Search

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]

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]

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]

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]

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.

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]

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]

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]

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.

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.

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]

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]

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]

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]

Copyright of Archives of Industrial Hygiene & Toxicology / Arhiv za Higijenu Rada I Toksikologiju is the property of Sciendo and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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

This study examined the effect of aspirin on olfactory discrimination and neurogenesis in experimental aging mice. The results from the buried food test (BFT) and odour preference test (OPT) indicated that aspirin treatment enhanced the olfactory functions in the experimental animals. The immunohistochemical assessment revealed increased amounts of doublecortin (DCX)-positive immature neurons and bromodeoxyuridine (BrdU)/neuronal nuclei (NeuN) double-positive new neurons in the olfactory bulb (OB) of aspirin-treated animals compared to the control group. Besides, aspirin treatment resulted in a decreased number of ionized calcium-binding adaptor molecule (Iba)-1 positive microglia, a main cellular element of neuroinflammation in the brain compared to the control group. In addition, the increased activities of key antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in OB of the aspirin-treated mice were evident. Acetylcholinesterase (AChE) is a key enzyme that hydrolyses acetylcholine (ACh), an important neurotransmitter, involved in cognition, and olfaction. While the enhanced activity of AChE has been linked to the severity of dementia and OB defects, the biochemical assessments indicated reduced activity of AChE in OB-derived homogenates of the aspirin-treated experimental animals than that of the control group. Taken together, this study validates the proneurogenic, cholinergic, and anti-neuroinflammatory properties of aspirin in the OB which can be considered in boosting neural regeneration and management of olfactory deficits in aging and various disorders.

Abstract Background Solanum lycopersicum Linn. (Tomato, Family Solanaceae) is one of the fruits that are most consumed worldwide. The current research intends to emphasise the possibility of positive and therapeutic effects of S. lycopersicum seed extract (SLSE) on Alzheimer's disease's neurodegeneration effects being reversed in a study utilising rats exposed to aluminium chloride. Investigations were done on the cholinesterase and antioxidant in vitro activity of SLSE. Rats with Alzheimer's disease were given SLSE, and donepezil (500, and 10 mg/kg.b.wt., daily for six weeks, respectively) to test SLSE biological activity. Beam-balance and T-maze tests, as well as serum levels of AChE, norepinephrine, dopamine, serotonin, IL-6, glycated end product, BDNF, MDA, TAC, and GSH were assessed, accompanied with histological investigation. To impact the effectiveness of this extract, bioinformatics study was validated. Results Crude SLSE showed in vitro DPPH scavenging and AChE inhibition activities, indicating the extract might have anti-Alzheimer potential, which was validated using an aluminium-intoxicated rat model, in vivo. In Alzheimer's rats, in vivo studies showed considerable improvements, as seen by improved beam balance, and T-maze tests and decreased serum levels of AChE, norepinephrine, dopamine, serotonin, IL-6, glycated end product, BDNF, and MDA, with increasing in TAC, and GSH levels. Brain tissue histological tests revealed a largely typical pattern of collagen fibre distribution. LC–HRESIMS metabolomic profiling of crude SLSE identified 33 compounds. Furthermore, the bioinformatics study discovered 378 targets related to the major identified compounds, of which only 133 were related to Alzheimer's and memory disorders, with APP, AChE, and PSEN2 targets which were marked as the top genes. Gene enrichment analysis identified the arachidonic acid metabolism and PPAR signalling pathway as the biological pathways enriched by all the gene sets under investigation. Conclusion As a result, the study findings are expected to pave the way for the creation of dietary supplements for Alzheimer's disease management. Graphic abstract

Ginkgo biloba (GB) extracts have been used in clinical studies as an alternative therapy for Alzheimer’s disease (AD), but the exact bioaction mechanism has not yet been elucidated. In this work, an in silico study on GB metabolites was carried out using SwissTargetPrediction to determine the proteins associated with AD. The resulting proteins, AChE, MAO-A, MAO-B, β-secretase and γ-secretase, were studied by molecular docking, resulting in the finding that kaempferol, quercetin, and luteolin have multitarget potential against AD. These compounds also exhibit antioxidant activity towards reactive oxygen species (ROS), so antioxidant tests were performed on the extracts using the DPPH and ABTS techniques. The ethanol and ethyl acetate GB extracts showed an important inhibition percentage, higher than 80%, at a dose of 0.01 mg/mL. The effect of GB extracts on AD resulted in multitarget action through two pathways: firstly, inhibiting enzymes responsible for degrading neurotransmitters and forming amyloid plaques; secondly, decreasing ROS in the central nervous system (CNS), reducing its deterioration, and promoting the formation of amyloid plaques. The results of this work demonstrate the great potential of GB as a medicinal plant.

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.

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.