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1.
Braz J Med Biol Res ; 53(6): e8885, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401925

RESUMO

In this study, we aimed to analyze the anti-cancer effects of ß-elemene combined with paclitaxel for ovarian cancer. RT-qPCR, MTT assay, western blot, flow cytometry, and immunohistochemistry were used to analyze in vitro and in vivo anti-cancer effects of combined treatment of ß-elemene and paclitaxel. The in vitro results showed that ß-elemene+paclitaxel treatment markedly inhibited ovarian cancer cell growth, migration, and invasion compared to either paclitaxel or ß-elemene treatment alone. Results demonstrated that ß-elemene+paclitaxel induced apoptosis of SKOV3 cells, down-regulated anti-apoptotic Bcl-2 and Bcl-xl gene expression and up-regulated pro-apoptotic P53 and Apaf1 gene expression in SKOV3 cells. Administration of ß-elemene+paclitaxel arrested SKOV3 cell cycle at S phase and down-regulated CDK1, cyclin-B1, and P27 gene expression and apoptotic-related resistant gene expression of MDR1, LRP, and TS in SKOV3 cells. In vivo experiments showed that treatment with ß-elemene+paclitaxel significantly inhibited ovarian tumor growth and prolonged the overall survival of SKOV3-bearing mice. In addition, the treatment inhibited phosphorylated STAT3 and NF-κB expression in vitro and in vivo. Furthermore, it inhibited migration and invasion through down-regulation of the STAT-NF-κB signaling pathway in SKOV3 cells. In conclusion, the data suggested that ß-elemene+paclitaxel can inhibit ovarian cancer growth via down-regulation of the STAT3-NF-κB signaling pathway, which may be a potential therapeutic strategy for ovarian cancer therapy.


Assuntos
Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/administração & dosagem , Sesquiterpenos/administração & dosagem , Animais , Western Blotting , Linhagem Celular Tumoral , Feminino , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Transfecção
2.
Virol J ; 16(1): 163, 2019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31870450

RESUMO

BACKGROUND: Patchouli alcohol (PA) is a tricyclic sesquiterpene extracted from Pogostemonis Herba, which is a traditional Chinese medicine used for therapy of inflammatory diseases. Recent studies have shown that PA has various pharmacological activities, including anti-bacterial and anti-viral effects. METHODS: In this study, the anti-influenza virus (IAV) activities and mechanisms were investigated both in vitro and in vivo. The inhibitory effects of PA against IAV in vitro were evaluated by plaque assay and immunofluorescence assay. The neuraminidase inhibition assay, hemagglutination inhibition (HI) assay, and western blot assay were used to explore the anti-viral mechanisms. The anti-IAV activities in vivo were determined by mice pneumonia model and HE staining. RESULTS: The results showed that PA significantly inhibited different IAV strains multiplication in vitro, and may block IAV infection through inactivating virus particles directly and interfering with some early stages after virus adsorption. Cellular PI3K/Akt and ERK/MAPK signaling pathways may be involved in the anti-IAV actions of PA. Intranasal administration of PA markedly improved mice survival and attenuated pneumonia symptoms in IAV infected mice, comparable to the effects of Oseltamivir. CONCLUSIONS: Therefore, Patchouli alcohol has the potential to be developed into a novel anti-IAV agent in the future.


Assuntos
Antivirais/farmacologia , Vírus da Influenza A/crescimento & desenvolvimento , Sesquiterpenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Administração Intranasal , Animais , Antivirais/administração & dosagem , Modelos Animais de Doenças , Pulmão/patologia , Camundongos , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/patologia , Sesquiterpenos/administração & dosagem , Análise de Sobrevida , Resultado do Tratamento
3.
Medicine (Baltimore) ; 98(44): e17813, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689867

RESUMO

BACKGROUND: To evaluate the short-term efficacy, long-term efficacy, and adverse events (AEs) of elemene plus transcatheter arterial chemoembolization (TACE) in comparison with TACE alone for the treatment of hepatocellular carcinoma (HCC). METHODS: PubMed, EMBASE, the Cochrane Library, the Chinese Scientific Journal Full-text Database, Wanfang Data, CBM, and VIP were searched by 2 reviewers using the same search strategy for clinical studies on elemene plus TACE in the treatment of HCC. These articles were screened according to pre-established inclusion and exclusion criteria, and the qualities of the included studies were assessed using the Newcastle-Ottawa scale. The primary outcomes were the objective response rate (ORR), the 1-year survival rate and AEs. Review Manager 5.3 and Stata 15.0 were used for the meta-analysis. RESULTS: A total of 10 studies involving 543 patients (TACE + elemene = 277, TACE alone = 266) were included. The results showed that the ORR was significantly improved in the combined treatment group compared to the TACE alone group (odds ratio [OR] = 2.72, 95% confidence interval [CI]: 1.84-4.00, P < .05). TACE + elemene significantly increased the 1-year survival rate (OR = 2.79, 95% CI: 1.58-4.95, P < .05). We also found no significant difference in gastrointestinal reactions (OR = 0.97, 95% CI: 0.57-1.64, P = .90), fever (OR = 0.80, 95% CI: 0.37-1.71, P = .56), or bone marrow suppression (OR = 0.73, 95% CI: 0.44-1.22, P = .23) between the 2 groups. CONCLUSION: Based on current findings, TACE + elemene injection may improve the ORR and the 1-year survival rate for HCC patients compared to TACE alone. Arterial perfusion may be superior to intravenous guttae.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Quimioembolização Terapêutica/métodos , Neoplasias Hepáticas/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Cateterismo , Quimioembolização Terapêutica/efeitos adversos , Humanos , Injeções Intra-Arteriais , Sesquiterpenos/administração & dosagem , Sesquiterpenos/efeitos adversos
4.
AAPS PharmSciTech ; 20(7): 301, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31485857

RESUMO

Huperzine A (hup A), extracted from the Chinese medicinal plant Huperzia serrata, is a reversible and highly selective second-generation acetylcholine esterase (AchE) inhibitor for treating Alzheimer's disease (AD), but it suffers from low bioavailability in the brain. This study aimed to develop a nasal temperature and pH dual-responsive in situ gel delivery system based on microemulsion of hup A (hup A-M-TPISG). The optimal formulation was obtained by central composite design and response surface methodology. The optimized mucoadhesive formulation, hup A-M-TPISG, was composed of pluronic F127 (20.80%), pluronic F68 (2.8%), and chitosan (0.88%) as the gel matrix, which could gelatinize under physiological conditions (29-34°C, pH 6.5) because of its temperature and pH responsiveness. The optimized hup A-M-TPISG formulation was further evaluated by in vitro release and in vivo pharmacokinetic studies via microdialysis. The in vitro release study showed continuous and steady drug release from hup A-M-TPISG, which was in accordance with the first-order model. Moreover, the pharmacokinetic results revealed that the optimized formulation for nasal administration, with convenient administration and improved patient compliance, could achieve similar brain-targeting properties as intravenous administration. In conclusion, the hup A-M-TPISG for intranasal administration, as an effective and safe vehicle, could enhance the absorption of hup A in vivo and would be a promising noninvasive alternative for partially improving brain-targeting therapy.


Assuntos
Alcaloides/administração & dosagem , Inibidores da Colinesterase/administração & dosagem , Sistemas de Liberação de Medicamentos , Sesquiterpenos/administração & dosagem , Administração Intranasal , Alcaloides/química , Alcaloides/farmacocinética , Animais , Encéfalo/efeitos dos fármacos , Composição de Medicamentos , Emulsões , Géis , Concentração de Íons de Hidrogênio , Masculino , Ratos , Ratos Sprague-Dawley , Sesquiterpenos/química , Sesquiterpenos/farmacocinética , Temperatura
5.
Reprod Biol ; 19(4): 386-393, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31526669

RESUMO

In bovine, correct oocyte artificial activation is a key step in ICSI and other reproductive biotechnologies, and still needs to be improved. The current study was designed to compare the activating efficiency of ionomycin (Io) followed by: a 4 h time window and ethanol (4h-Et), roscovitine (Rosc), dehydroleucodine (DhL), cycloheximide (CHX) or PD0325901 (PD), each as a single treatment, and then combine them in novel protocols. Parthenogenetic haploid activation was evaluated in terms of pronuclear (PN) formation, second polar body (2PB) extrusion, ploidy of day 2 embryos and in vitro development. Combined treatments with Io-4h-Et-Rosc and Io-Rosc/CHX increased PN formation (92.2% and 96%, respectively) compared with Io-Rosc, Io-CHX or Io-4h-Et, which were equally efficient at inducing PN formation (82-84%) and 2PB extrusion (62.1-70.5%). Oocyte activation with Io-DhL and Io-Rosc/DhL resulted in higher 2PB extrusion rates (90% and 95.9%, respectively) but lower PN formation (49.4-58.8%) and cleavage rates (36-57.9%), as occurred with Io-CHX/DhL (76.4% and 70.4%, respectively). For the first time, results show that Io followed by the MAPK inhibitor PD induces PN formation and 2PB extrusion, but PD combined with Rosc or CHX resulted in low rates of haploid day 2 embryos. In conclusion, DhL strongly induces 2PB extrusion but leads to poor PN formation and embryo development. PD induces bovine oocyte activation but results in low rates of haploid embryos. In contrast, the improved PN formation rates after treatment with combined Io-4h-Et-Rosc and Io-Rosc/CHX suggest they should be further evaluated in ART, aiming to increase success rates in bovine.


Assuntos
Benzamidas/administração & dosagem , Difenilamina/análogos & derivados , Lactonas/administração & dosagem , Oócitos/efeitos dos fármacos , Partenogênese/efeitos dos fármacos , Técnicas de Reprodução Assistida , Sesquiterpenos/administração & dosagem , Animais , Bovinos , Difenilamina/administração & dosagem , Etanol , Feminino , Ionomicina , Fator Promotor de Maturação/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Roscovitina
6.
Life Sci ; 233: 116750, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31408659

RESUMO

AIM: Rheumatoid arthritis (RA) is the most widespread inflammatory arthropathy, which causes severe disability. It is highly important to ameliorate the side effects caused by different drugs used to treat RA. Therefore, this study assessed the potential role of ß-caryophyllene (BCP) in treating adjuvant-induced arthritis (AIA), increasing the efficacy of methotrexate (MTX) and/or leflunomide (LEF), and ameliorating their side effects. MATERIAL AND METHODS: AIA was induced in rats by injecting complete Freund's adjuvant. The rats were divided into different groups such as sham group; control group; monotherapy groups, including BCP (300 mg/kg), MTX (1 mg/kg), and LEF (10 mg/kg); and combined groups, including MTX + BCP, LEF + BCP, MTX + LEF, and MTX + LEF + BCP groups. KEY FINDINGS: Monotherapy with BCP or MTX or LEF as well as MTX + LEF significantly reduced paw thickness and arthritic index; the histopathological changes in hind paw joints were recovered; and oxidative stress and tumor necrosis factor-alpha (TNF-α) levels in arthritic rats were reduced. The co-administration of BCP and MTX and/or LEF significantly improved the therapeutic efficacy of MTX and/or LEF and significantly reduced the myelosuppressive and hepatotoxic effects of MTX and/or LEF. Taken together, BCP could be used with MTX and/or LEF for the treatment of RA to reduce the side effects of the drugs and increase their efficacy.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Artrite Experimental/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Imunossupressores/administração & dosagem , Leflunomida/administração & dosagem , Metotrexato/administração & dosagem , Sesquiterpenos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antimetabólitos Antineoplásicos/efeitos adversos , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Quimioterapia Combinada , Imunossupressores/efeitos adversos , Leflunomida/efeitos adversos , Masculino , Metotrexato/efeitos adversos , Sesquiterpenos Policíclicos , Ratos , Ratos Wistar , Sesquiterpenos/administração & dosagem
7.
Medicina (Kaunas) ; 55(8)2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31409007

RESUMO

Background and Objectives: Microtubules are an attractive target for cancer chemotherapy. Previously, we reported that Ivalin exhibited excellent anti-migration and anti-invasion activities in human breast cancer cells. Here, we examined the microtubule inhibition effect of Ivalin in human hepatocellular carcinoma SMMC-7721 cells. Materials and Methods: We used the 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assay to evaluate the cell proliferation effect of Ivalin and flow cytometry analysis to detect the apoptotic and cell cycle arrest effects of Ivalin. Immunofluorescence staining was used to measure the effect of Ivalin on the cytoskeleton network, and Western blotting was used to detect the expression levels of Bax, Bcl-2, Cdc2, phosphor-Cdc2, Cdc25A, Cyclin B1, and tubulin. Results: Ivalin induced cell cycle G2/M arrest and subsequent triggered apoptosis in human hepatocellular carcinoma SMMC-7721 cells. Furthermore, microtubules were shown to be involved in Ivalin-meditated apoptosis. In this connection, Ivalin treatment suppressed cellular microtubule network formation by regulating microtubule depolymerization. Moreover, Western blotting revealed Cdc25A and Cyclin B1 were upregulated in Ivalin-meditated cell cycle arrest. Subsequently, the induction of Bax (a proapoptotic protein) and reduction of Bcl-2 (an anti-apoptotic protein) expression were observed in Ivalin-treated SMMC-7721 cells. Conclusion: Ivalin induced microtubule depolymerization, then blocked cells in mitotic phase, and eventually resulted in apoptosis in SMMC-7721 cells. Collectively, these data indicate that Ivalin, acting as a novel inhibitor of microtubules, could be considered as a promising lead in anticancer drug development.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Pontos de Checagem da Fase G2 do Ciclo Celular , Lactonas/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Microtúbulos/efeitos dos fármacos , Sesquiterpenos/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos
8.
Nutrients ; 11(8)2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31394768

RESUMO

To investigate the effect of a hot water extract of C. longa L. (WEC) containing anti-inflammatory agents, bisacurone, and turmeronol on chronic inflammation, a randomized double-blind placebo-controlled study was conducted in middle-aged and elderly subjects aged 50-69 years with overweight or prehypertension/mild hypertension. The subjects consumed 900 mg WEC tablets, containing 400 µg bisacurone, 80 µg turmeronol A and 20 µg turmeronol B (WEC group: n = 45), or placebo tablets without WEC (placebo group: n = 45) daily for 12 weeks. Serum inflammatory and metabolic markers were measured. The subjects also completed the MOS 36-item short-form health survey (SF-36) and the Profile of Mood States scale (POMS). In the WEC group, the serum levels of C-reactive protein, tumor necrosis factor-α, interleukin-6, and soluble vascular cell adhesion molecule-1 decreased significantly. Compared with the placebo group, the WEC group had significantly lower serum levels of glucose, hemoglobin A1c, and triglycerides, as well as higher serum levels of high-density lipoprotein cholesterol. The WEC group also showed significant improvement of SF-36 scores (for general health, vitality, mental health, and mental summary component) and POMS scores for positive mood states (vigor-activity and friendliness). In conclusion, WEC may ameliorate chronic low-grade inflammation, thus contributing to the improvement of associated metabolic disorders and general health.


Assuntos
Biomarcadores/sangue , Curcuma/química , Hipertensão/sangue , Inflamação/sangue , Sobrepeso/sangue , Extratos Vegetais/farmacologia , Idoso , Cicloexanóis/administração & dosagem , Método Duplo-Cego , Humanos , Saúde Mental , Pessoa de Meia-Idade , Placebos , Pré-Hipertensão/sangue , Sesquiterpenos/administração & dosagem , Água
9.
Molecules ; 24(14)2019 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-31337024

RESUMO

Cell-penetrating peptides (CPPs) are highly promising tools to deliver therapeutic molecules into tumours. αVß3 integrins are cell-matrix adhesion receptors, and are considered as an attractive target for anticancer therapies owing to their roles in the process of metastasis and angiogenesis. Therefore, this study aims to assess the effect of co-administration of zerumbone (ZER) and ZERencapsulated in hydroxypropyl-ß-cyclodextrin with TP5-iRGD peptide towards cell cytotoxicity, apoptosis induction, and proliferation of normal and cancerous breast cells utilizing in vitro assays, as well as to study the molecular docking of ZER in complex with TP5-iRGD peptide. Cell viability assay findings indicated that ZER and ZERencapsulated in hydroxypropyl-ß-cyclodextrin (ZER-HPßCD) inhibited the growth of estrogen receptor positivebreast cancer cells (ER+ MCF-7) at 72 h treatment with an inhibitory concentration (IC)50 of 7.51 ± 0.2 and 5.08 ± 0.2 µg/mL, respectively, and inhibited the growth of triple negative breast cancer cells (MDA-MB-231) with an IC50 of 14.96 ± 1.52 µg/mL and 12.18 ± 0.7 µg/mL, respectively. On the other hand, TP5-iRGD peptide showed no significant cytotoxicity on both cancer and normal cells. Interestingly, co-administration of TP5-iRGD peptide in MCF-7 cells reduced the IC50 of ZER from 7.51 ± 0.2 µg/mL to 3.13 ± 0.7 µg/mL and reduced the IC50 of ZER-HPßCD from 5.08 ± 0.2 µg/mL to 0.49 ± 0.004 µg/mL, indicating that the co-administration enhances the potency and increases the efficacy of ZER and ZER-HPßCD compounds. Acridine orange (AO)/propidium iodide (PI) staining under fluorescence microscopy showed evidence of early apoptosis after 72 h from the co-administration of ZER or ZER-HPßCD with TP5-iRGD peptide in MCF-7 breast cancer cells. The findings of the computational modelling experiment provide novel insights into the ZER interaction with integrin αvß3 in the presence of TP5-iRGD, and this could explain why ZER has better antitumor activities when co-administered with TP5-iRGD peptide.


Assuntos
Apoptose/efeitos dos fármacos , Integrina alfaVbeta3/antagonistas & inibidores , Integrina alfaVbeta3/metabolismo , Oligopeptídeos/farmacologia , Sesquiterpenos/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Integrina alfaVbeta3/química , Modelos Moleculares , Conformação Molecular , Oligopeptídeos/administração & dosagem , Oligopeptídeos/química , Sesquiterpenos/administração & dosagem , Sesquiterpenos/química
10.
BMC Complement Altern Med ; 19(1): 151, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31242894

RESUMO

BACKGROUND: Costunolide, a sesquiterpene lactone extracted from Radix Aucklandiae, has the activity against multiple cancers. However, the effect of costunolide on gastric cancer (GC) have remained to be ambiguous. In this study, we investigated the underlying mechanisms of apoptosis induced by costunolide in human gastric adenocarcinoma BGC-823 cells in vitro and in vivo. METHODS: The viability of BGC-823 cells was detected by MTT assay. The apoptosis and mitochondrial membrane potential (ΔΨm) of BGC-823 cells induced by costunolide were analyzed by flow cytometry. The inhibiton of costunolide on human gastric adenocarcinoma was estimated in xenografts in nude mice. Apoptosis related proteins and genes were detected by Western blot and Q-PCR. RESULTS: Costunolide inhibited the viability of BGC-823 cells in a time and concentration dependent manner. Costunolide induced the apoptosis and lowered the ΔΨm of BGC-823 cells significantly. Costunolide increased the expression of Bax, cleaved caspase 9, cleaved caspase 7, cleaved caspase 3 and cleaved poly ADP ribose polymerase (PARP) proteins and decreased the expression of Bcl-2, pro-caspase 9, pro-caspase 7, pro-caspase 3 and PARP proteins. Costunolide upregulated the expression of puma, Bak1 and Bax mRNA and downregulated the expression of Bcl-2 mRNA. In addition, we demonstrated that costunolide inhibited the growth and induced apoptosis of BGC-823 cells xenografted in athymic nude mice. Costunolide increased the expression of cleaved caspase 9, cleaved caspase 3 and Bax proteins and decreased the expression of Bcl-2 protein in xenografted tumor. Costunolide upregulated the expression of puma and Bax mRNA and decreased the expression of Bcl-2 mRNA in xenografted tumor. CONCLUSIONS: Collectively, our results suggested that costunolide induced mitochondria-mediated apoptosis in human gastric adenocarcinoma BGC-823 cells and could be the candidate drug against GC in clinical practice.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/administração & dosagem , Apoptose/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Sesquiterpenos/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/fisiopatologia , Animais , Caspases/genética , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/fisiopatologia
11.
Pharm Res ; 36(8): 121, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31214786

RESUMO

PURPOSE: ß-elemene and cisplatin combined chemotherapy currently is one of the most important settings available for lung cancer therapy in China. However, the clinical outcome is limited by their pharmacokinetic drawbacks. On the other hand, most of nanomedicines have failed in clinical development due to the huge differences between heterogeneous clinical tumor tissues and homogenous cell-derived xenografts. In this work, we fabricated a ß-elemene and cisplatin co-loaded liposomal system to effectively treat lung cancer. METHOD: In vitro cytotoxicity of co-loaded liposomes was studied by MTT, trypan and Hoechst/PI staining, and western blot in A549, A549/DDP, and LCC cells. In vivo antitumor efficacy was evaluated in cell-derived and clinically relevant patient-derived xenografts. RESULTS: Co-loaded liposomes were more cytotoxic to cancer cells, especially than the combination of single-loaded liposomes, benefiting from their simultaneous drug internalization and release. As a result, they exhibited desirable therapeutic outcome in both cell-derived and patient-derived xenografts. CONCLUSION: ß-elemene and cisplatin co-loaded liposomes are a clinically promising candidate for effective lung cancer therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cisplatino/farmacocinética , Lipossomos/química , Neoplasias Pulmonares/tratamento farmacológico , Sesquiterpenos/farmacocinética , Células A549 , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Sobrevivência Celular/efeitos dos fármacos , Colesterol/química , Cisplatino/administração & dosagem , Composição de Medicamentos , Liberação Controlada de Fármacos , Xenoenxertos , Humanos , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Fosfatidilcolinas/química , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Sesquiterpenos/administração & dosagem , Distribuição Tecidual
12.
BMC Complement Altern Med ; 19(1): 133, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31215421

RESUMO

BACKGROUND: Elemene is an effective anticancer component extracted from Zingiberaceae plants. This work was aimed to evaluate the anti-tumor effect and mechanism actions of elemene on pancreatic carcinoma in vitro and in vivo. METHODS: The anti-proliferation experiment was measured by Methylthiazolyldiphenyl-tetrazolium bromide (MTT) method in the time of 24, 48 and 72 h in three different dosages. The cell cycle was detected by flow cytometer after 12 h treatment. Forty-eight nude mice were subcutaneously xenograft with BxPC-3 pancreatic cancer cells and divided into four groups: Control group and high, medium, low dosage of elemene (20, 40 and 60 mg/kg) treatment groups. Immunoblot and immunohistochemical methods were applied to detect the protein expression of P53 and Bcl-2 in the tumor of pancreatic cancer xenografts. H & E staining was used to detect the histopathological changes in each group. RESULTS: A significant inhibition effect was observed in the anti-proliferation of BxPC-3 and Panc-1 cells in vitro in the time course of 24, 48 and 72 h with a dose dependent manner. The cell cycle results showed that elemene could arrest pancreatic cancer cells in the S phase after 12 h treatment in BxPC-3 and Panc-1 cell line. The in vivo BxPC-3 xenografts study exhibited that elemene was significantly decreased the tumor size in the high dosage group, compared to control group. And there is no any significant change in body weight of all animals. H&E pathology section result showed that treatment with elemene significantly decreased the inflammation cells and reduced the histopathological changes with a dose-dependent manner. Meanwhile, treatment with elemene significantly up-regulates the protein expression of P53, while down-regulate the protein expression of Bcl-2 in the tumor tissues, respectively. Furthermore, the western blot result showed that treatment with elemene increased the expression of P53 and decreased the expression of Bcl-2, compared with the control group, which is similar to the results of immunohistochemical staining. CONCLUSIONS: This study suggests that elemene has a potential anti pancreatic cancer effect, down-regulation the protein expression of Bcl-2 and up-regulation the protein expression of P53 in a dose dependent manner may be is the anti-tumor mechanism.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Sesquiterpenos/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/fisiopatologia , Proteína Supressora de Tumor p53 , Ensaios Antitumorais Modelo de Xenoenxerto , Zingiberaceae/química
13.
J Sci Food Agric ; 99(13): 5870-5880, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31206687

RESUMO

BACKGROUND: Sepsis is a set of serious organic manifestations caused by an infection, whose progression culminates in exacerbated inflammation and oxidative stress, poor prognosis, and high hospital costs. Antioxidants used against sepsis have been evaluated, including essential oils such as ß-caryophyllene (BCP), and polyunsaturated fatty acids, such as docosahexaenoic acid (DHA). The aim of this study was to evaluate the anti-inflammatory activity of the association of these two compounds. RESULTS: Treatment with BCP-DHA, at a dose of 200 µL/animal, significantly inhibited the migration of neutrophils in a Cg-induced peritonitis model. After Staphylococcus aureus infection, in the groups treated with BCP-DHA there was a significant decrease in the total and differential count of leukocytes, increased expression of cytokines TNF-α and IFN-γ in treated groups, an increase of IL-4 and IL-5 in B/D and B/D + SA groups, and an augmentation of IL-6 and IL-12 groups in B/D + SA groups. Histological and bacterial analysis revealed lower neutrophil migration and lower bacterial load in the infected and treated groups. CONCLUSION: In general, the BCP-DHA association presented anti-inflammatory activity against two different models of acute inflammation and infection, showing promising potential as a therapeutic adjuvant in sepsis. © 2019 Society of Chemical Industry.


Assuntos
Anti-Inflamatórios/administração & dosagem , Ácidos Docosa-Hexaenoicos/administração & dosagem , Peritonite/tratamento farmacológico , Sepse/tratamento farmacológico , Sesquiterpenos/administração & dosagem , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Animais , Citocinas/genética , Citocinas/imunologia , Modelos Animais de Doenças , Quimioterapia Combinada , Humanos , Interleucina-12/genética , Interleucina-12/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Peritonite/genética , Peritonite/imunologia , Peritonite/microbiologia , Sesquiterpenos Policíclicos , Sepse/genética , Sepse/imunologia , Sepse/microbiologia , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/fisiologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
14.
Drug Des Devel Ther ; 13: 1087-1098, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118562

RESUMO

Purpose: Co-delivery of drugs to achieve the synergistic anticancer effect is a promising strategy for lung cancer therapy. The purpose of this research is to develop a doxorubicin (DOX) and ß-elemene (ELE) co-loaded, pH-sensitive nanostructured lipid carriers (DOX/ELE Hyd NLCs). Methods: In this study, DOX/ELE Hyd NLCs were produced by a hot homogenization and ultrasonication method and used for lung cancer treatment. In vitro and in vivo efficiency as well as toxicity of the system was evaluated on lung cancer cell lines and lung tumor-bearing mice. Results: DOX/ELE Hyd NLCs had a particle size of 190 nm, with a PDI lower than 0.2. DOX/ELE Hyd NLCs exhibited a significantly enhanced cytotoxicity (drug concentration causing 50% inhibition was 7.86 µg/mL), synergy antitumor effect (combination index lower than 1), and profound tumor inhibition ability (tumor inhibition ratio of 82.9%) compared with the non pH-responsive NLCs and single-drug-loaded NLCs. Conclusion: Since the synergistic effect of the drugs was found in this system, it would have great potential to inhibit lung tumor cells and tumor growth.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Lipídeos/química , Neoplasias Pulmonares/tratamento farmacológico , Nanoestruturas/química , Sesquiterpenos/uso terapêutico , Células A549 , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Quimioterapia Combinada , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Sesquiterpenos/administração & dosagem , Sesquiterpenos/farmacocinética , Distribuição Tecidual
15.
Molecules ; 24(10)2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31121820

RESUMO

The natural compound Zerumbone (hereinafter referred to as ZER), a monocyclic sesquiterpenoid, has been reported to possess many pharmacological properties, including antioxidant and anti-inflammatory properties. This study aimed to investigate the underlying mechanism of ZER against acute liver injury (ALI) in CCl4-induced mice models. ICR mice were pretreated intraperitoneally with ZER for five days, then received a CCl4 injection two hours after the last ZER administration and were sacrificed 24 h later. Examination of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and the histopathological analysis confirmed the hepatoprotective effect of ZER. Biochemical assays revealed that ZER pretreatment recovered the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), restored the glutathione (GSH) reservoir, and reduced the production of malondialdehyde (MDA), all in a dose-dependent manner. Furthermore, administration of ZER in vivo reduced the release amounts of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) and inhibited the increased protein levels of Toll-like receptor 4 (TLR4), nuclear factor-kappaB (NF-κB) p-p65, and cyclooxygenase (COX-2). Further studies in lipopolysaccharide (LPS)-induced Raw264.7 inflammatory cellular models verified that ZER could inhibit inflammation via inactivating the TLR4/NF-κB/COX-2 pathway. Thus, our study indicated that ZER exhibited a hepatoprotective effect against ALI through its antioxidant and anti-inflammatory activities and the possible mechanism might be mediated by the TLR4/NF-κB/COX-2 pathway. Collectively, our studies indicate ZER could be a potential candidate for chemical liver injury treatment.


Assuntos
Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Tetracloreto de Carbono/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Sesquiterpenos/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Injeções Intraperitoneais , Lipopolissacarídeos/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células RAW 264.7 , Sesquiterpenos/farmacologia , Receptor 4 Toll-Like/metabolismo
16.
Molecules ; 24(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052317

RESUMO

Paclitaxel is highly effective at killing many malignant tumors; however, the development of drug resistance is common in clinical applications. The issue of overcoming paclitaxel resistance is a difficult challenge at present. In this study, we developed nano drugs to treat paclitaxel-resistant lung adenocarcinoma. We selected cabazitaxel and ß-elemene, which have fewer issues with drug resistance, and successfully prepared cabazitaxel liposome, ß-elemene liposome and cabazitaxel-ß-elemene complex liposome with good flexibility. The encapsulation efficiencies of cabazitaxel and ß-elemene in these liposomes were detected by precipitation microfiltration and microfiltration centrifugation methods, respectively. Their encapsulation efficiencies were all above 95%. The release rates were detected by a dialysis method. The release profiles of cabazitaxel and ß-elemene in these liposomes conformed to the Weibull equation. The release of cabazitaxel and ß-elemene in the complex liposome were almost synchronous. The pharmacodynamics study showed that cabazitaxel flexible liposome and ß-elemene flexible liposome were relatively good at overcoming paclitaxel resistance on paclitaxel-resistant lung adenocarcinoma. As the flexible complex liposome, the dosage of cabazitaxel could be reduced to 25% that of the cabazitaxel injection while retaining a similar therapeutic effect. It showed that ß-elemene can replace some of the cabazitaxel, allowing the dosage of cabazitaxel to be reduced, thereby reducing the drug toxicity.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Lipossomos , Sesquiterpenos/administração & dosagem , Sesquiterpenos/farmacocinética , Taxoides/administração & dosagem , Taxoides/farmacocinética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Lipossomos/química , Camundongos , Estrutura Molecular , Paclitaxel/farmacologia , Tamanho da Partícula , Sesquiterpenos/química , Taxoides/química , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Phytother Res ; 33(6): 1683-1688, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30937974

RESUMO

Costunolide, a sesquiterpene lactone, a small molecular monomer extracted from Inula helenium, has been reported to possess antiproliferative effects on several cancer cell lines. The current study was designed to evaluate the effect of costunolide on sensitivity of K562/ADR chronic myeloid leukemia cells to doxorubicin. The antiproliferative effect of costunolide was assessed by CCK-8 assay. Flow cytometry and Western blot were used to examine the mechanisms of antileukemia action. Costunolide dramatically enhanced doxorubicin-induced antiproliferative activity against K562/ADR cells through inhibition of PI3K/Akt pathway, activation of caspases 3, cleavage of poly (ADP-ribose) polymerase, and downregulation of p-glycoprotein expression. These results demonstrate that costunolide may be a potent therapeutic agent against CML.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Sesquiterpenos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Sinergismo Farmacológico , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sesquiterpenos/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas
18.
Food Funct ; 10(5): 2651-2657, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31025676

RESUMO

Recurrent cardiotoxicity limits the clinical application of doxorubicin (DOX); however the detailed molecular mechanism of DOX cardiotoxicity remains unclear. In the current study, we found that a natural product extracted from Illicium verum, isodunnianol (IDN), mitigates DOX-induced cardiotoxicity by regulating autophagy and apoptosis both in vitro and in vivo. DOX suppressed protective autophagy and induced apoptosis in H9C2 cardiac myoblasts. Additionally, IDN demonstrated up-regulated autophagy and reduced apoptosis through the activation of the AMPK-ULK1 pathway. In addition, the beneficial effects of IDN on DOX which induced myocardial injury were dependent on AMPK and ULK1 phosphorylation. Similar results were also observed in a DOX-induced cardiotoxicity rat model. The combination of IDN and DOX resulted in decreased apoptosis and inflammatory myocardial fibrosis compared to the DOX mono-treatment group. In summary, our findings provide novel insights into the prevention of DOX-related toxicity by isodunnianol, a food source natural product, warranting further investigation.


Assuntos
Antineoplásicos/efeitos adversos , Autofagia/efeitos dos fármacos , Cardiotoxicidade/tratamento farmacológico , Doxorrubicina/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Illicium/química , Sesquiterpenos/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/fisiopatologia , Humanos , Masculino , Mioblastos Cardíacos/citologia , Mioblastos Cardíacos/efeitos dos fármacos , Mioblastos Cardíacos/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Ratos , Ratos Sprague-Dawley
19.
Phytomedicine ; 59: 152787, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31005810

RESUMO

BACKGROUND: Elemene injection is an anticancer Chinese patent medicine that is widely used for the treatment of advanced lung cancer. Its active ingredients are ß-, γ- and δ-elemene, which are extracted from Curcumaaromatica Salisb. (Curcumawenyujin Y.H. Chen & C. Ling). PURPOSE: To evaluate the effects of Elemene injection as adjunctive treatment to platinum-based chemotherapy (PBC) in patients with stage III/IV non-small cell lung cancer. STUDY DESIGN: A systematic review and meta-analysis of randomized clinical trials (RCTs). MATERIALS AND METHODS: A systematic review and meta-analysis were conducted following the PRISMA (Preferred Reported Items for Systematic Review and Meta-analysis) guidelines. Analyses were performed using Review Manager 5.3, Comprehensive Meta-Analysis 3.0 and Trial Sequential Analysis software. All RCTs comparing Elemene injection combined with PBC vs. PBC alone were selected and assessed for inclusion. The disease control rate (DCR) was defined as the primary endpoint, and the objective Response rate (ORR), survival rate, quality of life (QOL), cellular immune function and toxicities were the secondary outcomes. RESULTS: 15 RCTs recruiting 1,410 patients with stage III/IV NSCLC were included. The methodological quality of most included trials was low to moderate. Compared with PBC alone, Elemene injection plus PBC can improve DCR (RR = 1.23, 95% CI 1.16 to 1.31, p < 0.00001), ORR (RR = 1.62, 95% CI 1.44 to 1.82, p < 0.00001), 1- and 2-year survival rates (RR = 1.33, 95% CI 1.11 to 1.59, p = 0.002; RR = 1.73, 95% CI 1.21 to 2.46, p = 0.002, respectively), QOL (RR = 1.91, 95% CI 1.58 to 2.32, p < 0.00001), CD4+T cell counts (WMD = 10.43, 95% CI 8.25 to 12.62, p < 0.00001), and the CD4+/CD8+ratio (WMD = 0.78, 95% CI 0.42 to 1.14, p < 0.0001) and can reduce severe toxicities by 58% (RR = 0.42, 95% CI 0.34 to 0.52, p < 0.00001). CONCLUSION: Elemene injection is a safe and effective adjunctive treatment to platinum-based chemotherapy in patients with stage III/IV NSCLC. Elemene injection can improve clinical efficacy, enhance cellular immune function and alleviate the toxicity of chemotherapy. High-quality RCTs with significant survival outcomes and longer follow-ups are warranted to confirm the results further.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Injeções , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Compostos de Platina/administração & dosagem , Compostos de Platina/uso terapêutico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Sesquiterpenos/administração & dosagem , Taxa de Sobrevida , Resultado do Tratamento
20.
Phytother Res ; 33(6): 1736-1747, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31006910

RESUMO

Glioblastoma multiforme (GBM) is a highly aggressive type of brain tumour. Patients with GBM respond poorly to chemotherapy and have poor survival outcomes. Neuron-glial antigen 2 (NG2), also known as chondroitin sulphate proteoglycan 4 (CSPG4), has been shown to contribute to critical processes, such as cell survival, proliferation, and chemotherapy resistance, during glioma progression. In this study, we found that furanodienone (FUR), a diene-type sesquiterpene isolated from the rhizomes of Rhizoma curcumae, exhibited a potential cytotoxic effect on temozolomide (TMZ)-resistant GBM cells in vitro by inhibiting CSPG4 and related signalling pathways. Studies investigating the mechanism demonstrated that FUR suppressed CSPG4-Akt-ERK signalling, inflammatory responses, and cytokine levels but activated caspase-dependent pathways and mitochondrial dysfunction. Furthermore, an immunofluorescence assay and a dual-luciferase reporter assay revealed that inhibition of EGR1-mediated transcription might have contributed to the FUR-dependent blockade of CSPG4 signalling and glioma cell survival. These results established a link between FUR-induced CSPG4 inhibition and the suppression of EGR1-dependent transcription. Attenuation of ERK1/2 and cytokine signalling might have generated the EGR1-dependent negative feedback loop of the CSPG4 pathway during FUR-induced apoptosis. These findings suggested that FUR could be a therapeutic candidate for the treatment of malignant glioma via targeting CSPG4 signalling.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína 1 de Resposta de Crescimento Precoce/fisiologia , Furanos/farmacologia , Glioblastoma/tratamento farmacológico , Sesquiterpenos/farmacologia , Temozolomida/uso terapêutico , Adulto , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Proteoglicanas de Sulfatos de Condroitina/genética , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Furanos/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sesquiterpenos/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Temozolomida/administração & dosagem , Transcrição Genética/efeitos dos fármacos
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