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1.
Angew Chem Int Ed Engl ; 62(32): e202304196, 2023 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-37186340

RESUMO

Complex nuclear magnetic resonance (NMR) signals of organic compounds containing multiple analogous substructures or mixtures pose a significant challenge to structural identification, thus resulting in frequent misassignment of structures. The GEMSTONE method, a single-scan technique that selectively excites a specific proton signal among the crowded NMR signals, was recently proposed as a solution. However, its extension to the polarization transfer method for heteronuclear spin systems was unsuccessful. Herein, we present an extension method that addresses the altered heteronuclear polarization transfer efficiency and enables the acquisition of ultraselective 13 C and 1 H-13 C correlation NMR subspectra with hertz-level signal selectivity in both dimensions. We demonstrate the effectiveness of this technique in the structural analysis of a chromopeptide pharmaceutical and a diastereomeric mixture of a fungicide.

2.
Mar Drugs ; 20(5)2022 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-35621932

RESUMO

Two new pyrrolosesquiterpenes, glaciapyrroles D (1) and E (2) were discovered along with the previously reported glaciapyrrole A (3) from Streptomyces sp. GGS53 strain isolated from deep-sea sediment. This study elucidated the planar structures of 1 and 2 using nuclear magnetic resonance (NMR), mass spectrometry (MS), ultraviolet (UV), and infrared (IR) spectroscopic data. The absolute configurations of the glaciapyrroles were determined by Mosher's method, circular dichroism spectroscopy, and X-ray crystallography. Under 366 nm UV irradiation, the glaciapyrroles were systematically converted to the corresponding photoglaciapyrroles (4-6) via photoisomerization, resulting in the diversification of the glaciapyrrole family compounds. The transformation of the glaciapyrrole Z to E isomers occurred in a 1:1 ratio, based on virtual validation of the photoisomerization of these olefinic compounds by 1H-NMR spectroscopy and liquid chromatography/mass spectrometry (LC/MS) analysis. Finally, when encapsulated in poly(lactic-co-glycolic acid) nanoparticles, glaciapyrrole E and photoglaciapyrrole E displayed significant inhibitory activity against influenza A virus. This is the first report of antiviral effects from glaciapyrrole family compounds, whose biological functions have only been subjected to limited studies so far.


Assuntos
Streptomyces , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Streptomyces/química
3.
Anal Chem ; 92(10): 7037-7044, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32384237

RESUMO

In NMR analysis of complex organic molecules, low natural abundance of 13C and the low resolution of two-dimensional (2D) experiments are significant difficulties. Also challenging is the analysis of a mixture spectrum without separation, which has been limited to simple molecules. Through nonuniform sampling using modified heteronuclear multiple bond correlation combined with indirect covariance, a high-resolution 13C-13C correlation spectrum was obtained with 1H sensitivity. Built on the thus-obtained 13C-13C connectivities, deconvolution of the mixture spectra was achieved through a new signal-processing procedure, termed DECODE, tailored to the indirect covariance eigendecomposition. When applied to a complex natural product mixture of rotenone and brucine with many quaternary carbons, the method resolved very close carbon peaks and extracted clean individual spectra. Essentially providing molecule-wide 13C connectivities for complex molecules from 1H-detected 2D spectra, our approach should prove useful in many areas of NMR analysis.

4.
Anal Chem ; 92(11): 7382-7387, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32392040

RESUMO

AMP-activated protein kinase (AMPK in human and AAK in C. elegans) is a master regulator of metabolism. It has many isotypes, but its isotype-dependent functions are largely unknown. By developing real-time in-organism NMR metabolomics for C. elegans, we were able to study different roles of the isotypic catalytic subunits of AAK/AMPK, AAK-1, and AAK-2 in live worms at the whole organism level. The aak-1 knockout animals exhibited enhanced glucose production under starvation, strikingly opposite to aak-2 knockout animals. Unusually high compensatory expression of the reciprocal isotypes in each KO strain and the results for the double KO animals suggested an unconventional phenotype-genotype relationship and the dominance of aak-2 in glucose production. The gene expression patterns showed that the differential phenotypes of aak-1 KO strain are due to reduced TCA and glycolysis and enhanced gluconeogenesis compared to the aak-2 KO strain. Subsequent 13C-isotope incorporation experiment showed that the glucose production in aak-1 KO occurs through the activation of fatty acid oxidation and glyoxylate shunt. Revealing differential roles of the isotypes of AAK/AMPK, our convenient approach is readily applicable to many C. elegans models for human metabolic diseases.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Metabolômica , Ressonância Magnética Nuclear Biomolecular , Animais , Caenorhabditis elegans/enzimologia , Domínio Catalítico , Humanos , Fatores de Tempo
5.
J Sci Food Agric ; 100(7): 2938-2945, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32031246

RESUMO

BACKGROUND: Gut microbiota are major contributors to host metabolism and are considered as potential targets of novel therapeutics. Microalgae have a strong potential for use as prebiotics because they are a rich source of proteins, fatty acids, fiber, and minerals for nutritional supplementation in humans. Nevertheless, there has been insufficient research into the effect of microalgae on gut microbiota. To investigate the effects of three edible microalgae (Chlorella vulgaris, Chlorella protothecoides, and Schizochytrium sp.) on gut microbiota, simulated digestion and colonic fermentation were examined. RESULTS: Following in vitro digestion, the microalgae displayed different levels of bioaccessibility and the nutrient analysis revealed that unabsorbed nutrients during the digestion process could be used for colonic fermentation. Following colonic fermentation, the control, inulin, and microalgae groups displayed different metabolite tendencies when investigated with nuclear magnetic resonance (NMR) spectroscopic analysis. In particular, microalgae supplementation increased the proportion of propionate in the colonic culture (control: 19.14%, Inulin: 18.38%, C. vulgaris: 25.80%, C. protothecoides: 25.46%, and Schizochytrium sp.: 25.56%). Microbial profiling analysis using 16S rRNA gene sequencing also disclosed that the relative abundance of Bacteroides (control: 1.91%, inulin: 2.61%, C. vulgaris: 14.77%, C. protothecoides: 11.17%, and Schizochytrium sp.: 5.51%) and Dialister (control: 0.08%, inulin: 2.06%, C. vulgaris: 6.79%, C. protothecoides: 4.45%, and Schizochytrium sp.: 4.48%), involved in propionate metabolism increased more than in the inulin group. CONCLUSION: Our findings suggest the potential use of microalgae as a functional food to increase propionate generation because propionate has been reported to be effective in weight loss and the inhibition of pathogen infection. © 2020 Society of Chemical Industry.


Assuntos
Bactérias/metabolismo , Microbioma Gastrointestinal/fisiologia , Microalgas , Prebióticos , Adulto , Bactérias/classificação , Bactérias/genética , Chlorella , Chlorella vulgaris , Alimento Funcional , Humanos , Inulina/metabolismo , RNA Ribossômico 16S , Estramenópilas
6.
Anal Chem ; 89(2): 1078-1085, 2017 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-28029042

RESUMO

Isotopomer analysis using either 13C NMR or LC/GC-MS has been an invaluable tool for studying metabolic activities in a variety of systems. Traditional challenges are, however, that 13C-detected NMR is insensitive despite its high resolution, and that MS-based techniques cannot easily differentiate positional isotopomers. In addition, current 13C NMR or LC/GC-MS has limitations in detecting metabolites in living cells. Here, we describe a non-uniform sampling-based 2D heteronuclear single quantum coherence (NUS HSQC) approach to measure metabolic isotopomers in both cell lysates and living cells. The method provides a high resolution that can resolve multiplet structures in the 13C dimension while retaining the sensitivity of the 1H-indirect detection. The approach was tested in L1210 mouse leukemia cells labeled with 13C acetate by measuring NUS HSQC with 25% sampling density. The results gave a variety of metabolic information such as (1) higher usage of acetate in acetylation pathway than aspartate synthesis, (2) TCA cycle efficiency changes upon the inhibition of mitochondrial oxidative phosphorylation by pharmacological agents, and (3) position-dependent isotopomer patterns in fatty acids in living cells. In addition, we were able to detect fatty acids along with other hydrophilic molecules in one sample of live cells without extraction. Overall, the high sensitivity and resolution along with the application to live cells should make the NUS HSQC approach attractive in studying carbon flux information in metabolic studies.


Assuntos
Isótopos de Carbono/metabolismo , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13/métodos , Redes e Vias Metabólicas , Metabolômica/métodos , Acetatos/análise , Acetatos/metabolismo , Animais , Isótopos de Carbono/análise , Linhagem Celular Tumoral , Sobrevivência Celular , Leucemia/metabolismo , Camundongos , Manejo de Espécimes/métodos
7.
Bioorg Med Chem Lett ; 25(22): 5083-6, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26483134

RESUMO

New phenazine derivatives with a methylamine linker, Pontemazines A (1) and B (2), were isolated from the culture broth of Streptomyces sp. UT1123. The structures of compounds 1 and 2 were determined by NMR spectroscopy and high-resolution mass spectrometry. These compounds consist of a 9-mehoxyphenazine connected to a benzamide functional group by a unique methylamine linker instead of the more common methyl ether. Pontemazines A and B possess a neuronal cell protective effect on glutamate-induced mouse hippocampal HT-22 cell damage.


Assuntos
Fármacos Neuroprotetores/farmacologia , Fenazinas/farmacologia , Streptomyces/química , Animais , Linhagem Celular , Ácido Glutâmico/toxicidade , Espectroscopia de Ressonância Magnética , Camundongos , Fármacos Neuroprotetores/isolamento & purificação , Fenazinas/isolamento & purificação
8.
Free Radic Biol Med ; 221: 98-110, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-38754743

RESUMO

Photodynamic therapy is a noninvasive treatment in which specific photosensitizers and light are used to produce high amounts of reactive oxygen species (ROS), which can be employed for targeted tissue destruction in cancer treatment or antimicrobial therapy. However, it remains unknown whether lower amounts of ROS produced by mild photodynamic therapy increase lifespan and stress resistance at the organism level. Here, we introduce a novel photodynamic treatment (PDTr) that uses 20 µM hypericin, a photosensitizer that originates from Hypericum perforatum, and orange light (590 nm, 5.4 W/m2, 1 min) to induce intracellular ROS formation (ROS), thereby resulting in lifespan extension and improved stress resistance in C. elegans. The PDTr-induced increase in longevity was abrogated by N-acetyl cysteine, suggesting the hormetic response was driven by prooxidative mechanisms. PDTr activated the translocation of SKN-1/NRF-2 and DAF-16/FOXO, leading to elevated expression of downstream oxidative stress-responsive genes, including ctl-1, gst-4, and sod-3. In summary, our findings suggest a novel PDTr method that extends the lifespan of C. elegans under both normal and oxidative stress conditions through the activation of SKN-1 and DAF-16 via the involvement of many antioxidant genes.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Longevidade , Estresse Oxidativo , Perileno , Fotoquimioterapia , Fármacos Fotossensibilizantes , Espécies Reativas de Oxigênio , Fatores de Transcrição , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Estresse Oxidativo/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Perileno/análogos & derivados , Perileno/farmacologia , Antracenos/farmacologia , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Luz , Acetilcisteína/farmacologia
9.
Biol Pharm Bull ; 36(11): 1747-53, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24189419

RESUMO

The oral consumption of capsicum has been reported to increase interleukin (IL)-2 and interferon (IFN)-γ production in Peyer's patches (PP); however, the active components responsible for these effects have not been completely identified. The beneficial biological effects of green peppers cultivated under environmentally friendly farming conditions (ECP), without the use of chemical pesticides, have rarely been compared with those of green peppers cultivated under conventional farming conditions (CCP). Oral administration of ECP extract significantly induced the production of IL-2 and IFN-γ in concanavalin A-treated cells from PP ex vivo; their levels were much higher than those in the CCP extract-treated group. A comparative analysis of the HPLC profiles indicated a 1.7-fold increase of a peak, named EF-1, at 415 nm in the ECP extract. The major component of EF-1 was identified as pheophytin a, which is a chlorophyll a molecule lacking a central Mg(2+) ion, as determined from NMR data. Intake of pheophytin a and chlorophyll a significantly increased IL-2 and IFN-γ production, and the percentage of IL-2- and IFN-γ-producing CD4+ T-cells in PP. Taken together, our data suggest that ECPs produce a higher content of pheophytin a than CCPs, and pheophytin a and chlorophyll a are immune-modulating components in green vegetables.


Assuntos
Capsicum , Clorofila/farmacologia , Interferon gama/metabolismo , Interleucina-2/metabolismo , Nódulos Linfáticos Agregados/efeitos dos fármacos , Feofitinas/farmacologia , Agricultura/métodos , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Clorofila/isolamento & purificação , Clorofila A , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nódulos Linfáticos Agregados/metabolismo , Feofitinas/isolamento & purificação , Extratos Vegetais/química
10.
J Nat Prod ; 75(9): 1648-51, 2012 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-22953793

RESUMO

A new lucentamycin analogue, lucentamycin E (5), was isolated from the culture broth of the marine-derived actinomycete Nocardiopsis lucentensis, strain CNR-712. The absolute stereostructure of 5 was assigned by comprehensive analyses of NMR data and by application of the advanced Marfey's method. The planar structure of 5 was analogous to lucentamycins A-D, whereas the olefin geometry of the 3-methyl-4-ethylideneproline moiety was found to be E, opposite of that previously reported. Consequently, a reinvestigation of the olefin geometries of the 3-methyl-4-ethylideneproline residues of lucentamycins A-D showed that the olefin geometries of the substituted proline functionalities must be revised to (2S,3R,E)-3-methyl-4-ethylideneproline.


Assuntos
Actinobacteria/química , Alcenos/química , Oligopeptídeos/química , Bahamas , Biologia Marinha , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Prolina/análogos & derivados , Prolina/química
11.
Antioxidants (Basel) ; 11(11)2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36358578

RESUMO

With the recent development of chemical analysis technology, attention has been placed on natural light-sensitive compounds that exhibit photoreactivity to expand the structural diversity of natural product chemistry. Photochemical reactions that proceed via a free radical mechanism could be used to modulate the radical-scavenging ability of natural products as well as involve structural change. As the health benefits of radicals are also presented, there is a need for a controllable radical scavenging method for topical and selective application. In this study, we developed a novel acquisition and processing method to identify light-controlled radical scavengers in plant extracts and evaluate their antioxidant activity under light irradiation based on in situ UV-LED NMR spectroscopy. Using the developed method, licochalcones A and B, in which the trans and cis isomers undergo reversible photoisomerization, were selectively identified from licorice root extract, and their light-induced free radical scavenging activity was confirmed.

12.
Chem Sci ; 12(13): 4958-4962, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-34168765

RESUMO

Metabolomic isotopic tracing can provide flux information useful for understanding drug mechanisms. For that, NMR has the unique advantage of giving positional isotope enrichment information, but the current 13C 1D NMR approach suffers from low sensitivity and high overlaps. We developed a new 2D heteronuclear NMR experiment incorporating J-scaling and distortion-free elements that allows for quantitative analysis of multiplets with high sensitivity and resolution. When applied to an old chemotherapeutic drug, the approach provided a quantitative estimation of TCA-cycle turns, confirming the conventional mechanism of its mitochondrial metabolic enhancement. Additionally, the approach identified a new mechanism of the higher contribution of the pentose phosphate pathway to serine synthesis in the cytosolic compartment, possibly explaining the broad pharmacological activities of the drug. Our approach may prove beneficial in helping to find new usages or metabolic mechanisms of other drugs.

13.
ACS Chem Biol ; 11(11): 3140-3145, 2016 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-27700045

RESUMO

Glutamine plays key roles as a biosynthetic precursor or an energy source in cancers, and interest in its metabolism is rapidly growing. However, the proper evaluation of glutamine hydrolysis, the very first reaction in the entire glutaminolysis, has been difficult. Here, we report a triple resonance NMR-based assay for specific detection of glutaminase activity carrying out this reaction using stable-isotope labeled glutamine. Compared to conventional methods involving coupled enzyme assays, the proposed approach is direct because it detects the presence of the H-N-CO amide spin system. In addition, the method is unique in enabling the measurement of glutamine hydrolysis reaction in real-time in live cells. The approach was applied to investigating the effects of a glutaminase inhibitor and the inhibitory effects of glucose on glutamine metabolism in live cells. It can be easily applied to studying other signals that affect cellular glutamine metabolism.


Assuntos
Glutamina/metabolismo , Ressonância Magnética Nuclear Biomolecular/métodos , Animais , Linhagem Celular Tumoral , Glucose/metabolismo , Hidrólise , Camundongos
14.
Org Lett ; 17(20): 5024-7, 2015 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-26446186

RESUMO

Salinazinones A (1) and B (2), two unprecedented pyrrolidinyl-oxazinones, were isolated from the culture broth of Streptomyces sp. KMF-004 from a solar saltern at Aphae Island, Korea. The structures of these salinazinones, which are unusual and consist of 2-methylpropenyl-1,3-oxazin-6-one bearing 1-oxopyrrolidinyl substituents, were assigned by spectral and chemical analyses using Mosher's method, circular dichroism (CD), and calculated ECD. Salinazinones are the first examples of a natural alkaloid class composed of an oxazinone-pyrrolidone conjugate.


Assuntos
Oxazinas/isolamento & purificação , Pirrolidinas/síntese química , Streptomyces/química , Animais , Dicroísmo Circular , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/biossíntese , Oxazinas/química , Oxazinas/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , República da Coreia
15.
J Ethnopharmacol ; 159: 93-101, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25449460

RESUMO

AIM OF THE STUDY: Previous studies in our laboratory revealed the neuroprotective effect of modified Yeoldahanso-tang (MYH) in models of Parkinson׳s disease (PD). In this study, we investigated another traditional Korean herbal formula, modified Chungsimyeolda-tang (termed DG), as a potential treatment for PD. Chungsimyeolda-tang has been used in Korea to treat cerebrovascular diseases, such as stroke. Here, we verify the neuroprotective and autophagy-inducing effects of DG to evaluate any potential anti-parkinsonian properties. MATERIALS AND METHODS: 1-Methyl-4-phenylpyridinium (MPP(+)) and rotenone were used to induce cytotoxicity in nerve growth factor (NGF)-differentiated rat pheochromocytoma (PC12) cells. Cell viability was measured using an MTT assay. Induction of autophagy by DG in NGF-differentiated PC12 cells was measured using an immunoblotting assay with an LC3 antibody. The proteasomal inhibitor lactacystin was used to induce ubiquitin-proteasome system (UPS) dysfunction in NGF-differentiated PC12 cells. DG-mediated clearance of aggregated proteins was measured using an immunoblotting assay with a ubiquitin antibody. RESULTS AND CONCLUSIONS: Our findings indicate that DG robustly protects NGF-differentiated PC12 cells against the neurotoxic effects of MPP(+) and rotenone in an in vitro model. Furthermore, DG protects NGF-differentiated PC12 cells against lactacystin-induced cell death. This effect is partially mediated by an increased autophagy associated with the enhanced degradation of aggregated proteins. This study suggests that DG is an attractive candidate drug for inducing autophagy and, therefore, may represent a promising strategy to prevent diseases associated with misfolded/aggregated proteins in various neurodegenerative disorders, including Parkinson׳s disease.


Assuntos
Antiparkinsonianos/farmacologia , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , 1-Metil-4-fenilpiridínio , Animais , Autofagia/efeitos dos fármacos , Medicina Tradicional Coreana , Células PC12 , Doença de Parkinson/tratamento farmacológico , Ratos , Rotenona
16.
J Agric Food Chem ; 63(31): 6979-88, 2015 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-26218758

RESUMO

We found that an extract of Lycoris chejuensis and its three isolated active components, narciclasine, 7-deoxynarciclasine, and 7-deoxy-trans-dihydronarciclasine, each significantly reduced the formation of amyloid-ß peptides in HeLa cells transfected with an amyloid precursor protein carrying the Swedish mutation up to 45 ± 3.6%. The extract down-regulated amyloid precursor protein, especially the mature form by up to 88%, and reduced the ability of secretases to generate toxic amyloid-ß. Double-transgenic mice treated with the extract for 4 months also showed significantly reduced levels of amyloid-ß and plaques while exhibiting improved memory functions in the Morris water maze and novel object recognition tests. In conclusion, the extract and isolated active components of L. chejuensis decreased the production of amyloid-ß by attenuating amyloid precursor protein levels. Furthermore, the extract improved the disrupted memory functions in animals while inhibiting amyloid plaque formation. Thus, this extract, as well as its active components, could prove beneficial in the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Lycoris/química , Extratos Vegetais/administração & dosagem , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Transgênicos
17.
Eur J Pharmacol ; 672(1-3): 45-55, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21978835

RESUMO

Amyloid ß-protein (Aß), which is deposited in neurons as neurofibrillary tangles, is known to exert cytotoxic effects by inducing mitochondrial dysfunction. Additionally, the PI3K/Akt-mediated interaction between Bad and Bcl(XL) plays an important role in maintaining mitochondrial integrity. However, the application of therapeutic drugs, especially natural products in Alzheimer's disease therapy via PI3K/Akt/Bad/Bcl(XL)-regulated mitochondrial apoptotic pathway has not aroused extensive attention. In the present study, we investigated the neuroprotective effects of hyperoside, a bioactive flavonoid compound from Hypericum perforatum, on Aß(25-35)-induced primary cultured cortical neurons, and also examined the potential cellular signaling mechanism for Aß detoxication. Our results showed that treatment with hyperoside significantly inhibited Aß(25-35)-induced cytotoxicity and apoptosis by reversing Aß-induced mitochondrial dysfunction, including mitochondrial membrane potential decrease, reactive oxygen species production, and mitochondrial release of cytochrome c. Further study indicated that hyperoside can activate the PI3K/Akt signaling pathway, resulting in inhibition of the interaction between Bad and Bcl(XL), without effects on the interaction between Bad and Bcl-2. Furthermore, hyperoside inhibited mitochondria-dependent downstream caspase-mediated apoptotic pathway, such as that involving caspase-9, caspase-3, and poly ADP-ribose polymerase (PARP). These results demonstrate that hyperoside can protect Aß-induced primary cultured cortical neurons via PI3K/Akt/Bad/Bcl(XL)-regulated mitochondrial apoptotic pathway, and they raise the possibility that hyperoside could be developed into a clinically valuable treatment for Alzheimer's disease and other neuronal degenerative diseases associated with mitochondrial dysfunction.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Apoptose/efeitos dos fármacos , Córtex Cerebral/citologia , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/toxicidade , Quercetina/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Animais , Caspase 3/metabolismo , Caspase 9/metabolismo , Células Cultivadas , Citoproteção/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/citologia , Neurônios/enzimologia , Neurônios/metabolismo , Neurotoxinas/toxicidade , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quercetina/farmacologia , Ratos , Ratos Sprague-Dawley , Proteína de Morte Celular Associada a bcl/metabolismo , Proteína bcl-X/metabolismo
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