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Three new eudesmane type rare sesquiterpene lactone galactosides, costunosides A-C (1-3) were isolated from the rhizomes of Aucklandia costus along with ten known compounds (4-13). Costunosides A-C (1-3) are the first example of naturally eudesmane glycosides containing a β-galactopyranoside moiety. The structure and relative configurations of these compounds were established by comprehensive analysis of MS and, in particular 1D/2D NMR spectroscopic data. The isolated compounds were tested against a panel of human cancer cell lines, where compounds 3, 6 and 7 have shown promising cytotoxic activity against PC-3, HCT-116 and A549 cell lines with IC50 values in the range of 3.4 µM to 9.3 µM, respectively. Costunosides A-C (1-3) were also screened for inhibition assay of acetyl-cholinesterase (AChE), and butyrylcholinesterase (BChE) and found inactive at a concentration of 10 µM. [ABSTRACT FROM AUTHOR]

An aberrant recapitulation of a developmental mechanism driven by a 14 mer peptide ('T14') derived from acetylcholinesterase (AChE) has been implicated in Alzheimer's disease. T14 was suggested as an upstream driver of neurodegeneration due to its ability to stimulate the production of phosphorylated tau and amyloid beta. The activation of this mechanism in adulthood is thought to be brought upon by insult to the primarily vulnerable subcortical nuclei. Here, we show that oxidative stress, induced by high glucose and confirmed by an analysis of antioxidant enzyme mRNA expression, increased the levels of T14 peptide in PC12 cells. This increase in T14 corresponded with an increase in the mRNA expression of AChE and a decrease in the cell viability. The increase in T14 could be blocked by the cyclic form of T14, NBP14, which prevented any cytotoxic effects. These observations suggest that oxidative stress can directly trigger the inappropriate activation of T14 in the adult brain through the upregulation of Ache mRNA. [ABSTRACT FROM AUTHOR]

Cadmium contamination in aquatic environments poses severe risks to aquatic organisms, particularly fish, where cadmium accumulation in tissues can lead to compromised organ functionality and reproductive issues. The present study aimed to assess the effects of cadmium (Cd) exposure on key biomarkers of oxidative stress, DNA damage, apoptosis, and enzyme activity in the liver and kidney tissues of rainbow trout (Oncorhynchus mykiss). Specifically, the study measured 8-hydroxy-2-deoxyguanosine (8-OHdG) levels, caspase-3 activation, acetylcholinesterase (AChE) activity, and oxidative stress indicators (ONOO−, MDA, GSH, SOD, and CAT) following exposure to three Cd concentrations (1, 3, and 5 mg/L) over three time points (24, 48, and 96 h). Tissue samples were collected post-exposure, and the analysis revealed a significant decrease in MDA levels in both tissues. GSH concentrations declined with prolonged exposure, while SOD activity increased, indicating a response to oxidative stress, contrasted by a reduction in CAT activity. An initial increase in ONOO− levels was observed at 24 h, followed by a subsequent decrease at the 48 and 96 h marks. These results suggest that cadmium induces oxidative stress in the liver and kidney tissues of fish. Cadmium exposure also significantly elevated 8-OHdG levels, signaling DNA damage, and increased caspase-3 activity, indicative of apoptosis, across all doses and time points (p < 0.05). The histological examination of liver and kidney showed tissue injury. Additionally, a negative correlation between AChE activity and exposure duration was noted, with prolonged exposure resulting in substantial AChE inhibition. Given the role of AChE in behavior regulation, these findings underscore the importance of exploring time-dependent, tissue-specific changes in AChE activity to further elucidate the mechanisms underlying cadmium-induced behavioral abnormalities. [ABSTRACT FROM AUTHOR]

Investigations into the phenolic constituents of the butanolic fraction of Crataegus monogyna were optimized using LC-ESI-MS/MS analysis, identifying and quantifying at least 23 fingerprint phytochemical compounds. The major phenolic compounds were epicatechin (99.916 ± 2.208 mg/g), isoquercetrin (53.31 ± 1.172 mg/g), chlorogenic acid (47.457 ± 1.010 mg/g), quinic acid (37.819 ± 1.406 mg/g), rutin (29.98 ± 0.740 mg/g), hesperidin (5.296 ± 0.177 mg/g, detected for the first time in the C. monogyna species), astragalin (1.774 ± 0.020 mg/g), and nicotiflorin (1.482 ± 0.016 mg/g). The antioxidant properties of the lyophilized butanolic fraction were evaluated using DPPH, GOR, ABTS, CUPRAC, and reducing power assays, all of which demonstrated that there was strong activity. Additionally, the neuroprotective effect was evaluated in vitro, showing a potent inhibitory effect on acetylcholinesterase (AChE) with an IC50 of 43.65 ± 2.10 µg/mL. The antidiabetic effect was investigated through α-amylase inhibition (IC50 = 91.19 ± 0.10 µg/mL), showing high inhibitory activity. In addition, the butanolic extract exhibited significant urease inhibition with an IC50 of 26.36 ± 0.05 µg/mL. These results suggest that Algerian C. monogyna has potential as a therapeutic agent for managing diabetes complications and as a natural source of AChE inhibitors, making it a promising subject for the treatment of urease-related conditions. Its high concentrations of natural antioxidants, such as epicatechin, isoquercetrin, chlorogenic acid, quinic acid, rutin, hesperidin, and astragalin, make it suitable for integration into medicine, pharmaceuticals, cosmetics, and the food sector. [ABSTRACT FROM AUTHOR]

Background: Perfluorooctane sulfonic acid (PFOS), a widely used industrial chemical, was reported to induce memory and learning process dysfunction. Some studies tried to reveal the mechanisms that mediate these effects, but how they are produced is still unknown. Basal forebrain cholinergic neurons (BFCN) maintain cognitive function and their selective neurodegeneration induces cognitive decline, as observed in Alzheimer's disease. PFOS was reported to disrupt cholinergic and glutamatergic transmissions and thyroid hormone action, which regulate cognitive processes and maintain BFCN viability. Objective/Methods: To evaluate PFOS neurodegenerative effects on BFCN and the mechanisms that mediate them, SN56 cells (a neuroblastoma cholinergic cell line from the basal forebrain) were treated with PFOS (0.1 µM to 40 µM) with or without thyroxine (T3; 15 nM), MK-801 (20 µM) or acetylcholine (ACh; 10 µM). Results: In the present study, we found that PFOS treatment (1 or 14 days) decreased thyroid receptor α (TRα) activity by decreasing its protein levels and increased T3 metabolism through increased deiodinase 3 (D3) levels. Further, we observed that PFOS treatment disrupted cholinergic transmission by decreasing ACh content through decreased choline acetyltransferase (ChAT) activity and protein levels and through decreasing muscarinic receptor 1 (M1R) binding and protein levels. PFOS also disrupted glutamatergic transmission by decreasing glutamate content through increased glutaminase activity and protein levels and through decreasing N-methyl-D-aspartate receptor subunit 1 (NMDAR1); effects mediated through M1R disruption. All these effects were mediated through decreased T3 activity and T3 supplementation partially restored to the normal state. Conclusions: These findings may assist in understanding how PFOS induces neurodegeneration, and the mechanisms involved, especially in BFCN, to explain the process that could lead to cognitive dysfunction and provide new therapeutic tools to treat and prevent its neurotoxic effects. [ABSTRACT FROM AUTHOR]

Background/Objectives: The Trypanosoma cruzi infection promotes an intense inflammatory process that affects several tissues. The cholinergic system may exert a regulatory immune response and control the inflammatory process. This study aimed to evaluate the comparative effect of free and nanoencapsulated benznidazole in acute T. cruzi infection to assess hematological, biochemical, and oxidative status triggered by the cholinergic system. Methods: For this, fifty female Swiss mice were distributed in eight groups, i.e., uninfected and infected animals under four treatment protocols: untreated (control—CT); vehicle treatment (Eudragit L 100—EL-100); benznidazole treatment (BNZ); and nanoencapsulated benznidazole treatment (NBNZ). After eight treatment days, the animals were euthanized for sample collection. Results: The peak of parasitemia was at day 7 p.i., and the BNZ and NBNZ controlled and reduced the parasite rate but showed no efficacy in terms of total elimination of parasites analyzed by RT-PCR in both infected groups. The infection promotes significant anemia, leukopenia, and thrombocytopenia, which the BNZ improves. There was an increase in AChE activity during infection, leading to a pro-inflammatory response and an increase in M1 and M2 mACh receptors in the BNZ group, showing that the treatment interacted with the cholinergic pathway. In addition, a pro-oxidative response was characterized in the infection and mainly in the infected BNZ and NBNZ groups. The histopathological analysis showed significative splenomegaly and inflammatory infiltrate in the heart, liver, and spleen. Conclusions: The administration of the BNZ or NBNZ reverses hematological, hepatic, and renal alterations through cholinergic signaling and stimulates a pro-inflammatory response during acute T. cruzi infection. [ABSTRACT FROM AUTHOR]

Amyloid β protein (Aβ) deposition has been implicated as the molecular driver of Alzheimer's disease (AD) progression. The modulation of the formation of abnormal aggregates and their post-translational modification is strongly suggested as the most effective approach to anti-AD. Beta-site APP-cleaving enzyme 1 (BACE1) acts upstream in amyloidogenic processing to generate Aβ, which rapidly aggregates alone or in combination with acetylcholinesterase (AChE) to form fibrils. Accumulated Aβ promotes BACE1 activation via glycogen synthase kinase-3β (GSK-3β) and is post-translationally modified by glutaminyl cyclase (QC), resulting in increased neurotoxicity. A novel multi-target inhibitor as a potential AD agent was identified using an in silico approach and experimental validation. Magnolia officinalis, which showed the best anti-AD activity in our preliminary study, was subjected to analysis, and 82 compounds were studied. Among 23 compounds with drug-likeness, blood–brain barrier penetration, and safety, honokiol emerged as a lead structure for the inhibition of BACE1, AChE, QC, and GSK-3β in docking and molecular dynamics (MD) simulations. Furthermore, honokiol was found to be an excellent multi-target inhibitor of these enzymes with an IC50 of 6–90 μM, even when compared to other natural single-target inhibitors. Taken together, the present study is the first to demonstrate that honokiol acts as a multiple enzyme inhibitor with an excellent pharmacokinetic and safety profile which may provide inhibitory effects in broad-range areas including the overproduction, aggregation, and post-translational modification of Aβ. It also provides insight into novel structural features for the design and discovery of multi-target inhibitors for anti-AD. [ABSTRACT FROM AUTHOR]

Objective: Novel 2,3-disubstituted 4-oxoquinazoline-3(4H) derivatives containing oxadiazole, thiazolidinone ring, the 4-oxoquinazoline-3(4H) Schiff bases, and carbothioamide structure were synthesized. All the synthesized compounds' urease and acetylcholinesterase enzyme inhibitions were evaluated in vitro. Methods: The chemical structures of the synthesized compounds were confirmed using IR, 1H, and 13C NMR spectral methods. For all newly synthesized compounds, the urease enzyme inhibition activity was measured using the Weatherburn method, and the acetylcholinesterase enzyme inhibition activity was measured using the Ellman method with slight modifications. Results and Discussion: All newly synthesized compounds showed urease enzyme inhibition in the range of IC50 = 11.00 ± 0.10 to 17.45 ± 0.25 µg/mL compared to standard thiourea (IC50 = 15.75 ± 0.25 µg/mL). Among the synthesized compounds, quinazolinone containing oxadiazole ring (IVa–IVd) and thiosemicarbazide structure (IXa–IXd) showed the most inhibition. Most of the synthesized compounds exhibited good inhibitory activities against acetylcholinesterase compared to the standard inhibitor Galantamine (IC50 = 20.45 ± 0.25 µg/mL), in the range of 16.44 ± 0.26 to 30.50 ± 0.50 µg/mL. Furthermore, the molecular docking study was performed to determine the interaction modes of newly synthesized compounds at the active site of the target enzymes. ADMET properties were calculated to evaluate the drug-likeness of all compounds. Conclusions: In this study, a new series of quinazolinone derivative compounds with potentially active antiurease and antiacetylcholinesterase inhibitions were synthesized, consistent with in silico studies. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) has always been one of the most common malignant tumors in the world. Whether the factors related to the diagnosis and risk of CRC can be found from the existing peripheral blood routine indicators. Methods: The relevant data of patients with colorectal diseases in our hospital of about ten years were collected, the differences among the biomarkers in serum were analyzed, the risk factors were analyzed by logistic regression, the ROC was drawn, and the diagnostic efficacy was evaluated. Results: Colorectal malignancies and benign diseases in AST, GGT, LDH, D-BIL, ALB, ALP, AchE, CR, TP, PA, RDW, LMR, NMR, TC, TG, HDL-C, CA19-9, CEA, Cyfra21-1, and Fer have statistical differences (p < 0.05). ALB, PLR, CEA, Fer, NLR, TP, GGT, and Cyfra21-1 in different malignant tumor types have statistical differences (p < 0.05). When CEA increased by 1, the risk of colorectal cancer increased by 45.7%. When AchE and HDL-C increased by 1, the risk of colorectal cancer decreased by 32% and 66.8%. Compared with other blood groups, blood group AB colorectal cancer patients had a shallower tumor invasion (p = 0.047). HDL-C were significantly weakly-correlated with tumor size (p < 0.05, |r| < 0.4). CEA, AchE, and HDL-C were combined diagnosed; the sensitivity, PPV, and accuracy were 94.35%, 95.43%, 90.77%, respectively. Conclusions: The occurrence and development of colorectal cancer is the result of multi-factors, and the combined detection of multi-indicators has positive significance for the diagnosis, pathological stage, and prevention of CRC. [ABSTRACT FROM AUTHOR]

Abstract Cadmium contamination in aquatic environments poses severe risks to aquatic organisms, particularly fish, where cadmium accumulation in tissues can lead to compromised organ functionality and reproductive issues. The present study aimed to assess the effects of cadmium (Cd) exposure on key biomarkers of oxidative stress, DNA damage, apoptosis, and enzyme activity in the liver and kidney tissues of rainbow trout (Oncorhynchus mykiss). Specifically, the study measured 8-hydroxy-2-deoxyguanosine (8-OHdG) levels, caspase-3 activation, acetylcholinesterase (AChE) activity, and oxidative stress indicators (ONOO−, MDA, GSH, SOD, and CAT) following exposure to three Cd concentrations (1, 3, and 5 mg/L) over three time points (24, 48, and 96 h). Tissue samples were collected post-exposure, and the analysis revealed a significant decrease in MDA levels in both tissues. GSH concentrations declined with prolonged exposure, while SOD activity increased, indicating a response to oxidative stress, contrasted by a reduction in CAT activity. An initial increase in ONOO− levels was observed at 24 h, followed by a subsequent decrease at the 48 and 96 h marks. These results suggest that cadmium induces oxidative stress in the liver and kidney tissues of fish. Cadmium exposure also significantly elevated 8-OHdG levels, signaling DNA damage, and increased caspase-3 activity, indicative of apoptosis, across all doses and time points (p

This study investigates using KOH-activated coffee grounds (KACGs) as an effective adsorbent for removing organophosphorus xenobiotics malathion and chlorpyrifos from water. Malathion and chlorpyrifos, widely used as pesticides, pose significant health risks due to their neurotoxic effects and environmental persistence. Spent coffee grounds, abundant biowaste from coffee production, are chemically activated with KOH to enhance their adsorptive capacity without thermal treatment. This offers a sustainable solution for biowaste management and water remediation. Adsorption kinetics indicating rapid initial adsorption with high affinity were observed, particularly for chlorpyrifos. Isotherm studies confirmed favorable adsorption conditions, with higher maximum adsorption capacities for chlorpyrifos compared to malathion (15.0 ± 0.1 mg g−1 for malathion and 22.3 ± 0.1 mg g−1 for chlorpyrifos), highlighting its potential in mitigating water pollution. Thermodynamic analysis suggested the adsorption process was spontaneous but with the opposite behavior for the investigated pesticides. Malathion interacts with KACGs via dipole–dipole and dispersion forces, while chlorpyrifos through π–π stacking with aromatic groups. The reduction in neurotoxic risks associated with pesticide exposure is also shown, indicating that no more toxic products were formed during the remediation. This research contributes to sustainable development goals by repurposing biowaste and addressing water pollution challenges through innovative adsorbent materials.

Abstract Background Neonicotinoids are widespread insecticides because of their potent effects against aphids and other piercing-sucking insects in addition to having high selectivity toward insects rather than vertebrates. However, they affect severely some non-target insects, mainly honeybee in a phenomenon called colony collapse disorder (CCD). Results Effects of imidacloprid (IMI), most used neonicotinoids, on aphid acetylcholinesterase (AChE), in vivo and in vitro were examined; besides, molecular modeling was used to investigate similarities and differences of AChE and nicotinic acetylcholine receptors α1-subunit (nAChRα1) in aphids, target insect, and honeybees, non-target insect. Results showed that aphid AChE was inhibited in vitro, with IC50 108.6 mg/L but not affected in vivo while the mortality was concentration-dependent with high toxicity (LC50 9.50 mg/L); in addition, aphid AChE was more inhibited, in vitro, but with much less effects, in vivo, than that of honeybees. These results indicate that AChE is not the main cause of the observed mortality, but it still has a role in insect resistance system with different responses in both insects. Molecular modeling showed high similarity in primary and secondary structures of AChE indicated by high identity (67%) and low gaps (1%); besides, the same template for both enzymes was auto-selected for homology. In addition, similar positions of the triad amino acids were found in AChE of both insects indicating high similarity. Conversely, the similarity in nAChRα1 in both insects is lower (50% identity and 9% gaps). These gaps (50 amino acids) are found in the intracellular large loop between TM3 and TM4 and account for the observed differences in the nAChRα1 binding sites of in both insects. Conclusion These observed variations in nAChRα1 structures and binding sites in different insect species can be used as good bases in designing new neonicotinoids that express high effects on target insects with better selectivity to minimize adverse effects on non-target organisms. Graphical Abstract

Abstract A series of new 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their anti-AD potential. The results revealed that eleven compounds (1b, 2a-c, 3b, 4a-c, and 5a-c) exhibited excellent inhibitory potential against AChE, with IC50 values ranging from 0.00098 to 0.07920 µM. Their potency was 1.55 to 125.47 times higher than that of donepezil (IC50 = 0.12297 µM). In contrast, the newly synthesized oxadiazole derivatives with IC50 values in the range of 16.64–70.82 µM exhibited less selectivity towards BuChE when compared to rivastigmine (IC50 = 5.88 µM). Moreover, oxadiazole derivative 2c (IC50 = 463.85 µM) was more potent antioxidant than quercetin (IC50 = 491.23 µM). Compounds 3b (IC50 = 536.83 µM) and 3c (IC50 = 582.44 µM) exhibited comparable antioxidant activity to that of quercetin. Oxadiazole derivatives 3b (IC50 = 140.02 µM) and 4c (IC50 = 117.43 µM) showed prominent MAO-B inhibitory potential. They were more potent than biperiden (IC50 = 237.59 µM). Compounds 1a, 1b, 3a, 3c, and 4b exhibited remarkable MAO-A inhibitory potential, with IC50 values ranging from 47.25 to 129.7 µM. Their potency was 1.1 to 3.03 times higher than that of methylene blue (IC50 = 143.6 µM). Most of the synthesized oxadiazole derivatives provided significant protection against induced HRBCs lysis, revealing the nontoxic effect of the synthesized compounds, thus making them safe drug candidates. The results unveiled oxadiazole derivatives 2b, 2c, 3b, 4a, 4c, and 5a as multitarget anti-AD agents. The high AChE inhibitory potential can be computationally explained by the synthesized oxadiazole derivatives’ significant interactions with the AChE active site. Compound 2b showed good physicochemical properties. All these data suggest that 2b could be considered as a promising candidate for future development.

This study investigates using KOH-activated coffee grounds (KACGs) as an effective adsorbent for removing organophosphorus xenobiotics malathion and chlorpyrifos from water. Malathion and chlorpyrifos, widely used as pesticides, pose significant health risks due to their neurotoxic effects and environmental persistence. Spent coffee grounds, abundant biowaste from coffee production, are chemically activated with KOH to enhance their adsorptive capacity without thermal treatment. This offers a sustainable solution for biowaste management and water remediation. Adsorption kinetics indicating rapid initial adsorption with high affinity were observed, particularly for chlorpyrifos. Isotherm studies confirmed favorable adsorption conditions, with higher maximum adsorption capacities for chlorpyrifos compared to malathion (15.0 ± 0.1 mg g−1 for malathion and 22.3 ± 0.1 mg g−1 for chlorpyrifos), highlighting its potential in mitigating water pollution. Thermodynamic analysis suggested the adsorption process was spontaneous but with the opposite behavior for the investigated pesticides. Malathion interacts with KACGs via dipole–dipole and dispersion forces, while chlorpyrifos through π–π stacking with aromatic groups. The reduction in neurotoxic risks associated with pesticide exposure is also shown, indicating that no more toxic products were formed during the remediation. This research contributes to sustainable development goals by repurposing biowaste and addressing water pollution challenges through innovative adsorbent materials. [ABSTRACT FROM AUTHOR]

New triheteroyclic compounds containing quinazolinone, thiophene, andthiadiazole /thiazolidinone structureswere synthesized and characterized by FT-IR, 1H–NMR, and13C–NMRspectral data. The new compounds' inhibitory activities on urease and acetylcholinesterase were assessed. All triheterocyclic compounds with thiadiazole ring have urease and acetylcholinesteraseinhibitory activities.Especially compound 5a; 3-[(5-(phenylamino)-1,3,4-thiadiazol-2-yl]methyl-2-(thiophen-3-ylmethyl)quinazolin-4(3H)-onehas the best urease inhibition result with 13.30 ± 0.15 µg/mL IC50 value, and it also has the best acetylcholinesterase inhibition with 20.30 ± 0.15 µg/mL IC50 value. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders that leads to dementia among elderly. Formation of senile plaques in the brain by amyloid-β proteins and neurofibrillary tangles by hyper-phosphorylated tau proteins causing widespread damage to nerve cells, are characteristic features of AD. Secondary metabolites of potential biotechnological interests, isolated from marine microorganisms, exhibit anti-inflammatory, neuro-protective properties, which can be potentially exploited for treating AD. Possible mechanisms to counter AD, as demonstrated in various studies already conducted, include prevention of amyloid-β protein neurotoxicity by inhibiting multiple enzymes inducing apoptosis and activating genes that stimulate neuronal survival by fucoidan; inactivating acetylcholinesterase by phlorotannins along with inhibiting β site amyloid precursor protein cleaving enzyme 1 which is also exhibited by caniferolide A in addition to reducing neuro-inflammatory markers and Reactive oxygen species. Amyloid-β neuro-toxicity can be kept in check by the compound homotaurine which has high affinity for Gamma aminobutyric acid receptors and also by neoechinulin A. Spirolides, on the other hand, have been shown to exert positive consequences on AD biomarkers. Various other marine bacterial, fungal, algal metabolites also exhibit similar properties and have potential to be marketed as future drugs. [ABSTRACT FROM AUTHOR]

Knema elegans Warb. is an evergreen tree belonging to the Myristicaceae family, primarily native to Southeast Asia. This study examined the chemical composition and assessed the antioxidant and anti-acetylcholinesterase properties of the essential oil from the leaves of K. elegans in Vietnam. Gas chromatography/mass spectrometry analysis revealed the main compounds in the essential oil, including bicyclogermacrene (23.8%), germacrene D (17.1%), β-caryophyllene (15.4%), δ-cadinene (8.2%), and α-cadinol (7.9%). Antioxidant activity was assessed using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'- azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) methods, with halfmaximum inhibitory concentration (IC50) values of 93.11 ± 1.95 μg/mL and 114.95 ± 2.41 μg/mL, respectively, indicating moderate antioxidant potential. Additionally, the essential oil exhibited significant anti-acetylcholinesterase effects, with an IC50 value of 87.44 ± 2.52 μg/mL. These findings highlight the biological significance of K. elegans essential oil and suggest avenues for further investigation, particularly in elucidating its mechanisms of action in antioxidant and anti-acetylcholinesterase activities. Notably, this research represents the first comprehensive exploration of the chemical composition, antioxidant activity, and acetylcholinesterase inhibition effects of K. elegans essential oil from its leaves. [ABSTRACT FROM AUTHOR]

Background: Neonicotinoids are widespread insecticides because of their potent effects against aphids and other piercing-sucking insects in addition to having high selectivity toward insects rather than vertebrates. However, they affect severely some non-target insects, mainly honeybee in a phenomenon called colony collapse disorder (CCD). Results: Effects of imidacloprid (IMI), most used neonicotinoids, on aphid acetylcholinesterase (AChE), in vivo and in vitro were examined; besides, molecular modeling was used to investigate similarities and differences of AChE and nicotinic acetylcholine receptors α1-subunit (nAChRα1) in aphids, target insect, and honeybees, non-target insect. Results showed that aphid AChE was inhibited in vitro, with IC50 108.6 mg/L but not affected in vivo while the mortality was concentration-dependent with high toxicity (LC50 9.50 mg/L); in addition, aphid AChE was more inhibited, in vitro, but with much less effects, in vivo, than that of honeybees. These results indicate that AChE is not the main cause of the observed mortality, but it still has a role in insect resistance system with different responses in both insects. Molecular modeling showed high similarity in primary and secondary structures of AChE indicated by high identity (67%) and low gaps (1%); besides, the same template for both enzymes was auto-selected for homology. In addition, similar positions of the triad amino acids were found in AChE of both insects indicating high similarity. Conversely, the similarity in nAChRα1 in both insects is lower (50% identity and 9% gaps). These gaps (50 amino acids) are found in the intracellular large loop between TM3 and TM4 and account for the observed differences in the nAChRα1 binding sites of in both insects. Conclusion: These observed variations in nAChRα1 structures and binding sites in different insect species can be used as good bases in designing new neonicotinoids that express high effects on target insects with better selectivity to minimize adverse effects on non-target organisms. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), a neurodegenerative condition is expected to affect 152 million in 2050. The current study comprises the evaluation of thiazole based thiadiazole bearing sulfonamide derivatives to treat Alzheimer's disease. A series of compounds (1‐15) were synthesized and were studied for their anti‐Alzheimer's potential. Their IC50 values lie in the range between (19.20±0.20 nM–2.50±0.20 nM) for AChE and (19.80±0.20 nM–3.30±0.50 nM) for AChE. Among all of them, analog 2, 7, 9, and 15 were reported to possess significant activity. Among all the members of series, compound 15 having IC50=2.50±0.20 nM and 3.30±0.50 nM for AChE and BuChE, respectively, emerged as the most promising candidate due to the presence of two electronegative fluorine (F) atoms. The small and highly electronegative fluorine atoms have the ability to block the enzyme's activity by forming strong hydrogen bonds with the amino acids of the target enzymes, thereby inhibiting their function. The efficacy of these novel compounds was studied in comparison to the standard drug donepezil having IC50=5.80±0.30 nM for AChE and IC50=6.30±0.81 nM BuChE. For further assessment of inhibition potential and mode of inhibition, molecular docking study of all the potent compounds was carried out. Further, the structural identity of the synthesized compounds was confirmed using various spectroscopic techniques, including 1H‐NMR, 13C‐NMR, and High‐Resolution Electron Impact (HREI) Mass spectrometry, which provided detailed information about their molecular structure. ADME analysis of all the synthesized compounds confirmed their potential as drugs, indicating favorable pharmacokinetic properties and a promising drug profile. [ABSTRACT FROM AUTHOR]

Oxidative stress from generation of increased reactive oxygen species or has been reported to play an important role in dementia. Oxidative stress due to free radicals of oxygen or reactive oxygen species could be precipitating factors in the etiology of dementia. Apomorphine has been reported to have neuroprotective effects. To monitor memory enhancing and neuroprotective effects of apomorphine, we determined the antioxidant enzymes activities, lipid peroxidation, acetylcholine esterase (AChE) activity in brain and plasma, following repetitive administration of apomorphine in rat model of dementia. Biogenic amine levels were also monitored in hippocampus. Repeated administration of scopolamine was taken as an animal model of dementia. Decreased glutathione peroxidase, superoxide dismutase and catalase activities were observed in these animal models of dementia. While increased lipid peroxidation was also observed in the brain and plasma samples. The results showed significant effects of apomorphine. The activities of antioxidant enzymes displayed increased activities in both brain and plasma. Glutathione peroxidase and catalase activities were found to be significantly higher in brain and plasma of apomorphine treated rats. Superoxide dismutase (SOD) was significantly decreased in plasma of scopolamine injected rats; and a decreased tendency (non-significant) of SOD in brain was also observed. AChE activity in brain and plasma was significantly decreased in scopolamine treated rats. Learning and memory of rats in the present study was assessed by Morris Water Maze (MWM). Short-term memory and long-term memory was impaired significantly in scopolamine treated rats, which was prevented by apomorphine. Moreover, a marked decrease in biogenic amines was also found in the brain of scopolamine treated rats and was reverted in apomorphine treated rats. Results showed that scopolamine-treatment induced memory impairment and induced oxidative stress in rats as compared to saline-treated controls. These impairments were significantly restored by apomorphine administration. In conclusion, our data suggests that apomorphine at the dose of 1 mg/kg could be a potential therapeutic agent to treat dementia and related disorders. [ABSTRACT FROM AUTHOR]

Thiosemicarbazone derivative was obtained by the addition of thiosemicarbazide to 5‐nitro‐thiophene‐2‐carbaldehyde. The addition–cyclization of the 2‐bromoacetophenone derivative to thiosemicarbazone derivative gave the new thiazole derivatives (2 a‐k). Acetylcholinesterase (AChE), butyrylcholinesterase (BChE), antioxidant, and human carbonic anhydrase (hCA) I and II isoform inhibitory activities of the thiazole derivatives 2 a‐k were investigated. The effects of thiazole derivatives on carbonic anhydrase I and II (hCA I–II) isoenzymes were examined in vitro using the esterase method. IC50 values for enzyme inhibition were found to be 2.661–22.712 μM for hCA I and 5.372–26.813 μM for hCA II. All derivatives reduced the activities of carbonic anhydrase I and II isoenzymes and were new potential inhibitor molecule candidates. These compounds were found to have minimal effects on AChE and BChE. The antioxidant properties of the target compounds were determined using DPPH and ferric ion‐chelating assays. In particular, compounds 2 k and 2 h had the highest antioxidant effect in the series with IC50 values of 30.11±0.008 μM and 30.21±0.006 μM, respectively. ADMET properties of the compounds found to be effective were evaluated and their interactions with the enzyme were determined by molecular docking. [ABSTRACT FROM AUTHOR]

Fourteen novel Chalcone‐Cu complexes were effectively synthesized in this work. The newly synthesized Chalcone‐Cu complexes were assessed for their effects on human carbonic anhydrase isoenzymes I and II, acetylcholinesterase enzymes, and antioxidant activity. The intricate compounds exhibited Ki values ranging from 41.65–190.42 nM against hCA I, 15.79–259.07 nM against hCA II, and 14.36–175.73 nM against AChE enzymes. These complexes demonstrated potent inhibitory profiles against the specified metabolic enzymes, surpassing the inhibitory effects of acetazolamide (for hCA I and II) and tacrine (for AChE). The antioxidant properties of the compounds were assessed using DPPH and ABTS radical scavenging assays, revealing that the complexes had moderate to high efficacy in neutralizing free radicals. All complexes underwent molecular docking experiments. Compounds 14, 22, and 23 yielded the highest docking scores. Compound 14 demonstrated a docking score of −6.414 kcal/mol against hCAI, whereas compound 23 attained a docking score of −6.697 kcal/mol against hCA II. Compound 22 exhibited the most favorable docking score of −9.645 kcal/mol against AChE. The acquired results have the potential to help towards the development of new drugs containing Cu complex structures for the treatment of prevalent ailments such as glaucoma and Alzheimer's diseases. [ABSTRACT FROM AUTHOR]

A series of new 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their anti-AD potential. The results revealed that eleven compounds (1b, 2a-c, 3b, 4a-c, and 5a-c) exhibited excellent inhibitory potential against AChE, with IC50 values ranging from 0.00098 to 0.07920 µM. Their potency was 1.55 to 125.47 times higher than that of donepezil (IC50 = 0.12297 µM). In contrast, the newly synthesized oxadiazole derivatives with IC50 values in the range of 16.64–70.82 µM exhibited less selectivity towards BuChE when compared to rivastigmine (IC50 = 5.88 µM). Moreover, oxadiazole derivative 2c (IC50 = 463.85 µM) was more potent antioxidant than quercetin (IC50 = 491.23 µM). Compounds 3b (IC50 = 536.83 µM) and 3c (IC50 = 582.44 µM) exhibited comparable antioxidant activity to that of quercetin. Oxadiazole derivatives 3b (IC50 = 140.02 µM) and 4c (IC50 = 117.43 µM) showed prominent MAO-B inhibitory potential. They were more potent than biperiden (IC50 = 237.59 µM). Compounds 1a, 1b, 3a, 3c, and 4b exhibited remarkable MAO-A inhibitory potential, with IC50 values ranging from 47.25 to 129.7 µM. Their potency was 1.1 to 3.03 times higher than that of methylene blue (IC50 = 143.6 µM). Most of the synthesized oxadiazole derivatives provided significant protection against induced HRBCs lysis, revealing the nontoxic effect of the synthesized compounds, thus making them safe drug candidates. The results unveiled oxadiazole derivatives 2b, 2c, 3b, 4a, 4c, and 5a as multitarget anti-AD agents. The high AChE inhibitory potential can be computationally explained by the synthesized oxadiazole derivatives' significant interactions with the AChE active site. Compound 2b showed good physicochemical properties. All these data suggest that 2b could be considered as a promising candidate for future development. [ABSTRACT FROM AUTHOR]

A significant number of World Health Organization (WHO)-registered drugs are available that combat the symptoms of Alzheimer's Disease. The mechanism of action for each drug differs to some extent, reflecting the various hypotheses explaining the causes of symptoms or the disruption of physiological functions in the body. However, many of the presented drugs have not yielded the desired results due to side effects associated with therapy. The relevance of discovering and verifying new bioactive compounds, or repurposing existing drugs, opens new opportunities in the fight against this disease. In this study, the results of interactions between pre-selected N-N-disubstituted piperazines as cholinomimetics are presented. In silico, conformational changes in AChE and BChE were observed when interacting with the selected compounds. Steric and biophysical parameters of the complexes were calculated. [ABSTRACT FROM AUTHOR]

Free enzymes cause difficulties in many applications due to their insufficient stability, loss of activity in a short time, and most importantly, although they are costly, they are used only once in reactions, lose their effect and cannot be recovered from the environment. Magnetic nanoparticles coated with biocompatible polymeric material are potential candidates for promising enzyme carriers due to their multifunctional pore surfaces, easy removal from the environment provided by the magnetization, ability to main stability under various harsh conditions. This study prepared a biosensor candidate based on the inhibiting acetylcholinesterase enzyme by organophosphate pesticides from chitosan-coated magnetic nanoparticles doped with gold. Transmission electron microscopy, scanning electron microscopy, X-ray diffraction diffractometry, and Fourier transform infrared spectroscopy analysis confirmed the structure of synthesized nanocomposites. Magnetic characteristics of the nanocomposites were assessed using VSM. Bio-nanocomposite (Fe3O4@Cht/Au/AChE) was used to determine environmental pollutants qualitatively. Remediation of organophosphate-containing wastewater is an essential issue for environmental sustainability. In this work, Dichlorvos and Chlorpyrifos were selected as organic pollutants to assess the enzymatic activity of immobilized Fe3O4@Cht/Au/AChE. Optimum conditions for AChE enzyme were immobilized nanostructures (Fe3O4@Cht/Au/AChE) were determined. The optimum pH for the immobilized enzyme was found to be 8, and the optimum temperature was found to be 60 °C. Retained immobilized enzyme activity is found to be around 50% for the 20th reuse. In the presence of 150 µL pesticide, retained immobilized enzyme activity is found to be around 25%. Method validation was performed for pesticides. When using immobilized AChE, the LOD (limit of detection)-LOQ (limit of quantitation) values for Dichlorovos and Chlorpyrifos was obtained in the range of 0.0087–0.029 nM and 0.0014–0.0046 nM, respectively. The relative standard deviation (RSD%) values, which are indicators of precision, were found to be below 2%. [ABSTRACT FROM AUTHOR]

Simple Summary: There has been no scientific evidence of the bioactivity of Sambucus ebulus (Adoxaceae) extracts against insects. Therefore, we extracted and chemically characterized the leaves and flowers of S. ebulus in methanol and water. The two crude extracts and some of the phenolic compounds and amino acids isolated were tested as larvicides against two cosmopolitan mosquito species, namely the Asian tiger mosquito (Aedes albopictus) and the common house mosquito (Culex pipiens). To better understand their mode of action, we evaluated the in vitro acetylcholinesterase inhibitor effect of crude extracts on the two mosquito larvae by means of a colorimetric method. In addition, the ovideterrent effect of the crude extracts against Ae. albopictus females ovipositing in the open field was evaluated. As there has been no scientific evidence of the bioactivity of Sambucus ebulus (Adoxaceae) extracts against insects, we chemically characterized S. ebulus leaves and flowers extracted in methanol and water. The crude extracts, phenolic compounds, and amino acids isolated were tested as larvicides against the fourth-instar larvae of Aedes albopictus and Culex pipiens (Diptera: Culicidae). To understand their mode of action, we evaluated the in vitro acetylcholinesterase (AChE) inhibitor effect of the crude extracts on the two mosquito larvae through a colorimetric method. Furthermore, the deterrent effect of the crude extracts against ovipositing Ae. albopictus females was assessed in the open field. Twelve phenylpropanoids and fourteen amino acids were detected in the extracts, with a prevalence of hydroxycinnamic acids and nonaromatic amino acids. The most toxic compound to Ae. albopictus larvae after 24 h was gallic acid, followed by the crude S. ebulus leaf extract; on Cx. pipiens, it was the crude flower extract. The AChE test showed higher inhibition on both mosquito species exerted by the leaf extract if compared to the flower extract, and it also deterred oviposition by Ae. albopictus females starting from the third day. The results indicated that vegetal extracts could effectively help in the integrated vector management of mosquitoes. [ABSTRACT FROM AUTHOR]

We have synthesized library of biphenyl-4-carboxamide derivatives via one-pot strategy. The synthesized molecules were pharmacologically tested for their anticancer, antimicrobial activities and inhibition potential against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and urease enzymes. Molecular docking studies were performed against AChE, BChE and urease to further investigate the inhibition mechanism of the synthesized compounds. Compound 4h (at conc. 100 μg/mL) was found to be most active against human liver cancer cell lines (Hep2) (cell viability = 29.33%). Compound 4c demonstrated potent inhibitory activity against AChE (% inhibition 84.36) at 0.5 mM concentration and urease (% inhibition 31.42) enzymes at 0.25 mM concentration while 4b showed good activity against BChE (% inhibition 52.19) at 0.5 mM concentration. Synthesized molecules showed potent antibacterial and antifungal activities. To rationalize the observed pharmacological activities, we performed docking studies against AChE, BChE and enzymes. Compounds 4f, 4b and 4h showed high binding affinity with AChE, BChE and urease, respectively, with lowest bonding energies values (− 12.4, − 11.5 and − 8.9), respectively, so molecular docking study showed that all the synthesized compounds have good binding capability targeted to AChE, BChE and urease enzymes. Pharmaceutical activities and molecular docking studies suggest that synthesized compounds may play a great role as pharmaceutical agents. [ABSTRACT FROM AUTHOR]

Targeting acetylcholinesterase is one of the most important strategies for developing therapeutics against Alzheimer’s disease. In this work, we have employed a new approach that combines machine learning models, a multi-step similarity search of the PubChem library and molecular dynamics simulations to investigate potential inhibitors for acetylcholinesterase. Our search strategy has been shown to significantly enrich the set of compounds with strong predicted binding affinity to acetylcholinesterase. Both machine learning prediction and binding free energy calculation, based on linear interaction energy, suggest that the compound CID54414454 would bind strongly to acetylcholinesterase and hence is a promising inhibitor.

Nucleotides are important components and the main indicators for judging Cordyceps quality. In this paper, the mixed fermentation process of Schisandra chinensis and Cordyceps tenuipes was systematically studied, and it was proposed that the fermentation products aqueous extract (S-ZAE) had antioxidant activity and anti-AChE ability. Herein, the results of a single factor showed that S. chinensis, yeast extract, inoculum amount, and pH had significant effects on nucleotide synthesis. The fermentation process optimization results were 3% glucose, 0.25% KH2PO4, 2.1% yeast extract, and S. chinensis 0.49% (m/v), the optimal fermentation conditions were 25℃, inoculum 5.8% (v/v), pH 3.8, 6 d. The yield of total nucleotides in the scale-up culture was 0.64 ± 0.027 mg/mL, which was 10.6 times higher than before optimization. S-ZAE has good antioxidant and anti-AChE activities (IC50 0.50 ± 0.050 mg/mL). This fermentation method has the advantage of industrialization, and its fermentation products have the potential to become good functional foods or natural therapeutic agents. [ABSTRACT FROM AUTHOR]

The present study provides the first information on the chemical composition and acetylcholinesterase inhibitory activity of the essential oil (EO) from the leaves of Mitrephora poilanei Weeras. & R.M.K.Saunders from Vietnam. Gas chromatography and gas chromatography-mass spectrometry analysis revealed that the main components of the M. poilanei EO were β-caryophyllene (13.2%), α-humulene (10.5%), germacrene D (8.1%), β-elemene (5.2%) and bicyclogermacrene (5.1%). The anti-acetylcholinesterase assay showed that the EO displayed moderate activity with IC50 value of 31.16 ± 3.06 μg/mL. These findings proposed that the plant can be exploited for its anti-acetylcholinestrate potential. [ABSTRACT FROM AUTHOR]

Eight new bisbenzimidazolium halides were prepared from alkyl halides and 4,4′-bis[(benzimidazol-1-yl)methyl]-1,1′-biphenyl.The structures of the benzimidazole salts were characterized using elemental analysis techniques as well as 1H, 13C NMR, and FT-IR spectroscopic methods. The inhibitory effects of the benzimidazole derivatives were measured against human carbonic anhydrase I (hCA I), human carbonic anhydrase II (hCA II), and acetylcholinesterase (AChE) enzymes. All benzimidazolium halides exhibited significant enzyme inhibitory properties. They showed highly potent inhibitory effect on AChE and hCAs (Ki values are in the range of 15.7 ± 0.8 to 49.7 ± 10.1 nM, 14.6 ± 1.5 to 70.7 ± 2.7 nM, and 17.4 ± 2.8 to 38 ± 10 nM for AChE, hCA I, and hCA II, respectively). The binding orientation of the synthesized bisbenzimidazolium halides was evaluated by molecular docking studies, reflecting the importance of the p-methylbenzyl, m-methylbenzyl, p-nitrophenethyl, and 3-(1,3-dioxoisoindolin-2-yl)methyl) groups in protein–ligand interaction. The docking results support the Ki values of the respective compounds in this study. The structure–activity relationships against the various targets are clearly shown in three dimensions at the atomic level by their interactions with the mentioned enzymes. [ABSTRACT FROM AUTHOR]

Cerebral amyloid plaques in the brain define the elderly neuralgic disorder, Alzheimer's disease (AD). The enzyme Acetylcholinesterase (AChE) was reported to play a vital role in AD. It was shown that AChE induces amyloid fibril formation forming highly toxic AChE-Amyloid-β (Aβ) complexes. AChE can accelerate amyloid formation, and its inhibition could prevent such alterations to the enzyme. Understanding the proteostasis of AChE and its binding site to cellular chaperone GRP78 (Glucose-regulated protein 78) would help find a treatment for AD. In this study, the state of the art computational tools were utilized to predict the binding location of AChE that can stably associate with the cellular chaperone, GRP78. Sequence comparison along with molecular docking predicts two binding locations on AChE (C69–C96 and C257–C272) that could bind to GRP78 substrate binding domain β (SBDβ). The analysis of the docking data suggests that the former location has the best average binding affinity value (-12.16 kcal/mol) and average interaction pattern (13.9 ± 3.5 H-bonds, 5.5 ± 1.4 hydrophobic contacts, and 1.4 ± 1.2 salt bridges). [ABSTRACT FROM AUTHOR]

The aerotoxic syndrome has been associated with exposure to tricresyl phosphate (TCP), which is used as additive in hydraulic fluids and engine lubricants. The toxic metabolite 2-(2-cresyl)-4H-1,3,2-benzodioxaphosphorin-2-oxide (CBDP) is formed from the TCP isomer tri- ortho -cresyl phosphate (TOCP) in vivo and is known to react with the active site serine in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) resulting in the inhibition of the enzymes. Previous in vitro studies showed pronounced species differences in the inhibition kinetics of cholinesterases by organophosphorus compounds (OP), which must be considered in the development of relevant animal models for the investigation of OP poisoning and the aerotoxic syndrome. The present study was designed to investigate the inhibition kinetics of human, Cynomolgus monkey, pig, mini pig, guinea pig, mouse, and rat AChE as well as BChE by CBDP under standardized conditions. There were similar rate constants for the inhibition (k i) of human, Cynomolgus monkey and mouse AChE by CBDP. In contrast, the k i values obtained for guinea pig, mini pig, pig, and rat AChE were 2.8- to 5.9-fold lower than that of human AChE. The results of the present study confirmed CBDP as one of the most potent inhibitors of human BChE, indicating a k i value of 3.24 ± 0.33 ×10 8 M −1 min −1 , which was about 1,140-fold higher than that of human AChE. Accordingly, a markedly more pronounced inhibition rate of BChE from the species guinea pig, mini pig, pig, rat, Cynomolgus monkey, and mouse by CBDP was found as compared to those of AChE from the respective sources, indicating 2.0- to 89.6-fold higher k i values. • A study of the inhibition kinetics of cholinesterases by CBDP was performed. • Obvious species differences were pointed out by the results. • A Cynomolgus monkey model seemed most suitable in comparison with humans. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

BACKGROUND: Occupational foot-transmitted vibration (FTV) exposure is common in industries like mining, construction, and agriculture, often leading to acute and chronic injuries. Vibration assessments require technical expertise and equipment which can be costly for employers to perform. Alternatively, researchers have observed that self-reported discomfort can be used as an effective indicator of injury risk. OBJECTIVE: This study aimed to investigate the effect of standing FTV exposure on self-reported ratings of discomfort, and whether these subjective ratings differed by body area and exposure frequency. METHODS: Participants (n = 30) were randomly exposed to standing FTV at six frequencies (25, 30, 35, 40, 45, and 50 Hz) for 20–45 seconds. Following each exposure, participants rated discomfort on a scale of 0–9 in four body areas: head and neck (HN), upper body (UB), lower body (LB), and total body. RESULTS: Results indicated that participants experienced the most discomfort in the LB at higher frequencies (p < 0.001), consistent with the resonance of foot structures. The HN discomfort tended to decrease as the exposure frequency increased, although not statistically significant (p > 0.0167). The UB discomfort remained relatively low across all frequencies. CONCLUSIONS: The study suggests a potential connection between resonant frequencies and discomfort, potentially indicating injury risk. Although self-reported discomfort is insufficient for directly assessing injury risk from FTV, it provides a simple method for monitoring potential musculoskeletal risks related to vibration exposure at resonant frequencies. While professional vibration assessment remains necessary, self-reported discomfort may act as an early indicated of vibration-induced injuries, aiding in implementing mitigation strategies. [ABSTRACT FROM AUTHOR]

Five putrescine and spermidine derivatives (1–5) together with five rotenoids (6–10) were isolated from a methanolic extract of the flowers of A. fruticosa that displayed promising inhibition of 76.0 ± 1.9% for AChE and 90.0 ± 4.0% for BuChE at a concentration of 1 mg/mL. Although the anticholinesterase activities of the isolated compounds did not reach that of galantamine, molecular docking revealed that all-trans-tri-p-coumaroylspermidine and trans-trans-cis-tri-p-coumaroylspermidine showed binding poses mimicking the known inhibitor galantamine and thus could serve as model molecules in future searches for new AChE and BuChE inhibitors. [ABSTRACT FROM AUTHOR]

AbstractTwo pairs of cyclohexene amide alkaloid enantiomers were obtained from the root of Piper nigrum. Their plane structures were established by NMR and HRESIMS spectra. The absolute configurations of 1a/1b and 2a/2b were determined by the comparison between the experimental and calculated electronic circular dichroism (ECD) spectra. All identified compounds were tested for inhibitory effects on acetylcholinesterase (AChE) in vitro. Notably, compounds 1b and 2b showed strong inhibitory effects on AChE and the interaction between proteins and compounds was discussed by molecular docking studies. [ABSTRACT FROM AUTHOR]

Triazoles and triazolium salts are very common subunits in the structures of various drugs. Medicaments with a characteristic 1,2,3-triazole core are also being developed to treat neurodegenerative disorders associated with cholinesterase enzyme activity. Several naphtho- and thienobenzo-triazoles from our previous research emerged as being particularly promising in that sense. For this reason, in this research, new naphtho- and thienobenzo-triazoles 23–34, as well as 1,2,3-triazolium salts 44–51, were synthesized and tested. Triazolium salts 44–46 showed excellent activity while salts 47 and 49 showed very good inhibition toward both butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) enzymes. In contrast, neutral photoproducts were shown to be selective towards BChE but with very good inhibition potential as molecules 24–27. The representative of newly prepared compounds, 45 and 50, were stable in aqueous solution and revealed intriguing fluorimetric properties, characterized by a strong Stokes shift of >160 nm. Despite their condensed polycyclic structure shaped similarly to well-known DNA-intercalator ethidium bromide, the studied compounds did not show any interaction with ds-DNA, likely due to the unfavorable steric hindrance of substituents. However, the studied dyes bind proteins, particularly showing very diverse inhibition properties toward AChE and BChE. In contrast, neutral photoproducts were shown to be selective towards a certain enzyme but with moderate inhibition potential. The molecular docking of the best-performing candidates to cholinesterases' active sites identified cation–π interactions as the most responsible for the stability of the enzyme–ligand complexes. As genotoxicity studies are crucial when developing new active substances and finished drug forms, in silico studies for all the compounds synthesized have been performed. [ABSTRACT FROM AUTHOR]

The designed flavone-hydroxypyridinone derivatives were screened in silico with the multiple targets of Alzheimer's disease (AD) for their binding affinity. In this study, 29 novel derivatives of flavone-hydroxypyridinone were docked with acetylcholinesterase, butyrylcholinesterase and amyloid beta to determine their binding interactions on these targets of AD. The designed ligands were passed through the Lipinski and Veber filter, of which 29 ligands (8 from series 1 and 21 from series 2) obeyed the rule. All the molecules were docked with all the targets. To refine and confirm the docking study results, the stability of complexes is verified using molecular dynamics simulations. As our aim is to develop Multi-Target Direct Ligand (MTDL), one ligand from both the series has been selected as MTDL, is one of the best-docked ligands, which interacts with the protein through hydrogen bond, Vander Waal interactions, π - π stacking and π -alkyl interactions. Where amino acid residues such as Leu17, Lys16, Phe20 and Ala21 play important role in receptor–ligand interactions. The studies imply that the best-docked MTDL complex has a good binding affinity which has been further confirmed by molecular dynamic simulations and different pharmacokinetics parameters calculated. The study provides guidance for the development of flavone-hydroxypyridinone derivatives as MTDL against AD. The designed flavone-hydroxypyridinone derivatives (29) were screened in silico with the multiple targets (AChE, BuChE and A β) of Alzheimer's disease (AD) for their binding affinity using computational tools. [ABSTRACT FROM AUTHOR]

Fissistigma balansae (A.DC.) Merr., a climbing shrub belonging to the Annonaceae family, is native to China and Vietnam. The present study provides the first information on the chemical composition, antimicrobial activity, and anticholinesterase activity of the essential oil from the leaves (LEO) of F. balansae from Vietnam. Gas chromatography-mass spectrometry analysis revealed that the main components of the LEO were bicyclogermacrene (19.5%), germacrene D (15.8%), β-caryophyllene (14.7%), β-pinene (9.2%), α-pinene (8.9%), and δ-elemene (5.5%). The antimicrobial activity, as measured by minimum inhibitory concentration (MIC) values, showed that LEO exhibited effective antibacterial activity against Staphylococcus aureus (MIC = 50 μg/mL), Bacillus subtilis (MIC = 100 μg/mL), and Pseudomonas aeruginosa (MIC = 200 μg/mL). Additionally, LEO exhibited antifungal activity with a MIC of 100 μg/mL against Aspergillus niger, Candida albicans, and Saccharomyces cerevisiae. Moreover, LEO displayed moderate activity against acetylcholinesterase and butyrylcholinesterase, with half maximal inhibitory concentration (IC50) values of 92.02 μg/mL and 127.23 μg/mL, respectively. These findings suggest that F. balansae LEO can be exploited for its antimicrobial and anticholinesterase potentials. [ABSTRACT FROM AUTHOR]

Prolonged and excessive use of chlorpyrifos (CPS) has caused severe pollution, particularly in crops, vegetables, fruits, and water sources. As a result, CPS is detected in various food and water samples using conventional methods. However, its applications are limited due to size, portability, cost, etc. In this regard, electrochemical sensors are preferred for CPS detection due to their high sensitivity, reliability, rapid, on-site detection, and user-friendly. Notably, graphene-based electrochemical sensors have gained more attention due to their unique physiochemical and electrochemical properties. It shows high sensitivity, selectivity, and quick response because of its high surface area and high conductivity. In this review, we have discussed an overview of three graphene-based different functional electrochemical sensors such as electroanalytical sensors, bio-electrochemical sensors, and photoelectrochemical sensors used to detect CPS in food and water samples. Furthermore, the fabrication and operation of these electrochemical sensors using various materials (low band gap material, nanomaterials, enzymes, antibodies, DNA, aptamers, and so on) and electrochemical techniques (CV, DPV, EIS, SWV etc.) are discussed. The study found that the electrical signal was reduced with increasing CPS concentration. This is due to the blocking of active sites, reduced redox reaction, impedance, irreversible reactions, etc. In addition, acetylcholinesterase-coupled sensors are more sensitive and stable than others. Also, it can be further improved by fabricating with low band gap nanomaterials. Despite their advantages, these sensors have significant drawbacks, such as low reusability, repeatability, stability, and high cost. Therefore, further research is required to overcome such limitations. [ABSTRACT FROM AUTHOR]

The turnover rate of melanogenesis in retinal pigment epithelium (RPE) and its molecular signaling remain unclear. This study aimed to investigate the role of cholinergic signaling in the process of melanogenesis of cultured RPE cells. Here, a human retinal pigment epithelia cell line, ARPE-19 cell, was used to study the process of melanogenesis. The mRNA and protein expressions of cholinergic molecules, e.g., acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and melanogenic molecules i.e., tyrosinase (TYR), microphthalmia-associated transcription factor (MITF), and melanin pigment were measured during melanogenesis of cultured ARPE-19 cells. Forskolin (a cAMP inducing agent), acetylcholine (ACh) and bethanechol (Bch; a muscarinic AChR agonist) were used to induce melanogenesis in the cultures. Muscarinic acetylcholine receptor (mAChR) antagonists were employed to identify the receptor subtype. During melanogenesis of ARPE-19 cells, the mRNA and protein expressions of cholinergic molecules, e.g., AChE and BChE, were increased along with melanogenic molecules, i.e., TYR, MITF and melanin pigment. Forskolin, ACh, and Bch induced an upregulation of melanogenesis in cultured ARPE-19 cultures: the induction was parallel to an increase of AChE expression. The Bch-induced enzymatic activities and mRNA levels of AChE and TYR were fully blocked by the treatments of gallamine (a M2 specific antagonist), tropicamide (a M4 specific antagonist) and atropine (non-specific antagonist for mAChRs). Cholinergic signaling via M2/M4 mAChRs regulates melanogenesis in cultured ARPE-19 cells through a cAMP-dependent pathway. This study provides insights into the regulation of RPE cell melanogenesis via a non-neuronal function of cholinergic system.

One of the major neurodegenerative disorders, Alzheimer’s disease (AD) was targeted in the current study synthesizing bis-Schiff bases derivatives. All the synthesized scaffolds were found to have a range of IC50 values (2.50 ± 0.10 µM to 19.20 ± 0.10 µM) for AChE and (3.60 ± 0.10 µM to 19.90 ± 0.20 µM) for BuChE enzyme in comparison to reference drug donepezil (10.10 ± 0.20 µM to 11.50 ± 0.20 µM). Among the members of novel series, analogue 9 exhibited surpassing potential against both enzymes. Additionally, anti-fungal and anti-bacterial potential were also determined, where analog 9 showed higher anti-fungal inhibition (46.5 %) and analog 8 displayed strong inhibition potential (35.5 %) as anti-bacterial. Furthermore, in silico molecular docking approach was employed to explore the linkage between active site of proteins and active ligands. ADMET analysis conducted in this study predicted the drug nature of the lead compounds. The reactivity of the potent compounds for the attack of electrophile and nucleophile was elucidated via DFT. Moreover, the basic structural skeleton of the synthesized derivatives was characterized through modern methods of structure elucidation such as HREI-MS, 1H NMR and 13C NMR.

The current study described the synthesis of pyrazine-based novel molecules (1–15) using stepwise processes and their structures have been identified using various characterization techniques such as 1HNMR, 13CNMR, and HREI-MS. Furthermore, biological assessment of these scaffolds as anti-Alzheimer, anti-bacterial, and anti-fungal activities were evaluated. Their inhibitory potentials were determined using the minimum inhibitory concentration (MIC) in the presence of standard drugs donepezil (IC50 = 8.90 ± 0.20 µM), streptomycin (inhibition = 36.5 %), and Terbinafine (inhibition = 31.7 %) respectively. Among the screened molecules against acetylcholinesterase enzyme, the potent behavior was shown by scaffolds 1 (IC50 = 3.20 ± 0.40 µM), 2 (IC50 = 2.10 ± 0.20 µM), 4 (IC50 = 2.90 ± 0.10 µM), 5 (IC50 = 5.80 ± 0.30 µM), 6 (IC50 = 7.20 ± 0.20 µM), 8 (IC50 = 6.30 ± 0.30 µM), 9 (IC50 = 6.50 ± 0.20 µM), 10 (IC50 = 7.30 ± 0.20 µM) and 11 (IC50 = 7.10 ± 0.20 µM). Structure-activity relationship was carried out which mainly depends upon the substitution pattern around the phenyl ring. These compounds were further investigated by molecular docking studies which explore the binding interaction of ligands with active sites of enzymes. Moreover, ADMET prediction was also studied for potent scaffolds that displayed drug-like properties.

The current study was conducted to establish a unique synthetic route for the synthesis of varied substituted benzimidazole derived thiazole base thiazolidinone derivatives by using molecular hybridization approach. For structural interpretation of these compounds, different spectroscopic techniques such as 13CNMR, 1HNMR and spectrometric technique HREI-MS were used. These compounds were examined in vitro against AChE and BuChE to evaluate their inhibitory profile in comparison with standard drug donepezil (IC50 = 1.60 ± 0.18 µM for AChE and IC50 = 5.3 ± 0.11 µM for BuChE). All the synthesized compounds exhibit excellent to moderate activity with IC50 ranging from 1.20 ± 1.07 µM to 28.14 ± 2.38 µM for AChE and 1.70 ± 3.10 µM to 27.65 ± 0.39 µM for BuChE in contrast to donepezil. Among the members of synthesized series, analog 2 and 7 emerged as most potent analogues having IC50 = 1.64 ± 0.04 µM (AChE) and 3.19 ± 0.18 µM (BuChE) and (IC50 = 1.20 ± 1.07 µM (AChE) and 2.38 ± 1.14 µM (BuChE), respectively. The active analogues were further explored by molecular docking to evaluate their degrees of binding interaction with active site of targeted enzymes.

Industrial and human activities contribute significantly to the environmental contamination of heavy metal ions (HMIs), which have detrimental effects on aquatic life, plants, and animals, causing major toxicological problems. The commercially available 4,4′-diamino-2,2′-stilbenedisulfonic acid (DSD) has been playing a vital role in the detection of heavy metal ions and has significantly inhibited a variety of cancer cells in numerous field of modern science. The current investigation aimed to ensure the detection of heavy metals ions from the environment and fluorescence imaging of DSD in the treatment of cancer cells. Fluorescence and UV–Visible spectroscopic analysis was performed to sense the selective behavior of the probe DSD with several heavy metal ions, including Fe2+, K1+, Co2+, Ni2+, Zn2+, Cd2+, Pb2+, Mn2+, Sn2+, and Cr3+. Furthermore, DSD was subjected to examine enzyme inhibition such as anti-Alzheimer, anti-inflammatory, antioxidant, anticancer, and antimicrobial activities in search of multifaceted drugs. Test compounds have demonstrated dose-dependent responses in the in-vitro enzyme inhibition assays for acetylcholinesterase (AChE), butyrylcholinesterase (BChE), cyclooxygenase (COX), and lipoxygenase (LOX), as well as antioxidant [DPPH = 2,2-diphenyl-1-picrylhydrazyl and ABTS = 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid]. The DSD were shown to be more effective than the conventional medication galantamine in inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with an IC50 value of 12.18 and 20.87 μM, which is equivalent to the standard drug. The results obtained has revealed that DSD has the potential to become an effective sensor for the detection of Sn2+ ions over competing metal ions due to the inhibition of photo-induced electron transfer pathway (PET). The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide tetrazolium) test, demonstrated that DSD had strong anticancer effects against the brain cancer cell line NIH/3T3, HeLa and MCF-7 with an IC50 value of 32.59, 15.31 and 96.46 μM respectively. The antimicrobial testing has shown that DSD outperforms the standard drug cefixime against Candida albicans and Pseudomonas aeruginosa, respectively. This study makes a substantial contribution to the ongoing search for efficient treatments for breast cancer.

The development of medical countermeasures (MCMs) against organophosphate (OP) induced poisoning is of substantial importance. Use of conventional therapeutics is complicated by off-target effects and restricted penetration of the blood-brain barrier (BBB). Therefore, a concerted effort is underway to discover improved acetylcholinesterase (AChE) reactivators, muscarinic acetylcholine receptor (mAChR) antagonists, and other countermeasures with broader spectrum activity and enhanced CNS efficacy. We recently developed a rat brain slice assay to assess the efficacy of AChE reactivators and mAChR antagonists against the acute effects of the organophosphorus AChE inhibitor 4-nitrophenyl isopropyl methylphosphonate (NIMP) in the basolateral amygdala (BLA). Here we introduce a complimentary anesthetized animal model to evaluate the same compounds in vivo with concurrent monitoring of EEG and respiratory rate. We find that intravenous delivery of 0.5 mg/kg NIMP reliably produces seizure like activity in the BLA, with concurrent respiratory depression and eventual respiratory failure. The central effects of AChE reactivators and mAChR antagonists delivered intravenously are consistent with their expected ability to cross the BBB. Combining our previously described in vitro assay with the methods described here provides a relatively comprehensive set of preclinical tools for evaluating the efficacy of novel MCMs. Notably, using these methods is expected to reduce the need to subject conscious animals to cholinergic crises, which aligns with the AAALAC’s 3Rs principle of refinement.

Glyphosate has remained the leading herbicide on the global market to date, despite the continuous debate between consumers, scientific community, and regulatory agencies over its carcinogenicity, genotoxicity, environmental persistence, and the role in the development of neurodegenerative disorders. Chemically, glyphosate belongs to a large family of organophosphorus pesticides, which exert a neurotoxic effect by inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), enzymes of the cholinergic system essential for maintaining neurotransmission. Although research shows that glyphosate is a weak cholinesterase inhibitor in fish and mammals compared to other OP compounds, no conclusive data exist concerning the inhibition of human AChE and BChE. In our study we analysed its inhibitory potency on human AChE and BChE, by establishing its IC50 and reversible inhibition in terms of dissociation inhibition constants. Glyphosate concentration of 40 mmol/L caused near total inhibition of enzyme activity (approx. 10 % activity remaining). Inhibition dissociation constants (Ki) of glyphosate-AChE and -BChE complexes were 28.4±2.7 mmol/L and 19.3±1.8 mmol/L, respectively. In conclusion, glyphosate shows a slight binding preference for BChE but exhibits inhibition only in a high concentration range. Our results are in line with studies reporting that its neurotoxic effect is not primarily linked to the cholinergic system.