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1.
Biomol Ther (Seoul) ; 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31697876

RESUMO

Alzheimer's disease (AD) is a devastating neurodegenerative disease and a major cause of dementia in elderly individuals worldwide. Increased deposition of insoluble amyloid ß (Aß) fibrils in the brain is thought be a key neuropathological hallmark of AD. Many recent studies show that natural products such as polyphenolic flavonoids inhibit the formation of insoluble Aß fibrils and/or destabilize ß-sheet-rich Aß fibrils to form non-cytotoxic aggregates. In the present study, we explored the structure-activity relationship of naturally-occurring biflavonoids on Aß amyloidogenesis utilizing an in vitro thioflavin T assay with Aß1-42 peptide which is prone to aggregate more rapidly to fibrils than Aß1-40 peptide. Among the biflavonoids we tested, we found amentoflavone revealed the most potent effects on inhibiting Aß1-42 fibrillization (IC50: 0.26 µM), as well as on disassembling preformed Aß1-42 fibrils (EC50: 0.59 µM). Our structure-activity relationship study suggests that the hydroxyl groups of biflavonoid compounds play an essential role in their molecular interaction with the dynamic process of Aß1-42 fibrillization. Our atomic force microscopic imaging analysis demonstrates that amentoflavone directly disrupts the fibrillar structure of preformed Aß1-42 fibrils, resulting in conversion of those fibrils to amorphous Aß1-42 aggregates. These results indicate that amentoflavone affords the most potent anti-amyloidogenic effects on both inhibition of Aß1-42 fibrillization and disaggregation of preformed mature Aß1-42 fibrils.

2.
Cell Death Dis ; 10(11): 810, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31649278

RESUMO

Mitochondria play a pivotal role in cancer bioenergetics and are considered a potential target for anticancer therapy. Considering the limited efficacy and toxicity of currently available mitochondria-targeting agents, it is necessary to develop effective mitochondria-targeting anticancer drugs. By screening a large chemical library consisting of natural products with diverse chemical entities, we identified gracillin, a steroidal saponin, as a mitochondria-targeting antitumor drug. Gracillin displayed broad-spectrum inhibitory effects on the viability of a large panel of human cancer cell lines, including those carrying acquired resistance to chemotherapy or EGFR-targeting drugs, by inducing apoptosis. We show that gracillin attenuates mitochondria-mediated cellular bioenergetics by suppressing ATP synthesis and by producing reactive oxygen species (ROS). Mechanistically, gracillin disrupts complex II (CII) function by abrogating succinate dehydrogenase (SDH) activity without affecting the succinate:ubiquinone reductase. The gracillin-induced cell death was potentiated by 3-nitropropionic acid (3-NPA) or thenoyltrifluoroacetone (TTFA), which inhibit CII by binding to the active site of SDHA or to the ubiquinone-binding site, respectively. Finally, we show that gracillin effectively suppressed the mutant-Kras-driven lung tumorigenesis and the growth of xenograft tumors derived from cell lines or patient tissues. Gracillin displayed no obvious pathophysiological features in mice. Collectively, gracillin has potential as a CII-targeting antitumor drug.

4.
J Nat Prod ; 78(12): 2983-93, 2015 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-26595875

RESUMO

The antiproliferative and antitumor activities of americanin A (1), a neolignan isolated from the seeds of Phytolacca americana, were investigated in human colon cancer cells. Compound 1 inhibited the proliferation of HCT116 human colon cancer cells both in vitro and in vivo. The induction of G2/M cell-cycle arrest by 1 was concomitant with regulation of the ataxia telangiectasia-mutated/ATM and Rad3-related (ATM/ATR) signaling pathway. Treatment with 1 activated ATM and ATR, initiating the subsequent signal transduction cascades that include checkpoint kinase 1 (Chk1), checkpoint kinase 2 (Chk2), and tumor suppressor p53. Another line of evidence underlined the significance of 1 in regulation of the S phase kinase-associated protein 2 (Skp2)-p27 axis. Compound 1 targeted selectively Skp2 for degradation and thereby stabilized p27. Therefore, compound 1 suppressed the activity of cyclin B1 and its partner cell division cycle 2 (cdc2) to prevent entry into mitosis. Furthermore, prolonged treatment with 1 induced apoptosis by producing excessive reactive oxygen species. The intraperitoneal administration of 1 inhibited the growth of HCT116 tumor xenografts in nude mice without any overt toxicity. Modulation of the ATM/ATR signaling pathway and the Skp2-p27 axis might be plausible mechanisms of action for the antiproliferative and antitumor activities of 1 in human colon cancer cells.


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Dioxinas/isolamento & purificação , Dioxinas/farmacologia , Phytolacca americana/química , Animais , Antineoplásicos Fitogênicos/química , Apoptose , Proteína Quinase CDC2/metabolismo , Quinase 1 do Ponto de Checagem , Quinase do Ponto de Checagem 2/metabolismo , Neoplasias do Colo , Dioxinas/química , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HCT116 , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Proteínas Quinases/metabolismo , Sementes/química , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo
5.
Int J Mol Sci ; 16(1): 1482-3, 2015 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-25580538

RESUMO

The authors want to change Figure 1 of the paper published in IJMS [1]. In Figure 1, 5-position of OH was at 6-position. Therefore, Figure 1 is revised as follows. The authors would like to apologize for any inconvenience caused to the readers by this change.[...].

6.
J Nat Prod ; 77(4): 917-24, 2014 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-24689881

RESUMO

The anti-inflammatory activity of handelin (1), a guaianolide dimer from Chrysanthemum boreale flowers, was evaluated in vivo, and the effects on mediators nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) and the nuclear factor-κB (NF-κB) and ERK/JNK signaling pathways were investigated in vitro. Compound 1 inhibited lipopolysaccharide (LPS)-induced production of NO and PGE2 in cultured mouse macrophage RAW 264.7 cells. The suppression of NO and PGE2 production by 1 was correlated with the downregulation of mRNA and protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Compound 1 also suppressed the induction of pro-inflammatory cytokines TNF-α and IL-1ß in LPS-stimulated RAW 264.7 cells. To further clarify the transcriptional regulatory pathway in the expression of iNOS and COX-2 by 1, the role of NF-κB was determined in RAW 264.7 cells. Compound 1 inhibits the binding activity of NF-κB into the nuclear proteins. The transcriptional activity of NF-κB stimulated with LPS was also suppressed by 1, which coincided with the inhibition of IκB degradation. Compound 1 also suppressed the activation of mitogen-activated protein kinases, including ERK and JNK signaling. In addition, the LPS-stimulated upregulation of miRNA-155 expression was suppressed by 1. The oral administration of 1 inhibited acute inflammation in carrageenan-induced paw and 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced ear edema models. The serum level of IL-1ß was also inhibited by 1 in a carrageenan-induced paw edema model. These findings suggest that the suppression of NF-κB activation and pro-inflammatory cytokine production may be a plausible mechanism of action for the anti-inflammatory activity of handelin.


Assuntos
Anti-Inflamatórios/farmacologia , Chrysanthemum/química , Citocinas/metabolismo , Proteínas I-kappa B/metabolismo , NF-kappa B/efeitos dos fármacos , Terpenos/farmacologia , Animais , Anti-Inflamatórios/química , Ciclo-Oxigenase 2 , Dinoprostona/metabolismo , Regulação para Baixo , Edema/induzido quimicamente , Edema/tratamento farmacológico , Proteínas I-kappa B/efeitos dos fármacos , Interleucina-1beta/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Modelos Animais , Estrutura Molecular , Inibidor de NF-kappaB alfa , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Fitoterapia , Transdução de Sinais/efeitos dos fármacos , Terpenos/química , Fator de Necrose Tumoral alfa/efeitos dos fármacos
7.
Pharmacol Biochem Behav ; 120: 88-94, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24582850

RESUMO

Spinosin is a C-glycoside flavonoid isolated from the seeds of Zizyphus jujuba var. spinosa. This study investigated the effect of spinosin on cholinergic blockade-induced memory impairment in mice. Behavioral tests were conducted using the passive avoidance, Y-maze, and Morris water maze tasks to evaluate the memory-ameliorating effect of spinosin. Spinosin (10 or 20mg/kg, p.o.) significantly ameliorated scopolamine-induced cognitive impairment in these behavioral tasks with a prolonged latency time in the passive avoidance task, an increased percentage of spontaneous alternation in the Y-maze task and a lengthened swimming time in target quadrant in the Morris water maze task. In addition, a single administration of spinosin in normal naïve mice also enhanced the latency time in the passive avoidance task. To identify the mechanism of the memory-ameliorating effect of spinosin, receptor antagonism analysis and Western blotting were performed. The ameliorating effect of spinosin on scopolamine-induced memory impairment was significantly antagonized by a sub-effective dose (0.5mg/kg, i.p.) of 8-hydroxy-2-(di-N-propylamino)tetralin, a 5-HT1A receptor agonist. In addition, spinosin significantly increased the expression levels of phosphorylated extracellular signal-regulated kinases and cAMP response element-binding proteins in the hippocampus. Taken together, these results indicate that the memory-ameliorating effect of spinosin may be, in part, due to the serotonergic neurotransmitter system, and that spinosin may be useful for the treatment of cognitive dysfunction in diseases such as Alzheimer's disease.


Assuntos
Flavonoides/farmacologia , Hipnóticos e Sedativos/farmacologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/prevenção & controle , Antagonistas Muscarínicos/toxicidade , Escopolamina/antagonistas & inibidores , Escopolamina/toxicidade , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Flavonoides/antagonistas & inibidores , Hipnóticos e Sedativos/antagonistas & inibidores , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos
8.
J Nat Prod ; 77(2): 370-6, 2014 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-24547878

RESUMO

Jujuboside B (1) is one of the saponins isolated from the seeds of Zizyphus jujuba var. spinosa, which are used as a well-known traditional medicine for the treatment of insomnia and anxiety in East Asian countries. This is the first study to investigate the antitumor mechanism of 1 in vivo and in vitro. The results showed that 1 induced apoptosis and autophagy in AGS and HCT 116 human cancer cells and also effectively suppressed tumor growth in a nude mouse xenograft model bearing HCT 116 cells. The apoptosis-inducing effect of 1 was characterized by annexin V/propidium iodide staining, sub-G1 phase increase, and caspase-3 activation. Mechanistic studies showed that 1-induced apoptosis is associated with the extrinsic pathway through an increase in FasL and caspase-8 activation. Moreover, 1 activated p38/c-Jun N-terminal kinase (JNK), and the extrinsic pathway-mediated apoptosis was attenuated by both SB202190 (a p38 inhibitor) and SP600125 (a JNK inhibitor). The autophagy-inducing effect was indicated by the formation of cytoplasmic vacuoles and microtubule-associated protein 1 light chain-3 II (LC3-II) conversion. The autophagy inhibitor bafilomycin A1 (BaF) decreased 1-induced cell viability and increased pp38, pJNK, FasL, caspase-8 activation, and caspase-3 activation. Taken together, these results demonstrate that 1 induced protective autophagy to retard extrinsic pathway-mediated apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Saponinas/farmacologia , Ziziphus/química , Animais , Antracenos/farmacologia , Caspase 3/efeitos dos fármacos , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células HCT116 , Humanos , Macrolídeos/farmacologia , Camundongos , Saponinas/química , Sementes/química
9.
Food Chem ; 142: 107-13, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24001819

RESUMO

A method based on HPLC with diode array detector (DAD) and electrospray ionisation mass spectrometry (ESI-MS) was established for the simultaneous determination of 5-HMF and its derivatives, including a new 5-HMF derivative, in Rehmanniae radix preparata. Validation parameters, such as linearity, limit of detection, limit of quantification, recovery, accuracy, and precision, were successfully obtained. In addition, the efficiencies of diverse extraction methods were compared for the development of a standard analytical method. The verified method was successfully applied to the quantitative determination of four representative metabolites in eighteen R. radix preparata samples from Korea and China. Additionally, the increase in the amount of 5-HMF derivatives was monitored during the processing of three dried R. radix samples. The results showed that a newly isolated diglycosylated 5-HMF derivative, 5-(α-D-galactopyranosyl-(1→6)-α-D-galactopyranosyloxymethyl)-2-furancarboxaldehyde, appeared in concentrations comparable to that of 5-HMF, suggesting its potential to serve as a marker compound in R. radix preparata.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/análise , Furaldeído/análise , Rehmannia/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Medicamentos de Ervas Chinesas/metabolismo , Furaldeído/metabolismo , Rehmannia/metabolismo
10.
Biomol Ther (Seoul) ; 21(4): 299-306, 2013 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-24244815

RESUMO

In the present study, we investigated the effect of ethanolic extract of the seed of Zizyphus jujuba var. spinosa (EEZS) on cholinergic blockade-induced memory impairment in mice. Male ICR mice were treated with EEZS. The behavioral tests were conducted using the passive avoidance, the Y-maze, and the Morris water maze tasks. EEZS (100 or 200 mg/kg, p.o.) significantly ameliorated the scopolamine-induced cognitive impairment in our present behavioral tasks without changes of locomotor activity. The ameliorating effect of EEZS on scopolamine-induced memory impairment was significantly reversed by a sub-effective dose of MK-801 (0.0125 mg/kg, s.c.). In addition, single administration of EEZS in normal naïve mouse enhanced latency time in the passive avoidance task. Western blot analysis was employed to confirm the mechanism of memory-ameliorating effect of EEZS. Administration of EEZS (200 mg/kg) increased the level of memory-related signaling molecules, including phosphorylation of extracellular signal-regulated kinase or cAMP response element-binding protein in the hippocampal region. Also, the time-dependent expression level of brain-derived neurotrophic factor by the administration of EEZS was markedly increased from 3 to 9 h. These results suggest that EEZS has memory-ameliorating effect on scopolamine-induced cognitive impairment, which is mediated by the enhancement of the cholinergic neurotransmitter system, in part, via NMDA receptor signaling, and that EEZS would be useful agent against cognitive dysfunction such as Alzheimer's disease.

11.
Bioorg Med Chem Lett ; 23(20): 5511-4, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24018191

RESUMO

Based on the Wnt inhibitors as potential targets in the development of anticancer agents, natural compounds were evaluated for ß-catenin-mediated transcriptional activity. A natural lignan hydnocarpin isolated from Lonicera japonica was considered a potential inhibitor for Wnt/ß-catenin signalings. The anti-proliferative activity of hydnocarpin was also found to be associated with the suppression of Wnt/ß-catenin-mediated signaling pathway in human colon cancer cells. These data suggest that hydnocarpin might be a novel Wnt inhibitor and has a potential of signaling regulator in ß-catenin-mediated signaling pathways.


Assuntos
Antineoplásicos Fitogênicos/química , Flavonolignanos/química , Lignanas/química , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/toxicidade , Proteína Axina/antagonistas & inibidores , Proteína Axina/genética , Proteína Axina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Flavonolignanos/isolamento & purificação , Flavonolignanos/toxicidade , Humanos , Lonicera/química , Lonicera/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
12.
Chem Pharm Bull (Tokyo) ; 61(9): 971-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23800854

RESUMO

An investigation of the Korean medicinal plant Patrinia villosa (THUNB.) JUSS. (Valerianaceae) led to the isolation of two new flavonoid glycosides, patrivilosides 1 (1) and 2 (2), a new iridoid glycoside, patrinovalerosidate (3), and two new saponins, patrinovilosides A (4) and B (5), along with six known compounds including three flavonoid glycosides and three iridoid glycosides. The structures of the new compounds were elucidated based on analysis of their one dimensional (1D)- and 2D-NMR spectra along with their mass spectrometric data and the results of acid hydrolysis.


Assuntos
Flavonoides/química , Glicosídeos/química , Patrinia/química , Componentes Aéreos da Planta/química , Flavonoides/isolamento & purificação , Glicosídeos/isolamento & purificação , Hidrólise , Plantas Medicinais/química
13.
Phytother Res ; 27(6): 829-34, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22893618

RESUMO

The seeds of Zizyphus jujuba (SZJ), a famous oriental traditional medicine, have been reported to exhibit diverse activities in biological systems including the cardiovascular system. However, little information is available on its antiplatelet activity. This study was undertaken to investigate the antiplatelet effects of the ethanolic extract of SZJ (ESZJ) and of its principal components jujuboside A and B. In the in vitro platelet aggregation study, ESZJ exhibited significant and concentration-dependent inhibitory effects on collagen-, thrombin-, and AA-induced platelet aggregation. In addition, ESZJ-treated mice showed significantly the prolongation of bleeding times and the protection against thromboembolic attack. A comparison of the effects of jujuboside A and B on platelet aggregation revealed that only jujuboside B had potent inhibitory effects on collagen-, thrombin-, AA-, and ADP-induced aggregation. Jujuboside B also exhibited superior protection on thromboembolic model. Furthermore, jujuboside B had a significant inhibitory effect on collagen-induced thromboxane A2 production in rat platelets. This study describes the antiplatelet effects of ESZJ and of its active component jujuboside B, and its findings suggest that these agents be considered as components of preventive and therapeutic herbal drugs targeting cardiovascular diseases associated with platelet hyperaggregation.


Assuntos
Extratos Vegetais/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Saponinas/farmacologia , Ziziphus/química , Animais , Plaquetas/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Embolia Pulmonar/tratamento farmacológico , Ratos , Ratos Sprague-Dawley
14.
Phytochem Anal ; 24(2): 148-54, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22930642

RESUMO

INTRODUCTION: The roots of Adenophorae species have been reported to exhibit anti-obese, anti-oxidant, anti-cancer, and anti-bacterial activities. However, there has been no single report regarding the preparative isolation and biological activities of the chemical components from Adenophora triphylla. OBJECTIVE: To develop an efficient method for the determination of the active fraction from the methanol extract from the roots of Adenophora triphylla and for the preparative isolation and purification of target compounds having cytotoxicity on carcinoma cells from the active fraction by high-speed counter-current chromatography (HSCCC). METHODS: The Plant (5 kg, dry weight) was extracted with methanol. Three hundred grams of the dried methanol extract (885 g) were fractionated by open-column chromatography with a stepwise gradient of water-methanol. Preparative isolation of bioactive components was performed by HSCCC with a two-phase solvent system composed of ethyl acetate-n-butanol-0.2% trifluoroacetic acid in water (5:5:10, v/v). The cytotoxicity of column fractions and isolated compounds was evaluated by 2-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay. RESULTS: The 70% MeOH column fraction showed inhibitory effects against three human carcinoma cells A549, AGS and HepG2. Two saponins were separated from 400 mg of the active fraction by HSCCC. After further purification with solid phase extraction column, 25 mg of peak fraction 1 and 20 mg of peak fraction 2 were obtained. Their structures were identified by ¹H-NMR, ¹³C-NMR, Fourier transform infrared, fast atom bombardment-MS and electrospray ionisation-MS/MS. They exhibited strong cytotoxic effects against three cancer cells. CONCLUSION: Two cytotoxic saponins were isolated for the first time from the roots of Adenophora triphylla by HSCCC.


Assuntos
Campanulaceae/química , Distribuição Contracorrente/métodos , Raízes de Plantas/química , Saponinas/isolamento & purificação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Estrutura Molecular , Saponinas/química , Saponinas/farmacologia , Solventes/química
15.
Arch Pharm Res ; 35(10): 1771-7, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23139128

RESUMO

As part of our continuous search for compounds from natural sources that can treat diabetes and its diabetic complications, in the present work, we investigated the protein tyrosine phosphatase 1B (PTP1B) and rat lens aldose reductase (RLAR) inhibitory activities of the roots of Aralia continentalis. The methanol extract showed a potent inhibitory activity against PTP1B and RLAR. Among the tested fractions, the n-hexane fraction exhibited the highest PTP1B inhibitory activity, while the EtOAc fraction showed highest RLAR inhibitory activity. Bioassayguided fractionation of the active n-hexane and EtOAc soluble fractions resulted in the isolation of the diterpenoids; ent-pimara-8(14),15-diene-19-oic acid (continentalic acid, 1); ent-kaur-16-en-19-oic-acid (kaurenoic acid, 2); ent-pimara-8(14),15-diene-19-ol (3); 7-oxo-ent-pimara-8(14),15-diene-19-oic acid (4); 16á-hydroxy-17-isovaleroyloxy-ent-kauran-19-oic acid (5); 17-hydroxy-entkaur-15-en-19-oic acid (6); 15á,16á-epoxy-17-hydroxy-ent-kauran-19-oic acid (7); 16á,17-dihydroxy-ent-kauran-19-oic acid (8); 8á-hydroxy-ent-pimara-15-en-19-ol (9); 4-epirulopezol (10) and 4â-hydroxy-19-nor-(-)-pimara-8(14),15-diene (11), from the n-hexane fraction, and 4-[formy-5-(methoxymethyl)-1H-pyrrol-1-yl] butanoic acid (12); vanillic acid (13); 4-hydroxybenzoic acid (14); protocatechuic acid (15); nicotinic acid (16); aralia cerebroside (17); 5-O-feruloly quinic acid (18) from the EtOAc fraction. Of these, compounds 12∼14, 16 and 18 were isolated from A. continentalis for the first time. Compounds 1∼10 exhibited inhibitory potential against PTP1B, while compounds 12, 17, and 18 were found to be active against RLAR. Taken together, these results clearly demonstrate that the roots of A. continentalis displayed anti-diabetic and antidiabetic properties, which could be further explored to develop therapeutic and preventive agents for the treatment of diabetes and related complications.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Aralia/química , Diterpenos/isolamento & purificação , Inibidores Enzimáticos/isolamento & purificação , Hipoglicemiantes/isolamento & purificação , Cristalino/enzimologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Animais , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/enzimologia , Diterpenos/farmacologia , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Raízes de Plantas/química , Plantas Medicinais , Ratos , Ratos Sprague-Dawley , Especificidade por Substrato
16.
Cell Biol Toxicol ; 28(6): 421-33, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23011636

RESUMO

Oxidative stress caused by reactive oxygen species (ROS) induces DNA base modifications and DNA strand breaks. In this study, the protective effect of baicalein against H(2)O(2)-induced DNA damage was investigated in V79-4 Chinese hamster fibroblast cells. H(2)O(2) treatment increased the levels of intracellular ROS and DNA double-strand breaks (DSBs) and decreased the level of Ku70 protein and the phosphorylation (activation) of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which are involved in the repair of DSBs by nonhomologous end joining. Baicalein effectively scavenged intracellular ROS induced by H(2)O(2), reduced DSBs, and rescued Ku70 protein level and phosphorylation of DNA-PKcs. In cellular response to DNA base damage, 8-oxoguanine DNA glycosylase 1 (OGG1) plays a vital role in the removal of 8-oxoguanine (8-OxoG), which is formed mainly by oxidative stress. Baicalein significantly decreased the levels of 8-OxoG induced by H(2)O(2), and this correlated with increases in OGG1 promoter activity and OGG1 mRNA and protein expression. The phosphorylated form of Akt kinase, which is a regulator of OGG1, was sharply decreased by H(2)O(2), but was prevented by baicalein. A specific Akt inhibitor abolished the cytoprotective effects of baicalein, suggesting that OGG1 induction by baicalein involves the Akt pathway. In conclusion, baicalein exerted protective effects against DNA damage induced by oxidative stress by activating DNA repair systems and scavenging ROS.


Assuntos
Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Flavanonas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Antígenos Nucleares/biossíntese , Linhagem Celular , Cricetinae , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , DNA Glicosilases/genética , DNA Glicosilases/metabolismo , Proteína Quinase Ativada por DNA/metabolismo , Proteínas de Ligação a DNA/biossíntese , Guanina/análogos & derivados , Guanina/biossíntese , Peróxido de Hidrogênio/farmacologia , Autoantígeno Ku , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
J Med Food ; 15(6): 505-10, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22510152

RESUMO

Rehmanniae Radix Preparata, the steamed root of Rehmannia glutinosa Libosch, has been widely used for the treatment of inflammatory conditions in Oriental medicines. In this study we evaluated the effects of 2,5-dihydroxyacetophenone (DHAP) isolated from Rehmanniae Radix Preparata on inflammatory responses in lipopolysaccharide (LPS)-stimulated RAW264.7 mouse macrophages. LPS-stimulated RAW264.7 cells were used to investigate the anti-inflammatory activity of DHAP on the production of inflammatory mediators such as nitric oxide (NO), inducible NO synthase (iNOS), tumor necrosis factor-α (TNF-α), and interleukin (IL)-6. DHAP significantly inhibited NO production via the suppression of iNOS expression and significantly decreased levels of the pro-inflammatory cytokines TNF-α and IL-6 via the down-regulation of their mRNA expression in LPS-stimulated RAW264.7 cells. DHAP potently inhibited the phosphorylation of extracellular signal-related kinase (ERK) 1/2 and the nuclear translocation of nuclear factor-κB (NF-κB) p65 in LPS-stimulated cells. These results indicate that DHAP inhibits the production of inflammatory mediators in activated macrophages by blocking the ERK1/2 and NF-κB signaling pathways. Our results suggest that DHAP from Rehmanniae Radix Preparata has anti-inflammatory activity in activated macrophages, raising the possibility that this compound has a therapeutic potential for inflammatory conditions.


Assuntos
Acetofenonas/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Mediadores da Inflamação/metabolismo , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Fitoterapia , Rehmannia/química , Acetofenonas/isolamento & purificação , Acetofenonas/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Citocinas/biossíntese , Citocinas/genética , Citocinas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Lipopolissacarídeos , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Fosforilação , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Raízes de Plantas , RNA Mensageiro/metabolismo , Transdução de Sinais
18.
Chem Pharm Bull (Tokyo) ; 60(3): 306-14, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22382409

RESUMO

Six new germacranolides, zawadskinolides A-F (1-6), and a new eudesmane glucoside, chrysantiloboside (7) were isolated from the aerial parts of Dendranthema zawadskii var. latilobum, along with thirteen known constituents. Their structures were elucidated by means of spectroscopic evidence. Bioassay showed that flavonoids such as apigenin (9), (-)-eriodictyol (10) and nepetin (12), as well as the sesquiterpene lactone, zawadskinolide F (6), inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells with IC50 values of 66.15, 132.55, 35.44, and 91.32 µM, respectively.


Assuntos
Chrysanthemum/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Animais , Células Cultivadas , Flavonoides/química , Flavonoides/farmacologia , Concentração Inibidora 50 , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Óxido Nítrico/antagonistas & inibidores , Sesquiterpenos de Eudesmano/química , Sesquiterpenos de Eudesmano/farmacologia , Sesquiterpenos de Germacrano/química , Sesquiterpenos de Germacrano/farmacologia , Análise Espectral/métodos
19.
J Nat Prod ; 75(1): 67-71, 2012 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-22233348

RESUMO

Phytochemical investigation of Leonurus japonicus has led to the isolation of a labdane diterpene derivative, 15,16-epoxy-3α-hydroxylabda-8,13(16),14-trien-7-one (1), which was tested for its in vitro anti-inflammatory effects. The results demonstrated that 1 exhibits an inhibitory effect on LPS-stimulated RAW 264.7 macrophages. The anti-inflammatory action shown by 1 suppressed LPS-induced NF-κB activation, resulting in the down-regulation of iNOS and COX-2 protein expression, attributable to the inhibitory action of LPS-induced NO and PGE(2) production. Compound 1 inhibited LPS-induced phosphorylation and the degradation of inhibitory kappa B (IκBα) and decreased the nuclear translocation of p50 and p65. In addition, 1 exhibited an inhibitory effect on LPS-induced NF-κB-DNA and AP-1-DNA binding activity, using an electrophoretic mobility shift assay with NF-κB- and AP-1-specific (32)P-labeled probes. The LPS-induced mitogen-activated protein kinases (p-JNK, p-p38, and p-ERK) and p-Akt were inhibited after 30 and 10 min of LPS stimulation, respectively. In addition, TNF-α production was suppressed by 1.


Assuntos
Anti-Inflamatórios/farmacologia , Diterpenos/farmacologia , Lamiaceae/química , Lipopolissacarídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Diterpenos/química , Diterpenos/imunologia , Diterpenos/isolamento & purificação , Coreia (Geográfico) , Macrófagos/efeitos dos fármacos , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Estrutura Molecular , NF-kappa B/antagonistas & inibidores , Óxido Nítrico/análise , Óxido Nítrico/biossíntese , Raízes de Plantas/química , Fator de Transcrição AP-1/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores
20.
Biomol Ther (Seoul) ; 20(1): 57-61, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24116275

RESUMO

The matrix metalloproteinase (MMP) family is involved in the breakdown of the extracellular matrix during normal physiological processes such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes such as pathological aging, arthritis, and metastasis. Oxidative conditions generate reactive oxygen species (ROS) (e.g., hydrogen peroxide [H2O2]) in cells, which subsequently induce the synthesis of matrix metalloproteinase-1 (MMP-1). MMP-1, an interstitial collagenase, in turn stimulates an aging phenomenon. In this study, baicalein (5,6,7-trihydroxyflavone) was investigated for its in vitro activity against H2O2-induced damage using a human skin keratinocyte model. Baicalein pretreatment significantly inhibited H2O2-induced up-regulation of MMP-1 mRNA, MMP-1 protein expression and MMP-1 activity in cultured HaCaT keratinocytes. In addition, baicalein decreased the transcriptional activity of activator protein-1 (AP-1) and the expression of c-Fos and c-Jun, both components of the heterodimeric AP-1 transcription factor. Furthermore, baicalein reduced phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun-N-terminal kinase (JNK), which are upstream of the AP-1 transcription factor. The results of this study suggest that baicalein is involved in the inhibition of oxidative stress-induced expression of MMP-1 via inactivation of the ERK/JNK/AP-1 signaling pathway.

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