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In a previous in vitro study, dihydropyrimidinone-derived selenoesteres demonstrated antioxidant properties, metal chelators and inhibitory acetylcholinesterase (AChE) activity, making these compounds promising candidates for Alzheimer’s Disease (AD) treatment. However, these effects have yet to be demonstrated in an in vivo animal model; therefore, this study aimed to evaluate the safety and efficacy of eight selenoester compounds in a Caenorhabditis elegans model using transgenic strains for amyloid-beta peptide (Aβ) aggregation. The L1 stage worms were acutely exposed (30 min) to the compounds at concentrations ranging from 5 to 200 μM and after 48 h the maintenance temperature was increased to 25 ° C for Aβ expression and aggregation. After 48 h, several parameters related to phenotypic manifestations of Aβ toxicity and mechanistic elucidation were analyzed. At the concentrations tested no significant toxicity of the compounds was found. The selenoester compound FA90 significantly reduced the rate of paralyzed worms and increased the number of swimming movements compared to the untreated worms. In addition, FA90 and FA130 improved egg-laying induced by levamisole and positively modulated HSP-6 and HSP-4 expression, thereby increasing reticular and mitochondrial protein folding response in C. elegans, which could attenuate Aβ aggregation in early exposure. Therefore, our initial screening using an alternative model demonstrated that FA90, among the eight selenoesters evaluated, was the most promising compound for AD evaluation screening in more complex animals.

Essential oil (EO) was hydrodistilled from Achillea biebersteinii and analyzed using gas chromatography–flame ionization detection (GC–FID) and (GC–MS). Three monoterpenes, α-terpinene, p-cymene, and camphor were isolated as the main terpenes in the EO. Oil-in-water nanoemulsion (particle size 52.7 ± 4.4 nm) was prepared and characterized from EO through a hydrothermal approach. The EO products caused insecticidal effects and altered F1 progeny of the red flour beetle, Tribolium castaneum (Herbst) in a dose and exposure time-dependent manner. The nanoemulsion was superior in bioactivity, followed EO. At 12.5 µl/cm2, nanoemulsion and EO caused 100% mortality of the second larvae after 4 days of exposure with reduction of F1 progeny of 100.0 and 89.2%, respectively. At 50.0 µl/cm2, percentage mortality and reduction in progeny of EO products ranged between (61.4–100%) and (53.0–100%), respectively. Upon fumigation, nanoemulsion at 10 µl/L air caused 100% mortality of the second larvae after 4 days of exposure. At 20 µl/L air and 4 days after treatment, percentage mortality with the remainder botanicals ranging between 64.7 and 100. LC50′s of products after 48 h exposure ranging between 6.7 and 58.1 µg/cm2 in insecticidal bioassay, and between 3.6 and 26.3 µl/L upon fumigation. Botanicals caused a remarkable inhibition of acetylcholinesterase activity (AChE), where nanoemulsion (IC50 = 14.22 mM), EO (IC50 = 35.12 mM) and camphor (IC50 = 23.93 mM) were superior as AChE inhibitors. There is a potential for using of A. biebersteinii EO, its nanoemulsion and monoterpenes as natural grain protectants after the required toxicological investigations.

© 2021 SAABEthanolic extracts prepared from forty-seven macroalgae species collected from the Mediterranean Sea, Aegean Sea, and Sea of Marmara were tested at 200 μg/mL against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and tyrosinase (TYR), crucial for insect vivacity. Only one alga extract, e.g. Dictyota dichotoma var. intricata (C.Agardh) Greville 1830, had a notable inhibition of BChE (72.0 ± 0.07%), whereas the rest of the macroalgae possessed no or low inhibition of AChE (2.20 ± 0.39% - 14.20 ± 2.16%), BChE (0.62 ± 0.07% - 41.20 ± 3.07%), and TYR (< 10%). Several known diterpenes (isoamijiol, 14-deoxyamijiol, amijidictyol, dictyodial, and 4α-acetoxydictyodial) found earlier in this species were proceeded to molecular docking experiments to figure out its interactions with BChE. Eleven of the 47 macroalgal extracts were selected based on sufficient availability for testing in larvicidal and adulticidal activity assays against female Aedes aegypti “Orlando1952” the mosquito vector of yellow fever and dengue. The selected extracts displayed a high adulticidal activity ranging between 80–100% activity at 5 μg/mosquito. In contrast, only the ethanol extract of Ceramium siliquosumvar. elegans showed larvicidal mortality of 93.3 ± 11.5% at 0.5 μg/mL. Our findings show that the macroalgae and their metabolites could be sources of novel insecticidal agents.

Rutin (RUT) is a biologically active flavonoid that is reported to modulate radiation-induced brain dysfunctions. However, RUT's poor water solubility and low brain bioavailability limit its clinical use. To increase its brain bioavailability, RUT was loaded onto nanoplatforms based on chitosan/diacrylated pluronic (CS/DA-PLUR) nanogels synthesized by gamma radiation. The optimized formulation was investigated as a carrier system for RUT. Based on pilot experiments' results, the cranial radiation (CR) dose that induced cognitive dysfunction was selected. In the main experiment, rats were pre-treated orally with either free RUT or RUT-CS/DA-PLUR. Rats' cognitive and motor functions were assessed; 24 h later, rats were sacrificed, and the whole brain was separated for histopathological examination and biochemical estimation of brain content of acetylcholine esterase (AChE), neurotransmitters, oxidative stress markers, and interleukin-1β. CR produced prominent impairment in spatial and non-spatial learning memory, motor coordination, and muscular strength. Moreover, histopathological and biochemical alterations in brain contents of neurotransmitters, oxidative stress, and interleukin-1β were induced by CR. Conversely, RUT-CS/DA-PLUR, but not free RUT, successfully guarded against all the detrimental effects induced by CR. Based on the current findings, loading of RUT enhanced its bioavailability and therapeutic effectiveness by restoring the cognitive functions impaired by CR.

The analgesic, antidiarrheal, and neuro-pharmacological potentials of Medicago denticulata leaves extract were screened in animal models. Potential analgesic response was noted (*P

Hippeastrum elegans is a Brazilian Amaryllidaceae plant producing galantamine (GAL), an anticholinesterase drug for Alzheimer's disease, besides other alkaloids such as pseudolycorine (PSE), narciclasine (NAR) and sanguinine (SAN). Therefore, we used a metabolomic approach to investigate the influence of the harvest time on its chemical composition and acetylcholinesterase activity (AChE). Alkaloid extracts were analyzed by UPLC-ESI-MS and 1H NMR, then assessed for AChE inhibitory activity. These data were combined and analyzed by Partial Least Square (PLS) regression. H. elegans was found to be rich in PSE and NAR, achieving higher contents in 270 and 390 days of cultivation, respectively. However, the highest anti-AChE activities were observed for 450 days-bulbs extracts. PLS indicated pseudolycorine as the discriminant compound for this extract, hence responsible for its higher anti-AChE activity jointly with the known AChE inhibitors GAL and SAN. Thus, the cultivation of H. elegans appears to be a promising way for providing bioactive alkaloids.

Natural product bufotenine (5) which could be isolated from Venenum Bufonis, has been widely used as a tool in central nervous system (CNS) studies. We present here its quaternary ammonium salt (6) which was synthesized with high yields using 5-benzyloxyindole as raw materials, and we firstly discover its analgesic effects in vivo. The analgesic evaluation showed that compounds 5 and 6 had stronger effects on the behavior of formalin induced pain in mice. Moreover, the combination of compound 6 and morphine has a synergistic effect. We intended to explain the molecular mechanism of this effect. Therefore, 36 analgesic-related targets (including 15 G protein-coupled receptors, 6 enzymes, 13 ion channels, and 2 others) were systemically evaluated using reverse docking. The results indicate that bufotenine and its derivatives are closely related to acetyl cholinesterase (AChE) or α4β2 nicotinic acetylcholine receptor (nAChR). This study provides practitioners a new insight of analgesic effects.

Two new unsaturated fatty acid esters (1 and 2) and five new unsaturated fatty acids (4–8), together with two known analogs (3 and 9) were isolated from the aerial parts of Lycopodiastrum casuarinoides. Their structures were unambiguously elucidated by obtaining extensive spectroscopic data and comparing them with data in the literature. The absolute configurations of 1 and 2 were established by a modified Mosher's method. All compounds were evaluated in vitro for their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compound 8 exhibited the most potent inhibitory activity against AChE with an IC50 value of 1.16 ± 0.13 μM.

Highlight • The role of Amaryllidaceae species from Ecuador as source of new drugs. • High amount of lycorine-type alkaloids in Phaedranassa dubia by GC-MS. • In vitro potential of Phaedranassa brevifolia as cholinesterase inhibitor. • Theoretical inhibitory activity of alkaloids against cholinesterase enzymes., Alzheimer's disease is considered the most common cause of dementia and, in an increasingly aging population worldwide, the quest for treatment is a priority. Amaryllidaceae alkaloids are of main interest because of their cholinesterase inhibition potential, which is the main palliative treatment available for this disease. We evaluated the alkaloidal profile and the in vitro inhibitory activity on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) of bulb alkaloid extract of Phaedranassa dubia and Phaedranassa brevifolia collected in Ecuador. Using gas chromatography coupled to mass spectrometry (GC-MS), we identified typical Amaryllidaceae alkaloids in these species, highlighting the presence of lycorine-type alkaloids in P. dubia and haemanthamine/crinine-type in P. brevifolia. The species P. dubia and P. brevifolia showed inhibitory activities against AChE (IC50 values of 25.48 ± 0.39 and 3.45 ± 0.29 μg.mL−1, respectively) and BuChE (IC50 values of 114.96 ± 4.94 and 58.89 ± 0.55 μg.mL−1, respectively). Computational experiments allowed us to understand the interactions of the alkaloids identified in these samples toward the active sites of AChE and BuChE. In silico, some alkaloids detected in these Amaryllidaceae species presented higher estimated binding free energy toward BuChE than galanthamine. This is the first study about the alkaloid profile and biological potential of P. brevifolia species.

Two series of dimethoxyindanone imbedded novel fluorinated spiropyrrolidine heterocyclic hybrids were synthesized employing two different less explored azomethine ylides and were measured for their efficiency as inhibitors for Alzheimer’s disease. Among the spiropyrrolidine heterocyclic hybrids, the indole based fluorinated compound with a methoxy substituent at the meta- position of the aryl ring exhibited the utmost potent AChE and BChE inhibitory activities with an IC50 of 1.97 ± 0.19 µM and 7.08 ± 0.20 µM respectively. The plausible mechanism of inhibition on ChE receptors was unveiled via molecular docking studies.

Organophosphate pesticides as diazinon disrupt the neuroimmune communication, affecting the innate and adaptive immune response of the exposed organisms. Since the target molecule of diazinon is typically the acetylcholinesterase enzyme (AChE), the existence of a non-neuronal cholinergic system in leukocytes makes them susceptible to alterations by diazinon. Therefore, the aim of this work was to evaluate the activity of AChE, acetylcholine (ACh) concentration, and the expression of nicotinic ACh receptors (nAChR) and muscarinic ACh receptors (mAChR) in spleen mononuclear cells (SMNC) of Nile tilapia (O. niloticus) exposed in vitro to diazoxon, a diazinon metabolite. SMNC were exposed in-vitro to 1 nM, 1 μM, and 10 μM diazoxon for 24 h. The enzyme activity of AChE was then evaluated by spectrophotometry, followed by ACh quantification by ultra-performance liquid chromatography. Finally, mAChR and nAChR expression was evaluated by RT-qPCR. The results indicate that AChE levels are significantly inhibited at 1 and 10 μM diazoxon, while the relative expression of (M3, M4, and M5) mAChR and (β2) nAChR is reduced significantly as compared against SMNC not exposed to diazoxon. However, ACh levels show no significant difference with respect to the control group. The data indicate that diazoxon directly alters elements in the cholinergic system of SMNC by AChE inhibition or indirectly through the interaction with AChR, which is likely related to the immunotoxic properties of diazinon and its metabolites.

A series of novel conjugates of 4-amino-2,3-polymethylene quinolines and phenolic antioxidant vanillin was synthesized by the condensation of aminoquinolines with vanillin followed by reduction of imines with sodium borohydride. The conjugates effectively inhibit AChE and BChE with preferable BChE inhibition and displace propidium from the PAS AChE. Compounds with aminoalkyl spacer have preferable esterase profile being more potent cholinesterases inhibitors with lower anti-CES activity and are the most potent antioxidants in ABTS and FRAP tests.

A series of eleven 1-methyl, 5-phenyl substituted thiosemicarbazones (MT1–MT11) with the phenyl ring substitutions were prepared and investigated for their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). [4-(dimethylamino) phenyl]methylidene}-N-methylhydrazine-1-carbothioamide (MT5) inhibited MAO-B potently with an IC50 of 8.77 μM. Potencies for MAO-B increased in the order N(CH3)2 in MT5 > OCH3 in MT3 > Br in MT9. Most of the 11 compounds weakly inhibited AChE by

Acetylcholine (ACh) regulates inflammation via α7 nicotinic acetylcholine receptor (α7 nAChR). Acetylcholinesterase (AChE), an enzyme hydrolyzing ACh, is expressed in immune cells suggesting non-classical function in inflammatory responses. Here, the expression of PRiMA-linked G4 AChE was identified on the surface of macrophages. In lipopolysaccharide-induced inflammatory processes, AChE was upregulated by the binding of NF-κB onto the ACHE promotor. Conversely, the overexpression of G4 AChE inhibited ACh-suppressed cytokine release and cell migration, which was in contrast to that of applied AChE inhibitors. AChEmt, a DNA construct without enzymatic activity, was adopted to identify the protein role of AChE in immune system. Overexpression of G4 AChEmt induced cell migration and inhibited ACh-suppressed cell migration. The co-localization of α7 nAChR and AChE was found in macrophages, suggesting the potential interaction of α7 nAChR and AChE. Besides, immunoprecipitation showed a close association of α7 nAChR and AChE protein in cell membrane. Hence, the novel function of AChE in macrophage by interacting with α7 nAChR was determined. Together with hydrolysis of ACh, AChE plays a direct role in the regulation of inflammatory response. As such, AChE could serve as a novel target to treat age-related diseases by anti-inflammatory responses.

Donepezil (DPZ) is a well-known drug for Alzheimer's disease that inhibits acetylcholinesterase activity (AChE). In the present study, the inhibitory effect of DPZ on non-enzymatic glycated-AChE (GLY-AChE) was studied by different experimental and simulation techniques. The initial investigation revealed that glycation process could reduce AChE activity approximately 60% in the pure enzyme and 38% in the extracted crude AChE from neural cells cultured in the presence of high glucose (HG) concentration. It is suggested that glycation of lysine residues on the structure of AChE could change the conformation of the active site (Trp-86 and His-447) in a way that the orientation of acetylcholine interrupted. The further studies indicated that DPZ is although a strong inhibitor for the native enzyme, it is not able to affect the GLY-AChE activity. The KD values of AChE-DPZ and GLY-AChE-DPZ complexes were estimated to be 1.88 × 10−9 and 2.10 × 10−6, respectively. The stability assessment showed that AChE-DPZ complex is more stable than the glycated complex. Our results indicate that, glycation process could impact on the conformation of the residues involved in the DPZ binding cavity on α-helix domain. Therefore, DPZ is not able to bind its specific cavity to induce its inhibitory effects on GLY-AChE.

Background The plant Cajanus cajan had earlier shown protective effect against hypoxic-ischemic brain damage in rats. Objective Hence, hydroalcoholic extract of C. cajan Linn leaves (HECC) was evaluated for its protective role against memory impairment in sleep-deprived Sprague Dawley rats. Materials and methods Adult rats were divided into five groups each consisting of 5 rats (n = 5). Groups I, II, III, IV and V received 1 mL/kg 1% CMC, 1 mL/kg 1% CMC, 200 mg/kg HECC, 400 mg/kg HECC and 200 mg/kg piracetam respectively as per b.wt. orally everyday for 14 days. Animals of every groups except group-I were subjected to sleep-deprivation from 15th to 19th day for induction of memory impairment. Behavioral activities i.e., elevated plus maze test and locomotor activity were evaluated. Afterwards, brain was isolated from the sacrificed animals for biochemical investigation of acetylcholinesterase (AChE); antioxidant activities i.e., catalase (CAT), superoxide dismutase (SOD), lipid peroxide; and histopathological changes. Results The percent number of entries, number of entries in open arm, AChE activity, lipid peroxide activity of HECC-treated group-III and group-IV were significantly (p, Graphical abstract Image 1

Cypermethrin (CYP) can cause neurotoxicity and plays a role as an inducer for mitochondrial dysfunction. The defensive capability of Moringa oleifera versus neuronal issues prompted by CYP intoxication in adult male albino rats was investigated. Sixty male rats were divided into six experimental groups; G1: controlled group. G2 and G3 were exposed to CYP at different doses of 26.15 mg/Kg/day (representing 1/10 LD50) and 8.72 mg/kg/day (representing1/30 LD50) respectively. G4 treated with moringa extract at 250 mg/kg/day by gavage. G5 and G6 were given moringa extract by gavage (250 mg/kg/day) and CYP as G2 and G3 respectively. G4, G5, and G6 were given moringa extract by gavage (250 mg/kg/day) for 14 days before starting the experiment and during it (28 days). The results indicated that exposure to CYP resulted in a significant reduction in the NADH dehydrogenase, ATPase in mitochondria, and AchE enzyme activity, while the brain caspase-3 activity and DNA fragmentation were increased significantly compared to the controlled group. The co-treatment of moringa extract alleviated the adverse effect of CYP in the treated groups. Moringa declined mitochondrial dysfunction, apoptotic markers, and enhanced AchE activity. In conclusion, moringa extract has an impact to minimize cypermethrin-induced neurotoxicity and apoptosis in rats’ brains.

This study investigated the effect of naringin (NRG) on extracellular metabolism of ATP through the NOS/cGMP/PKG signaling pathway induced by Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) on exposure to Bisphenol-A (BPA) in penis. Fifty-six adult male albino rats were randomly distributed into eight (n = 7) groups. Group I: control animals, Group II was treated with 40 mg/kg L-NAME, Group III was treated with 50 mg/kg BPA, Group IV was treated with 40 mg/kg L-NAME +50 mg/kg BPA. Group V was administered with 40 mg/kg L-NAME +80 mg/kg NRG. Group VI was administered with 50 mg/kg BPA + 80 mg/kg NRG. Group VII was administered with 40 mg/kg L-NAME+50 mg/kg BPA + 80 mg/kg NRG. Lastly, group VIII was treated with 80 mg/kg NRG for 14 days. NRG prevented hypertension and erectile dysfunction by inhibiting the activities of angiotensin-converting enzymes, arginase, and phosphodiesterase-51 (PDE-51) with corresponding down-regulation of inflammatory markers including TNF-α and IL-B. Additionally, hypertensive erectile dysfunction was remarkably prevented by NRG as manifested by the declined activities of AChE, MAO-A and enzymes of ATP hydrolysis (ATPase, ADPase, AMPase and ADA) with resultant increase in NO level. Also, penile expression of antigen presenting cells, CD43 transcript, caspace-9 and tumor suppressor P53 proteins were repressed on treatment with NRG. This study validates the hypothesis that NRG may be a valuable remedy in abrogating penile inflammatory markers, apoptosis and enzymes of ATP-hydrolysis via NOS/cGMP/PKG signaling pathways in hypertensive rat model on exposure to environmental toxicant.

Nineteen compounds were isolated from the stems of Maackia amurensis by activity-guided screening for new human monoamine oxidase-B (hMAO-B) inhibitors. Among the compounds isolated, flavonoids calycosin (5) and 8-O-methylretusin (6) were found to potently and selectively inhibit hMAO-B (IC50 = 0.24 and 0.23 μM, respectively) but not hMAO-A with high selectivity index (SI) values (SI = 293.8 and 81.3, respectively). In addition, 5 and 6 reversibly and competitively inhibited hMAO-B with Ki values of 0.057 and 0.054 μM, respectively. A pterocarpan (−)-medicarpin (18) was also observed to strongly inhibit hMAO-B (IC50 = 0.30 μM). Most of the compounds weakly inhibited AChE, except isolupalbigenin (13) (IC50 = 20.6 μM), which suggested 13 be considered a potential dual function inhibitor of MAO-B and AChE. Molecular docking simulation revealed that the binding affinities of 5 and 6 for hMAO-B (both −9.3 kcal/mol) were higher than those for hMAO-A (−7.4 and −7.2 kcal/mol, respectively). Compound 5 was found to interact by hydrogen bonding with hMAO-B at Cys172 residue (distance: 3.250 A); no hydrogen bonding was predicted between 5 and hMAO-A. These findings suggest that compounds 5 and 6 be considered novel potent, selective, and reversible hMAO-B inhibitors and candidates for the treatment of neurological disorders.

Background: Several studies have proven a correlation of renin-angiotensin system with neurodegenerative diseases such Alzheimer's disease. Alzheimer's is associated with memory and cognitive dysfunction .The present study was conducted to investigate whether perindopril and azilsartan combination have neuroprotective effect against aluminum chloride-induced cognitive impairment in rats than either alone. Methodology: Fifty-four male albino Westar rats were used in this study. Alzheimer's was induced by daily administration of aluminum chloride (AlCl3) (100 mg/kg), groups of rats were categorized into nine groups. Normal control (saline), vehicle received carboxymethyl cellulose (CMC), positive control (Alcl3, 100 mg/kg), perindopril groups (0.5 and 1mg /kg/day) plus (Alcl3, 100 mg/kg), azilsartan groups ( 3.5 and 7 mg/kg/day) plus (Alcl3, 100 mg/kg) and combined groups 1&2 [(perindopril 0.5 mg/kg + azilsartan 3.5 mg/kg ) and (perindopril 1 mg/kg + azilsartan 7 mg/kg)], respectively, plus (Alcl3, 100 mg/kg). The duration of treatment was 60 days. The behavioral test was used to assess cognitive function, followed by estimation levels of beta-amyloid-42 (Aβ-42), acetylcholine esterase (AChE), malondialdehyde (MDA), tumour necrosis factor alpha (TNF-α), nitric oxide (NO) in the hippocampus by ELISA kits and histological examination of different hippocampal regions. Results and discussion: Chronic treatment with perindopril and azilsartan either alone or in combination significantly alleviated cognitive decline evaluated by the Y-maze test with a significant decrease in the hippocampal levels of Aβ-42, AChE, MDA, and TNF-α versus non treated control (positive control). Furthermore, most hippocampus histopathological changes were improved. Conclusion and recommendations: based on behavioral, biochemical, and histopathological findings of the present study, it is concluded that this study showed neuroprotective effect of ACEIs and ARBs either combined or alone.

Purpose The present research was designed to evaluate the toxicity of tellurium and its prevention by selenium on the pituitary gland in male Wistar rats. Methods 30 rats were used weighing 200–250 gm, and randomly divided them into five groups. Each group contained an equal number of animals. Group-1 was nominated as control group. Group-2 received an intraperitoneal dose of selenium 0.3 mg per kg body wt. Group-3 was administered with tellurium 4.15 mg per kg body wt. Group-4 was given low-dose (L) of both selenium 0.15 and tellurium 2.075, Group-5 was given High-dose (H) of both selenium 0.3 and tellurium 4.15 mg/kg body wt. orally once in a day. After 15 days of dosing, the behavioral activities- motor co-ordination rotarod and grip strength test were measured. On 16th-day animals were sacrificed and activity of LPO, GSH, caspase-3, caspase-9, GPx, GR, SOD, catalase, and AChE were performed on the pituitary gland as per standard method reported. Results Se when given together with Te, significantly protects the motor coordination up to 32.5%, and also protects the grip strength up to 75% in group 4 and 5 respectively as compared to group- 3. Se + Te treatment protects the activity of TBARS up to 48.68% and GSH is 58%. As compared to control, it protects caspase-3 up to 118% and caspase-9 up to 83%. The level of AChE was also observed to be modulated by the administration of Se in Group- 4 and 5. Se + Te protected AChE up to 28.6%. Similar findings were observed for the biochemical activities of GPx (140% protection), SOD (458%), GR (159%), and catalase (95%) activities that were protected significantly Se + Te in Group- 4 and 5. Conclusion Selenium dose-dependently protects behavioral activities. It also protects apoptosis, oxidative stress, and AChE activities in the pituitary gland.

Eleven monoterpenes, phenylpropenes and sesquiterpenes were evaluated for their insecticidal and growth inhibitory activities against the second and fourth larval instars of Spodoptera littoralis. Among the tested compounds, 1,8-cineole revealed the highest fumigant toxicity against the 2nd and 4th larval instars with LC50 values of 2.32 and 3.13 mg/L air, respectively. The monoterpenes, p-cymene, α-terpinene, (−)α-pinene and (−)-carvone were highly toxic to both larval stages as their LC50 values ranged between 7.35 and 13.79 mg/L air against 2nd larval instar and between 14.66 and 32.02 mg/L air against 4th larval instar. In topical application assay against the 4th larval instar, (−)-carvone (LD50 = 0.15 mg/larva) and cuminaldehyde (LD50 = 0.27 mg/larva) were the most potent contact toxicants. In residual film assay, trans-cinnamaldehyde, (−)-citronellal and p-cymene showed the highest insecticidal activity against the 2nd larval instar, while α-terpinene and (−)-carvone were most effective compounds against the 4th larval instar. Moreover, the tested compounds caused strong growth reduction of both larval stages with growth inhibition higher than 80% in the 2nd larval instar and higher than 70% in the 4th larval instar. On the other hand, (−)-carvone, cuminaldehyde and (Z,E)-nerolidol showed pronounced inhibitory effects on acetylcholinesterase (AChE) and adenosine triphosphatases (ATPases) activity of S. littoralis larvae. Cuminaldehyde (IC50 = 1.04 mM) and (Z,E)-nerolidol (IC50 = 0.02 mM) caused the highest inhibition of AChE and ATPases, respectively. Taken together, the results indicate that monoterpenes, phenylpropenes and phenylpropenes could be used to develop new botanical insecticides for S. littoralis management.

Aims The aim of the present study was to evaluate the toxicity of magnetic iron oxide nanoparticles (MIONs) which were synthesized using carob leaf extract on various brain areas of Wistar rats. Main methods Carob leaf synthesized-MIONs were characterized using different techniques: Dynamic Light Scattering (DLS), Transmission Electron Microscope (TEM), UV–vis spectrophotometer, Fourier Transform infrared (FTIR), X-Ray Diffraction (XRD) and Atomic Force Microscope (AFM). The toxicity of MIONs in vivo was evaluated by: monitoring rat’s body weight, measuring iron content in different brain areas, evaluating some oxidative stress parameters, estimating acetylcholinesterase (AChE) in addition to histopathological investigations. Key findings The present study demonstrated no body weight changes of MIONs- treated rats. According to the conditions of the present study, the hippocampus and striatum were the most affected areas and demonstrated neuronal degeneration due to MIONs exposure. MIONs treatment of Wistar rats, also affected the iron homeostasis in both striatum and midbrain by decreasing iron content in these areas. The least affected areas were thalamus and cerebellum. The histopathological examination of brain areas demonstrated moderate neuronal degeneration in hippocampus and striatum, mild neuronal degeneration in cortex and slight degeneration in hypothalamus and pons-medulla areas were detected. Significance The results suggested that MIONs have a toxic impact on different brain areas and the effect varies according to the brain area.

Two new cyclic diarylheptanoids, casuaritriol A (1) and casuaritriol B (2), were isolated from the EtOAc extract of litters (including branches and leaves) of Casuarina equisetifolia, along with a new triterpene casuariene (3), and two known compounds diarylheptanoids adanin (4) and ostryopsitriol (5). Their structures were elucidated by spectroscopic analysis (including HRESIMS, 1D NMR and 2D NMR data), and the absolute configuration of 3 was determined by analysis of the ECD data according to the octant rule. Compound 1 exhibited inhibitory activity against α-glycosidase with inhibition rate of 45.1 ± 1.4 % at a concentration of 500 μg/mL. In addition, compound 4 showed weak inhibitory activity against acetyl cholinesterase (AChE) with inhibition rate of 14.9 ± 1.1 % at a concentration of 50 μg/mL.

The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixed-function oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance. P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover. Such P450 proteolytic turnover occurs through a process known as ER-associated degradation (ERAD) that involves ubiquitin-dependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD). Herein, on the basis of available literature reports and our own recent findings of in vitro as well as in vivo experimental studies, we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance. We specifically (i) describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibody pathogenesis in drug-induced acute hypersensitivity reactions and liver injury, or viral hepatitis; (ii) discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates; and (iii) detail the pathophysiological consequences of disrupted P450 ERAD, contributing to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) under certain synergistic cellular conditions., Graphical abstract In this article, we discuss the physiological, therapeutic and pathophysiological relevance of cytochrome P450 protein degradation. Employing mice with genetic ablation of CHIP and gp78/AMFR E3 ubiquitin-ligases that stabilize hepatic CYP2E1, we document why this stabilization not always leads to non-alcoholic fatty liver disease: It requires concomitantly enhanced hepatic lipogenesis.Image 1

Illigera aromatica was fermented by Clonostachys rogersoniana. The acetylcholinesterase (AChE) inhibitory effects of unfermented and fermented I. aromatica revealed that C. rogersoniana-fermented I. aromatica (CFIA) induced significantly more AChE inhibitory activity (IC50: 35.4 ± 2.1 μg/mL). The biotransformation of actinodaphnine (1) into (4R,6aS)-4-hydroxyactinodaphnine (2) was found during the fermentation, which played an important role in the improvement of the AChE inhibitory activity of I. aromatica. Subsequently, the fermentation conditions—including the solid–liquid ratio, fermentation temperature, and fermentation time—were optimized. I. aromatica immersed in 100–200% water and fermented with C. rogersoniana at ambient temperature for 30 days was conducive to the biotransformation of actinodaphnine (1) and improved the AChE inhibitory activity of I. aromatica. The present study provides a novel approach for improving the pharmacological effect of I. aromatica and suggests that CFIA may be used as an alternative AChE inhibitor.

The cure from Alzheimer's disease is a challenging mission. Acetylcholinesterase enzyme (AChE) inhibitors, including tacrine, are considered the most important line for Alzheimer's therapy. In the current study, we aimed at designing and synthesizing new thienopyridine-tacrine analogues. The molecular structures of the synthesized compounds were illustrated by spectroscopic and elemental analysis. These compounds have been screened for their in vivo brain acetyl cholinesterase inhibition activities. The majority of the tested compounds exhibited inhibitory activity towards AChE. The IC 50 for the most promising members was determined in vitro . Interestingly, compound 11a displayed the best profile with IC 50 of about 172 nM.

BACKGROUND: Preliminary evidence suggests an association of hypovitaminosis D (hypo.D) with mechanical Low back ache (mLBA). AIM: This study was designed to 1. Explore the relationship of hypovitaminosis D with mLBA in the absence of other confounding factors 2. Formulate and validate an appropriate treatment protocol and 3. Explore the differences in outcomes with various oral formulations of vitamin D available in Indian market. MATERIALS & METHODS: Three randomised groups of patients with mLBA and hypo.D between 18 and 45 years of age without any co morbid conditions were studied for the effectiveness of adjunctive vit.D supplementation of 6,00,000 IUs (60,000 IUs/day for ten consecutive days) in the form of granule or nano syrup or soft gel capsule for the treatment of mLBA. Review evaluation of pain, functional disability and vit.D was done at three weeks and an additional evaluation of vit.D was done at nine months. Evaluation with 3,00,000 IUs of vit.D (60,000 IUs/day for five consecutive days) was done with nano syrup in a different cohort. RESULTS: High prevalence of hypo.D (96%) was noted in patients with mLBA. Significant improvement was noted after supplementation of vit.D. The subjects of nano syrup group have shown significantly better improvement compared to others (P

To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a series of chalcone-O-carbamate derivatives was designed and synthesized based on the multitarget-directed ligands strategy. The in vitro biological activities were evaluated including AChE/BChE inhibition, MAO-A/MAO-B inhibition, antioxidant activities, Aβ1-42 aggregation inhibition, metal-chelating properties and neuroprotective effects against H2O2-induced PC12 cell injury. The results showed compounds 5b and 5h indicated highly selective BChE inhibitory activity with IC50 values of 3.1 μM and 1.2 μM, respectively and showed highly selective MAO-B inhibitory potency with IC50 values of 1.3 μM and 3.7 μM, respectively. In addition, compounds 5b and 5h could inhibit self-induced Aβ1-42 aggregation with 63.9% and 53.1% inhibition percent rate, respectively. Particularly, compound 5b was a potent antioxidant agent and neuroprotectant, as well as a selective metal chelator by chelating Cu2+ and Al3+. Moreover, compound 5b could inhibit and disaggregate Cu2+-induced Aβ1-42 aggregation, which was further supported by the TEM images. Furthermore, compounds 5b and 5h could cross the blood-brain barrier (BBB) in vitro and conformed to the Lipinski's rule of five. Finally, the in vivo assay exhibited that compound 5b could improve scopolamine-induced cognitive impairment. Taken together, these results revealed that compound 5b might be a potential multifunctional agent for the treatment of AD, and deserved to do further structure optimization.

Emerging data indicate that prenatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) could interfere with myogenic differentiation in vivo. Acetylcholinesterase (EC3.1.1.7; AChE), an enzyme critical for cholinergic neurotransmission, is abundantly expressed in neurons and mature myotubes, and we recently found that muscle AChE expression was suppressed in parallel with the inhibition of myogenic differentiation upon TCDD treatment in mouse C2C12 cells. This TCDD-induced suppression of muscle AChE was proposed to involve an aryl hydrocarbon receptor (AhR)-independent mechanism, but the precise underlying mechanism remains unclear. Considering the widely recognized role of muscular activity in AChE expression and its potential crosstalk with the AhR signaling pathway, we sought to investigate the effect of TCDD on muscle AChE expression in the presence of muscular activity. Therefore, we employed a highly contractile rat primary skeletal muscle culture system in which AChE activity and the expression of genes related to it (AChE T subunit and collagen Q (ColQ)) were increased during the myogenic differentiation process. Although TCDD treatment successfully induced the expression of genes regulated by AhR activation, the treatment exerted no notable effects on myogenic differentiation. Moreover, muscle AChE enzymatic activity and mRNA level remained unchanged following TCDD treatment, and only ColQ mRNA expression was slightly increased after 4-day treatment with TCDD (10−10 M). The compensatory role of muscle-contraction-related signaling pathways in this newly identified unresponsiveness of muscle AChE to TCDD warrants further investigation.

Acetylcholinesterase (AChE) plays an important role in the therapy of Alzheimer's disease and in the detection of pesticides such as organophosphates which are also widely used in chemical warfare. The aim of this study is the physicochemical and kinetic characterization of brain and muscle ChE from Danio rerio (Zebrafish). Optimal activity was found for brain ChE at alkaline pH 9.0 at 30 °C, and for muscle ChE at alkaline pH 8.5 at temperatures between 20 °C and 35 °C. The apparent kinetic constants, Kmapp and Vmaxapp, for brain ChE were determined as 0.191 ± 0.024 mM and 0.566 ± 0.028 U/mg protein, and for muscle ChE as 0.230 ± 0.030 mM and 0.677 ± 0.039 U/mg protein. Both brain and muscle ChE showed inhibition at high substrate concentrations. Brain and muscle ChE showed IC50 values for physostigmine of 0.61 μM and 0.37 μM, respectively. The ChE activity in brain was significantly inhibited by BW254c51 in all concentrations tested, but not by Iso-OMPA, while muscle ChE presented a moderate decrease (13 to 29%) in the activity values, indicating that BuChE is present.

Novel 4-oxobenzo[d]1,2,3-triazin derivatives bearing pyridinium moiety 6a–q were synthesized and screened against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Most of the synthesized compounds showed good inhibitory activity against AChE. Among the synthesized compounds, the compound 6j exhibited the highest AChE inhibitory activity. It should be noted that these compounds displayed low anti-BuChE activity with the exception of the compound 6i, as it exhibited BuChE inhibitory activity more than donepezil. The kinetic study of the compound 6j revealed that this compound inhibited AChE in a mixed-type inhibition mode. This finding was also confirmed by the docking study. The latter study demonstrated that the compound 6j interacted with both the catalytic site and peripheral anionic site of the AChE active site. The compound 6j was also observed to have significant neuroprotective activity against H2O2-induced PC12 oxidative stress, but low activity against β-secretase.

In previous experiments, human and rat small bowel samples have been successfully used to study the spasmolytic effect of (potential) therapeutics in carbamate-constricted bowel specimens. Additionally, transferability from rat to human data was shown in the previous study. In the present study, the effects of atropine, scopolamine, MB327, HI-6 as well as obidoxime were examined in organophosphorus-poisoned human small bowel specimens. All substances were tested with at least seven concentrations in samples previously exposed to the nerve agent sarin. Furthermore, the cholinesterase reactivation potential of all substances was investigated. The test substances displayed a spasmolytic effect allowing the calculation of dose-response curves and EC50s. The parasympatholytic compound scopolamine had the strongest relaxing effect (EC50 = 0.05 μM) followed by atropine (EC50 = 0.07 μM). HI-6 and obidoxime were capable to reactivate the sarin-inhibited cholinesterase activity in small bowel samples. Both substances restored AChE activity in a dose-dependent way, with HI-6 being more potent (HI-6 EC50 = 3.8 μM vs obidoxime EC50 = 197.8 μM). Summarizing, our isolated human small bowel setup is a suitable tool to investigate the smooth muscle relaxing effect of (candidate) therapeutics for organophosphorus compound poisoning i.e. sarin exposure in a complex 3D tissue model.

Donepezil is used to treat symptomatically the Alzheimer's disease (AD). This drug is a specific inhibitor of the enzyme acetylcholinesterase (AChE), whose main physiological function is to hydrolyze the neurotransmitter acetylcholine. The main objective of this work was to study the effect of donepezil on human erythrocytes as AChE is present in its membrane. For this purpose, human erythrocytes and molecular model of its membrane built-up of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE) were used. The latter correspond to classes of phospholipids present in the outer and inner monolayers of the human erythrocyte membrane, respectively. Our experimental evidences obtained from X-ray diffraction and differential scanning calorimetry (DSC) analysis indicated that donepezil was capable of interacting with both phospholipids. Fluorescence spectroscopy results showed a moderate increase in the fluidity of the hydrophobic tails of DMPC and isolated unsealed human erythrocyte membranes (IUM). On the other hand, results by scanning electron microscopy (SEM) and optical defocusing microscopy (DM) showed that the drug changed the normal biconcave shape of the erythrocytes inducing the formation of stomatocytes (cup-shaped cells). This effect was explained by the incorporation of donepezil molecules into the erythrocyte membrane and interactions with AChE.

Ganoderma mushrooms are widely used as effective medicines for treating and preventing chronic diseases. In this study, five new meroterpenoids, dayaolingzhiols A (1) and B (2) featuring a 6/6/6 ring system, dayaolingzhiols C−E (3–5) harboring a γ-lactone motif, along with eight known ones (6–13), were purified from G. lucidum. To clarify their chemical structures, spectroscopic and ECD and OR computational methods were used. In addition, the inhibition of all the new meroterpenoids against AChE was evaluated, disclosing that (+)-4 and (±)-5 possess potent AChE inhibitory activities with respective IC50 values of 8.52 ± 1.90 μM and 7.37 ± 0.52 μM.

The objective of this study was to evaluate whether antiparasitic eprinomectin may be an environmental contaminant in water compartment in low concentrations, negatively affecting neurotransmission and, consequently, the natural behavior of the jundia (Rhamdia quelen). Fish were randomly allocated in tanks and exposed for 24 and 48 h to eprinomectin concentrations in water [0.0 (Control), 1.124 (T1), 1.809 (T2) and 3.976 (T3) μg L−1], followed by 48 h of recovery in eprinomectin-free water, in order to evaluate the behavioral parameters, levels of reactive oxygen species (ROS) in the brain, as well as cerebral enzymatic activities of acetylcholinesterase (AChE) and of the sodium-potassium ATPase pump (Na+/K+-ATPase). Especially at the two highest concentrations of eprinomectin (T2 and T3), the fish showed alterations in natural behavior, particularly hyperlocomotion and longer time on the surface. Furthermore, at these same concentrations, cerebral ROS levels increased and cerebral AChE activity decreased. At the highest concentration (T3) cerebral Na+/K+-ATPase activity was reduced. Increased ROS and impairment of AChE and Na+/K+-ATPase enzymes in the brain may have contributed directly to behavioral changes, due to neuronal damage and synapse impairment. Even after 48 h in water without eprinomectin, behavioral changes and neurotoxic effects were observed in fish, suggesting residual effects of the antiparasitic. In conclusion, eprinomectin even in low concentrations may be a hazardous environmental contaminant for aquatic organisms, as it causes brain damage and affects the natural behavior of fish.

Free-ranging animals are often used as bioindicators of both short- and long-term changes in ecosystem health, mainly to detect the presence and effects of contaminants. Birds, and gulls in particular, have been used as bioindicators over a broad range of marine and terrestrial ecosystems. In this study, we standardise the conditions for the use of a suite of biochemical markers in non-destructive matrices of Lesser Black-backed Gull (Larus fuscus) to facilitate future biomonitoring of marine and terrestrial contaminants. We characterized cholinesterase (ChE) in plasma and optimized assay conditions for ChE activity as a marker of neurotoxic damage. Moreover, we quantified variation in activity of ChE, lactate dehydrogenase (LDH), glutathione-S-transferase (GST) and catalase (CAT) as well as variation ranges of lipid peroxidation (LPO), in free-ranging adults and captive chicks. The main ChE form present in plasma of both adults and chicks was butyrylcholinesterase (BChE) followed by acetylcholinesterase (AChE), whose relative proportion in plasma tended to decrease with increased chick age. LPO levels and GST activity in blood cells (BCs) decreased significantly with increasing chick age, while BChE and LDH activity in plasma were not age-dependent. CAT in BCs tended to decline non-significantly in older chicks. Results of this study underscore the importance of standardising assay conditions and assessing intrinsic baseline variation in biochemical markers, before biochemical quantification. Data presented here provide a foundation for future use of BChE and LDH activity in plasma, as well as oxidative stress markers (LPO, CAT and GST) in BCs, to monitor environmental stress effects in Lesser Black-backed gulls.

Organophosphates insecticides (OPs) are common surface water contaminants in both urban and agricultural landscapes. Neurobehavioral effects on larval fish are known to occur at concentrations higher than those reported in the environment. The aim of this study was to perform a comparative analysis of neurobehavioral, molecular, and biochemical responses of four OPs (diazinon, dichlorvos, malathion, methyl-parathion) via the following endpoint measurements: distance traveled, velocity, gene expression (AChE, c-Fos, LINGO-1B, GRIN-1B), enzymatic acetylcholinesterase (AChE) activity, and carboxylesterase (CES) activity. OP exposures (5 hpf - 120 dpf) on embryo-larval zebrafish (Danio rerio) were assessed using a larval zebrafish behavior assay at concentrations: 0.01, 0.1, 10, and 100 μg/L. Individual OPs had varying degrees of neurotoxicity. Significant hypoactivity was observed in the 100 μg/L treatments for diazinon and malathion (p 0.05) as compared to the controls. Diazinon-exposed larvae exhibited a 26% locomotor decrease, and hypoactivity was observed in malathion-exposed larvae at a reduction of 22% and 29% for distance traveled and velocity, respectively. Gene regulation and enzymatic activity changes were measured for both 0.1 and 100 μg/L exposures across OP treatments. Increased CES activity was observed for the 0.1 μg/L treatments of diazinon and methyl-parathion as well as the 100 μg/L treatment of dichlorvos; meanwhile, decreased CES activity was observed for 100 μg/L treatments of diazinon and malathion. Relative enzymatic activity of AChE was inhibited as compared to the control for the 0.1 μg/L diazinon. No other treatment group exhibited a significant effect on biochemical AChE activity; however, AChE upregulation was observed in the 0.1 μg/L exposure for diazinon, dichlorvos, and malathion. Methyl-parathion was observed to downregulate c-Fos at 0.1 μg/L exposure. Malathion upregulated LINGO-1B at 100 μg/L, a gene associated with neuronal regeneration; meanwhile, downregulation of LINGO-1B was observed for 0.1 μg/L exposure of methyl-parathion. Additional downregulation was observed for GRIN-1B in the 100 μg/L diazinon, 100 μg/L dichlorvos, and 0.1 μg/L methyl-parathion treatments. Exposure of ZF embryos to independent concentrations of 100 μg/L concentrations of diazinon and malathion resulted in hypoactivity and decreased CES activity at 5 dfp. No changes in swimming behavior were observed for either the 0.1 μg/L or 100 μg/L dichlorvos or methyl-parathion treatments. Observations from this study indicate that AChE inhibition may not be the most sensitive biomarker of OP pesticide exposure in zebrafish. Rather, the enzyme CES demonstrated higher sensitivity as a biomarker of OP toxicity.

A series of novel isoflavone analogs were designed, synthesized, and evaluated as multitarget-directed ligands for the treatment of Alzheimer's disease. In vitro evaluations revealed that some ligands had multifunctional profiles, including potent blockage of histamine 3 receptor (H3R), excellent inhibition of acetylcholinesterase (AChE), neuroprotective effects and anti-neuroinflammatory properties. Among these derivatives, compound 9b exhibited the highest ability to block H3R (IC50 = 0.27 μM) and good inhibitory activity against AChE (IC50 = 0.08 μM). Additionally, compound 9b showed obvious neuroprotective effect on SH-SY5Y by preventing copper-induced neuronal damage and potent anti-neuroinflammatory activity by inhibiting the production of inflammatory factors on BV-2 cells. A molecular modeling study revealed that 9b acts as a mixed-type inhibitor that interacts simultaneously with H3R and AChE. Moreover, in vivo data revealed that compound 9b did not cause acute toxicity in mice at doses up to 1000 mg/kg, and had desirable pharmacokinetic properties, as well as a good blood-brain barrier (BBB) permeability (log BB = 1.24 ± 0.07). Further studies demonstrated that chronic oral treatment with 9b significantly improved cognitive dysfunction in scopolamine-induced AD mice in the step-down passive avoidance test. Taken together, the present study showed that compound 9b is a promising multifunctional drug candidate for the treatment of Alzheimer's disease.

The aim of this study was to evaluate whether rupture on blood-brain barrier (BBB) can be a pathway for trichlorfon-induced neurotoxic effects, and to investigate its implications on oxidative status, cell viability and brain neurotransmitters in silver catfish (Rhamdia quelen). The BBB permeability was increased in fish exposed for 24 h to 22 mg/L of trichlorfon compared to the control group, as well as in those exposed to 11 and 22 mg/L of trichlorfon for 48 h. Compared to the control group, brain reactive oxygen species and lipid peroxide levels were higher when exposed to 22 mg/L of trichlorfon and 11 and 22 mg/L of trichlorfon after 24 h and 48 h, respectively, while the antioxidant capacity against peroxyl radical levels was lower. Exposure to 22 mg/L of trichlorfon for 24 h reduced brain cell viability compared to the control group, together with 11 and 22 mg/L of trichlorfon for 48 h. Also, brain AChE, Na+ and K+-ATPase activities were reduced in those fish exposed to trichlorfon compared to the control group. Thus, the rupture of BBB can be considered an important pathway involved in trichlorfon-induced neurotoxic effects, which contributes to brain oxidative damage and important changes on brain neurotransmitters.

Background Due to complex pathogenesis of Alzheimer's disease (AD), currently there is no effective disease-modifying treatment. Acetylcholinesterase (AChE) has introduced itself as an important target for AD therapy. Linarin as the representative active ingredient of flavonoid glycoside in Flos chrysanthemi indici has been found to have anti-acetylcholinesterase effect. Aims The present study intended to explore the potential effect of linarin for treatment of AD. Main methods In this study, molecular docking simulation was used to evaluate whether linarin could dock with AChE and decipher the mechanism of linarin as an AChE inhibitor. After molecular docking simulation, AlCl3-induced Alzheimer's disease zebrafish model was established. Effects of linarin on treating AD zebrafish dyskinesia and AChE inhibition were compared with donepezil (DPZ) which was used as a positive control drug. Key findings Molecular docking simulation showed that linarin plays a critical role in AChE inhibition by binding AChE active sites. The experiments illustrated that the dyskinesia recovery rate of AD zebrafish could be significantly improved by linarin. The dyskinesia recovery and AChE inhibition rate were 88.0% and 74.5% respectively, while those of DPZ were 79.3% and 43.6%. Significance These findings provide evidences for supporting linarin to be developed into an AD drug by inhibiting the activity of AChE.

Polycyclic aromatic hydrocarbons (PAH) have been reported as acetylcholinesterase (AChE) inibitors, although in vitro studies on PAH effects on AChE activity are scarce and have only been performed using electric eel brain extracts. Thus, this study investigated PAH effects on brain AChE activity in a tropical fish species in Southeastern Brazil, mullet (Mugil liza). Mullet specimens were obtained from Guanabara Bay (N = 20), Rio de Janeiro, Brazil. Brain AChE was extracted and exposed to an environmentally relevant concentration of Pyrene, Chrysene, Phenanthrene, and Naphthalene, and PAH metabolites, 2-Naphthol and 1-OH-Pyrene. AChE activity inhibition was observed, although no difference was observed between high- and low- molecular weight PAH. 2-Naphthol was a less potent AChE inhibitor than Naphthalene, albeit non-significantly. Further studies are required, since only one PAH concentration was used herein. Mullet brain extracts seem to be adequate to assess possible neurotoxic PAH effects on fish AChE.

Alzheimer's disease is a progressive neurodegenerative disorder causing common health problem with increasing age. Evidences show that the key symptoms of AD are mainly caused by cholinergic system dysfunction which has a role in cognitive disorders. Cholinergic pathways especially muscarinic receptors like M1 subtype also have a major role in learning, memory, cognitive functions and emotional state. There is no available permanent treatment currently to cure AD or to change its progression. This study was designed to investigate the factors that play important role in pathogenesis of AD and to compare the effects of Galantamine treatment with effects of Myrtus communis treatment. The expression level of M1, ACh, BDNF; AChE activity, GSH level, MDA and MPO activity and AChE gene expression were investigated in scopolamine-induced rat model. Results showed that, administration of MC significantly improves the SCOP-induced reduction of latency and object recognition time; increasing BDNF, M1 and ACh receptor expression levels in the different brain regions. Additionally, MC showed an increased in AChE by enhancing GSH activity and reducing MDA level and MPO activity. In conclusion MC considered as a possible novel therapeutic approach that can be a valuable alternative way in the prevention and treatment of AD.

Manganese (Mn) induces cognitive disorders and basal forebrain (BF) cholinergic neuronal loss, involved on learning and memory regulation, which could be the cause of such cognitive disorders. However, the mechanisms through which it induces these effects are unknown. We hypothesized that Mn could induce BF cholinergic neuronal loss through oxidative stress generation, cholinergic transmission and AChE variants alteration that could explain Mn cognitive disorders. This study shows that Mn impaired cholinergic transmission in SN56 cholinergic neurons from BF through alteration of AChE and ChAT activity and CHT expression. Moreover, Mn induces, after acute and long-term exposure, AChE variants alteration and oxidative stress generation that leaded to lipid peroxidation and protein oxidation. Finally, Mn induces cell death on SN56 cholinergic neurons and this effect is independent of cholinergic transmission alteration, but was mediated partially by oxidative stress generation and AChE variants alteration. Our results provide new understanding of the mechanisms contributing to the harmful effects of Mn on cholinergic neurons and their possible involvement in cognitive disorders induced by Mn.

The effects of Jobelyn® (JB) on neurological deficits and biochemical alterations associated with ischemic stroke induced by bilateral common carotid artery occlusion (BCCAO) in rats were investigated in this study. Male Wistar rats were divided into five groups (n = 8): group 1 served as Sham control; group 2, which served as negative control received normal saline while groups 3-5 were given JB (25, 50 and 100 mg/kg, p.o) daily for 28 days. Then, rats in groups 2-5 were subjected to BCCAO for 30 min and reperfusion afterwards. Neurological deficits were assessed 3 h post-reperfusion using a 9-point neurological scoring scale. The levels of biomarkers of oxidative stress and pro-inflammatory cytokines (tumour necrotic factor-α and interleukin-6), expressions of immunopositive cells of nuclear factor-kappa B (NF-κB) and acetyl-cholinesterase (AChE) activity were determined in brain tissues. Histology of the striatum, prefrontal cortex (PFC) and hippocampus (CA1) was also evaluated. JB improved BCCAO-induced neurological deficits and attenuated increased oxidative stress and AChE activity in rats subjected to BCCAO (p 0.05). Increased brain levels of tumour necrotic factor-α and interleukin-6 as well as expressions of immunopositive cells of NF-κB were decreased by JB. JB reduced brain damage and also increased population of viable neurons in the striatum, PFC and hippocampus of ischemic stroke rats. These findings suggest that the positive effect of JB on neurological function in rats with ischemic stroke may be related to inhibition of oxidative stress, release of pro-inflammatory cytokines and expressions of immunopositive cells of NF-κB.

A series of eighteen pyrano[4,3-b][1]benzopyranone derivatives (1a-9b) were synthesized, and structure-activity relationships of their monoamine oxidase (MAO) A and B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activities were evaluated. Most of the synthesized compounds exhibited weak inhibitory activity toward MAO-A, whereas compounds 2a, 2b, 4a, 4b, 5a, 5b, 6a, 6b, 8a and 8b showed potent inhibitory activities toward MAO-B. Intriguingly, compounds 5a, 5b, and 8a showed inhibitory activities comparable to pargylin, used as a positive control for MAO-B. Substitution of butoxy at the C3 position or of chlorine at the C8 position of pyrano[4,3-b][1]benzopyranone increased the inhibitory activity of the compound toward MAO-B. The results of a molecular docking study supported this structural effect. Most of the compounds exhibited no or slight inhibitory activity toward AChE and BChE, with exo type compounds bearing a butoxy group, such as compounds 2b, 5b and 8b, showing weak but distinct inhibitory activities toward BChE. This report is the first to identify pyrano[4,3-b][1]benzopyranone derivatives as potent and selective MAO-B inhibitors. 3-Butoxy-8-chloro-pyrano[4,3-b][1]benzopyranone (5b) may be useful as a lead compound for the development of MAO-B inhibitors.

Dementia defines wide-ranging symptoms related to a decline in memory or coherent thinking. The focused endeavor of the present study was to develop and assess the efficacy of rivastigmine hydrogen tartrate (RHT) loaded nanostructured lipid carrier (RHT-NLCs) for the cure of dementia. The rise of dementia cases necessitates a curative therapy which is safe as well as effective. RHT-NLCs were developed by a modified solvent emulsification-diffusion method. Box-Behnken design was used for optimization of the developed formulation. The particle size, polydispersity index, zeta potential and percent entrapment efficiency of the optimized RHT-NLCs formulation was found to be 266 ± 0.94 nm, 0.233, −16.58 mV and 61.82 ± 2.52% respectively. RHT-NLCs displayed 81.23 ± 2.14% drug diffusion in 12 h through goat nasal mucosa and aldicarb assay exhibited increased worm paralysis due to increased concentration of acetylcholine in C. elegans model. Quantitative RT-PCR of RHT-NLCs displayed acetylcholinesterase expressing enzymes (AChE 1 and AChE 2) down-regulation, responsible for the expression of acetylcholinesterase by 4.92 ± 0.06 and 5.42 ± 0.33 respectively. Significant improvement was found in escape latency and transfer latency after treatment with RHT-NLCs in a rat model. Above results point towards the treatment/cure of dementia through RHT-NLCs developed using Compritol 888 ATO, Ryoto Sugar ester and Triacetin.

Determining precisely the postmortem interval (PMI) is a key parameter for forensic researches, given that various physical, biochemical and metabolic changes begin to occur in the body after death. In the present study, the Na+/K+-ATPase, glutathione S-transferase (GST) and acetylcholinesterase (AChE) activities were evaluated. For this, male adult Swiss mice were killed by isoflurane inhalation anesthesia and divided into four groups according to time of death (0, 6, 24 and 48 h). The brain, liver, kidney and skeletal muscle tissues were removed. Our results revealed that at the time of 6 h, there was a decrease on Na+/K+-ATPase and GST activities in the brain and liver tissues, respectively. In addition, at this time point, an increase on renal GST activity was verified. At the time of 24 h, an increase on the cerebral AChE and renal GST activities was observed, while the cerebral Na+/K+-ATPase activity was decreased. Forty-eight hours after death, cerebral Na+/K+-ATPase and renal GST activities remained decreased and increased, respectively. In addition, no alteration was observed on the GST activity in the skeletal muscle and brain (in PMIs evaluated). The present study revealed that the brain and kidney (at the times of 24 and 48 h) were the tissues that suffered the most changes in almost all the enzymes evaluated. Our results demonstrated that enzyme activity assessments are reliable, easy-to-perform and low-cost determinations, and could be promising postmortem markers.

Numerous studies suggested that reptiles are sensitive to environmental pollution and the abundance of many species are in decline. Our research is aim to assess the toxic effects of pesticide in reptiles. And we also want to supply some data about nondestructive samples for environmental risk assessment in reptiles. Lizards were orally administered a single-dose of beta-cypermethrin (BCP) or myclobutanil (MC) at the concentration of 20 mg/kg body weight (bw). The results showed that pesticides could induce changes in enzymatic activities (SOD, CAT, LDH, AChE) and MDA levels in organs or tissues of lizards. BCP could cause more severe oxidative damage than that of MC. Salivary enzymes activities showed sensitivity changes to the toxicity of pesticides. We could use saliva to reflect whether the reptiles are toxic by pesticides. We also agree that buccal swabs could be used as a tool for saliva sampling.

Two new pyranones, Wortmannine F (1) and G (2), were isolated from Talaromyces wortmannii LGT-4, which is an endophytic fungus from Tripterygium Wilfordii. Their structures were elucidated on the basis of NMR and ESI-MS spectral data, as well as chemical calculation. Additional known compounds (4–8) were also isolated. The isolates were tested for monoamine oxidase (MAO), acetylcholinesterase (AChE) and phosphoinositide 3-kinase α (PI3Kα) inhibitory activities. Compounds 1, 2 showed potent PI3Kα inhibitory activity with IC50 of 25 and 5 μM, respectively.