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1.
Arch Oral Biol ; 109: 104586, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31630005

RESUMO

OBJECTIVE: Dental caries is caused by plaque associated oral bacteria including a pioneer species Streptococcus mutans. It has ability to form biofilm and produce acids in the oral cavity. Many oral hygiene products containing plant derived compounds have been investigated for their anti-S. mutans activity. Dodonaea viscosa var. angustifolia (DVA), has been found to have this property. However, beneficial concentrations are difficult to maintain in the oral cavity due to continual saliva flow which can be overcome using nanotechnology. The aim of this study was to investigate the anti-acidogenic, anti-biofilm and slow release properties of DVA derived flavone stabilized polymeric nanoparticles. METHODS: Crude extract prepared from DVA leaves was fractionated to produce subfractions and the beneficial subfraction (F5.1) was obtained. Polymeric nanoparticles (PLGA-PEG) were prepared, stabilized with the DVA subfraction (F5.1/NPs) and characterized. Anti-S. mutans, anti-acidogenic and antibiofilm properties were determined. The subfraction release profile (substantivity) and cytotoxicity was determined. Results were analyzed using the Wilcoxon sum test (Mann-Whitney). RESULTS: F5.1/NPs showed anti-S. mutans property (MIC 1.56 mg/ml). Subinhibitory concentrations of these nanoparticles significantly reduced the acid production in S. mutans (p < 0.01) and also reduced the biofilm formation by 92%. The retention and slow release of the beneficial compound was detected up to 12 h, reaching 0.1 mg/ml concentration at pH 7.4 after 4 h and at pH 5.5 after 5 h. IC50 of F5.1/NPs was 62.5 µg/ml. CONCLUSION: the DVA flavone containing nanoparticles showed anticariogenic activity with improved substantivity. Therefore, they have potential for use to control dental caries.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Flavonas/farmacologia , Extratos Vegetais/farmacologia , Sapindaceae/química , Portadores de Fármacos , Nanopartículas , Folhas de Planta/química , Streptococcus mutans
2.
Fitoterapia ; 139: 104387, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31678632

RESUMO

Aqueous and acetone extracts of O. stamineus leaves reduce the adhesion of uropathogenic E. coli (UPEC, strain UTI89) to T24 bladder cells significantly (IC25 ~ 524 mg/mL, resp. 40 µg/mL). The acteonic extract had no cytotoxic effects against UPEC in concentrations that inhibited the bacterial adhesion. The extract significantly reduced the gene expression of fimH, fimC, fimD, csgA and focG, which are strongly involved in the formation of bacterial adhesins. The antiadhesive effect was due to the presence of polymethoxylated flavones, enriched in the acetonic extract. Five flavones have been isolated by fast centrifugal partition chromatography, followed by preparative HPLC. Eupatorin, ladanein, salvigenin, sinensetin, 5,6,7,4'-tetramethoxyflavone and 5-hydroxy-6,7,3',4'-tetramethoxyflavone were identified as the main polymethoxylated flavones. With the exception of eupatorin, all of these flavones reduced the bacterial adhesion in a concentration depending manner, indicating that B-ring hydroxylation and methoxylation seems to have a major impact on the antiadhesive activity. In addition, this was confirmed by investigation of the flavones chrysoeriol and diosmetin, which had only very weak antiadhesive activity. From these data, Orthosiphon extracts can be assessed to have a pronounced antiadhesive activity against UPEC, based on a variety of polymethoxylated flavones.


Assuntos
Aderência Bacteriana/efeitos dos fármacos , Flavonas/farmacologia , Orthosiphon/química , Folhas de Planta/química , Escherichia coli Uropatogênica/efeitos dos fármacos , Linhagem Celular Tumoral , Flavonas/isolamento & purificação , Flavonoides , Alemanha , Humanos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia
3.
Molecules ; 24(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505804

RESUMO

The screening of drug metabolites in biological matrixes and structural characterization based on product ion spectra is among the most important, but also the most challenging due to the significant interferences from endogenous species. Traditionally, metabolite detection is accomplished primarily on the basis of predicted molecular masses or fragmentation patterns of prototype drug metabolites using ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS). Although classical techniques are well-suited for achieving the partial characterization of prototype drug metabolites, there is a pressing need for a strategy to enable comprehensive drug metabolism depiction. Therefore, we present drug metabolite clusters (DMCs), different from, but complementary to, traditional approaches for mining the information regarding drugs and their metabolites on the basis of raw, processed, or identified tandem mass spectrometry (MS/MS) data. In this paper, we describe a DMC-based data-mining method for the metabolite identification of 5-hydroxy-6,7,3',4'-tetramethoxyflavone (HTF), a typical hydroxylated-polymethoxyflavonoid (OH-PMF), which addressed the challenge of creating a thorough metabolic profile. Consequently, eight primary metabolism clusters, sixteen secondary metabolism clusters, and five tertiary metabolism clusters were proposed and 106 metabolites (19 potential metabolites included) were detected and identified positively and tentatively. These metabolites were presumed to generate through oxidation (mono-oxidation, di-oxidation), methylation, demethylation, methoxylation, glucuronidation, sulfation, ring cleavage, and their composite reactions. In conclusion, our study expounded drug metabolites in rats and provided a reference for further research on therapeutic material basis and the mechanism of drugs.


Assuntos
Mineração de Dados , Flavonas/metabolismo , Metaboloma/efeitos dos fármacos , Animais , Cromatografia Líquida de Alta Pressão , Desmetilação/efeitos dos fármacos , Flavonas/farmacologia , Humanos , Hidroxilação/efeitos dos fármacos , Hidroxilação/genética , Metaboloma/genética , Metilação/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Ratos , Espectrometria de Massas em Tandem
4.
Phytomedicine ; 63: 153036, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31401534

RESUMO

BACKGROUND: Genkwanin is a flavone isolated from the traditional Chinese herb Daphne genkwa. Our previous work proved that four flavonoids (including genkwanin) isolated from D. genkwa (FFD) significantly improved the symptoms of arthritis in rat models. Recent studies have revealed that genkwanin exhibited anti-inflammatory and immunomodulatory activities, both of which were closely related to the pathology of rheumatoid arthritis (RA). Therefore, studying the anti-RA effects and mechanisms of genkwanin may give us insight into FFD's therapeutic effects on RA. PURPOSE: This study aimed to investigate the anti-rheumatoid arthritis activity of genkwanin on adjuvant-induced arthritis (AIA) model in rats and explore the underlying mechanisms. METHODS: The anti-rheumatoid arthritis activity of genkwanin was evaluated on AIA rat model by determining the paw swelling degrees and arthritis index scores, along with histopathological analysis of joint tissues. The serum cytokine levels were measured by ELISA method, and serum NO levels were measured by Griess method. The expression and phosphorylation levels of proteins in JAK/STAT and NF-κB signaling pathways were determined by western blot analysis and immunohistochemistry analysis. RESULTS: Genkwanin significantly decreased the paw swelling and arthritis index in AIA rats and also decreased the inflammation and bone destruction in joint tissues. The serum TNF-α, IL-6, and NO concentrations were markedly reduced while the IL-10 concentration was markedly increased with the treatment of genkwanin. Genkwanin inhibited the activation of JAK/STAT and NF-κB signaling pathways in synovial tissues of AIA rats. CONCLUSION: Genkwanin exerted anti-rheumatoid arthritis effects on AIA rats through inhibiting the activation of JAK/STAT and NF-κB signaling pathways. The results obtained in this work lead us to suggest that Genkwanin could play a crucial role on the previously demonstrated anti-rheumatoid arthritis activity of flavonoid extract of D. genkwa (namely FFD).


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Flavonas/farmacologia , NF-kappa B/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Citocinas/sangue , Citocinas/metabolismo , Inflamação/tratamento farmacológico , Inibidores de Janus Quinases/farmacologia , Masculino , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia
5.
J Agric Food Chem ; 67(36): 10222-10234, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31385700

RESUMO

The emergence and rapid spread of methicillin-resistant Staphylococcus aureus (MRSA) critically requires alternative therapeutic options. New antibacterial drugs and strategies are urgently needed to combat MRSA-associated infections. Here, we investigated the antibacterial activity of flavones from Morus alba and the potential mode of action against MRSA. Kuwanon G, kuwanon H, mulberrin, and morusin displayed high efficiency in killing diverse MRSA isolates. On the basis of structure-activity analysis, the cyclohexene-phenyl ketones and isopentenyl groups were critical to increase the membrane permeability and to dissipate the proton motive force. Meanwhile, mechanistic studies further showed that kuwanon G displayed rapid bactericidal activity in vitrowith difficulty in developing drug resistance. Kuwanon G targeted phosphatidylglycerol and cardiolipin in the cytoplasmic membrane through the formation of hydrogen bonds and electrostatic interactions. Additionally, kuwanon G promoted wound healing in a mouse model of MRSA skin infection. In summary, these results indicate that flavones are promising lead compounds to treat MRSA-associated infections through disrupting the proton motive force and membrane permeability.


Assuntos
Antibacterianos/farmacologia , Flavonas/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/metabolismo , Morus/química , Extratos Vegetais/farmacologia , Infecções Estafilocócicas/microbiologia , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Permeabilidade da Membrana Celular/efeitos dos fármacos , Feminino , Flavonas/química , Flavonas/isolamento & purificação , Flavonoides/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Humanos , Masculino , Meticilina/farmacologia , Staphylococcus aureus Resistente à Meticilina/genética , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Raízes de Plantas/química , Força Próton-Motriz/efeitos dos fármacos
6.
Molecules ; 24(16)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398899

RESUMO

Nobiletin (NOB) is a polymethoxylated flavonoid isolated from citrus fruit peel that has been shown to possess anti-tumor, antithrombotic, antifungal, anti-inflammatory and anti-atherosclerotic activities. The main purpose of this study was to explore the potential of using NOB to induce apoptosis in human bladder cancer cells and study the underlying mechanism. Using an MTT assay, agarose gel electrophoresis, a wound-healing assay, flow cytometry, and western blot analysis, this study investigated the signaling pathways involved in NOB-induced apoptosis in BFTC human bladder cancer cells. Our results showed that NOB at concentrations of 60, 80, and 100 µM inhibited cell growth by 42%, 62%, and 80%, respectively. Cells treated with 60 µM NOB demonstrated increased DNA fragmentation, and flow cytometry analysis confirmed that the treatment caused late apoptotic cell death. Western blot analysis showed that mitochondrial dysfunction occurred in NOB-treated BFTC cells, leading to cytochrome C release into cytosol, activation of pro-apoptotic proteins (caspase-3, caspase-9, Bad, and Bax), and inhibition of anti-apoptotic proteins (Mcl-1, Bcl-xl, and Bcl-2). NOB-induced apoptosis was also mediated by regulating endoplasmic reticulum stress via the PERK/elF2α/ATF4/CHOP pathway, and downregulating the PI3K/AKT/mTOR pathway. Our results suggested that the cytotoxic and apoptotic effects of NOB on bladder cancer cells are associated with endoplasmic reticulum stress and mitochondrial dysfunction.


Assuntos
Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Flavonas/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Bexiga Urinária/metabolismo , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
7.
Nat Commun ; 10(1): 3923, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462679

RESUMO

Circadian disruption aggravates age-related decline and mortality. However, it remains unclear whether circadian enhancement can retard aging in mammals. We previously reported that the small molecule Nobiletin (NOB) activates ROR (retinoid acid receptor-related orphan receptor) nuclear receptors to potentiate circadian oscillation and protect against metabolic dysfunctions. Here we show that NOB significantly improves metabolic fitness in naturally aged mice fed with a regular diet (RD). Furthermore, NOB enhances healthy aging in mice fed with a high-fat diet (HF). In HF skeletal muscle, the NOB-ROR axis broadly activates genes for mitochondrial respiratory chain complexes (MRCs) and fortifies MRC activity and architecture, including Complex II activation and supercomplex formation. These mechanisms coordinately lead to a dichotomous mitochondrial optimization, namely increased ATP production and reduced ROS levels. Together, our study illustrates a focal mechanism by a clock-targeting pharmacological agent to optimize skeletal muscle mitochondrial respiration and promote healthy aging in metabolically stressed mammals.


Assuntos
Envelhecimento/efeitos dos fármacos , Antioxidantes/farmacologia , Flavonas/farmacologia , Mitocôndrias Musculares/efeitos dos fármacos , Músculo Esquelético/metabolismo , Envelhecimento/metabolismo , Animais , Linhagem Celular , Dieta Hiperlipídica , Complexo de Proteínas da Cadeia de Transporte de Elétrons/genética , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/metabolismo , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo
8.
Molecules ; 24(14)2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336931

RESUMO

The abnormal regulation of melanin synthesis leads to a wide range of pigmentary disorders. Although various melanin biosynthesis inhibitors have been developed, their efficacy and long-term safety needs to be further improved, and thus the goal of this study is to develop promising natural compound inhibitors of melanin biosynthesis. Here, we obtained aglycone flavonoid extract through the microwave-assisted hydrolysis of glycoside extract from Korean mistletoe in acidic condition. The aglycone extract inhibited tyrosinase activity more efficiently with better antioxidant activity than glycoside extract in vitro. The microwave-assisted aglycone extract of mistletoe was further analyzed for in vivo activity, and the results showed the aglycone extract inhibited both early melanocyte development and melanin synthesis more efficiently in zebrafish embryo in a dose-dependent manner. Our in vivo toxicity assay quantitatively measured cell death in zebrafish embryos and showed that the microwave-assisted aglycone extract of mistletoe had no significant effect on cell death (p < 0.001), indicating that aglycone extract is more biocompatible than glycoside extract. Furthermore, our in vitro and in vivo analyses successfully identified and characterized velutin, an aglycone of a homoflavoyadorinin B glycoside, as a major inhibitory component in the microwave-assisted mistletoe extract. Ultimately, this study showed that the novel natural compound inhibitor velutin, which was generated through microwave-assisted extraction from mistletoe, improved the efficacy of melanin biosynthesis inhibition with little toxicity.


Assuntos
Vias Biossintéticas/efeitos dos fármacos , Flavonas/farmacologia , Melaninas/biossíntese , Erva-de-Passarinho/química , Extratos Vegetais/farmacologia , Animais , Linhagem Celular Tumoral , Fracionamento Químico , Cromatografia Líquida de Alta Pressão , Flavonas/química , Flavonas/isolamento & purificação , Flavonoides/química , Flavonoides/farmacologia , Glicosídeos/química , Hidrólise , Melanócitos/metabolismo , Micro-Ondas , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Peixe-Zebra
9.
Molecules ; 24(14)2019 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-31337014

RESUMO

Ochratoxin A (OTA) is a mycotoxin with a serious impact on human health. In Mediterranean countries, the black Aspergilli group, in particular Aspergillus carbonarius, causes the highest OTA contamination. Here we describe the synthesis of three polyphenolic flavonoids: 5-hydroxy-6,7-dimethoxy-flavone (MOS), 5,6-dihydroxy-7-methoxy-flavone (NEG), and 5,6 dihydroxy-flavone (DHF), as well as their effect on the prevention of OTA biosynthesis and lipoxygenase (LOX) activity in A. carbonarius cultured in a conducive liquid medium. The best control effect on OTA biosynthesis was achieved using NEG and DHF. In fungal cultures treated with these compounds at 5, 25, and 50 µg/mL, OTA biosynthesis significantly decreased throughout the 8-day experiment. NEG and DHF appear to have an inhibiting effect also on the activity of LOX, whereas MOS, which did not significantly inhibit OTA production, had no effect on LOX activity. The presence of free hydroxyls in catecholic position in the molecule appears to be a determining factor for significantly inhibiting OTA biosynthesis. However, the presence of a methoxy group in C-7 in NEG could slightly lower the molecule's reactivity increasing OTA inhibition by this molecule at 5 µg/mL. Polyphenolic flavonoids present in edible plants may be easily synthesized and used to control OTA biosynthesis.


Assuntos
Aspergillus/efeitos dos fármacos , Aspergillus/metabolismo , Flavonoides/síntese química , Flavonoides/farmacologia , Ocratoxinas/biossíntese , Vias Biossintéticas/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Flavonas/química , Flavonas/farmacologia , Flavonoides/química , Lipoxigenase/metabolismo , Micotoxinas
11.
Int J Mol Sci ; 20(14)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295812

RESUMO

Alzheimer's disease (AD), which is characterized by the presence of amyloid-ß (Aß) plaques and neurofibrillary tangles, accompanied by neurodegeneration, is the most common form of age-related neurodegenerative disease. Parkinson's disease (PD) is the second most common neurodegenerative disease after AD, and is characterized by early prominent loss of dopaminergic neurons in the substantia nigra pars compacta. As currently available treatments are not able to significantly alter the progression of these diseases, successful therapeutic and preventive interventions are strongly needed. In the course of our survey of substances from natural resources having anti-dementia and neuroprotective activity, we found nobiletin, a polymethoxylated flavone from the peel of Citrus depressa. Nobiletin improved cognitive deficits and the pathological features of AD, such as Aß pathology, hyperphosphorylation of tau, and oxidative stress, in animal models of AD. In addition, nobiletin improved motor and cognitive deficits in PD animal models. These observations suggest that nobiletin has the potential to become a novel drug for the treatment and prevention of neurodegenerative diseases such as AD and PD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Citrus/química , Flavonas/farmacologia , Flavonoides/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/prevenção & controle , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Biomarcadores , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Flavonas/química , Flavonas/uso terapêutico , Flavonoides/química , Flavonoides/uso terapêutico , Humanos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/prevenção & controle , Transdução de Sinais/efeitos dos fármacos
12.
Int J Mol Sci ; 20(13)2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31323961

RESUMO

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with poor prognosis, largely due to resistance to current radiotherapy and Temozolomide chemotherapy. The constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) is evidenced as a pivotal driver of GBM pathogenesis and therapy resistance, and hence, is a promising GBM drug target. 5-acetyloxy-6,7,8,4'-tetramethoxyflavone (5-AcTMF) is an acetylated derivative of Tangeretin which is known to exert anticancer effects on breast, colon, lung, and multiple myeloma; however, its effect on GBM remains elusive. Herein, we reported that 5-AcTMF suppressed the viability and clonogenicity along with inducing apoptosis in multiple human GBM cell lines. Mechanistic analyses further revealed that 5-AcTMF lowered the levels of Tyrosine 705-phosphorylated STAT3 (p-STAT3), a canonical marker of STAT3 activation, but also dampened p-STAT3 upregulation elicited by Interleukin-6. Notably, ectopic expression of dominant-active STAT3 impeded 5-AcTMF-induced suppression of viability and clonogenicity plus apoptosis induction in GBM cells, confirming the prerequisite of STAT3 blockage for the inhibitory action of 5-AcTMF on GBM cell survival and growth. Additionally, 5-AcTMF impaired the activation of STAT3 upstream kinase JAK2 but also downregulated antiapoptotic BCL-2 and BCL-xL in a STAT3-dependent manner. Moreover, the overexpression of either BCL-2 or BCL-xL abrogated 5-AcTMF-mediated viability reduction and apoptosis induction in GBM cells. Collectively, we, for the first time, revealed the anticancer effect of 5-AcTMF on GBM cells, which was executed via thwarting the JAK2-STAT3-BCL-2/BCL-xL signaling axis. Our findings further implicate the therapeutic potential of 5-AcTMF for GBM treatment.


Assuntos
Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Flavonas/química , Flavonas/farmacologia , Glioblastoma/metabolismo , Fases de Leitura Aberta/genética , Fator de Transcrição STAT3/metabolismo , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Interleucina-6/metabolismo , Fator de Transcrição STAT3/genética , Proteína bcl-X/metabolismo
13.
Pharmacology ; 104(3-4): 187-195, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31344704

RESUMO

BACKGROUND/AIMS: Tangeretin (TAN), a major phytochemical in tangerine peels and an important Chinese herb, has multiple biological properties, especially antioxidative and anti-inflammatory effects. However, the mechanisms remain unclear. Based on these findings, the aim of the present study was to assess the antioxidant and anti-inflammatory properties of TAN in bovine type II collagen-induced arthritis rats. METHODS: TAN (50 mg/kg) was given orally once daily for 14 days. The effects of treatment were evaluated by biochemical assay (articular elastase, myeloperoxidase, end products of lipid peroxidation [MDA], antioxidant enzyme, such as superoxide dismutase, catalase, glutathione), nitric oxide, and inflammatory cytokines (interleukin-1ß [IL-1ß], -IL-10, tumor necrosis factor-alpha [TNF-α], interferon-γ [IFN-γ], and prostaglandin E2 [PGE2]). The protective effects of TAN against rheumatoid arthritis (RA) were evident from the decrease in arthritis scoring. Furthermore, the Nrf-2 signaling pathway was assessed to illustrate the molecular mechanism. RESULTS: TAN had therapeutic effects on RA by decreasing the oxidative stress damage and regulating inflammatory cytokine expression, including suppression of the accumulation of MDA products, decreasing the IL-1ß, TNF-α, IFN-γ, and PGE2 levels, enhancing the IL-10 and the activity of antioxidant enzymes, which was through upregulating Nrf-2 signaling pathway. CONCLUSION: TAN might have potential as a therapeutic agent for the treatment of RA.


Assuntos
Artrite Experimental/tratamento farmacológico , Colágeno/farmacologia , Flavonas/farmacologia , Inflamação/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Artrite Experimental/metabolismo , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Catalase , Citocinas/metabolismo , Dinoprostona/metabolismo , Glutationa/metabolismo , Inflamação/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Articulações/efeitos dos fármacos , Articulações/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos
14.
J Biomed Sci ; 26(1): 53, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307481

RESUMO

BACKGROUND: Intracerebral hemorrhage (ICH) induces a complex sequence of apoptotic cascades that contribute to secondary neuronal damage. Tropomyosin-related kinase receptor B (TrkB) signaling plays a crucial role in promoting neuronal survival following brain damage. METHODS: The present study investigated the protective effects and underlying mechanisms of TrkB activation by the specific TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), in a model of collagenase-induced ICH and in neuronal cultures. Mice subjected to collagenase-induced ICH were intraperitoneally injected with either 7,8-DHF or vehicle 10 min after ICH and, subsequently, daily for 3 days. Behavioral studies, brain edema measurement, and histological analysis were conducted. Levels of TrkB signaling-related molecules and apoptosis-related proteins were analyzed by western blots. RESULTS: Treatment with 20 mg/kg 7,8-DHF significantly improved functional recovery and reduced brain damage up to 28 days post-ICH. Reduction in neuronal death, apoptosis, and brain edema were also observed in response to 7,8-DHF treatment at 3 days post-ICH. These changes were accompanied by a significant increase in the phosphorylation of TrkB and Akt (Ser473/Thr308) at 1 and 3 days, but had no effect on Erk 44/42 phosphorylation. 7,8-DHF also enhanced the phosphorylation of Ask-1 Ser967 and FOXO-1, downstream targets of Akt at 1 and 3 days. Moreover, 7,8-DHF increased brain-derived neurotrophic factor levels at 1 day. In primary cultured neurons stimulated with hemin, 7,8-DHF promoted survival and reduced apoptosis. Furthermore, delaying the administration of 7,8-DHF to 3 h post-ICH reduced brain tissue damage and neuronal death. CONCLUSIONS: Our findings demonstrate that the activation of TrkB signaling by 7,8-DHF protects against ICH via the Akt, but not the Erk, pathway. These data provide new insights into the role of TrkB signaling deficit in the pathophysiology of ICH and highlight TrkB/Akt as possible therapeutic targets in this disease.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Flavonas/farmacologia , Glicoproteínas de Membrana/agonistas , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Hemorragia Cerebral/induzido quimicamente , Colagenases/toxicidade , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo
15.
Eur J Med Chem ; 180: 253-267, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31310917

RESUMO

Herein, we address repurposing hybrids of mosloflavone or 5,6,7-trimethoxyflavone with amide analogs of resveratrol from anticancer leads to novel potent anti-inflammatory chemical entities. To unveil the potent anti-inflammatory molecules, biological evaluations were initiated in LPS-induced RAW 264.7 macrophages at 1 µM concentration. Promising compounds were further evaluated at various concentrations. Multiple proinflammatory mediators were assessed including NO, PGE2, IL-6, TNF-α and IL-1ß. Compound 5z inhibited the induced production of NO, PGE2, IL-6, TNF-α and IL-1ß at the low 1 µM concentration by 44.76, 35.71, 53.48, 29.39 and 41.02%, respectively. Compound 5z elicited IC50 values as low as 2.11 and 0.98 µM against NO and PGE2 production respectively. Compounds 5q and 5g showed potent submicromolar IC50 values of 0.31 and 0.59 µM respectively against PGE2 production. Reverse docking of compound 5z suggested p38-α MAPK, which is a key signaling molecule within the pathways controlling the transcription of proinflammatory mediators, as the molecular target. Biochemical testing confirmed these compounds as p38-α MAPK inhibitors explaining its potent inhibition of proinflammatory mediators' production. Collectively, the results presented 5z as a promising compound for further development of anti-inflammatory agents for treatment of macrophages-and/or immune mediated inflammatory diseases.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Flavonas/farmacologia , Flavonoides/farmacologia , Mediadores da Inflamação/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Resveratrol/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Flavonas/química , Flavonoides/química , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Células RAW 264.7 , Resveratrol/química , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Pak J Pharm Sci ; 32(3): 1081-1089, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31278723

RESUMO

A series of flavonoid derivatives, flavones (F1-F3) and flavonols (OF1-OF3) were synthesized. Their structures were confirmed through various spectroscopic techniques and elemental analysis. These were then tested for cytotoxic activity against mouse fibroblast (NIH 3T3), human endothelial cervical (HeLa) and breast (MCF7) cell lines in vitro by MTT assay. The flavonol series showed prominent potentials than the flavones. The compound OF2 in flavonols exhibited greater potentials MCF7 cell with IC50 value of 0.96µM and OF3 has 1.04µM. In contrast, the OF3 exhibited higher activity against HeLa cell with IC50 value of 0.51µM and OF2 has 1.06µM. The compounds OF2 and OF3 exhibited activity against mouse fibroblast (NIH 3T3) cell with IC50 values 2.48 and 1.24µM. The OF1 was found to be moderate to inactive against all cells. Cytotoxic screening of the tested flavones, F1 to F3 were also active against all cells but the activity was less in comparison to flavonol series of compounds suggestion the possible involvement of hydroxyl (OH) at position 3 in case of flavonols. These results indicated a cheering scaffold that may lead to innovation of potent anti-breast cancer activity.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Flavonas/síntese química , Flavonas/farmacologia , Flavonóis/síntese química , Flavonóis/farmacologia , Animais , Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Flavonas/química , Flavonóis/química , Células HeLa , Humanos , Células MCF-7 , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , Células NIH 3T3 , Relação Estrutura-Atividade
17.
J Nutr Sci Vitaminol (Tokyo) ; 65(3): 278-282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257269

RESUMO

We examined the effect of nobiletin (5,6,7,8,3',4'-hexamethoxyflavone) on immune response in ovalbumin (OVA)-immunized mice. Treatment with nobiletin increased OVA-specific IL-4 and IL-10 production. In addition, mice that received nobiletin showed higher levels of OVA-specific IgE, IgG and IgG1 production than did control mice. The antibody response to the thymus-independent antigen 2,4,6-trinitrophenyl-Ficoll was not different in the control and nobiletin groups, suggesting that nobiletin does not directly stimulate antibody production. An in vitro study showed that treatment with nobiletin enhanced the ability of antigen presentation of bone marrow-derived dendritic cells. The in vivo and in vitro results indicate that nobiletin regulates immune function.


Assuntos
Flavonas/farmacologia , Imunidade Celular , Imunidade Humoral , Ovalbumina/imunologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Ficoll/análogos & derivados , Ficoll/imunologia , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Imunidade Humoral/efeitos dos fármacos , Imunidade Humoral/imunologia , Imunização , Camundongos , Camundongos Endogâmicos BALB C , Trinitrobenzenos/imunologia
18.
Fitoterapia ; 137: 104275, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31351126

RESUMO

The non-small cell lung cancer (NSCLC) represents a malignant type of cancer worldwide. The atalantraflavone (AFL) is a natural product isolated from leaves of Atalantia monophylla (L.) DC. However, the function of atalantraflavone in NSCLC is still elusive. In present work, we have unraveled a novel function of AFL in NSCLC. AFL significantly inhibited NSCLC cell viability and colony formation. AFL increased sub-G1 fraction and apoptotic rates in a dose-dependent manner. Furthermore, Twist-related protein 1 (Twist1) was identified as the target of AFL. The association between AFL and Twist1 markedly decreased the stability of Twist1 via elevated ubiquitin mediated proteasomal degradation. AFL induced NSCLC suppression was mediated by Twist1 as Twist1 overexpression could partially reverse the inhibitory effect of AFL on migration and metastasis. Furthermore, AFL could also sensitize NSCLC cells to cisplatin treatment and consistently impair NSCLC proliferation and metastasis. Our current data have identified a tumor suppressive function for AFL in NSCLC by increasing Twist1 degradation. Therefore, the anti-tumor activity of AFL might provide critical insight into pharmaceutic lung cancer intervention to overcome cisplatin resistance.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Flavonas/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Rutaceae/química , Proteína 1 Relacionada a Twist/antagonistas & inibidores , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Flavonas/isolamento & purificação , Humanos , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Folhas de Planta/química , Estabilidade Proteica
19.
Molecules ; 24(15)2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31357486

RESUMO

Seventeen new flavone derivatives substituted at the 4'-OH position were designed, synthesized and evaluated for their anticancer and antibacterial activities. Among them, compounds 3, 4, 6f, 6e, 6b, 6c and 6k demonstrated the most potent antiproliferative activities against a human erythroleukemia cell line (HEL) and a prostate cancer cell line (PC3). The results also showed that the IC50 value of compounds 3, 4, 6f, 6e, 6b, 6c and 6k were close to that of the anticancer drug cisplatin (DDP) and lower than that of apigenin. All of the derivatives did not present antibacterial activities. The structure-activity relationships evaluation showed that the configuration of methyl amino acid might affect their biological activities.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Flavonas/química , Flavonas/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Flavonas/síntese química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
20.
ACS Chem Biol ; 14(7): 1536-1545, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31184855

RESUMO

Diversity-oriented synthesis (DOS) has historically focused on the development of small-molecule collections with considerable chemical diversity with the hypothesis that chemical diversity will lead to diverse biological activities. We took a systematic approach to DOS to develop a focused library of reduced flavones from γ-pyrones with diversity of appendage, stereochemistry, and chemical properties to determine which features of small molecules are most predictive of biological performance diversity. The effects of these systematic modifications on biodiversity were determined using Cell Painting and cytotoxicity assays to compare the results of multiple methods of assessment. We observed that a greater fraction of sp3 hybridized atoms (fsp3) does not always lead to enhanced biodiversity, that stereochemistry and appendage diversity both contribute to biodiversity, and that lipophilicity of the pyrone class of compounds correlates with biodiversity. These results will contribute to the development of a general algorithm to predict which chemical features should be considered during the synthesis of DOS libraries to create biological performance-diverse collections of small molecules for probe and drug discovery.


Assuntos
Antineoplásicos/química , Flavonas/química , Pironas/química , Bibliotecas de Moléculas Pequenas/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas/métodos , Flavonas/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Oxirredução , Pironas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia
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