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1.
Front Cell Dev Biol ; 9: 736298, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34616742

RESUMO

Immunotherapy is a novel clinical approach that has shown clinical efficacy in multiple cancers. However, only a fraction of patients respond well to immunotherapy. Immuno-oncological studies have identified the type of tumors that are sensitive to immunotherapy, the so-called hot tumors, while unresponsive tumors, known as "cold tumors," have the potential to turn into hot ones. Therefore, the mechanisms underlying cold tumor formation must be elucidated, and efforts should be made to turn cold tumors into hot tumors. N6-methyladenosine (m6A) RNA modification affects the maturation and function of immune cells by controlling mRNA immunogenicity and innate immune components in the tumor microenvironment (TME), suggesting its predominant role in the development of tumors and its potential use as a target to improve cancer immunotherapy. In this review, we first describe the TME, cold and hot tumors, and m6A RNA modification. Then, we focus on the role of m6A RNA modification in cold tumor formation and regulation. Finally, we discuss the potential clinical implications and immunotherapeutic approaches of m6A RNA modification in cancer patients. In conclusion, m6A RNA modification is involved in cold tumor formation by regulating immunity, tumor-cell-intrinsic pathways, soluble inhibitory mediators in the TME, increasing metabolic competition, and affecting the tumor mutational burden. Furthermore, m6A RNA modification regulators may potentially be used as diagnostic and prognostic biomarkers for different types of cancer. In addition, targeting m6A RNA modification may sensitize cancers to immunotherapy, making it a promising immunotherapeutic approach for turning cold tumors into hot ones.

2.
J Int Med Res ; 49(3): 300060521997718, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33752504

RESUMO

OBJECTIVE: C-X-C motif chemokine ligand 5 (CXCL5), a member of the chemokine family, is associated with remodeling of connective tissues. However, its role in formation of intrauterine adhesions (IUA) remains unclear. We aimed to investigate the expression and mechanism underlying the role of CXCL5 in IUA. METHODS: Expression of CXCL5 in IUA was detected by immunohistochemistry in a rat model of IUA and by real-time PCR and western blotting in patients with IUA. The protein levels of matrix metalloproteinase 9 (MMP9) and transcription factor p65 in human endometrial cells were assessed by western blotting after CXCL5 overexpression. RESULTS: Protein expression of CXCL5 was significantly decreased in the endometria of IUA rats compared with that of control and sham-operated rats. Real-time PCR and western blotting in patients with IUA showed similar results to those from the rat model. After overexpression, CXCL5 significantly upregulated expression of MMP9 and slightly upregulated expression of p65 in human endometrial cells. CONCLUSIONS: CXCL5 plays an important role in IUA formation after endometrial injury. We propose a molecular mechanism to explain formation of IUA, including downregulation of MMP9 by low CXCL5 expression. These findings provide valuable information for the prevention and targeted therapy of IUA.


Assuntos
Doenças Uterinas , Animais , Quimiocina CXCL5/genética , Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Metaloproteinase 9 da Matriz/genética , Ratos , Aderências Teciduais/patologia , Doenças Uterinas/patologia
3.
Mediators Inflamm ; 2021: 6676510, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33574731

RESUMO

Objective: Intrauterine adhesions affect menstruation and fertility, and endometrial fibrosis is the final manifestation of IUA. MMP-9 is closely related to fibrosis. The purpose of the study was to assess the role of MMP-9 in intrauterine adhesion (IUA) in rats and patients. Methods: 40 rats and 24 women were enrolled in this study. 40 rats were randomly divided into 3 groups: IUA group (n = 20), sham group (n = 10), and control group (n = 10). Rat IUA models were established by intrauterine mechanical and chemical injured. In this study, 12 patients of intrauterine adhesions were detected and underwent TCRA (transcervical resection of adhesion) surgery, and endometrial tissue specimens were obtained during operation. One month later, an office hysteroscopy procedure was performed, and endometrial tissue specimens were obtained during operation again (postoperative group). A group of 12 normal age-matched control individuals served as controls underwent hysteroscopy and endometrial sampling. We used immunohistochemistry to detect MMP-9 expressions in rats and human endometrial tissues and to detect MMP-9 protein levels by Western blotting. In addition, we detected mRNA expression levels with qRT-PCR. Results: The expression of MMP-9 in the IUA rats was reduced compared with that in the sham group and Ctrl group (P < 0.05), and the expression of MMP-9 was also reduced in the IUA patients compared with that in the Ctrl group (P < 0.05). The mRNA levels of MMP-9 in the endometrium reflected similar results (P < 0.05). The MMP-9 clearly increased even in the endometrium after TCRA surgery (P < 0.05). Conclusion: Our study suggests that MMP-9 may play an important role in IUA. In the future, more in-depth research should be conducted on MMP-9.


Assuntos
Metaloproteinase 9 da Matriz/metabolismo , Aderências Teciduais/enzimologia , Útero/metabolismo , Adulto , Animais , Estudos de Casos e Controles , Endométrio/metabolismo , Feminino , Fibrose , Humanos , Histeroscopia , Masculino , Menstruação , Ratos , Ratos Sprague-Dawley , Doenças Uterinas/metabolismo , Adulto Jovem
4.
Front Pharmacol ; 11: 1281, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013364

RESUMO

Nod-like receptor (NLR) family caspase activation and recruitment domain containing 5 (NLRC5) is a newly identified sub-class of the NLR family. It regulates inflammation and has a key function in innate and adaptive immunologic reactions. Autophagy has been reported to be crucially linked to the pathogenesis of endometriosis. Our recent study identify there is a negative correlation between NLRC5 and autophagy in endometriosis, indicating that NLRC5 and autophagy together act as promising predictors in endometriosis patients. However, the mechanism associating NLRC5 and autophagy in endometriosis is still not completely understood. We hypothesize that autophagy could be involved in NLRC5-mediated inflammation in endometriosis. In order to validate the assumption, we evaluate the effects of NLRC5 and autophagy in the inflammation of ectopic endometrial stromal cells (EESCs) of ovarian endometriosis patients, to specifically determine whether autophagy is involved in NLRC5-mediated inflammation in EESCs. Our results show that over-expression of NLRC5 results in the up-regulation of autophagy in EESCs and inhibition of NLRC5 restricts the level of autophagy in EESCs. Furthermore, over-expression of NLRC5 and promotion of autophagy inhibit interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) expressions, whereas inhibition of NLRC5 and autophagy up-regulate IL-6 and TNF-α expressions in EESCs. Additionally, promotion of autophagy contributes to the NLRC5-mediated inhibition of IL-6 and TNF-α expressions in EESCs; inhibition of autophagy restricts NLRC5-mediated inhibition of IL-6 and TNF-α expressions in EESCs. Our results suggest that over-expression of NLRC5 promotes autophagy, thereby inhibiting inflammation in ovarian endometriosis.

5.
J Int Med Res ; 48(5): 300060520925352, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32431202

RESUMO

OBJECTIVE: NOD-like receptor family caspase recruitment domain family domain-containing 5 (NLRC5) is involved in the development of cancer. Our objective was to explore the role of NLRC5 in the progression of endometrial cancer (EC). METHODS: The roles of NLRC5 in migration and invasion of AN3CA EC cells were examined by cell wound-healing assay, Transwell migration, and invasion analysis. Overexpression of NLRC5 was achieved with NLRC5 plasmid, and knockdown of NLRC5 was achieved using small interfering (si)RNA-NLRC5 in AN3CA cells. The expression of NLRC5 was detected by immunohistochemical, western blot, and quantitative real-time PCR. LY294002 was used to inhibit the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway. RESULTS: NLRC5 was downregulated in EC tissue compared with normal endometrium. Overexpression of NLRC5 led to upregulation of cell migration and invasion in AN3CA cells and expression of matrix metallopeptidase (MMP)-9. Inhibition of NLRC5 restricted migration and invasion of AN3CA cells and expression of MMP9. Overexpression of NLRC5 promoted the activation of PI3K/AKT signaling pathway. Inhibiting PI3K/AKT signaling pathway by using LY294002 blocked the positive role of NLRC5 in migration and invasion of AN3CA cells and expression of MMP9. CONCLUSIONS: These results demonstrate that NLRC5 promotes EC progression by activating the PI3K/AKT signaling pathway.


Assuntos
Neoplasias do Endométrio/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromonas/farmacologia , Progressão da Doença , Neoplasias do Endométrio/cirurgia , Endométrio/patologia , Endométrio/cirurgia , Feminino , Humanos , Histerectomia , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Morfolinas/farmacologia , Invasividade Neoplásica/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
Eur J Ophthalmol ; 30(3): 455-461, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-30832500

RESUMO

PURPOSE: To report the laboratory findings, management strategies, and visual outcomes of culture-proven exogenous fungal endophthalmitis in North China. METHODS: The microbiological and treatment records of patients with culture-positive exogenous fungal endophthalmitis who visited the Affiliated Hospital of Qingdao University from January 2012 to December 2016 were reviewed. RESULTS: A total of 39 eyes (39 patients) were identified over a 5-year period. Exogenous fungal endophthalmitis was associated with penetrating trauma in 22 eyes (56.4%), fungal keratitis in 15 eyes (38.5%), and intraocular surgery in 2 eyes (5.1%). Hyphae were found in 29 of 37 smear samples (78.4%) by direct microscopic examination. Fungal pathogens cultured from 39 samples were identified as 10 genera and 15 species. Filamentous fungi (molds) accounted for 94.9% (37 samples), including Fusarium (19, 48.7%) and Aspergillus (11, 28.2%). Most keratitis cases were caused by Fusarium (11 of 15; 73.3 %). Aspergillus was isolated from nine penetrating ocular trauma cases (9 of 22; 40.9%). Three eyes receiving evisceration had fungal and bacteria coinfection (3 of 39, 7.7%) with Aspergillus and Bacillus. At least, one surgical intervention was performed in all 39 eyes and 28 (71.8%) eyes underwent two or more procedures, including surgeries and intraocular injections. Twenty-nine patients received intraocular antifungal therapy with amphotericin B and/or voriconazole. Visual acuity at discharge from the hospital was significantly better than the initial visual acuity (p < 0.001). Final vision of 20/400 or better was achieved in 22 (56.4%) eyes. CONCLUSIONS: This study highlighted the differences between clinical categories of exogenous fungal endophthalmitis. Trauma was the major etiological factor. Molds were the most common pathogens, with Fusarium ranking first, followed by Aspergillus. Fungal and bacterial coinfection mostly occurred after metal penetrating trauma, and Bacillus was the primary bacterial pathogen. Coinfection may be one reason of evisceration. Immediate intravitreal antifungal therapy combined with vitrectomy was effective for exogenous fungal endophthalmitis. Amphotericin B and voriconazole were commonly used antifungal agents.


Assuntos
Úlcera da Córnea/microbiologia , Endoftalmite/microbiologia , Infecções Oculares Fúngicas/microbiologia , Ferimentos Oculares Penetrantes/microbiologia , Adolescente , Adulto , Idoso , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Criança , Pré-Escolar , China , Úlcera da Córnea/diagnóstico , Úlcera da Córnea/tratamento farmacológico , Quimioterapia Combinada , Endoftalmite/diagnóstico , Endoftalmite/tratamento farmacológico , Infecções Oculares Fúngicas/diagnóstico , Infecções Oculares Fúngicas/tratamento farmacológico , Ferimentos Oculares Penetrantes/diagnóstico , Ferimentos Oculares Penetrantes/tratamento farmacológico , Feminino , Fungos/isolamento & purificação , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Acuidade Visual/fisiologia , Vitrectomia/métodos , Voriconazol/uso terapêutico
7.
Toxicol In Vitro ; 61: 104626, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31419505

RESUMO

It is well known that embryonic development can be perturbed by environmental factors such as heavy metals. Mercury is one of the most significant threats to the environment and human health. Mercury can damage many parts of the human body, including lungs, kidneys, nerves and fetus. However, the effect of mercury on human embryo remains unknown. Here, we showed that HgCl2 treatment resulted in a significant increase in apoptosis in HTR-8/SVneo cells. However, the effect of HgCl2 on apoptosis was partially reduced by the combination treatment with TGF-ß1 and HgCl2 in HTR-8/SVneo cells. Moreover, HgCl2 treatment gradually decreased the expression of TGF-ß1 in a dose dependent manner. Furthermore, a P38 MAPK inhibitor, SB202190, decreased the cell apoptosis and caspase activation induced by HgCl2 in trophoblast cells. In addition, TGF-ß1 alleviated HgCl2 induced apoptosis of HTR-8/SVneo cells via p38 MAPK signaling pathway, which was involved in the TAK1 expression. These results might provide a theoretical basis for mercury induced trophoblast associated embryo damage and a potential avenue of intervention.


Assuntos
Cloreto de Mercúrio/toxicidade , Fator de Crescimento Transformador beta1/metabolismo , Trofoblastos/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Humanos , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/genética , Trofoblastos/metabolismo
8.
Cancer Cell Int ; 19: 86, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30996686

RESUMO

Background: Ovarian cancer is known as one of the most common cancers in the world among women. ST6GALNAC1 is highly expressed in cancer stem cells (CSCs), which correlates to high tumor-initiating, self-renewal and differentiation abilities. This present study aims to investigate how ST6GALNAC1 affects ovarian cancer stem cells (OCSCs). Methods: In order to identify the differentially expressed genes related to ovarian cancer, microarray-based gene expression profiling of ovarian cancer was used, and ST6GALANC1 was one of the identified targets. After that, levels of ST6GALNAC1 in OCSCs and ovarian cancer cells were examined. Subsequently, an Akt signaling pathway inhibitor LY294002 was introduced into the cluster of differentiation 90+ (CD90+) stem cells, and cell proliferation, migration and invasion, levels of CXCL16, EGFR, CD44, Nanog and Oct4, as well as tumorigenicity of OCSCs were examined. Results: By using a comprehensive microarray analysis, it was determined that ST6GALNAC1 was highly expressed in ovarian cancer and it regulated the Akt signaling pathway. High levels of ST6GALNAC1 were observed in OCSCs and ovarian cancer cells. Silencing ST6GALNAC1 was shown to be able to reduce cell proliferation, migration, invasion, self-renewal ability, tumorigenicity of OCSCs. In accordance with these results, the effects of ST6GALNAC1 in OCSCs were dependent on the Akt signaling pathway. Conclusions: When taken together, our findings defined the potential stimulative roles of ST6GALNAC1 in ovarian cancer and OCSCs, which relied on the Akt signaling pathway.

9.
BMC Womens Health ; 19(1): 16, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683081

RESUMO

BACKGROUND: SNF5 is a key protein in regulating cell proliferation and apoptosis in various cancers. However, the physiological roles of SNF5 in Endometrial carcinoma (EC), which is one of the most frequent malignancies of the female reproduction worldwide, remains unclear. This study aims to investigate the role of SNF5 and its correlation with clinicopathologic characteristics in EC. METHODS: We performed immunohistochemistry to detect the SNF5 expression in 46 endometrial carcinomas and 20 normal endometrium (non-EC) specimens, as well as analyzed the correlations between SNF5 expression and clinicopathologic features of patients using a statistics software (GraphPad Prism V6.0). Western blotting had been used to confirm the protein level of SNF5 in endometrial tissues. In addition, we evaluated the correlations between SNF5 and p21 in EC. RESULTS: The positive immunostaining rate for SNF5 in EC and non-EC specimens were 65% (30/46) and 25% (5/20) respectively, and the expression of SNF5 was dramatically increased in EC compared with the normal endometrium (P < 0.01). The overexpression of SNF5 was associated with the PR levels, but not with age, FIGO stage, grade, lymphatic metastasis, myometrial invasion or ER status. Knockdown of SNF5 inhibits the expression of p21. CONCLUSIONS: Our results indicate that SNF5 plays an important role of promoting oncogenesis in EC. These findings open up the possibility for various novel and effective combination therapies targeting SNF5 in the EC.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias do Endométrio/metabolismo , Proteína SMARCB1/metabolismo , Adulto , Idoso , Neoplasias do Endométrio/patologia , Endométrio/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Pessoa de Meia-Idade , Miométrio/patologia , Estadiamento de Neoplasias , Prognóstico
10.
Fertil Steril ; 110(5): 949-956, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30316442

RESUMO

OBJECTIVE: To investigate the levels of NLRC5 and autophagy in women with leiomyoma and endometriosis and the correlation between NLRC5 level and autophagy level. DESIGN: Case-control study. SETTING: Clinics. PATIENT(S): Sixty-five patients were recruited: 30 women with endometriosis were compared with 35 women with leiomyoma. INTERVENTION(S): Endometriosis was definitively diagnosed during surgery by laparoscopy or laparotomy and was confirmed by histopathological evaluation (n=30). Secretory phase ectopic endometrium tissues and eutopic endometrium tissues were obtained from 30 women with endometriosis. Control endometrium tissues were collected at hysterectomy from 35 women with leiomyoma. Immunohistochemical staining of NLRC5, LC3, Beclin1 and P62 were performed. MAIN OUTCOME MEASURE(S): A semiquantitative analysis was performed. Correlations between NLRC5 level and LC3, Beclin1, P62 levels were compared. RESULT(S): The expressions of NLRC5 and P62 in the ectopic and eutopic endometrium of endometriosis groups were significantly higher than that in the endometrium of leiomyoma group. And their expressions in ectopic endometrium were significantly up-regulated compared to the eutopic endometrium. The expressions of LC3 and Beclin1 were down-regulated in the ectopic and eutopic endometrium of endometriosis groups compared to the leiomyoma group. LC3 and Beclin1 levels were lower in ectopic endometrium than in the eutopic endometrium. There is a negative correlation between NLRC5 level and LC3, Beclin1 levels. There is a positive correlation between NLRC5 level and P62 level. CONCLUSION(S): There is a negative correlation between NLRC5 level and autophagy level. NLRC5 and autophagy combined may as promising predictors in patients with endometriosis.


Assuntos
Autofagia/fisiologia , Endometriose/metabolismo , Endométrio/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Adulto , Biomarcadores/metabolismo , Endometriose/diagnóstico , Endométrio/patologia , Feminino , Humanos , Leiomioma/diagnóstico , Leiomioma/metabolismo , Pessoa de Meia-Idade , Valor Preditivo dos Testes
11.
J Cell Biochem ; 119(7): 5233-5242, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29236306

RESUMO

The objective of this study was to explore the role of rs4705342 located in the miR-143 promoter in relation to the control of HBV positive HCC and the underlying molecular mechanism. A luciferase assay was performed to explore the factors which influenced miR-143 transcription activity and the target gene of miR-143. This would further be confirmed by ChIP assay. Western blot and real-time PCR were performed to identify the relationship between miR-143 and ORP8. Luciferase activity of miR-143 SNP was increased with the presence of C allele. The presence of T allele partially restored the transcription ability. NF-κB displayed a much higher degree of luciferase activity in relation to the cells transfected with vectors containing either T or C allele rather than control cells with a greater extent in C allele group than T allele group. At the same time, ChIP assay indicated that the affinity of NF-ΚB in the miR-143 promoter was higher in C/C cells. The over-expression of HBX promotes NF-kB expression thus increasing the extent of binding of NF-kB on the CC allele of the miR-143 promoter. The binding is also abolished by NF-kB siRNA. ORP8 was proven to be a target gene of miR-143 using bioinformatics algorithm analysis. It was further confirmed by the luciferase assay that miR-143 substantially inhibited luciferase activities of wild-type ORP8. However, it did not affect the mutant ORP8. HBx induced by HBV infection up-regulated miR-143 expression. NF- kB can partially abolish the promotion effect of HBx on the miR-143 level in cells genotyped as CC but not in cells genotyped as TT. Tissues derived from participants genotyped as CC exhibited a higher level of miR-143, but a lower level of ORP8. The presence of the minor allele of rs4705342 in the promoter of miR-143 attenuated the transcription ability. This promoted ORP8 expression and could be a factor contributing to the oncogenesis in HBV positive HCC.


Assuntos
Vírus da Hepatite B/patogenicidade , Neoplasias Hepáticas/genética , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Polimorfismo Genético/genética , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Imunoprecipitação da Cromatina , Genótipo , Humanos , Imuno-Histoquímica , MicroRNAs/genética , Regiões Promotoras Genéticas/genética , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo
12.
Nucleic Acids Res ; 44(17): 8112-28, 2016 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-27226492

RESUMO

BPTF associated protein of 18 kDa (BAP18) has been reported as a component of MLL1-WDR5 complex. However, BAP18 is an uncharacterized protein. The detailed biological functions of BAP18 and underlying mechanisms have not been defined. Androgen receptor (AR), a member of transcription factor, plays an essential role in prostate cancer (PCa) and castration-resistant prostate cancer (CRPC) progression. Here, we demonstrate that BAP18 is identified as a coactivator of AR in Drosophilar experimental system and mammalian cells. BAP18 facilitates the recruitment of MLL1 subcomplex and AR to androgen-response element (ARE) of AR target genes, subsequently increasing histone H3K4 trimethylation and H4K16 acetylation. Knockdown of BAP18 attenuates cell growth and proliferation of PCa cells. Moreover, BAP18 depletion results in inhibition of xenograft tumor growth in mice even under androgen-depletion conditions. In addition, our data show that BAP18 expression in clinical PCa samples is higher than that in benign prostatic hyperplasia (BPH). Our data suggest that BAP18 as an epigenetic modifier regulates AR-induced transactivation and the function of BAP18 might be targeted in human PCa to promote tumor growth and progression to castration-resistance.


Assuntos
Proteínas de Transporte/metabolismo , Progressão da Doença , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas/metabolismo , Receptores Androgênicos/metabolismo , Sequência de Aminoácidos , Animais , Proteínas de Transporte/química , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Proteínas de Ligação a DNA , Drosophila melanogaster/metabolismo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HEK293 , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Masculino , Camundongos , Proteína de Leucina Linfoide-Mieloide/metabolismo , Regiões Promotoras Genéticas/genética , Neoplasias da Próstata/genética , Ligação Proteica , Proteínas/química , Proteínas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ativação Transcricional/genética , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Int J Biol Sci ; 11(9): 992-1005, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26221067

RESUMO

Estrogen receptor α (ERα) is a key transcriptional factor in the proliferation and differentiation in mammary epithelia and has been determined to be an important predictor of breast cancer prognosis and therapeutic target. Meanwhile, diverse transcriptional co-regulators of ERα play crucial and complicated roles in breast cancer progression. Mediator of DNA damage checkpoint 1 (MDC1) has been identified as a critical upstream mediator in the cellular response to DNA damage, however, some non-DNA damage responsive functions of MDC1 haven't been fully defined. In this study, we have identified MDC1 as a co-activator of ERα in breast cancer cells and demonstrated that MDC1 associates with ERα. MDC1 was also recruited to estrogen response element (ERE) of ERα target gene. Knockdown of MDC1 reduced the transcription of the endogenous ERα target genes, including p21. MDC1 depletion led to the promotion of breast cancer progression, and the expression of MDC1 is lower in breast cancer. Taken together, these results suggested that MDC1 was involved in the enhancement of ERα-mediated transactivation in breast cancer cells. This positive regulation by MDC1 might contribute to the suppression of breast cancer progression by acting as a barrier of positive to negative ERα function transformation.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas Nucleares/metabolismo , Transativadores/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Western Blotting , Neoplasias da Mama/genética , Proteínas de Ciclo Celular , Linhagem Celular , Proliferação de Células/genética , Proliferação de Células/fisiologia , Citometria de Fluxo , Imunofluorescência , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoprecipitação , Células MCF-7 , Camundongos , Proteínas Nucleares/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Transativadores/genética , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Nucleic Acids Res ; 43(10): 4893-908, 2015 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-25934801

RESUMO

Mediator of DNA damage checkpoint protein 1 (MDC1) is essential for DNA damage response. However, the role of MDC1 in modulating gene transcription independently of DNA damage and the underlying mechanisms have not been fully defined. Androgen receptor (AR) is the central signaling pathway in prostate cancer (PCa) and its target genes are involved in both promotion and suppression of PCa. Here, we functionally identified MDC1 as a co-activator of AR. We demonstrate that MDC1 facilitates the association between AR and histone acetyltransferase GCN5, thereby increasing histone H3 acetylation level on cis-regulatory elements of AR target genes. MDC1 knockdown promotes PCa cells growth and migration. Moreover, depletion of MDC1 results in decreased expression of a subset of the endogenous androgen-induced target genes, including cell cycle negative regulator p21 and PCa metastasis inhibitor Vinculin, in AR positive PCa cell lines. Finally, the expression of MDC1 and p21 correlates negatively with aggressive phenotype of clinical PCa. These studies suggest that MDC1 as an epigenetic modifier regulates AR transcriptional activity and MDC1 may function as a tumor suppressor of PCa, and provide new insight into co-factor-AR-signaling pathway mechanism and a better understanding of the function of MDC1 on PCa.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/metabolismo , Coativadores de Receptor Nuclear/metabolismo , Neoplasias da Próstata/genética , Receptores Androgênicos/metabolismo , Transativadores/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Animais Geneticamente Modificados , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiologia , Células HEK293 , Humanos , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Elementos de Resposta , Ativação Transcricional , Fatores de Transcrição de p300-CBP/metabolismo
15.
Invest Ophthalmol Vis Sci ; 55(12): 8031-43, 2014 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-25406294

RESUMO

PURPOSE: Cataract-microcornea syndrome (CCMC) is an autosomal dominant inherited disease characterized by the association of congenital cataract and microcornea without any other systemic anomaly or dysmorphism. Although mutations of several genes have been shown to cause dominant CCMC, in many patients the causative gene has not yet been identified. Our aim was to identify the disease-associated gene in Chinese patients with CCMC. METHODS: The CCMC patients from two unrelated Chinese families and 26 sporadic patients were enrolled. All the patients were screened by Sanger sequencing with no identified mutations. Genetic variations were screened by whole-exome sequencing and then validated using Sanger sequencing. RESULTS: By sequencing the whole exome of three patients in a Chinese four-generation dominant CCMC family (Family A), three heterozygous missense mutation (c.115C>G, c.277G>A, and c.4393G>A) were identified in ATP-binding cassette protein A3 (ABCA3). At highly conserved positions, changes (c.115C>G and c.4393G>A) were predicted to have functional impacts and completely cosegregated with the phenotype. We further confirmed our finding by identifying another heterozygous missense mutation, c.2408C>T, in ABCA3 in an additional dominant CCMC family (Family B), which also cosegregated with the phenotype. Moreover, four heterozygous mutations, two missense mutations (c.4253A>T, c.2069A>T) and two splice site mutations (c.4053+2T>C, c.2765-1G>T) were identified from the sporadic patients. The ABCA3 protein was expressed in human lens capsule, choroid-retinal pigment epithelium and retinal pigment epithelial cells. CONCLUSIONS: Mutations in the human ABCA3 gene were associated with lethal respiratory distress. Our study showed, for the first time to our knowledge, that mutations in ABCA3 were associated with CCMC, warranting further investigations on the pathogenesis of this disorder.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Catarata/genética , Doenças da Córnea/genética , Mutação de Sentido Incorreto , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Catarata/metabolismo , Catarata/patologia , Criança , Doenças da Córnea/metabolismo , Doenças da Córnea/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Lactente , Masculino , Linhagem , Fenótipo , Sítios de Splice de RNA/genética , Análise de Sequência de DNA , Adulto Jovem
16.
Bioresour Technol ; 155: 144-51, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24445191

RESUMO

The mutual interactions among the consortium constructed by four indigenous bacteria and five inter-kingdom fusants and the effects of nitrogen and carbon supplementations on lignin degradation and laccase activity were investigated. Analyzed by Plackett-Burman and central composite design, the microbial consortium were optimized, Bacillus sp. (B) and PE-9 and Pseudomonas putida (Pp) and PE-9 had significant interactions on lignin degradation based on a 5% level of significance. The nitrogen and carbon supplementations played an important role in lignin degradation and laccase production. The ultimate lignin degradation efficiency of 96.0% and laccase activity of 268U/L were obtained with 0.5g/L of ammonium chloride and 2g/L of sucrose. Results suggested that a stable and effective microbial consortium in alkalescent conditions was successfully achieved through the introduction of fusants, which was significant for its industrial application.


Assuntos
Bactérias/metabolismo , Biodegradação Ambiental/efeitos dos fármacos , Carbono/farmacologia , Microbiologia Industrial/métodos , Lignina/metabolismo , Consórcios Microbianos/fisiologia , Nitrogênio/farmacologia , Lacase/metabolismo
17.
Zhonghua Yan Ke Za Zhi ; 50(11): 808-13, 2014 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-25582205

RESUMO

OBJECTIVE: To evaluate epidemiologic features and laboratory findings of fungal endophthalmitis in north China. METHODS: Eighty-one patients (81 eyes) were diagnosed with fungal endophthalmitis at our institution from January 2000 to December 2012. Patient history, etiological agents, direct smear examination, fungal culture and pathogen sensitivity to antifungal drug were evaluated. RESULTS: The fungal endophthalmitis was exogenous in 73 cases (90.1%), among which 43 had fungal keratitis in which Fusarium was the first pathogen occupied 88.4% (38 of 43 cases). Twenty seven of 73 cases (33.3%) occurred after penetrating ocular trauma and Aspergillus was the most common pathogens isolated in these cases (11 of 27; 40.7%). The left 3 cases were associated with ocular surgery. Four of the other eight eyes (9.9%) with endogenous infection had association with drug abuse. Aspergillus was the main isolated pathogens from the endogenous fungal endophthalmitis (4 of 8 cases). Hyphae were found in 52 (77.6%) of 67 smear samples by direct microscopic examination. Fungal pathogens cultured from 81 samples were identified as 10 genera and 18 species; Fusarium accounted for 60.5% (49 eyes), Aspergillus for 21.0% (17 eyes) and Candida for 6.2% (5/81). The total sensitive rate of Fusarium and Aspergillus in vitro to voriconazole, amphotericin B, ketconazole, itraconazole and fluconazole was 84.7% (33/39), 71.8% (28/39), 43.6% (17/39), 17.9% (7/39) and 7.7% (3/39) respectively. CONCLUSIONS: Fungal endophthalmitis in north China is predominantly exogenous. Fungal keratitis and penetrating trauma are the main common etiological factors. Fusarium ranks first in pathogens, followed by Aspergillus and Candida. Fusarium was the first pathogen of exogenous fungal endophthalmitis caused by fungal keratitis. Aspergillus was the most common isolated pathogens from exogenous fungal endophthalmitis caused by penetrating ocular trauma and it also was the first pathogen of endogenous fungal endophthalmitis. Microscopic detection of hyphae from samples is helpful in the diagnosis. Fusarium ranks first in pathogens, followed by Aspergillus. They both are more sensitive to voriconazole and amphotericin B than ketconazole, fluconazole and itraconazole.


Assuntos
Endoftalmite/microbiologia , Infecções Oculares Fúngicas/microbiologia , Ceratite/microbiologia , Antifúngicos , Aspergilose/tratamento farmacológico , Aspergilose/microbiologia , China , Infecções Oculares Fúngicas/tratamento farmacológico , Fusariose/tratamento farmacológico , Fusariose/microbiologia , Humanos
18.
Mol Cell Endocrinol ; 365(1): 36-43, 2013 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-22975079

RESUMO

Endocrine disrupting chemicals (EDCs) have emerged as a major public health issue because of their potentially disruptive effects on physiological hormonal actions. SXR (steroid xenobiotic receptor), also known as NR1I2, regulates CYP3A expression in response to exogenous chemicals, such as EDCs, after binding to SXRE (SXR response element). In our study, luciferase assay showed that 14 out of 55 EDCs could enhance SXR-mediated rat or human CYP3A gene transcription nearly evenly, and could also activate rat CYP7A1 gene transcription by cross-interaction of SXR and LXRE (LXRα response element). SXR diffused in the nucleus without ligand, whereas intranuclear foci of liganded SXR were produced. Furthermore, endogenous mRNA expression of CYP3A4 gene was enhanced by the 14 positive EDCs. Our results suggested a probable mechanism of EDCs disrupting the steroid or xenobiotic metabolism homeostasis via SXR.


Assuntos
Colesterol 7-alfa-Hidroxilase/biossíntese , Citocromo P-450 CYP3A/biossíntese , Disruptores Endócrinos/farmacologia , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Receptores de Esteroides/agonistas , Ativação Transcricional/efeitos dos fármacos , Animais , Linhagem Celular , Chlorocebus aethiops , Colesterol 7-alfa-Hidroxilase/genética , Citocromo P-450 CYP3A/genética , Disruptores Endócrinos/toxicidade , Genes Reporter/efeitos dos fármacos , Células Hep G2 , Humanos , Rim/citologia , Rim/enzimologia , Rim/metabolismo , Fígado/enzimologia , Fígado/metabolismo , Receptores X do Fígado , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Receptores Nucleares Órfãos/agonistas , Receptores Nucleares Órfãos/química , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/metabolismo , Receptor de Pregnano X , Regiões Promotoras Genéticas/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Ratos , Receptores de Esteroides/química , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Elementos de Resposta/efeitos dos fármacos
19.
Chin Med J (Engl) ; 125(3): 470-5, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22490405

RESUMO

BACKGROUND: Hypopyon is common in eyes with fungal keratitis. The evaluation of the clinical features, culture results and the risk factors for hypopyon and of the possible correlation between hypopyon and the treatment outcome could be helpful for making treatment decisions. METHODS: The medical records of 1066 inpatients (1069 eyes) with fungal keratitis seen at the Shandong Eye Institute from January 2000 to December 2009 were reviewed retrospectively for demographic features, risk factors, clinical characteristics, laboratory findings and treatment outcomes. The incidence of hypopyon, the fungal culture positivity for hypopyon, risk factors for hypopyon and the effect of hypopyon on the treatment and prognosis were determined. RESULTS: We identified 1069 eyes with fungal keratitis. Of the 850 fungal culture-positive eyes, the Fusarium species was the most frequent (73.6%), followed by Alternaria (10.0%) and Aspergillus (9.0%). Upon admission, 562 (52.6%) eyes with hypopyon were identified. The hypopyon of 66 eyes was evaluated via fungal culturing, and 31 eyes (47.0%) were positive. A total of 194 eyes had ocular hypertension, and 172 (88.7%) of these eyes had hypopyon (P < 0.001). Risk factors for incident hypopyon included long duration of symptoms (P < 0.001), large lesion size (P < 0.001) and infection caused by the Fusarium and Aspergillus species (P < 0.001). The positivity of fungal culture for hypopyon was associated with duration of symptoms and lesion size. Surgical intervention was more common in cases with hypopyon (P < 0.001). Hypopyon was a risk factor for the recurrence of fungal keratitis after corneal transplantation (P = 0.002). CONCLUSIONS: Hypopyon is common in patients with severe fungal keratitis and can cause ocular hypertension. About half of the hypopyon cases were positive based on fungal culture. Long duration of symptoms, large lesion size and infection with the Fusarium and Aspergillus species were risk factors for hypopyon. The presence of hypopyon increases the likelihood of surgical intervention.


Assuntos
Câmara Anterior/patologia , Infecções Oculares Fúngicas/microbiologia , Ceratite/microbiologia , Adulto , Aspergillus/patogenicidade , Infecções Oculares Fúngicas/cirurgia , Feminino , Fusarium/patogenicidade , Humanos , Ceratite/cirurgia , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
20.
Zhonghua Yi Xue Za Zhi ; 92(1): 32-5, 2012 Jan 03.
Artigo em Chinês | MEDLINE | ID: mdl-22490655

RESUMO

OBJECTIVE: To retrospectively analyze the etiological characteristics of infectious endophthalmitis so as to improve the positive detection rate of its pathogens in laboratory test. METHODS: The epidemiological features and laboratory findings of 319 inpatients (319 eyes) diagnosed with infectious endophthalmitis at our institute from January 2000 to December 2010 were retrospectively reviewed and analyzed. RESULTS: Ocular trauma (n = 230, 72.10%) was a major risk factor for infectious endophthalmitis. Bacteria and fungi were isolated from intraocualr specimens with the positive rates of 43.57% (139/319) and 18.22% (49/269) respectively. The positive rates of bacteria culture were 29.00% for nutrient broth medium and 50.23% for blood enrichment medium respectively. And the difference was statistically significant (χ(2) = 12.58, P < 0.01). The sensitivity of isolated bacteria to levofloxacin was 81.82%. The geometric mean of minimal inhibitory concentrations of amphotericin B, fluconazole, ketoconazole and itraconazole against fungi were 1.05, 5.07, 3.00 and 2.42 µg/ml respectively. CONCLUSION: The major cause of infectious endophthalmitis is ocular trauma and the dominant pathogen is bacteria. The use of blood enrichment medium may improve the positive rate of bacteria culture. Levofloxacin and amphotericin B are indicated for the treatment of bacterial and fungal endophthalmitis.


Assuntos
Endoftalmite/microbiologia , Infecções Oculares Bacterianas/microbiologia , Infecções Oculares Fúngicas/microbiologia , Feminino , Humanos , Masculino , Técnicas Microbiológicas , Estudos Retrospectivos
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