Search Results (2,631)

Background/Objectives: Malaria is a prominent vector-borne disease, with a high mortality rate, particularly in children under five years old. Despite the use of various insecticides for its control, the emergence of resistant mosquitoes poses a significant public health threat. Acetylcholinesterase (AChE) is a crucial enzyme in nerve transmission and a primary target for insecticide development due to its role in preventing repeated nerve impulses. Recent studies have identified difluoromethyl ketone (DFK) as a potent inhibitor of both sensitive and resistant Anopheles gambiae acetylcholinesterase (AgAChE). This study aimed to identify novel AgAChE inhibitors that could be explored for malaria prevention. Methods: We performed a virtual screening on the PubChem database using a pharmacophore model from difluoromethyl ketone-inhibited AgAChE’s crystal structure. The most promising compound was then subjected to molecular docking and dynamics studies with AgAChE to confirm initial findings. ADMET and agrochemical likeness (ag-like) properties were also analyzed to assess its potential as an agrochemical agent. Results: PubChem18463786 was identified as the most suitable compound from the virtual screening. Molecular docking and molecular dynamics studies confirmed its strong interaction with AgAChE. The ADMET and ag-like analyses indicated that PubChem18463786 possesses physicochemical properties suggesting a high probability of non-absorption in humans and meets the criteria for agrochemical similarity. Conclusions: Our findings suggest that PubChem18463786 is a potential AgAChE inhibitor candidate. After validation through in vitro and in vivo experiments, it could be exploited for malaria prevention and serve as a lead compound for the synthesis of new, more effective, and selective agrochemical agents. Full article

Bisphenol A (BPA) and bisphenol S (BPS) are frequently used in the plastic industry. Despite significant alimentary exposure, their effects on the gastrointestinal (GI) tract remain largely unknown. Cholinergic and/or purinergic neurotransmission facilitates GI tract motility and secretion, indirectly controlling the absorption and toxicity of xenobiotics. Hence, this study examined the neurochemical effects of BPA and BPS in the tripartite cholinergic myenteric synapse of CD1 mice colon. Short time exposure to both bisphenols showed a partial loss of VAChT-positive neurons and Ano-1-positive interstitial cells of Cajal (ICCs), without affecting the amount of glial cells labelled with S100β. Both bisphenols reduced the spontaneous myographic activity and the release of [³H]acetylcholine ([³H]ACh) and adenosine from stimulated myenteric neurons and pacemaker ICCs, respectively, without affecting the outflow of ATP. Overall data suggest that both bisphenols inhibit the cholinergic neurotransmission of CD1 mice colon by affecting the amount and/or function of ICCs at the tripartite myenteric synapse. Full article

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN), leading to motor impairments and numerous non-motor manifestations, including anxiety. Notably, anxiety has been shown to exacerbate disease progression and hinder treatment outcomes in PD. Botulinum neurotoxin (BoNT), recognized for its ability to block excessive release of acetylcholine (ACh), has been shown to provide clinical effectiveness in managing motor symptoms. BoNT appears to enhance neuroregenerative plasticity and mitigate neuroinflammation through mechanisms speculated to extend beyond its classical mode of action. Nevertheless, reports on its potential anxiolytic and neuroprotective effects in PD remain limited. Aim: This study investigated the effect of BoNT on motor and anxiety-like behaviors in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Methods: The experimental animals were assessed for behavioral changes using the open field test (OFT), rotarod, pole test, light-dark box test (LDBT), and elevated plus maze (EPM). Immunohistochemistry was employed to enumerate tyrosine hydroxylase (TH)-positive dopaminergic neurons and ionized calcium-binding adapter molecule (Iba)-1 expressing microglia in SN. Results: BoNT treatment markedly alleviated motor deficits and anxiety. Quantification of TH- and Iba-1-positive cells revealed that BoNT promotes neuroprotection and minimizes microglial burden in the SN of the PD model. Conclusions: The outcome of the study represents the anxiolytic, neuroprotective, and microglial modulatory potentials of BoNT in PD, supporting its therapeutic promise beyond the management of motor symptoms. Given its multifaceted properties, BoNT can be considered a potential therapeutic candidate for PD and other neurological disorders. Full article

A novel series of multifunctional tacrine–quinoline hybrids were designed, synthesized, and evaluated as potential anti-Alzheimer’s agents. These compounds incorporate tacrine for cholinesterase’s inhibition and 8-hydroxyquinoline for metal chelation. Piperazine was selected as a linker to provide conformational flexibility and to create favorable cation–π interactions with residues in the mid-gorge region of AChE, enhancing dual-site binding with AChE to inhibit Aβ aggregation. In vitro studies demonstrated submicromolar inhibitory activity toward both AChE and BuChE, particularly for compounds 16e (IC₅₀ = 0.10 μM for AChE, 0.043 μM for BuChE) and 16h (IC₅₀ = 0.21 μM for AChE, 0.10 μM for BuChE). These compounds also exhibited potent inhibition of self-induced Aβ_1–42 aggregation (16e: 80.5% ± 4.4%, 16h: 93.2% ± 3.9% at 20 μM). Kinetic analyses revealed mixed-type inhibition, suggesting dual binding to both CAS and PAS of AChE. UV–vis spectrometry confirmed the chelation of Cu²⁺ and Zn²⁺ ions by the 8-hydroxyquinoline moiety. These findings highlight the tacrine–quinoline scaffold as a promising platform for the discovery of a multitarget-directed anti-AD drug. Full article

Paralipsa gularis (Zeller) has become an increasingly destructive pest in both storage and field ecosystems, particularly affecting maize crops across China. As chemical control methods face limitations due to resistance development and environmental concerns, biological control presents a promising alternative. In this study, we isolated and identified a novel strain of Metarhizium sp. from naturally infected P. gularis larvae collected in Yunnan Province, China. Morphological characterization, along with ITS-rDNA and EF-1α-rDNA sequencing, confirmed the fungus as Metarhizium rileyi. The optimal growth medium for this strain was SMAY, and the optimal conditions were 25 °C under continuous light (L:D = 24:0). Laboratory bioassays showed that the strain exhibited high virulence against P. gularis larvae, with cumulative mortality reaching 82% following infestation with 5 × 10⁸ conidia/mL. Biochemical analyses revealed that fungal infection significantly inhibited the activity of the key antioxidant enzyme SOD in the host, while activities of POD, CAT, and detoxification enzymes (P450, CarE, AChE, and GSTs) were significantly increased. These results indicate that immune responses were triggered, and systemic colonization of the host was achieved. Overall, this native M. rileyi strain demonstrates strong potential as an effective biological control agent. Its ability to overcome insect defenses and induce high mortality supports its integration into pest management programs targeting P. gularis. This work advances the understanding of fungal–insect interactions and contributes to sustainable, environmentally safe strategies for managing a pest of economic importance in agricultural ecosystems. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, with current therapies offering only limited symptomatic relief and lacking disease-modifying efficacy. Addressing this critical therapeutic gap, natural multi-target compounds like mulberroside A (MsA)—a bioactive glycoside from Morus alba L.—present promising alternatives. This study investigated MsA’s neuroprotective potential using scopolamine-induced AD-like mice and N2a/APP695swe cells. In vivo, MsA significantly ameliorated cognitive deficits and neuronal loss, concurrently enhancing cholinergic neurotransmission through increased acetylcholine levels and inhibited acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) activities. MsA also upregulated neurotrophic factors (BDNF, CREB) in critical brain regions. In vitro, MsA restored cholinergic function, mitigated oxidative stress, and crucially reduced amyloid-β (Aβ) production by dual regulation of APP processing: promoting the non-amyloidogenic pathway via ADAM10 upregulation and inhibiting the amyloidogenic pathway via suppression of BACE1 and γ-secretase components. Mechanistically, these multi-target benefits were mediated by MsA’s activation of the PI3K/AKT pathway, which triggered downstream inhibitory phosphorylation of GSK3β—directly reduced tau hyperphosphorylation—and activation of CREB/BDNF signaling. Collectively, our findings demonstrate that MsA confers comprehensive neuroprotection against AD pathology by simultaneously targeting cholinergic dysfunction, oxidative stress, Aβ accumulation, tau phosphorylation, and impaired neurotrophic signaling, highlighting its strong therapeutic candidacy. Full article

Apigenin (AP) is a natural flavonoid with senomorphic potential and neuroprotective action; however, poor aqueous solubility (<1 μg/mL) limits its bioavailability and therapeutic use. Therefore, the aim of this study was to obtain an amorphous dispersion of AP and evaluate its biological properties. Screening of AP solubilization capabilities under supercritical carbon dioxide processing conditions showed that the system with Soluplus (SOL) achieved the greatest improvement in AP dissolution (6455.4 ± 27.2 μg/mL). Using optimized process parameters (50 °C, 6500 PSI), the AP solubility increased to 8050.2 ± 35.1 μg/mL. X-ray powder diffraction (XRPD) confirmed amorphization, aligning with improved dissolution of AP in both acidic and neutral pH media. As a result, using the PAMPA model, an improvement in AP penetration through membranes simulating gastrointestinal and blood–brain barriers was demonstrated. The significant stability of the obtained amorphous AP dispersion (12 months at room conditions) was associated with stabilizing AP–solubilizer intermolecular interactions, mainly expressed as the shifts in the bands of AP in the range of 1018–1269 cm⁻¹ observed in ATR-FT-IR spectra. Chromatographic analysis confirmed the lack of AP decomposition immediately after the preparation of the amorphous dispersion, as well as after 12 months. As expected, the improvement of AP solubility is correlated with better biological activity assessed in selected in vitro tests such as antioxidant properties (2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and cupric ion reducing antioxidant capacity (CUPRAC) assays) and anticholinesterase inhibition capabilities (AChE and BChE assays). The effect of the studies on improving AP solubility under supercritical carbon dioxide processing conditions is obtaining a stable amorphous AP dispersion (up to 12 months). Regardless of the pH of the media, an improvement in AP dissolution and penetration, conditioned by the passive diffusion process, through biological membranes was noted. Moreover, a more efficient antioxidant and neuroprotective effect of AP in the developed amorphous dispersion can also be suggested. Full article

In the absence of commercialized vaccines for most arboviruses, including dengue, chikungunya, and Zika, which are transmitted by Aedes aegypti, the management of vector populations to prevent disease transmission remains the cornerstone of arbovirus control strategies. Larviciding targets the early stages of the mosquito life cycle and subsequently reduces the capacity of adult population to transmit pathogens. Here, we report the susceptibility profile of Ae. aegypti larval populations from two West Africa cities, namely Niamey and Ouagadougou, to organophosphates larvicides. In Niamey, sampling was carried out using ovitraps at two sites, whereas in Ouagadougou, larvae were collected from three different types of larval containers at a single site. Temephos and fenitrothion were tested at six different concentrations each. Mosquito populations from Niamey and Ouagadougou were found susceptible to temephos and fenitrothion, with LD₅₀ < 0.015 mg/L and RR₅₀ < 5. However, Ae. aegypti populations from Ouagadougou showed reduced susceptibility to temephos compared to baseline data from 2016, as indicated by RR₅₀ values. This observation highlights the need for regular surveillance of larval susceptibility, as it may signal the emergence of temephos resistance in Ouagadougou. The acetylcholinesterase (AChE) mutation and the expression levels of metabolic genes Carboxy-/Cholinesterase (CCE) should be characterized to understand the molecular mechanisms underlying the observed phenotype response. Our results provide up-to-date data that could inform the potential deployment of these larvicides for the prevention and control of dengue and chikungunya outbreaks in Ouagadougou and Niamey. Full article

Background: The active ingredients of essential plant oils appear as potentially effective antinematodal drugs or substances that can potentiate the action of already-existing anthelmintics. So far, we have verified that, aside from the direct effect on the neuromuscular system of nematodes, some of them can potentiate the effects of drugs that are agonists or antagonists of nematode cholinergic receptors. Methods: In this study, the antinematodal effects of geraniol and carvacrol were compared, as well as their interaction in the experimental model Caenorhabditis elegans, on the contractile properties of Ascaris suum neuromuscular preparations and on the ACR-16 nicotinic acetylcholine receptor (nAChR) of A. suum expressed in Xenopus leavis oocytes. Results: The combination of geraniol and carvacrol showed a synergistic nematocidal effect in the tests on C. elegans, reducing the value of individual LC₅₀ by almost 10-times. This combination also exerted a synergistic inhibitory effect on the contractions of A. suum, significantly increased the EC₅₀ of ACh and reduced the maximal contractile effect. The synergistic interaction of these two monoterpenes on Asu-ACR-16 nAChR expressed in Xenopus oocytes resulted in a significant decrease in the maximum current, while the ACh EC₅₀ value remained unchanged. Conclusions: Our findings provide a better understanding of the mode of action of monoterpene plant compounds. The possible antiparasitic application of active ingredients of essential plant oils that exhibit a synergistic anthelmintic effect represents an important basis for the development of new drugs and new therapeutic procedures. Full article

Background: It has been shown previously that thienobenzo-1,2,3-triazoles exhibit very good selective inhibition toward butyrylcholinesterase (BChE), while the same derivatives converted into salts also display inhibitory activity against acetylcholinesterase (AChE), enzymes relevant to Alzheimer’s disease therapy. They show even better BChE inhibition potential than neutral analogs. Methods: This study presents the synthesis and biological evaluation of a novel series of charged thienobenzo-1,2,3-triazolinium salts (1–17) as inhibitors of AChE and BChE. The basic skeleton of the targeted compounds was synthesized via a photochemical method and subsequently converted into corresponding bromide salts. Their structures were confirmed using NMR and HRMS analyses. Results: In vitro testing showed that all synthesized compounds exhibit moderate to strong BChE inhibition and, to a lesser extent, AChE inhibition. Compounds 8 and 11 emerged as the most potent AChE inhibitors (IC₅₀ ~ 2.6–3.2 µM), while compounds 1, 2, and 8 demonstrated excellent and selective BChE inhibition (IC₅₀ ~ 0.3–0.4 µM), outperforming the reference drug galantamine. Anti-inflammatory evaluation revealed limited activity, with compound 17 slightly reducing LPS-induced TNF-α production at the highest tested concentration. Conclusions: These findings highlight the role of the electric charge and substituent type in modulating biological activity and confirm the therapeutic potential of these molecules as dual cholinesterase inhibitors for further development in neurodegenerative disease treatment. Full article

(1) Background: Tolypocladium spp. are fungi known for producing cyclosporin A and their ability to infect insects. However, their pathogenicity against the lepidopteran pest Plutella xylostella has not been previously reported. (2) Methods: Four Tolypocladium strains were isolated from soil and identified through morphological and phylogenetic analyses (ITS, gene sequencing). Growth rates, sporulation capacity, and stress tolerance (45 °C heat, UV) were evaluated. Pathogenicity was assessed via larval bioassays, and immune responses were analyzed by quantifying Toll pathway gene expression and enzyme activities (PO, CAT, POD, GSTs, CarE, AChE) from 24 to 96 h post-inoculation. (3) Results: Strains N8-SF-04092 and O1/O2/O3-SF-04630/04927/04931 were identified as Tolypocladium cylindrosporum and Tolypocladium inflatum, respectively. Strain O2 showed the highest growth rate (p < 0.05), while O3 and N8 exhibited superior sporulation (>7 × 10⁵ spores/mm²). N8 also demonstrated notable thermotolerance. In pathogenicity assays, O1, O3, and N8 caused 98.3%, 93.3%, and 96.7% larval mortality, respectively, with LT₅₀ values (3.89–4.45 days) significantly lower than O2 (p < 0.05). Immune gene expression in P. xylostella was transiently activated at 24 h but suppressed from 48 to 96 h by N8 (p < 0.05), while O1 induced partial activation at 24 h and 96 h but suppression at 48 h and 72 h. Protective enzymes (PO, CAT) were initially upregulated (24–48 h) but inhibited after 72 h (p < 0.01). POD activity showed opposing trends between O1 (initially activated then suppressed) and N8 (initially suppressed then activated). Detoxification enzymes (GSTs, CarE, AchE) were predominantly suppressed, except for GSTs, which increased at 72–96 h. (4) Conclusions: Strains O1 and N8 exhibit high virulence against P. xylostella by disrupting immune responses through dynamic modulation of Toll pathway genes and enzyme activities. The thermotolerance of strain N8 further enhances its promising biocontrol agent for field application. Full article

Natural ventilation could be established as an effective passive design strategy for increasing air changes per hour in a built environment. Modern air conditioning systems often fail to provide sufficient fresh air, potentially causing health issues for occupants. In contrast, natural ventilation offers an effective alternative for maintaining sufficient indoor air quality in buildings. This study explores the application of grouped airfoil arrays on building façades as an innovative passive design to enhance the air change rate. Numerical simulations were conducted to analyze various airfoil configurations, determining the most effective design for building a façade. Three groups, including symmetrical, semi-symmetrical, and flat-bottomed grouped airfoils, were selected according to their aerodynamic properties and potential impacts on airflow dynamics. For this purpose, a typical high-rise residential building was selected as a case study for field measurement and CFD simulation. The results indicated that symmetrical airfoil arrays could increase the air changes per hour (ACH) up to 23 times per hour with a wind velocity of 0.37 m/s at 10 m above ground, whereas their bidirectional performance ensured stable airflow regardless of wind direction. Although semi-symmetrical airfoil arrays maximize air capture and induce beneficial turbulence, the ACH within a residential unit was boosted up to 16 times per hour under the same outdoor wind velocity conditions. The ACH was 14 times per hour for the flat-bottom airfoils, serving as a comparative baseline and providing insights into the performance advantages of more complex designs. Full article

Honeybees (Apis mellifera) are indispensable pollinators vital to global biodiversity, ecosystem stability, and agricultural productivity, and they promote over 35% of food crops and 75% of flowering plants. Yet, they are in unprecedented decline, partly as a result of neonicotinoid pesticide use elsewhere. These effects on honey bee health are synthesized in this paper through molecular, physiological, and behavioral data showing that sublethal effects of neonicotinoids impair honey bee health. As neurotoxic insecticides that target nicotinic acetylcholine receptors (nAChRs), these insecticides interfere with neurotransmission and underlie cognitive impairment, immune suppression, and oxidative stress. Developmental toxicity is manifested in larvae as retarded growth, reduced feeding, and increased death; queen and drone reproduction are impaired, lowering colony viability. As a result, adult bees have shortened lives and erratic foraging, are further disoriented, and experience impaired navigation, communication, and resource collection. Together, these effects cascade to reduced brood care, thermoregulatory failure, and heretofore unrecognized increased susceptibility to pathogens, increasing the probability of colony collapse at the colony level. Contaminants such as pesticides may cause pollinator exposure and, in turn, may cause their population to be undermined if they are not mitigated; therefore, urgent mitigation strategies, including integrated pest management (IPM), regulatory reforms, and adoption of biopesticides, are needed to mitigate pollinator exposure. The focus of this review lies in the ecological necessity of restructuring how agriculture is managed to simultaneously meet food security and the conservation of honeybee health, the linchpin of global ecosystems. Full article

At present, a novel herbal regimen targeting anti-insomnia, anti-anxiety, cognitive performance, and anti-depression effects is required due to the limitations of the current therapy. Based on the crucial role of oxidative stress in the pathophysiology of stress-related brain disorders, it was hypothesized that the functional ingredient derived from mulberry leaves and butterfly pea flowers, which exhibits potent antioxidant activity, should protect against the disorders just mentioned. Male Wistar rats (180–200 g) were orally administered at doses of 125, 250, and 500 mg/kg BW once daily, 45 min before exposure to a 6-h immobilization stress for 14 days. Behavioral assessments, including sleep, anxiety, spatial memory, and depression, were assessed every 7 days. At the end of the study, corticosterone levels, oxidative stress markers, neurotransmitters, IL-6, BDNF, and neuron density in the prefrontal cortex and hippocampus were measured. The functional ingredients demonstrated anti-insomnia, anxiolytic, memory-enhancing, and antidepressant properties. It also increased neuron density and BDNF and activity of SOD and CAT enzymes, whereas corticosterone, GABA-T, AChE, MAO, IL-6, and MDA levels were reduced. A potential regimen targeting showed the benefits of anti-insomnia, anxiolytic, memory-enhancing, and antidepressant properties. However, further studies regarding the precise underlying mechanism and a clinical trial are essentially required. Full article

Background: Alzheimer’s disease (AD) is largely linked with oxidative stress, the accumulation of amyloid-β plaques, and hyperphosphorylated τ-protein aggregation. Alterations in dopaminergic and serotonergic neurotransmission have also been implicated in various AD-related symptoms. Methods: To explore new therapeutic agents, a series of bicyclic and tricyclic thieno-oxazepine derivatives were synthesized as potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The resultant compounds were purified via HPLC and characterized using spectral analysis techniques. Histopathological examinations, other antioxidants, and anti-inflammatory biomarkers were evaluated, and in silico ADMET calculations were performed for synthetic hybrids. Molecular docking was utilized to validate the new drugs’ binding mechanisms. Results: The most powerful AChE inhibitors were 14 and 16, with respective values of IC₅₀ equal to 0.39 and 0.76 µM. Derivative 15 demonstrated remarkable BChE-inhibitory efficacy, on par with tacrine, with IC₅₀ values of 0.70 µM. Hybrids 13 and 15 showed greater selectivity towards BChE, despite substantial inhibition of AChE. Compounds 13 and 15 reduced escape latency and raised residence time, with almost equal activity to donepezil. Conclusions: According to these findings, the designed hybrids constitute multipotent lead compounds that could be used in the creation of novel anti-AD medications. Full article