Lemongrass essential oil and its major component citronellol: evaluation of larvicidal activity and acetylcholinesterase inhibition against Anopheles sinensis.

Mosquito-borne diseases, such as malaria, dengue fever, and the Zika virus, pose significant global health challenges, affecting millions annually. Due to increasing insecticide resistance, there is a growing interest in natural alternatives for mosquito control. Lemongrass essential oil, derived from Cymbopogon citratus, has shown promising repellent and larvicidal properties against various mosquito species. In this study, we investigated the larvicidal effect of lemongrass oil and its major compounds on Anopheles sinensis, the primary malaria vector in China. GC-MS analysis identified the major compounds of lemongrass oil as ( +)-citronellal (35.60%), geraniol (21.84%), and citronellol (13.88%). Lemongrass oil showed larvicidal activity against An. sinensis larvae, with an LC50 value of 119.20 ± 3.81 mg/L. Among the major components, citronellol had the lowest LC50 value of 42.76 ± 3.18 mg/L. Moreover, citronellol demonstrated inhibitory effects on acetylcholinesterase (AChE) activity in An. sinensis larvae, assessed by homogenizing larvae at different time points following treatment. Molecular docking studies further elucidated the interaction between citronellol and AChE, revealing the formation of hydrogen bonds and Pi-Sigma bonds. Aromatic amino acid residues such as Tyr71, Trp83, Tyr370, and Tyr374 played a pivotal role in these interactions. These findings may contribute to understanding lemongrass oil's larvicidal activity against An. sinensis and the mechanisms underlying these effects.

The synthesis of novel unnatural amino acid by intramolecular aza-Michael addition reaction as multitarget enzyme inhibitors.

Synthesis of novel unnatural amino acids (UAAs) from 4-oxo-4-phenylbut-2-enoic acid derivatives with intramolecular aza-Michael addition reaction in the presence of chlorosulfonyl isocyanate (CSI) was reported in soft conditions without any metal catalyst. Acids and base as a catalyst, and solvents effects were investigated for the synthesis of novel UAAs. This novel method provides inexpensive, practicable, and efficient approach to generate UAAs. The use of UAAs has attracted great interest in the development of therapeutic agents and drug discovery to improve their properties. In this context, in addition to the synthesis of new UAAs, their inhibition effects on important metabolic enzymes of acetylcholinesterase (AChE) and carbonic anhydrases I and II (hCA I and II) enzymes were investigated. The compound 2g showed the best inhibition for CA I and AChE enzymes, while compound 2i exhibited the best inhibition profile against CA II isoenzyme. The inhibition values of these compounds were found as 1.85 ± 0.64 for AChE, 0.53 ± 0.07 for hCA I, 0.44 ± 0.15 µM for hCA II, respectively, and they showed a stronger inhibitory property than acetazolamide (standard inhibitor for hCA I and II) and tacrine (standard inhibitor for AChE) molecules. The activity of the studied molecule against different proteins that are hCA I (PDB ID: 2CAB), hCA II (PDB ID: 5AML), and AChE (PDB ID: 1OCE) was examined. Finally, the drug properties of the studied molecule were examined by performing absorption, distribution, metabolism, excretion, and toxicity analysis.

Lipid Composition, Cytotoxic and Acetylcholinesterase Inhibition Effects of Two Brown Algae Species Lobophora tsengii and Lobophora australis.

In this paper, the lipid classes, compositions of the neutral lipids, phospholipids and fatty acids, acetylcholinesterase inhibition and cytotoxic activity of two brown algae Lobophora tsengii D. Tien & Z. Sun and Lobophora australis Z. Sun, F. C. Gurgel & H. Kawai have been investigated. The polar lipid class had the highest content in total lipid (TL) (43.47% in L. tsengii and 48.95% in L. australis). Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were the main components in the phospholipids of two studied brown algae with contents varied from 32.27% to 52.33%. Total lipids were rich in PUFA (42.54% of total fatty acids for L. australis and 32.98% for L. tsengii), with EPA (11.46%, 14.30%) and AA (8.0%, 11.96%). L. tsengii methanol extract inhibited acetylcholinesterase (AChE) in in vitro assay with an IC50 value of 25.45 µg/mL. Both Lobophora methanol extracts display cytotoxic effects against four human cancer cell lines (KB, MCF7, HepG2 and A549) with IC50 in the range of 21.11-83.61 µg/mL. Especially, L. australis extract showed a strong cytotoxicity against KB cell lines with IC50 value of 21.11±0.39 µg/mL.

Pharmacology of Adenosine A1 Receptor Agonist in a Humanized Esterase Mouse Seizure Model Following Soman Intoxication.

Recently a novel genetically modified mouse strain with serum carboxylesterase knocked-out and the human acetylcholinesterase gene knocked-in (KIKO) was created to simulate human responses to nerve agent (NA) exposure and its standard medical treatment. A1 adenosine receptor (A1AR) agonist N-bicyclo-(2.2.1)-hept-2-yl-5'-chloro-5'-deoxyadenosine (ENBA) alone is a potent anticonvulsant and neuroprotectant (A/N) in both rat and KIKO mouse soman (GD) seizure models. In this study we utilized the KIKO mouse to evaluate further the basic pharmacologic A/N effects of ENBA as an adjunct to standard NA medical treatments (i.e., atropine sulfate, pralidoxime chloride [2-PAM], and midazolam). Male mice, implanted with cortical electroencephalographic (EEG) electrodes, were pretreated with asoxime (HI-6) and exposed to an epileptogenic dose of GD (33 µg/kg, s.c.) or saline (sham exposure) and then treated 15 min after seizure onset with ENBA at 15 mg/kg, i.p. (a minimum efficacy dose in suppressing NA-induced seizure) alone or as an adjunct to standard medical treatments. We collected EEG activity, seizure suppression outcomes, daily body temperature and weight, heart rate, toxic signs, neuropathology, and lethality data for up to 14 days. Without ENBA, death from NA exposure was 45%, while with ENBA, either alone or in combination with midazolam, the survival improved to 80% and 90%, respectively. Additionally, seizure was suppressed quickly and permanently, toxic signs, hypothermia, and bradycardia recovered by 48 h, and no neuropathology was evident. Our findings confirmed that ENBA is a potent A/N adjunct for delayed medical treatments of NA exposure.

In Silico Investigation of Suillin Derived from Suillus luteus Mushroom (Agaricomycetes) Targeting Acetylcholinesterase: Docking and Virtual Screening Study.

This study integrates bioinformatics and computer-aided drug discovery to assess suillin's therapeutic potential, particularly its interaction with acetylcholinesterase (AChE). Alzheimer's disease presents profound challenges, necessitating effective treatments to mitigate cognitive decline and improve patients' quality of life. Although current medications offer symptomatic relief, they often entail adverse effects and do not address the underlying disease progression. Natural sources, such as macrofungi mushrooms, hold promise for novel drug discovery due to their bioactive compounds' diverse therapeutic properties. Suillin, derived from Suillus luteus mushrooms, shows promise as a mixed-type AChE inhibitor, crucial for maintaining acetylcholine levels in neurodegenerative disorders like Alzheimer's disease. Computational docking studies reveal suillin's distinctive interactions with AChE, suggesting potential modulation of enzyme function through various bonding mechanisms. The Molinspiration drug-likeness score further supports suillin's efficacy, indicating its suitability for enzyme inhibition. By combining computational and bioinformatics approaches, this study elucidates suillin's molecular interactions and underscores its potential as a therapeutic agent.

Design, synthesis, molecular modeling, in vitro evaluation of novel piperidine-containing hydrazone derivatives as cholinesterase inhibitors.

In an effort to develop new and effective therapeutic agents for Alzheimer's disease, a series of hydrazone derivatives bearing piperidine rings have been designed and synthesized. The chemical structures of the compounds were characterized by various spectroscopic techniques. In vitro antioxidant and cholinesterase activities of the compounds were evaluated. Among the compounds, N12 exhibited the most antioxidant activity in all methods (CUPRAC, FRAP, DPPH, ABTS). In vitro acetylcholinesterase (AChE) activity results of the compounds showed good IC50 values between 14.124 ± 0.084 and 49.680 ± 0.110 µM were obtained (IC50 = 38.842 ± 0.053 µM for Donepezil). Among the compounds, N7 and N6 are much more effective derivatives than the standard compound donepezil with IC50 values of 14.124 ± 0.084 and 17.968 ± 0.072 µM, respectively. In vitro, butyrylcholinesterase (BChE) inhibition values of the compounds were between 13.505 ± 0.025 and 52.230 ± 0.027 µm. Among the compounds, N6 has the highest BChE inhibition with an IC50 value of 13.505 µm in the series. The cytotoxicity and AChE inhibitory activity of the compounds on SH-SY5Y cell lines were also evaluated. Kinetic studies were also performed to determine the behavior of the compounds as competitive or noncompetitive inhibitors. The binding modes of N6, which was determined to be highly effective according to in vitro analyses, with AChE and BChE were investigated using molecular docking studies, and the stability of the complexes was determined by molecular dynamics simulations. These findings indicated that AChE and BChE enzymes maintained their overall structural stability and compactness during interactions with compound N6.

A Series of Novel 1-H-isoindole-1,3(2H)-dione Derivatives as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: In Silico, Synthesis and In Vitro Studies.

The derivatives of isoindoline-1,3-dione are interesting due to their biological activities, such as anti-inflammatory and antibacterial effects. Several series have been designed and evaluated for Alzheimer's therapy candidates. They showed promising activity. In this work, six new derivatives were first tested in in silico studies for their inhibitory ability against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Molecular docking and molecular dynamic simulation were applied. Next, these compounds were synthesized and characterized by 1H NMR, 13C NMR, FT-IR, and ESI-MS techniques. For all imides, the inhibitory activity against AChE and BuChE was tested using Ellaman's method. IC50 values were determined. The best results were obtained for the derivative I, with a phenyl substituent at position 4 of piperazine, IC50 = 1.12 µM (AChE) and for the derivative III, with a diphenylmethyl moiety, with IC50 = 21.24 µM (BuChE). The compounds tested in this work provide a solid basis for further structural modifications, leading to the effective design of potential inhibitors of both cholinesterases.

Development of Delivery Systems with Prebiotic and Neuroprotective Potential of Industrial-Grade Cannabis sativa L.

This study delves into the transformative effects of supercritical carbon dioxide (scCO2) cannabis extracts and prebiotic substances (dextran, inulin, trehalose) on gut bacteria, coupled with a focus on neuroprotection. Extracts derived from the Bialobrzeska variety of Cannabis sativa, utilising supercritical fluid extraction (SFE), resulted in notable cannabinoid concentrations (cannabidiol (CBD): 6.675 ± 0.166; tetrahydrocannabinol (THC): 0.180 ± 0.006; cannabigerol (CBG): 0.434 ± 0.014; cannabichromene (CBC): 0.490 ± 0.017; cannabinol (CBN): 1.696 ± 0.047 mg/gD). The assessment encompassed antioxidant activity via four in vitro assays and neuroprotective effects against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The extract boasting the highest cannabinoid content exhibited remarkable antioxidant potential and significant inhibitory activity against both enzymes. Further investigation into prebiotic deliveries revealed their proficiency in fostering the growth of beneficial gut bacteria while maintaining antioxidant and neuroprotective functionalities. This study sheds light on the active compounds present in the Bialobrzeska variety, showcasing their therapeutic potential within prebiotic systems. Notably, the antioxidant, neuroprotective, and prebiotic properties observed underscore the promising therapeutic applications of these extracts. The results offer valuable insights for potential interventions in antioxidant, neuroprotective, and prebiotic domains. In addition, subsequent analyses of cannabinoid concentrations post-cultivation revealed nuanced changes, emphasising the need for further exploration into the dynamic interactions between cannabinoids and the gut microbiota.

Atomistic Origins of Resurrection of Aged Acetylcholinesterase by Quinone Methide Precursors.

Nerve agents are organophosphates (OPs) that act as potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of acetylcholine. After inhibition, a dealkylation reaction of the phosphorylated serine, known as the aging of AChE, can occur. When aged, reactivators of OP-inhibited AChE are no longer effective. Therefore, the realkylation of aged AChE may offer a pathway to reverse AChE aging. In this study, molecular modeling was conducted to propose new ligands as realkylators of aged AChE. We applied a methodology involving docking and quantum mechanics/molecular mechanics (QM/MM) calculations to evaluate the resurrection kinetic constants and ligand interactions with OP-aged AChE, comparing them to data found in the literature. The results obtained confirm that this method is suitable for predicting kinetic and thermodynamic parameters of ligands, which can be useful in the design and selection of new and more effective ligands for AChE realkylation.

Metabolites profiling, in-vitro and molecular docking studies of five legume seeds for Alzheimer's disease.

Even though legumes are valuable medicinal plants with edible seeds that are extensively consumed worldwide, there is little information available on the metabolic variations between different dietary beans and their influence as potential anti-cholinesterase agents. High-resolution liquid chromatography coupled with mass spectrometry in positive and negative ionization modes combined with multivariate analysis were used to explore differences in the metabolic profiles of five commonly edible seeds, fava bean, black-eyed pea, kidney bean, red lentil, and chickpea. A total of 139 metabolites from various classes were identified including saponins, alkaloids, phenolic acids, iridoids, and terpenes. Chickpea showed the highest antioxidant and anti-cholinesterase effects, followed by kidney beans. Supervised and unsupervised chemometric analysis determined that species could be distinguished by their different discriminatory metabolites. The major metabolic pathways in legumes were also studied. Glycerophospholipid metabolism was the most significantly enriched KEGG pathway. Pearson's correlation analysis pinpointed 18 metabolites that were positively correlated with the anti-cholinesterase activity. Molecular docking of the biomarkers to the active sites of acetyl- and butyryl-cholinesterase enzymes revealed promising binding scores, validating the correlation results. The present study will add to the metabolomic analysis of legumes and their nutritional value and advocate their inclusion in anti-Alzheimer's formulations.

Neuroprotective effect of long-term resistance physical exercise against memory damage elicited by a lipopolysaccharide-induced neuroinflammation model in male rats.

Resistance exercise training (RET) is considered an excellent tool for preventing diseases with an inflammatory background. Its neuroprotective, antioxidant, and anti-inflammatory properties are responsible for positively modulating cholinergic and oxidative systems, promoting neurogenesis, and improving memory. However, the mechanisms behind these actions are largely unknown. In order to investigate the pathways related to these effects of exercise, we conducted a 12-week long-term exercise training protocol and used lipopolysaccharide (LPS) to induce damage to the cortex and hippocampus of male Wistar rats. The cholinergic system, oxidative stress, and histochemical parameters were analyzed in the cerebral cortex and hippocampus, and memory tests were also performed. It was observed that LPS: (1) caused memory loss in the novel object recognition (NOR) test; (2) increased the activity of acetylcholinesterase (AChE) and Iba1 protein density; (3) reduced the protein density of brain-derived neurotrophic factor (BDNF) and muscarinic acetylcholine receptor M1 (CHRM1); (4) elevated the levels of lipid peroxidation (TBARS) and reactive species (RS); and (5) caused inflammatory damage to the dentate gyrus. RET, on the other hand, was able to prevent all alterations induced by LPS, as well as increase per se the protein density of the alpha-7 nicotinic acetylcholine receptor (nAChRα7) and Nestin, and the levels of protein thiols (T-SH). Overall, our study elucidates some mechanisms that support resistance physical exercise as a valuable approach against LPS-induced neuroinflammation and memory loss.

Protective effect of menthol against thioacetamide-induced hepatic encephalopathy by suppressing oxidative stress and inflammation, augmenting expression of BDNF and α7-nACh receptor, and improving spatial memory.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that can occur in people with acute or chronic liver disease. Here, we investigated the effects of menthol, a natural monoterpene, on HE induced by thioacetamide (TA) in male Wistar rats. The rats received 200 mg/kg of TA twice a week for four weeks and were administered 10 mg/kg of menthol intraperitoneally daily for the same period. The results showed that menthol treatment reduced oxidative stress and inflammation in the livers and hippocampi of the rats that received TA. It also lowered the levels of ammonium and liver enzymes AST, ALT, ALP, and GGT in the serum of these animals and prevented liver histopathological damage. In addition, the expression and activity of acetylcholinesterase in the hippocampus of HE model rats were decreased by menthol. Likewise, this monoterpene reduced the expression of TLR4, MyD88, and NF-κB in the hippocampus while increasing the expression of BDNF and α7-nACh receptor. Menthol also reduced neuronal death in the hippocampal cornu ammonis-1 and dentate gyrus regions and reduced astrocyte swelling, which led to improved learning and spatial memory in rats with HE. In conclusion, the study suggests that menthol may have strong protective effects on the liver and brain, making it a potential treatment for HE and neurodegenerative diseases.

A New Class of Benzo[b]thiophene-chalcones as Cholinesterase Inhibitors: Synthesis, Biological Evaluation, Molecular Docking and ADME Studies.

In this study, heterocyclic compounds containing a benzothiophene scaffold were designed and synthetized, and their inhibitory activity against cholinesterases (ChE) and the viability of SH-SY5Y cells have been evaluated. Benzothiophenes 4a-4i and benzothiophene-chalcone hybrids 5a-5i were tested against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), revealing interesting structure-activity relationships. In general, benzothiophene-chalcone hybrids from series 5 proved to be better inhibitors of both enzymes, with compound 5f being the best AChE inhibitor (IC50 = 62.10 µM) and compound 5h being the best BChE inhibitor (IC50 = 24.35 µM), the last one having an IC50 similar to that of galantamine (IC50 = 28.08 µM), the reference compound. The in silico ADME profile of the compounds was also studied. Molecular docking calculations were carried out to analyze the best binding scores and to elucidate enzyme-inhibitors' interactions.

Neural acetylcholinesterase and monoamine oxidase deregulation during streptozotocin-induced behavioral, metabolic and redox modification in Nauphoeta cinerea.

Genetic and environmental factors have been linked with neurodegeneration, especially in the elderly. Yet, efforts to impede neurodegenerative processes have at best addressed symptoms instead of underlying pathologies. The gap in the understanding of neuro-behavioral plasticity is consistent from insects to mammals, and cockroaches have been proven to be effective models for studying the toxicity mechanisms of various chemicals. We therefore used head injection of 74 and 740 nmol STZ in Nauphoeta cinerea to elucidate the mechanisms of chemical-induced neurotoxicity, as STZ is known to cross the blood-brain barrier. Neurolocomotor assessment was carried out in a new environment, while head homogenate was used to estimate metabolic, neurotransmitter and redox activities, followed by RT-qPCR validation of relevant cellular signaling. STZ treatment reduced the distance and maximum speed travelled by cockroaches, and increased glucose levels while reducing triglyceride levels in neural tissues. The activity of neurotransmitter regulators - AChE and MAO was exacerbated, with concurrent upregulation of glucose sensing and signaling, and increased mRNA levels of redox regulators and inflammation-related genes. Consequently, STZ neurotoxicity is conserved in insects, with possible implications for using N. cinerea to target the multi-faceted mechanisms of neurodegeneration and test potential anti-neurodegenerative agents.

Evaluation of genotoxic effects in workers and residents of rural areas exposed to pesticides in Brazil.

Brazil is one of the world's largest consumers of pesticides. This intense use impacts the environment and exposes a wide range of individuals to pesticides, including rural workers who are occupationally exposed and rural residents who are environmentally exposed. We aimed to evaluate the effects of occupational exposure to pesticides on the health of rural workers and rural residents. We conducted an epidemiological study with 104 farmers and 23 rural residents of Casimiro de Abreu (Rio de Janeiro, Brazil). A comparison group (urban residents) comprised 103 residents of the urban area of the same city. We determined the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using a modified version of Ellman's method to evaluate exposure. In addition, we performed genotoxic and mutagenic analyses with the comet assay and the cytokinesis-block micronucleus (CBMN) assay. There was a reduction in cholinesterase activity, mainly BChE, in rural workers and rural residents compared with urban residents (p = 0.002). There was an increase in genotoxic effects in rural workers compared with urban residents (comet assay, p < 0.001; CBMN assay, p < 0.001). In addition, there was a greater chance of genotoxic changes in rural workers exposed to pesticides based on the comet assay (odds ratio [OR] 7.6, 95 % confidence interval [CI] 6.6-15.9) and the CBMN assay (OR 22.7, 95 % CI 10.3-49.9). We found that individuals occupationally exposed to pesticides are more likely to have genotoxic effects. These findings are useful for the development of programs to monitor populations exposed to genotoxic substances and allow the development of strategies for the prevention, control, and surveillance of effects that result from occupational and environmental exposures to pesticides.

Ultra-small CuOx/GDYO nanozyme with boosting peroxidase-like activity via electrochemical strategy: Toward applicable colorimetric detection of organophosphate pesticides.

In this paper, an ultra-small-sized CuOx/GDYO nanozyme in situ grown on ITO glass was rationally synthesized from mixed precursors of graphdiyne oxide (GDYO) and copper based infinite coordination polymer (Cu-ICP, consisting of Cu ions and two organic ligands 3,5-di-tert-butylcatechol and 1,4-bis(imidazole-1-ylmethyl)benzene) via mild and simple electrochemical strategy. On one hand, the preferential electro-reduction of Cu-ICP enabled the formation of ultra-small CuOx with Cu(I) as the main component and avoided the loss of oxygen-containing functional groups and defects on the surface of GDYO; on the other hand, GDYO can also serve as electroless reductive species to facilitate the electrochemical deposition of CuOx and turn itself to a higher oxidation state with more exposed functional groups and defects. This one-stone-two-birds electrochemical strategy empowered CuOx/GDYO nanozyme with superior peroxidase-mimicking activity and robust anchoring stability on ITO glass, thus enabled further exploration of the portable device with availability for point-of-use applications. Based on the organophosphorus pesticides (OPs) blocked acetylcholinesterase (AChE) activity, the competitive redox reaction was regulated to initiate the chromogenic reaction of 3,3',5,5'-tetramethylbenzidine (TMB) catalyzed by CuOx/GDYO peroxidase-like nanozyme, which laid out a foundation for the detection of OPs (with chlorpyrifos as an example). With a detection of limit low to 0.57 nM, the OPs residues during agricultural production can be directly monitored by the portable device we developed.

Unusual norcucurbitacin glycosides from the roots of Siraitia grosvenorii.

Siraitia grosvenorii Swingle is one of the first approved medicine food homology species in China, and it has been used as a natural sweetener in the food industry and as a traditional medicine to relieve cough and reduce phlegm. However, many S. grosvenorii roots are discarded yearly, which results in a great waste of resources. Twelve undescribed norcucurbitacin-type triterpenoid glycosides, siraitiaosides A-L (1-12), and six known analogs (13-18) were isolated from the roots of S. grosvenorii. The structures of isolated norcucurbitacin glycosides were elucidated by comprehensive data analyses, including HRESIMS, UV, IR, NMR, ECD calculations, and X-ray crystallography analysis. Siraitiaosides A-E (1-5) featured an unusual 19,29-norcucurbitacin framework while siraitiaosides F-L (6-12) featured a rare 29-norcucurbitacin framework. Notably, compound 4 displayed moderate anti-acetylcholinesterase (AChE) activity with an IC50 of 21.0 µM, meanwhile, compounds 16 and 18 exhibited pronounced cytotoxic activities against MCF-7, CNE-1, and HeLa cancer cell lines with IC50 values of 2.1-15.2 µM. In silico studies showed that compound 4 bound closely to AChE with a binding energy of -5.04 kcal/mol, and compound 18 could tightly bind to PI3K, AKT1, ERK2, and MMP9 proteins that related to autophagy, apoptosis, migration/invasion, and growth/proliferation. In summary, the roots of Siraitia grosvenorii have potential medicinal values due to the multiple bioactive components.

Advances in Cholinesterase Inhibitor Research-An Overview of Preclinical Studies of Selected Organoruthenium(II) Complexes.

Cholinesterase (ChE) inhibitors are crucial therapeutic agents for the symptomatic treatment of certain chronic neurodegenerative diseases linked to functional disorders of the cholinergic system. Significant research efforts have been made to develop novel derivatives of classical ChE inhibitors and ChE inhibitors with novel scaffolds. Over the past decade, ruthenium complexes have emerged as promising novel therapeutic alternatives for the treatment of neurodegenerative diseases. Our research group has investigated a number of newly synthesized organoruthenium(II) complexes for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Three complexes (C1a, C1-C, and C1) inhibit ChE in a pharmacologically relevant range. C1a reversibly inhibits AChE and BChE without undesirable peripheral effects, making it a promising candidate for the treatment of Alzheimer's disease. C1-Cl complex reversibly and competitively inhibits ChEs, particularly AChE. It inhibits nerve-evoked skeletal muscle twitch and tetanic contraction in a concentration-dependent manner with no effect on directly elicited twitch and tetanic contraction and is promising for further preclinical studies as a competitive neuromuscular blocking agent. C1 is a selective, competitive, and reversible inhibitor of BChE that inhibits horse serum BChE (hsBChE) without significant effect on the peripheral neuromuscular system and is a highly species-specific inhibitor of hsBChE that could serve as a species-specific drug target. This research contributes to the expanding knowledge of ChE inhibitors based on ruthenium complexes and highlights their potential as promising therapeutic candidates for chronic neurodegenerative diseases.

Evaluation of the Ameliorative Potential of 3,5-bis(2-hydroxyethyl)-1,3,5-thiadiazinane-2-thione against Scopolamine-Induced Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, marked by cognitive impairment. Currently, the available treatment provides only symptomatic relief and there is a great need to design and formulate new drugs to stabilize AD. In the search for a new anti-Alzheimer's drug, 3,5-bis(2-hydroxyethyl)-1,3,5-thiadiazinane-2-thione (THTT), a tetrahydro-2H-1,3,5-thiadiazine-2-thione derivative, was investigated against a scopolamine-induced Alzheimer's model. The selected test compound was administered intraperitoneally in three doses (15 mg/kg, 30 mg/kg, and 45 mg/kg). The test compound exhibited an IC50 value of 69.41 µg/mL, indicating its ability to inhibit the acetylcholinesterase enzyme. An antioxidant DPPH assay revealed that the IC50 value of the test compound was 97.75 µg/mL, which shows that the test compound possesses antioxidant activity. The results of behavior tests including the Y-maze and elevated plus maze (EPM) show that the test compound improved short-term memory and spatial memory, respectively. Furthermore, in the Morris water maze (MWM) and light/dark model, the test compound shows improvements in learning and memory. Moreover, the results of histological studies show that the test compound can protect the brain against the harmful effects of scopolamine. Overall, the findings of our investigation suggest that our chosen test compound has disease-modifying and neuroprotective activities against the scopolamine-induced Alzheimer's model. The test compound may be beneficial, subject to further elaborate investigation for anti-amyloid disease-modifying properties in AD.

Neurotoxicity and intestinal microbiota dysbiosis induced by per- and polyfluoroalkyl substances in crucian carp (Carassius auratus).

Per- and polyfluoroalkyl substances (PFAS) have been called "forever chemicals" due to their inherent chemical stability. Their potential toxic effects on aquatic animals and health risk assessments have not been fully elucidated. In this study, we investigated the toxic effects of PFASs at environmentally relevant concentrations (200 ng/L) on crucian carp (Carassius auratus). The results showed that PFAS reduced the comfort behaviour of crucian carp and was associated with reduced levels of acetylcholinesterase and dopamine in the brain. PFAS exposure also decreased the activities of total superoxide dismutase, catalase and glutathione peroxidase, while increasing the levels of malondialdehyde. PFAS caused over-expression of the pro-inflammatory cytokines TNF-α, IFN-γ and stress-related genes Caspase-3, HSP-70 in the fish brain. Pathological staining showed that PFAS caused multifocal demyelination and perineural vacuolization in brain, intestinal tissue also showed reduced villus length and focal damage. PFASs altered the composition of the gut microbiota of crucian carp, significantly increasing the abundance of potentially pathogenic bacteria and the potential pathogenicity of the microbiota. It is suggested that PFASs may cause varying degrees of tissue damage by destabilising the gut microbiota. These results provide insights for assessing the toxicity of PFAS contaminants at aquatic environmental concentrations.