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1.
Acta Pharmacol Sin ; 41(5): 733-734, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32060412

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

2.
Haematologica ; 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31289198

RESUMO

Aberrant expression of CDK9/cyclin T1 has been found in diffuse large B-cell lymphoma, and suggest that CDK9 seems to be a potential therapeutic target for diffuse large B-cell lymphoma. Here, we firstly demonstrated that CDKI-73, a novel CDK inhibitor, potently blocks CDK9, triggered apoptosis and dramatically repressed diffuse large B-cell lymphoma cell growth owing to CDK9 inhibition. CDK9 inhibitors specifically elevated the trimethylation of H3K27, which we speculate was due to reduced expression of JMJD3/UTX. Considering the important role of the trimethylation of H3K27 in tumor progression, the synergistic effect of the combination therapy of CDK9 inhibitors with EZH2 inhibitors was investigated. EZH2 inhibitors reversed the upregulation of trimethylation of H3K27, and synergistically inhibited diffuse large B-cell lymphoma and other solid tumors growth in vitro and in vivo. These findings provide a rational basis for the application of CDK9 inhibitors in combination with EZH2 inhibitors in clinical trials.

3.
Acta Pharmacol Sin ; 40(12): 1587-1595, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31171828

RESUMO

Deregulated Polycomb repressive complex 2 (PRC2) is intimately involved in tumorigenesis and progression, making it an invaluable target for epigenetic cancer therapy. Disrupting the EZH2-EED interaction, which is required for PRC2 enzymatic activity, is a promising strategy for cancer treatment. However, this kind of inhibitors are still limited. The in-cell protein-protein interaction screening was conducted for approximately 1300 compounds by NanoBRET technology. Co-immunoprecipitation (Co-IP), protein thermal shift assay (PTSA), and cellular thermal shift assay (CETSA) were performed to investigate the regulation of PRC2 by AZD9291. The anti-tumor effects of AZD9291 on breast cancer (BC) cells and diffuse large B-cell lymphoma (DLBCL) cells were detected. MicroRNA array assay, luciferase reporter assay, and qRT-PCR were conducted to identify the interaction and regulation among AZD9291, EZH2, and miR-34a. We discovered that, AZD9291, a potent and selective EGFR inhibitor, disrupted the interaction of EZH2-EED, leading to impairment of PRC2 activity and downregulation of EZH2 protein. In addition, AZD9291 declined EZH2 mRNA expression via upregulating the expression of a tumor suppressor, miR-34a. Our results suggest that AZD9291 can serve as a lead compound for further development of antagonist of PRC2 protein-protein interactions and EZH2 mRNA may be a direct target of miR-34a through non-canonical base pairing.

4.
Nanoscale ; 11(22): 10927-10931, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31139811

RESUMO

Due to the elusive nature of polyoxometallates (POMs) in the assembly of silver clusters, POMs trapped by silver clusters are usually different from the pristine form, which surely increases the novelty of the assembly results but makes the final structure predictability challenging. Herein, three novel high-nuclearity silver-thiolate clusters trapping two kinds of classical POMs, Lindqvist-Mo6O192- and V10O286-, are reported. They are identified to be [(V10O28)@Ag44] (SD/Ag44a), [(V10O28)@Ag46] (SD/Ag46), and [(Mo6O19)@Ag44] (SD/Ag44b) clusters, which are further extended to 1D chain, 2D sql layer, and 3D pcu framework, respectively. Of note, SD/Ag44b contains a regular cubic Mo6O19 core sealed by an Ag44(EtS)24 shell in a pseudo-sodalite unit and six SCl4 planar squares connecting the respective adjacent silver tetragonal faces. This structure is a novel zeolite closely related to the natural alumino-silicate 'sodalite' but exceptionally made of core-shell silver clusters. Moreover, the Oh symmetric Mo6O192- templates an Oh symmetric Ag44 cluster in SD/Ag44b, realizing authentic symmetry delivery from guest to host in this system. This is a rare silver cluster family with classical POMs encapsulated.

5.
Zhonghua Nan Ke Xue ; 25(1): 62-67, 2019.
Artigo em Chinês | MEDLINE | ID: mdl-32212508

RESUMO

Objective: To observe the clinical efficacy of acupoint injection of Shuxuetong (SXT) in the treatment of chronic prostatitis / chronic pelvic pain syndrome (CP/CPPS) complicated by premature ejaculation (PE). METHODS: A total of 78 cases of CP/CPPS complicated by PE were randomly assigned to receive acupuncture injection of SXT (n = 38) and placebo acupuncture as the control (n = 40) for two 15-day courses. The therapeutic effects were evaluated based on the patients' scores on National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) and Premature Ejaculation Diagnostic Tool (PEDT) before and after treatment. RESULTS: Compared with the controls, the SXT group showed a significantly higher total effectiveness rate based on either NIH-CPSI (27.5% vs 63.2%, P < 0.05) or PEDT (25% vs 47.4%, P < 0.05) and a lower deterioration rate (17.5% vs 7.9%, P < 0.05). Statistically significant differences were observed between the baselines and post-treatment scores on NIH-CPSI in the SXT group (24.82 ± 5.89 vs 15.45 ± 6.74, P < 0.05) and the controls (26.10 ± 6.59 vs 22.10 ± 8.42, P < 0.05) as well as on PEDT in the SXT group (14.87 ± 3.70 vs 10.29 ± 4.25, P < 0.05) and the controls (14.98 ± 3.09 vs 13.00 ± 4.53, P < 0.05), and both the NIH-CPSI and PEDT scores were markedly lower in the SXT than in the control group after treatment (P < 0.05). Linear regression analysis exhibited a positive correlation between the NIH-CPSI and PEDT scores before and after treatment in the SXT group (R = 0.340, P < 0.037) but not in the control group (R = 0.133, P < 0.413). CONCLUSIONS: Acupoint injection of Shuxuetong can significantly improve the symptoms of CP/CPPS and CP/CPPS-induced PE as well.


Assuntos
Pontos de Acupuntura , Dor Crônica , Medicamentos de Ervas Chinesas , Dor Pélvica , Ejaculação Precoce , Prostatite , Doença Crônica , Dor Crônica/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Humanos , Masculino , Dor Pélvica/tratamento farmacológico , Dor Pélvica/etiologia , Ejaculação Precoce/complicações , Prostatite/complicações , Prostatite/tratamento farmacológico
6.
Cancer Lett ; 433: 273-282, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30003928

RESUMO

PI3Ks are frequently hyper-activated in breast cancer and targeting PI3Kα has exhibited promising but variable response in preclinical and clinical settings. CYH33 is a novel PI3Kα-selective inhibitor in phase I clinical trial. We investigated the efficacy of CYH33 against breast cancer and explored potential predictive biomarkers. CYH33 potently restrained tumor growth in mice bearing human breast cancer cell xenografts and in R26-Pik3caH1047R;MMTV-Cre transgenic mice. CYH33 significantly inhibited proliferation of a panel of human breast cancer cells, while diversity in sensitivity has been observed. Cells harboring activating PIK3CA mutation, amplified HER2 were more responsive to CYH33 than their counterparts. Besides, cells in HER2-enriched or luminal subtype were more sensitive to CYH33 than basal-like breast cancer. Sensitivity to CYH33 has been further revealed to be associated with induction of G1 phase arrest and simultaneous inhibition of Akt and ERK. Sensitivity of patient-derived xenograft to CYH33 was also positively correlated with decrease in phosphorylated ERK. Taken together, CYH33 is a promising PI3Kα inhibitor for breast cancer treatment and decrease in ERK phosphorylation may indicate its efficacy, which provides useful clues for rational design of the ongoing clinical trials.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Morfolinas/farmacologia , Piperazinas/farmacologia , Pirróis/farmacologia , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/genética , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Camundongos , Camundongos Transgênicos , Morfolinas/uso terapêutico , Fosforilação , Piperazinas/uso terapêutico , Pirróis/uso terapêutico , Receptor ErbB-2/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
JCI Insight ; 3(3)2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29415882

RESUMO

Despite the fact that many therapeutic strategies have been adopted to delay the development of sepsis, sepsis remains one of the leading causes of death in noncoronary intensive care units. Recently, sepsis-3 was defined as life-threatening organ dysfunction due to a dysregulated host response to infection. Here, we report that swiprosin-1 (also known as EFhd2) plays an important role in the macrophage immune response to LPS-induced or cecal ligation and puncture-induced (CLP-induced) sepsis in mice. Swiprosin-1 depletion causes higher mortality, more severe organ dysfunction, restrained macrophage recruitment in the lung and kidney, and attenuated inflammatory cytokine production (including IL-1ß, IL-6, TNF-α, IL-10, and IFN-γ). The immunosuppression caused by swiprosin-1 deficiency is manifested by impaired bactericidal capacity and decreased HLA-DR expression in macrophages. Swiprosin-1 affects the activation of the JAK2/STAT1/STAT3 pathway by regulating the expression of IFN-γ receptors in macrophages. Our findings provide a potential target for the regulation of the macrophage immune response in sepsis.


Assuntos
Proteínas de Ligação ao Cálcio/deficiência , Macrófagos/imunologia , Sepse/imunologia , Transdução de Sinais/imunologia , Animais , Proteínas de Ligação ao Cálcio/genética , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Escherichia coli , Humanos , Rim/citologia , Rim/imunologia , Lipopolissacarídeos/toxicidade , Pulmão/citologia , Pulmão/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células RAW 264.7 , Sepse/microbiologia , Sepse/mortalidade
8.
Acta Pharmacol Sin ; 38(7): 1038-1047, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28414200

RESUMO

Over half of patients with BRCA1-deficient cancers do not respond to treatment with poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we report that a combination of 53BP1 and BRCA1 may serve as a biomarker of PARP inhibitor sensitivity. Based on the mRNA levels of four homologous recombination repair (HR) genes and PARP inhibitor sensitivity, we selected BRCA1-deficient MDA-MB-436 cells to conduct RNA interference. Reducing expression of 53BP1, but not the other three HR genes, was found to lower simmiparib sensitivity. Additionally, we generated 53BP1-/-/BRCA1-/- clonal variants by the transcription activator-like effector nuclease (TALEN) technique and found that depleting 53BP1 impaired PARP inhibitor sensitivity with a 36.7-fold increase in their IC50 values. Consistent with its effect on PARP inhibitor sensitivity, 53BP1 loss alleviated cell cycle arrest and apoptosis and partially restored HR function. Importantly, 53BP1 depletion dramatically reduced the ability of PARP inhibitors to suppress tumor growth in vivo. The inhibition rate of simmiparib was 74.16% for BRCA1-deficient MDA-MB-436 xenografts, but only 7.79% for 53BP1/BRCA1-deficient xenografts. Re-expressing 53BP1 in the dual-deficient cells restored PARP inhibitor sensitivity and the levels of HR regulators. Considering that at least 10% of BRCA1-deficient breast and ovarian cancers have reduced expression of 53BP1, using a combination of 53BP1 with BRCA1 as a biomarker for patient selection should reduce the number of patients undergoing futile treatment with PARP inhibitors.


Assuntos
Antineoplásicos/farmacologia , Proteína BRCA1/antagonistas & inibidores , Biomarcadores Tumorais/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/antagonistas & inibidores , Animais , Antineoplásicos/química , Proteína BRCA1/deficiência , Proteína BRCA1/metabolismo , Biomarcadores Tumorais/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/química , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Relação Estrutura-Atividade , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/deficiência , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo
9.
Theranostics ; 7(4): 974-986, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28382169

RESUMO

PI3Kα-selective inhibitor BYL719 is currently in phase II/III clinical trial for the treatment of breast cancer, but highly variable response has been observed among patients. We sought to discover predictive biomarker for the efficacy of BYL719 by dissecting the proliferative signaling pathway mediated by PI3K in breast cancer. BYL719 concurrently inhibited the phosphorylation of AKT and ERK in PIK3CA-mutated human breast cancer cells. PI3K-regulated ERK phosphorylation was independent of canonical PDK1/AKT/mTOR pathway, while it was associated with RAF/MEK. Hyper-activation of EGFR or RAS abrogated inhibition of ERK phosphorylation by BYL719. Furthermore, hyper-activation of receptor tyrosine kinases (RTKs) including EGFR, c-MET, FGFR and HER3 but not IGF-1R restored ERK phosphorylation and cell viability suppressed by BYL719, suggesting the discriminative functions of RTKs in cell signaling and proliferation. By profiling 22 breast cancer cell lines, we found that BYL719 was more potent in cell lines where phosphorylation of both AKT and ERK was attenuated than those where only AKT phosphorylation was inhibited. The potency of BYL719 was further found to be significantly correlated with the expression profile of RTKs in breast cancer cells. Specifically, overexpression of EGFR, c-MET and/or FGFR1 forecasted resistance, while overexpression of IGF-1R and/or HER2 predicted sensitivity to BYL719 in breast cancer cells. Similar correlation between BYL719 efficacy and expression profile of RTKs was found in patient-derived xenograft models of breast cancer. Thus, inhibition of ERK phosphorylation by PI3Kα inhibitor BYL719 contributes to its antitumor efficacy and is determined by the converged signaling from RTKs. The expression profile of RTKs in breast cancer tissue could be potentially developed as a predictive biomarker for the efficacy of PI3Kα inhibitors.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Resistência a Medicamentos , Proteínas Tirosina Quinases/biossíntese , Tiazóis/uso terapêutico , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Xenoenxertos , Humanos , Camundongos SCID , Tiazóis/farmacologia , Falha de Tratamento
10.
Cancer Lett ; 386: 47-56, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27847302

RESUMO

Poly(ADP-ribose)polymerase (PARP)1/2 inhibitors have been proved to be clinically effective anticancer drugs. Here we report a new PARP1/2 inhibitor, simmiparib, displaying apparently improved preclinical anticancer activities relative to the first approved inhibitor olaparib. Simmiparib inhibited PARP1/2 approximately 2-fold more potently than olaparib, with more than 90-fold selectivity over the other tested PARP family members. Simmiparib and olaparib caused similar cellular PARP1-DNA trapping. Simmiparib selectively induced the accumulation of DNA double-strand breaks, G2/M arrest and apoptosis in homologous recombination repair (HR)-deficient cells. Consistently, simmiparib showed 26- to 235-fold selectivity in its antiproliferative activity against HR-deficient cells over the corresponding isogenic HR-proficient cells. Notably, its antiproliferative activity was 43.8-fold more potent than that of olaparib in 11 HR-deficient cancer cell lines. Simmiparib also potentiated the proliferative inhibition of several conventional anticancer drugs. Simmiparib reduced the poly(ADP-ribose) formation in HR-deficient cancer cells and xenografts. When orally administered to nude mice bearing xenografts, simmiparib revealed excellent pharmacokinetic properties. Simmiparib caused approximately 10-fold greater growth inhibition than olaparib against HR-deficient human cancer cell- or tissue-derived xenografts in nude mice. Collectively, these findings support the undergoing clinical trials of simmiparib.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Ftalazinas/farmacologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios Clínicos como Assunto , Cricetinae , Quebras de DNA de Cadeia Dupla , Relação Dose-Resposta a Droga , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Genes BRCA1 , Genes BRCA2 , Humanos , Camundongos Nus , Ftalazinas/administração & dosagem , Ftalazinas/farmacocinética , Piperazinas/farmacologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Oncotarget ; 8(3): 4156-4168, 2017 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-27926532

RESUMO

The approval of poly(ADP-ribose) polymerase (PARP) inhibitor AZD2281 in 2014 marked the successful establishment of the therapeutic strategy targeting homologous recombination repair defects of cancers in the clinic. However, AZD2281 has poor water solubility, low tissue distribution and relatively weak in vivo anticancer activity, which appears to become limiting factors for its clinical use. In this study, we found that mefuparib hydrochloride (MPH) was a potent PARP inhibitor, possessing prominent in vitro and in vivo anticancer activity. Notably, MPH displayed high water solubility (> 35 mg/ml) and potent PARP1/2 inhibition in a substrate-competitive manner. It reduced poly(ADP-ribose) (PAR) formation, enhanced γH2AX levels, induced G2/M arrest and subsequent apoptosis in homologous recombination repair (HR)-deficient cells. Proof-of-concept studies confirmed the MPH-caused synthetic lethality. MPH showed potent in vitro and in vivo proliferation and growth inhibition against HR-deficient cancer cells and synergistic sensitization of HR-proficient xenografts to the anticancer drug temozolomide. A good relationship between the anticancer activity and the PARP inhibition of MPH suggested that PAR formation and γH2AX accumulation could serve as its pharmacodynamic biomarkers. Its high bioavailability (40%~100%) and high tissue distribution in both monkeys and rats were its most important pharmacokinetic features. Its average concentrations were 33-fold higher in the tissues than in the plasma in rats. Our work supports the further clinical development of MPH as a novel PARP1/2 inhibitor for cancer therapy.


Assuntos
Antineoplásicos/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Neoplasias/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Sinergismo Farmacológico , Haplorrinos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Humanos , Camundongos , Neoplasias/enzimologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Ratos , Temozolomida , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Exp Ther Med ; 12(4): 2681-2687, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27698772

RESUMO

Traditional Chinese medicine (TCM) is important in the provision of anti-tumor drugs. Recently, studies have shown that certain types of TCM agents are able to control the growth of tumors, enhance the body's immune function and enhance the therapeutic effect of chemotherapeutic drugs. In women, breast carcinoma is the most common tumor type and the second most common cause of death from cancer. Polygonatum odoratum (P. odoratum) is commonly used in TCM. The aim of the present study was to investigate the effects of P. odoratum extract on the proliferation and apoptosis of MDA-MB-231 breast cancer cells. Cell proliferation was assessed using MTT and colony formation assays. In addition, propidium iodide (PI)/Annexin V-FITC staining was used to investigate the apoptosis of MDA-MB-231 cells following treatment with P. odoratum extract. The protein expression levels of B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax) were also detected using western blot analysis, while a JC-1 staining assay was used to assess the mitochondrial membrane potential (ΔΨm). The results of the MTT assay showed that the proliferation and colony formation of MDA-MB-231 cells were inhibited following treatment with the extract. Furthermore, the PI/Annexin-V staining showed that the apoptosis of MDA-MB-231 cells was enhanced by the extract, in a concentration-dependent manner. The extract also lowered the ΔΨm of MDA-MB-231 cells, upregulated the expression of Bax and inhibited the expression of Bcl-2. In conclusion, these results showed that the P. odoratum extract inhibited the proliferation and induced apoptosis of breast cancer MDA-MB-231 cells.

13.
Acta Pharmacol Sin ; 37(3): 398-407, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26806300

RESUMO

AIM: Targeting the VEGF/VEGF receptor (VEGFR) pathway has proved to be an effective antiangiogenic approach for cancer treatment. Here, we identified 6-((2-((3-acetamidophenyl)amino)pyrimidin-4-yl)oxy)-N-phenyl-1-naphthamide (designated herein as DW10075) as a novel and highly selective inhibitor of VEGFRs. METHODS: In vitro tyrosine kinase activity was measured using ELISA, and intracellular signaling pathway proteins were detected by Western blot analysis. Endothelial cell proliferation was examined with CCK-8 assays, and tumor cell proliferation was determined with SRB assays. Cell migration, tube formation and rat aortic ring assays were used to detect antiangiogenic activity. Antitumor efficacy was further evaluated in U87-MG human glioblastoma xenograft tumors in nude mice receiving DW10075 (500 mg · kg(-1) · d(-1), po) for two weeks. RESULTS: Among a panel of 21 kinases tested, DW10075 selectively inhibited VEGFR-1, VEGFR-2 and VEGFR-3 (the IC50 values were 6.4, 0.69 and 5.5 nmol/L, respectively), but did not affect 18 other kinases including FGFR and PDGFR at 10 µmol/L. DW10075 significantly blocked VEGF-induced activation of VEGFR and its downstream signaling transduction in primary human umbilical vein endothelial cells (HUVECs), thus inhibited VEGF-induced HUVEC proliferation. DW10075 (1-100 nmol/L) dose-dependently inhibited VEGF-induced HUVEC migration and tube formation and suppressed angiogenesis in both the rat aortic ring model and the chicken chorioallantoic membrane model. Furthermore, DW10075 exhibited anti-proliferative activity against 22 different human cancer cell lines with IC50 values ranging from 2.2 µmol/L (for U87-MG human glioblastoma cells) to 22.2 µmol/L (for A375 melanoma cells). In U87-MG xenograft tumors in nude mice, oral administration of DW10075 significantly suppressed tumor growth, and reduced the expression of CD31 and Ki67 in the tumor tissues. CONCLUSION: DW10075 is a potent and highly selective inhibitor of VEGFR that deserves further development.


Assuntos
Inibidores da Angiogênese/química , Inibidores da Angiogênese/uso terapêutico , Glioblastoma/tratamento farmacológico , Pirimidinas/química , Pirimidinas/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Galinhas , Glioblastoma/irrigação sanguínea , Glioblastoma/metabolismo , Glioblastoma/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Ratos Sprague-Dawley , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo
14.
Huan Jing Ke Xue ; 37(6): 2101-2112, 2016 Jun 08.
Artigo em Chinês | MEDLINE | ID: mdl-29964875

RESUMO

Qixiang River watershed, as a typical case study area, was divided into five types of buffer zones according to elevation and slope. Based on the remote sensing images, DEM and real-time monitoring data in April, May, June 2015, the relationship between land use type and pattern in all buffer zones and water quality under different rainfall intensities was explored. The results showed that land use type and pattern in different buffer zones had obvious discrepancies. The proportion of construction land was the highest in low flat area, secondary flat area and high flat area. The main land use type of moderately steep area and high steep area was forest land. Secondly, the low flat area appeared to have the greatest influence on the water quality. Thirdly, construction land had a greater influence on water quality than other land use types in low flat area. In addition, in secondary flat area, wetland was the key factor under small rainfall intensity. However, construction land was the key factor under moderate rainfall intensity and large rainfall intensity. In moderately steep area and high buffer zones, construction land influenced the water quality most under small rainfall intensity but forest land was the greatest factor under moderate rainfall intensity and large rainfall intensity. Fourthly, the relationship between the land use pattern and water quality was complicated. SH-MN had the greatest influence on water quality and the influence increased with increasing rainfall intensity in low flat area. Furthermore, PD, SH-MN and SHDI were the key factors in secondary flat area while SH-MN, SHDI and PD were the key factors in high flat area under all the three types of rainfall intensity. SH-MN and CONTAG influenced the water quality most in moderately steep area and high steep area under small and high rainfall intensity. CONTAG influenced the water quality most in moderately steep area and SHDI was the key factor in high steep area under moderate rainfall intensity.


Assuntos
Monitoramento Ambiental , Chuva , Rios/química , Qualidade da Água , China , Florestas , Tecnologia de Sensoriamento Remoto , Análise Espacial
15.
Yao Xue Xue Bao ; 51(8): 1285-9, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-29906019

RESUMO

A new sesquiterpene, bakkenolide-Ⅵa (1), was isolated from the rhizome of Petasites japonicas (Sieb. et Zucc.) Maxim. The structure was characterized on the basis of various NMR ((1)H, (13)C, (1)H-(1)H COSY, HMQC, HMBC and NOESY) and mass spectrometry data. Bakkenolide-Ⅵa showed potent cerebral hypoxia- ischemia protective activity in mice subjected to decapitation through prolonging the survival time and gasping time. It also exhibited a protective activity against hypoxia injury in PC12 cells in anaerobic culture by inhibition of lactate dehydrogenase (LDH) release.


Assuntos
Hipóxia-Isquemia Encefálica/tratamento farmacológico , Petasites/química , Rizoma/química , Sesquiterpenos/química , Animais , Hipóxia Celular , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Células PC12 , Extratos Vegetais/química , Ratos , Sesquiterpenos/isolamento & purificação
16.
J Hazard Mater ; 302: 232-240, 2016 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-26476310

RESUMO

Pseudomonas putida S-1 was isolated from activated sludge. This novel strain was capable of degrading malodorous 1-propanethiol (PT). PT degradation commenced with no lag phase by cells pre-grown in nutrition-rich media, such as Luria-Bertani (LB), and PT-contained mineral medium at specific growth rates of 0.10-0.19 h(-1); this phenomenon indicated the operability of a large-scale cell culture. A possible PT degradation pathway was proposed on the basis of the detected metabolites, including dipropyl disulfide, 3-hexanone, 2-hexanone, 3-hexanol, 2-hexanol, S(0), SO4(2-), and CO2. P. putida S-1 could degrade mixed pollutants containing PT, diethyl disulfide, isopropyl alcohol, and acetaldehyde, and LB-pre-cultured cells underwent diauxic growth. Waste gas contaminated with 200-400 mg/m(3) PT was continuously treated by P. putida S-1 pre-cultured in LB medium in a completely stirred tank reactor. The removal efficiencies exceeded 88% when PT stream was mixed with 200 mg/m(3) isopropanol; by contrast, the removal efficiencies decreased to 60% as the empty bed residence time was shortened from 40 s to 20 s.


Assuntos
Pseudomonas putida/isolamento & purificação , Pseudomonas putida/metabolismo , Compostos de Sulfidrila/metabolismo , Biodegradação Ambiental , Reatores Biológicos , Esgotos/microbiologia
17.
Zhonghua Nan Ke Xue ; 21(4): 291-3, 2015 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-26027093

RESUMO

Andrology and gynecology have a similar or the same theoretical basis in Traditional Chinese Medicine (TCM). Andrology has a history of less than 3 decades in China, while TCM gynecology has developed for over a thousand years. The development of andrology could be greatly promoted with the guidance of the theories and prescriptions of gynecology.


Assuntos
Andrologia , Ginecologia , Medicina Tradicional Chinesa , China , Humanos
18.
Huan Jing Ke Xue ; 36(1): 274-9, 2015 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-25898675

RESUMO

Adolescents' (11-19 years old) hair samples (n =39) collected from Liangshan prefecture, Sichuan Province were analyzed for 12 dioxin-like polychlorinated biphenyl(DL-PCBs) congeners by gas chromatography-mass spectrometry(GC-MS). The levels and distribution characteristics of DL-PCBs in Tibetan and Yi Adolescents' hair were studied, meanwhile, the relationships between the levels of DL-PCBs and the nationalities, eating habits and genders were addressed. The results indicated that the average concentration of PCBs was (102.2 +/- 14. 3) pg x g(-1) with the range from 9.6 pg x g(-1) to 991.6 pg x g(-1). The concentration levels of this region were relatively low. PCB-77, PCB-105 and PCB-118 were the major congeners, contributing to 84.7% of the total. The levels of PCBs in Yi teenagers' hair were higher than those in Tibetan, and the concentration in hair was related to the frequency of eating meats and drinking milk per week. It might be attributed to the different eating habits of these two nationalities. When gender was considered, significantly higher concentrations were found in female than in male (P < 0.05).


Assuntos
Cabelo/química , Bifenilos Policlorados/análise , Adolescente , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Adulto Jovem
19.
Oncotarget ; 6(11): 8960-73, 2015 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-25840421

RESUMO

Both microtubule and topoisomerase II (Top2) are important anticancer targets and their respective inhibitors are widely used in combination for cancer therapy. However, some combinations could be mutually antagonistic and drug resistance further limits their therapeutic efficacy. Here we report YCH337, a novel α-carboline derivative that targets both microtubule and Top2, eliciting tumor proliferation and growth inhibition and overcoming drug resistance. YCH337 inhibited microtubule polymerization by binding to the colchicine site and subsequently led to mitotic arrest. It also suppressed Top2 and caused DNA double-strand breaks. It disrupted microtubule more potently than Top2. YCH337 induced reversible mitotic arrest at low concentrations but persistent DNA damage. YCH337 caused intrinsic and extrinsic apoptosis and decreased MCL-1, cIAP1 and XIAP proteins. In this aspect, YCH337 behaved differently from the combination of vincristine and etoposide. YCH337 inhibited proliferation of tumor cells with an averaged IC50 of 0.3 µM. It significantly suppressed the growth of HT-29 xenografts in nude mice too. Importantly, YCH337 nearly equally killed different-mechanism-mediated resistant tumor cells and corresponding parent cells. Together with the novelty of its chemical structure, YCH337 could serve as a promising lead for drug development and a prototype for a dual microtubule/Top2 targeting strategy for cancer therapy.


Assuntos
Carbolinas/uso terapêutico , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores da Topoisomerase II/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Ligação Competitiva , Carbolinas/farmacologia , Linhagem Celular Tumoral , Colchicina/metabolismo , Neoplasias do Colo/tratamento farmacológico , DNA Topoisomerases Tipo II/fisiologia , DNA Super-Helicoidal/efeitos dos fármacos , Interações Medicamentosas , Ensaios de Seleção de Medicamentos Antitumorais , Etoposídeo/farmacologia , Humanos , Concentração Inibidora 50 , Metáfase/efeitos dos fármacos , Camundongos , Camundongos Nus , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Estrutura Molecular , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/fisiologia , Paclitaxel/farmacologia , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/farmacologia , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/farmacologia , Vincristina/farmacologia
20.
BMC Genomics ; 16 Suppl 2: S12, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25707768

RESUMO

BACKGROUND: MicroRNAs (miRNAs) simultaneously target many transcripts through partial complementarity binding, and have emerged as a key type of post-transcriptional regulator for gene expression. How miRNA accomplishes its pleiotropic effects largely depends on its expression and its target repertoire. Previous studies discovered thousands of miRNAs and numerous miRNA target genes mainly through computation and prediction methods which produced high rates of false positive prediction. The development of Argonaute cross-linked immunoprecipitation coupled with high-throughput sequencing (CLIP-Seq) provides a system to effectively determine miRNA target genes. Likewise, the accuracy of dissecting the transcriptional regulation of miRNA genes has been greatly improved by chromatin immunoprecipitation of the transcription factors coupled with sequencing (ChIP-Seq). Elucidation of the miRNA target repertoire will provide an in-depth understanding of the functional roles of microRNA pathways. To reliably reconstruct a miRNA-mediated regulatory network, we established a computational framework using publicly available, sequence-based transcription factor-miRNA databases, including ChIPBase and TransmiR for the TF-miRNA interactions, along with miRNA-target databases, including miRTarBase, TarBase and starBase, for the miRNA-target interactions. We applied the computational framework to elucidate the miRNA-mediated regulatory network in the Mir122a⁻/⁻ mouse model, which has an altered transcriptome and progressive liver disease. RESULTS: We applied our computational framework to the expression profiles of miRNA/mRNA of Mir122a⁻/⁻ mutant mice and wild-type mice. The miRNA-mediated network involves 40 curated TFs contributing to the aberrant expression of 65 miRNAs and 723 curated miRNA target genes, of which 56% was found in the differentially-expressed genes of Mir122a--mice. Hence, the regulatory network disclosed previously-known and also many previously-unidentified miRNA-mediated regulations in mutant mice. Moreover, we demonstrate that loss of imprinting at the chromosome 12qF1 region is associated with miRNA overexpression in human hepatocellular carcinoma and stem cells, suggesting initiation of precancerous changes in young mice deficient in miR-122. A group of 9 miRNAs was found to share miR-122 target genes, indicating synergy between miRNAs and target genes by way of multiplicity and cooperativity. CONCLUSIONS: The study provides significant insight into miRNA-mediated regulatory networks. Based on experimentally verified data, this network is highly reliable and effective in revealing previously-undetermined disease-associated molecular mechanisms. This computational framework can be applied to explore the significant TF-miRNA-miRNA target interactions in any complex biological systems with high degrees of confidence.


Assuntos
Biologia Computacional/métodos , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Fígado/metabolismo , MicroRNAs/genética , Animais , Carcinoma Hepatocelular/genética , Imunoprecipitação da Cromatina , Bases de Dados Genéticas , Regulação da Expressão Gênica , Ensaios de Triagem em Larga Escala , Humanos , Neoplasias Hepáticas/genética , Camundongos Knockout , Modelos Genéticos , Reprodutibilidade dos Testes , Transdução de Sinais/genética , Fatores de Transcrição/genética
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