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1.
Medicine (Baltimore) ; 99(2): e18670, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914056

RESUMO

This retrospective study is to explore the clinicopathologic, immunophenotypic, and molecular genetic features of Waldeyer ring B-cell lymphoma (WR-BCL).Tissue arrays from 65 WR-BCL cases were subjected to pathologic and immunophenotypic detections. Expression of Epstein-Barr virus-encoded small RNA (EBER) was detected by in situ hybridization. Interferon regulatory factor 4 (IRF4), BCL-2, BCL-6, and C-myelocytomatosis viral oncogeneav (MYC) gene abnormalities were investigated using interphase fluorescence in situ hybridization.Among the 65 patients, there were 12 nasopharynx cases, 49 tonsil cases, and 4 tongue root cases. Moreover, there were 49 cases of diffuse large BCL (DLBCL) and 16 cases of follicular lymphoma (FL). More than 60% of the patients had Ann Arbor stage III/IV disease, with infiltrated neighboring organs, invaded spleens, and increased lactate dehydrogenase (LDH) levels. Tumor cells were positive for multiple myeloma antigen 1 (MUM1), BCL-2, BCL-6, and C-MYC. EBER expression was detected in lymphoma cells of 2 cases. Alteration frequencies of IRF4, BCL-2, BCL-6, and C-MYC were 24.6%, 32.3%, 27.7%, and 30.7%, respectively. Approximately 67.69% cases had stages 0 to II disease, while 32.31% cases had stage III disease. Five-year overall survival rate was 65.12%. Eastern Cooperative Oncology Group performance status (ECOG) score ≥2 was the only adverse factor for overall survival. IRF4/MUM1, C-MYC, and CD10 expressions were related to poor disease prognosis. WR-BCLs were largely dependent on ECOG, LDH, and bone marrow involvement. WR-DLBCL was associated with poor survival outcomes compared with WR-FL.The WR-DLBCLs have distinct clinicopathologic features, with correlations between the IRF4/MUM1, C-MYC and CD10 expressions, ECOG, LDH, bone marrow involvement, and the disease prognosis.


Assuntos
Linfoma de Células B/epidemiologia , Linfoma de Células B/fisiopatologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Feminino , Humanos , Hibridização in Situ Fluorescente , Fatores Reguladores de Interferon/biossíntese , Linfoma de Células B/classificação , Linfoma de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-6/biossíntese , Proteínas Proto-Oncogênicas c-myc/biossíntese , Proteínas de Ligação a RNA/biossíntese , Estudos Retrospectivos , Proteínas Ribossômicas/biossíntese , Fatores Sexuais
2.
Life Sci ; 235: 116840, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494171

RESUMO

AIMS: Ovarian ischemia as a consequence of torsion constitutes a gynecologic emergency affecting females during reproductive age. Its management by detorsion results in ovarian ischemia-reperfusion (IR) injury. Thus, a conservative treatment with detorsion is highly recommended. Therefore, we attempted to investigate the effect and underlying mechanisms of angiotensin 1-7 (Ang-(1-7)) treatment against ovarian IR injury. MAIN METHODS: Female rats were included into: Sham group; Ang-(1-7) (300 µg/kg, i.p.) group; ovarian IR groups with and without Ang-(1-7) treatment. We determined ovarian Ang-(1-7), malondialdehyde (MDA) and nitric oxide (NO) in addition to serum total anti-oxidant capacity (TAC) levels. Ovarian gene expressions of angiotensin converting enzyme 2 (ACE2), Mas receptor, tumor necrosis factor alpha (TNF-α) and B-cell leukemia/lymphoma-2 (BCL-2) were estimated. Furthermore, histopathological changes and ovarian expressions of nuclear factor kappa B (NF-κB), inducible and endothelial nitric oxide synthases (iNOS and eNOS) were done. KEY FINDINGS: Treatment of ovarian IR rats with Ang-(1-7) led to marked improvement of ovarian damage through histological examination which was accompanied with marked increase in ovarian Ang-(1-7) level and expressions of ACE2 and Mas receptor, decrease in MDA and NO levels and expressions of NF-kB, iNOS and TNF-α with increase in serum TAC levels and ovarian expressions of eNOS and BCL-2. SIGNIFICANCE: Our results proved the protective effect of Ang-(1-7) against ovarian IR injury in rats and this may be attributed to ACE2/Ang (1-7)/Mas axis which showed anti-oxidant, anti-inflammatory and anti-apoptotic effects. Therefore, Ang-(1-7) can be used in the future for treatment of ovarian IR injury.


Assuntos
Angiotensina I/farmacologia , Ovário/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Antioxidantes/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Malondialdeído/metabolismo , NF-kappa B/biossíntese , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo III/biossíntese , Ovário/lesões , Ovário/metabolismo , Peptidil Dipeptidase A/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Ratos , Receptores Acoplados a Proteínas-G/biossíntese , Soro/metabolismo , Fator de Necrose Tumoral alfa/biossíntese
3.
Med Sci Monit ; 25: 4583-4589, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31257361

RESUMO

BACKGROUND The apoptosis of corneal epithelial cells participates in the pathological processes of dry eye, which is expected to be a treatment target for dry eye. The aim of this study was to investigate the effects of vitamin A (VA) on apoptosis of corneal epithelial cells in a mouse model with dry eye induced by benzalkonium chloride (BAC). MATERIAL AND METHODS We randomly divided 60 male BALB/c mice aged 8-10 weeks into 3 groups: the blank control group, the dry eye + vehicle group, and the dry eye + drug group. On the 7th day after the dry eye model successfully induced, the mouse eyeballs removed, and the mouse corneal tissues were isolated. The expression levels of Bax and Bcl-2 in corneal tissues were detected via reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. The apoptotic corneal epithelial cells were quantified using terminal deoxynucleotidyl transferase (TdT) deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) staining technique. RESULTS VA suppressed the upregulation of the Bax gene at the mRNA and protein levels, and upregulated the expression of the Bcl-2 gene (P<0.05). TUNEL results revealed that the number of apoptotic epithelial cells in the dry eye group was 40 times larger as that in the blank control group. After the intervention of VA at an appropriate concentration, the number of apoptotic corneal epithelial cells was remarkably reduced to about 10 times that in the blank control group (P<0.05). CONCLUSIONS VA can inhibit upregulation of the expressions of Bax and Bcl-2 in the epithelial cells of mice with dry eye induced by BAC, so as to suppress the apoptosis of epithelial cells in mice with dry eye.


Assuntos
Proteínas Proto-Oncogênicas c-bcl-2/genética , Vitamina A/farmacologia , Proteína X Associada a bcl-2/genética , Animais , Apoptose/efeitos dos fármacos , Compostos de Benzalcônio/farmacologia , Córnea/efeitos dos fármacos , Córnea/metabolismo , Córnea/patologia , Modelos Animais de Doenças , Síndromes do Olho Seco/tratamento farmacológico , Síndromes do Olho Seco/metabolismo , Células Epiteliais/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteína X Associada a bcl-2/biossíntese
4.
Life Sci ; 232: 116583, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31226417

RESUMO

TP53 mutation is an indicator of poor prognostic in chronic lymphocytic leukemia (CLL). Worse still, CLL patients with TP53 mutation are associated with poor efficacy to current chemotherapeutic, such as Fludarabine. Here, we confirmed that high expression of HDAC1 in CLL patients with TP53 mutation, which is closely related to poor prognosis and drug-resistance. Subsequently, we demonstrated Entinostat (HDAC1 inhibitor) combination with Fludarabine significantly induced apoptosis in TP53 mutations CLL cells. Its mechanism was associated with up-regulation of the pro-apoptotic protein Bax and the down-regulation of HDAC1, HO-1 and BCL-2 proteins. More importantly, we also confirmed that upregulation of HDAC1 could resistant Entinostat-induced apoptosis in TP53 mutations CLL cells by activating the HDAC1/P38/HO-1 pathway. In vivo, we found that Entinostat combination with Fludarabine significantly induced tumor cells apoptosis and prolong survival time in xenograft mouse model. Finally, combining vitro and vivo experiments, we presented the first demonstration that Entinostat combination with Fludarabine had a synergistic effect on the induction of apoptosis in TP53 mutations CLL cells. In conclusion, we provide valuable pre-clinical experimental evidence for the treatment of CLL patients with poor prognosis, especially for TP53 mutations.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzamidas/farmacologia , Heme Oxigenase-1/metabolismo , Histona Desacetilase 1/metabolismo , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piridinas/farmacologia , Proteína Supressora de Tumor p53/genética , Vidarabina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/efeitos dos fármacos , Benzamidas/administração & dosagem , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Histona Desacetilase 1/biossíntese , Histona Desacetilase 1/genética , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Piridinas/administração & dosagem , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Vidarabina/administração & dosagem , Vidarabina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/biossíntese , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
5.
Mol Cell Biochem ; 459(1-2): 131-139, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31114934

RESUMO

To investigate the expression status of FAM98A and its potential involvement in endometrial carcinoma, the relative expression of FAM98A in clinical endometrial carcinoma tissues was analyzed by immunohistochemistry and real-time polymerase chain reaction. Endogenous FAM98A protein was determined by Western blotting. The overall survival was calculated by the Kaplan-Meier's analysis. Cell growth/viability/proliferation was evaluated by cell counting, 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide assay, and clonogenic assay, respectively. Cell apoptosis was determined by the Annexin V/7-AAD double-staining methods followed by flow cytometry analysis. The regulatory effect of miR-142-3p on FAM98A was interrogated by luciferase reporter assay. Aberrant overexpression of FAM98A was found in endometrial carcinoma both in vitro and in vivo. Furthermore, high level of FMA98A was associated with poor prognosis. FAM98A deficiency in Ishikawa and RL95-2 cells significantly inhibited cell growth, cell viability, and cell proliferation. In addition, FAM98A-knockdown stimulated remarkable cell apoptosis, which might be mediated by down-regulation of BCL2 and up-regulation of BAX. Mechanistically, it was demonstrated that miR-142-3p directly targeted FAM98A, and modulated its expression. In conclusion, we unraveled the oncogenic properties of FAM98A in endometrial carcinoma and highlighted the miR-142-3p-FAM98A signaling in this disease.


Assuntos
Proliferação de Células , Neoplasias do Endométrio/metabolismo , Proteínas/metabolismo , Apoptose , Linhagem Celular Tumoral , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas/genética , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Proteína X Associada a bcl-2/biossíntese , Proteína X Associada a bcl-2/genética
6.
Molecules ; 24(8)2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991627

RESUMO

Peperomin E is a natural secolignan existing distributed in the plants of the genus Peperomia. Previous investigations demonstrated that peperomin E showed potential antitumor activity in some cancer lines, but it is unclear whether peperomin E has an effect on prostate cancer cell lines. The aim of the present study is to investigate its effects on proliferation inhibition, apoptosis-inducing and cell-cycle arrest activity using a prostate cancer PC-3 cell line. The proliferation inhibition was evaluated by MTT assay, apoptosis was detected by Annexin V/propidium iodide (PI) staining and Hoechst 33258 staining, cell cycle distributions were measured by flow cytometry, and western blot analysis was used to determine specific cellular apoptotic protein expressions of Bcl-2, Bax, caspase-3 and cleaved-caspase-3. According to the results of this study, peperomin E exhibited significant anti-proliferation activity on PC-3 cell lines in vitro in a dose-dependent manner. Peperomin E treatments lead to marked morphological changes. Apoptotic cell count and cell-cycle distribution at G2/M phase significantly increased with increasing concentrations of peperomin E. The down-regulated expression level of Bcl-2 and up-regulated expression level of Bax and cleaved-caspase-3 compared with the controls were also observed after peperomin E treatment. These data suggest that peperomin E exhibited proliferation inhabitation, apoptosis-inducing and cell-cycle arrest activity on PC-3 cell lines. The anti-proliferation effect of peperomin E on PC-3 cells should result partly from its cell-cycle arrest and apoptosis-inducing activity, whereas the increasing of the Bax/Bcl-2 ratio and activation of caspases-3 play an important role in the development of apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Benzodioxóis/farmacologia , Caspase 3/biossíntese , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Células PC-3 , Neoplasias da Próstata/patologia , Regulação para Cima/efeitos dos fármacos
7.
Mol Cell Biochem ; 458(1-2): 185-195, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31004308

RESUMO

In this study, we aimed to evaluate whether the encapsulation of ellagic acid (EA) into nanoliposomes would improve its potential in preventing cyclophosphamide-induced liver damage. Stability and antioxidative potential of free and encapsulated EA were determined. Experimental study conducted in vivo included ten groups of rats treated with cyclophosphamide and ellagic acid in its free and encapsulated form during 5 days. The protective effect of EA in its free and encapsulated form was determined based on serum liver function, liver tissue antioxidative capacities, and oxidative tissue damage parameters. Also, tissue morphological changes following cyclophosphamide administration were studied using standard histopathological and immunohistochemical analyses. The encapsulation of EA significantly prevented its degradation and improved its antioxidant properties in in vitro conditions. In in vivo experiments in both forms of EA were found to prevent rat liver damage induced by cyclophosphamide estimated through the changes in serum liver-damage parameters and tissue antioxidant capacities, as well as based on oxidatively modified lipids and proteins. Also, changes in morphology of liver cells and the expressions of Bcl-2, HIF-1α, and CD15 molecules in livers of animals of different experimental groups are in accordance with the obtained biochemical parameters. Thus, the encapsulation process might be effective in preventing EA from different environmental influences and could significantly increase its hepatoprotective potential. The encapsulation could prevent ellagic acid degradation and might deliver this potent compound to its target tissue in significantly larger quantities than when it is administered in its free form.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Ciclofosfamida/efeitos adversos , Ácido Elágico/farmacologia , Fígado/metabolismo , Nanopartículas , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Ciclofosfamida/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Antígenos CD15/biossíntese , Lipossomos , Fígado/lesões , Fígado/patologia , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Ratos , Ratos Wistar
8.
J Biochem Mol Toxicol ; 33(7): e22324, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30951608

RESUMO

INTRODUCTION: Due to their unique properties including cellular uptake and the delivery efficiency to biological systems, nanoparticles are used in various preclinical and clinical applications. The aim of this study was to investigate the toxicity impacts of zinc oxide nanoparticles (ZnO-NPs) on morphology and functionality of the rat's liver and spleen and illustrated its safe-therapeutic doses. METHODS: The 28 female Swiss albino rats (180-220 g) and two human hepatocyte cell lines (HepG2 and HUH7) were designed as an in vivo and in vitro study, respectively. Samples were treated with certain doses of ZnO-NPs. The rat's liver morphology and functionality and apoptotic genes expression profile (Bax, Bcl-2, and P53) were analyzed to detect the cytotoxicity and antitumor impacts of ZnO-NPs, respectively. RESULTS: The results showed a positive significant association between the increasing doses of ZnO-NPs and alanine aminotransferase/aspartate aminotransferase values. Moreover, a meaningful correlation was detected between the rat's liver and spleen weight and ZnO-NPs doses. Furthermore, the histopathological analysis of rat's liver showed the individual cytotoxic properties of ZnO-NPs. Finally, the positive significant correlation was detected among the expression of Bax and P53 genes with ZnO-NPs. In addition, the negative correlation was demonstrated between the expression of Bcl-2 and ZnO-NPs. CONCLUSION: In general, in the current study, the antitumor effects of ZnO-NPs were confirmed by the enhancement of P53 and Bax genes expression profile, which are indicated the apoptotic induction in HUH7 cell line. Moreover, we introduced a safe-clinical ZnO-NPs dosage, have antitumor effects.


Assuntos
Citotoxinas , Neoplasias Hepáticas , Fígado , Nanopartículas , Baço , Óxido de Zinco , Animais , Citotoxinas/química , Citotoxinas/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Nanopartículas/química , Nanopartículas/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Ratos , Baço/metabolismo , Baço/patologia , Proteína Supressora de Tumor p53/biossíntese , Óxido de Zinco/química , Óxido de Zinco/farmacologia , Proteína X Associada a bcl-2/biossíntese
9.
Med Sci Monit ; 25: 1283-1290, 2019 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-30772887

RESUMO

BACKGROUND Ursolic acid is an important bioactive triterpenoid that has been reported to be of tremendous pharmacological importance. However, the anticancer potential of ursolic acid has not been examined against metastatic melanoma cells. Therefore, in this study we examined the anticancer potential of ursolic acid and its mode of action. MATERIAL AND METHODS WST-1 and colony formation assays were used for cell viability assessment. Cell cycle analysis was performed by flow cytometry. Apoptosis was detected by AO/EB staining using fluorescence microscopy. Cell migration and invasion were assessed by Boyden chamber assay. Protein expression was checked by Western blotting. RESULTS The results revealed that ursolic acid exerts significant (p<0.01) growth-inhibitory effects on SK-MEL-24 cells. The IC50 of ursolic acid against SK-MEL-24 cells was 25 µM. Our investigation of the underlying mechanism revealed that ursolic acid prompts apoptotic cell death of the SK-MEL-24 cells, which was linked with increased expression of Bax and Caspase 3 and 9, and decreased expression of Bcl-2. Ursolic acid also halted the SK-MEL-24 cells at G0/G1 phase of the cell cycle and also downregulated the expression of Cyclin B1 and Cdc25. Ursolic acid significantly (p<0.01) inhibited the migration and invasion of SK-MEL-2 cells, indicative of its anti-metastatic potential. Finally, ursolic acid inhibited the MAPK/ERK pathway by suppressing the expression of p-P38 and p-ERK. CONCLUSIONS Ursolic acid appears to be a potent molecule for the treatment of melanoma.


Assuntos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melanoma/tratamento farmacológico , Triterpenos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/biossíntese , Caspase 9/biossíntese , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Melanoma/enzimologia , Melanoma/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese
10.
Med Sci Monit ; 25: 730-738, 2019 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-30681073

RESUMO

BACKGROUND Berberine, a natural isoquinoline alkaloid derived from Berberis genus plants, has been reported to have anti-cancer effects. While cell behavior can be modulated by long non-coding RNAs (lncRNAs), the contributions of lncRNAs in progression and berberine effects on colorectal cancer are largely unknown. Therefore, the present study investigated the involvement and regulatory function of lncRNA cancer susceptibility candidate 2 (CASC2) during the treatment of human colorectal cancer using berberine. MATERIAL AND METHODS Reverse transcription-quantitative PCR (RT-qPCR) was performed to detect the expression levels of lncRNA CASC2 and Bcl-2 mRNA in colorectal cancer cells. MTT assay was performed to evaluate cell viability. Flow cytometry and TUNEL assay were used to analyze the apoptosis of cancer cells. RNA immunoprecipitation (RIP) assay was done to verify the interaction between lncRNA CASC2 and (AU-binding factor 1) AUF1, or AUF1 and B-cell CLL/lymphoma 2 (Bcl-2). RESULTS Treatment with berberine suppressed cell viability of colorectal cancer by promoting apoptosis level. LncRNA CASC2 was upregulated in cells treated with berberine, and knockdown of lncRNA CASC2 reversed the berberine-induced apoptosis. In addition, anti-apoptotic gene Bcl-2 was suppressed by berberine treatment and lncRNA CASC2, inducing the pro-apoptotic effects. Moreover, lncRNA CASC2 binds to AUF1, which sequestered AUF1 from binding to Bcl-2 mRNA, thus inducing the inactivation of Bcl-2 translation. CONCLUSIONS Our study reveals that lncRNA CASC2 mediates the berberine-induced pro-apoptotic effect via inhibition of Bcl-2 expression at the post-transcriptional level.


Assuntos
Berberina/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , RNA Longo não Codificante/genética , Proteínas Supressoras de Tumor/genética , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Progressão da Doença , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HT29 , Ribonucleoproteínas Nucleares Heterogêneas Grupo D/metabolismo , Humanos , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima
11.
Artigo em Inglês | MEDLINE | ID: mdl-30595209

RESUMO

Color Index (C.I.) Disperse Blue 291 (DB291) is an azo dye used by the textile industry. After yarn dyeing, wastewater containing the dye, released into the aquatic environment, may pollute drinking water sources. We investigated the mutagenicity and genotoxicity of DB291 in male Swiss mice, following oral administration. Micronucleated cells, primary DNA damage (comet assay) in blood, liver, and kidney cells, and BAX, BCL2, SMAD4 and TNFA gene expression in leukocytes were evaluated. An increased frequency of micronucleated polychromatic erythrocytes (MNPCEs) was observed in animals treated with 50 mg/kg bw; no other genetic alteration was detected. Neither primary DNA damage nor changes in gene expression were observed.


Assuntos
Compostos Azo/toxicidade , Medula Óssea/efeitos dos fármacos , Corantes/toxicidade , Eritrócitos Anormais/efeitos dos fármacos , Animais , Compostos Azo/farmacologia , Ensaio Cometa , Dano ao DNA/genética , Expressão Gênica/efeitos dos fármacos , Leucócitos/metabolismo , Masculino , Camundongos , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteína Smad4/biossíntese , Fator de Necrose Tumoral alfa/biossíntese , Águas Residuárias/química
12.
Pathol Oncol Res ; 25(2): 471-476, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29270778

RESUMO

The relationship between PAX2 and another anti-apoptotic gene, BCL-2, has been shown in a limited number of studies. The aims of this study are to investigate the value of PAX2 and BCL-2 expressions in lesions which have been defined as nonatypical hyperplasia in terms of detecting EIN and to evaluate the relations of these proteins in EIN. For this purpose, 108 cases of non-atypical endometrial hyperplasia diagnosed from 2006 to 2011 were re-evaluated. Immunohistochemical studies with PAX2 and BCL-2 were performed in 20 cases with EIN and 34 cases with benign hyperplasia. The mean BCL-2 immunohistochemistry scores of benign hyperplasia and EIN cases were 4.06 ± 1.04 and 4.63 ± 2.03, respectively. The mean BCL-2 score of EIN cases was significantly higher than benign hyperplasia (p = 0.021). The mean PAX2 scores of benign hyperplasia and EIN cases were 4.32 ± 1.07 and 2.19 ± 2.34, respectively. The mean PAX2 scores of EIN cases were significantly lower than benign hyperplasia (p = 0.001). BCL-2 expression was increased compared to normal endometrium in 66.7% of EIN cases, and PAX2 expression was decreased in 73.3%. Consistent with this, in 60% of cases, BCL-2 expression was increased compared to normal endometrium, while PAX2 expression was decreased. BCL-2 and PAX2 protein expression changes occur in early phases of endometrial tumorigenesis. These changes are often seen as a simultaneous increase in BCL-2 expression and decrease in PAX2 expression.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma in Situ/diagnóstico , Neoplasias do Endométrio/diagnóstico , Fator de Transcrição PAX2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Adulto , Idoso , Carcinoma in Situ/patologia , Carcinoma Endometrioide/diagnóstico , Carcinoma Endometrioide/patologia , Hiperplasia Endometrial/diagnóstico , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/patologia , Adulto Jovem
13.
J Biol Chem ; 294(1): 195-209, 2019 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-30409903

RESUMO

Lineage specification of the three germ layers occurs during early embryogenesis and is critical for normal development. The nucleosome remodeling and deacetylase (NuRD) complex is a repressive chromatin modifier that plays a role in lineage commitment. However, the role of chromodomain helicase DNA-binding protein 4 (CHD4), one of the core subunits of the NuRD complex, in neural lineage commitment is poorly understood. Here, we report that the CHD4/NuRD complex plays a critical role in neural differentiation of mouse embryonic stem cells (ESCs). We found that RNAi-mediated Chd4 knockdown suppresses neural differentiation, as did knockdown of methyl-CpG-binding domain protein Mbd3, another NuRD subunit. Chd4 and Mbd3 knockdowns similarly affected changes in global gene expression during neural differentiation and up-regulated several mesendodermal genes. However, inhibition of mesendodermal genes by knocking out the master regulators of mesendodermal lineages, Brachyury and Eomes, through a CRISPR/Cas9 approach could not restore the impaired neural differentiation caused by the Chd4 knockdown, suggesting that CHD4 controls neural differentiation by not repressing other lineage differentiation processes. Notably, Chd4 knockdown increased the acetylation levels of p53, resulting in increased protein levels of p53. Double knockdown of Chd4 and p53 restored the neural differentiation rate. Furthermore, overexpression of BCL2, a downstream factor of p53, partially rescued the impaired neural differentiation caused by the Chd4 knockdown. Our findings reveal that the CHD4/NuRD complex regulates neural differentiation of ESCs by down-regulating p53.


Assuntos
Diferenciação Celular , DNA Helicases/metabolismo , Regulação para Baixo , Neurônios/metabolismo , Nucleossomos/metabolismo , Proteína Supressora de Tumor p53/biossíntese , Animais , Linhagem Celular , DNA Helicases/genética , Técnicas de Silenciamento de Genes , Camundongos , Células-Tronco Embrionárias Murinas , Neurônios/citologia , Nucleossomos/genética , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína Supressora de Tumor p53/genética
14.
Pathol Res Pract ; 215(3): 446-452, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30558966

RESUMO

Hydatidiform moles (HM) are characterized by an abnormal proliferating trophoblast with a potential for a malignant transformation. Similar to other human tumors, trophoblastic pathogenesis is likely a multistep process involving several molecular and genetic alterations. The study was performed to investigate the expression patterns of c-erbB-2 and Bcl-2 oncoproteins, p53, p21WAF1/CIP1 and p63 tumor suppressor proteins and Ki-67 cell proliferation marker in HM. We conducted a retrospective study of 220 gestational products, including 39 hydropic abortions (HA), 41 partial HM (PHM) and 140 complete HM (CHM). The expression of c-erbB-2, Bcl-2, p53, p21WAF1/CIP1, p63 and Ki-67 was investigated by immunohistochemistry on archival tissues. c-erbB-2 expression was observed in three PHM and 10 CHM. Bcl-2 immunostaining was significantly higher in PHM (61%) and CHM (70.7%) compared with HA (7.7%, p = 0.001 and p < 0.0001, respectively). p53 expression was stronger in CHM (73.6%) compared with PHM (24.4%, p < 0.0001) and HA (12.8%, p < 0.0001). p21WAF1/CIP1 staining was observed as well in molar and non-molar gestations (p > 0.05). p63 immunoexpression was significantly described in CHM (85.7%) and PHM (78%) compared with HA (10.2%, p < 0.0001 and p = 0.0001, respectively). Ki-67 was significantly expressed in CHM (72.1%) compared with HA (46.2%, p = 0.005). Altered expression of Bcl-2, p53, p63 and Ki-67 reflects the HM pathological development. Immunohistochemical analysis is beneficial to recognize the HM molecular and pathogenic mechanisms. Furthermore, it could serve as a useful adjunct to conventional methods for refining HM diagnosis.


Assuntos
Biomarcadores Tumorais/análise , Mola Hidatiforme/patologia , Neoplasias Uterinas/patologia , Adolescente , Adulto , Inibidor de Quinase Dependente de Ciclina p21/análise , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Feminino , Humanos , Mola Hidatiforme/metabolismo , Imuno-Histoquímica , Antígeno Ki-67/análise , Antígeno Ki-67/biossíntese , Proteínas de Membrana/análise , Proteínas de Membrana/biossíntese , Pessoa de Meia-Idade , Gravidez , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Receptor ErbB-2/análise , Receptor ErbB-2/biossíntese , Estudos Retrospectivos , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/biossíntese , Neoplasias Uterinas/metabolismo , Adulto Jovem
15.
J Cutan Pathol ; 46(3): 182-189, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30511443

RESUMO

BACKGROUND: Primary cutaneous follicular center-cell lymphoma (PCFCL) is one of the most common types of cutaneous B-cell lymphoma. Differences in immunohistochemical expression of BCL2 and CD10 antigens along with the presence of t(14:18) translocation in neoplastic cells have been postulated as relevant clues in differentiating PCFCL from cutaneous lesions secondary to a systemic follicular lymphoma (SCFL). The aim of this study is to evaluate the significance and usefulness of these parameters in a large series of patients. METHODS: Patients with PCFCL and SCFL diagnosed at three university hospitals in Barcelona, from 2000 to 2015 were reviewed. Clinical, histopathological, immunophenotypical, genetic, and outcome parameters were analyzed. RESULTS: Eighty-one cases (59 PCFCL and 22 SCFL) were included. There were no significant differences between PCFCL and SCFL cases regarding clinical presentation, site of involvement, or predominant type of skin lesions. Most patients in both groups showed positivity for BCL2 and CD10, but strong expression of BCL2 and CD10 was associated with SCFL cases. Although more frequent in SCFL, a small proportion of PCFCL cases also showed the t(14:18) on FISH analysis. CONCLUSION: The intensity of BCL2 expression was found to be the single most valuable clue in differentiating PCFCL from SCFL cases on histopathological grounds.


Assuntos
Biomarcadores Tumorais/análise , Linfoma Folicular/diagnóstico , Neoplasias Cutâneas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 18/genética , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neprilisina/análise , Neprilisina/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Translocação Genética/genética , Adulto Jovem
16.
Biomed Pharmacother ; 109: 2192-2202, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551476

RESUMO

Chemotherapy is the main postsurgical and adjuvant therapy for glioma, and intrinsic or acquired temozolomide (TMZ) resistance may result in poor prognosis. The miR-181 family was discovered to play an important role in regulating biological functions in glioma, and miR-181b is less expressed in human gliomas as a tumor-suppressive miRNA. The aim of this study was to explore the molecular mechanism of miR-181b-5p and its target gene on modulating TMZ chemosensitivity in glioma cells. The enhanced chemosensitivity effect of miR-181b-5p to TMZ in glioma cells U87MG and U251 was detected by MTT method. Dual luciferase reporter assay, quantitative real-time PCR (qRT-PCR) and Western blotting were performed to demonstrate that miR-181b-5p directly targets Bcl-2 to reduce the expression. Transwell and flow cytometry assays showed that combination of miR-181b-5p and TMZ exerted stronger effects on inhibiting U87MG cells proliferation, migration and invasion as well as promoting apoptosis and S phase arrest than miR-181b-5p and TMZ alone. The same tendency was observed in the upregulation of apoptosis-related protein Bax and downregulation of cycle-related proteins CyclinD1 and CDK4. In vivo experiments indicated that miR-181b-5p could enhance the tumor-suppressive effect of TMZ. In conclusion, our findings indicate that upregulation of miR-181b-5p targets Bcl-2 directly and may function as an important modifier to sensitize glioma cells to TMZ.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , MicroRNAs/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Temozolomida/administração & dosagem , Animais , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Glioma/tratamento farmacológico , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/administração & dosagem , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
17.
Rev Bras Ginecol Obstet ; 40(12): 733-739, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30536268

RESUMO

OBJECTIVE: To determine the role of caspase-3, apoptosis-inducing factor (AIF), and B-cell lymphoma-2 (Bcl-2) expressions in term premature rupture of membrane (PROM). METHODS: An analytic observational study with case-control design was conducted, involving 52 subjects (37-42 weeks of gestation) who were divided into 2 groups: 26 cases of term delivery with PROM, and 26 controls of term delivery without PROM. The expressions of caspase-3, AIF, and Bcl-2 in the amniotic membrane were determined by immunohistochemistry. Data were analyzed using the chi-squared test. The risk of PROM was expressed by odds ratio (OR). RESULTS: There were no significant differences in age, parity and body mass index between the two groups (p > 0.05). High caspase-3 and AIF expressions increased the risk of PROM 17.64 times (OR = 17.64; 95% CI = 4.44-70.07; p = 0.001) and 9.45 times (OR = 9.45; 95% CI= 2.62-34.07; p = 0.001), respectively, while low Bcl-2 expression increased 10.39 times (OR = 10.39; 95% CI = 2.73-39.56; p = 0.001)the risk of PROM . CONCLUSION: High caspase-3 and AIF expressions and low Bcl-2 expression were risk factors for term PROM. Caspase-dependent and independent pathways of apoptosis were involved in the mechanism of PROM in term pregnancy.


Assuntos
Fator de Indução de Apoptose/biossíntese , Caspase 3/biossíntese , Ruptura Prematura de Membranas Fetais/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Gravidez
18.
Med Sci Monit ; 24: 8391-8400, 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30459299

RESUMO

BACKGROUND The aims of this study were to investigate the expression of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) in human tissue containing clear cell renal cell carcinoma (CCRCC) compared with normal renal tissue, and the effects of upregulating the expression of MTHFD1 in the human CCRCC cell line, Caki-1. MATERIAL AND METHODS Tumor and adjacent normal renal tissue were obtained from 44 patients who underwent radical nephrectomy for CCRCC. Caki-1 human CCRCC cells were divided into the control group, the empty vector (EV) group, and the plasmid-treated group that overexpressed MTHFD1. MTHFD1 mRNA and protein levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot, respectively. The cell counting kit-8 (CCK-8) assay measured cell viability. Flow cytometry evaluated apoptosis and the cell cycle. Western blot measured the protein levels of MTHFD1, Bax, Bcl-2, Akt, p53, and cyclin D1, and qRT-PCR determined the gene expression profiles. RESULTS MTHFD1 mRNA and protein levels in CCRCC tumor tissues were significantly lower compared with adjacent normal renal tissue. MTHFD1 over-expression in Caki-1 cells inhibited cell proliferation, arrested cells in the G1 phase, increased cell apoptosis, and upregulated gene and protein expression of Bax/Bcl-2 and p53 and inhibited p-Akt, and cyclin D1. CONCLUSIONS MTHFD1 was underexpressed in CCRCC tissue when compared with normal renal tissue. MTHFD1 transfection of human CCRCC Caki-1 cells in vitro inhibited cell proliferation and promoted apoptosis, associated with reduced expression of cyclin D1, reduced Akt phosphorylation, and increased expression of Bax/Bcl-2 and p53.


Assuntos
Carcinoma de Células Renais/enzimologia , Neoplasias Renais/enzimologia , Metilenotetra-Hidrofolato Desidrogenase (NADP)/biossíntese , Antígenos de Histocompatibilidade Menor/biossíntese , Apoptose/fisiologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Ciclina D1/biossíntese , Ciclina D1/genética , Ciclina D1/metabolismo , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Metilenotetra-Hidrofolato Desidrogenase (NADP)/metabolismo , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/biossíntese , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcriptoma , Proteína Supressora de Tumor p53/biossíntese , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/biossíntese , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
19.
Biomed Res Int ; 2018: 1942451, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30402464

RESUMO

Barbatimão (Stryphnodendron adstringens, Mart.) is a native Brazilian species used in traditional medicine and some commercial preparations owing to its strong wound-healing activity. However, controversy regarding its use due to safety concerns over the potential genotoxic effect of this plant remains. In order to clarify this issue, the effect of hydroalcoholic extract of barbatimão in vitro on cell viability, DNA damage, and induction of apoptosis in two commercial cell lines of keratinocytes (HaCaT) and fibroblasts (HFF-1) was evaluated. Barbatimão stem bark hydroalcoholic extract (70% ethanol) was obtained and lyophilized for subsequent use in all experiments. The main bioactive molecules quantified by HPLC were gallic acid, caffeic acid, quercetin, catechin, and epigallocatechin gallate (EGCG). Barbatimão (0.024 to 1.99 mg/mL) was found to decrease cellular mortality as compared to the control group. GEMO assay, a noncellular DNA protocol that uses H2O2-exposed calf thymus DNA, revealed not only a genotoxic effect of barbatimão, but also a potential genoprotective action against H2O2-triggered DNA fragmentation. These results indicated that barbatimão at concentrations of 0.49 and 0.99 mg/mL, which are near to the levels found in commercial preparations, exerted an in vitro genoprotective effect on cells by decreasing the levels of DNA oxidation quantified by 8-hydroxy-2'-deoxyguanosine (8-OHdG) and reactive oxygen species (ROS) levels. Gene and protein apoptotic markers, quantified by qRT-PCR (BAX/Bcl-2 genes) and immunoassays (Caspases 3 and 8), respectively, also indicated a decrease in apoptotic events in comparison with control cells. Collectively, the results suggest that barbatimão could exert genoprotective and antiapoptotic effects on human keratinocytes and fibroblasts.


Assuntos
Dano ao DNA , Fragmentação do DNA/efeitos dos fármacos , Fabaceae/química , Fibroblastos/metabolismo , Queratinócitos/metabolismo , Extratos Vegetais/farmacologia , Caspase 3/biossíntese , Caspase 8/biossíntese , Fibroblastos/patologia , Humanos , Peróxido de Hidrogênio/farmacologia , Queratinócitos/patologia , Extratos Vegetais/química , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteína X Associada a bcl-2/biossíntese
20.
Med Sci Monit ; 24: 7869-7874, 2018 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-30390390

RESUMO

BACKGROUND This study investigated the expression of Bax/Bcl-2, TGF-ß1 and type III collagen fiber in sternocleidomastoid of congenital muscular torticollis (CMT), and explored the possible mechanisms of fibrosis in sternocleidomastoid of CMT. MATERIAL AND METHODS The localization and expression of Bax, Bcl-2, TGF-ß1, and type III collagen were detected in the control group and experimental group by using immunohistochemical staining method. The RT-PCR assay was used to measure the expression of TGF-ß1 in the control group and experimental group. RESULTS HE staining results showed that the collagen fiber in the experimental group had more abundant hyperplasia compared to the control group (p<0.05). Immunohistochemical staining results showed that the expression of Bax, Bax/Bcl-2, TGF-ß1, and type III collagen in the experimental group was significantly increased compared to the control group (p<0.01). There were positive correlations between expression of Bax/Bcl-2 and TGF-b1, and between expression of TGF-ß1 and type III collagen fiber (p<0.05, r=0.32 and 0.83, respectively). The RT-PCR results showed that the expression of TGF-ß1 mRNA was also significantly elevated in the experimental group compared to the control group (p<0.05). CONCLUSIONS Increased muscular apoptosis may aggravate the formation of muscular fibrosis, which may be involved in the pathogenesis of sternocleidomastoid of CMT.


Assuntos
Colágeno Tipo III/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Torcicolo/congênito , Fator de Crescimento Transformador beta1/biossíntese , Proteína X Associada a bcl-2/biossíntese , Apoptose/fisiologia , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Feminino , Fibrose/metabolismo , Humanos , Imuno-Histoquímica , Lactente , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Torcicolo/genética , Torcicolo/metabolismo , Transcriptoma , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
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