 showing the most significant interactions suggestive of inhibitory potential. Key binding modes included hydrogen bonding and π–π stacking with active site residues, underscoring the suitability of these derivatives as potential lead candidates for lung cancer therapy.The test compound FA-6 exhibited the highest binding affinity with a MolDock score of −172.892, forming multiple hydrogen-bond interactions with Ala 146, Lys 147, Asp 119, Thr 35, Ser 17, Asp 33, Tyr 32, Arg 12, Gly 60, and Lys 16 indicating strong and stable binding within the active site. In comparison, the standard drug gefitinib showed a lower MolDock score (−157.872) with fewer hydrogen-bond interactions (Thr35, Ser17, and Glu31). Overall, FA-11 demonstrated superior docking performance compared to gefitinib and other tested ligands, highlighting its potential as a promising lead compound. Conclusion: This study demonstrates that the selected 4-hydroxy-3-methoxycinnamic acid(Ferulic acid)derivatives possess favourable ADMET profiles, strong drug-likeness, and notable tyrosine kinase inhibitory activity. These findings highlight their promise as potential lead candidates for the development of lung cancer therapeutics.

In vitro inhibition of monoamine transport by amphetamine-like pre-workout supplement ingredients.

Transcriptomic analysis reveals the multifaceted inhibitory mechanisms of thymol on the survival and virulence of Vibrio alginolyticus.

NatProCP: A plant-derived natural products database for crop protection targeting SDH1 protein of Magnaporthe oryzae.

Excitation/inhibition balance is crucial to homeostatic brain function and disrupted in several neurodevelopmental and neurodegenerative diseases. Cortical inhibitory neurons derived from the medial ganglionic eminence (MGE) provide input to glutamatergic projection neurons, an essential function in neural processing. While neural grafts for stroke improve motor function following engraftment, these grafts typically contain only excitatory neurons (and glia), and little effort has been directed at understanding the role of inhibitory neurons in this context. Here, we generate a channelrhodopsin line to optogenetically control grafted human pluripotent stem cell-derived MGE interneurons in the context of a mixed inhibitory-excitatory chimeric transplantation model. We demonstrate robust differentiation toward either dorsal cortical excitatory or ventral MGE inhibitory fates. Co-grafts of inhibitory and excitatory neurons demonstrate lineage-specific maturation-predominantly excitatory CTIP2 + layer 5 projection neurons or inhibitory Calretinin + and SST+ interneurons. Co-grafts integrate and densely innervate both the graft and host tissues. We observed juxtaposition of excitatory and inhibitory fibres and synapses. Optogenetic stimulation confirmed that grafted inhibitory neurons are functionally integrated with grafted excitatory neurons, inducing inhibitory post-synaptic potentials, which were blocked with gabazine. Together, these data provide evidence of functional inhibitory-excitatory circuit reconstruction following transplantation and provide a platform for advanced cell therapies and disease modelling.

This study comparatively evaluated the phytochemical and biological profiles of Origanum leptocladum and O. vulgare subsp. hirtum (Lamiaceae). Aqueous extracts yielded more material than methanolic ones, with O. leptocladum showing superior extractability. GC–MS analysis revealed distinct chemotypes: O. leptocladum was rich in cis-sabinene hydrate and p-cymene, whereas O. vulgare was dominated by carvacrol. Methanol extracts of O. leptocladum exhibited the highest α-glucosidase inhibition (90.10%) and antioxidant capacity, correlating with elevated phenolic content. Molecular docking indicated strong binding affinities of carvacrol, cis-sabinene hydrate, and p-cymene to α-glucosidase, α-amylase, AChE, and BChE, implying multitarget inhibitory potential. ADME predictions confirmed favourable pharmacokinetic properties and BBB permeability, especially for carvacrol and cis-sabinene hydrate. This first report on α-glucosidase and α-amylase inhibition by O. leptocladum underscores its promising antidiabetic and neuroprotective potential, supporting its value for pharmaceutical and nutraceutical development.

The journal retracts the article titled “Rheological Characterization and Shale Inhibition Potential of Single- and Dual-Nanomaterial-Based Drilling Fluids for High-Pressure High-Temperature Wells” [...]

Rice false smut (RFS), caused by Ustilaginoidea virens, severely reduces rice yield and grain quality, threatening food security. Although chemical control is the primary management strategy, prolonged use of fungicides has led to widespread resistance in U. virens. To address this issue, we evaluated the inhibitory potential of albendazole, a promising candidate fungicide, against U. virens. The sensitivity of 103 U. virens strains from five Chinese provinces was assessed using the mycelial growth rate method. The sensitivity baseline exhibited a unimodal distribution, with EC50 values ranging from 0.4246 to 2.6600 μg/ml (mean: 1.0984 ± 0.4590 μg/ml), indicating strong inhibition of U. virens by albendazole. Despite its efficacy, the resistance risk of U. virens to albendazole remains unclear. To evaluate the potential for resistance development, we generated albendazole-resistant laboratory mutants through fungicide domestication and UV mutagenesis, with resistance frequencies of 3.3 and 6.7%, respectively. Among the nine resistant mutants, eight displayed high-level resistance (resistance factor [RF] > 100), and one showed moderate resistance (RF > 80), with stable inheritance of resistance. Resistant mutants displayed significant fitness costs, including reduced mycelial growth, sporulation, biomass production, inhibitory effect on the radicle of rice seeds, and cold tolerance. Cross-resistance assays revealed no cross-resistance with azoxystrobin or propiconazole but confirmed cross-resistance with carbendazim. Based on resistance frequency and fitness penalties, the resistance risk was evaluated as moderate. These findings provide critical guidance for the rational use of albendazole and highlight its potential as an alternative fungicide in RFS management.

Design, synthesis, and biological evaluation of 2-amino-1,3,4-thiadiazoles as new potential EGFR inhibitors for treatment of cancer.

Pedaling and schoolwork: Stability in academic performance, cognition, and neuroelectric function during moderate-intensity cycling in children.