Photoreaction products of extract from the fruiting bodies of Polyozellus multiplex.

Photochemical reactions are powerful tools for synthesizing organic molecules. The input of energy provided by light offers a means to produce strained and unique molecules that cannot be assembled using thermal protocols, allowing for the production of immense molecular complexity in a single chemical step. Furthermore, unlike thermal reactions, photochemical reactions do not require active reagents such as acids, bases, metals, or enzymes. Photochemical reactions play a central role in green chemistry. This article reports the isolation and structure determination of four new compounds (1-4) from the photoreaction products of the Polyozellus multiplex MeOH ext. The structures of the new compounds were elucidated using MS, IR, comprehensive NMR measurements and microED. The four compounds were formed by deacetylation of polyozellin, the main secondary metabolite of P. multiplex, and addition of singlet oxygen generated by sunlight. To develop drugs for treating Alzheimer's disease (AD) on the basis of the amyloid cascade hypothesis, the compounds (1-4) obtained by photoreaction were evaluated for BACE1 inhibitory activity. The hydrolysates (5 and 6) of polyozellin, the main secondary metabolites of P. multiplex, were also evaluated. The photoreaction products (3 and 4) and hydrolysates (5 and 6) of polyozellin showed BACE1 inhibitory activity (IC50: 2.2, 16.4, 23.3, and 5.3 µM, respectively).

In silico screening of potential ß-secretase (BACE1) inhibitors from VIETHERB database.

For the purpose of discovering potential inhibitors of ß-amyloid (BACE1), which is a crucial element in Alzheimer's disease (AD) pathogenesis, an in silico study of naturally occurring compounds was performed using precise computational approaches. Autodock4 package was preliminary used to predict the binding affinities to BACE1 of more than four thousand compounds presented in the Vietnamese plants (VIETHERB) database. Based on docking results, twenty top-lead compounds having the largest docking energy to BACE1 were rigorously examined using steered molecular dynamics (SMD) simulations. Interestingly, SMD results found that the binding affinity values of three compounds, including myricetin 3-O-(3''-galloylrhamnopyranoside), quercetin 3-O-neohesperidoside, and hydroxysafflor yellow A, are remarkably higher than that of the well-known BACE1 inhibitor, 23I, and these compounds can thus be considered the promising candidates for inhibitors of BACE1.

Cannabis Sativa L. Flower and Bud Extracts Inhibited In vitro Cholinesterases and ß-Secretase Enzymes Activities: Possible Mechanisms of Cannabis Use in Alzheimer Disease.

BACKGROUND: There are anecdotal claims on the use of Cannabis sativa L. in the treatment of Alzheimer's disease, but there is a lack of scientific data to support the efficacy and safety of Cannabis sativa L. for Alzheimer's disease. AIM: The aim of the study was to evaluate the effect of aerial parts of Cannabis sativa L. on the cholinesterases and ß-secretase enzymes activities as one of the possible mechanisms of Alzheimer's disease. METHODS: The phytochemical and heavy metal contents were analysed. The extracts were screened for acetylcholinesterase, butyrylcholinesterase and ß-secretase activity. Cytotoxicity of extracts was performed in normal vero and pre-adipocytes cell lines. The extracts were characterized using high-performance thin layer chromatography and high-performance liquid chromatography for their chemical fingerprints. Alkaloids, flavonoids and glycosides were present amongst the tested phytochemicals. Cannabidiol concentrations were comparatively high in the hexane and dichloromethane than in dichloromethane: methanol (1:1) and methanol extracts. RESULTS: Hexane and dichloromethane extracts showed a better inhibitory potential towards cholinesterase activity, while water, hexane, dichloromethane: methanol (1:1) and methanol showed an inhibitory potential towards ß-secretase enzyme activity. All extracts showed no cytotoxic effect on pre-adipocytes and vero cells after 24- and 48-hours of exposure. CONCLUSION: Therefore, this may explain the mechanism through which AD symptoms may be treated and managed by Cannabis sativa L. extracts.

The modulatory role of prime identified compounds in Geophila repens in mitigating scopolamine-induced neurotoxicity in experimental rats of Alzheimer's disease via attenuation of cholinesterase, ß-secretase, MAPt levels and inhibition of oxidative stress imparts inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Geophila repens (L.) I.M. Johnst (Rubiaceae) is a small perennial creeper native to India, China, and other countries in Southeast Asia. The hot decoction of leaves is used orally for memory enhancing by the local folk of Andhra Pradesh, India. The ethnomedicinal claim of G. repens as memory enhancer was initially studied by the authors. Results demonstrated the important antioxidant and anticholinesterase activities of isolated molecule Pentylcurcumene and bioactive hydroalcohol extract of leaves of G. repens (GRHA). AIM OF THE STUDY: Based on the previous findings, additional research is needed to examine the efficacy of GRHA for memory enhancing properties. We therefore investigated the modulatory role of prime identified compounds in GRHA in mitigating scopolamine-induced neurotoxicity in experimental rats of Alzheimer's disease (AD) via attenuation of cholinesterase, ß-secretase, MAPt levels and inhibition of oxidative stress imparts inflammation. METHODS: Scopolamine (3 mg/kg) induced experimental rats of AD were treated with GRHA (300, 400 mg/kg) for 14 days. During the experimental period, elevated T-maze and locomotion-activity were performed to assess learning and memory efficacy of GRHA. At the end of the experiment, biochemical, neurochemical, neuroinflammation and histopathological observation of brain cortex were examined. GC-MS/MS analysis reported 31 compounds, among them 8 bioactive compounds possess antioxidant, neuroinflammation, neuroprotective activities, and were considered for docking analysis towards cholinesterase, ß-secretase activities in AD. RESULTS: GRHA 400 significantly improved learning and memory impairment with the improvement of oxidative stress (MDA, SOD, GSH, CAT), DNA damage (8-OHdG), neurochemical (AChE, BuChE, BACE1, BACE2, MAPt), neuroinflammation (IL-6, TNF-α) markers in neurotoxic rats. Docking studies of 8 compounds demonstrated negative binding energies for cholinesterase and ß-secretase indicating high affinity for target enzymes in AD. Test results were corroborated by the improvement of cellular tissue architecture of brain cortex in AD rats. CONCLUSION: Synergistic action of genistin, quercetin-3-D-galactoside, 9,12,15-octadecatrienoic-acid methyl-ester, phytol, retinal, stigmasterol, n-hexadecanoic acid, ß-sitosterol in GRHA restores memory-deficits via attenuation of cholinesterase, ß-secretase, MAPt level and inhibition of oxidative-stress imparts inflammation in AD.

Inhibition of BACE1 and amyloid ß aggregation by polyketide from Streptomyces sp.

Alzheimer's disease (AD) causes cognitive impairment in the elderly and is a severe problem worldwide. One of the major reasons for the pathogenesis of AD is thought to be due to the accumulation of amyloid beta (Aß) peptides that result in neuronal cell death in the brain. In this study, bioassay-guided fractionation was performed to develop seed compounds for anti-AD drugs that can act as dual inhibitors of BACE1 and Aß aggregation from secondary metabolites produced by Streptomyces sp. To improve the solubility, the crude extracts were methylated with trimethylsilyl (TMS) diazomethane and then purified to yield polyketides 1-5, including the new compound 1. We synthesized the compounds 6 and 7 (original compounds 2 and 3, respectively), and their activities were evaluated. KS-619-1, the demethylated form of 4 and 5, was isolated and evaluated for its inhibitory activity. The IC50 values for BACE1 and Aß aggregation were found to be 0.48 and 1.1 µM, respectively, indicating that KS-619-1 could be a lead compound for the development of therapeutic agents for AD.

Imino-2H-Chromene Based Derivatives as Potential Anti-Alzheimer's Agents: Design, Synthesis, Biological Evaluation and in Silico Study.

A new series of imino-2H-chromene derivatives were rationally designed and synthesized as novel multifunctional agents against Alzheimer's disease. A set of phenylimino-2H-chromenes as well as the newly synthesized iminochromene derivatives were evaluated as BACE1, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) inhibitors. The results indicated that among the iminochromene set, 10c bearing fluorobenzyl moiety was the most potent BACE1 inhibitor with an IC50 value 6.31 µM. In vitro anti-cholinergic activities demonstrated that compound 10a bearing benzyl pendant was the best inhibitor of AChE (% inhibition at 30 µM=24.4) and BuChE (IC50 =3.3 µM). Kinetic analysis of compound 10a against BuChE was also performed and showed a mixed-type inhibition pattern. The neuroprotective assessment revealed that compound 11b, a phenylimino-2H-chromene derivative with hydroxyethyl moiety, provided 32.3 % protection at 25 µM against Aß-induced PC12 neuronal cell damage. In addition, docking and simulation studies of the most potent compounds against BACE1 and BuChE confirmed the experimental results.

From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects.

Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Aß42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead.

BACE inhibitor treatment of mice induces hyperactivity in a Seizure-related gene 6 family dependent manner without altering learning and memory.

BACE inhibitors, which decrease BACE1 (ß-secretase 1) cleavage of the amyloid precursor protein, are a potential treatment for Alzheimer's disease. Clinical trials using BACE inhibitors have reported a lack of positive effect on patient symptoms and, in some cases, have led to increased adverse events, cognitive worsening and hippocampal atrophy. A potential drawback of this strategy is the effect of BACE inhibition on other BACE1 substrates such as Seizure-related gene 6 (Sez6) family proteins which are known to have a role in neuronal function. Mice were treated with an in-diet BACE inhibitor for 4-8 weeks to achieve a clinically-relevant level of amyloid-ß40 reduction in the brain. Mice underwent behavioural testing and postmortem analysis of dendritic spine number and morphology with Golgi-Cox staining. Sez6 family triple knockout mice were tested alongside wild-type mice to identify whether any effects of the treatment were due to altered cleavage of Sez6 family proteins. Wild-type mice treated with BACE inhibitor displayed hyperactivity on the elevated open field, as indicated by greater distance travelled, but this effect was not observed in treated Sez6 triple knockout mice. BACE inhibitor treatment did not lead to significant changes in spatial or fear learning, reference memory, cognitive flexibility or anxiety in mice as assessed by the Morris water maze, context fear conditioning, or light-dark box tests. Chronic BACE inhibitor treatment reduced the density of mushroom-type spines in the somatosensory cortex, regardless of genotype, but did not affect steady-state dendritic spine density or morphology in the CA1 region of the hippocampus. Chronic BACE inhibition for 1-2 months in mice led to increased locomotor output but did not alter memory or cognitive flexibility. While the mechanism underlying the treatment-induced hyperactivity is unknown, the absence of this response in Sez6 triple knockout mice indicates that blocking ectodomain shedding of Sez6 family proteins is a contributing factor. In contrast, the decrease in mature spine density in cortical neurons was not attributable to lack of shed Sez6 family protein ectodomains. Therefore, other BACE1 substrates are implicated in this effect and, potentially, in the cognitive decline in longer-term chronically treated patients.

Anti-Alzheimer chemical constituents of Morus macroura Miq.: chemical profiling, in silico and in vitro investigations.

Herein, we investigated both fruits and leaves of Morus macroura Miq. as a potential source of bioactive compounds against Alzheimer's disease (AD). LC-HRMS-assisted chemical profiling of its extracts showed that they are a rich source of diverse phytochemicals. Among the 29 identified compounds in both the fruit and leaf extracts, moracin D, chrysin, resveratrol, and ferulic acid were predicted to pass the human blood-brain barrier (BBB), and hence, reach their therapeutic targets in the brain. Subsequently, these compounds were subjected to a comprehensive pharmacophore-based screening for their protein targets relevant to AD using two independent software programs (i.e. Swiss Target Prediction and PharmMapper). The results of this initial virtual screening were further refined by a number of docking and molecular dynamic simulation experiments to suggest a number of crucial AD-related proteins (e.g. acetylcholine esterase, ß-secretase, and monoamine oxidase) as potential targets for these compounds. Finally, in vitro testing was performed to validate the in silico investigation's results, where chrysin, resveratrol, and ferulic acid were found to inhibit the predicted AD-related enzymes with IC50 values comparable with those of the reference inhibitors. Additionally, they were able to inhibit the aggregation of amyloid-beta, one of the hallmarks in AD pathogenesis, and to exhibit considerable antioxidant capacity. Our results highlighted Morus macroura compounds as future anti-Alzheimer chemical leads.

Investigation of anti-Alzheimer's activity of aqueous extract of areca nuts (Areca catechu L): in vitro and in vivo studies / Investigación de la actividad anti-Alzheimer del extracto acuoso de nueces de areca (Areca catechu L): estudios in vitro e in vivo

Alzheimer's disease (AD) is an age-related neurodegenerative disorder. Sever cognitive and memory impairments, huge increase in the prevalence of the disease, and lacking definite cure have absorbed worldwide efforts to develop therapeutic approaches. Since many drugs have failed in the clinical trials due to multifactorial nature of AD, symptomatic treatments are still in the center attention and now, nootropic medicinal plants have been found as versatile ameliorators to reverse memory disorders. In this work, anti-Alzheimer's activity of aqueous extract of areca nuts (Areca catechu L.) was investigated via in vitro and in vivo studies. It depicted good amyloid ß (Aß) aggregation inhibitory activity, 82% at 100 µg/mL. In addition, it inhibited beta-secretase 1 (BACE1) with IC50 value of 19.03 µg/mL. Evaluation of neuroprotectivity of the aqueous extract of the plant against H2O2-induced cell death in PC12 neurons revealed 84.5% protection at 1 µg/mL. It should be noted that according to our results obtained from Morris Water Maze (MWM) test, the extract reversed scopolamine-induced memory deficit in rats at concentrations of 1.5 and 3 mg/kg.

La enfermedad de Alzheimer (EA) es un trastorno neurodegenerativo relacionado con la edad. Los severos deterioros cognitivos y de la memoria, el enorme aumento de la prevalencia de la enfermedad y la falta de una cura definitiva han absorbido los esfuerzos mundiales para desarrollar enfoques terapéuticos. Dado que muchos fármacos han fallado en los ensayos clínicos debido a la naturaleza multifactorial de la EA, los tratamientos sintomáticos siguen siendo el centro de atención y ahora, las plantas medicinales nootrópicas se han encontrado como mejoradores versátiles para revertir los trastornos de la memoria. En este trabajo, se investigó la actividad anti-Alzheimer del extracto acuoso de nueces de areca (Areca catechu L.) mediante estudios in vitro e in vivo. Representaba una buena actividad inhibidora de la agregación de amiloide ß (Aß), 82% a 100 µg/mL. Además, inhibió la beta-secretasa 1 (BACE1) con un valor de CI50 de 19,03 µg/mL. La evaluación de la neuroprotección del extracto acuoso de la planta contra la muerte celular inducida por H2O2 en neuronas PC12 reveló una protección del 84,5% a 1 µg/mL. Cabe señalar que, de acuerdo con nuestros resultados obtenidos de la prueba Morris Water Maze (MWM), el extracto revirtió el déficit de memoria inducido por escopolamina en ratas a concentraciones de 1,5 y 3 mg/kg.

Desmoid-type fibromatosis: toward a holistic management.

PURPOSE OF REVIEW: Desmoid-type fibromatosis, a rare locally aggressive fibroblastic proliferation, is a treatment challenge. This review aimed to explore recent data about the management of desmoid-type fibromatosis. RECENT FINDINGS: New data underline the role of kinases and ɣ-secretase in stimulating cell proliferation and invasiveness in desmoid-type fibromatosis. This explains the proven activity of multikinase inhibitors (sorafenib or pazopanib) in the management of desmoid-type fibromatosis or the emerging role of a ɣ-secretase inhibitor. An international guideline for management was recently published, and this guideline take into account patient point of view. Lastly, recent studies highlight the multidimensional burden of desmoid-type fibromatosis, particularly health-related quality of life (HRQoL). SUMMARY: Active surveillance with planned MRI is the first-line management in desmoid-type fibromatosis. A site-specific and stepwise approach should be considered for progressive desmoid-type fibromatosis. Further, a risk-benefit analysis that considers the side effects and long-term sequelae should be conducted before deciding to start any treatment. A less aggressive approach should be considered. Multikinase inhibitors are effective, but their tolerability and side effects should be discussed with the patients. The symptoms and HRQoL should be integrated in decision-making. Desmoid-type fibromatosis patients should be offered support to address their needs supportive care.

Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures.

Notch1 is a crucial oncogenic driver in T-cell acute lymphoblastic leukemia (T-ALL), making it an attractive therapeutic target. However, the success of targeted therapy using γ-secretase inhibitors (GSIs), small molecules blocking Notch cleavage and subsequent activation, has been limited due to development of resistance, thus restricting its clinical efficacy. Here, we systematically compare GSI resistant and sensitive cell states by quantitative mass spectrometry-based phosphoproteomics, using complementary models of resistance, including T-ALL patient-derived xenografts (PDX) models. Our datasets reveal common mechanisms of GSI resistance, including a distinct kinase signature that involves protein kinase C delta. We demonstrate that the PKC inhibitor sotrastaurin enhances the anti-leukemic activity of GSI in PDX models and completely abrogates the development of acquired GSI resistance in vitro. Overall, we highlight the potential of proteomics to dissect alterations in cellular signaling and identify druggable pathways in cancer.

Synthesis and evaluation of multi-target-directed ligands with BACE-1 inhibitory and Nrf2 agonist activities as potential agents against Alzheimer's disease.

Cumulative evidence suggests that ß-amyloid and oxidative stress are closely related with each other and play key roles in the process of Alzheimer's disease (AD). Multitarget regulation of both pathways might represent a promising therapeutic strategy. Here, a series of selenium-containing compounds based on ebselen and verubecestat were designed and synthesized. Biological evaluation showed that 13f exhibited good BACE-1 inhibitory activity (IC50 = 1.06 µΜ) and potent GPx-like activity (ν0 = 183.0 µM min-1). Aß production experiment indicated that 13f could reduce the secretion of Aß1-40 in HEK APPswe 293T cells. Moreover, 13f exerted a cytoprotective effect against the H2O2 or 6-OHDA caused cell damage via alleviation of intracellular ROS, mitochondrial dysfunction, Ca2+ overload and cell apoptosis. The mechanism studies indicated that 13f exhibited cytoprotective effect by activating the Keap1-Nrf2-ARE pathway and stimulating downstream anti-oxidant protein including HO-1, NQO1, TrxR1, GCLC, and GCLM. In addition, 13f significantly reduced the production of NO and IL-6 induced by LPS in BV2 cells, which confirmed its anti-inflammatory activity as a Nrf2 activator. The BBB permeation assay predicted that 13f was able to cross the BBB. In summary, 13f might be a promising multi-target-directed ligand for the treatment of AD.

Balancing potency and basicity by incorporating fluoropyridine moieties: Discovery of a 1-amino-3,4-dihydro-2,6-naphthyridine BACE1 inhibitor that affords robust and sustained central Aß reduction.

ß-Site amyloid precursor protein cleaving enzyme 1 (BACE1) has been pursued as a prime target for the treatment of Alzheimer's disease (AD). In this report, we describe the discovery of BACE1 inhibitors with a 1-amino-3,4-dihydro-2,6-naphthyridine scaffold. Leveraging known inhibitors 2a and 2b, we designed the naphthyridine-based compounds by removing a structurally labile moiety and incorporating pyridine rings, which showed increased biochemical and cellular potency, along with reduced basicity on the amidine moiety. Introduction of a fluorine atom on the pyridine culminated in compound 11 which had improved cellular activity as well as further reduced basicity and demonstrated a robust and sustained cerebrospinal fluid (CSF) Aß reduction in dog. The crystal structure of compound 11 bound to BACE1 confirmed van der Waals interactions between the fluorine on the pyridine and Tyr71 in the flap.

Inhibitory mechanism of O-methylated quercetins, highly potent ß-secretase inhibitors isolated from Caragana balchaschensis (Kom.) Pojark.

ETHNOPHARMACOLOGICAL RELEVANCE: Caragana has a standing history of implementation in Traditional Chinese Medicine (TCM). Most species of this genus have been explored for multi-functional purposes, such as promoting blood circulation and curing neuralgia, fatigue, migraine, arthritis, and vascular hypertension (Meng et al., 2009). Among them, the well-known species C. sinica showed the most promising potential to increase the expression of ADAM10 among 313 tested medicinal plants, which is one of the promising approach for the treatment of Alzheimer's disease (AD). (Schuck et al., 2015). AIM OF THIS STUDY: The aim of this work is to explore ß-secretase inhibitory activity of compounds isolated from the aerial part of endemic Caragana balchaschensis (Kom.) Pojark. We provided a full characterization of their inhibitory mechanisms, binding affinities, and binding modes. MATERIALS AND METHODS: The isolation of quercetin derivatives was accomplished by various chromatographical approaches and their structures were annotated by spectroscopic analysis. The detailed kinetic behavior of ß-secretase inhibitors was determined by estimation of kinetic parameters (Km, Vmax, KI, and KIS). Binding affinities (KSV) and binding modes of inhibitors were elucidated by fluorescence quenching and molecular docking studies, respectively. RESULTS: O-methylated quercetins (2-7) were significantly effective in ß-secretase inhibition with IC50 ranging from 1.2 to 6.5 µM. The most active one (6) was 20-fold effective than the mother skeleton, quercetin. The O-methyl motif was a critical factor in ß-secretase inhibition: tri-O-methylated (1.2 µM) > di-O-methylated (3.5 µM) > mono-O-methylated (6.5 µM) > quercetin (25.2 µM). In the kinetic study, all quercetins (1-7) showed a noncompetitive inhibition, but glucoside ones (8 and 9) were mixed type I inhibitors. The binding affinities (KSV) were agreed with inhibitory potencies. The O-methylated quercetins were annotated as the most natural abundant metabolites in the aerial part by LC-ESI-TOF/MS. Binding modes of inhibitors to enzyme were elucidated by molecular docking experiments. CONCLUSION: This study disclosed that most of the major phenolic metabolites of the aerial part of C. balchaschensis are O-methylated quercetins, which have a significant inhibitory effect on ß-secretase, which is a critical factor for AD.

Identification of new BACE1 inhibitors for treating Alzheimer's disease.

Alzheimer's disease (AD) is a type of brain disorder, wherein a person experiences gradual memory loss, state of confusion, hallucination, agitation, and personality change. AD is marked by the presence of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) and synaptic losses. Increased cases of AD in recent times created a dire need to discover or identify chemical compounds that can cease the development of AD. This study focuses on finding potential drug molecule(s) active against ß-secretase, also known as ß-site amyloid precursor protein cleaving enzyme 1 (BACE1). Clustering analysis followed by phylogenetic studies on microarray datasets retrieved from GEO browser showed that BACE1 gene has genetic relatedness with the RCAN1 gene. A ligand library comprising 60 natural compounds retrieved from literature and 25 synthetic compounds collected from DrugBank were screened. Further, 350 analogues of potential parent compounds were added to the library for the docking purposes. Molecular docking studies identified 11-oxotigogenin as the best ligand molecule. The compound showed the binding affinity of - 11.1 Kcal/mole and forms three hydrogen bonds with Trp124, Ile174, and Arg176. The protein-ligand complex was subjected to 25 ns molecular dynamics simulation and the potential energy of the complex was found to be - 1.24579e+06 Kcal/mole. In this study, 11-oxotigogenin has shown promising results against BACE1, which is a leading cause of AD, hence warrants for in vitro and in vivo validation of the same. In addition, in silico identification of 11-oxotigogenin as a potential anti-AD compound paves the way for designing of chemical scaffolds to discover more potent BACE1 inhibitors.Graphical abstract.

Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice.

The combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in C57BL6 mice, with one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced Aß42/Aß40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound 5i emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.

Lepidine B from Lepidium sativum Seeds as Multi-Functional Anti- Alzheimer's Disease Agent: In Vitro and In Silico Studies.

OBJECTIVE: The present study is carried out to screen the anticholinesterase effect of the total alkaloids of L. sativum seeds and other plants, and studied the ability of Lepidine B & E to inhibit AChE, BuChE, BACE, and MAGL. Hence, determining the main interactions in the inhibitorenzyme complex. METHODS: Inhibitory effect of Lepidium sativum, Juniperus phoenicea and Juniperus oxycedrus extracts on acetylcholinesterase using the Ellman method was investigated with Donepezil as the positive control. A molecular docking study is achieved using Autodock Vina. The structures of target molecules Lepidine B & E and the four enzymes were obtained from the PubChem database and Protein databank. RESULTS: Alkaloidal extract of Lepidium sativum and ethyl acetate extracts of Juniperus phoenicea and Juniperus oxycedrus exhibit a strong acetylcholinesterase inhibitory activity with IC50 values of 0.59 ± 0.04, 0.57 ± 0.00 and 0.49 ± 0.00 mg/mL, respectively using Donepezil <0.25 mg/mL as a positive control. The major components of alkaloids of L. sativum, Lepidine B & E bind tightly to AChE and BuChE as much as galantamine and donepezil. We suggest that Lepidine B is a noncompetitive inhibitory by interacting with PAS of AChE and BuChE, therefore it is capable to prevent the HuAChE-induced Aß aggregation. All the complexes of Lepidine B &E with the four enzymes show significant, several and different interactions. CONCLUSION: Our current study indicates that Lepidine B & E are promising anti-AD drugs and might become drug candidates to prevent Alzheimer's disease due to their multiple roles as potent inhibitors for AChE, BuChE, BACE, and MAGL. Indeed, they could inhibit Aß fibrillogenesis. No previous results about the inhibitory effect of Lepidine B & E on the AChE, BuChE, ß secretase, and monoacylglycerol lipase were reported.

Potent In Vitro α-Glucosidase and ß-Secretase Inhibition of Amyrin-Type Triterpenoid Isolated from Datura metel Linnaeus (Angel's Trumpet) Fruits.

This study deals with α-glucosidase and ß-secretase inhibitory screening of extract/fractions and isolated daturaolone (1), namely, 3-oxo-6-ß-hydroxy-ß-amyrin (daturaolone) from chloroform fraction of Datura metel L. Among entire fractions, the chloroform soluble fraction showed excellent activity against α-glucosidase with % inhibition 90.8 with IC50160.2 ± 1.85 µg and daturaolone (1) with 98.7% inhibition with IC50840.4 ± 1.74 µM, respectively. Similarly, extract and daturaolone (1) also exhibited significant activity against the ß-secretase enzyme (BACE1) with % activities 88.27 and 95.19 and with IC50 values 304.21 ± 2.98 µg and 260.70 ± 1.87 µM, respectively, as compared to the standard inhibitor (Ans670, Sta671, Val672)-amyloid-ß/A4 precursor protein 770 fragments 662-675) with % activity 94.21 and IC50 value 289.24 ± 1.60 µM. This finding encourages and opens a new window for further detail phytochemical investigation on D. metel in order to isolate novel compounds with promising enzyme inhibitory potential.

The Effect of Sacred Lotus (Nelumbo nucifera) and Its Mixtures on Phenolic Profiles, Antioxidant Activities, and Inhibitions of the Key Enzymes Relevant to Alzheimer's Disease.

Sacred lotus (Nelumbo nucifera) has long been used as a food source and ingredient for traditional herbal remedies. Plant parts contain neuroprotective agents that interact with specific targets to inhibit Alzheimer's disease (AD). Organic solvents including methanol, ethyl acetate, hexane, and n-butanol, are widely employed for extraction of sacred lotus but impact food safety. Seed embryo, flower stalk, stamen, old leaf, petal, and leaf stalk of sacred lotus were extracted using hot water (aqueous extraction). The extractions were analyzed for their bioactive constituents, antioxidant and anti-AD properties as key enzyme inhibitory activities toward acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ß-secretase 1 (BACE-1). Results showed that the sacred lotus stamen exhibited significant amounts of phenolics, including phenolic acids and flavonoids, that contributed to high antioxidant activity via both single electron transfer (SET) and hydrogen atom transfer (HAT) mechanisms, with anti-AChE, anti-BChE, and anti-BACE-1 activities. To enhance utilization of other sacred lotus parts, a combination of stamen, old leaf and petal as the three sacred lotus plant components with the highest phenolic contents, antioxidant activities, and enzyme inhibitory properties was analyzed. Antagonist interaction was observed, possibly from flavonoids-flavonoids interaction. Further in-depth elucidation of this issue is required. Findings demonstrated that an aqueous extract of the stamen has potential for application as a functional food to mitigate the onset of Alzheimer's disease.