Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 36
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
BMC Complement Med Ther ; 20(1): 68, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32126993

RESUMO

BACKGROUND: Osteosarcoma is the most common primary malignant bone tumor in children and adolescents and has also been associated with a high degree of malignancy and enhanced metastatic capacity. Curcumin (CUR) is well known for its anti-osteosarcoma activity. However, both demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) are natural curcumin analogues/congeners from turmeric whose role in osteosarcoma development remains unknown. METHODS: To evaluate the growth inhibitory effects of CUR, DMC and BDMC on osteosarcoma (HOS and U2OS), breast (MDA-MB-231), and melanoma (A2058) cancer cells, we employed the MTT assay, annexin V-FITC /7-AAD staining, and clonogenic assay. RESULTS: CUR,DMC, and BDMC all decreased the viability of HOS, U2OS, MDA-MB-231, and A2058 cancer cells. Additionally, CUR,DMC, and BDMC induced the apoptosis of HOS cells through activation of Smad 2/3 or repression of Akt signaling pathway. Furthermore, the combination of CUR,DMC, and BDMC synergistically reduced cell viability, colony formation and increased apoptosis than either two or a single agent in HOS cells. CONCLUSIONS: The combination of these three compounds could be used as a novel target for the treatment of osteosarcoma.

2.
Mol Carcinog ; 59(3): 293-303, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31916307

RESUMO

Chondrosarcoma is the second most common form of bone cancer and is characterized by its ability to produce an extracellular matrix of the cartilage. High-grade chondrosarcoma is highly aggressive and can metastasize to other parts of the body. Chondrosarcoma is resistant to both conventional chemotherapy and radiotherapy; hence, the current main treatment is still surgical resection. Doxorubicin (Dox) has been shown to significantly improve patient survival compared with untreated chondrosarcoma. However, for patients with metastasis, surgical resection alone can hardly treat them. In addition, drug resistance is one of the leading causes of death in patients with chondrosarcoma. Secreted proteins can mediate cell-cell interactions in the cancer microenvironment, which may be associated with the development of drug resistance. In the present study, chondrosarcoma cells were treated with Dox, the conditioned medium was then collected and changes in secreted proteins were analyzed using the antibody array. Results showed that the Dox-treated group had the highest secretion of basic fibroblast growth factor (bFGF), indicating the effect of bFGF on Dox sensitivity in chondrosarcoma. Furthermore, lentiviral-mediated knockdown and treatment of exogenous recombinant protein were employed to further investigate the effect of bFGF on Dox resistance. Results demonstrated that bFGF can promote the expression of X-ray repair cross-complementing protein 5 (XRCC5), leading to Dox resistance. Secreted bFGF is likely to be detected in serum, in addition to being a biomarker for predicting Dox resistance, the combination of Dox and bFGF/XRCC5 blockers may be a new therapeutic strategy to improve the efficacy of Dox in future.

3.
Br J Pharmacol ; 177(2): 239-253, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31497874

RESUMO

BACKGROUND AND PURPOSE: Non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis, is closely related to metabolic diseases such as obesity and diabetes. Despite an accumulating number of studies, no pharmacotherapy that targets NAFLD has received general approval for clinical use. EXPERIMENTAL APPROACH: Inhibition of the sodium-glucose cotransporter 2 (SGLT2) is a promising approach to treat diabetes, obesity, and associated metabolic disorders. In this study, we investigated the effect of a novel SGLT2 inhibitor, NGI001, on NAFLD and obesity-associated metabolic symptoms in high-fat diet (HFD)-induced obese mice. KEY RESULTS: Delayed intervention with NGI001 protected against body weight gain, hyperglycaemia, hyperlipidaemia, and hyperinsulinaemia, compared with HFD alone. Adipocyte hypertrophy was prevented by administering NGI001. NGI001 inhibited impaired glucose metabolism and regulated the secretion of adipokines associated with insulin resistance. In addition, NGI001 supplementation suppressed hepatic lipid accumulation and inflammation but had little effect on kidney function. In-depth investigations showed that NGI001 ameliorated fat deposition and increased AMPK phosphorylation, resulting in phosphorylation of its major downstream target, acetyl-CoA carboxylase, in human hepatocyte HuS-E/2 cells. This cascade ultimately led to the down-regulation of downstream fatty acid synthesis-related molecules and the up-regulation of downstream ß oxidation-associated molecules. Surprisingly, NGI001 decreased gene and protein expression of SGLT1 and SGLT2 and glucose uptake in oleic acid-treated HuS-E/2 cells. CONCLUSION AND IMPLICATIONS: Our findings suggest the novel SGLT2 inhibitor, NGI001 has therapeutic potential to attenuate or delay the onset of diet-induced metabolic diseases and NAFLD.

4.
BMC Complement Altern Med ; 19(1): 368, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31836013

RESUMO

BACKGROUND: Obesity and its associated health conditions, type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), are worldwide health problems. It has been shown that insulin resistance is associated with increased hepatic lipid and causes hepatic steatosis through a myriad of mechanisms, including inflammatory signaling. METHODS: Helminthostachys zeylanica (HZ) is used widely as a common herbal medicine to relieve fever symptoms and inflammatory diseases in Asia. In the present study, we evaluated whether HZ has therapeutic effects on obesity, NAFLD and insulin resistance. The protective effects of HZ extract were examined using free fatty acid-induced steatosis in human HuS-E/2 cells and a high-fat diet-induced NAFLD in mice. RESULTS: The major components of the HZ extract are ugonins J and K, confirmed by HPLC. Incubation of human hepatocytes, HuS-E/2 cells, with palmitate markedly increased lipid accumulation and treatment with the HZ extract significantly decreased lipid deposition and facilitated AMPK and ACC activation. After 12 weeks of a high-fat diet with HZ extract treatment, the HFD mice were protected from hyperlipidemia and hyperglycemia. HZ extract prevented body weight gain, adipose tissue expansion and adipocyte hypertrophy in the HFD mice. In addition, fat accumulation was reduced in mice livers. Moreover, the insulin sensitivity-associated index, which evaluates insulin function, was also significantly restored. CONCLUSIONS: These results suggest that HZ has a promising pharmacological effect on high-fat diet-induced obesity, hepatic steatosis and insulin resistance, which may have the potential for clinical application.


Assuntos
Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Extratos Vegetais/farmacologia , Traqueófitas , Adipócitos/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Dieta Hiperlipídica/efeitos adversos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/química
5.
Biochem Biophys Res Commun ; 513(3): 608-615, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-30981506

RESUMO

Haloperidol is a common butyrophenone-derivative antipsychotic drug that is used clinically to treat schizophrenia and to control Tourette disorder. Haloperidol has been shown to be an embryonic toxicant and to cause a variety of adverse effects that affect human embryonic development. However, the pathway impaired by haloperidol during the developmental stages remains unclear. To elucidate the innate toxicological pathway of haloperidol, we investigated the lethality of haloperidol during the embryonic development of zebrafish. We observed that haloperidol caused serious morphological changes, with an LD50 of 9.7 x 10-6 ± 2.4 x 10-6 µg/L. Next, we established a systematic approach to perform metabolite profiling in embryonic zebrafish with various concentrations of haloperidol and analyzed the metabolites using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS). A total of 304 metabolites were identified and 86 metabolites were chosen to predict potential pathways. Among the metabolites, we found through prediction that numerous metabolomics-biological pathways are associated with haloperidol, including peroxisome-proliferator-activated receptor (ppar), thromboxane, and mTOR signaling. Quantitative real time-qPCR was then used to validate the gene expression potentially associated with the thromboxane, which is a metabolic product of arachidonic acid and considered to be important for cell proliferation and the inflammatory response. To sum up, analysis of metabolites in the zebrafish model provides a system for mining biomarkers that reflect biological significance and highlight the therapeutic potency in humans. In addition, it may show potential for application to other pharmaceuticals to identify their various activities and clarify functional mechanisms in the future.

6.
J Agric Food Chem ; 67(10): 2818-2830, 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30789269

RESUMO

Ampelopsins A and C are resveratrol oligostilbenes whose role in cancer development remains unknown. This study evaluated the antimetastatic and apoptosis-inducing properties of ampelopsins A and C in MDA-MB-231 cells. The IC50 values of ampelopsins A and C against MDA-MB-231 cells at 72 h were 38.75 ± 4.61 and 2.71 ± 0.21 µM, respectively. However, at 24 h, ampelopsins A and C decreased cell metastasis significantly. Among the 71 proteins present on the human phosphoreceptor tyrosin kinase array, ampelopsin C decreased the phosphorylated protein level of AXL, Dtk (TYRO3), EphA2, EphA6, Fyn, Hck, and SRMS. Additionally, antiproliferation effects of ampelopsin C were enhanced when combined with luteolin and chrysin compared to either two or a single agent in MDA-MB-231 cells. Overall, ampelopsins A and C extracted from Vitis thunbergii are both novel antimetastatic agents and potential therapeutic targets in patients with breast cancer.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Flavonoides/farmacologia , Proteínas Proto-Oncogênicas c-fyn/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Metástase Neoplásica , Fosforilação , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo
7.
BMC Complement Altern Med ; 18(1): 248, 2018 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-30189898

RESUMO

BACKGROUND: Persistent hepatitis B virus (HBV) infection causes liver cirrhosis and hepatocellular carcinoma and constitutes a major worldwide health problem. Currently, anti-HBV drugs are limited to peginterferon and nucleos(t)ide analogs, which are costly and have considerable side effects; the development of novel, effective anti-HBV agents is crucial. METHODS: Catechins are a major group of compounds found in green tea extract and epigallocatechin gallate (EGCG) has been shown to have antiviral properties, including inhibition of cellular entry by HBV. FRG (Fah-/-/ Rag2-/-/ IL-2Rγ/-) mice were used in this study to generate chimeras carrying human primary hepatocytes, to facilitate investigation of the inhibitory effect of EGCG on HBV infection. RESULTS: Here, we show the inhibitory effect of EGCG on HBV infection and replication in HuS-E/2 cells. The inhibitory effect of EGCG on HBV infection in vivo was confirmed by monitoring HBV DNA and HBsAg in serum and immunostaining the liver tissues of the human liver chimeric mice. CONCLUSIONS: The effects of EGCG suggest a robust strategy for the treatment of HBV infection and EGCG may have therapeutic potential for the treatment of HBV-associated liver diseases.


Assuntos
Antivirais/farmacologia , Catequina/análogos & derivados , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B , Animais , Catequina/farmacologia , DNA Viral/sangue , Feminino , Células Hep G2 , Hepatite B/imunologia , Hepatite B/virologia , Antígenos de Superfície da Hepatite B/sangue , Humanos , Fígado/efeitos dos fármacos , Fígado/virologia , Camundongos , Replicação Viral/efeitos dos fármacos
8.
Arch Phys Med Rehabil ; 99(6): 1042-1048.e6, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29108967

RESUMO

OBJECTIVE: To determine the relation between rehabilitation intensity and poststroke mortality. DESIGN: Retrospective cohort study. SETTING: Nationwide claims data. PARTICIPANTS: From Taiwan's National Health Insurance claims databases, patients (N=6737; mean age, 66.9y; 40.3% women) hospitalized between 2001 and 2013 for a first-ever stroke who had mild to moderate stroke and survived the first 90 days of stroke were enrolled. INTERVENTIONS: The intensity of rehabilitation therapy within 90 days after stroke was categorized into low, medium, or high based on the tertile distribution of the number of rehabilitation sessions. MAIN OUTCOME MEASURES: Long-term all-cause mortality. The Cox proportional hazard models with Bonferroni correction were used to assess the association between rehabilitation intensity and mortality, adjusting for age, comorbidities, stroke severity, and other covariates. RESULTS: Patients in the high-intensity group were younger but had a higher burden of comorbidities and greater stroke severity. During follow-up, the high-intensity group was associated with a significantly lower adjusted risk (hazard ratio [HR], .73; 95% confidence interval [CI], .63-.84) of mortality than the low-intensity group, whereas the medium-intensity group carried a similar risk of mortality (HR, 0.94; 95% CI, 0.84-1.06) compared with the low-intensity group. This association was not modified by stroke severity. CONCLUSIONS: Among patients with mild to moderate stroke severity, high-intensity rehabilitation therapy within the first 90 days was associated with a lower mortality risk than low-intensity therapy. Efforts to promote high-intensity rehabilitation therapy for this group of patients with stroke should be encouraged.


Assuntos
Reabilitação do Acidente Vascular Cerebral/mortalidade , Reabilitação do Acidente Vascular Cerebral/métodos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Feminino , Humanos , Revisão da Utilização de Seguros/estatística & dados numéricos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Fatores Socioeconômicos , Taiwan/epidemiologia
9.
Antiviral Res ; 150: 69-78, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29247673

RESUMO

Hepatitis D virus (HDV) contains a single-stranded circular RNA genome that encodes two forms of hepatitis delta antigen (HDAg), the small delta antigen (HDAg-S) and the large delta antigen (HDAg-L). The two proteins have an identical amino acid sequence, except that HDAg-L has a 19-amino-acid extension at the C terminus. The domain spanning amino acid residues 198-210 of the HDAg-L (HDAg-L(198-210)) contains a nuclear export signal (NES), which is important for the nuclear export of HDV ribonucleoprotein to the cytoplasm. In this study, we established a cell permeable TAT-HA-HDAg-L(198-210) fusion protein using an E. coli protein expression system, to determine its function during HDV infection. The cytotoxicity of the TAT-HA-HDAg-L(198-210) fusion protein was investigated using an MTT assay, while a GST pull-down assay revealed that the TAT-HA-HDAg-L(198-210) fusion protein interfered with the interaction between HDAg-L and clathrin heavy chain (CHC). In addition, the cellular distribution of HDAg-L, in the presence of HBsAg, was observed by immunofluorescence staining and the TAT-HA-HDAg-L(198-210) fusion protein was found to impede the nuclear export of HDAg-L. Furthermore, assembly of HDV virus-like particles (VLPs) was decreased by the expression of the TAT-HDAg-L(198-210) fusion protein. The TAT-HA-HDAg-L(198-210) fusion protein also inhibited virus particle assembly and HDV secretion in a mouse model. These results suggest that the TAT-HA-HDAg-L(198-210) fusion protein inhibits the nuclear export of HDAg-L and competes with the C terminus of HDAg-L for interaction with CHC, and may have potential as a therapeutic agent for HDV infection.


Assuntos
Vírus Delta da Hepatite/fisiologia , Antígenos da Hepatite delta/metabolismo , Domínios e Motivos de Interação entre Proteínas , Montagem de Vírus , Replicação Viral , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular , Expressão Gênica , Genes Reporter , Hepatite D/virologia , Antígenos da Hepatite delta/química , Humanos , Masculino , Camundongos , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas/genética , Transporte Proteico , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética
10.
Artigo em Inglês | MEDLINE | ID: mdl-28018473

RESUMO

Background. Radix Paeoniae Rubra (Chi Shao) contains several phytochemicals with hypoglycemic actions. Current research aims to explore potential insulinotropic effects and long-term therapeutic efficacy of such herb against type 2 diabetes. Methods. Composition analysis for the ethanol extract (PRExt) was executed by high performance liquid chromatography. Polyphenol-enriched fraction was characterized by high pressure size exclusion chromatography. Multiple cell platforms were employed to evaluate hypoglycemic bioactivities. In animal experiments, blood glucose, the homeostasis model assessment (HOMA)-index assessment, glucose tolerance test, and in vivo glucose uptake were all measured. Additional effects of PRExt on obesity and hepatic steatosis were evaluated by serum and histological analysis. Results. PRExt provides multiple hypoglycemic effects including the enhancement of glucose-mediated insulin secretion. Pentagalloylglucose and polyphenol-enriched fraction are two insulinotropic constituents. Moreover, PRExt intraperitoneal injection causes acute hypoglycemic effects on fasted db/db mice. Oral administration of PRExt (200 mg/kg b.w.) gradually reduces blood glucose in db/db mice to the level similar to that in C57J/B6 mice after 30 days. The improvement of glucose intolerance, HOMA-index, and in vivo glucose uptake is evident in addition to the weight loss effect and attenuation of hepatic steatosis. Conclusion. PRExt is an effective antidiabetic herbal extract with multiple hypoglycemic bioactivities.

11.
BMC Complement Altern Med ; 16(1): 432, 2016 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-27809830

RESUMO

BACKGROUND: In this study, we aimed to develop a Stigmata Maydis (corn silk) fraction with dual bio-activities against oxidative stress and protein glycation to protect ß-cells from diabetes-induced failure. METHODS: Corn silk fractions were prepared by partition and chemically characterised by thin-layer chromatography. Free radical scavenging assay, glycation assay, and cell-based viability test (neutral red) were employed to decide the best fraction. Cell death analysis was executed by annexin V/ Propidium iodide staining. Cell proliferation was measured by WST-1. Finally, ß-cell function was evaluated by ß-cell marker gene expression (RT-PCR) and acute insulin secretion test. RESULTS: Four corn silk fractions were prepared from an ethanolic crude extract of corn silk. In vitro assays indicate ethyl acetate fraction (YMS-EA) was the most potent fraction. YMS-EA also attenuated the hydrogen peroxide- or methylglyoxal-induced induction of reactive oxygen species, reduction of cell viability, and inhibition of cell proliferation. However, YMS-EA was unable to prevent hydrogen peroxide-induced apoptosis or advanced glycation end-products-induced toxicity. Under hyperglycemic conditions, YMS-EA effectively reduced ROS levels, improved mRNA expression of insulin, glucokinase, and PDX-1, and enhanced glucose-stimulated insulin secretion. The similarity of bioactivities among apigenin, luteolin, and YMS-EA indicated that dual activities of YMS-EA might be derived from those compounds. CONCLUSIONS: We concluded that YMS-EA fraction could be developed as a preventive food agent against the glucotoxicity to ß-cells in Type 2 diabetes.


Assuntos
Antioxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Zea mays/química , Acetatos/química , Animais , Antioxidantes/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Feminino , Produtos Finais de Glicação Avançada/análise , Produtos Finais de Glicação Avançada/metabolismo , Peróxido de Hidrogênio/toxicidade , Masculino , Camundongos , Extratos Vegetais/química , Ratos , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo
12.
J Biol Chem ; 291(50): 26226-26238, 2016 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-27807029

RESUMO

Hepatitis delta virus (HDV) is a satellite virus of hepatitis B virus (HBV). HDV genome encodes two forms of hepatitis delta antigen (HDAg), small HDAg (HDAg-S), which is required for viral replication, and large HDAg (HDAg-L), which is essential for viral assembly. HDAg-L is identical to HDAg-S except that it bears a 19-amino acid extension at the C terminus. Both HDAgs contain a nuclear localization signal (NLS), but only HDAg-L contains a CRM1-independent nuclear export signal at its C terminus. The nuclear export activity of HDAg-L is important for HDV particle formation. However, the mechanisms of HDAg-L-mediated nuclear export of HDV ribonucleoprotein are not clear. In this study, the host cellular RNA export complex TAP-Aly was found to form a complex with HDAg-L, but not with an export-defective HDAg-L mutant, in which Pro205 was replaced by Ala. HDAg-L was found to colocalize with TAP and Aly in the nucleus. The C-terminal domain of HDAg-L was shown to directly interact with the N terminus of TAP, whereas an HDAg-L mutant lacking the NLS failed to interact with full-length TAP. In addition, small hairpin RNA-mediated down-regulation of TAP or Aly reduced nuclear export of HDAg-L and assembly of HDV virions. Furthermore, a peptide, TAT-HDAg-L(198-210), containing the 10-amino acid TAT peptide and HDAg-L(198-210), inhibited the interaction between HDAg-L and TAP and blocked HDV virion assembly and secretion. These data demonstrate that formation and release of HDV particles are mediated by TAP and Aly.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Núcleo Celular/metabolismo , Vírus Delta da Hepatite/fisiologia , Antígenos da Hepatite delta/metabolismo , Sinais de Localização Nuclear/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/metabolismo , Vírion/metabolismo , Montagem de Vírus/fisiologia , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/genética , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Transporte Ativo do Núcleo Celular/genética , Núcleo Celular/genética , Núcleo Celular/virologia , Células Hep G2 , Antígenos da Hepatite delta/genética , Humanos , Sinais de Localização Nuclear/genética , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Peptídeos/farmacologia , Domínios Proteicos , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/genética , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Vírion/genética , Montagem de Vírus/efeitos dos fármacos
13.
Int J Mol Sci ; 17(8)2016 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-27527160

RESUMO

The natural agent, 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione (HMDB), has been reported to have growth inhibitory effects on several human cancer cells. However, the role of HMDB in cervical cancer remains unclear. Herein, we found that HMDB dose- and time-dependently inhibited growth of HeLa cervical cancer cells, accompanied with G1 cell cycle arrest. HMDB decreased protein expression of cyclins D1/D3/E and cyclin-dependent kinases (CDKs) 2/4/6 and reciprocally increased mRNA and protein levels of CDK inhibitors (p15, p16, p21, and p27), thereby leading to the accumulation of hypophosphorylated retinoblastoma (Rb) protein. HMDB also triggered the accumulation of acidic vesicles and formation of microtubule-associated protein-light chain 3 (LC3), followed by increased expression of LC3 and Beclin-1 and decreased expression of p62, suggesting that HMDB triggered autophagy in HeLa cells. Meanwhile, suppression of the expression of survivin and Bcl-2 implied that HMDB-induced autophagy is tightly linked to apoptosis. Exploring the action mechanism, HMDB induced autophagy via the modulation of AMP-activated protein kinase (AMPK) and mTOR signaling pathway rather than the class III phosphatidylinositol 3-kinase pathway. These results suggest that HMDB inhibits HeLa cell growth by eliciting a G1 arrest through modulation of G1 cell cycle regulators and by concomitantly inducing autophagy through the mediation of AMPK-mTOR and Akt-mTOR pathways, and may be a promising antitumor agent against cervical cancer.


Assuntos
Autofagia/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Cetonas/farmacologia , Propano/análogos & derivados , Neoplasias do Colo do Útero/patologia , Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Cetonas/química , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Modelos Biológicos , Propano/química , Propano/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Vacúolos/efeitos dos fármacos , Vacúolos/metabolismo
14.
J Agric Food Chem ; 64(21): 4235-45, 2016 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-27137679

RESUMO

The composition of Morinda citrifolia (M. citrifolia) was determined using high-performance liquid chromatography (HPLC), and the anticancer effects of M. citrifolia extract evaluated in HepG2, Huh7, and MDA-MB-231 cancer cells. M. citrifolia fruit extracts were obtained by using five different organic solvents, including hexane (Hex), methanol (MeOH), ethyl acetate (EtOAc), chloroform (CHCl3), and ethanol (EtOH). The water-EtOAc extracts from M. citrifolia fruits was found to have the highest anticancer activity. HPLC data revealed the predominance of chrysin in water-EtOAc extracts of M. citrifolia fruit. Furthermore, the combined effects of cotreatment with apigenin and chrysin on liver and breast cancer were investigated. Treatment with apigenin plus chrysin for 72-96 h reduced HepG2 and MDA-MB-231 cell viability and induced apoptosis through down-regulation of S-phase kinase-associated protein-2 (Skp2) and low-density lipoprotein receptor-related protein 6 (LRP6) expression. However, the combination treatment for 36 h synergistically decreased MDA-MB-231 cell motility but not cell viability through down-regulation of MMP2, MMP9, fibronectin, and snail in MDA-MB-231 cells. Additionally, chrysin combined with apigenin also suppressed tumor growth in human MDA-MB-231 breast cancer cells xenograft through down-regulation of ki-67 and Skp2 protein. The experimental results showed that chrysin combined with apigenin can reduce HepG2 and MDA-MB-231 proliferation and cell motility and induce apoptosis. It also offers opportunities for exploring new drug targets, and further investigations are underway in this regard.


Assuntos
Apigenina/administração & dosagem , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Flavonoides/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Morinda/química , Extratos Vegetais/administração & dosagem , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células , Sinergismo Farmacológico , Feminino , Flavonoides/isolamento & purificação , Frutas/química , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/fisiopatologia , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Extratos Vegetais/isolamento & purificação , Proteínas Quinases Associadas a Fase S/genética , Proteínas Quinases Associadas a Fase S/metabolismo
15.
Oncotarget ; 7(24): 35874-35893, 2016 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-27078842

RESUMO

Avicennia marina is the most abundant and common mangrove species and has been used as a traditional medicine for skin diseases, rheumatism, ulcers, and smallpox. However, its anticancer activities and polyphenol contents remain poorly characterized. Thus, here we investigated anticancer activities of secondary A. marina metabolites that were purified by sequential soxhlet extraction in water, ethanol, methanol, and ethyl acetate (EtOAc). Experiments were performed in three human breast cancer cell lines (AU565, MDA-MB-231, and BT483), two human liver cancer cell lines (HepG2 and Huh7), and one normal cell line (NIH3T3). The chemotherapeutic potential of A. marina extracts was evaluated in a xenograft mouse model. The present data show that EtOAc extracts of A. marina leaves have the highest phenolic and flavonoid contents and anticancer activities and, following column chromatography, the EtOAc fractions F2-5, F3-2-9, and F3-2-10 showed higher cytotoxic effects than the other fractions. 1H-NMR and 13C-NMR profiles indicated that the F3-2-10 fraction contained avicennones D and E. EtOAc extracts of A. marina leaves also suppressed xenograft MDA-MB-231 tumor growth in nude mice, suggesting that EtOAc extracts of A. marina leaves may provide a useful treatment for breast cancer.


Assuntos
Apoptose/efeitos dos fármacos , Avicennia/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Folhas de Planta/química , Polifenóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Acetatos/química , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células NIH 3T3 , Extratos Vegetais/farmacologia , Carga Tumoral/efeitos dos fármacos
16.
Eur J Pharmacol ; 770: 16-24, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26643169

RESUMO

Microglia are the primary immune cells that contribute to neuroinflammation by releasing various proinflammatory cytokines and neurotoxins in the brain. Microglia-mediated neuroinflammation is one of the key characteristics of Alzheimer's disease (AD). Therefore, inhibitory reagents that prevent microglial activation may be used as potential therapeutic agents for treating AD. Recently, many studies have been performed to determine the bioactivities of green tea polyphenol epigallocatechin-3-gallate (EGCG), an efficient antioxidant that prevents neuroinflammation. However, limited information is available on the effects of EGCG on microglia-mediated neuroinflammation. In this study, we investigated the inhibitory effects of EGCG on amyloid ß (Aß)-induced microglial activation and neurotoxicity. Our results indicated that EGCG significantly suppressed the expression of tumor necrosis factor α (TNFα), interleukin-1ß, interleukin-6, and inducible nitric oxide synthase (iNOS) in Aß-stimulated EOC 13.31 microglia. EGCG also restored the levels of intracellular antioxidants nuclear erythroid-2 related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), thus inhibiting reactive oxygen species-induced nuclear factor-κB (NF-κB) activation after Aß treatment. Furthermore, EGCG effectively protected neuro-2a neuronal cells from Aß-mediated, microglia-induced cytotoxicity by inhibiting mitogen-activated protein kinase-dependent, Aß-induced release of TNFα. Taken together, our findings suggested that EGCG suppressed Aß-induced neuroinflammatory response of microglia and protected against indirect neurotoxicity. These results suggest that EGCG is a possible therapeutic agent for preventing Aß-induced inflammatory neurodegeneration.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Catequina/análogos & derivados , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Animais , Catequina/farmacologia , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Inflamação/induzido quimicamente , Inflamação/patologia , Interleucina-1beta/genética , Interleucina-6/genética , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Camundongos , Microglia/citologia , Microglia/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/genética
17.
Artigo em Inglês | MEDLINE | ID: mdl-26508982

RESUMO

Obesity and associated conditions, such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), are currently a worldwide health problem. In Asian traditional medicine, Bai-Hu-Jia-Ren-Shen-Tang (BHJRST) is widely used in diabetes patients to reduce thirst. However, whether it has a therapeutic effect on T2DM or NAFLD is not known. The aim of this study was to examine whether BHJRST had a lipid-lowering effect using a HuS-E/2 cell model of fatty liver induced by palmitate and in a db/db mouse model of dyslipidemia. Incubation of HuS-E/2 cells with palmitate markedly increased lipid accumulation and expression of adipose triglyceride lipase (ATGL), which is involved in lipolysis. BHJRST significantly decreased lipid accumulation and increased ATGL levels and phosphorylation of AMP-activated protein kinase (AMPK) and its primary downstream target, acetyl-CoA carboxylase (ACC), which are involved in fatty acid oxidation. Furthermore, after twice daily oral administration for six weeks, BHJRST significantly reduced hepatic fat accumulation in db/db mice, as demonstrated by increased hepatic AMPK and ACC phosphorylation, reduced serum triglyceride levels, and reduced hepatic total lipid content. The results show that BHJRST has a lipid-lowering effect in the liver that is mediated by activation of the AMPK signaling pathway.

18.
Mol Carcinog ; 54(12): 1613-25, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25358452

RESUMO

Triple-negative breast cancer (TNBC) is difficult to treat because there is no targeted therapy available. Clinical studies have demonstrated that S-phase kinase-associated protein 2 (Skp2) and low-density lipoprotein receptor-related protein 6 (LRP6) are highly expressed in TNBC. Therefore, therapeutic strategies designed to downregulate LRP6 or Skp2 may play an important clinical role in the treatment of TNBC. However, the regulatory effects of many drugs on Skp2 and LRP6 expression are currently unknown. In the present study, combined treatment with chrysin and 1,2,3,4,6-penta-O-galloyl-ß-D-glucose (5GG) synergistically induced apoptosis and cell cycle arrest and inhibited cell proliferation and colony formation in AU565 and MDA-MB-231 human breast cancer cells. Furthermore, the combination of chrysin and 5GG suppressed tumor growth in nude mice with xenografted MDA-MB-231 cells by downregulating the phospho-LRP6 (pLRP6) and Skp2 proteins. Overall, our findings suggested that the combination of chrysin and 5GG has a potential therapeutic value in treating breast cancer, particularly for TNBC associated with Skp2/LRP6 overexpression, and hence warrants further investigation.


Assuntos
Flavonoides/farmacologia , Taninos Hidrolisáveis/farmacologia , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/análise , Proteínas Quinases Associadas a Fase S/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Xenoenxertos/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus
19.
Antiviral Res ; 111: 100-11, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25260897

RESUMO

Hepatitis B virus (HBV) is a major cause of liver disease and hepatocellular carcinoma. Chronic HBV infection is currently managed with either nucleoside/nucleotide-based or interferon-based therapies, but fails to clear infection in a substantial proportion of cases, and antiviral strategies targeting the early stages of infection are therefore required for the prevention of HBV infection. In this study, we examined some common phytochemicals and identified epigallocatechin-3-gallate (EGCG) as a new inhibitor of HBV entry. EGCG, a flavonoid present in green tea extract, belongs to the subclass of catechins. We demonstrated that EGCG at a concentration of 50µM inhibited HBV entry into immortalized human primary hepatocytes by more than 80%, whereas the other four catechins tested had much weaker inhibitory effects. DMSO-differentiated HuS-E/2 cells expressed sodium taurocholate cotransporting polypeptide (NTCP), which is a receptor for HBV. Application of EGCG during HBV inoculation markedly inhibited infection in both DMSO-differentiated HuS-E/2 cells and HA-NTCP-expressing Huh7 cells. Interestingly, EGCG induced clathrin-dependent endocytosis of NTCP from the plasma membrane followed by protein degradation. In addition, EGCG inhibited the clathrin-mediated endocytosis of transferrin. Treatment of cells with EGCG had no effect on HBV genome replication or virion secretion. Moreover, the characteristic of HBV virion and the expression of known HBV entry factors were unaltered by EGCG. Finally, the antiviral activity of EGCG on HBV entry was observed using four different genotypes, A to D. These results show that the green tea-derived molecule EGCG potently inhibits HBV entry and could be used in prevention of HBV reinfection.


Assuntos
Antivirais/farmacologia , Catequina/análogos & derivados , Vírus da Hepatite B/efeitos dos fármacos , Hepatócitos/virologia , Extratos Vegetais/farmacologia , Catequina/farmacologia , Linhagem Celular , Hepatite B/virologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/fisiologia , Hepatócitos/efeitos dos fármacos , Humanos , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
20.
J Agric Food Chem ; 61(26): 6430-45, 2013 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-23731217

RESUMO

Breast cancer is the most universal cancer in women, but the medications for breast cancer usually cause serious side effects and offer no effective treatment for triple-negative breast cancer. Here, we investigated the growth inhibitory effects of gallic acid (GA), (-)-epigallocatechin gallate (EGCG), or 1,2,3,4,6-penta-O-galloyl-ß-D-glucose (5GG) combined with quercetin (Que) on breast cancer cells. In this study, we tested the combined effects of these compounds on estrogen receptor (ER)/human epidermal growth factor 2 (Her2)-negative (MDA-MB-231), ER-positive/Her2-negative (BT483), and ER-negative/Her2-positive (AU565) breast cancer cells. After treatment of each cell line with these compounds, we found that Que combined with 5GG induced S-phase arrest and apoptosis in MDA-BM-231 cells through downregulation of S-phase kinase protein 2 expression, but induced G2/M-phase arrest and apoptosis in AU565 cells through downregulation of Her2 expression. Additionally, Que combined with 5GG was more effective in inhibiting MDA-MB-231 cell growth than Que combined with EGCG (5GG analogue) or GA. The combination of 5GG and Que can offer great potential for the chemoprevention of ER-negative breast cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Taninos Hidrolisáveis/farmacologia , Quercetina/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA