RESUMO
Chemical investigation of a methanol extract obtained from the roots of Lespedeza bicolor identified one new pterocarpene (1), three new pterocarpans (2-4), and three new arylbenzofurans (5-7), and two known compounds (8 and 9). Their structures were determined by interpretations obtained from combined UV, NMR, and HRTOFMS spectroscopic data. Furthermore, the absolute configurations of compounds 2 and 3 were established by the combination of electronic circular dichroism (ECD) calculations and NMR calculations with DP4+ probability analysis. All isolated compounds (1-9) were evaluated for cytotoxicity against the human lung carcinoma cell line A549 and the human hepatoma cell line Huh-7. Compound 4 showed antiproliferative activity against A549 cell line with IC50 value of 24.9 µM. Furthermore, compound 9 exhibited cytotoxicity against Huh-7 cell line with IC50 value of 68.7 µM.
Assuntos
Lespedeza , Neoplasias Hepáticas , Humanos , Lespedeza/química , Estrutura Molecular , Linhagem Celular , Espectroscopia de Ressonância MagnéticaRESUMO
Leukemia, despite currently being one of the most lethal cancers worldwide, still lacks a focused treatment. The purpose of the present investigation was to evaluate the pharmacological effect of 1-methoxyerythrabyssin II, a pterocarpan identified in the roots of Lespedeza bicolor, on leukemic cells and to explore its underlying mechanism using a network pharmacology strategy. 1-Methoxyerythrabyssin II showed an antiproliferative effect in a concentration-dependent manner and exhibited a higher potency in human acute leukemia T cells (Jurkat). The G1 phase arrest induced by 1-methoxyerythrabyssin II was confirmed using a cell cycle assay, and the downregulation of CDK2 and cyclin D1 was observed using an immunoblot assay. Moreover, 1-methoxyerythrabyssin II-treated cells exhibited higher expression levels of LC3B, Atg-7, and Beclin 1 in addition to an enhanced fluorescence intensity in monodansylcadaverine staining, indicating autophagy induction by 1-methoxyerythrabyssin II. Furthermore, network pharmacology and molecular docking analyses revealed that the PI3K/Akt/mTOR pathway is a potential target of 1-methoxyerythrabyssin II in leukemic cells. In vitro assays further demonstrated that 1-methoxyerythrabyssin II promoted autophagy and suppressed cell proliferation by inhibiting the PI3K/Akt/mTOR pathway in leukemic cells. This discovery will contribute to the development of novel therapeutics and prophylactics against leukemia.
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Symplocos sumuntia Buch.-Ham. ex D. Don (S. sumuntia) is a traditional medicinal herb used in Asia to treat various pathologies, including cough, stomachache, tonsillitis, hypertension, and hyperlipidemia. Although the anti-inflammatory activity of S. sumuntia has been reported, little is known about its anti-inflammatory activity and molecular mechanisms in microglial cells. Therefore, we investigated the inhibitory effects of S. sumuntia methanol extract (SSME) on the inflammatory responses in lipopolysaccharide (LPS)-treated BV2 cells. The SSME significantly inhibited the LPS-stimulated inducible nitric oxide synthase and cyclooxygenase-2 expression, as well as the production of nitric oxide (NO), a proinflammatory mediator. The production of proinflammatory cytokines, including interleukin (IL)-6, tumor necrosis factor-α, and IL-1ß, was suppressed by the SSME in the LPS-induced BV2 cells. The mechanism underlying the anti-inflammatory effects of SSME involves the suppression of the LPS-stimulated phosphorylation of mitogen-activated protein kinases (MAPKs) such as JNK. Moreover, we showed that the LPS-stimulated nuclear translocation of the nuclear factor-κB (NF-κB)/p65 protein, followed by IκB degradation, was decreased by the SSME treatment. Collectively, these results showed that the SSME induced anti-inflammatory effects via the suppression of the MAPK signaling pathways, accompanied by changes in the NF-κB translocation into the nucleus. Therefore, SSME may be employed as a potential therapeutic candidate for various inflammatory diseases.
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ETHNOPHARMACOLOGICAL RELEVANCE: Activated astrocytes are involved in the progression of neurodegenerative diseases. Traditionally, Ailanthus altissima (Mill.) Swingle, widely distributed in East Asia, has been used as a medicine for the treatment of fever, gastric diseases, and inflammation. Although A. altissima has been reported to play an anti-inflammatory role in peripheral tissues or cells, its role in the central nervous system (CNS) remains unclear. AIM OF THE STUDY: In the present study, we investigated the anti-inflammatory effects and mechanism of action of A. altissima in primary astrocytes stimulated by lipopolysaccharide (LPS). MATERIALS AND METHODS: A nitrite assay was used to measure nitric oxide (NO) production, and the tetrazolium salt 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was performed to determine cytotoxicity. The expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and mitogen-activated protein kinase (MAPK) were determined with western blotting. Reverse-transcription PCR was used to assess the expression of inflammatory cytokines. The levels of reactive oxygen species were measured using 2,7-dichlorodihydrofluorescein diacetate. Luciferase assay and immunocytochemistry were used for assessing nuclear factor-kappa B (NF-κB) transcription and p65 localization, respectively. Memory and social interaction were analyzed using the Y-maze and three-chamber tests, respectively. RESULTS: The ethanol extract of A. altissima leaves (AAE) inhibited iNOS and COX-2 expression in LPS-stimulated astrocytes. Moreover, AAE reduced the transcription of various proinflammatory mediators, hindered NF-κB activation, and suppressed extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) activation without p38 activation. Ultra-high performance liquid chromatography with mass spectrometry analysis revealed that AAE comprised ethyl gallate, quercetin, and kaempferol, along with luteolin, which has anti-inflammatory properties, and repressed LPS-induced nitrite levels and the nuclear translocation of p65. Finally, oral administration of AAE attenuated LPS-induced memory and social impairment in mice and repressed LPS-induced ERK and JNK activation in the cortices of mice. CONCLUSION: AAE could have therapeutic uses in the treatment of neuroinflammatory diseases via suppression of astrocyte activation.
Assuntos
Ailanthus/química , Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Citocinas/metabolismo , Inflamação/patologia , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias/tratamento farmacológico , Óxido Nítrico/metabolismo , Extratos Vegetais/isolamento & purificação , Folhas de PlantaRESUMO
An overload of hepatic fatty acids, such as oleic acid is a key trigger of non-alcoholic fatty liver disease (NAFLD). Here, we investigated whether Artemisia frigida, a valuable traditional medicine used to treat various diseases, could mitigate OA-induced lipid accumulation in HepG2 cells. Then, to identify the active substances in A. frigida, a phytochemistry investigation was conducted using a bioassay-guided isolation method. Consequently, one terpene (1) and one flavone (2) were identified. Compound 1 ((+)-dehydrovomifoliol) exhibited potent effects against lipid accumulation in OA-induced HepG2 cells, without causing cyto-toxicity. Notably, treatment with (+)-dehydrovomifoliol decreased the expression levels of three genes related to lipogenesis (SREBP1, ACC, and FASN) and increased those of three genes related to fatty acid oxidation (PPARα, ACOX1, and FGF21). In addition, similar results were observed for SREBP1, PPARα, and FGF21 protein levels. The effects of (+)-dehydrovomifoliol were partially reversed by treatment with the PPARα antagonist GW6471, indicating the important role of the PPARα-FGF21 axis in the effects of (+)-dehydrovomifoliol. Based on its effects on hepatic lipogenesis and fatty acid oxidation signaling via the PPARα-FGF21 axis, (+)-dehydrovomifoliol isolated from A. frigida could be a useful early lead compound for developing new drugs for NAFLD prevention.
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Rumex japonicus Houtt (RJH) is a valuable plant used in traditional medicine to treat several diseases, such as scabies and jaundice. In this study, Jurkat cell growth inhibitory extracts of R. japonicus roots were subjected to bioassay-guided fractionation, resulting in the isolation of three naphthalene derivatives (3-5) along with one anthraquinone (6) and two phenolic compounds (1 and 2). Among these compounds, 2-methoxystypandrone (5) exhibited potent anti-proliferative effects on Jurkat cells. Analysis by flow cytometry confirmed that 2-methoxystypandrone (5) could significantly reduce mitochondrial membrane potential and promote increased levels of mitochondrial reactive oxygen species (ROS), suggesting a strong mitochondrial depolarization effect. Real-time quantitative polymerase chain reaction (qPCR) analysis was also performed, and the results revealed that the accumulation of ROS was caused by reduced mRNA expression levels of heme oxygenase (HO-1), catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD). In addition, 2-methoxystypandrone (5) triggered strong apoptosis that was mediated by the arrest of the G0/G1 phase of the cell cycle. Furthermore, 2-methoxystypandrone (5) downregulated p-IκB-α, p-NF-κB p65, Bcl2, and Bcl-xl and upregulated BAX proteins. Taken together, these findings revealed that 2-methoxystypandrone (5) isolated from RJH could potentially serve as an early lead compound for leukemia treatment involving intracellular signaling by increasing mitochondrial ROS and exerting anti-proliferative effects.
Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Jurkat/efeitos dos fármacos , Mitocôndrias/metabolismo , Extratos Vegetais/farmacologia , Rumex/química , Antraquinonas , Proteínas Reguladoras de Apoptose/metabolismo , Ciclo Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Naftoquinonas , Raízes de Plantas/química , Espécies Reativas de Oxigênio/metabolismo , República da Coreia , Transdução de Sinais/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismoRESUMO
Aucklandia lappa Decne., known as "Mok-hyang" in Korea, has been used for the alleviation of abdominal pain, vomiting, diarrhea, and stress gastric ulcers in traditional oriental medicine. We investigated the anti-inflammatory and antioxidative effects of the ethanol extract of Aucklandia lappa Decne. (ALDE) in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. ALDE significantly inhibited the LPS-induced nitric oxide (NO) production and reduced inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells. The production of other proinflammatory mediators, including COX-2, interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α, was reduced by ALDE in LPS-stimulated RAW 264.7 cells. The mechanism underlying the anti-inflammatory effects of ALDE was elucidated to be the suppression of LPS-induced nuclear translocation of p65, followed by the degradation of IκB and the inhibition of the phosphorylation of mitogen-activated protein kinases (MAPK). In addition, ALDE showed enhanced radical scavenging activity. The antioxidant effect of ALDE was caused by the enhanced expression of heme oxygenase (HO-1) via stabilization of the expression of the nuclear transcription factor E2-related factor 2 (Nrf2) pathway. Collectively, these results indicated that ALDE not only exerts anti-inflammatory effects via the suppression of the NF-κB and MAPK pathways but also has an antioxidative effect through the activation of the Nrf2/HO-1 pathway.
Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Saussurea/química , Animais , Antioxidantes/metabolismo , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Heme Oxigenase-1/metabolismo , Proteínas I-kappa B/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacosRESUMO
Betula platyphylla bark has been evaluated for the treatment of dermatitis, inflammatory conditions, and cancer. Diarylheptanoids are the major constituents of the B. platyphylla bark and possess various pharmacological effects. Our previous study confirmed the selective antiproliferative effect of platyphylloside (BPP) isolated from B. platyphylla on colon cancer and leukemic cells using 60 different cancer cell lines from thr National Cancer Institution (NCI). In line with previous reports, this study focuses on the apoptotic pathway of BPP, a phenolic glycoside composed of two aromatic rings joined by a seven-carbon chain. Cytotoxicity assays in solid tumor and blood cancer cell models demonstrated that BPP possesses potent antiproliferative activity. The level of apoptosis increased with BPP treatment, causing cell cycle arrest at the G1 phase along with the downregulation of IκBα phosphorylation and BCL-2, as well as upregulation of cleaved caspase 3 and BAX proteins. In addition, BPP displayed potent mitochondrial depolarization effects in Jurkat cells. The combined findings revealed that the cytotoxic effects of BPP were mediated by intracellular signaling, possibly through a mechanism involving the upregulation of mitochondrial reactive oxygen species (ROS). Thus, BPP could be a potential multitarget therapeutic agent in leukemia and colon cancer.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Betula/química , Diarileptanoides/farmacologia , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo , Diarileptanoides/química , Humanos , Células Jurkat , Leucemia , Estrutura Molecular , Extratos Vegetais/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
Lignans are known to be an important class of phenylpropanoid secondary metabolites. In the course of our studies on the chemodiversity of lignans, the necessity arose to develop a method for the fast detection and identification of bioactive lignan subclasses. In this study, we detected 10 lignan derivatives of different extracts of F. viridissima by UHPLC-ESI-QTOF-MS. Lignan glycosides (1 and 2), lignans (3 and 4), and lignan dimers (5-10) were identified by analysis of their exact masses and MSe spectra along with the characteristic mass fragmentation patterns and molecular formulas. We further investigated NO inhibitory effects of F. viridissima fractions and their major lignan derivatives to evaluate those anti-inflammatory effects. The methylene chloride fraction of F. viridissima as well as compounds 8 and 10 showed potent dose-dependent NO inhibitory effects on RAW 264.7 cells. Corresponding to the NO inhibition by compounds 8 and 10, lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expression was notably reduced by both compounds. Our combined data with the bioactive results and the component analysis by UHPLC-ESI-QTOF-MS suggest that the methylene chloride fraction of F. viridissima roots could be potential anti-inflammatory agents and these are related to major lignans including dimeric dibenzylbutyrolactone lignans.
Assuntos
Forsythia/química , Lignanas/química , Lignanas/farmacologia , Óxido Nítrico/antagonistas & inibidores , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Sobrevivência Celular , Cromatografia Líquida de Alta Pressão , Camundongos , Estrutura Molecular , Óxido Nítrico/metabolismo , Raízes de Plantas/química , Células RAW 264.7 , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
A bioassay-guided fractionation and chemical investigation of Amaryllis belladonna Steud. bulbs resulted in the isolation and identification of the new crinane alkaloid 1,4-dihydroxy-3-methoxy powellan (1), along with the 3 known crinane alkaloids 2-4 and the two lycorane alkaloids 5-6. The structures were elucidated by interpretation of combined HR-ESIMS, CD and 2D NMR spectroscopic data. Among these isolated compounds the lycorane-type alkaloid acetylcaranine (5) exhibited strong antiplasmodial activity, while compounds 3 and 4 were moderately active, and compounds 1 and 6 were inactive.
Assuntos
Alcaloides/química , Alcaloides de Amaryllidaceae/química , Antimaláricos/química , Asparagales/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Alcaloides de Amaryllidaceae/isolamento & purificação , Alcaloides de Amaryllidaceae/farmacologia , Antimaláricos/isolamento & purificação , Antimaláricos/farmacologia , Asparagales/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dicroísmo Circular , Humanos , Espectroscopia de Ressonância Magnética , Conformação Molecular , Extratos Vegetais/química , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
A simple and rapid method using high-speed counter-current chromatography (HSCCC), along with bioassay-guided fractionation based on the anti-proliferative activity against renal and colon cancer cells, has been developed for the preparative separation of aceroside VIII (1) and platyphylloside (2) from Betula platyphylla. A solvent system composed of ethyl acetate/acetonitrile/water (1:0.1:1, v/v/v) was optimized for the separation. The upper phase was used as the stationary phase, and the lower phase was used as the mobile phase. Among these isolated diarylheptanoids, platyphylloside (2) showed anti-proliferative activity in the COLO205 and KM12 colon cells and renal cancer cell lines A498, U031, as well as in MG63 and MG 63.3 osteosarcoma cells. In addition, it showed dose dependent inhibitory effects in the NCI 60 cell line assay. These results suggest that the diarylheptanoids isolated from B. platyphylla with an efficient HSCCC method could be potential multi-targeted therapeutic agents for cancer.
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Betula/química , Proliferação de Células/efeitos dos fármacos , Diarileptanoides/isolamento & purificação , Extratos Vegetais/administração & dosagem , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Diarileptanoides/administração & dosagem , Diarileptanoides/química , Humanos , Neoplasias Renais/tratamento farmacológico , Extratos Vegetais/química , Solventes/químicaRESUMO
It is well known that activated microglia produce nitric oxide (NO), which has an important role in the pathophysiology of several neurodegenerative diseases such as Alzheimer's disease. In the course of searching for novel therapeutic agents from medicinal plants against neuroinflammatory diseases, the methanolic extract of Tetrapanax papyriferus was found to have significant NO inhibitory activity in lipopolysaccharide (LPS)-stimulated BV2 microglia cells. Nine oleanane-type triterpenes, including two new compounds, epipapyriogenin C-3-O-ß-d-glucopyranoside (6) and 11-O-butylpapyrioside LIIc (9), were isolated from the leaves and stems of Tetrapanax papyriferus. The structures of these compounds were elucidated with 1D- and 2D-NMR and MS data. Among these Δ(11,13) oleanane-type triterpenes, compound 3 showed significant NO inhibitory activity in BV-2 cells, reducing the LPS-induced expression of COX-2 and pro-inflammatory cytokines such as TNF-α and IL-6. Compounds 7 and 9 also showed NO inhibitory activities among the Δ(12) oleanane-type triterpene saponins. These results show that oleanane-type triterpenes isolated from T. papyriferus could be a potential natural resource of NO inhibitors used in the treatment of neurodegenerative disorders.
Assuntos
Anti-Inflamatórios/química , Óxido Nítrico/biossíntese , Ácido Oleanólico/química , Extratos Vegetais/química , Anti-Inflamatórios/administração & dosagem , Araliaceae/química , Ciclo-Oxigenase 2 , Citocinas/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Lipopolissacarídeos/toxicidade , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Doenças Neurodegenerativas/tratamento farmacológico , Óxido Nítrico/antagonistas & inibidores , Ácido Oleanólico/administração & dosagem , Ácido Oleanólico/isolamento & purificação , Extratos Vegetais/administração & dosagem , Folhas de Planta/química , Plantas Medicinais/químicaRESUMO
Alzheimer's disease (AD) is a neurodegenerative disease induced by cholinergic neuron damage or amyloid-beta aggregation in the basal forebrain region and resulting in cognitive disorder. We previously reported on the neuroprotective effects of Betula platyphylla bark (BPB) in an amyloid-beta-induced amnesic mouse model. In this study, we obtained a cognitive-enhancing compound by assessing results using a scopolamine-induced amnesic mouse model. Our results show that oral treatment of mice with BPB and betulin significantly ameliorated scopolamine-induced memory deficits in both passive avoidance and Y-maze tests. In the Morris water maze test, administration of BPB and betulin significantly improved memory and cognitive function indicating the formation of working and reference memories in treated mice. Moreover, betulin significantly increased glutathione content in mouse hippocampus, and the increase was greater than that from betulinic acid treatment. We conclude that BPB and its active component betulin have potential as therapeutic, cognitive enhancer in AD.
Assuntos
Amnésia/tratamento farmacológico , Betula/química , Memória/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Triterpenos/farmacologia , Administração Oral , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Amnésia/induzido quimicamente , Amnésia/metabolismo , Amnésia/fisiopatologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Glutationa/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Fármacos Neuroprotetores/isolamento & purificação , Nootrópicos/isolamento & purificação , Triterpenos Pentacíclicos , Casca de Planta/química , Extratos Vegetais/química , Escopolamina , Triterpenos/isolamento & purificação , Ácido BetulínicoRESUMO
Excessive NO (nitric oxide) has been associated with the pathogenesis of various neurodegenerative diseases including Alzheimer's disease (AD). In our screening system using LPS-activated BV2 microglial cells, the methanolic extract of Disporum viridescens leaves was found to have significant NO inhibitory activity. Bioactivity-guided isolation yielded a new phenylpropanoid characterized as 4-ally-2,6-dimethoxyphenyl 1-O-ß-D-apiofuranosyl (1â6)-ß-D-glucopyranoside (12) with 21 known compounds from the leaves of D. viridescens. Among them, compounds 2 and 4 significantly inhibited NO production. Thus, we further elucidated the anti-inflammatory mechanism of these lignans. Especially, compound 4 inhibited the expression of both inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) through the suppression of the MAPK signaling pathway. Taken together, the anti-inflammatory activities of the active constituents isolated from D. viridescens leaves could have therapeutic potential against neurodegenerative diseases.
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Lignanas/farmacologia , Liliaceae/química , Microglia/metabolismo , Óxido Nítrico/metabolismo , Extratos Vegetais/farmacologia , Folhas de Planta/química , Animais , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Lignanas/isolamento & purificação , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Microglia/citologia , Microglia/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismoRESUMO
Alzheimer's disease (AD) is closely associated with amyloid ß (Aß)-induced neurotoxicity and oxidative stress in the brain. Betula platyphylla, which has been used to treat various oxidative-stressed related diseases, has recently received attention for its preventive activity on age-related neurodegenerative diseases. In this study, we attempted to investigate the effects of B. platyphylla bark (BPB-316) on Aß(1-42)-induced neurotoxicity and memory impairment. Oral treatment using BPB-316 significantly attenuated Aß-induced memory impairment which was evaluated by behavioral tests including the passive avoidance, Y-maze and Morris water maze test. BPB-316 also inhibited the elevation of ß-secretase activity accompanying the reduced Aß(1-42) levels in the hippocampus of the brain. Furthermore, BPB-316 significantly decreased the acetylcholinesterase activity and increased the glutathione content in the hippocampus. In addition, we confirmed that the expression of both cAMP responsive element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus of Aß(1-42)-injected mice were markedly upregulated by the treatment of BPB-316. Our data suggest that the extracts of B. platyphylla bark might be a potential therapeutic agent against AD.
Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/toxicidade , Betula/química , Deficiências da Aprendizagem/induzido quimicamente , Deficiências da Aprendizagem/prevenção & controle , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/prevenção & controle , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/toxicidade , Extratos Vegetais/farmacologia , Acetilcolinesterase/metabolismo , Secretases da Proteína Precursora do Amiloide/biossíntese , Secretases da Proteína Precursora do Amiloide/genética , Animais , Ácido Aspártico Endopeptidases/biossíntese , Ácido Aspártico Endopeptidases/genética , Aprendizagem da Esquiva/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Glutationa/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Deficiências da Aprendizagem/psicologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/psicologia , Camundongos , Camundongos Endogâmicos ICR , Casca de Planta/químicaRESUMO
The neuroprotective potential of flavonoids within the brain comprises anti-apoptosis of neuronal cells, anti-neuroinflammation and enhancement of cognitive function. We reported that Rhus vernciflua inhibits glutamate-induced neurotoxicity in primary cultured rat cortical cells. Here we narrowed it down to get neuroprotective fractions from the plant yielding flavonoid-rich ethyl acetate fraction (PREF). Among its active flavonoids, fisetin exhibited not only inhibitory effect against lipopolysaccharide (LPS)-induced neuroinflammation by suppressing inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 but also memory enhancing effects via reactivation of cAMP responsive element binding protein (CREB)-brain derived neurotrophic factor (BDNF) pathway in memory-impaired mice by scopolamine. Butein also showed a similar activity to fisetin even though to a lesser extent. The neuroprotection by PREF and selected flavonoids may involve maintenance of antioxidant defense mechanism including glutathione peroxidase (GSH-Px), glutathione reductase (GR) and superoxide dismutase (SOD). Conclusively, we demonstrate the R. vernciflua bark extract and its active flavonoids with potent neuroprotective and anti-inflammatory effects might be good therapeutic candidates as cognitive-enhancers.
Assuntos
Anti-Inflamatórios/farmacologia , Cognição/efeitos dos fármacos , Flavonoides/farmacologia , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Rhus/química , Animais , Antioxidantes/farmacologia , Cromatografia Líquida de Alta Pressão , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteínas do Tecido Nervoso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Casca de Planta/química , Escopolamina/farmacologiaRESUMO
Diarylheptanoids have been the center of the intensive research efforts for Alzheimer's disease and other neurodegenerative diseases. The present study aimed to determine the effect of the standardized extract of B. platyphylla bark and its major diarylheptanoids in scopolamine-induced amnesic mice through cyclic AMP response element-binding protein (CREB) activation. Oral administration of the standardized extract of B. platyphylla bark (100mg/kg body weight), aceroside VIII (1mg/kg body weight) and platyphylloside (1 or 2mg/kg body weight) significantly ameliorated scopolamine-induced amnesia in passive avoidance test. CREB phosphorylation and brain-derived neurotrophic factor (BDNF) expression in the cortex and hippocampus of the scopolamine-treated mice were markedly increased by the treatment of the standardized extract of B. platyphylla bark and platyphylloside. The standardized extract of B. platyphylla bark and its major diarylheptanoids also significantly protected HT22 cells against neurotoxicity induced by glutamate insult. The standardized extract of B. platyphylla bark and platyphylloside may ameliorate memory deficits by activating the CREB-BDNF pathway and prevent a neurodegeneration by inhibiting neuronal cell death.
Assuntos
Amnésia/prevenção & controle , Betula/química , Cognição/efeitos dos fármacos , Diarileptanoides/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Administração Oral , Amnésia/induzido quimicamente , Amnésia/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Morte Celular/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Diarileptanoides/farmacologia , Ácido Glutâmico , Masculino , Camundongos , Camundongos Endogâmicos ICR , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Casca de Planta , Extratos Vegetais/farmacologia , Padrões de Referência , Escopolamina , Transdução de SinaisRESUMO
The neuroprotective and anti-inflammatory activities of the methanolic extract of Rhus verniciflua Stokes (Anacardiaceae) were investigated with mouse hippocampal and microglial cells. Bioactivity-guided isolation yielded 10 flavonoids including fustin (1), fisetin (2), sulfuretin (3), butein (4), butin (5), eriodictyol (6), morin hydrate (7), quercetin (8), kaempferol (9) and isoliquiritigenin (10). Among the isolated flavonoids, compounds 2-5 significantly protected the murine hippocampal HT22 cells against glutamate-induced neurotoxicity and attenuated reactive oxygen species (ROS) generations. In addition, these flavonoids significantly maintained antioxidative defense systems preserving the activities of superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GSH-Px) and the content of glutathione (GSH) decreased by glutamate insult. These compounds also showed significant inhibitory effects on LPS-induced nitric oxide (NO) production in BV2 cells. Especially, compound 4 dose-dependently suppressed the expression of both inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). These results suggest that these flavonoids possess therapeutic potentials as a multipotent agent against neurodegenerative diseases related to oxidative stress and pathological inflammatory responses.
Assuntos
Anti-Inflamatórios , Flavonoides/farmacologia , Fármacos Neuroprotetores , Rhus/química , Actinas/metabolismo , Antioxidantes/metabolismo , Western Blotting , Linhagem Celular , Ciclo-Oxigenase 2/biossíntese , Flavonoides/química , Flavonoides/isolamento & purificação , Radicais Livres/metabolismo , Ácido Glutâmico/toxicidade , Humanos , Peróxidos Lipídicos/metabolismo , Lipopolissacarídeos/farmacologia , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/biossíntese , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Relação Estrutura-AtividadeRESUMO
A methanolic extract of the roots of Polygala tenuifolia (Polygalaceae) significantly attenuated nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated BV2 microglia cells. Five xanthones, 1-hydroxy-7-methoxyxanthone (1), 3,6-dihydroxy-1,2,7-trimethoxyxanthone (2), 1,3,6-trihydroxy-2,7-dimethoxyxanthone (3), 1,7-dihydroxy-2,3-dimethoxyxanthone (4) and 1,7-dihydroxy-3-methoxyxanthone (5), and five phenylpropanoids, 4-hydroxy-3-methoxypropiophenone (6), methyl 4-hydroxy-3-methoxycinnamic acid (7), 3,4,5-trimethoxycinnamic acid (8), 4-methoxycinnamic acid (9) and ß-d-(3-O-sinapoyl) fructofuranosyl-α-d-(6-O-sinapoyl)glucopyranoside (10), were isolated from CHCl(3) fraction using bioactivity-guided fractionation. Among these compounds, compounds 1, 2, 4, 5 and 7 showed significant inhibitory effects on LPS-induced NO production in BV2 microglia cells at the concentration ranging from 10.0 to 100.0 µM.