Acetylcholinesterase Enzyme Research Articles

Antioxidant activity and in silico anticholinesterase studies of major phenolic constituents of three commercial olive oils: A comparative study

This study aimed to compare the physicochemical properties, in vitro antioxidant, and total phenolic content of three commercially available olive oils in Oman and to investigate the potential neuroprotective effects of phenolic compounds through molecular docking studies. Three samples of extra virgin olive oil viz., RS (Spain), Tunisian olive oil and locally produced olive oil (Aljabal Al'akhdar) were purchased from the local market. The physicochemical parameters, total phenolic (TP) content, in vitro antioxidant activity and total antioxidant capacity were studied for comparison. In silico molecular docking studies of five phenolic compounds viz., tyrosol, hydroxy tyrosol, luteolin, oleuropein aglycone and oleocanthal on Acetylcholinesterase (AChE) enzyme was carried out to explore their possible role in Alzheimer’s disease (AD). All three samples of olive oil were found to be acidic with slight variation. The refractive indices were noted to be similar to the values reported in the literature. The oils showed excellent antioxidant activity (92.11–95.34%) and were observed to have a linear correlation with their TP content. Tunisian olive oil was observed to exhibit the best antioxidant activity, highest total antioxidant capacity and contained the maximum amount of phenolic compounds. In silico molecular docking studies showed interaction with the key residues of the active site on the target AChE protein. The inhibition of the cholinesterase activity as an additional inhibitory property makes good use of the antioxidant activity rationalizing the significance of bioactive polyphenolic compounds luteolin and oleuropein aglycone present in the olive oil, thus paving the development of natural therapeutics against AD.

Identification of cholinesterases inhibitors from flavonoids derivatives for possible treatment of Alzheimer's disease: In silico and in vitro approaches

Nowadays, one of the methods to prevent the progress of Alzheimer's disease (AD) is to prescribe compounds that inhibit the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Researchers are actively pursuing compounds, particularly of natural origin, that exhibit enhanced efficacy and reduced side effects. The inhibition of AChE and BChE using natural flavonoids represents a promising avenue for regulating AD. This study aims to identify alternative flavonoids capable of modulating AD by down-regulating AChE and BChE activity through a molecular docking approach. Molecular docking analysis identified Ginkgetin and Kolaflavanone as potent inhibitors of AChE and BChE, respectively, among the selected flavonoids. Asn87 and Ala127 involved in the interactions of AChE-Ginkgetin complex through conventional hydrogen bonds. While in the BChE-Kolaflavanone complex, Asn83, Ser79, Gln 47, and Ser287 are involved. In vitro analysis further corroborated the inhibitory potential, with Ginkgetin exhibiting an IC50 of 3.2 mM against AChE, and Kolaflavanone displaying an IC50 of 3.6 mM against BChE. These findings underscore the potential of Ginkgetin and Kolaflavanone as candidate inhibitors for the treatment of AD through the inhibition of AChE and BChE enzymes. Nevertheless, additional in vitro and in vivo studies are imperative to validate the efficacy of these compounds.

Evaluation of Bauhinia ungulata Essential Oil as a New Acetylcholinesterase Inhibitor from an in silico and in vitro Perspective in the Northern Amazon of Brazil.

The Bauhinia ungulata, also known by its common name "pata de vaca", is one of the species used in Brazil for medicinal purposes, and is commonly used for the treatment of diabetes. In this study, the authors studied the interaction between the chemical constituents which are present in the essential oil of Bauhinia ungulata (EOBU), collected in Boa Vista-RR, Legal Amazon, and their effects on the enzyme acetylcholinesterase (AChE) in the essential oil. The analysis that we perform includes proton magnetic resonance ( 1H NMR), enzymatic inhibition, molecular docking, in silico toxicity prediction, enrichment analysis, and target prediction for biological interactions. According to the tests performed on the essential oil, it obtained 100% inhibition of the enzyme AChE. During 1H NMR experiments, it was found that α- Bisabolol, one of the main components, had a significant alteration in its chemical shift. A molecular docking analysis confirmed that this compound binds to the AChE enzyme, which confirms the 1H NMR analysis. The results of this work showed that the major component of EOBU acted as a possible inhibitor of AChE enzyme in vitro and in silico assays. These results show that EOBU could be potentially applied in Alzheimer's disease treatment.

Ora-pro-nobis (Pereskia aculeata) supplementation promotes increased longevity associated with improved antioxidant status in Drosophila melanogaster.

This study evaluated the effects of ora-pro-nobis (Pereskia aculeate) flour supplementation on the in vivo basal antioxidant system of Drosophila melanogaster, and its action on the neural modulation observed by the enzyme acetylcholinesterase (AChE). The flies will receive a standard diet with flour incorporated at 5, 10 and 20% for 7 days. There was no change in food consumption, body weight, protein thiol levels and negative geotaxis behavior. The flies showed a reduction in the basal production of reactive species at concentrations of 10 and 20%, while there was a reduction in lipid peroxidation and catalase activity at all concentrations, accompanied by an increase in the levels of non-protein thiols. Superoxide dismutase activity was reduced in the 5 and 20% groups, while the reduction of superoxide anion in the 10% group may have contributed to the increase in longevity also in the 10% group. Longevity increased in groups 5 and 10%. The open field test may be related to the reduction in AChE activity in the 5, 10 and 20% groups. In general, the data show that supplementation with ora-pro-nobis flour at the concentrations tested did not cause toxicity and modulated the cholinergic system, demonstrating a therapeutic potential.

A theoretical screening of phytochemical constituents from Millettia brandisiana as inhibitors against acetylcholinesterase.

Alzheimer's disease is one of the causes associated with the early stages of dementia. Nowadays, the main treatment available is to inhibit the actions of the acetylcholinesterase (AChE) enzyme, which has been identified as responsible for the disease. In this study, computational methods were used to examine the structure and therapeutic ability of chemical compounds extracted from Millettia brandisiana natural products against AChE. This plant is commonly known as a traditional medicine in Vietnam and Thailand for the treatment of several diseases. Furthermore, machine learning helped us narrow down the choice of 85 substances for further studies by molecular docking and molecular dynamics simulations to gain deeper insights into the interactions between inhibitors and disease proteins. Of the five top-choice substances, γ-dimethylallyloxy-5,7,2,5-tetramethoxyisoflavone emerges as a promising substance due to its large free binding energy to AChE and the high thermodynamic stability of the resulting complex.

Evaluation of the Ecotoxicology of Seaweed-Based Biopesticide Used in Combat of the Polyphagous Pest Using Eudrilus eugeniae Kinb.

Fundamental techniques for determining the toxicity of pesticides to soil organisms are ecotoxicological laboratory assays. Due to their expanding potential and rise in use as a sustainable agricultural strategy toward the biological pest management, we quantified the effects of the compounds from the active fraction of the green seaweed Chaetomorpha antennina (Chlorophyceae), which is found in abundance in coastal areas of India that was used for the control of the polyphagous lepidopteran Spodoptera litura. Since the seaweed compounds were able to affect the morphology, physiology, and biochemical aspects of the pest, it is essential to perform an ecotoxicological assessment against the bioindicator organism Eudrilus eugeniae Kinb. This comprehensive assessment includes a morphological assay as well as the possible effects of the compounds on the earthworm's physiological and biochemical aspects such as acetylcholinesterase, catalase, and superoxide dismutase enzyme activities. The benignity of the compounds should also be confirmed by analyzing the gut histology of the earthworms treated with the compounds.

Biological andcomputational evaluation of novel benzofuranyl derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors.

Aim: A highly efficient one-step method has been developed for the synthesis of benzofuranyl derivatives from 2-benzoylcyclohexane-1-carboxylic acid derivatives using chlorosulfonyl isocyanate. This novel method provides a practical, cost-effective and efficient approach. Materials & methods: The inhibitory effects of benzofuranyl derivatives on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes were investigated. Ki values were determined to range from 0.009 to 0.61μM for AChE and 0.28 to 1.60μM for BChE. Molecular docking analysis provided insights into the interaction modes and binding patterns of these compounds with AChE and BChE. Conclusion: Kinetic findings of our study suggest that some of our compounds exhibited more effective low micromolar inhibition compared with the reference, and these derivatives could be usedto design more powerful agents.

Protective effects of Embelin in Benzo[α]pyrene induced cognitive and memory impairment in experimental model of mice

Alzheimer's disease (AD) is a neurodegenerative disease that affects the neurons in the hippocampus, resulting in cognitive and memory impairment. The most prominent clinical characteristics of AD are the production of amyloid-beta (Aβ) plaques, neurofibrillary tangles, and neuroinflammation in neurons. It has been proven that embelin (Emb) possesses antioxidant, anti-inflammatory, and neuroprotective properties. Therefore, we assessed the therapeutic potential of Emb in Benzo [α]pyrene (BaP)-induced cognitive impairment in experimental mice. BaP (5 mg/kg, i. p) was given to mice daily for 28 days, and Emb (2.5, 5, and 10 mg/kg, i. p) was given from 14 to 28 days of a protocol. In addition, locomotor activity was evaluated using open-field and spatial working, and non-spatial memory was evaluated using novel object recognition tasks (NORT), Morris water maze (MWM), and Y- maze. At the end of the study, the animal tissue homogenate was used to check biochemicals, neuroinflammation, and neurotransmitter changes. BaP-treated mice showed a significant decline in locomotor activity, learning and memory deficits and augmented oxidative stress (lipid peroxidation, nitrite, and GSH). Further, BaP promoted the release of inflammatory tissue markers, decreased acetylcholine, dopamine, GABA, serotonin, and norepinephrine, and increased glutamate concentration. However, treatment with Emb at dose-dependently prevented biochemical changes, improved antioxidant levels, reduced neuroinflammation, restored neurotransmitter concentration, and inhibited the NF-κB pathway. The current study's finding suggested that Emb improved cognitive functions through antioxidant, anti-inflammatory, and neuroprotective mechanisms and inhibition of acetylcholinesterase (AChE) enzyme activities and Aβ-42 accumulation.

Optimization of the Extraction Process of Bioactive Compounds from Zingiber officinale Roscoe, Evaluation of Acetylcholinesterase Enzyme Inhibition and Cytotoxic Activity of the Free and Encapsulated Extract

The present study optimized the extraction process of bioactive compounds present in ginger (Zingiber officinale) dried at 80 °C, using ethanol:water 70:30 (v/v) as solvent. The extracts were evaluated for antioxidant activity by the 2,2’-azino-bis(3-ethylbenzothiazoline6-sulfonic acid (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical reduction methods and by the chelating activity of FeII ions. It was found that the extraction condition with a temperature of 60 °C and an extraction time of 12 h showed better responses to the tests. Then, the characterization of the compounds was carried out by mass spectrometry and thermal analysis (thermogravimetric (TG), differential thermal analysis (DTA), and differential scanning calorimetry (DSC)), identifying that the main compounds of ginger were gingerols and shogaols, being confirmed by the intensities and characteristics of the thermal graphs. The inhibition of the enzyme acetylcholinesterase (AChE) was evaluated using the Ellman test, which did not show an inhibitory action. Regarding cytotoxic activity, the free extract and encapsulated in liposomes were tested, showing antiproliferative effect at different concentrations for human kidney tumor cells (786-0), liver cells (HUH7.5), and Macaca mullata normal kidney cells (LLC-MK2). Given the results obtained, ginger presents itself as a renewable source of bioactive compounds and can be indicated for applications in the pharmaceutical industry

Repurposing of USFDA-approved drugs to identify leads for inhibition of acetylcholinesterase enzyme: a plausible utility as an anti-Alzheimer agent.

In the quest to identify new anti-Alzheimer agents, we employed drug repositioning or drug repositioning techniques on approved USFDA small molecules. Herein, we report the structure-based virtual screening (SBVS) of 1880 USFDA-approved drugs. The in silico-based identification was followed by calculating Prime MMGB-SA binding energy and molecular dynamics simulation studies. The cumulative analysis led to identifying domperidone as an identified hit. Domperidone was further corroborated in vitro using anticholinesterase-based assessment, keeping donepezil as a positive control. The analysis revealed that the identified lead (domperidone) could induce an inhibitory effect on AChE in a dose-dependent manner with an IC50 of 3.67 μM as compared to donepezil, which exhibited an IC50 of 1.37 μM. However, as domperidone is known to have poor BBB permeability, we rationally proposed new analogues utilizing the principles of bioisosterism. The bioisostere-clubbed analogues were found to have better BBB permeability, affinity, and stability within the catalytic domain of AChE via molecular docking and dynamics studies. The proposed bioisosteres may be synthesized in the future. They may plausibly be explored for their implication in the developmental progress of new anti-Alzheimer agent achieved via repurposing techniques in future.

Pharmacological inhibition of acetylcholinesterase improves the locomotion defective phenotype of a SCA3 C. elegans model.

Inhibition of acetylcholinesterase (AChE) is a common used treatment option for Alzheimer's disease. However, there has been limited research on the potential use of AChE inhibitors for the treatment of Machado-Joseph disease (MJD)/Spinocerebellar Ataxia 3 (SCA3), in spite of the positive results using AChE inhibitors in patients with other inherited ataxias. MJD/SCA3, the most common form of dominant Spinocerebellar Ataxia worldwide, is caused by an expansion of the polyglutamine tract within the ataxin-3 protein, and is characterized by motor impairments. Our study shows that administration of the AChE inhibitor neostigmine is beneficial in treating the locomotion defective phenotype of a SCA3/MJD model of C. elegans and highlights the potential contribution of AChE enzymes to mutant ataxin-3-mediated toxicity.

Ruta chalepensis L. (Rutaceae) uçucu yağının beş coleopteran depo ürün zararlısına karşı fumigant ve kontak toksisitesi ile kolinesterazlar üzerine etkileri

The essential oil composition of aerial parts of Ruta chalepensis L. was analyzed with GC-MS. Seventy-nine compounds were detected representing 85.93 ± 1.08% (n = 3) of the essential oil. The major components of the essential oil were 2-undecanone 21.52 ± 0.21%, 2-nonanone 18.31 ± 0.27%, and 2-nonyl acetate 13.22%. The highest insecticidal contact toxicity of the oil was observed against Rhyzopertha dominica F. with 0.018 μl/insect LD50 and 0.039 μl/insect LD90 after 24h. Essential oil also produced considerably low 0.50 and 0.59 μl/insect LD50 values after 24h against Sitophilus oryzae L. and Sitophilus granarius L. respectively. The lowest contact toxicity was observed against Tribolium castaneum Herbst. and Tribolium confusum Jacquelin du Val. 0.138 and 0.078 μl/insect LD50 after 24h respectively. The highest fumigant toxicity was observed against S. granarius for the application concentration of 10 μl, 10% oil/acetone (v:v) in a 10 ml chamber which afforded 100.00 ± 0.00% mortality after 48h. The essential oil also produced high fumigant toxicity against S. oryzae, T. castaneum and R. dominica which were 95.47 ± 3.41%, 93.30 ± 5.54%, and 85.47 ± 3.41% mortality at 20 μl application concentration of the oil solution after 48h. The R. chalepensis essential oil produced low acetylcholinesterase enzyme 5.29 ± 1.20% (n=3) inhibition and mediocre butyrylcholinesterase enzyme inhibition 42.6 ± 0.71% (n=3). According to the insecticidal activity assays performed, the essential oil R. chalepensis seems to be a promising source that could yield natural compounds that could be employed in stored product pest management.

Toxicity of two pesticides in binary mixture on survival and enzymatic response of Cerastoderma edule – The warming influence

Pesticide application increased by about 1 million tonnes in the last 3 decades. Pesticides' overuse, coupled with the need for several pesticides to control different pests in the same crop, and its application many times per year, results in dangerous chemical cocktails that enter in aquatic systems, with impacts to the ecosystems and its communities. Climatic changes are currently another great concern, is predicted by the end of the 21st century, the earth's surface temperature will increase by about 4 °C. Bivalve species are reported as essential to the ecosystems' balance. However, they are also indicated as the organisms that will suffer the most serious effects of the temperature increase. So, this work intends to: a) verify the harm of the sub-lethal concentrations of two worldwide used pesticides, oxyfluorfen and copper (Cu), when combined, to Cerastoderma edule at 15 °C and 20 °C; b) assess the changes in the antioxidant defence system, the activity of the neurological enzyme acetylcholinesterase and the nutritive value of C. edule, after exposure to sub-lethal concentrations of oxyfluorfen and Cu, single and in the mixture, at 15 °C and 20 °C; c) observe the interaction between Cu and oxyfluorfen, considering the different biomarkers. Bivalves were exposed to oxyfluorfen and Cu, single and combined, for 96 h, at 15 °C and 20 °C. Results showed lethal effects to the organisms exposed at 20 °C when exposed to the highest binary mixture concentrations. Biochemical effects were observed on the organisms exposed to 15 °C, despite not observing any lethal effects. Briefly, there was a reported increase in oxidative stress and a decrease in protein content, regardless of the increase in the activity of antioxidant enzymes. These results suggest the potentially dangerous effects of the chemicals' mixture combined with the temperature, on this species and its consumers, impacting the trophic chain, and consequently, the community structure and function.

Neuroprotective Potential of Total Extract of Ulva Lactuca: An In vitro study

Alzheimer's disease (AD) is mainly general form of dementia that is linked to the increase of extracellular amyloid beta (Aβ) plaques. Oxidative stress and neurotoxicity events that are linked to the aetiology of AD have been postulated to be influenced by genetic, environmental, and dietary variables. Using the use of in vitro models, we attempted to determine whether or not Ulva lactuca had antioxidant and neuroprotective properties. SH-SY5Y The research employed pre-existing Neuroblastoma cell lines. Caspase 3 expression was also determined to know the level of protection of neuronal cells. Our results showed that the total extract of UL effectively reduced cell death and caspase 3 levels were also decreased in the cells treated with TEUL. The extract also has effective antioxidant properties proved. Further, it was also proved that the extract also has acetylcholinesterase enzyme inhibitory activity which is essential in treating AD.

Polyamines in Edible and Medicinal Fungi from Serbia: A Novel Perspective on Neuroprotective Properties.

The therapeutic effectiveness of current neurodegenerative disease treatments is still under debate because of problems with bioavailability and a range of side effects. Fungi, which are increasingly recognized as sources of natural antioxidants and acetylcholinesterase (AChE) enzyme inhibitors, may thus serve as potent neuroprotective agents. Previous studies have associated the anti-AChE and antioxidant activities of fungi mostly with polysaccharides and phenolic compounds, while other secondary metabolites such as polyamines (PAs) have been neglected. This study aimed to investigate eight edible and medicinal fungi from Serbia, marking the initial investigation into the neuroprotective capabilities of Postia caesia, Clitocybe odora, Clitopilus prunulus, and Morchella elata. Neuroprotective activity was examined using the Ellman assay, while the antioxidant capacity was tested by conducting DPPH, NO, ABTS, and FRAP tests. PA levels were determined by high-performance liquid chromatography (HPLC) coupled with fluorescent detection. Ganoderma applanatum and Lepista nuda exhibited the most robust anti-AChE (98.05 ± 0.83% and 99.94 ± 3.10%, respectively) and antioxidant activities, attributed to the synergistic effects of the total protein, total phenolic, and PA levels. Furthermore, P. caesia displayed significant AChE inhibition (88.21 ± 4.76%), primarily linked to the elevated spermidine (SPD) (62.98 ± 3.19 mg/kg d.w.) and putrescine (PUT) levels (55.87 ± 3.16 mg/kg d.w.). Our results highlight the need for thorough research to comprehend the intricate relationships between distinct fungus species and AChE inhibition. However, it is important to recognize that more research is required to identify the precise substances causing the reported inhibitory effects.

Larvicidal Activity of Ethanol Extract of Cinnamomum sintoc Blume Bark against Aedes aegypti: Role of the Extract as an Acetylcholinesterase Enzyme Inhibitor

The display ponders evaluated the larvicidal exercises of ethanol bark extricates of Cinnamomum sintoc BI against the third instar hatchlings of Aedes aegypti. For superior understanding, this show ponders moreover examined the instrument of plant extricates against the hatchlings through in silico examination. Larvicidal exercises of plant extricate were considered within the extent of 0.01 to 0.1% and two control bunch with aquades and temephos within the research facility bioassays against early third instar hatchlings of A. aegypti. The mortality was checked and subjected to probit investigation to decide the deadly concentrations (LC50 and LC90) to murder 50 and 90% of the treated hatchlings of the particular species. Also, to examine the instrument, four dynamic compounds within the plant extricate with the most noteworthy substance analyzed in silico with the acetylcholinesterase protein in A. aegypti. The appears about appear expanding the concentration will increment the passing of the hatchlings and the viability of the extricate is found to be superior to temephos. The comes about of in silico investigation appeared that the two dynamic compounds in plant extricates, specifically α-copaene and γ-muurolene have a component of activity comparable to temephos. Both of these compounds work as inhibitors of acetylcholinesterase chemicals. Our information recommends that the bark ethanol extricate of C. sintoc BI have the potential to be utilized as a larvicidal operator for the control of the A. aegypti.

In-vitro and in-silico cholinesterase inhibitory activity of bioactive molecules isolated from the leaves of Andrographis nallamalayana J.L. Ellis and roots of Andrographis beddomei C.B. Clarke

Cholinesterase inhibitors remain the best therapeutic strategies to treat Alzheimer's disease. In search for the potent and long-acting cholinesterase (AChE/BChE) inhibitors, we studied the inhibitory activities of three species of Andrographis genus viz, Andrographis paniculata (Burm.f.) Nees Andrographis nallamalayana J.L. Ellis , and Andrographis beddomei C.B. Clarke. It was demonstrated that the methanolic extract of these plants was able to inhibit acetylcholinesterase and butyrylcholinesterase. Furthermore, the phytochemical investigation led to the isolation of 11 known compounds. Echioidinin (1), skullcapflavone I (2), 5,2′,6′-trihydroxy-7-methoxyflavone (3), 5.,2′,6′-trihydroxy-7-methoxyflavone 2′-O-β-D-glucopyranoside (4), and chrysin 7-glucuronide (5) were isolated from leaves of A. nallamalayana whereas 7-O-methylwogonin (9), wogonin (10), viscidulin II (11), andrographidine C (12), andrographidine G (13), 5,8,2′-trihydroxy-7-methoxyflavone-5-O-ß-D glucopyranoside (14) were isolated from roots of A. beddomei. Their structures were elucidated by 1H, 13CNMR spectra, mass spectrometry, and X-ray single crystal diffraction experiments. The SC-XRD and Hirshfeld Surface analysis of eight flavonoids (Compound 1, 2, 4, 6, 9, 11, 12, 13 and positive control drug galantamine hydrobromide is reported for the first time. Compound 6, 4, 10, 9 were potent inhibitors of acetylcholinesterase enzyme with IC50 values of 1.86 ± 0.139 μM, 3.37 ± 0.086 μM, 6.38 ± 0.098 μM, 9.11 ± 0.116 μM respectively. Compound 6 was more potent than the positive control, galantamine (IC50 = 4.68 ± 0.032 μM). All these compounds showed moderate to weak inhibitory activity against BChE. In addition, molecular docking studies were performed to explore the binding mode of the compounds, and the results were in good agreement with the experimental results. These results clearly indicate the potential of these compounds as powerful lead molecules for further investigations.

Prospects for the use of layer-by-layer technology for the development of an enzyme biosensor used for milk quality control

This article presents the results of scientific research on the development of a biosensor system for the determination of salts of heavy metals (cadmium and lead) in milk. When developing a biosensor system, much attention is paid to the selection of biological material and the method of their stabilization using physical and chemical forces, namely, immobilization. In this regard, studies were carried out on the selection of the enzyme and the method of its immobilization in the development of a biosensor for the detection of salts of heavy metals in milk. The development of a biosensor for the determination of toxic elements in food products is of scientific and practical importance. In world practice, special attention is paid to the contamination of raw materials and food products with toxic chemicals, mainly of anthropogenic origin, which are persistent organic pollutants. Therefore, quality control of raw materials, food products is important for consumers, and, accordingly, for the food industry. Experimental studies are based on the methods of Filippova A. M., Vorobieva O. V. to determine the specific activity of the enzyme acetylcholinesterase. Determination of the activity of the catalase enzyme was carried out in accordance with the gasometric method according to the method of Warburg. As a result of experimental studies, the catalase enzyme as a biological material was chosen as a sensitive element. As a carrier for the immobilization of enzymes, a 5-bilayer combination of "chitosan-sodium alginate" was selected. The layer-by-layer technology was used to immobilize the enzyme on the substrate surface when creating an enzyme biosensor. The results of the research are recommended to be applied in the study of food safety issues and in the assessment of safety indicators of raw materials and food products by the express method.

Unveiling the connections: Chlorpyrifos and its association with breast cancer

Chlorpyrifos, a broad-spectrum insecticide categorized within the organophosphate family, is recognized for its potent inhibition of the enzyme Acetylcholinesterase (AChE), resulting in the manifestation of cholinergic syndrome in humans. Beyond its well-established toxicity in the central nervous system, recent studies have explored additional pathways through which this pesticide may adversely impact human health. Breast cancer, characterized by the uncontrolled proliferation of epithelial cells in the mammary gland, stands as the most diagnosed cancer in women and is a leading global cause of female cancer-related deaths. Chlorpyrifos, extensively employed worldwide for pest control in agriculture, domestic settings, and industries, has notably faced recent bans in the European Union, marking a significant regulatory shift. This bibliographical review aims to unravel the intricate mechanisms by which chlorpyrifos may contribute to the development of breast cancer. Collating findings from human studies, as well as in vitro and in vivo research spanning the past decade, the review sheds light on chlorpyrifos as a potent endocrine disruptor. It influences female sex hormones, exhibits estrogenic effects on breast cancer cells, and induces alterations in breast tissue. Additionally, chlorpyrifos acts as an agonist of Estrogen Receptor α(ERα) and Aryl hydrocarbon Receptor (AhR), contributing to cell proliferation, oxidative stress, and engaging epigenetic and angiogenic mechanisms. This comprehensive review underscores the compelling association between chlorpyrifos exposure and mammary cancer. It emphasizes the urgent need for further research on pesticide usage to mitigate potential adverse health consequences.

Profiling Novel Quinuclidine-Based Derivatives as Potential Anticholinesterase Drugs: Enzyme Inhibition and Effects on Cell Viability.

The cholinergic system, relying on the neurotransmitter acetylcholine (ACh), plays a significant role in muscle contraction, cognition, and autonomic nervous system regulation. The enzymes acetylcholinesterase, AChE, and butyrylcholinesterase, BChE, responsible for hydrolyzing ACh, can fine-tune the cholinergic system's activity and are, therefore, excellent pharmacological targets to address a range of medical conditions. We designed, synthesized, and profiled 14 N-alkyl quaternary quinuclidines as inhibitors of human AChE and BChE and analyzed their impact on cell viability to assess their safety in the context of application as potential therapeutics. Our results showed that all of the 14 tested quinuclidines inhibited both AChE and BChE in the micromolar range (Ki = 0.26 - 156.2 μM). The highest inhibition potency was observed for two bisquaternary derivatives, 7 (1,1'-(decano)bis(3-hydroxyquinuclidinium bromide)) and 14 (1,1'-(decano)bis(3-hydroxyiminoquinuclidinium bromide)). The cytotoxic effect within 7-200 μM was observed only for monoquaternary quinuclidine derivatives, especially those with the C12-C16 alkyl chain. Further analysis revealed a time-independent mechanism of action, significant LDH release, and a decrease in the cells' mitochondrial membrane potential. Taking all results into consideration, we can confirm that a quinuclidine core presents a good scaffold for cholinesterase binding and that two bisquaternary quinuclidine derivatives could be considered as candidates worth further investigations as drugs acting in the cholinergic system. On the other hand, specific cell-related effects probably triggered by the free long alkyl chain in monoquaternary quinuclidine derivatives should not be neglected in future N-alkyl quaternary quinuclidine derivative structure refinements. Such an effect and their potential to interact with other specific targets, as indicated by a pharmacophore model, open up a new perspective for future investigations of these compounds' scaffold in the treatment of specific conditions and diseases other than cholinergic system-linked disorders.