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1.
Oncogene ; 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420377

RESUMO

The advanced or recurrent endometrial cancer (EC) has a poor prognosis because of chemoresistance. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a glycolytic enzyme, is overexpressed in a variety of human cancers and plays important roles in promoting tumor cell growth. Here, we showed that high expression of PFKFB3 in EC cell lines is associated with chemoresistance. Pharmacological inhibition of PFKFB3 with PFK158 and or genetic downregulation of PFKFB3 dramatically suppressed cell proliferation and enhanced the sensitivity of EC cells to carboplatin (CBPt) and cisplatin (Cis). Moreover, PFKFB3 inhibition resulted in reduced glucose uptake, ATP production, and lactate release. Notably, we found that PFK158 with CBPt or Cis exerted strong synergistic antitumor activity in chemoresistant EC cell lines, HEC-1B and ARK-2 cells. We also found that the combination of PFK158 and CBPt/Cis induced apoptosis- and autophagy-mediated cell death through inhibition of the Akt/mTOR signaling pathway. Mechanistically, we found that PFK158 downregulated the CBPt/Cis-induced upregulation of RAD51 expression and enhanced CBPt/Cis-induced DNA damage as demonstrated by an increase in γ-H2AX levels in HEC-1B and ARK-2 cells, potentially revealing a means to enhance PFK158-induced chemosensitivity. More importantly, PFK158 treatment, either as monotherapy or in combination with CBPt, led to a marked reduction in tumor growth in two chemoresistant EC mouse xenograft models. These data suggest that PFKFB3 inhibition alone or in combination with standard chemotherapy may be used as a novel therapeutic strategy for improved therapeutic efficacy and outcomes of advanced and recurrent EC patients.

2.
BMC Med Genomics ; 14(1): 8, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407456

RESUMO

BACKGROUND: The abnormal expression of activating transcription factor 3 (ATF3), a member of the basic leucine zipper (bZIP) family of transcription factors, is associated with carcinogenesis. However, the expression pattern and exact role of ATF3 in the development and progression of hepatocellular carcinoma (HCC) remain unclear. METHODS: We used UALCAN, ONCOMINE, Kaplan-Meier plotter, and cBioPortal databases to investigate the prognostic value of ATF3 expression in HCC. RESULTS: ATF3 was found to be expressed at low levels in multiple HCC tumor tissues. Moreover, low ATF3 expression was significantly associated with clinical cancer stage and pathological tumor grade in patients with HCC. Therefore, low expression of ATF3 was significantly associated with poor overall survival in patients with HCC. Functional network analysis showed that ATF3 regulates cytokine receptors and signaling pathways via various cancer-related kinases, miRNAs, and transcription factors. ATF3 expression was found to be correlated with macrophage infiltration levels and with macrophage immune marker sets in HCC patients. CONCLUSIONS: Using data mining methods, we clarified the role of ATF3 expression and related regulatory networks in HCC, laying a foundation for further functional research. Future research will validate our findings and establish clinical applications of ATF3 in the diagnosis and treatment of HCC.

3.
Cancer Med ; 2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33314779

RESUMO

BACKGROUND: The aim of this study was to determine the specific side detection rate of the sentinel lymph node biopsy and the accuracy in predicting lymph node metastasis in early stage cervical cancer. METHODS: A systematic search of databases was performed from the inception of the databases to 27 June 2020. Studies of cervical cancer patients with FIGO stage FIGO ⅠA~ⅡB, evaluating the sentinel lymph node biopsy with blue dye, technetium 99, combined technique (blue dye with technetium 99) or indocyanine green with a reference standard of systematic pelvis lymph node dissection or clinical follow-up were included. Stata12.0 and Meta-Disc 1.4 were used for the meta-analysis. RESULTS: Of 2825 articles found, 21 studies (2234 women) were eventually included. Out of 21 studies, 20 met the detection rate evaluation criteria and six were included for sensitivity meta-analysis. Due to heterogeneity, it was inappropriate to pool all studies. The pooled specific side detection rates were 85% in tumors up to 2 cm, 67% in tumors over 2 cm, 75.2% for blue dye, 74.7% for technetium 99, 84% for combined technique, and 85.5% for indocyanine green. The sentinel lymph node biopsy had a pooled specific side sensitivity of 88%. Adverse effects of sentinel lymph node biopsy appear minimal for most patients and are mainly related to the injection of blue dye. CONCLUSIONS: Sentinel lymph node biopsy using a tracer with a high detection rate and ultrastaging is highly accurate and reliable when limited to seriously selected patients, with satisfactory bilateral lymph node mapping and where enough cases for learning curve optimization exist. Indocyanine green sentinel lymph node mapping seems to be a superior sentinel lymph node mapping technique compared to other methods at present.

4.
Aging (Albany NY) ; 122020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33232273

RESUMO

Endometriosis is an estrogen-dependent inflammatory disorder, usually causing infertility, pelvic pain, and ovarian masses. This study intended to investigate the implication of N6-methyladenosine (m6A) regulators in endometriosis. We acquired 34 normal, 127 eutopic, and 46 ectopic, samples of endometrium from the Gene Expression Omnibus (GSE7305, GSE7307, GSE51981) database and the Array-express (E-MTAB-694) database. These samples were then used to profile the expression of 20 m6A regulators in endometriosis. The results indicated that most dysregulated (19/20) m6A regulators were significantly downregulated in eutopic vs. normal endometrium and also significantly downregulated in ectopic vs. eutopic endometrium. Several dysregulated m6A regulators were common to both contrast matrices: METTL3, YTHDF2, YTHDF3, HNRNPA2B1, HNRNPC, and FTO. Both HNRNPA2B1 and HNRNPC were associated with the severity of endometriosis in eutopic samples, and also exhibited diagnostic potential for endometriosis. HNRNPA2B1 and HNRNPC may influence immune pathways and the infiltration of immune cells in endometriosis. Abnormalities in the gene transcription factors network associated with endometriosis might affect the expression of HNRNPA2B1 and HNRNPC. In conclusion, we observed significant dysregulation of m6A regulators in endometriosis, and found that HNRNPA2B1 and HNRNPC might correlate with the immune response and serve as useful diagnostic biomarkers for endometriosis.

5.
Int J Immunopathol Pharmacol ; 34: 2058738420976309, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33237828

RESUMO

The current study intended to explore the interaction of the long non-coding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA) under the background of competitive endogenous RNA (ceRNA) network in endometriosis (EMs). The differentially expressed miRNAs (DEmiRs), differentially expressed lncRNA (DELs), and differentially expressed genes (DEGs) between EMs ectopic (EC) and eutopic (EU) endometrium based on three RNA-sequencing datasets (GSE105765, GSE121406, and GSE105764) were identified, which were used for the construction of ceRNA network. Then, DEGs in the ceRNA network were performed with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) analysis. Besides, the DEmiRs in the ceRNA network were validated in GSE124010. And the target DELs and DEGs of verified DEmiRs were validated in GSE86534. The correlation of verified DEmiRs, DEGs, and DELs was explored. Moreover, gene set enrichment analysis (GSEA) was applied to investigate the function of verified DEmiRs, DEGs, and DELs. Overall, 1352 DEGs and 595 DELs from GSE105764, along with 27 overlapped DEmiRs between GSE105765 and GSE121406, were obtained. Subsequently, a ceRNA network, including 11 upregulated and 16 downregulated DEmiRs, 7 upregulated and 13 downregulated DELs, 48 upregulated and 46 downregulated DEGs, was constructed. The GO and KEGG pathway analysis showed that this ceRNA network probably was associated with inflammation-related pathways. Furthermore, hsa-miR-182-5p and its target DELs (LINC01018 and SMIM25) and DEGs (BNC2, CHL1, HMCN1, PRDM16) were successfully verified in the validation analysis. Besides, hsa-miR-182-5p was significantly negatively correlated with these target DELs and DEGs. The GSEA analysis implied that high expression of LINC01018, SMIM25, and CHL1, and low expression of hsa-miR-182-5p would activate inflammation-related pathways in endometriosis EU samples.LINC01018 and SMIM25 might sponge hsa-miR-182-5p to upregulate downstream genes such as CHL1 to promote the development of endometriosis.

6.
Parkinsons Dis ; 2020: 1216568, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33062247

RESUMO

Introduction: This study investigated the influence of lockdown during the 2019 coronavirus disease (COVID-19) pandemic on the quality of life of patients with Parkinson's disease (PD). Methods: We conducted a questionnaire survey involving 113 patients with PD from Xihu District, Hangzhou, Zhejiang. During the epidemic prevention and control period (February 1 to March 31, 2020), patients enrolled were asked to fill out questionnaires, including the "COVID-19 Questionnaire for PD Patients during the Period of Epidemic Prevention and Control" and "39-item Parkinson's Disease Questionnaire (PDQ-39)." During the phase of gradual release of epidemic prevention and control (April 1 to April 30, 2020), all patients were followed up again, and PDQ-39 questionnaires were completed. Results: The quality of life for patients during the period of epidemic prevention and control was worse than that after epidemic prevention and control (P < 0.001). The biggest problem that they faced was that they could not receive their doctor's advice or guidance regularly. The quality of life of patients who had difficulty getting doctors' guidance or those who changed their routine medication due to lockdown was even worse. Telemedicine was quite effective and efficient for patients to get doctors' guidance during lockdown. Conclusions: The inconvenient treatment during the pandemic directly caused the aggravation of patients' symptoms and the decline in their quality of life. It is suggested that social media (such as WeChat or Tencent QQ) are used for regular interactions and follow-up appointments for patients with inconvenient medical treatment.

7.
Oncol Rep ; 44(5): 1929-1938, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32901849

RESUMO

Endometrial cancer is one of the three major malignant tumors of the female reproductive system. Although cyclin­dependent kinase 9 (CDK9) has a definitive pathogenic role in various types of cancer, little is known concerning its function in endometrial cancer. Our study was conducted to evaluate the expression and therapeutic potential of CDK9 in endometrial cancer. CDK9 expression was determined by immunohistochemistry in endometrial cancer tissues constructed with paired primary, metastatic, and recurrent tumor tissues from 32 endometrial cancer patients. Small interfering RNA (siRNA) and inhibitors of CDK9 were used to evaluate the effect of CDK9 inhibition on the anti­apoptotic activity and proliferation in endometrial cancer cells. Colony formation assay and wound­healing assays were adopted to assess clonal formation and migratory capacity. The results of the immunohistochemistry demonstrated that CDK9 was highly expressed in the human endometrial cancer cell lines; moreover, it was elevated in metastatic and recurrent endometrial tumor tissue compared when compared with that in patient­matched primary endometrial tumor tissue. Knockdown of CDK9 with siRNA and inhibition of CDK9 activity with the inhibitor suppressed cell proliferation and promoted apoptosis in endometrial cancer. In conclusion, our results provide evidence that CDK9 may be a potential prognostic biomarker and a promising therapeutic target for the treatment of endometrial cancer in the future.

8.
PeerJ ; 8: e9950, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983650

RESUMO

Background: Endometriosis (EMs) is a non-malignant gynecological disease, whose pathogenesis remains to be clarified. Recent studies have found that hypoxia induces epithelial-mesenchymal transition (EMT) as well as epigenetic modification in EMs. However, the relationship between EMT and demethylation modification under hypoxia status in EMs remains unknown. Methods: The expression of N-cadherin, E-cadherin and TET1 in normal endometria, eutopic endometria and ovarian endometriomas was assessed by immunohistochemistry and immunofluorescence double staining. 5-hmC was detected by fluorescence-based ELISA kit using a specific 5-hmC antibody. Overexpression and inhibition of TET1 or hypoxia-inducible factor 2α (HIF-2α) were performed by plasmid and siRNA transfection. The expression of HIF-2α, TET1 and EMT markers in Ishikawa (ISK) cells (widely used as endometrial epithelial cells) was evaluated by western blotting. The interaction of HIF-2α and TET1 was analyzed by chromatin immunoprecipitation. Results: Demethylation enzyme TET1 (ten-eleven translocation1) was elevated in glandular epithelium of ovarian endometrioma, along with the activation of EMT (increased expression of N-cadherin, and decreased expression of E-cadherin) and global increase of epigenetic modification marker 5-hmC(5-hydroxymethylcytosine). Besides, endometriosis lesions had more TET1 and N-cadherin co-localized cells. Further study showed that ISK cells exhibited enhanced EMT, and increased expression of TET1 and HIF-2α under hypoxic condition. Hypoxia-induced EMT was partly regulated by TET1 and HIF-2α. HIF-2α inhibition mitigated TET1 expression changes provoked by hypoxia. Conclusions: Hypoxia induces the expression of TET1 regulated by HIF-2α, thus may promote EMT in endometriosis.

9.
Br J Ophthalmol ; 2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32675061

RESUMO

AIMS: To determine the association between albuminuria and primary open-angle glaucoma (POAG). METHODS: Participants of the Singapore Chinese Eye study were recruited and underwent standardised ocular and systemic examinations. Albuminuria was determined using urinary albumin-to-creatinine ratio (UACR, mg/g) based on random spot urinary albumin and creatinine measurements. POAG was defined using the International Society of Geographic and Epidemiological Ophthalmology classification. Multivariable logistic regression with generalised estimating equation model was used to evaluate the association between albuminuria and POAG, while accounting for correlation between eyes. RESULTS: A total of 3009 Chinese adults (5963 eyes), aged 40-80 years, were included in this study, of which, 52 subjects (75 eyes) had POAG. Higher UACR (per 50 mg/g increase) was independently associated with POAG (OR=1.04, 95% CI 1.01 to 1.07, p=0.003) following adjustment for age, gender, intraocular pressure, diabetes mellitus, hyperlipidaemia, hypertension, anti-hypertensive medication, history of cardiovascular disease, current smoking status, alcohol intake, body mass index and estimated glomerular filtration rate. Further stratification revealed that individuals with macroalbuminuria were 8.00 times likely to have POAG (95% CI 2.97 to 21.54, p<0.001), compared with those with normoalbuminuria. Microalbuminuria was not significantly associated with POAG (OR=0.49, 95% CI 0.19 to 1.29, p=0.150). The association between macroalbuminuria and POAG remained significant among individuals who were diabetic (OR=9.89, 95% CI 2.49 to 39.30, p=0.001) and hypertensive (OR=8.39, 95% CI 3.07 to 22.94, p<0.001). CONCLUSION: In this population-based study of Chinese adults, albuminuria was independently associated with POAG. Our findings provide further understanding on the pathogenesis of POAG and may potentially help to better identify individuals at risk of POAG.

10.
Epigenomics ; 12(14): 1193-1213, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32462942

RESUMO

Aim: To investigate exosomal RNAs (long noncoding RNAs (lncRNAs), microRNAs (miRNAs) and messenger RNAs (mRNAs)) profiling and their related networks in endometriosis (EMs). Materials & methods: RNA sequence was performed in exosomes from ovarian endometriomas (EC), eutopic endometria (EU) and normal endometria (Control) stromal cells. The bioinformatics algorithms evaluated competing endogenous RNA (ceRNA) networks. The top-ranked ceRNA networks were confirmed by RT-PCR. Results: Overlapped differentially expressed 938 lncRNAs, 39 miRNAs and 1449 mRNAs were identified. 13 co-expression modules and 61 ceRNA networks were constructed. Conclusion: This study for the first time shows exosomal RNA biomarkers and lncRNA-related networks in EMs, which reveals a novel molecular mechanism of EMs and provides new resources for EM diagnosis and treatment.

11.
Asia Pac J Ophthalmol (Phila) ; 9(2): 88-95, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32349116

RESUMO

The rising popularity of artificial intelligence (AI) in ophthalmology is fuelled by the ever-increasing clinical "big data" that can be used for algorithm development. Cataract is one of the leading causes of visual impairment worldwide. However, compared with other major age-related eye diseases, such as diabetic retinopathy, age-related macular degeneration, and glaucoma, AI development in the domain of cataract is still relatively underexplored. In this regard, several previous studies explored algorithms for automated cataract assessment using either slit lamp of color fundus photographs. However, several other study groups proposed or derived new AI-based calculation for pre-cataract surgery intraocular lens power. Along with advancements in digitization of clinical data, data curation for future cataract-related AI developmental work is bound to undergo significant improvements in the foreseeable future. Even though most of these previous studies reported early promising performances, limitations such as lack of robust, high-quality training data, and lack of external validations remain. In the next phase of work, apart from algorithm's performance, it will also be pertinent to evaluate deployment angles, feasibility, efficiency, and cost-effectiveness of these new cataract-related AI systems.

12.
PeerJ ; 8: e8730, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32185115

RESUMO

Aims: To identify the common and specific molecular mechanisms of three well-defined subtypes of endometriosis (EMs): ovarian endometriosis (OE), peritoneal endometriosis (PE), and deep infiltrating endometriosis (DIE). Methods: Four microarray datasets: GSE7305 and GSE7307 for OE, E-MTAB-694 for PE, and GSE25628 for DIE were downloaded from public databases and conducted to compare ectopic lesions (EC) with eutopic endometrium (EU) from EMs patients. Differentially expressed genes (DEGs) identified by limma package were divided into two parts: common DEGs among three subtypes and specific DEGs in each subtype, both of which were subsequently performed with the Kyoto Encyclopedia of Genes (KEGG) pathway enrichment analysis. The protein-protein interaction (PPI) network was constructed by common DEGs and five hub genes were screened out from the PPI network. Besides, these five hub genes together with selected interested pathway-related genes were further validated in an independent OE RNA-sequencing dataset GSE105764. Results: A total of 54 EC samples from three EMs subtypes (OE, PE, DIE) and 58 EU samples were analyzed, from which we obtained 148 common DEGs among three subtypes, and 729 specific DEGs in OE, 777 specific DEGs in PE and 36 specific DEGs in DIE. The most enriched pathway of 148 shared DEGs was arachidonic acid (AA) metabolism, in which most genes were up-regulated in EC, indicating inflammation was the most common pathogenesis of three subtypes. Besides, five hub genes AURKB, RRM2, DTL, CCNB1, CCNB2 identified from the PPI network constructed by 148 shared DEGs were all associated with cell cycle and mitosis, and down-regulated in EC, suggesting a slow and controlled proliferation in ectopic lesions. The KEGG pathway analysis of specific DEGs in each subtype revealed that abnormal ovarian steroidogenesis was a prominent feature in OE; OE and DIE seems to be at more risk of malignant development since both of their specific DEGs were enriched in the pathways in cancer, though enriched genes were different, while PE tended to be more associated with dysregulated peritoneal immune and inflammatory microenvironment. Conclusion: By integrated bioinformatic analysis, we explored common and specific molecular signatures among different subtypes of endometriosis: activated arachidonic acid (AA) metabolism-related inflammatory process and a slow and controlled proliferation in ectopic lesions were common features in OE, PE and DIE; OE and DIE seemed to be at more risk of malignant development while PE tended to be more associated with dysregulated peritoneal immune and inflammatory microenvironment, all of which could deepen our perception of endometriosis.

13.
Vascul Pharmacol ; 127: 106659, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32068091

RESUMO

Macrophage plays critical roles in the pathogenesis of atherosclerosis (AS), and is an attractive target for detecting and treating vulnerable plaque. Our previous study showed that melatonin (MLT) ameliorated AS by suppressing the pro-inflammatory Toll-like receptor 4/nuclear factor kappa B system in high-fat-fed rabbit. However, it is unknown whether the anti-atherosclerotic properties of MLT are associated with the upregulation of anti-inflammatory hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-Met) system. In present study, we examined whether MLT could inhibit macrophage infiltration and promote plaque stabilization by upregulating HGF/c-Met system with ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) assessment in AS rabbit. Rabbits in this study were randomly divided into three groups and treated with a standard diet, high-fat diet, and high-fat diet plus 10 mg/kg/day MLT for 12 weeks, respectively. MLT treatment significantly reversed spotty signal void in 3D-TOF MRI, standard signal intensity reduction in T2WI MRI and aortic luminal area reduction in 2D-TOF MRI of the atherosclerotic abdominal aorta 72 h after USPIO injection. It also decreased serum interleukin-6 (IL-6), intima/media thickness ratio of the abdominal aorta, CD68 and iron-positive areas in the aortic intima, and increased serum IL-10, HGF and c-Met protein expression and the accumulation of vascular smooth muscle cell and collagen fiber in the aortic intima of AS rabbit. Our data demonstrated that MLT significantly decreased plaque macrophage infiltration and promoted plaque stability in AS rabbit assessed by USPIO-enhanced MRI. Remarkably, it was very first revealed that upregulation of anti-inflammatory HGF/c-Met system might contribute to the atheroprotective mechanisms of MLT.


Assuntos
Anti-Inflamatórios/farmacologia , Aorta Abdominal/efeitos dos fármacos , Doenças da Aorta/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Meios de Contraste/administração & dosagem , Dextranos/administração & dosagem , Fator de Crescimento de Hepatócito/metabolismo , Macrófagos/efeitos dos fármacos , Imagem por Ressonância Magnética , Nanopartículas de Magnetita/administração & dosagem , Melatonina/farmacologia , Placa Aterosclerótica , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/metabolismo , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/metabolismo , Aterosclerose/diagnóstico por imagem , Aterosclerose/metabolismo , Modelos Animais de Doenças , Macrófagos/metabolismo , Masculino , Valor Preditivo dos Testes , Coelhos , Ruptura Espontânea , Transdução de Sinais
14.
Int J Nanomedicine ; 15: 779-793, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32099365

RESUMO

Purpose: Cancer chemotherapy effect has been largely limited by cell autophagy and little drug accumulation at the action sites. Herein, we designed an intelligent strategy involving paclitaxel (PTX) polymer micelles in response to biological functions of ambroxol (Ax). The amphiphilic polymers polyethyleneglycol-polylactic acid (PEG-PLA) and Pluronic P105 were selected as nanocarriers to encapsulate PTX to form into lung affinity PEG-PLA/P105/PTX micelles. Ax which can up-regulate the secretion of pulmonary surfactant (PS) and inhibit autophagy was hired to change the microenvironment of the lung, thereby promoting the lung accumulation and increasing cell-killing sensitivity of the micelles. Methods: The physical and chemical properties of the micelles were characterized including size, morphology, critical micellar concentration (CMC) and in vitro drug release behavior. The therapeutic effects of the combination regimen were characterized both in vitro and in vivo including study on Ax in promoting the secretion of pulmonary surfactant, in vitro cytotoxicity, cellular uptake, Western blotting, in vivo biodistribution, in vivo pharmacokinetics and in vivo antitumor efficacy. Results: The PEG-PLA/P105/PTX micelles showed a particle size of 16.7 ± 0.5 nm, a nearly round shape, small CMC and sustained drug release property. Moreover, the in vitro results indicated that Ax could increase PS and LC3 protein secretion and enhance the cytotoxicity of PEG-PLA/P105/PTX micelles toward A549 cells. The in vivo results indicated that the combination therapeutic regimen could promote the micelles to distribute in lung and enhance the therapeutic effect on lung cancer. Conclusion: This multifunctional approach of modulating the tumor microenvironment to enhance drug transportation and cell-killing sensitivity in the action sites might offer a new avenue for effective lung cancer treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Portadores de Fármacos/química , Neoplasias Pulmonares/tratamento farmacológico , Ambroxol/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Micelas , Paclitaxel/administração & dosagem , Paclitaxel/farmacologia , Tamanho da Partícula , Poloxâmero/química , Polietilenoglicóis/química , Polímeros/química , Ratos Sprague-Dawley , Distribuição Tecidual
15.
Arch Gynecol Obstet ; 301(3): 707-714, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31903498

RESUMO

PURPOSE: Recent studies have demonstrated the differential expression of micro(mi)RNAs in endometriosis. Previously, we reported the low expression of miR-141 in patients with this disease. Epithelial-to-mesenchymal transition (EMT) and the transforming growth factor-beta1 (TGF-ß1)-induced SMAD2 signalling pathway are central to tumour proliferation and invasion. However, the role of miR-141 in regulating the TGF-ß1/SMAD2 signalling pathway and the associated EMT to be elucidated. METHODS: The levels of TGF-ß1/SMAD2 signalling and EMT markers expression in eutopic and ectopic endometria of endometriosis were determined by immunohistochemistry and western blot analyses. MiR-141 expression was analysed by quantitative reverse-transcription polymerase chain reaction. Cellular invasion and proliferation were determined by transwell and CCK-8 assays, respectively. Functional assay of miR-141 was performed using plasmid and shRNA transfection methods. RESULT: The presence of miR-141, EMT, and TGF-ß1/SMAD2 signalling markers were detected in eutopic and ectopic endometria of endometriosis. TGF-ß1-induced EMT in Ishikawa (ISK) cells by activating the SMAD2 signalling pathway, whereas miR-141 inhibited the TGF-ß1-induced EMT, proliferation and invasion abilities of these cells. CONCLUSION: These data identify miR-141 as a novel driver of EMT in endometriosis, implicates the link between miR-141 and TGF-ß1/SMAD2 signalling pathway in the context of endometriosis, and underscore the role of EMT in the development of endometriosis.


Assuntos
Endometriose/genética , Transição Epitelial-Mesenquimal/genética , MicroRNAs/uso terapêutico , Fator de Crescimento Transformador beta1/efeitos dos fármacos , Endometriose/patologia , Feminino , Humanos , MicroRNAs/farmacologia , Transdução de Sinais , Transfecção
16.
PLoS One ; 14(12): e0227043, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31881062

RESUMO

OBJECTIVE: Endometriosis is a common chronic, gynecological disease. Despite many studies on the role of N-acetyltransferase 2 (NAT2) in endometriosis, its clinical significance is unclear. In this study, associations between NAT2 phenotypes as well as single nucleotide polymorphisms (SNPs) within NAT2 (i.e. rs1799929, rs1799930, rs1208, and rs1799931) and endometriosis risk were evaluated using a meta-analysis approach. METHODS: Embase, PubMed, ClinicalTrials.gov, CNKI (China National Knowledge Infrastructure), Wanfang databases, Cochrane Library for clinical trials, and Web of Science were searched to identify relevant articles. ORs (odds ratios) and 95% CIs (95% confidence intervals) were used to estimate the associations between NAT2 polymorphisms and endometriosis risk. Heterogeneity among included studies was also assessed. In addition, a subgroup analysis of NAT2 phenotypes and endometriosis risk based on ethnicity was performed. RESULTS: Nine case-control studies met the inclusion criteria. The odds ratio was 2.30 (95% CI: 1.61-3.28) for the NAT2 slow acetylation phenotype versus the intermediate + fast acetylation phenotype in the Asian population. These results suggest that Asian individuals with the NAT2 slow acetylation phenotype have a 130% increased risk of endometriosis. A significant association was also found for rs1799930 (OR = 0.74; 95% CI, 0.59-0.92), suggesting that individuals with this mutant genotype have a 26% decreased risk of endometriosis. CONCLUSIONS: The rs1799930 mutant genotypes are associated with a decreased risk of endometriosis. No statistically significant associations were found between rs1799931, rs1208, or rs1799929 and endometriosis. Based on a subgroup analysis based on ethnicity, the NAT2 slow acetylation phenotype was found to increase the risk of endometriosis in Asians. No statistically significant associations were found between the NAT2 slow acetylation phenotype and endometriosis risk in Caucasians. Accordingly, NAT2 phenotypes and SNPs are potential biomarkers for the diagnosis and treatment of endometriosis.


Assuntos
Arilamina N-Acetiltransferase/genética , Endometriose/genética , Polimorfismo de Nucleotídeo Único , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Humanos , Fenótipo
17.
Int J Nanomedicine ; 14: 7339-7352, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686810

RESUMO

Purpose: To deliver the chemotherapeutics through the nanoparticles, the delivery system should accumulate at the tumor site first and then penetrate through the interstitium into the interior. The specific tumor-targeting pathway mediated via the receptor-ligand binding could achieve the desirable accumulation of nanoparticles, and the nanoparticles with smaller sizes were required for penetration. Methods and materials: We constructed a size-shrinkable nanocluster modified with a tumor-targeting motif IF-7 (IF-7-MNC) based on a pH-sensitive framework which could be disintegrated in an acid environment to release the micelles aggregated inside. The micelles were constructed by amphiphilic block copolymers PEG-PLA to encapsulate paclitaxel (PTX), while the cross-linked framework consisting of TPGS-PEI was used as a net to gather and release micelles. This nanoplatform could specifically bind with the tumor receptor Annexin A1 through the ligand IF-7 and then shrunk into small micelles with a desirable size for penetration. Conclusion: IF-7-MNC of 112.27±6.81 nm could shrink into micelles in PBS (0.01 M, pH 5.0) with sizes of 14.89±0.32 nm. The cellular-uptake results showed that IF-7-MNC could be significantly internalized by A549 cells and HUVEC cells, while the penetration of IF-7-MNC could be more prominent into the 3D-tumor spheroids compared with that of MNC. The biodistribution results displayed that the fluorescence of IF-7-MNC in the tumor site at 24 hrs was 4.5-fold stronger than that of MNC. The results of anti-tumor growth demonstrated that IF-7-MNC was more favorable for the tumor therapy than MNC, where the inhibitory rate of tumor growth was 88.29% in the PTX-loaded IF-7-MNC (IF-7-PMNC) treated group, significantly greater than PMNC treatment group (p<0.05).


Assuntos
Antineoplásicos/farmacologia , Carboidratos/química , Sistemas de Liberação de Medicamentos , Micelas , Nanopartículas/química , Neoplasias/tratamento farmacológico , Tamanho da Partícula , Peptídeos/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Endocitose , Humanos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/ultraestrutura , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Polietilenoglicóis , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Eletricidade Estática , Distribuição Tecidual
18.
BMC Cancer ; 19(1): 1157, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31779593

RESUMO

BACKGROUND: Cervical cancer (CC), causing significant morbidity and mortality worldwide, is one of the most common gynecological malignancies in women. SFN has been reported as a potential prognostic marker with apparent high expression in tumors. Nevertheless, the function mechanism of SFN is not clear yet in CC. METHODS: The relative expressions of RNAs were detected by real-time quantitative PCR (RT-qPCR). Colony formation assay, EdU stained assay and CCK-8 assay were to check cell proliferation ability in CC. Flow cytometry and apoptosis related proteins analysis were used to measure cells apoptosis capacity. Luciferase reporter assay and RNA pull down assay were to verify the molecular mechanism. RESULTS: SFN was highly expressed in CC tissues and CC cell lines compared with normal tissues and normal cell line. After interfering SFN, cell proliferation, migration and invasion ability was inhibited as well as cell apoptosis ability was promoted. In subsequence, miR-383-5p exhibited conspicuous low expression in CC tissues. And miR-383-5p was found to bind to SFN and have anti-cancerous effects in CC. Moreover, LINC01128 displayed remarkable high expression in CC tissues. Besides, LINC01128 shortage could reduce the expression of SFN at mRNA and protein levels. And the affinity between LINC01128 and miR-383-5p was verified. In the end, it was proved that LINC01128 could enhance cell proliferation, migration and invasion as well as inhibit cell apoptosis by binding with miR-383-5p and upregulating SFN. CONCLUSION: LINC01128 expedited cells cellular process in CC by binding with miR-383-5p to release SFN.


Assuntos
Proteínas 14-3-3/genética , Biomarcadores Tumorais/genética , Exorribonucleases/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Neoplasias do Colo do Útero/genética , Proteínas 14-3-3/metabolismo , Apoptose , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Exorribonucleases/metabolismo , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Neoplasias do Colo do Útero/patologia
19.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(7): 731-740, 2019 Jul 28.
Artigo em Chinês | MEDLINE | ID: mdl-31413210

RESUMO

OBJECTIVE: To explore the effect of adipose-derived mesenchymal stem cells (ADMSCs) on ovarian damage induced by cyclophosphamide (CTX) and its mechanism.
 Methods: ADMSCs isolated from adipose tissue of female SD rats were cultured and divided into a blank group and a CTX group (n=15 in each group). CTX (75 mg/kg) was injected intraperitoneally to establish a model of ovarian damage in rats. A total of 45 female SD rats were also divided into 3 groups: Group A (15 rats, only injected intraperitoneally with 75 mg/kg CTX diluted with 1 mL 0.9% saline), Group B [15 rats, injected intraperitoneally with 75 mg/kg CTX diluted with 1 mL 0.9% saline, after 4 estrus cycles, injected 0.6 mL ADMSCs (6×105 cells) by the tail vein], and Group C [15 rats, injected intraperitoneally with 75 mg/kg CTX diluted with 1 mL 0.9% saline, after 4 estrus cycles, injected 40 mL ADMSCs (20 mL per side, 2×104 cells) in situ ovarian]. After 4 estrus cycles, the changes of quality of life, ponderal growth were recorded, the sex hormone levels [estradiol (E2), follicle-stimulating hormone (FSH)] were tested by ELISA, and the morphology of ovarian tissue and follicle count were observed by HE staining. The expression of BMP-15, Bcl-2 and Bax in ovarian tissues were tested by immunohistochemistry, real-time PCR or Western blotting. The apoptosis rate of follicular cells was detected by TdT-mediated dUTP nick end labeling (TUNEL) assay.
 Results: After transplantation of ADMSCs, compared with the Group A, their quality of life of rats in the Group B and C was improved, and the ponderal growth was increased (both P<0.01). Compared with the Group A, the serum E2 levels in the Group B and the Group C were increased (P<0.01, P<0.05), and the FSH levels in the Group B and C were decreased (both P<0.01). The granular cell layer, the number of corpus lutein and the count of various grade follicles were significantly increased, and many new follicles and mature oocytes were observed in the Group B and C. Compared with Group A, the count of primitive follicles, sinusoidal follicles, pre-ovulation follicles and total follicles, and pre-sinusoidal follicles were dramatically increased in the Group B. The follicle at all levels count was increased in the Group C than that in the Group A (all P<0.01). Comparing with the Group A, the expressions of BMP-15 and Bcl-2 were increased (all P<0.01), the expressions of Bax was decreased (both P<0.01), and the apoptosis rates of follicular cells were decreased in the Group B and C (both P<0.01). However, there was no difference between the Group B and the Group C in the above indexes (all P>0.05).
 Conclusion: ADMSCs transplantation can effectively repair ovarian damage induced by CTX in rats, which may be achieved by inhibiting mitochondrial apoptosis of granulosa cells.


Assuntos
Células-Tronco Mesenquimais , Animais , Ciclofosfamida , Feminino , Ovário , Qualidade de Vida , Ratos , Ratos Sprague-Dawley
20.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(4): 449-454, 2019 Apr 28.
Artigo em Chinês | MEDLINE | ID: mdl-31113923

RESUMO

DNA methylation is a significant epigenetic modification mode, which plays an important role in embryo reprogramming, stem cell differentiation and tumor occurrence. The ten-eleven translocation (TET) enzyme is a crucial demethylation enzyme, which can catalyze 5-methylcytosine(5mC) to 5-hydroxymethylcytosine(5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine(5caC). These bases represent the epigenetic modifications of DNA and regulate the process of DNA methylation. Understanding the role of TET enzyme in regulating the DNA methylation modification and gene expression can help us to gain the knowledge for the normal growth development and epigenetic regulation in human diseases.


Assuntos
5-Metilcitosina/metabolismo , Metilação de DNA , Epigênese Genética , Diferenciação Celular , DNA , Proteínas de Ligação a DNA , Humanos
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