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2.
Biomed Environ Sci ; 33(4): 238-247, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32438961

RESUMO

Objective: This study aimed to explore the protective effect of procyanidin B2 (PCB2) on acute liver injury induced by aflatoxin B 1 (AFB 1) in rats. Methods: Forty Sprague Dawley rats were randomly divided into control, AFB 1, AFB 1 + PCB2, and PCB2 groups. The latter two groups were administrated PCB2 intragastrically (30 mg/kg body weight) for 7 d, whereas the control and AFB 1 groups were given the same dose of double distilled water intragastrically. On the sixth day of treatment, the AFB 1 and AFB 1 + PCB2 groups were intraperitoneally injected with AFB 1 (2 mg/kg). The control and PCB2 groups were intraperitoneally administered the same dose of dimethyl sulfoxide (DMSO). On the eighth day, all rats were euthanized: serum and liver tissue were isolated for further examination. Hepatic histological features were assessed by hematoxylin and eosin-stained sections. Weight, organ coefficient (liver, spleen, and kidney), liver function (serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, and direct bilirubin), oxidative index (catalase, glutathione, superoxide dismutase, malondialdehyde, and 8-hydroxy-2'-deoxyguanosine), inflammation factor [hepatic interleukin-6 (IL-6) mRNA expression and serum IL-6], and bcl-2/bax ratio were measured. Results: AFB 1 significantly caused hepatic histopathological damage, abnormal liver function, oxidative stress, inflammation, and bcl-2/bax ratio reduction compared with DMSO-treated controls. Our results indicate that PCB2 treatment can partially reverse the adverse liver conditions induced by AFB 1. Conclusion: Our findings indicate that PCB2 exhibits a protective effect on acute liver injury induced by AFB 1.


Assuntos
Aflatoxina B1/toxicidade , Biflavonoides/farmacologia , Catequina/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Venenos/toxicidade , Proantocianidinas/farmacologia , Substâncias Protetoras/farmacologia , Animais , Biflavonoides/administração & dosagem , Catequina/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Masculino , Proantocianidinas/administração & dosagem , Substâncias Protetoras/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
3.
J Appl Microbiol ; 129(3): 601-611, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32281733

RESUMO

AIMS: To study the mechanism of the antibacterial action of tea polyphenols such as catechins and theaflavins against Bacillus coagulans, and the interaction of epigallocatechin gallate (EGCg) or theaflavin 3,3'-di-O-gallate (TFDG) with the surface of B. coagulans cells was investigated. METHODS AND RESULTS: The antibacterial activities of EGCg and TFDG against B. coagulans cells were measured by counting of the viable cells after the mixing with each polyphenol. Bactericidal effect of TFDG was shown at the concentration of greater than or equal to 62·5 mg l-1 ; however, at the same concentration, EGCg did not. According to the results of two dimensional (2D)-electrophoresis analysis, TFDG seemed to interact with cytoplasmic membrane proteins. The activity of the glucose transporters of the cells decreased 40% following the treatment with TFDG of 62·5 mg l-1 ; however, this decrease was only slight in case of EGCg. This result was in accordance with the strength of their bactericidal activities. CONCLUSION: Our results suggest that the direct interaction between membrane proteins and TFDG is an important factor in the antibacterial activity of polymerized catechins, affecting their functions and leading to cell death. SIGNIFICANCE AND IMPACT OF THE STUDY: Tea polyphenols can effectively use the prevention of product spoilage in the food and beverage industry.


Assuntos
Antibacterianos/farmacologia , Bacillus coagulans/efeitos dos fármacos , Biflavonoides/farmacologia , Catequina/análogos & derivados , Bacillus coagulans/metabolismo , Biflavonoides/metabolismo , Catequina/metabolismo , Catequina/farmacologia , Membrana Celular/efeitos dos fármacos , Glucose/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Viabilidade Microbiana/efeitos dos fármacos , Polifenóis/química , Polifenóis/farmacologia , Chá/química
4.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(1): 14-19, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32314719

RESUMO

Objective To investigate the block effect of amentoflavone (AF) on the inflammation of mouse BV-2 microglial cells induced by lipopolysaccharide (LPS). Methods BV-2 microglial cells were treated with AF at different concentrations, and cell viability was determined by CCK-8 assay to get the AF concentration that had no effect on the cell viability. BV-2 microglia cells were pretreated with 10 mol/L AF, and 1 hour later, 1.0 g/mL LPS was used to induce inflammatory response in the BV-2 microglial cells. Real-time quantitative PCR was performed to detect the gene expression of interleukin 1ß (IL-1ß), tumor necrosis factor α (TNF-α), cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS). The protein expression of COX2 and iNOS were measured by Western blot analysis. Immunofluorescence staining was used to observe the location and expression of COX2 and iNOS. Results CCK-8 showed that 10 mol/L AF did not affect the viability in BV-2 microglial cells. The treatment of 1.0 g/mL LPS could significantly up-regulate the mRNA expression of IL-1ß, TNF-α, COX2, iNOS, and the protein expression of COX2 and iNOS. Compared with the only LPS treatment, 10 mol/L AF pretreatment markedly decreased the elevated gene and protein expression induced by LPS. In addition, AF significantly inhibited the expression of COX2 and iNOS, and less microglial cells were activated. Conclusion AF can inhibit the inflammation of BV-2 microglial cells induced by LPS.


Assuntos
Biflavonoides/farmacologia , Inflamação , Microglia/efeitos dos fármacos , Animais , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
5.
Arch Biochem Biophys ; 687: 108384, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32343974

RESUMO

Epithelial mesenchymal transition (EMT) is a well-known and important step in metastasis and thus can be a key target in cancer treatment. Here, we tested the EMT inhibitory actions of Selaginella tamariscina and its active component, amentoflavone (AF). EMT was examined in vitro using wound-healing and invasion assays and by monitoring changes in the expression of the EMT-related proteins, E-cadherin, Snail, and Twist. Metastasis was examined in vivo using SCID mice injected with luciferase-labeled A549 cells. We confirmed that aqueous extracts of S. tamariscina (STE) and AF inhibited EMT in human cancer cell lines. We found that STE and AF at nontoxic concentrations exerted remarkable inhibitory effects on migration (wound healing assay) and invasion (Transwell assay) in tumor necrosis factor (TGF)-ß-treated cancer cells. Western blotting and immunofluorescence imaging show that AF treatment also restored E-cadherin expression in these cells compared to cells treated with TGF-ß only. Suppression of metastasis by AF was investigated by monitoring migration of tail-vein-injected, circulating A549-luc cells to the lungs in mice. After 3 wk, fewer nodules were observed in mice co-treated with AF compared with those treated with TGF-ß only. Our findings indicate that STE and AF are promising EMT inhibitors and, ultimately, potentially potent antitumor agents.


Assuntos
Antineoplásicos/uso terapêutico , Biflavonoides/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Metástase Neoplásica/prevenção & controle , Selaginellaceae/química , Células A549 , Animais , Antígenos CD/metabolismo , Antineoplásicos/farmacologia , Biflavonoides/farmacologia , Caderinas/metabolismo , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Camundongos SCID , Proteínas Nucleares/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Proteína 1 Relacionada a Twist/metabolismo
6.
Pharm Biol ; 58(1): 200-207, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32114864

RESUMO

Context: Oxidative imbalance-induced cognitive impairment is among the most urgent clinical concerns. Isoflurane has been demonstrated to impair cognitive function via an increase in oxidative stress. GSP has strong antioxidant capacities, suggesting potential cognitive benefits.Objective: This study investigates whether GSP pre-treatment can alleviate isoflurane-induced cognitive dysfunction in mice.Materials and methods: C57BL/6J mice were pre-treated with either GSP 25-100 mg/kg/d for seven days or GSP 100-400 mg/kg as a single dose before the 6 h isoflurane anaesthesia. Cognitive functioning was examined using the fear conditioning tests. The levels of SOD, p-NR2B and p-CREB in the hippocampus were also analysed.Results: Pre-treatment with either a dose of GSP 50 mg/kg/d for seven days or a single dose of GSP 200 mg/kg significantly increased the % freezing time in contextual tests on the 1st (72.18 ± 12.39% vs. 37.60 ± 8.93%; 78.27 ± 8.46% vs. 52.72 ± 2.64%), 3rd (93.80 ± 7.62% vs. 52.94 ± 14.10%; 87.65 ± 10.86% vs. 52.89 ± 1.73%) and 7th (91.36 ± 5.31% vs. 64.09 ± 14.46%; 93.78 ± 3.92% vs. 79.17 ± 1.79%) day after anaesthesia. In the hippocampus of mice exposed to isoflurane, GSP 200 mg/kg increased the total SOD activity on the 1st and 3rd day and reversed the decreased activity of the NR2B/CREB pathway.Discussion and conclusions: These findings suggest that GSP improves isoflurane-induced cognitive dysfunction by protecting against perturbing antioxidant enzyme activities and NR2B/CREB pathway. Therefore, GSP may possess a potential prophylactic role in isoflurane-induced and other oxidative stress-related cognitive decline.


Assuntos
Anestésicos Inalatórios/toxicidade , Antioxidantes/farmacologia , Biflavonoides/farmacologia , Catequina/farmacologia , Disfunção Cognitiva/prevenção & controle , Isoflurano/toxicidade , Proantocianidinas/farmacologia , Vitis/química , Animais , Antioxidantes/isolamento & purificação , Biflavonoides/isolamento & purificação , Catequina/isolamento & purificação , Cognição/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proantocianidinas/isolamento & purificação , Receptores de N-Metil-D-Aspartato/metabolismo , Sementes/química , Transdução de Sinais , Superóxido Dismutase/metabolismo
7.
J Med Virol ; 92(6): 693-697, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32167173

RESUMO

An outbreak of coronavirus disease 2019 (COVID-19) occurred in Wuhan and it has rapidly spread to almost all parts of the world. For coronaviruses, RNA-dependent RNA polymerase (RdRp) is an important polymerase that catalyzes the replication of RNA from RNA template and is an attractive therapeutic target. In this study, we screened these chemical structures from traditional Chinese medicinal compounds proven to show antiviral activity in severe acute respiratory syndrome coronavirus (SARS-CoV) and the similar chemical structures through a molecular docking study to target RdRp of SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV). We found that theaflavin has a lower idock score in the catalytic pocket of RdRp in SARS-CoV-2 (-9.11 kcal/mol), SARS-CoV (-8.03 kcal/mol), and MERS-CoV (-8.26 kcal/mol) from idock. To confirm the result, we discovered that theaflavin has lower binding energy of -8.8 kcal/mol when it docks in the catalytic pocket of SARS-CoV-2 RdRp by using the Blind Docking server. Regarding contact modes, hydrophobic interactions contribute significantly in binding and additional hydrogen bonds were found between theaflavin and RdRp. Moreover, one π-cation interaction was formed between theaflavin and Arg553 from the Blind Docking server. Our results suggest that theaflavin could be a potential SARS-CoV-2 RdRp inhibitor for further study.


Assuntos
Antivirais/química , Betacoronavirus/efeitos dos fármacos , Biflavonoides/química , Catequina/química , Medicamentos de Ervas Chinesas/química , RNA Replicase/química , Proteínas Virais/química , Sequência de Aminoácidos , Antivirais/farmacologia , Betacoronavirus/enzimologia , Betacoronavirus/genética , Biflavonoides/farmacologia , Domínio Catalítico , Catequina/farmacologia , Biologia Computacional/métodos , Medicamentos de Ervas Chinesas/farmacologia , Expressão Gênica , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/enzimologia , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Simulação de Acoplamento Molecular , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , RNA Replicase/antagonistas & inibidores , RNA Replicase/genética , RNA Replicase/metabolismo , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/enzimologia , Vírus da SARS/genética , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Termodinâmica , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/genética , Proteínas Virais/metabolismo
8.
Chem Pharm Bull (Tokyo) ; 68(2): 140-149, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32009081

RESUMO

Previously, we reported that the c-Met inhibitory effect of Ephedra Herb extract (EHE) is derived from ingredients besides ephedrine alkaloids. Moreover, analgesic and anti-influenza activities of EHE and ephedrine alkaloids-free Ephedra Herb extract (EFE) have been reported recently. In this study, we examined the fractions containing c-Met kinase inhibitory activity from EHE and the fractions with analgesic and anti-influenza activities from EFE, and elucidated the structural characteristics of the active fractions. Significant c-Met kinase activity was observed in 30, 40, and 50% methanol (MeOH) eluate fractions obtained from water extract of EHE using Diaion HP-20 column chromatography. Similarly, 20 and 40% MeOH, and MeOH eluate fractions obtained from water extract of EFE were found to display analgesic and anti-influenza activities. Reversed phase-HPLC analysis of the active fractions commonly showed broad peaks characteristic of high-molecular mass condensed tannin. The active fractions were analyzed using 13C-NMR and decomposition reactions; the deduced structures of active components were high-molecular mass condensed tannins, which were mainly procyanidin B-type and partly procyanidin A-type, including pyrogallol- and catechol-type flavan 3-ols as extension and terminal units. HPLC and gel permeation chromatography (GPC) analyses estimated that the ratio of pyrogallol- and catechol-type was approximately 9 : 2, and the weight-average molecular weight based on the polystyrene standard was >45000. Furthermore, GPC-based analysis was proposed as the quality evaluation method for high-molecular mass condensed tannin in EHE and EFE.


Assuntos
Ephedra/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Alcaloides/química , Alcaloides/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Animais , Antivirais/química , Antivirais/farmacologia , Biflavonoides/química , Biflavonoides/farmacologia , Catequina/química , Catequina/farmacologia , Linhagem Celular Tumoral , Cães , Efedrina/química , Efedrina/farmacologia , Humanos , Células Madin Darby de Rim Canino , Masculino , Camundongos , Proantocianidinas/química , Proantocianidinas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores
9.
Life Sci ; 247: 117425, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32057904

RESUMO

AIMS: Glioma is the most common type of malignant tumor of the nervous system, and aggressiveness and recurrence are major obstacles for treatment. This study is designed to explore the effects of amentoflavone (AF) on glioma, and to investigate the underlying mechanism of the anti-cancer activities of AF. METHODS: Cell morphology was recorded under microscopy. Cell viability and cell death ratio were determined by CCK-8 assay and lactate dehydrogenase (LDH) release assay, respectively. Cell cycle progression was assessed by flow cytometry. The levels of iron, MDA (malondialdehyde), lipid ROS, and GSH (reduced glutathione) were assessed by ELISA kit. The cycle-related proteins, ferroptosis-related protein, autophagy-related protein, and the phosphorylation of AMPK, mTOR and p70S6K were analyzed by western blotting. The autophagic flux was observed by transfecting cells with mRFP-GFP-LC3 plasmids. The xenograft murine models were established to analyze the effects of amentoflavone in vivo. The immunohistochemistry assay was performed to analyze the expression of LC3B, Beclin1, ATG5, ATG7, and ferritin heavy chain (FTH). RESULTS: Our results showed that AF treatment led to reduction in cell viability and cell death. In addition, AF was found to block cell cycle progression in a dose-dependent manner in vitro. Following treatment with AF, the intracellular levels of iron, MDA, and lipid OS were increased, and the levels of GSH and the mitochondrial membrane potential were reduced. In addition, our results showed that AF promoted the autophagic by regulating autophagy-relevant proteins. Our results also showed that the autophagy-induction by AF was associated with regulation of AMPK/mTOR signaling. Mechanistically, the inhibition effects of AF on glioma cell were reversed by DFO, ferreostatin-1 as well as upregulation of FTH. Meanwhile, the FTH levels were increased by compound C and knockdown of ATG7. Moreover, both autophagy inhibitor Baf A1 and knockdown of ATG7 were able to compromising AF-induce ferroptosis and cell death. In vivo, the tumor growth was suppressed by AF in a dose-dependent manner. The level of MDA in the tumor tissue was increased while the level of GSH in tumor tissue was decreased by AF in a dose-dependent manner. Furthermore, the expression of LC3B, Beclin1, ATG5, ATG7 were increased, and the expression of FTH were decreased by AF in a dose-dependent manner in vivo. Conclusion These results demonstrate that AF triggered ferroptosis in autophagy-dependent manner. Our results suggest that AF has the potential to be considered as a novel treatment agent in glioma.


Assuntos
Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Biflavonoides/uso terapêutico , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Ferroptose/efeitos dos fármacos , Glioma/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Proteínas Relacionadas à Autofagia/metabolismo , Proteína Beclina-1/metabolismo , Biflavonoides/farmacologia , Linhagem Celular Tumoral , Inibidores do Citocromo P-450 CYP3A/farmacologia , Glioma/metabolismo , Glioma/patologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Quinases/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/metabolismo
10.
J Agric Food Chem ; 68(9): 2673-2683, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32050765

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the leading cause of chronic liver diseases throughout the world. The deficit of pharmacotherapy for NAFLD calls for an urgent need for a new drug discovery and lifestyle management. Black tea is the most popular and functional drink consumed worldwide. Its main bioactive constituent theaflavin helps to prevent obesity-a major risk factor for NAFLD. To find new targets for the development of effective and safe therapeutic drugs from natural plants for NAFLD, we found a theaflavin monomer theaflavin-3,3'-digallate (TF3), which significantly reduced lipid droplet accumulation in hepatocytes, and directly bound and inhibited the activation of plasma kallikrein (PK), which was further proved to stimulate adenosine monophosphate activated protein kinase (AMPK) and its downstream targets. Taken together, we proposed that the TF3-PK-AMPK regulatory axis is a novel mechanism of lipid deposition mitigation, and PK could be a new target for NAFLD treatment.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Biflavonoides/farmacologia , Catequina/farmacologia , Hepatócitos/metabolismo , Gotículas Lipídicas/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Extratos Vegetais/farmacologia , Calicreína Plasmática/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Apoptose/efeitos dos fármacos , Camellia sinensis/química , Células Hep G2 , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Humanos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Transdução de Sinais/efeitos dos fármacos
11.
J Agric Food Chem ; 68(5): 1306-1314, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31957433

RESUMO

Dimer procyanidin B2 [epicatechin-(4ß-8)-epicatechin] (PB2) has attracted a lot of interest in nutrition and medicine because of its significant health-promoting abilities. However, the function of PB2 on different types of skeletal myofiber is still unclear. Here, we have found that PB2 significantly increased protein expression of the slow myosin heavy chain (MyHC) and decreased fast MyHC protein in C2C12 myotubes, accompanied by upregulation of mRNA expression of MyHC I, MyHC IIa, and Tnni1 and downregulation of MyHC IIx and MyHC IIb. We have also found that PB2 enhanced the activities of malate dehydrogenase and succinic dehydrogenase and reduced lactate dehydrogenase activity. PB2 promoted phosphorylation of AMPK and significantly increased mRNA expression of AMPKα1. The upstream factors of AMPK, such as phospho-LKB1, NRF1, and CaMKKß, and the downstream factors of AMPK, including Sirt1 and PGC-1α, were also increased by PB2. Specific suppression of AMPK signaling by AMPKα1 siRNA or by AMPK inhibitor compound C significantly attenuated the PB2-induced upregulation of phospho-AMPK, PGC-1α, and slow MyHC and downregulation of fast MyHC. Our findings suggested that PB2 promotes skeletal slow-twitch myofiber gene expression through the AMPK signaling pathway in C2C12 myotubes.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Biflavonoides/farmacologia , Catequina/farmacologia , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Proantocianidinas/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Animais , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Fibras Musculares de Contração Lenta/efeitos dos fármacos , Fibras Musculares de Contração Lenta/metabolismo , Músculo Esquelético/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
Curr Top Med Chem ; 20(2): 111-120, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31854280

RESUMO

BACKGROUND: Neuraminidase inhibitors (NAIs) are the only class of antivirals in clinical use against influenza virus approved worldwide. However, approximately 1-3% of circulating strains present resistance mutations to oseltamivir (OST), the most used NAI. Therefore, it is important to catalogue new molecules to inhibit influenza virus, especially OST-resistant strains. Natural products from tropical plants used for human consumption represent a worthy class of substances. Their use could be stimulated in resource-limited setting where the access to expensive antiviral therapies is restricted. METHODS: We evaluated the anti-influenza virus activity of agathisflavone derived from Anacardium occidentale L. RESULTS: The neuraminidase (NA) activity of wild-type and OST-resistant influenza virus was inhibited by agathisflavone, with IC50 values ranging from 20 to 2.0 µM, respectively. Agathisflavone inhibited influenza virus replication with EC50 of 1.3 µM. Sequential passages of the virus in the presence of agathisflavone revealed the emergence of mutation R249S, A250S and R253Q in the NA gene. These changes are outside the OST binding region, meaning that agathisflavone targets this viral enzyme at a region different than conventional NAIs. CONCLUSION: Altogether our data suggest that agathisflavone has a promising chemical structure for the development of anti-influenza drugs.


Assuntos
Anacardium/química , Biflavonoides/farmacologia , Inibidores Enzimáticos/farmacologia , Neuraminidase/antagonistas & inibidores , Orthomyxoviridae/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Animais , Biflavonoides/química , Biflavonoides/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Células Madin Darby de Rim Canino/efeitos dos fármacos , Células Madin Darby de Rim Canino/virologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Neuraminidase/metabolismo , Orthomyxoviridae/enzimologia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
13.
J Pharmacol Sci ; 142(3): 101-108, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31874782

RESUMO

Cardioprotective abilities of procyanidins, might, at least in part, attribute to their vasodilator properties. The present study was undertaken to assess the vasorelaxant effect of procyanidin B2 on isolated human saphenous vein (HSV) and its underlying mechanisms. Procyanidin B2 relaxed phenylephrine-induced contraction of HSV rings in concentration-dependent manner. The relaxation was dependent on the presence of endothelium and was strongly affected by l-NAME, hydroxocobalamin or ODQ, the inhibitors of NO/cGMP pathway. Indomethacin significantly affected only the relaxation produced by the highest concentrations of procyanidin B2. Apamin and TRAM-34 combination, in the presence of l-NAME and indomethacin, did not additionally decreased procyanidin B2-induced relaxation. In the presence of K+ channel blockers, relaxation induced by procyanidin B2 was partially attenuated by 4-aminopyridine, significantly inhibited by glibenclamide and almost abolished by iberiotoxin. Procyanidin B2 also relaxed the contractions induced by phenylephrine or caffeine in Ca2+-free solution. Finally, nifedipine slightly, while thapsigargin strongly antagonized HSV relaxation. Our results indicate that procyanidin B2 induces endothelium-dependent relaxation of HSV, which results primarily from stimulation of NO production, as well K+ channels opening, especially BKCa, and partially KATP and KV. Regulation of the intracellular Ca2+ release and inhibition of Ca2+ influx probably contribute to procyanidin B2-induced relaxation.


Assuntos
Biflavonoides/farmacologia , Cardiotônicos , Catequina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Proantocianidinas/farmacologia , Veia Safena/efeitos dos fármacos , Vasodilatadores , Canais de Cálcio/metabolismo , Relação Dose-Resposta a Droga , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Canais de Potássio/metabolismo
14.
Oxid Med Cell Longev ; 2019: 1076512, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827667

RESUMO

Oxidative stress is a causal factor and key promoter of all kinds of reproductive disorders related to granulosa cell (GC) apoptosis that acts by dysregulating the expression of related genes. Various studies have suggested that grape seed procyanidin B2 (GSPB2) may protect GCs from oxidative injury, though the underlying mechanisms are not fully understood. Therefore, whether the beneficial effects of GSPB2 are associated with microRNAs, which have been suggested to play a critical role in GC apoptosis by regulating the expression of protein-coding genes, was investigated in this study. The results showed that GSPB2 treatment protected GCs from a H2O2-induced apoptosis, as detected by an MTT assay and TUNEL staining, and increased let-7a expression in GCs. Furthermore, let-7a overexpression markedly increased cell viability and inhibited H2O2-induced GC apoptosis. Furthermore, the overexpression of let-7a reduced the upregulation of Fas expression in H2O2-treated GCs at the mRNA and protein levels. Dual-luciferase reporter assay results indicated that let-7a directly targets the Fas 3'-UTR. Furthermore, the overexpression of let-7a enhanced the protective effects of GSPB2 against GC apoptosis induced by H2O2. These results indicate that GSPB2 inhibits H2O2-induced apoptosis of GCs, possibly through the upregulation of let-7a.


Assuntos
Biflavonoides/farmacologia , Catequina/farmacologia , MicroRNAs/metabolismo , Proantocianidinas/farmacologia , Regulação para Cima/efeitos dos fármacos , Vitis/química , Regiões 3' não Traduzidas , Animais , Apoptose/efeitos dos fármacos , Sequência de Bases , Sobrevivência Celular/efeitos dos fármacos , Feminino , Células da Granulosa/citologia , Células da Granulosa/metabolismo , Extrato de Sementes de Uva/química , Peróxido de Hidrogênio/farmacologia , Ovário/citologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Alinhamento de Sequência , Suínos , Vitis/metabolismo , Receptor fas/química , Receptor fas/genética , Receptor fas/metabolismo
15.
Sci Rep ; 9(1): 19183, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31844118

RESUMO

Advanced glycation end-products (AGEs) have been reported as results of increased oxidative stress. Consequently, the search for new antioxidant and anti-glycating agents is under intense investigation. Plant-derived procyanidins have previously demonstrated anti-glycation properties. Thus, this study aimed to isolate procyanidins from Annona crassiflora fruit peel, a species from the Brazilian Savanna, and investigate their antioxidant and anti-glycation effects. Free radical scavenging and quenching properties, formation of reactive oxygen species (ROS), AGEs, protein carbonyl and thiol groups, lipid peroxidation, crosslinked AGEs, as well as glycated catalase activity, were analyzed. In addition, in silico assessment of absorption, distribution, metabolism, excretion and toxicity was carried out. The procyanidins-enriched fraction, named here as F7, showed high antioxidant and anti-glycation capacities, with inhibitory activities against lipid peroxidation, and AGEs and ROS formation. In addition, there were reductions in AGEs-induced crosslinks and protein carbonyls and protective effects against oxidation of thiol groups and glycated-catalase. ADMET predictions of F7 showed favorable absorption and distribution, with no hepatotoxicity or mutagenicity. Together, our results support the anti-glycation activities of the procyanidins-enriched fraction from A. crassiflora, and suggest that these effects are triggered, at least in part, by scavenging free radical and dicarbonyls intermediates.


Assuntos
Annona/química , Biflavonoides/farmacologia , Catalase/metabolismo , Catequina/farmacologia , Frutas/química , Peroxidação de Lipídeos/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Proantocianidinas/farmacologia , Substâncias Protetoras/farmacologia , Carbonilação Proteica/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Biflavonoides/química , Catequina/química , Bovinos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Reagentes para Ligações Cruzadas/química , Fluorescência , Produtos Finais de Glicação Avançada/metabolismo , Glicosilação , Fenóis/análise , Proantocianidinas/química , Espécies Reativas de Oxigênio/metabolismo , Soroalbumina Bovina/metabolismo , Compostos de Sulfidrila/metabolismo
16.
Int J Nanomedicine ; 14: 6691-6706, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692515

RESUMO

Purpose: Amentoflavone, robustaflavone, 2'',3''-dihydro-3',3'''-biapigenin, 3',3'''-binaringenin and delicaflavone are five major active ingredients in the total biflavonoids extract from Selaginella doederleinii (TBESD) with favorable anticancer properties. However, the natural-derived potent antitumor agent of TBESD is undesirable due to its poor solubility. The present study was to develop and optimize a proliposomal formulation of TBESD (P-TBESD) to improve its solubility, oral bioavailability and efficacy. Materials and methods: P-TBESD containing a bile salt, a protective hydrophilic isomalto-oligosaccharides (IMOs) coating, were successfully prepared by thin film dispersion-sonication method. The physicochemical and pharmacokinetic properties of P-TBESD were characterized, and the antitumor effect was evaluated using the HT-29 xenograft-bearing mice models in rats. Results: Compared with TBESD, the relative bioavailability of amentoflavone, robustaflavone, 2'',3''-dihydro-3',3'''-biapigenin, 3',3'''-binaringenin and delicaflavone from P-TBESD were 669%, 523%, 761%, 955% and 191%, respectively. The results of pharmacodynamics demonstrated that both TBESD and P-TBESD groups afforded antitumor effect without systemic toxicity, and the antitumor effect of P-TBESD was significantly superior to that of raw TBESD, based on the tumor growth inhibition and histopathological examination. Conclusion: Hence, IMOs-modified proliposomes have promising potential for TBESD solving the problem of its poor solubility and oral bioavailability, which can serve as a practical oral preparation for TBESD in the future cancer therapy.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Biflavonoides/administração & dosagem , Lipossomos/administração & dosagem , Extratos Vegetais/administração & dosagem , Selaginellaceae/química , Administração Oral , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Biflavonoides/farmacocinética , Biflavonoides/farmacologia , Ácidos e Sais Biliares/química , Disponibilidade Biológica , Células HT29 , Humanos , Lipossomos/química , Lipossomos/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Oligossacarídeos/química , Extratos Vegetais/química , Ratos Sprague-Dawley , Solubilidade , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Cell Biochem Biophys ; 77(4): 367-377, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31659617

RESUMO

Cisplatin is a widely used anti-cancer drug. However, cisplatin is limited in clinical treatment because of its severe nephrotoxicity. This study reported whether O-GSP can antagonize the cisplatin-induced cytotoxicity in HEK293 cells through inducing HO-1 protein expression. We previously demonstrated O-GSP can increase the survival rate of HEK293 and have protective effect on HEK293 cells. Herein, We found that O-GSP can antagonize cisplatin nephrotoxicity through regulating the expression of HO-1. O-GSP promotes the translocation of Nrf2 in the nucleus, and activates the ERKN JNK pathway and p38 MAPK pathway. Interestingly, p38 MAPK plays a major role in HO-1 expression induced by O-GSP. And O-GSP can modulate the decrease of Nrf2 and HO-1 expression induced by cisplatin, and improve the cisplatin-induced activity and apoptosis rate of cells by stimulating the expression of HO-1. However, the protective effects of O-GSP are inhibited by ZnPP IX. Collectively, the results indicated that O-GSP induced the expression of HO-1 through p38MAPK and Nrf2 pathway in HEK293 cells.


Assuntos
Antineoplásicos/farmacologia , Biflavonoides/farmacologia , Catequina/farmacologia , Cisplatino/farmacologia , Heme Oxigenase-1/metabolismo , Proantocianidinas/farmacologia , Regulação para Cima/efeitos dos fármacos , Vitis/química , Apoptose/efeitos dos fármacos , Núcleo Celular/metabolismo , Células HEK293 , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Sementes/química , Sementes/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vitis/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
Nutrients ; 11(10)2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31546671

RESUMO

The possibility of counteracting inflammation-related barrier defects with dietary compounds such as (poly)phenols has raised much interest, but information is still scarce. We have investigated here if (+)-catechin (CAT) and procyanidin B2 (PB2), two main dietary polyphenols, protect the barrier function of intestinal cells undergoing inflammatory stress. The cell model adopted consisted of co-cultured Caco-2 and HT29-MTX cells, while inflammatory conditions were mimicked through the incubation of epithelial cells with the conditioned medium of activated macrophages (MCM). The epithelial barrier function was monitored through trans-epithelial electrical resistance (TEER), and ROS production was assessed with dichlorofluorescein, while the expression of tight-junctional proteins and signal transduction pathways were evaluated with Western blot. The results indicated that MCM produced significant oxidative stress, the activation of NF-κB and MAPK pathways, a decrease in occludin and ZO-1 expression, and an increase in claudin-7 (CL-7) expression, while TEER was markedly lowered. Neither CAT nor PB2 prevented oxidative stress, transduction pathways activation, ZO-1 suppression, or TEER decrease. However, PB2 prevented the decrease in occludin expression and both polyphenols produced a huge increase in CL-7 abundance. It is concluded that, under the conditions adopted, CAT and PB2 do not prevent inflammation-dependent impairment of the epithelial barrier function of intestinal cell monolayers. However, the two compounds modify the expression of tight-junctional proteins and, in particular, markedly increase the expression of CL-7. These insights add to a better understanding of the potential biological activity of these major dietary flavan-3-ols at intestinal level.


Assuntos
Biflavonoides/farmacologia , Catequina/farmacologia , Permeabilidade/efeitos dos fármacos , Proantocianidinas/farmacologia , Substâncias Protetoras/farmacologia , Proteínas de Junções Íntimas/metabolismo , Células CACO-2 , Técnicas de Cultura de Células , Células Epiteliais , Células HT29 , Humanos , Intestinos/citologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Ocludina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/metabolismo
19.
Mater Sci Eng C Mater Biol Appl ; 104: 109909, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499983

RESUMO

Redox-active quinones have been reported to show good potential for biological activities, while efforts are directed to explore the usefulness of these materials further in cancer management. Our previous study demonstrated that theaflavin and theaflavin-gallates (tea-extracted polyphenols) selectively induce apoptosis of tumour cells in vitro, but its concentration for showing half-maximal therapeutic response remains a matter of concern. In this report, we demonstrated that if theaflavin is conjugated with gold nanoparticles (AuNPs) to form a nanoconjugate AuNP@TfQ, its apoptotic ability increases significantly in comparison to the bare theaflavin (Tf). The nanoconjugate is prepared by following a one-step green synthesis ̶ a reaction between HAuCl4 and the aflavin at room temperature. AuNP@TfQ is characterized using particle size analysis, FESEM, UV-vis, FTIR, fluorescence, and X-ray photoelectron spectroscopytechniques. We assume that the enhanced anti-cancer effect of AuNP@TfQ appears due to the facile oxidation of the pristine theaflavin to its quinone derivative on the surface of AuNPs. The presence of quinone motif in AuNP@TfQ induces an increased level of ROS generation probably through the depolarization of mitochondria and resulted in the caspase-mediated apoptotic cell death which may hold the potential for a "magic bullet"-mediated ovarian cancer treatment.


Assuntos
Biflavonoides/farmacologia , Catequina/farmacologia , Ouro/farmacologia , Nanopartículas Metálicas/química , Neoplasias Ovarianas/patologia , Apoptose/efeitos dos fármacos , Biflavonoides/síntese química , Biflavonoides/química , Biomarcadores Tumorais/metabolismo , Catequina/síntese química , Catequina/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Feminino , Hemólise/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Espectroscopia Fotoeletrônica , Espécies Reativas de Oxigênio/metabolismo
20.
Drug Discov Ther ; 13(4): 222-227, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534074

RESUMO

Based on the anti-virulence activity on Salmonella, the ethyl acetate extract (EAE) of Mesua ferrea flower was investigated for its chemical constituents. Ten purified compounds were identified and assayed for their inhibitory activity against Type III secretion system (T3SS) by polyacrylamide gel electrophoresis (SDS-PAGE) and Western blots experiments. We found the biflavonoids, rhusflavanone and mesuaferrone B, exhibited inhibitory effects on the secretion of Salmonella pathogenicity island 1 (SPI-1) effector proteins (SipA, B, C and D) without effecting the bacterial growth. In addition, 5, 6, 6'-trihydroxy-[1,1'-biphenyl]-3,3'-dicarboxylic acid (6) is a new natural product from M. ferrea flower.


Assuntos
Antibacterianos/farmacologia , Biflavonoides/farmacologia , Magnoliopsida/química , Salmonella/efeitos dos fármacos , Antibacterianos/química , Biflavonoides/química , Flores/química , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Salmonella/metabolismo , Salmonella/patogenicidade , Sistemas de Secreção Tipo III/efeitos dos fármacos , Fatores de Virulência/metabolismo
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