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1.
J Chin Med Assoc ; 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34610623

RESUMO

BACKGROUND: Cisplatin-based chemotherapy (CBC) is highly efficacious for advanced cervical cancer; its efficacy can be enhanced by combining with 15 mg/kg (standard dose) bevacizumab (BEV). However, this standard dose is associated with various adverse events. Therefore, in this retrospective study, we analyzed the survival outcomes and adverse events in patients with advanced or recurrent cervical cancer treated with CBC in combination with BEV 7.5 mg/kg. METHODS: Registered patient data were retrieved between October 2014 and September 2019, and 64 patients with advanced or recurrent cervical cancer treated with CBC+BEV (n=21) or CBC alone (n=43) were analyzed. The primary endpoints were progression-free survival (PFS) and overall survival (OS); the secondary endpoints were the frequency and severity of adverse events (AEs). The Cox proportional-hazards model was applied to explore prognostic factors associated with PFS and OS. RESULTS: The 1-, 2-, and 3-year PFS rates (95% confidence interval (CI)) were 36.24% (22.0-50.5), 20.7% (9.8-34.2), and 17.7% (7.7-31.1) for the CBC group; and 71.4% (47.1-86.0), 51.0% (27.9-70.1), and 51.0% (27.9-70.1) for the CBC+BEV group, respectively. The 1-, 2-, and 3-year OS rates were 62.6% (46.4-75.18), 32.4% (18.8-46.9), and 23.2% (11.2-37.6) for the CBC group; and 85.7% (61.9-95.1), 66.6% (42.5-82.5), and 55.5% (27.1-76.7) for the CBC+BEV group, respectively. The CBC+BEV group presented higher PFS and OS rates, p=0.003 and p=0.005, respectively. Proteinuria (6 vs. 9, p=0.025) and hypertension (0 vs. 10, p<0.001) were less common, but anemia was more common in the CBC group (35 vs. 11, p=0.021). CONCLUSION: Overall, CBC+BEV significantly improved the PFS and OS compared with CBC alone. CBC+BEV also prevents severe adverse events and hence is an efficacious and safe therapeutic option.

3.
Taiwan J Obstet Gynecol ; 58(2): 302-303, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30910161
5.
Eur J Pharmacol ; 812: 113-120, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28694068

RESUMO

Con A-induced hepatitis in mice is an established model of autoimmune hepatitis (AIH). JKB-122, a toll-like receptor 4 (TLR4) antagonist, was tested for hepatotprotectant activity. Within several hours of Con A challenge (15mg/kg iv), increased production of proinflammatory cytokines with inflammatory infiltrate occurred in the liver. The severity of tissue necrosis and the amount of circulating liver enzymes peak at 24h post Con A challenge. JKB-122 was given 24 and 16h before, then concurrently, and 4 and 8h (× 5 doses) after challenge with Con A. Serum and liver were harvested at 3, 9 and 24h post Con A challenge. JKB-122 at 20 and 50mg/kg po prevented the increase of serum liver enzymes by 47% and 95% respectively vs vehicle control 24h post Con A. JKB-122 significantly inhibited Con A-induced pathological lesions in the liver and the amount of IFN-γ IL-1ß, IL-4, IL-5, IL-6, IL-17A and TNF-α starting as early as 3h post Con A. Moreover, JKB-122 given concurrently (× 3 doses) with Con A showed similar effect. Finally, JKB-122 enhanced the therapeutic effects of submaximal dose of prednisolone with improved lesion score. It is concluded that JKB-122 at 20 and 50mg/kg po caused dose-dependent inhibition of elevated liver enzymes in Con A-induced hepatitis in mice, indicating hepatoprotectant activity. The results suggest that JKB-122 as monotherapy or in combination with prednisolone may offer a viable approach to the treatment of AIH.


Assuntos
Concanavalina A/efeitos adversos , Hepatite/tratamento farmacológico , Hepatite/etiologia , Compostos Orgânicos/farmacologia , Prednisolona/farmacologia , Animais , Citocinas/metabolismo , Citoproteção/efeitos dos fármacos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Hepatite/metabolismo , Hepatite/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Compostos Orgânicos/uso terapêutico , Receptor 4 Toll-Like/antagonistas & inibidores
6.
Oncol Rep ; 35(3): 1356-64, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26707189

RESUMO

Development of an efficient treatment for triple-negative breast cancer is an urgent issues. Compounds from plant extracts are a potential source of novel cancer treatment. Isolinderalactone, a kind of sesquiterpenoids compound, was purified from the root of Lindera strychnifolia and Neolitsea daibuensis and shows anti-inflammatory and anticancer capacity. In the present study, isolinderalactone induced apoptosis in MDA-MB-231 cells which is a kind of triple-negative breast cancer cell line through induction of an intrinsic mitochondria-mediated and caspase-independent cell death. Treatment of isolinderalactone increased the protein level of the suppressor of cytokine signaling 3 (SCOS3), decreased phosphorylation of the signal transducer and activator of transcription 3 (STAT3), and suppressed expression of the down-stream genes of the X-linked inhibitor of apoptosis protein in MDA-MB-231 cells. Our results further showed that the level of SOCS3 expression was induced by isolinderalactone due to inhibiting the microRNA hsa-miR-30c-5p (miR-30c) expression. In addition, intraperitoneal injection of isolinderalactone induced apoptosis in a xenograft breast tumor while it did not significantly affect the histology of liver, kidney and lung of the treated mice. In conclusion, isolinderalactone induces apoptosis in MDA-MB­231 cells and suppresses STAT3 signaling pathway through regulation of SOCS3 and miR-30c. It may become a novel treatment for triple-negative breast cancer in the future.


Assuntos
MicroRNAs/genética , Fator de Transcrição STAT3/biossíntese , Sesquiterpenos/administração & dosagem , Proteínas Supressoras da Sinalização de Citocina/biossíntese , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/biossíntese , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lindera/química , Camundongos , MicroRNAs/biossíntese , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Proteomics ; 15(19): 3338-48, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26205848

RESUMO

The precipitation of monosodium urate crystals within joints triggers an acute inflammatory reaction that is the root cause of gout. The inflammation induced by the injection of MSU crystals into the murine air pouch for 1, 3, and 5 h was examined by iTRAQ-based proteomic profiling. The iTRAQ-labeled peptides were fractionated by SCX, basic-RP or solution-IEF, followed by LC-MS/MS analysis. A total of 951 proteins were quantified from the total combined fractions. Among them, 317 proteins exhibited a differential expression, compared to that of the controls at one time point or more. The majority of the differentially expressed proteins were found in the sample after a 5-h MSU treatment. Western blot revealed that the expression levels of cathelin-related antimicrobial peptide and S100A9 were positively correlated with the time-course treated with MSU. Further analysis of GeneGO pathway demonstrated that these differentially expressed proteins are primarily related to the immune-related complement system and the tricarboxylic acid cycle. Moreover, seven genes from the TCA cycle were found to be significantly downregulated at the transcriptional level and its correlation with gout and possible therapeutic applications are worth further investigation. Last, we found that pyruvate carboxylation could be potential targets for antigout treatment.


Assuntos
Sacos Aéreos/efeitos dos fármacos , Regulação da Expressão Gênica , Inflamação/induzido quimicamente , Proteínas/genética , Proteômica , Ácido Úrico/toxicidade , Sacos Aéreos/metabolismo , Animais , Cromatografia Líquida , Inflamação/metabolismo , Masculino , Camundongos , Espectrometria de Massas em Tandem , Ácido Úrico/farmacologia
8.
Chin Med ; 7(1): 19, 2012 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-22920833

RESUMO

BACKGROUND: α-Mangostin (α-MG) is a main constituent of the fruit hull of the mangosteen. Previous studies have shown that α-MG has pharmacological activities such as antioxidant, antitumor, anti-inflammatory, antiallergic, antibacterial, antifungal and antiviral effects. This study aims to investigate the anti-inflammatory molecular action of α-MG on gene expression profiles. METHODS: U937 and EL4 cells were treated with different concentrations of α-MG in the presence of 0.1 ng/mL lipopolysaccharide (LPS) for 4 h. The anti-inflammatory effects of α-MG were measured by the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-4 in cell culture media, which were determined with enzyme-linked immunosorbent assay kits. The gene expression profiles of all samples were analyzed with a whole human genome microarray, Illumina BeadChip WG-6 version 3, containing 48804 probes. The protein levels were determined by Western blotting analyses. RESULTS: α-MG decreased the LPS induction of the inflammatory cytokines TNF-α (P = 0.038) and IL-4 (P = 0.04). α-MG decreased the gene expressions in oncostatin M signaling via mitogen-activated protein kinase (MAPK) pathways, including extracellular signal-regulated kinases (P = 0.016), c-Jun N-terminal kinase (P = 0.01) , and p38 (P = 0.008). α-MG treatment of U937 cells reduced the phosphorylation of MAPK kinase 3 / MAPK kinase 6 (P = 0.0441), MAPK-activated protein kinase-2 (P = 0.0453), signal transducers and activators of transcription-1 (STAT1) (P = 0.0012), c-Fos (P = 0.04), c-Jun (P = 0.019) and Ets-like molecule 1 (Elk-1) (P = 0.038). CONCLUSION: This study demonstrates that α-MG attenuates LPS-mediated activation of MAPK, STAT1, c-Fos, c-Jun and EIK-1, inhibiting TNF-α and IL-4 production in U937 cells.

9.
Bioorg Med Chem Lett ; 20(20): 6129-32, 2010 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-20833039

RESUMO

A series of azulene-based derivatives were synthesized as potent inhibitors for receptor tyrosine kinases such as FMS-like tyrosine kinase 3 (FLT-3). Systematic side chain modification of prototype 1a was carried out through SAR studies. Analogue 22 was identified from this series and found to be one of the most potent FLT-3 inhibitors, with good pharmaceutical properties, superior efficacy, and tolerability in a tumor xenograft model.


Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Azulenos/química , Azulenos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacologia , Azulenos/sangue , Azulenos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ratos , Receptores Proteína Tirosina Quinases/metabolismo , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores
10.
Bioorg Med Chem ; 18(13): 4674-86, 2010 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-20570526

RESUMO

A series of new ureidoindolin-2-one derivatives were synthesized and evaluated as inhibitors of receptor tyrosine kinases. Investigation of structure-activity relationships at positions 5, 6, and 7 of the oxindole skeleton led to the identification of 6-ureido-substituted 3-pyrrolemethylidene-2-oxindole derivatives that potently inhibited both the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) families of receptor tyrosine kinases. Several derivatives showed potency against the PDGFR inhibiting both its enzymatic and cellular functions in the single-digit nanomolar range. Among them, compound 35 was a potent inhibitor against tyrosine kinases, including VEGFR and PDGFR families, as well as Aurora kinases. Inhibitor 36 (non-substituted on the pyrrole or phenyl ring) had a moderate pharmacokinetic profile and completely inhibited tumor growth initiated with the myeloid leukemia cell line, MV4-11, in a subcutaneous xenograft model in BALB/c nude mice.


Assuntos
Receptores ErbB/antagonistas & inibidores , Indóis/química , Inibidores de Proteínas Quinases/síntese química , Pirróis/química , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Ureia/análogos & derivados , Animais , Aurora Quinases , Sítios de Ligação , Linhagem Celular Tumoral , Simulação por Computador , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Humanos , Indóis/uso terapêutico , Indóis/toxicidade , Leucemia Mieloide/tratamento farmacológico , Camundongos , Oxindóis , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/toxicidade , Pirróis/uso terapêutico , Pirróis/toxicidade , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Relação Estrutura-Atividade , Transplante Heterólogo , Ureia/química , Ureia/uso terapêutico , Ureia/toxicidade
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