AChE Inhibitory Activity Research Articles

Development of novel 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives as balanced multifunctional agents against Alzheimer's disease

Based on multitarget-directed ligands approach, through two rounds of screening, a series of 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives were designed, synthesized and evaluated as innovative multifunctional agents against Alzheimer's disease. In vitro biological assays indicated that most of the hybrids were endowed with great AChE inhibitory activity, excellent antioxidant activity and moderate Aβ1-42 aggregation inhibition. Taken both efficacy and balance into account, 12a was identified as the optimal multifunctional ligand with significant inhibition of AChE (EeAChE, IC50 = 0.20 μM; HuAChE, IC50 = 37.02 nM) and anti-Aβ activity (IC50 = 1.92 μM for self-induced Aβ1-42 aggregation; IC50 = 1.80 μM for disaggregation of Aβ1-42 fibrils; IC50 = 2.18 μM for Cu2+-induced Aβ1-42 aggregation; IC50 = 1.17 μM for disaggregation of Cu2+-induced Aβ1-42 fibrils; 81.7% for HuAChE-induced Aβ1-40 aggregation). Moreover, it was equipped with the potential to serve as antioxidant (3.03 Trolox equivalents), metals chelator and anti-neuroinflammation agent for synergetic treatment. Finally, in vivo study demonstrated that 12a, with suitable BBB permeability (log BB = −0.61), could efficaciously ameliorate cognitive dysfunction on scopolamine-treated mice by regulating cholinergic system and oxidative stress simultaneously. Altogether, these results highlight the potential of 12a as an innovative balanced multifunctional candidate for Alzheimer's disease treatment.

Synthesis and Characterization of Schiff Bases Containing 1,2,3-Triazole Unit: Photophysical and Acetyl Choline (AChE) Inhibitory Properties

In this study, new salicylaldehyde derivatives containing a 1,2,3-triazole group (5a-c) and their Schiff bases (6a-c) were synthesized and their structures were characterized by FT-IR, 1H(13C) NMR and elemental analysis spectroscopic methods. The crystal structure of the triazole compound 5c was investigated by X-ray diffraction study. Then, UV-Vis absorption properties were studied and the effects of different solvents on absorption were investigated. In the UV-vis spectra, π-π* and n-π* transitions were observed in the range of 280-480 nm. Especially, the absorption band at 400-480 nm range for 6a-c in MeOH gave the idea that they were caused by tautomeric conversion from phenol-imine to keto-amine in their structure. Acetylcholinesterase Inhibitory activity studies are very important for research on the treatment of Alzheimer's disease, so the synthesized compounds were screaned for their AChE inhibitory activities. According to the results obtained, both 1,2,3-triazole compounds and Schiff bases showed comperable inhibitory activity. In particular, the activity of compound 6b (IC50: 12.85 ± 0.026 µM) was determined to be approximately considerably higher than the standard Galantamine (IC50: 139.4 µM).

The anti-Alzheimer potential of Tamarindus indica: an in vivo investigation supported by in vitro and in silico approaches.

Tamarindus indica Linn. (Tamarind, F. Fabaceae) is one of the most widely consumed fruits in the world. A crude extract and different fractions of T. indica (using n-hexane, dichloromethane, ethyl acetate, and n-butanol) were evaluated in vitro with respect to their DPPH scavenging and AchE inhibition activities. The results showed that the dichloromethane and ethyl acetate fractions showed the highest antioxidant activities, with 84.78 and 86.96% DPPH scavenging at 0.10 μg mL−1. The n-hexane, dichloromethane, and ethyl acetate fractions inhibited AchE activity in a dose-dependent manner, and the n-hexane fraction showed the highest inhibition at 20 μg mL−1. The results were confirmed by using n-hexane, dichloromethane, and ethyl acetate fractions in vivo to regress the neurodegenerative features of Alzheimer's dementia in an aluminum-intoxicated rat model. Phytochemical investigations of those three fractions afforded two new diphenyl ether derivative compounds 1–2, along with five known ones (3–7). The structures of the isolated compounds were confirmed via 1D and 2D NMR and HRESIMS analyses. The isolated compounds were subjected to extensive in silico-based investigations to putatively highlight the most probable compounds responsible for the anti-Alzheimer activity of T. indica. Inverse docking studies followed by molecular dynamics simulation (MDS) and binding free energy (ΔG) investigations suggested that both compounds 1 and 2 could be promising AchE inhibitors. The results presented in this study may provide potential dietary supplements for the management of Alzheimer's disease.

Structurally diverse biflavonoids from Dysosma versipellis and their bioactivity.

Five pairs of new biflavonoid enantiomers, (±)-dysosmabiflavonoids A-E (1-5), two new biflavonoids, dysosmabiflavonoids F-G (6-7), and four biosynthetically related precursors (8-11) were isolated from the roots and rhizomes of Dysosma versipellis. Their structures were elucidated by extensive spectroscopic analysis, including HR-ESI-MS and 2D NMR. Their absolute configurations were determined by comparison of the calculated and experimental ECD spectra. All isolated compounds were evaluated for AChE inhibitory activity. Compounds 6 and 7 exhibited more potent inhibitory activities with IC50 values of 1.42 and 0.73 µM, respectively, than their biosynthetically related precursors kaempferol (8, 17.90 µM) and quercetin (9, 3.96 µM). The preliminary structure-activity relationship study indicated that the connection mode of biflavonoid subunits, oxidation degree of the C ring, and 3,4-dihydroxy group of the B ring were important structural factors for AChE inhibitory activity. Racemates 1-5 and their corresponding levorotatory and dextrorotatory enantiomers were tested for their potential to impede the generation of NO in lipopolysaccharide-stimulated RAW264.7 cells, and their mushroom tyrosinase inhibitory effect. Racemate 1 displayed more potent mushroom tyrosinase inhibitory activity (IC50, 28.27 µM) than the positive control kojic acid (IC50, 32.59 µM). D. versipellis may have therapeutic potential for melanogenesis disorders and neurodegenerative diseases.

저분자 진세노사이드를 함유한 산삼배양근 증숙 추출물의 Acetylcholinesterase 억제 및 신경세포 보호효과

Background: Ginsenosides are known to have anti-cancer, anti-inflammatory, and antioxidant effects. Additionally, they are known to improve cognitive ability and memory, and prevent dementia. In this study, the physiological activity of cultured wild ginseng adventitious root (ginseng root, GS) containing low molecular weight ginsenosides was investigated in vitro.<BR>Methods and Results: This experiment was conducted to confirm the acetylcolinesterase (AChE) inhibitory activity, neuroprotectivie effect, and antioxidant effect of GS steam treatment. Through the steaming process, a GS steam treatment containing low molecular weight ginsenosides was prepared and evaluated. The results showed that AChE inhibitory activity, neuroprotective effect, reactive oxygen species (ROS) inhibitory effect, and catalase (CAT) activity effect by H₂O₂ were concentration-dependent in the group treated with GS steam treatment compared to those in the control group.<BR>Conclusions: In this study, it was demonstrated that the GS steam treatment influenced the AChE inhibitory activity, the neuroprotective effect, and the oxidative stress protective effect of GS.

In vitro DPPH and AChE inhibitory activity of hydroethanolic extract from Camellia sinensis (L.) O. Kuntze

In vitro DPPH and AChE inhibitory activity of hydroethanolic extract from Camellia sinensis (L.) O. Kuntze

Acorenone C: A New Spiro-Sesquiterpene from a Mangrove-Associated Fungus, Pseudofusicoccum sp. J003.

Mangrove-derived endophytes are rich in bioactive secondary metabolites with a variety of biological activities. Recently, a fungus Pseudofusicoccum sp. J003 was first isolated by our research group from mangrove species Sonneratia apetala Buch.-Ham. The subsequent chemical investigation of the methanol extract of the culture broth of this strain has led to the isolation of a new sesquiterpenoid named acorenone C (1), two alkaloids (2–3), four phenolic compounds (4–7), and four steroid derivatives (8–11). The new structure of 1 was established by extensive spectroscopic analysis, including 1D, 2D NMR spectroscopy, and HRESIMS. Its absolute configuration was elucidated by experimental ECD and ECD calculation. The in vitro AChE inhibitory, anti-inflammatory, and cytotoxic activities of the selected compounds were evaluated. The results showed that compound 1 showed mild AChE inhibitory activity, with an inhibition rate of 23.34% at the concentration of 50 μM. Compound 9 exerted a significant inhibitory effect against nitric oxide (NO) production in LPS-stimulated RAW 264.7 mouse macrophages, with an inhibition rate of 72.89% at the concentration of 25 μM, better than that of positive control L-NMMA. Compound 9 also displayed obvious inhibition effects on the growth of two human tumor cell lines, HL-60 and SW480 (inhibition rates 98.68 ± 0.97% and 60.40 ± 4.51%, respectively). The antimicrobial activities of the compounds (1–11) against Escherichia coli, Bacillus subtilis, Staphylococcus aureus, and Pseudomonas aeruginosa were also tested; however, none of them showed antimicrobial activities.

The Amaryllidaceae alkaloids: an untapped source of acetylcholinesterase inhibitors

The AChE inhibitory activity of alkaloid extracts and compounds has been in the focus of research on the plants of Amaryllidoideae subfamily since the approval of galanthamine in 2001 by FDA for treatment of mild to moderate Alzheimer's disease. A small fraction of the huge biodiversity of the plants producing Amaryllidaceae alkaloids has been studied as a source of AChE inhibitors. Less than 20% of the known Amaryllidaceae alkaloids have been tested in vitro for their ability to inhibit AChE. Galanthamine, lycorine and haemanthamine are scaffolds for semi-synthesis of potent AChE inhibitors. In the last years, galanthamine has been studied in silico for drug optimization and synthesis of potent dual-binding AChE inhibitors. In silico studies of other Amaryllidaceae alkaloids have also provoked the interest of researchers in the last years. The aim of this article is to provide a comprehensive review on studies of the AChE inhibitory activity of extracts and compounds from the plants of Amaryllidoideae subfamily covering the literature from the last two decades.

Epoxiconazole profoundly alters rat brain and properties of neural stem cells

Epoxiconazole (EPX), a widely used fungicide for domestic, medical, and industrial applications, could cause neurodegenerative diseases. However, the underling mechanism of neurotoxicity is not well understood. This study aimed to investigate the possible toxic outcomes of Epoxiconzole, a triazole fungicide, on the brain of adult rats in vivo, and in vitro on neural stem cells derived from the subventricular zone of newborn Wistar rats. Our results revealed that oral exposure to EPX at these concentrations (8, 24, 40, 56 mg/kg bw representing respectively NOEL (no observed effect level), NOEL × 3, NOEL × 5, and NOEL × 7) for 28 days caused a considerable generation of oxidative stress in adult rat brain tissue. Furthermore, a significant augmentation in lipid peroxidation and protein oxidation has been found. Moreover, it induced an elevation of DNA fragmentation as assessed by the Comet assay. Indeed, EPX administration impaired activities of antioxidant enzymes and inhibited AChE activity. Concomitantly, this pesticide produced histological alterations in the brain of adult rats. Regarding the embryonic neural stem cells, we demonstrated that the treatment by EPX reduced the viability of cells with an IC50 of 10 μM. It also provoked the reduction of cell proliferation, and EPX triggered arrest in G1/S phase. The neurosphere formation and self-renewal capacity was reduced and associated with decreased differentiation. Moreover, EPX induced cytoskeleton disruption as evidenced by immunocytochemical analysis. Our findings also showed that EPX induced apoptosis as evidenced by a loss of mitochondrial transmembrane potential (ΔΨm) and an activation of caspase-3. In addition, EPX promoted ROS production in neural stem cells. Interestingly, the pretreatment of neural stem cells with the N-acetylcysteine (ROS scavenger) attenuated EPX-induced cell death, disruption of neural stem cells properties, ROS generation and apoptosis. Thus, the use of this hazardous material should be restricted and carefully regulated.

Protective Effect of Melatonin Against Malathion Induced Alterations in Antioxidant Defense System and Morphology of Erythrocytes in Wistar Rats

Malathion intoxication has been shown to produce oxidative stress due to the generation of free radicals and alter the antioxidant defense system in erythrocytes. Previous studies have shown the ameliorative role melatonin against oxidative stress induced by generation of free radicals. Present study was designed to investigate the protective effect of melatonin against malathion induced oxidative stress. For this purpose, male Wistar rats were randomly divided into four groups: Control; Melatonin (10mg/Kg body weight) group; Malathion (250mg/Kg body weight) treated group; Malathion + Melatonin treated group. Animals were administered an acute dose of malathion orally. The result of this study shows that in vivo administration of malathion caused inhibition in AChE activity in erythrocytes. Malathion intoxication also significantly increased the oxidative damage as evidenced by increased level of LPO and GSH content. The Inhibition of GSH level and increased lipid peroxidation in erythrocytes was relieved in malathion + melatonin group. Enhanced activities of SOD, CAT, GR and GPx were observed in erythrocytes of malathion treated rats as compared to control group. Moreover, melatonin supplementation in malathion treated rats maintain normal level of antioxidant enzymes as compared to malathion treated rats which indicates that melatonin provide protection against malathion-induced oxidative stress in erythrocytes. No significant change in the membrane bound enzymes such as Na+/K+-ATPase, Mg2+-ATPase and Ca2+-ATPase was observed in malathion intoxicated rats. Findings of scanning electron micrographs of erythrocytes revealed that both the malathion treated and malathion+melatonin treated groups exhibited morphological changes in erythrocytes. However, concomitant melatonin supplementation normalized the morphological alterations in erythrocytes induced by malathion toxicity. In conclusion, melatonin supplementation may ameliorate malathion-induced oxidative imbalance by enhancing the glutathione level, reducing lipid peroxidation and normalizing antioxidant enzyme activities in erythrocytes.

A Lab-in-a-Syringe Device Integrated with a Smartphone Platform: Colorimetric and Fluorescent Dual-Mode Signals for On-Site Detection of Organophosphorus Pesticides

Herein, a portable lab-in-a-syringe device integrated with a smartphone sensing platform was designed for rapid, visual quantitative determination of organophosphorus pesticides (OPs) via colorimetric and fluorescent signals. The device was chiefly made up of a conjugate pad labeled with cetyltrimethylammonium bromide-coated gold nanoparticles (CTAB-Au NPs) and a sensing pad modified by ratiometric probes (red-emission quantum dots@SiO2 nanoparticles@green-emission quantum dots, rQDs@SiO2@gQDs probe), which was assembled through a disposable syringe and reusable plastic filter. In the detection system, thiocholine (Tch), the hydrolysis product of thioacetylcholine (ATch) by acetylcholinesterase (AchE), could trigger the aggregation of CTAB-Au NPs, resulting in a significant color change from red to purple. Then, CTAB-Au NPs flowed vertically upward and bound to the rQDs@SiO2@gQDs probe on the sensing pad, reducing the fluorescence resonance energy transfer effect between CTAB-Au NPs and gQDs. Meanwhile, rQDs embedded in SiO2 NPs remained stable as internal reference fluorescence, achieving a color transition from red to green. Thus, based on the inhibition of AChE activity by OPs, a colorimetric and fluorescent dual-mode platform was constructed for on-site detection of OPs. Using glyphosate as a model, with the support of a color recognizer application (APP) on a smartphone, the ratio of red and green channel values could be utilized for accurate OP quantitative analysis ranging from 0 to 10 μM with a detection limit of 2.81 nM (recoveries, 90.8-122.4%; CV, 1.2-3.4%). Overall, the portable lab-in-a-syringe device based on a smartphone sensing platform integrated sample monitoring and result analysis in the field, implying great potential for on-site detection of OPs.

Synthesis, characterization, in vitro cholinesterase and hRBCs hemolysis assay and computational evaluation of novel 2,3,4,5-tetrahydrobenzothiazepine appended α-aminophosphonates

A series of novel 2,3,4,5-tetrahydrobenzothiazepine appended α-aminophosphonate derivatives were synthesized by subjecting 2,3-dihydrobenzothiazepine to Pudovik reaction using diethyl phosphite. Tested derivatives exhibited better AChE inhibition (0.86–12.85 µM) when compared to BuChE (3.13–19.36 µM). Derivative 5f (IC50 = 0.86 ± 0.08 µM), 5g (IC50 = 1.05 ± 0.06 µM) and 5d (IC50 = 1.64 ± 0.06 µM) exhibited higher AChE inhibitory activity as compared to standard drug galantamine (IC50 = 2.15 ± 0.05 µM). Similarly, derivative 5e (IC50 = 3.13 ± 0.11 µM) and 5f (IC50 = 3.64 ± 0.06 µM) demonstrated comparable BuChE inhibitory activity to reference drug galantamine (IC50 = 3.86 ± 0.03 µM). Further, enzyme kinetic studies were carried out for the most active molecule i.e. derivative 5f (for AChE) and derivative 5e (for BuChE) and the results imply that derivatives 5f and 5e show mixed-type inhibition with Ki values of 1.779 µM and 3.851 µM respectively. Enzyme reversibility inhibition studies demonstrated that all the tested derivatives possess reversible inhibitor characteristics. In addition, % hemolysis studies were carried out using human red blood cells (hRBCs) and the results demonstrated that the synthesized derivatives were biocompatible in nature as they impart very less cytotoxicity to hRBCs (CC50 > 1000 μg/mL). Also, cell viability studies for tested derivatives revealed no cytotoxicity in N2a cells. Moreover, molecular docking studies revealed that derivative 5e and 5f bind to the PAS and CAS of the AChE. ADME predictions suggested that synthesized derivatives have high possibility of being drug-like.

Chemical Profile and Evaluation of the Antioxidant and Anti-Acetylcholinesterase Activities of Annona squamosa L. (Annonaceae) Extracts.

This study presents the chemical profile of extracts from the pulp and seed of Annona squamosa L., as well as the evaluation of their antioxidant and acetylcholinesterase inhibition activities. In the chemical prospection, qualitative assays were performed, and the contents of total phenols, flavonoids, vitamin C, and carotenoids were quantified. For the compounds identification, analyses of the extracts were performed by liquid chromatography coupled to mass spectrometry. Antioxidant evaluation was performed using the DPPH, ABTS, Fe3+ reduction, 2-DR protection, and β-carotene protection methods. The assay for inhibition of acetylcholinesterase activity was determined using the method described by Ellman. The secondary metabolites identified were anthocyanidins, flavones, flavonols, and alkaloids. Phenol analysis showed a higher quantitative value of total phenols and flavonoids for the seed extract, and the vitamin C content was higher in the pulp extract. There was no significant difference in relation to the carotenoids quantification. The best results obtained for antioxidant activity, for both seed and pulp extracts, were with the ABTS method with IC50 of 0.14 ± 0.02 and 0.38 ± 0.02 mg/mL, respectively. Compared to A. squamosa seed extract, the pulp extract demonstrates higher AChE inhibitory activity with IC50 of 18.82 ± 0.17 µg/mL. A. squamosa is a nutritious food source. The continuity of the studies is fundamental to relate the consumption of this food and its effects on neurodegenerative diseases.

Acetylcholine esterase inhibitory activity of green synthesized nanosilver by naphthopyrones isolated from marine-derived Aspergillus niger.

Aspergillus niger metabolites exhibited a wide range of biological properties including antioxidant and neuro-protective effects and some physical properties as green synthesis of silver nanoparticles AgNP. The present study presents a novel evidence for the various biological activities of green synthesized AgNPs. For the first time, some isolated naphtho-γ-pyrones from marine-derived Aspergillus niger, flavasperone (1), rubrofusarin B (2), aurasperone A (3), fonsecinone A (4) in addition to one alkaloid aspernigrin A (7) were invistigated for their inhibitory activity of acetylcholine esterase AChE, a hallmark of Alzheimer's disease (AD). The ability to synthesize AgNPs by compounds 3, 4 and 7 has been also tested for the first time. Green synthesized AgNPs were well-dispersed, and their size was ranging from 8-30 nm in diameter, their morphology was obviously spherical capped with the organic compounds. Further biological evaluation of their AChE inhibitory activity was compared to the parent compounds. AgNps dramatically increased the inhibitory activity of Compounds 4, 3 and 7 by 84, 16 and 13 fold, respectively to be more potent than galanthamine as a positive control with IC50 value of 1.43 compared to 0.089, 0.311 and 1.53 of AgNPs of Compounds 4, 3 and 7, respectively. Also compound 2 showed moderate inhibitory activity. This is could be probably explained by closer fitting to the active sites or the synergistic effect of the stabilized AgNPs by the organic compouds. These results, in addition to other intrinsic chemical and biological properties of naphtho-γ-pyrones, suggest that the latter could be further explored with a view towards other neuroprotective studies for alleviating AD.

A strategy to discover lead chemome from traditional Chinese medicines based on natural chromatogram-effect correlation (NCEC) and natural structure-effect correlation (NSEC): Mahonia bealei and Mahonia fortunei as a case study

Lead compound is an important concept for modern drug discovery. In this study, a new concept of lead chemome and an efficient strategy to discover lead chemome were proposed. Compared with the concept of lead compound, lead chemome can provide not only the starting point for drug development, but also the direction for structure optimization. Two traditional Chinese medicines of Mahonia bealei and Mahonia fortunei were used as examples to illustrate the strategy. Based on natural chromatogram-effect correlation (NCEC), berberine, palmatine and jatrorrhizine were discovered as acetylcholinesterase (AchE) inhibitors. Taking the three compounds as template molecules, a lead chemome consisting of 10 structurally related natural compounds were generated through natural structure-effect correlation (NSEC). In the lead chemome, the IC50 values of jatrorrhizine, berberine, coptisine, palmatine and epiberberine are at nanomolar level, which are comparable to a widely used drug of galantamine. Pharmacophore modeling shows that the positive ionizable group and aromatic rings are important substructures for AchE inhibition. Molecular docking further shows that pi-cation interaction and pi-pi stacking are critical for compounds to maintain nanomolar IC50 values. The structure–activity information is helpful for drug design and structure optimization. This work also expanded the traditional understanding of “stem is the medicinal part of Mahonia bealei and Mahonia fortunei”. Actually, all parts except the leaf of Mahonia bealei exhibited potent AchE-inhibitory activity. This study provides not only a strategy to discover lead chemome for modern drug development, but also a reference for the application of different parts of medicinal plants.

Anticholinesterase activities of novel indole-based hydrazide-hydrazone derivatives: Design, synthesis, biological evaluation, molecular docking study and in silico ADME prediction

A series of novel indole-based hydrazide-hydrazone derivatives were synthesized and evaluated for their AChE and BuChE inhibitory activities. The structural elucidations of the novel compounds (2a–k) were performed by IR, 1H-NMR, 13C-NMR, mass, and elemental analysis. The inhibitory potential of the novel compounds on AChE (from electric eel) and BuChE (from equine serum) enzymes were carried out using in vitro modified Ellman's spectrophotometric method. Compounds 2f and 2d displayed the highest AChE inhibitory activity. Furthermore, 2d displayed the best BuChE inhibitory activity which was comparable with Galantamine. In addition to the in vitro analysis, docking studies targeting AChE (PDB ID: 1EVE) and BuChE (PDB ID: 4BDS) were performed to understand the possible interactions of these compounds with the enzymes. Structure-activity relationships, as well as in silico ADME studies, were performed and a relationship between biological, electronic, and physicochemical qualifications of the title compounds was determined.

Toxicity of isoprocarb to earthworms (Eisenia fetida): Oxidative stress, neurotoxicity, biochemical responses and detoxification mechanisms

Isoprocarb (IPC) is a conventional carbamate with high insecticidal activity, however, generalized use of it may cause soil contamination and adversely implicate non-target biota. Following OECD standardized toxicological protocols, the toxic effects of IPC on Eisenia fetida at lethal and sublethal concentrations were examined to elucidate its toxic modes of action as well as biochemical and detoxification responses of E. fetida. Acute toxicity tests showed that IPC induced a concentration-dependent rise of mortality, with LC50 of 8.20 μg/cm2 (48 h) in FPCT and 3.37 mg/kg (14 d) in AST, respectively. The ecotoxicological effects of IPC chronic exposure were measured by physiochemical, qRT-PCR and western blot analysis. Specifically, ROS, MDA and 8-OHdG contents were enhanced and T-AOC, SOD, CAT and POD activities diminished with increasing concentrations. While activities of CYP3A4 and CarE as well as expressions of Hsp70, GPx and GST were elevated upon IPC treatments, responsible for detoxifying mechanisms as implied by principal component analysis (PCA). Meanwhile, IPC diminished NRRT and inhibited AChE activities along with expressions of AChE-related genes. All these striking alterations between IPC-exposed earthworms and controls were illustrated in PCA model. More importantly, growth, reproductive and regenerative toxicity of IPC were observed with reduced cast production and soluble protein content, suppressed ANN protein and gene expressions, reversely modulated TCTP and Sox2 gene and protein, respectively. Taken together, deleterious perturbations could be induced by IPC in biophysiological homeostasis of E. fetida primarily through oxidative stress and neural dysfunction. This study not only highlighted potential hazard of IPC to earthworms in the terrestrial ecosystem, but also expounded upon mechanisms underlying toxic modes of action for IPC and detoxification of earthworms.

Curcumin-Coumarin Hybrid Analogues as Multitarget Agents in Neurodegenerative Disorders.

Neurodegenerative diseases have a complex nature which highlights the need for multitarget ligands to address the complementary pathways involved in these diseases. Over the last decade, many innovative curcumin-based compounds have been designed and synthesized, searching for new derivatives having anti-amyloidogenic, inhibitory of tau formation, as well as anti-neuroinflammation, antioxidative, and AChE inhibitory activities. Regarding our experience studying 3-substituted coumarins with interesting properties for neurodegenerative diseases, our aim was to synthesize a new series of curcumin–coumarin hybrid analogues and evaluate their activity. Most of the 3-(7-phenyl-3,5-dioxohepta-1,6-dien-1-yl)coumarin derivatives 11–18 resulted in moderated inhibitors of hMAO isoforms and AChE and BuChE activity. Some of them are also capable of scavenger the free radical DPPH. Furthermore, compounds 14 and 16 showed neuroprotective activity against H2O2 in SH-SY5Y cell line. Nanoparticles formulation of these derivatives improved this property increasing the neuroprotective activity to the nanomolar range. Results suggest that by modulating the substitution pattern on both coumarin moiety and phenyl ring, ChE and MAO-targeted derivatives or derivatives with activity in cell-based phenotypic assays can be obtained.

Effect of extrusion technology on hempseed (Cannabis sativa L.) oil cake: Polyphenol profile and biological activities.

Effects of extrusion with varying barrel temperature, moisture content, and screw speed on hempseed oil cake were studied for the first time. Extrusion at lower moisture (30%) and higher screw speed (300rpm) significantly increased the proportion of free polyphenols, flavonoids, and phenylpropionamide content, and -glucosidase and acetylcholinesterase inhibition activities. Full factorial design confirmed the three-way interactions among all extrusion parameters for all chemical assays with the bound phenolic fraction, total flavonoid content, and DPPH inhibition activity of the free phenolic fraction. HPLC-DAD-ESI-QTOF-MS/MS analysis tentatively identified 26 phenylpropionamides, and the contents of N-trans-caffeoyltyramine (66.26µg/g) and total phenylpropionamides (85.77µg/g) were significantly increased after extrusion at the lower moisture and higher screw speed extrusion conditions. The higher -glucosidase inhibition activity at higher screw speed could be due to the N-trans-caffeoyltyramine (r=0.99, p<0.01), while the AChE inhibition activity appeared to be influenced more by the cannabisins A-C, M (r>0.8, p<0.01). PRACTICAL APPLICATION: Hempseed oil cake is a byproduct of oil extraction, with high protein and high fiber contents. The results of this research could be used directly in food industry to improve the nutritional and commercial value of hempseed oil cake by extrusion technology.

Chemical composition and anticholinesterase activity of cultivated bulbs from Hippeastrum elegans, a potential tropical source of bioactive alkaloids

Abstract 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.