Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.634
Filtrar
1.
PLoS One ; 15(11): e0242747, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33232375

RESUMO

BACKGROUND: J wave syndromes (JWS), including Brugada (BrS) and early repolarization syndromes (ERS), are associated with increased risk for life-threatening ventricular arrhythmias. Pharmacologic approaches to therapy are currently very limited. Here, we evaluate the effects of the natural flavone acacetin. METHODS: The effects of acacetin on action potential (AP) morphology and transient outward current (Ito) were first studied in isolated canine RV epicardial myocytes using whole-cell patch clamp techniques. Acacetin's effects on transmembrane APs, unipolar electrograms and transmural ECGs were then studied in isolated coronary-perfused canine RV and LV wedge preparations as well as in whole-heart, Langendorff-perfused preparations from which we recorded a 12 lead ECG and unipolar electrograms. Using floating glass microelectrodes we also recorded transmembrane APs from the RVOT of the whole-heart model. The Ito agonist NS5806, sodium channel blocker ajmaline, calcium channel blocker verapamil or hypothermia (32°C) were used to pharmacologically mimic the genetic defects and conditions associated with JWS, thus eliciting prominent J waves and provoking VT/VF. RESULTS: Acacetin (5-10 µM) reduced Ito density, AP notch and J wave area and totally suppressed the electrocardiographic and arrhythmic manifestation of both BrS and ERS, regardless of the experimental model used. In wedge and whole-heart models of JWS, increasing Ito with NS5806, decreasing INa or ICa (with ajmaline or verapamil) or hypothermia all resulted in accentuation of epicardial AP notch and ECG J waves, resulting in characteristic BrS and ERS phenotypes. Phase 2-reentrant extrasystoles originating from the RVOT triggered VT/VF. The J waves in leads V1 and V2 were never associated with a delay of RVOT activation and always coincided with the appearance of the AP notch recorded from RVOT epicardium. All repolarization defects giving rise to VT/VF in the BrS and ERS models were reversed by acacetin, resulting in total suppression of VT/VF. CONCLUSIONS: We present experimental models of BrS and ERS capable of recapitulating all of the ECG and arrhythmic manifestations of the JWS. Our findings provide definitive support for the repolarization but not the depolarization hypothesis proposed to underlie BrS and point to acacetin as a promising new pharmacologic treatment for JWS.


Assuntos
Síndrome de Brugada , Eletrocardiografia , Flavonas/farmacologia , Miócitos Cardíacos/metabolismo , Pericárdio/metabolismo , Ajmalina/farmacologia , Animais , Síndrome de Brugada/induzido quimicamente , Síndrome de Brugada/tratamento farmacológico , Síndrome de Brugada/metabolismo , Síndrome de Brugada/fisiopatologia , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Humanos , Hipotermia/metabolismo , Hipotermia/patologia , Hipotermia/fisiopatologia , Compostos de Fenilureia/farmacologia , Tetrazóis/farmacologia , Verapamil/farmacologia
2.
Gen Physiol Biophys ; 39(5): 471-479, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33084600

RESUMO

7,8-Dihydroxyflavone (7,8-DHF) is a natural flavonoid compound that act as Trk-B agonist. 7,8-DHF is also a potent antioxidant. When applied systematically, 7,8-DHF can pass through blood-brain barrier and exhibit potential therapeutic effects in several animal models of neurodegenerative disorders. This study investigates the remedial effects of 7,8-DHF on behavioral impairments and biochemical changes associated with aging with a species emphasis on cortex. For this purpose three experimental groups were formed which are young control group, old group and old-DHF groups. 5 mg/kg 7,8-DHF was administered intraperitoneally to old-DHF group for 3 weeks. We assessed the hang wire and adhesive removal performances of mice. Also, oxidative stress, neuroinflammation and synaptic protein levels in the cortex were measured. We observed that chronic administration of 7,8-DHF improved behavioral performance of old mice. Besides, 7,8-DHF reversed MDA level which was increased in old control animals. However, 3 weeks application of 7,8-DHF failed to recover the levels of neuroinflammation markers (TNF-α and IL-6) and synaptic proteins (PSD-95 and Synaptophysin) which were reduced in old group. These findings demonstrate that improvement of age-dependent behavioral impairments and MDA levels by 7,8-DHF could be attributed to its antioxidant actions.


Assuntos
Envelhecimento , Antioxidantes/farmacologia , Flavonas , Peroxidação de Lipídeos , Animais , Comportamento Animal , Flavonas/farmacologia , Malondialdeído , Camundongos , Doenças Neurodegenerativas
3.
Life Sci ; 260: 118419, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32931795

RESUMO

AIMS: In our study, the anticancer effects of a semisynthetic p-quinol, protoapigenone 1'-O-butyl ether (PABut), were tested in human melanoma A375 cells also in comparison with natural congener, protoapigenone (PA). MAIN METHODS: The cytotoxic effect of PABut and PA was determined using MTT assay. Flow cytometry analysis was used to evaluate the influence of the compounds tested on ROS generation and cell cycle distribution in A375 cells. Moreover, apoptosis was evaluated by AO/EB dual staining as well as by flow cytometry. Markers of senescence were quantified by spectrofluorimetry and by Western blot analysis. KEY FINDINGS: Both PABut and PA showed significant cytotoxicity against melanoma A375 cells at sub-micromolar concentrations. Both protoflavones induced comparable cell cycle arrest in G2/M phase. However, a more profound upregulation of intracellular ROS levels was found following PABut treatment. An increased apoptosis in the cells following 48 h treatment with both protoflavones tested was also confirmed. Both compounds tested remarkably upregulated p21 protein levels in A375 cells. Unlike PA, PABut significantly decreased protein levels of NAD+-dependent deacetylase SirT1 and ß-actin accompanied by mild significant upregulation of mitochondrial SOD2 and senescence markers, p16 protein and SA-ß-Gal activity. However, a significant upregulation of p53 only following PA treatment was found. SIGNIFICANCE: These results suggest that PABut and PA confer high chemotherapeutic potential in melanoma cells and are suitable for further testing. Furthermore, modification of protoapigenone with 1'-O-butyl ether moiety can be associated with improved senescence-inducing effect and, thus, enhanced chemotherapeutic potency of PABut compared to the unmodified natural protoflavone.


Assuntos
Cicloexanonas/farmacologia , Flavonas/farmacologia , Melanoma/tratamento farmacológico , Melanoma/patologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Autofagia/efeitos dos fármacos , Biomarcadores/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Cicloexanonas/química , Flavonas/química , Humanos , Melanoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , beta-Galactosidase/metabolismo
4.
Life Sci ; 260: 118398, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32920004

RESUMO

AIMS: We investigate the effect of nobiletin on vascular and renal alterations and possible mechanisms involved in high-fat diet (HFD)-fed rats. MAIN METHODS: Male Sprague-Dawley rats were fed a HFD with fructose 15% in drinking water for 16 weeks. HFD-fed rats were treated with nobiletin (20 or 40 mg/kg/day) or vehicle for the last 4 weeks. KEY FINDINGS: HFD-fed rats treated with nobiletin was significantly reduced obesity, hypertension, dyslipidemia and hyperinsulinemia. Nobiletin improved vascular endothelial function, restored creatinine clearance, and reduced plasma urea and creatinine levels, as well as urinary protein excretion. Nobiletin markedly alleviated vascular medial cross-sectional area (CSA) and collagen deposition, glomerular extracellular matrix (ECM) accumulation, and renal fibrosis. Nobiletin significantly elevated plasma adiponectin levels, together with upregulated adiponectin receptor 1 (AdipoR1) and suppressed transforming growth factor-ß1 (TGF-ß1) expression in kidney. In addition, an increase of plasma tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) was significantly attenuated after nobiletin treatment. SIGNIFICANCE: Our results suggest that nobiletin attenuates HFD-induced vascular and renal alterations in rats, which is possibly related to the modulation of AdipoR1 and TGF-ß1expression, and suppression of inflammation.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Flavonas/farmacologia , Inflamação/prevenção & controle , Nefropatias/tratamento farmacológico , Receptores de Adiponectina/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Doenças Vasculares/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Regulação da Expressão Gênica , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Adiponectina/genética , Fator de Crescimento Transformador beta1/genética , Doenças Vasculares/etiologia , Doenças Vasculares/metabolismo , Doenças Vasculares/patologia
5.
Phytomedicine ; 79: 153351, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32987362

RESUMO

BACKGROUND: Since enhanced bone resorption due to osteoclast differentiation and activation cause skeletal diseases, there is a growing need in therapeutics for combating bone-resorbing osteoclasts. Botanical antioxidants are being increasingly investigated for their health-promoting effects on bone. Edible Cirsium setidens contains various polyphenols of linarin, pectolinarin, and apigenin with antioxidant and hepatoprotective effects. PURPOSE: This study aimed to determine whether linarin present in Cirsium setidens water extracts (CSE) and its aglycone acacetin inhibited osteoclastogenesis of RANKL-exposed RAW 264.7 murine macrophages for 5 days. METHODS: This study assessed the osteoprotective effects of CSE, linarin and acacetin on RANKL-induced differentiation and activation of osteoclasts by using MTT assay, TRAP staining, Western blot analysis, bone resorption assay actin ring staining, adhesion assay and immunocytochemical assay. This study explored the underlying mechanisms of their osteoprotection, and identified major components present in CSE by HPLC analysis. RESULTS: Linarin and pectolinarin were identified as major components of CSE. Nontoxic linarin and acacetin as well as CSE, but not pectolinarin attenuated the RANKL-induced macrophage differentiation into multinucleated osteoclasts, and curtailed osteoclastic bone resorption through reducing lacunar acidification and bone matrix degradation in the osteoclast-bone interface. Linarin and acacetin in CSE reduced the transmigration and focal contact of osteoclasts to bone matrix-mimicking RGD peptide. Such reduction was accomplished by inhibiting the induction of integrins, integrin-associated proteins of paxillin and gelsolin, cdc42 and CD44 involved in the formation of actin rings. The inhibition of integrin-mediated actin ring formation by linarin and acacetin entailed the disruption of TRAF6-c-Src-PI3K signaling of bone-resorbing osteoclasts. The functional inhibition of c-Src was involved in the loss of F-actin-enriched podosome core protein cortactin-mediated actin assembly due to linarin and acacetin. CONCLUSION: These observations demonstrate that CSE, linarin and acacetin were effective in retarding osteoclast function of focal adhesion to bone matrix and active bone resorption via inhibition of diffuse cloud-associated αvß3 integrin and core-linked CD44.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Flavonas/farmacologia , Adesões Focais/efeitos dos fármacos , Glicosídeos/farmacologia , Osteoclastos/efeitos dos fármacos , Actinas/metabolismo , Animais , Matriz Óssea/efeitos dos fármacos , Matriz Óssea/metabolismo , Reabsorção Óssea/metabolismo , Cirsium/química , Adesões Focais/metabolismo , Receptores de Hialuronatos/metabolismo , Integrina alfaVbeta3/metabolismo , Camundongos , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/farmacologia , Células RAW 264.7
6.
Toxicol Appl Pharmacol ; 402: 115129, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32673656

RESUMO

Urothelial carcinoma (UC) is one of the highest incidence cancers that rank the fourth commonly diagnosed tumors worldwide. The unresectable lesions that are resistant to therapeutic interventions is the major cause leading to death. Previous studies had shown that the resistance and metastatic consequence may arise from cancer stem-like cells population. The phytochemical flavonoids have promised bioactivity and potent anti-carcinogenic effects, and trap great attentions for cancer chemoprevention and/or adjuvant chemotherapy. However, the mechanisms of flavonoids on cancer stemness is still obscured. In this study, we analyzed the biofunctional effects of as-prepared flavonoid derivative-WYC0209 on T24, BFTC905 and BFTC909 human UC cell lines. Our results demonstrated that WYC0209 significantly induced anti-cell viability on UC cells through decreased Akt/NFkB signaling. Moreover, WYC0209 enhanced the cell apoptosis through activated the caspase-3 activity and inactivated Bcl-xL expression. Interestingly, WYC0209 dramatically inhibited the cancer stem cells (CSCs) traits, including attenuation of side population and tumorsphere formation in which were through declined EMT-CSCs markers including MDR1, ABCG2 and BMI-1. We further validated the effects of WYC0209 on several CSC surface markers including CD133, CD44, SOX-2 and Nanog. Our results showed that WYC0209 markedly inhibited CD133 expressions in both transcriptional and translational levels. High expression levels of CD133 was also demonstrated in human upper tract UC specimens. In summary, our study showed that WYC0209 may potentially as an adjuvant agent to against CD133-driven UC CSCs and provide a beneficial strategy to against UC cancer therapeutics resistant.


Assuntos
Antígeno AC133/metabolismo , Cicloexanonas/farmacologia , Flavonas/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Urotélio/citologia , Antígeno AC133/genética , Biomarcadores Tumorais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimioterapia Adjuvante , Cicloexanonas/química , Flavonas/química , Humanos , Estrutura Molecular , Estudos Retrospectivos , Neoplasias da Bexiga Urinária
7.
Sci Rep ; 10(1): 12324, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32704000

RESUMO

It has been shown that bamboo leaf flavone (BLF) displays biological and pharmacological activities in mammals. However, the effects of BLF on broiler gut microbiota and related immune function have not been investigated. The aim of this study was to test our hypothesis that BLF can improve the health status of broilers by modulating the gut microbiota. A total of 300 one-day-old Arbor Acres (AA) broilers were used to characterize their gut microbiota and immune status after feeding diet supplemented with BLF. The V4 hypervariable region of the 16S rRNA gene from cecal bacteria was sequenced via the Illumina MiSeq platform. The Immune status and related parameters were assessed, including the immune organ index (the spleen, thymus, and bursa), serum concentrations of IL-2 and INF-γ, and spleen IL-2 and INF-γ gene expressions. The results showed the BLF diet had an Immune enhancement effect on broilers. In addition, BFL caused the changes of the gut microbial community structure, resulting in greater proportions of bacterial taxa belonging to Lactobacillus, Clostridiales, Ruminococcus, and Lachnospiraceae. These bacteria have been used as probiotics for producing short chain fatty acids in hosts. These results indicate that BLF supplement improves immune function in chicken via modulation of the gut microbiota.


Assuntos
Bambusa/química , Ceco/microbiologia , Galinhas/imunologia , Galinhas/microbiologia , Flavonas/farmacologia , Microbiota/efeitos dos fármacos , Folhas de Planta/química , Animais , Bactérias/efeitos dos fármacos , Biodiversidade , Ceco/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Interferon gama/sangue , Interferon gama/genética , Interleucina-2/sangue , Interleucina-2/genética , Masculino , Filogenia , Baço/efeitos dos fármacos , Baço/metabolismo
8.
Eur J Drug Metab Pharmacokinet ; 45(6): 809-815, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32661908

RESUMO

BACKGROUND AND OBJECTIVES: Citrus flavonoids are not only components of daily nutrition, they are also promoted as dietary supplements and are important ingredients in traditional medicines. Interactions of flavonoids with synthetic drugs represent an often neglected issue. We therefore investigated in vitro whether the polymethoxyflavones nobiletin, sinensetin, and tangeretin and the flavonoid rutinosides didymin, hesperidin, and narirutin can inhibit human organic anion transporting polypeptides (OATP) 1B1, 1B3, and 2B1, which are important transporters mediating drug-drug and food-drug interactions. METHODS: Inhibition was investigated by quantifying the decreased uptake of the fluorescent OATP1B1 and OATP1B3 substrate 8-fluorescein-cAMP in HEK293 cells overexpressing OATP1B1 or OATP1B3 and of the fluorescent OATP2B1 substrate 4',5'-dibromofluorescein in HEK293 cells overexpressing OATP2B1. RESULTS: We demonstrate that all flavonoids investigated inhibit OATP2B1 in the lower micromolar range (IC50 between 1.6 and 14.2 µM), but only the polymethoxyflavones also inhibit OATP1B1 and 1B3 (IC50 between 2.1 and 21 µM). CONCLUSIONS: All flavonoids investigated might contribute to the intestinal OATP2B1-based interactions with drugs observed with citrus juices or fruits. In contrast, the concentration of the polymethoxyflavones after consumption of citrus juices or fruits is most likely too low to reach relevant systemic concentrations and thus to inhibit hepatic OATP1B1 and OATP1B3, but there might be a risk when they are consumed as medicines or as dietary supplements.


Assuntos
Citrus/química , Flavonas/farmacologia , Interações Alimento-Droga , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Bebidas , Células HEK293 , Humanos , Fígado/metabolismo , Proteína 1 Transportadora de Ânions Orgânicos/antagonistas & inibidores , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Relação Estrutura-Atividade
9.
PLoS One ; 15(7): e0236315, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32706791

RESUMO

The natural product nobiletin is a small molecule, widely studied with regard to its therapeutic effects, including in cancer cell lines and tumors. Recently, nobiletin has also been shown to affect circadian rhythms via their enhancement, resulting in protection against metabolic syndrome. We hypothesized that nobiletin's anti-oncogenic effects, such as prevention of cell migration and formation of anchorage independent colonies, are correspondingly accompanied by modulation of circadian rhythms. Concurrently, we wished to determine whether the circadian and anti-oncogenic effects of nobiletin differed across cancer cell lines. In this study, we assessed nobiletin's circadian and therapeutic characteristics to ascertain whether these effects depend on cell line, which here also varied in terms of baseline circadian rhythmicity. Three cell culture models where nobiletin's effects on cell proliferation and migration have been studied previously were evaluated: U2OS (bone osteosarcoma), which possesses robust circadian rhythms; MCF7 (breast adenocarcinoma), which has weak circadian rhythms; and MDA-MB-231 (breast adenocarcinoma), which is arrhythmic. We found that circadian, migration, and proliferative effects following nobiletin treatment were subtle in the U2OS and MCF7 cells. On the other hand, changes were clear in MDA-MB-231s, where nobiletin rescued rhythmicity and substantially reduced oncogenic features, specifically two-dimensional cell motility and anchorage-independent growth. Based on these results and those previously described, we posit that the effects of nobiletin are indeed cell-type dependent, and that a positive correlation may exist between nobiletin's circadian and therapeutic effects.


Assuntos
Antineoplásicos Fitogênicos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Flavonas , Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Flavonas/farmacologia , Flavonas/uso terapêutico , Humanos , Osteossarcoma/tratamento farmacológico
10.
Nihon Yakurigaku Zasshi ; 155(4): 209-213, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32612030

RESUMO

The number of patients with type 2 diabetes mellitus (T2DM) has rapidly increased, especially in East and Southeast Asia. In these areas, in general, people have especially vulnerable ß-cells and insulin secretion deficiency and reduced ß-cell mass are the primary cause of T2DM. Therefore, the alleviation of such ß-cell dysfunction would provide therapeutic approaches to prevent the development of T2DM. Nobiletin, a polymethoxylated flavonoid found in citrus fruits, has been shown to improve obesity and insulin resistance in T2DM model mice. We focused on ß-cells and investigated the effects of nobiletin on insulin secretion and ß-cell apoptosis. In ß-cell line INS-1, nobiletin increased glucose-induced insulin secretion (GSIS) in a concentration-dependent manner, which was inhibited by an Epac inhibitor. In addition, nobiletin at 10 µM inhibited thapsigargin-induced apoptosis, which was inhibited by a PKA inhibitor. Nobiletin also suppressed thapsigargin-induced increases in cleaved caspase-3 and phosphorylated JNK. Thus, nobiletin is suggested to promote GSIS and prevent ER stress-induced ß-cell apoptosis, which are mediated via Epac and PKA-dependent pathways, respectively. In summary, nobiletin is suggested to exhibit insulinotropic and anti-apoptotic effects on ß-cells, which are one of the causes of its anti-diabetic effect. Moreover, nobiletin seems to be able to alleviate the development of T2DM by protecting ß-cells from apoptosis.


Assuntos
Citrus , Diabetes Mellitus Tipo 2 , Flavonas , Células Secretoras de Insulina , Animais , Apoptose , Diabetes Mellitus Tipo 2/tratamento farmacológico , Flavonas/farmacologia , Flavonas/uso terapêutico , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Humanos , Camundongos
11.
J Environ Pathol Toxicol Oncol ; 39(1): 13-21, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32479009

RESUMO

Breast cancer is a widespread disease that affects women globally. Diagnostic processes and remedial approaches to breast carcinogenesis have improved in recent decades, but continuous survival of patients with breast carcinogenesis is still lacking due to increased cell proliferation. The aim of the present work is to explore the anticell proliferative effects of nobiletin (NOB) against 7,12-dimethylbenz[a]anthracene (DMBA)-treated mammary tumorigenesis in rats. We stimulate mammary carcinogenesis using oral gavage of DMBA (25 mg/kg body weight) mixed with olive oil (1 mL). This results in reduced body weight; increased liver marker enzymes such as alkaline phosphatase, acid phosphatase, aspartate aminotransferase, and alanine aminotransferase; and cell proliferative markers such as c-Jun, proliferating cell nuclear antigen, c-Fos, cyclin D1, and activating protein-1 (AP-1) in the DMBA-treated cancer-bearing animals. NOB administration improved body weight, significantly reduced hepatic marker enzymes, and altered histopathological changes. Furthermore, NOB efficiently reduced tumor cell proliferation markers in DMBA-induced mammary carcinogenesis. Overall, these results suggest that NOB has an anticell proliferative effect on DMBA-induced mammary cancer via modulation of the AP-1 signaling pathway.


Assuntos
9,10-Dimetil-1,2-benzantraceno/toxicidade , Antioxidantes/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Flavonas/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Carcinógenos/toxicidade , Transformação Celular Neoplásica/efeitos dos fármacos , Feminino , Ratos , Ratos Sprague-Dawley , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo
12.
J Environ Pathol Toxicol Oncol ; 39(1): 77-88, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32479014

RESUMO

Helicobacter pylori causes a Gram-negative bacterial infection that can increase the risk of gastric cancer. Consequently, meticulous prevention of an H. pylori infection is significant for averting gastric cancer in humans. Nobiletin, an important dietary polymethoxylated flavonoid in citrus fruits, possesses multidimensional pharmaceutical properties, including its ability to act as an anticancer, anti-inflammatory, antioxidative, cardiovascularly defensive, neuroprotective, and antimetabolic agent. Our study evaluates the role of nobiletin in inflammation-mediated gastric carcinogenic signaling of H. pylori-arbitrated coculture in the human gastric epithelial (GES)-1 cell line. Our results show that the culture system of H. pylori-tainted GES-1 cells demonstrates maximum fabrication of reactive oxygen species (ROS), mediating DNA injury and augmenting nuclear fragmentations. Treatment with nobiletin reduces ROS levels and apoptotic morphological changes by dual staining and decreases levels of lipid peroxides and glutathione content in H. pylori-infected GES-1 cells. Phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT)/phosphatase and tensin homolog signaling have been implicated to affect cell endurance, inflammation, proliferation, and carcinogenic activity in gastric GES-1 cells. We find that nobiletin strongly impedes tumor necrosis factor-α, interleukin-6, cyclooxygenase-2, PI3K, AKT, and mitogen-activated protein kinase molecules, including p38, extracellular receptor kinase 1, and c-Jun amino-terminal expression in H. pylori-infected GES-1 cells. We conclude that nobiletin potentially impedes H. pylori infection and its related activation, likely preventing H. pylori infection-mediated gastric cancer.


Assuntos
Antioxidantes/farmacologia , Carcinogênese/efeitos dos fármacos , Flavonas/farmacologia , Infecções por Helicobacter/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular , Células Epiteliais , Infecções por Helicobacter/microbiologia , Helicobacter pylori/fisiologia , Inflamação/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Gástricas/microbiologia
13.
Chem Biol Interact ; 325: 109109, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32376239

RESUMO

A series of 10 natural and semisynthetic flavonoids (1 to 10) were obtained from Gardenia oudiepe (Rubiaceae), an endemic plant from New Caledonia. Most of them were polymethoxylated flavones (PMFs) of rare occurrence. After a cell viability screening test, PMFs 2 and 3 showed significant cytotoxic activity against A2058 human melanoma cells (IC50 = 3.92 and 8.18 µM, respectively) and were selected for in-depth pharmacological assays. Both compounds inhibited cell migration and induced apoptosis and cell cycle arrest after 72h of treatment. Immunofluorescence assays indicated that these outcomes were possibly related to the induction of cytoskeleton disruption associated to actin and tubulin depolymerization. These data were confirmed by molecular docking studies, which showed a good interaction between PMFs 2 and 3 and tubulin, particularly at the colchicine binding site. As A2058 are considered as chemoresistant to conventional chemotherapy, compounds 2 and 3 (½IC50) were associated to clinically-used antimelanoma drugs (vemurafenib and dacarbazine) and combined therapies efficacy was assessed by the MTT assay. PMFs 2 restored the sensitivity of A2058 cells to dacarbazine treatment (IC50 = 49.38 µM vs. >100 µM). Taken together, these data suggest that PMFs from G. oudiepe could be potential leaders for the design of new antimelanoma drugs.


Assuntos
Apoptose/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Flavonas/farmacologia , Gardenia/química , Melanoma/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Antineoplásicos/farmacologia , Caspase 3/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citoesqueleto/metabolismo , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Flavonas/química , Flavonas/metabolismo , Humanos , Simulação de Acoplamento Molecular , Conformação Proteica , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo
14.
Biomed J ; 43(4): 363-367, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32426388

RESUMO

Background: The present study demonstrates the potential of flavanoid narcissoside against the novel corona virus (COVID-19) complications using molecular docking studies. Methods: The computation molecular docking screening was performed using Molegro Virtual Docker software (MVD) with grid resolution of 30 Å. Protein of COVID 19 virus was taken from protein data bank. Results: The standard inhibitor X77 (N-(4-tert-butylphenyl)-N-[(1R)-2-(cyclohexylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-1H-imidazole-4-carboxamide) identified from the protein inhibitor complex 6W63 from protein data bank was docked with COVID 19 protein 6W63 which showed MolDock score of -156.913, rerank Sore -121.296 and H Bond -5.7369, while the flavanoid narcissoside had showed MolDock score -180.739, Rerank Sore -137.092 and H Bond -18.6771. The narcissoside showed potent inhibitory effect which is greater than standard X77. The result showed that narcissoside have high affinity towards 6W63 as it showed thirteen hydrogen bonds with nine amino acids (Arg 188, Glu 166, His 164, Cys 145 (2 bonds), Asn 14 (2 bonds), Cys 44 (2 bonds), His 41 (2 bonds), Gln 192, Thr 190) while X777 showed four hydrogen bonds with amino acids (Gly 143, Cys 145, Glu 166, Ser 144). Conclusion: From computation approach it was concluded that narcissoside is a potent inhibitor of viral COVID 19 protein 6W63. The narcissoside have high affinity and inhibition potential than standard inhibitor X77 (N-(4-tert-butylphenyl)-N-[(1R)-2-(cyclohexylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-1H-imidazole-4-carboxamide). The narcissoside predicted as more potent inhibitor which can be further optimize, pharmacologically and clinically evaluated for the treatment of novel coronavirus COVID-19.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Flavonas/farmacologia , Simulação de Acoplamento Molecular , Pneumonia Viral/tratamento farmacológico , Flavonas/química , Humanos , Simulação de Acoplamento Molecular/métodos , Pandemias , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia
15.
Oncol Rep ; 43(6): 1995-2003, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32236602

RESUMO

Hispidulin is a medicinal natural compound isolated from S. involucrata, which exhibits potent anticancer properties. However, there are few reports on its effects on lung cancer cells. Therefore, the current study investigated the effects of hispidulin on cell viability and apoptosis in human non­small­cell lung cancer (NSCLC) cell lines NCI­H460 and A549 in vitro and in vivo. Methyl thiazolyl tetrazolium, colony formation assay, Hoechst 33342 staining, flow cytometry and western blotting were performed on Human NCI­H460 and A549 cells. A mouse xenograft model was also established using NCI­H460 cells. The results showed that the growth of NCI­H460 and A549 cells was inhibited, while apoptosis was promoted by hispidulin via increased generation of reactive oxygen species (ROS) in a dose­dependent manner. Furthermore, hispidulin triggered apoptosis in NSCLC cells through upregulating the expression of cleaved caspase­3 and cleaved poly [ADP­ribose] polymerase. All these effects were reversed upon pretreatment with glutathione, a selective ROS inhibitor. In addition, endoplasmic reticulum stress (ER stress) in NCI­H460 cells was activated by hispidulin. Pretreatment with tauroursodeoxycholic acid, a specific ER stress inhibitor, effectively reduced the cell apoptosis induced by hispidulin. In conclusion, hispidulin induces ROS­mediated apoptosis via activating the ER stress pathway. The current study provides theoretical basis for the antitumor effect of hispidulin in NSCLC.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Flavonas/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Células A549 , Animais , Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Flavonas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Tumour Biol ; 42(4): 1010428320914475, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32252611

RESUMO

Hepatocellular carcinoma is a major cause of cancer mortality worldwide. The outcome of hepatocellular carcinoma depends mainly on its early diagnosis. To date, the performance of traditional biomarkers is unsatisfactory. Polo-like kinase 1 is a serine/threonine kinase that plays essential roles in cell cycle progression and deoxyribonucleic acid damage. Moreover, polo-like kinase 1 knockdown decreases the survival of hepatocellular carcinoma cells; therefore, polo-like kinase 1 is an attractive target for anticancer treatments. Nobiletin, a natural polymethoxy flavonoid, exhibits a potential antiproliferative effect against a wide variety of cancers. This study targets to identify a reliable diagnostic biomarker for hepatocellular carcinoma and provide a potential therapeutic target for its treatment. Polo-like kinase 1 levels were analyzed in 44 hepatocellular carcinoma patients, 33 non-hepatocellular carcinoma liver cirrhosis patients and 15 healthy controls using the enzyme-linked immunosorbent assay method. Receiver operating characteristics curve analysis was used to establish a predictive model for polo-like kinase 1 relative to α-fetoprotein in hepatocellular carcinoma diagnosis. Furthermore, in the in vitro study, gene expressions were assessed by quantitative polymerase chain reaction in two human hepatocellular carcinoma cell lines after treatment with doxorubicin and polo-like kinase 1 inhibitor volasertib (Vola) either alone or in combination with nobiletin. Cell viability was also determined using the crystal violet assay.: Serum polo-like kinase 1 levels in hepatocellular carcinoma patients were significantly higher than liver cirrhosis and control groups (p < 0.0001). Polo-like kinase 1 showed a reasonable sensitivity, specificity, positive predictive value, and negative predictive value in hepatocellular carcinoma diagnosis. Moreover, nobiletin improved inhibition of cell growth induced by Vola and doxorubicin. Regarding reverse transcription polymerase chain reaction results, nobiletin suppressed expressions of polo-like kinase 1 and proliferating cell nuclear antigen and elevated expressions of P53, poly (ADPribose) polymerase 1, and caspase-3. Nobiletin/doxorubicin and nobiletin/Vola showed a significant increase in caspase-3 activity indicating cell apoptosis. Polo-like kinase 1 may be a potential biomarker for hepatocellular carcinoma diagnosis and follow-up during treatment with chemotherapies. In addition, nobiletin synergistically potentiates the doxorubicin and Vola-mediated anticancer effect that may be attributed partly to suppression of polo-like kinase 1 and proliferating cell nuclear antigen expression and enhancement of chemotherapy-induced apoptosis.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas de Ciclo Celular/metabolismo , Neoplasias Hepáticas/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Caspase 3/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Flavonas/farmacologia , Células Hep G2 , Humanos , Cirrose Hepática/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Pteridinas/farmacologia
17.
Mol Biol (Mosk) ; 54(1): 153-163, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32163399

RESUMO

Antibiotic resistance is a global problem nowadays and in 2017 the World Health Organization published the list of bacteria for which treatment are urgently needed, where Pseudomonas aeruginosa is of critical priority. Current therapies lack efficacy because this organism creates biofilms conferring increased resistance to antibiotics and host immune responses. The strategy is to "not kill, but disarm" the pathogen and resistance will be developed slowly. It has been shown that LasI/LasR system is the main component of the quorum sensing system in P. aeruginosa. LasR is activated by the interaction with its native autoinducer. A lot flavones and their derivatives are used as antibacterial drug compounds. The purpose is to search compounds that will inhibit LasR. This leads to the inhibition of the synthesis of virulence factors thus the bacteria will be vulnerable and not virulent. We performed virtual screening using AutoDock Vina, rDock, LeDock for obtaining consensus predictions. The results of virtual screening suggest benzamides which are synthetical derivatives of flavones as potential inhibitors of transcriptional regulator LasR. These are consistent with recently published experimental data, which demonstrate the high antibacterial activity of benzamides. The compounds interact with the ligand binding domain of LasR with higher binding affinity than with DNA binding domain. Among the selected compounds, by conformational analysis, it was found that there are compounds that bind to the same amino acids of ligand binding domain as the native autoinducer. This could indicate the possibility of competitive interaction of these compounds. A number of compounds that bind to other conservative amino acids ligand binding domain have also been discovered, which will be of interest for further study. Selected compounds meet the criteria necessary for their consideration as drugs and can serve as a basis for conducting further in vitro/in vivo experiments. It could be used for the development of modern anti-infective therapy based on the quorum sensing system of P. aeruginosa.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Simulação por Computador , Flavonas/química , Flavonas/farmacologia , Pseudomonas aeruginosa , Percepção de Quorum/efeitos dos fármacos , Transativadores/antagonistas & inibidores , Pseudomonas aeruginosa/efeitos dos fármacos
18.
Molecules ; 25(6)2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32197377

RESUMO

In this study, we isolated from the aerial parts of Baccharis conferta Kunth (i) a new neoclerodane, denominated "bacchofertone"; (ii) four known terpenes: schensianol A, bacchofertin, kingidiol and oleanolic acid; and (iii) two flavonoids: cirsimaritin and hispidulin. All structures were identified by an exhaustive analysis of nuclear magnetic resonance (NMR) and mass spectroscopy (MS). Extracts from aerial parts were screened for anti-inflammatory activity in the mice ear edema model of 12-O-tetradecanoylforbol-13-acetate mice. Dichloromethane extract (BcD) exhibited 78.5 ± 0.72% inhibition of edema, followed by the BcD2 and BcD3 fractions of 71.4% and 82.9% respectively, at a dose of 1 mg/ear. Kingidiol and cirsimaritin were the most potent compounds identified, with a median effective dose of 0.12 and 0.16 mg/ear, respectively. A histological analysis showed that the topical application of TPA promoted intense cell infiltration, and this inflammatory parameter was reduced with the topical application of isolated compounds.


Assuntos
Anti-Inflamatórios , Baccharis/química , Otopatias , Edema , Flavonas , Terpenos , Acetato de Tetradecanoilforbol/toxicidade , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Otopatias/induzido quimicamente , Otopatias/tratamento farmacológico , Otopatias/metabolismo , Otopatias/patologia , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Edema/patologia , Flavonas/química , Flavonas/isolamento & purificação , Flavonas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Terpenos/química , Terpenos/isolamento & purificação , Terpenos/farmacologia
19.
Pak J Pharm Sci ; 33(1): 11-20, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32122825

RESUMO

Three substituted flavone derivatives have been synthesized from substituted O-hydroxy acetophenones and 4-trifluoromethyl benzaldehyde in good yield. These compounds were characterized by NMR spectroscopy and single crystal X-ray Diffraction. Compound F1 and F3 were re-crystallized from their concentrated solutions in chloroform ethyl acetate mixture while F2 was re-crystallized in ethyl acetate n-hexane mixture. Compound F1 and F3 are monoclinic (space group P21/c) with lattice parameters: [a, b, c (A) / ß (°)] = 13.332 (2), 15.616 (2) / 6.2898 (8) and 13.9716 (15), 7.1868 (7), 13.6912 (14) / 91.113(6) respectively. Compound F2 is Triclinic (space group P-1) and has lattice parameters: [a, b, c (Å) / α, ß, γ (°)] = 6.5002 (6), 8.3801 (9), 13.5989 (14) / 89.348(5), 85.141(4), 84.521(5). Antioxidant, antibacterial and cytotoxic profile was investigated. The compounds showed moderate to less activity on 1,1-diphenyl-2-picryl-hydrazyl (DPPH), Hydrogen peroxide (H/2/O/2) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) models of radical scavenging activity while promising antibacterial potentials were recorded. Furthermore, these molecules can also be used as potential candidates for new antitumor agents.


Assuntos
Flavonas/química , Flavonas/síntese química , Flavonas/farmacologia , Flavonas/toxicidade , Animais , Antibacterianos/farmacologia , Antioxidantes/farmacologia , Artemia/efeitos dos fármacos , Cristalografia , Depuradores de Radicais Livres/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular
20.
BMC Complement Med Ther ; 20(1): 78, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164676

RESUMO

BACKGROUND: The active components of Dracocephalum moldavica L. (TFDM) can inhibit myocardial ischemia by inhibiting oxidative stress. However, the effects of TFDM on astrocytes have not been investigated in vitro. The current study aimed to explore whether TFDM protects astrocytes against H2O2-induced apoptosis through a mitochondria-dependent pathway. METHODS: The human glioma cell line U87 was used to investigate the ability of TFDM to protect astrocytes against H2O2-induced apoptosis. The cell counting kit-8 assay and flow cytometry were used to detect cell viability, apoptosis, MMP, Ca2+ influx and reactive oxygen species (ROS). Lactate dehydrogenase (LDH) and malonic dialdehyde (MDA) levels were measured by ELISA. In addition, protein and mRNA expression changes were detected by Western blotting and qRT-PCR. RESULTS: TFDM (0.78~200 µg/ml) had limited cytotoxic effects on the viability of U87 cells. Compared with the model group (treated with H2O2 only), cells treated with medium- and high-dose TFDM exhibited reduced MDA concentrations (P < 0.05) and ROS production (P < 0.05) and decreased MMP (P < 0.05) and reduced apoptosis (P < 0.05). The percentage of annexin V-FITC-stained cells was markedly suppressed by TFDM, confirming its anti-apoptotic properties. WB results showed that protein expression of Bcl-2-associated X protein (BAX), Caspase-3, Caspase-9, Caspase-12, and B-cell leukemia/lymphoma 2 (Bcl2) was reduced in the TFDM group compared with that in the model group (P < 0.05) and that expression of these proteins was normalized by TFDM treatment in a dose-dependent manner. According to RT-qPCR results, TFDM pretreatment resulted in reduced mRNA expression of BAX, Caspase-9, Caspase-12, p38MAPK, and CaMKII and increased mRNA expression of mTOR compared with the model group. CONCLUSIONS: The current study revealed the protective effects of TFDM on U87 cells under oxidative stress conditions through the inhibition of a mitochondria-dependent pathway that is associated with the CaMKII/P38MAPK/ERK1/2 and PI3K/AKT/mTOR pathways.


Assuntos
Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Flavonas/farmacologia , Lamiaceae/química , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Peróxido de Hidrogênio , Medicina Tradicional Chinesa
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA