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1.
Nat Commun ; 12(1): 4230, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244494

RESUMO

Extracellular matrix protein-1 (ECM1) promotes tumorigenesis in multiple organs but the mechanisms associated to ECM1 isoform subtypes have yet to be clarified. We report in this study that the secretory ECM1a isoform induces tumorigenesis through the GPR motif binding to integrin αXß2 and the activation of AKT/FAK/Rho/cytoskeleton signaling. The ATP binding cassette subfamily G member 1 (ABCG1) transduces the ECM1a-integrin αXß2 interactive signaling to facilitate the phosphorylation of AKT/FAK/Rho/cytoskeletal molecules and to confer cancer cell cisplatin resistance through up-regulation of the CD326-mediated cell stemness. On the contrary, the non-secretory ECM1b isoform binds myosin and blocks its phosphorylation, impairing cytoskeleton-mediated signaling and tumorigenesis. Moreover, ECM1a induces the expression of the heterogeneous nuclear ribonucleoprotein L like (hnRNPLL) protein to favor the alternative mRNA splicing generating ECM1a. ECM1a, αXß2, ABCG1 and hnRNPLL higher expression associates with poor survival, while ECM1b higher expression associates with good survival. These results highlight ECM1a, integrin αXß2, hnRNPLL and ABCG1 as potential targets for treating cancers associated with ECM1-activated signaling.


Assuntos
Processamento Alternativo , Carcinoma Epitelial do Ovário/genética , Proteínas da Matriz Extracelular/metabolismo , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Ovarianas/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/terapia , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas da Matriz Extracelular/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas/genética , Humanos , Integrina alfaXbeta2/genética , Integrina alfaXbeta2/metabolismo , Estimativa de Kaplan-Meier , Camundongos , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Ovário/patologia , Ovário/cirurgia , Fosforilação/genética , Prognóstico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA-Seq , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
2.
PLoS One ; 16(1): e0245968, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33493204

RESUMO

BACKGROUND: Tympanic membrane (TM) perforation is quite common in the clinical setting. Chronic TM perforations require surgical treatments such as myringoplasty. Currently, platelet-rich plasma (PRP) is a novel, effective substance that is increasingly utilized for TM perforation repair. This study aims to evaluate the effectiveness of PRP in the application of TM perforation repair. METHODS: A systematic search was conducted to screen the Medline, Embase, Cochrane, Scopus and Web of Science databases up to July 2020. Studies were identified in accordance with the selection criteria by two coauthors independently. Data regarding the healing and hearing outcomes were pooled and analyzed via Review Manager version 5.3 and STATA version 12.0 software. Odds ratio (OR) was utilized to compare the closure rate. Furthermore, the results of hearing improvements and incidence of complications were also compared to evaluate the effectiveness of PRP. RESULTS: A total of eight studies with 455 participants were eligible according to the selection criteria. Compared to conventional surgery, the OR of closure was 2.70 (95% CI: 1.27 to 5.76, P = 0.01, I2 = 0%) in randomized controlled trial (RCT) subgroup and 6.18 (95% CI: 2.22 to 17.25, P = 0.0005, I2 = 0) in non-RCT subgroup. The overall OR of closure was 3.69 (95% CI: 2.02 to 6.74, P<0.0001, I2 = 0%), suggesting a significant effect on the healing of TM perforation. Between preoperative and postoperative hearing results, there is no statistical difference between the PRP and the control groups. Additionally, the use of PRP resulted in a lower incidence of complication than the use of conventional approaches. CONCLUSION: The application of PRP during the TM surgeries can enhance the closure rate, provide similar hearing improvements and decrease the incidence of postoperative complications. Given these advantages, PRP can be considered an effective treatment for TM regeneration.


Assuntos
Miringoplastia/métodos , Plasma Rico em Plaquetas , Perfuração da Membrana Timpânica/cirurgia , Membrana Timpânica/cirurgia , Humanos , Resultado do Tratamento
3.
Otolaryngol Head Neck Surg ; 164(2): 381-390, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32662734

RESUMO

OBJECTIVE: To evaluate the efficacy of acellular collagen scaffold (ACS) in combination with basic fibroblast growth factor (bFGF) for the repair of traumatic tympanic membrane (TM) perforation in a rat model. STUDY DESIGN: A prospective controlled animal study in a rat model of traumatic TM perforation. SETTING: Tertiary medical center. SUBJECTS AND METHODS: Sprague-Dawley rats (N = 84) with unilateral traumatic perforation of the right TMs were randomized to receive ACS, bFGF, ACS in combination with bFGF (ACS/bFGF), or nothing (spontaneous healing without any interventions as a control group). The healing outcomes were evaluated by otoscopy, optical coherence tomography, histology, and transmission electron microscopy at 1, 2, and 4 weeks postoperatively. The hearing outcomes were assessed with auditory brainstem response testing. RESULTS: ACS/bFGF resulted in higher perforation closure rates at an earlier stage than spontaneous healing, ACS, and bFGF. Based on histology, optical coherence tomography, and transmission electron microscopy, a trilaminar structure and uniform thickness with mature, densely packed collagen fibers were seen in the ACS/bFGF group. Auditory brainstem response evaluation also showed that ACS/bFGF treatment promoted faster functional hearing recovery as compared with the control group. CONCLUSIONS: ACS is an effective TM scaffold and a carrier for bFGF. ACS/bFGF improves the TM closure rate, results in better-reconstructed TMs, and improves hearing. ACS/bFGF serves as a potential substitute for TM perforations in clinical settings.


Assuntos
Audição/fisiologia , Recuperação de Função Fisiológica , Tecidos Suporte , Perfuração da Membrana Timpânica/cirurgia , Membrana Timpânica/cirurgia , Cicatrização/efeitos dos fármacos , Animais , Colágeno/farmacologia , Modelos Animais de Doenças , Fator 2 de Crescimento de Fibroblastos/farmacologia , Otoscopia/métodos , Estudos Prospectivos , Ratos , Ratos Sprague-Dawley , Perfuração da Membrana Timpânica/fisiopatologia
4.
Oncol Lett ; 16(5): 6445-6457, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30405782

RESUMO

Wentilactone A (WA), a marine-derived compound, inhibits proliferation of NCI-H446, as demonstrated by previous research; however, the anti-SCLC mechanism underlying WA was not fully investigated. The present study aimed to investigate the anti-SCLC mechanism underlying WA in vitro and in vivo. Cell Counting Kit-8 was used to assay cell growth, flow cytometry was conducted to analyze cell apoptosis and nude mice xenografts were used to examine SCLC growth following WA treatment. Bioinformatics was used for verification of the target gene of WA. Reverse transcription-quantitative polymerase chain reaction and western blot were used to examine aldo-keto reductase family 1 member C1 (AKR1C1) mRNA and protein levels, and AKR1C1-associated proteins prior to and following WA treatment. Cell growth, apoptosis and growth of nude mice xenografts were assayed prior to and following transfection with AKR1C1 knockdown or overexpression carriers, respectively. It was determined that AKR1C1 was a target gene of WA. Decreased AKR1C1 expression and WA treatment promoted apoptosis in SCLC via the insulin like growth factor-1 receptor/insulin receptor substrate 1/phosphoinositide 3-kinase/AKT/nuclear factor-erythroid 2-associated factor 2/Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein/Caspase-3 pathway. WA attenuated the proliferation and induced the apoptosis of SCLC cells in vitro and in vivo by targeting the AKR1C1 gene. WA may be a novel AKR1C1-targeted drug candidate for the treatment of SCLC in the future.

5.
Lung Cancer (Auckl) ; 7: 53-61, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28210161

RESUMO

AKR1C1 is a member of the AKR1C family, which not only plays an important role in hormone metabolism but is believed to be involved in carcinogen metabolism. Our previous study demonstrated that AKR1C1 was highly expressed in lung tumor tissues as compared with the tumor-adjacent tissues. Small-cell lung cancer (SCLC) is a special type of lung cancer. Surgical treatment of SCLC is usually difficult due to the high degree of malignancy and early metastasis, and difficulty in obtaining clinical specimens. There is not much basic or clinical research on SCLC in the People's Republic of China even in recent years. To investigate the mechanism of AKR1C1 in the pathogenesis of SCLC, the present study used H446 cell line to see whether AKR1C1 could affect the proliferation or migration of SCLC cells, and used a lentivirus to build the AKR1C1 overexpression and under-expression cell lines. The results indicated that AKR1C1 was an important inducement in the proliferation and migration of H446 cells. AKR1C1 promoted cell proliferation and played a vital role in the migration of SCLC cells. These results were also verified in nude mice in vivo. In conclusion, AKR1C1 plays an important role in the development and progression of SCLC and may represent an independent biomarker for assessment of the primary prognosis and therapy of SCLC.

6.
Mar Drugs ; 13(1): 431-43, 2015 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-25603341

RESUMO

Ophiobolin O is a member of ophiobolin family, which has been proved to be a potent anti-tumor drug candidate for human breast cancer. However, the anti-tumor effect and the mechanism of ophiobolin O remain unclear. In this study, we further verified ophiobolin O-induced G1 phase arrest in human breast cancer MCF-7 cells, and found that ophiobolin O reduced the phosphorylation level of AKT and GSK3ß, and induced down-regulation of cyclin D1. The inverse docking (INVDOCK) analysis indicated that ophiobolin O could bind to GSK3ß, and GSK3ß knockdown abolished cyclin D1 degradation and G1 phase arrest. Pre-treatment with phosphatase inhibitor sodium or thovanadate halted dephosphorylation of AKT and GSK3ß, and blocked ophiobolin O-induced G1 phase arrest. These data suggest that ophiobolin O may induce G1 arrest in MCF-7 cells through interaction with AKT/GSK3ß/cyclin D1 signaling. In vivo, ophiobolin O suppressed tumor growth and showed little toxicity in mouse xenograft models. Overall, these findings provide theoretical basis for the therapeutic use of ophiobolin O.


Assuntos
Aspergillus/química , Ciclina D1/efeitos dos fármacos , Fase G1/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/efeitos dos fármacos , Células MCF-7/efeitos dos fármacos , Proteína Oncogênica v-akt/efeitos dos fármacos , Sesterterpenos/farmacologia , Animais , Neoplasias da Mama/tratamento farmacológico , Feminino , Glicogênio Sintase Quinase 3 beta , Humanos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Fosforilação/efeitos dos fármacos , Sesterterpenos/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos
7.
J Nat Prod ; 77(8): 1921-7, 2014 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-25105722

RESUMO

Six new disulfide-bridged diketopiperazine derivatives, brocazines A-F (1-6), along with one known analogue (7), were isolated and identified from the cytotoxic extract of Penicillium brocae MA-231, a fungus obtained from the fresh tissue of the marine mangrove plant Avicennia marina. The structures of these compounds were established on the basis of detailed interpretation of NMR and mass spectroscopic data. X-ray crystallographic analysis confirmed the structure of 1 and established the structure and absolute configuration of 5, while the absolute configurations for compounds 1, 4, and 6 were deduced by comparison of the CD data with those of 5. Compounds 1, 2, 5, and 6 showed cytotoxic activities against several tumor cell lines.


Assuntos
Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Avicennia/microbiologia , Dicetopiperazinas/isolamento & purificação , Dicetopiperazinas/farmacologia , Penicillium/química , Antineoplásicos/química , China , Cristalografia por Raios X , Dicetopiperazinas/química , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Biologia Marinha , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular
8.
Tumour Biol ; 35(2): 1157-68, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24272336

RESUMO

Single-chain Fv fragments (scFvs) consist of the variable heavy-chain (VH) and variable light-chain (VL) domains, which are the smallest immunoglobulin fragments containing the whole antigen-binding site. Human soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) proves to acquire a potent pro-apoptotic activity only after selective binding to a predefined tumor cell surface antigen and has no off-target effects towards normal cells. Glioblastoma multiforme (GBM) is the most frequent and aggressive type of brain tumor and overexpresses human multidrug resistance protein 3 (MRP3). In this study, we designed a novel fusion protein, termed scFvM58-sTRAIL, in which the MRP3-specific scFv antibody M58 was genetically fused to the N-terminus of human soluble TRAIL (sTRAIL). The recombinant scFvM58-sTRAIL fusion protein, expressed in Escherichia coli, was purified by chromatography and tested for cytotoxicity. scFvM58-sTRAIL showed a significant apoptosis-inducing activity towards MRP3-positive GBM cells in vitro. The pro-apoptotic activity of scFvM58-sTRAIL towards GBM cells was strongly inhibited in the presence of the parental scFvM58 antibody, suggesting that cytotoxic activity is MRP3-restricted. In a control experiment with MRP3-negative Jurkat cells, scFvM58-sTRAIL did not induce apparent apoptosis. In addition, through target antigen-restricted binding, scFvM58-sTRAIL was capable of activating not only TRAIL-R1 but also TRAIL-R2. In conclusion, our results suggest that fusion protein scFvM58-sTRAIL with specificity for MRP3 is a highly selective therapeutic agent and may provide an alternative therapy for human GBM.


Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/imunologia , Proteínas Recombinantes de Fusão/genética , Ligante Indutor de Apoptose Relacionado a TNF/imunologia , Antígenos de Superfície/genética , Antígenos de Superfície/imunologia , Apoptose/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Células Jurkat , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/uso terapêutico , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/uso terapêutico , Anticorpos de Cadeia Única/genética , Anticorpos de Cadeia Única/imunologia , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêutico
9.
J Nat Prod ; 76(11): 2145-9, 2013 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-24195466

RESUMO

Sumalarins A-C (1-3), the new and rare examples of sulfur-containing curvularin derivatives, along with three known analogues (4-6), were isolated and identified from the cytotoxic extract of Penicillium sumatrense MA-92, a fungus obtained from the rhizosphere of the mangrove Lumnitzera racemosa . Their structures were established by detailed interpretation of NMR and MS data, and compound 1 was confirmed by X-ray crystallographic analysis. Compounds 1-3 and 5 showed potent cytotoxicity against some of the tested tumor cell lines. Sulfur substitution at C-11 or a double bond at C-10 significantly increased the cytotoxic activities of the curvularin analogues.


Assuntos
Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Combretaceae/microbiologia , Macrolídeos/isolamento & purificação , Macrolídeos/farmacologia , Penicillium/química , Enxofre/análise , Zearalenona/análogos & derivados , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antineoplásicos/química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Macrolídeos/química , Conformação Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Zearalenona/química , Zearalenona/isolamento & purificação , Zearalenona/farmacologia
10.
Mar Drugs ; 11(11): 4570-84, 2013 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-24240979

RESUMO

Multidrug-resistance is a major obstacle facing cancer chemotherapy. This paper demonstrates that novel compound Ophiobolin-O reverses MCF-7/ADR resistance to adriamycin (ADM). The IC50 of ADM treated MCF-7 cells was 2.02 ± 0.05 µM and 74.00 ± 0.18 µM treated MCF-7/ADR cells, about 37-fold, compared to the former. However, 0.1 µM Ophiobolin-O (less than 20% inhibition concentration) combined with ADM caused the decreased IC50 of ADM to 6.67 ± 0.98 µM, indicating it reversed ADM resistance of MCF-7/ADR cells (11-fold). Furthermore, Ophiobolin-O increased ADM-induced mitochondrial pathway apoptosis and G2/M phase arrest, which is partly due to the elevation level of ROS in MCF-7/ADR cells. As we described in this paper, the reversal effect of Ophiobolin-O may be due to the reduction of resistance-related protein P-Glycoprotein (P-gp, also known as MDR1) through inhibiting the activity of the multidrug resistance 1 (MDR1) gene promoter, which makes MCF-7/ADR cells more sensitive to ADM treatment. Assays in nude mice also showed that the combination of ADM and Ophiobolin-O significantly improved the effect of ADM.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sesterterpenos/farmacologia , Linhagem Celular Tumoral , Humanos , Células MCF-7
11.
Mar Drugs ; 11(2): 316-31, 2013 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-23434831

RESUMO

Here we first demonstrate that asperolide A, a very recently reported marine-derived tetranorditerpenoid, leads to the inhibition of NCI-H460 lung carcinoma cell proliferation by G2/M arrest with the activation of the Ras/Raf/MEK/ERK signaling and p53-dependent p21 pathway. Treatment with 35 µM asperolide A (2 × IC(50)) resulted in a significant increase in the proportion of G2/M phase cells, about a 2.9-fold increase during 48 h. Immunoblot assays demonstrated time-dependent inhibition of G2/M regulatory proteins. Moreover, asperolide A significantly activated MAP kinases (ERK1/2, JNK and p38 MAP kinase) by phosphorylation, and only the inhibition of ERK activation by PD98059 reversed downregulation of G2/M regulatory proteins CDC2, and suppressed upregulation of p21 and p-p53 levels. Transfection of cells with dominant-negative Ras (RasN17) mutant genes up-regulated asperolide A-induced the decrease of cyclin B1 and CDC2, suppressed Raf, ERK activity and p53-p21 expression, and at last, abolished G2/M arrest. This study indicates that asperolide A-induced G2/M arrest in human NCI-H460 lung carcinoma cells relys on the participation of the Ras/Raf/MEK/ERK signaling pathway in p53-p21 stabilization. An in vivo study with asperolide A illustrated a marked inhibition of tumor growth, and little toxcity compared to Cisplatin therapy. Overall, these findings provide potential effectiveness and a theoretical basis for the therapeutic use of asperolide A in the treatment of malignancies.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ligação a DNA/metabolismo , Diterpenos/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas ras/metabolismo , Animais , Antineoplásicos/química , Carcinoma/tratamento farmacológico , Linhagem Celular Tumoral , Cisplatino/toxicidade , Proteínas de Ligação a DNA/genética , Diterpenos/química , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imunossupressores , Neoplasias Pulmonares/tratamento farmacológico , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Transdução de Sinais , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , Quinases raf/genética , Quinases raf/metabolismo , Proteínas ras/genética
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