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1.
Int J Mol Med ; 48(1)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34080640

RESUMO

Diabetic encephalopathy (DE) is one of the main chronic complications of diabetes, and is characterized by cognitive defects. MicroRNAs (miRNAs/miRs) are widely involved in the development of diabetes­related complications. The present study evaluated the role of miR­130b in DE and investigated its mechanisms of action. PC12 cells and hippocampal cells were exposed to a high glucose environment to induce cell injuries to mimic the in vitro model of DE. Cells were transfected with miR­130b mimic, miR­130b inhibitor and small interfering RNA (si)­phosphatase and tensin homolog (PTEN) to evaluate the protective effect of the miR­130b/PTEN axis against oxidative stress in high glucose­stimulated cells involving Akt activity. Furthermore, the effect of agomir­130b was also assessed on rats with DE. The expression of miR­130b was reduced in the DE models in vivo and in vitro. The administration of miR­130b mimic increased the viability of high glucose­stimulated cells, prevented apoptosis, increased the activity of superoxide dismutase (SOD), decreased the malondialdehyde (MDA) content, activated Akt protein levels and inhibited the mitochondria­mediated apoptotic pathway. The administration of miR­130b inhibitor exerted opposite effects, while si­PTEN reversed the effects of miR­130b inhibitor. In vivo, the administration of agomir­130b attenuated cognitive disorders and neuronal damage, increased SOD activity, reduced the MDA content, activated Akt protein levels and inhibited the mitochondria­mediated apoptosis pathway in rats with DE. On the whole, these results suggest that miR­130b activates the PI3K/Akt signaling pathway to exert protective effects against oxidative stress injury via the regulation of PTEN in rats with DE.

2.
Mol Immunol ; 130: 113-121, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33308900

RESUMO

Macrophages are the most abundant cells in tumor stroma and their polarization within tumor microenvironment exert the key roles in tumorigenesis. Astragaloside IV is a natural extract from traditional Chinese herbal Radix Astragali, and fulfills pleiotropic function in several cancers. Nevertheless, its function in ovarian cancer microenvironment remains elusive. In the present research, astragaloside IV exhibited little cytotoxicity within a certain dose range in THP-1 cells. Moreover, astragaloside IV suppressed the ratio of CD14+CD206+ cells in IL-4/IL-13-treated THP-1 macrophages and transcripts of M2 macrophage markers (including CD206, CCL24, PPARγ, Arg-1, IL-10), indicating the inhibitory effects of astragaloside IV on IL-4/IL-13-induced macrophage M2 polarization. Intriguingly, astragaloside IV antagonized M2 macrophages coculture-evoked cell proliferation, invasion and migration in ovarian cancer cells. During this process, administration with astragaloside IV restrained the high expression of high-mobility group box1 (HMGB1) and TLR4 in macrophages co-cultured with ovarian cancer cells, concomitant with decreases in release of M2 marker TGF-ß, MMP-9 and IL-10. Moreover, targeting the HMGB1 signaling reversed M2 macrophages-induced ovarian cancer cell proliferation, invasion and migration. Noticeably, exogenous HMGB1 overturned the inhibitory efficacy of astragaloside IV against macrophage M2 polarization-evoked malignant potential in ovarian cancer cells. Together, these findings suggest that astragaloside IV may protect against M2 macrophages-evoked malignancy in ovarian cancer cells by suppressing the HMGB1-TLR4 signaling. Therefore, astragaloside may alleviate the progression of ovarian cancer by regulating macrophage M2 polarization within tumor microenvironment, implying a promising therapeutic strategy against ovarian cancer.


Assuntos
Polaridade Celular/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Neoplasias Ovarianas/patologia , Saponinas/farmacologia , Triterpenos/farmacologia , Movimento Celular/efeitos dos fármacos , Polaridade Celular/imunologia , Progressão da Doença , Feminino , Proteína HMGB1/metabolismo , Humanos , Macrófagos/fisiologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Células THP-1 , Receptor 4 Toll-Like/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
3.
Hum Cell ; 33(3): 780-789, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32409958

RESUMO

Emerging evidences have indicated that abnormal expression of microRNAs (miRNAs) contributed to carcinogenesis of ovarian cancer. However, the molecular mechanism of many aberrant expressed miRNAs was not known. Here, we discovered that miR-1224-5p was a downregulated miRNA in ovarian cancer via bioinformatic analysis and RT-qPCR. It was found that upregulation of miR-1224-5p inhibited cell proliferation and invasion ability of ovarian cancer cells. SND1, a well-characterized oncogene, was predicted as a target gene of miR-1224-5p. The western blotting, dual luciferase reporter assay, RNA-binding protein immunoprecipitation assay, and RT-qPCR demonstrated SND1 as a target gene of miR-1224-5p in ovarian cancer. MiR-1224-5p inhibited the expression of mesenchymal markers and increased the expression of epithelial markers in ovarian cancer cells via targeting SND1, indicating miR-1224-5p was involved in epithelial mesenchymal transition. The rescue assay manifested that miR-1224-5p-regulated cell proliferation and invasion mainly rely on downregulation of SND1 in ovarian cancer cells. In conclusion, our study revealed a direct regulatory association between miR-1224-5p and SND1 and their involvement in ovarian carcinogenesis.


Assuntos
Proliferação de Células/genética , Endonucleases/genética , Endonucleases/metabolismo , MicroRNAs/fisiologia , Invasividade Neoplásica/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos
4.
Biosci Rep ; 40(6)2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32441301

RESUMO

PURPOSE: To investigate the regulation mechanism of long non-coding RNA (lncRNA) plasmocytoma variant translocation 1 (PVT1) in ovarian cancer (OC). METHODS: The levels of PVT1, microRNA (miR)-543, serpin peptidase inhibitor-clade I (neuroserpin)-member 1 (SERPINI1) in OC tissues and OVCAR-3, A2780, TOV-112D of OC cell lines were detected by quantitative real-time PCR (qRT-PCR) and Western Blot (WB). Cell proliferation, migration, invasion, apoptosis and the regulatory relationship between genes and target genes were analyzed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Transwell, flow cytometry and dual luciferase reporter (DLR). The OC patients were followed up for 5 years to analyze the relationship between PVT1 and 5-year overall survival (OS). RESULTS: In contrast with miR-543, PVT1 and SERPINI1 were highly expressed in OC tissues and cell lines, and high levels of PVT1 were significantly associated with lower 5-year OS of patients. Down-regulating PVT1 not only inhibited the malignant proliferation, migration and invasion of OC cells, but promoted cell apoptosis. PVT1 regulated miR-543 in a targeted manner, and its overexpression could attenuate the anticancer effect of miR-543 on OC cells. In addition, miR-543 also directly targeted SERPINI1, and miR-543 knockdown weakened the inhibitory effect of down-regulated SERPINI1 on OC progression. Furthermore, we found that PVT1 acted as a competitive endogenous RNA to sponge miR-543, thereby regulating the expression of SERPINI1. CONCLUSION: PVT1 can mediate the molecular mechanism of OC by miR-543/SERPINI1 axis regulatory network, which is a new therapeutic direction for OC.


Assuntos
MicroRNAs/metabolismo , Neuropeptídeos/metabolismo , Neoplasias Ovarianas/metabolismo , RNA Longo não Codificante/metabolismo , Serpinas/metabolismo , Adulto , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Neuropeptídeos/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , RNA Longo não Codificante/genética , Serpinas/genética , Transdução de Sinais
5.
Immunopharmacol Immunotoxicol ; 41(6): 599-606, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31691624

RESUMO

Purpose: Immunotherapy has demonstrated durable clinical responses in various cancers by disinhibiting the immune system, largely attributed to the success of immune-checkpoint blockade. However, there are still subsets of patients across multiple cancers not showing robust responses to these agents and one significant barrier to their efficacy may be the recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. In this study, we demonstrated that functional inhibition of MDSCs with (3 R)-5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one (TIMO), a potent PI3Kδ/γ inhibitor, enhanced the therapeutic efficacy of anti-PD1 antibody in the tumor model.Materials and methods: A syngeneic ovarian tumor model was established. MDSCs from the peripheral blood and tumor parenchyma were analyzed by flow cytometry. Proliferation and killing effects of T-lymphocytes were measured. IFNγ production was measured by ELISA assay. qPCR and western blot were used to detect the gene and protein expression. Furthermore, the therapeutic effects of TIMO combined with anti-PD1 antibody were assessed by the tumor model.Results: Our data demonstrated that inhibition of granulocytic myeloid-derived suppressor cells (G-MDSCs) function with TIMO could overcome MDSCs-mediated immunosuppression and promote antigen-specific T-lymphocyte responses, resulting in the restoration of cytotoxic T cell-mediated tumor control. We further demonstrated that TIMO and anti-PD1 combination therapy promoted tumor growth control in a syngeneic ovarian tumor model.Conclusions: Our results provided proof of concept for a new combination strategy involving the use of a selective inhibitor of PI3Kδ/γ to inhibit the function of MDSCs to enhance tumor responses to immune checkpoint blocking antibodies.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Cromanos/farmacologia , Classe I de Fosfatidilinositol 3-Quinases , Classe Ib de Fosfatidilinositol 3-Quinase/imunologia , Imunoterapia , Células Supressoras Mieloides/imunologia , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias Experimentais , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente Tumoral , Animais , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Feminino , Camundongos , Células Supressoras Mieloides/patologia , Proteínas de Neoplasias/imunologia , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
6.
Anticancer Res ; 39(11): 5991-5998, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704824

RESUMO

BACKGROUND/AIM: This study aimed to discuss the effect and possible molecular mechanisms of Aurora-A/NF-ĸB signaling on the radiotherapy resistance of human docetaxel-resistant lung adenocarcinoma cells. MATERIALS AND METHODS: The human lung adenocarcinoma SPC-A1 and SPC-A1/DTX cell lines were utilized in the present study. The MTT assay measured the sensitivity of cells to radiotherapy. The tumor-initiating ability of the cells was detected in vitro by cloning assays. Apoptosis was quantified by flow cytometry. Real-time quantitative PCR and western blotting were used to detect the mRNA and protein expression of the Aurora-A/NF-ĸB, respectively. Tumors transplanted subcutaneously into nude mice were used to test the effect of Aurora-A on the in vivo sensitivity of the tumors to radiotherapy. RESULTS: The SPC-A1/DTX docetaxel-resistant lung adenocarcinoma cells were radio-resistant compared with the parental SPC-A1 cells. Up-regulated aurora-A was responsible for the in vitro radio-resistance of docetaxel-resistant SPC-A1/DTX cells. Nuclear transcription factor NF-ĸB was identified as a downstream target gene of Aurora-A in SPC-A1/DTX cells, and NF-ĸB also participated in the radio-resistance of SPC-A1/DTX cells regulated by Aurora-A. CONCLUSION: The Aurora-A/NF-ĸB pathway is association with radio-resistance of human lung adenocarcinoma docetaxel-resistant cells.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Aurora Quinase A/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Neoplasias Pulmonares/metabolismo , NF-kappa B/metabolismo , Tolerância a Radiação , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/radioterapia , Animais , Antineoplásicos/farmacologia , Apoptose , Aurora Quinase A/genética , Proliferação de Células , Docetaxel/farmacologia , Resistência a Múltiplos Medicamentos/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Am J Physiol Gastrointest Liver Physiol ; 317(4): G387-G397, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31411894

RESUMO

The cardiac glycoside digoxin was identified as a potent suppressor of pyruvate kinase isoform 2-hypoxia-inducible factor-α (PKM2-HIF-1α) pathway activation in liver injury mouse models via intraperitoneal injection. We have assessed the therapeutic effects of digoxin to reduce nonalcoholic steatohepatitis (NASH) by the clinically relevant oral route in mice and analyzed the cellular basis for this effect with differential involvement of liver cell subsets. C57BL/6J male mice were placed on a high-fat diet (HFD) for 10 wk and started concurrently with the gavage of digoxin (2.5, 0.5, 0.125 mg/kg twice a week) for 5 wk. Digoxin significantly reduced HFD-induced hepatic damage, steatosis, and liver inflammation across a wide dosage range. The lowest dose of digoxin (0.125 mg/kg) showed significant protective effects against liver injury and sterile inflammation. Consistently, digoxin attenuated HIF-1α sustained NLRP3 inflammasome activation in macrophages. We have reported for the first time that PKM2 is upregulated in hepatocytes with hepatic steatosis, and digoxin directly improved hepatocyte mitochondrial dysfunction and steatosis. Mechanistically, digoxin directly bound to PKM2 and inhibited PKM2 targeting HIF-1α transactivation without affecting PKM2 enzyme activation. Thus, oral digoxin showed potential to therapeutically inhibit liver injury in NASH through the regulation of PKM2-HIF-1α pathway activation with involvement of multiple cell types. Because of the large clinical experience with oral digoxin, this may have significant clinical applicability in human NASH.NEW & NOTEWORTHY This study is the first to assess the therapeutic efficacy of oral digoxin on nonalcoholic steatohepatitis (NASH) in a high-fat diet (HFD) mouse model and to determine the divergent of cell type-specific effects. Oral digoxin reduced liver damage, steatosis, and inflammation in HFD mice. Digoxin attenuated hypoxia-inducible factor (HIF)-1α axis-sustained inflammasome activity in macrophages and hepatic oxidative stress response in hepatocytes via the regulation of PKM2-HIF-1α axis pathway activation. Oral digoxin may have significant clinical applicability in human NASH.


Assuntos
Digoxina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Hepatócitos/enzimologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Piruvato Quinase/antagonistas & inibidores , Ativação Transcricional/efeitos dos fármacos , Animais , Linhagem Celular , Dieta Hiperlipídica , Hepatite/patologia , Hepatócitos/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Piruvato Quinase/metabolismo
8.
Anticancer Res ; 39(4): 1689-1698, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952707

RESUMO

BACKGROUND/AIM: This study aimed to identify biomarkers for predicting the prognosis of advanced gastric cancer patients who received docetaxel, cisplatin, and S-1 (DCS). MATERIALS AND METHODS: Gene expression profiles were obtained from the Gene Expression Omnibus database (GSE31811). Gene-Ontology-enrichment and KEGG-pathway analysis were used for evaluating the biological functions of differentially-expressed genes. Protein-protein interaction (PPI) network and Kaplan-Meier survival analyses were employed to assess the prognostic values of hub genes. RESULTS: A total of 1,486 differentially expressed genes (DEGs) were identified, including 13 up-regulated and 1,473 down-regulated genes. KEGG pathways such as metabolic pathways, cell adhesion molecules (CAMs), PI3K-Akt signaling pathway and pathways in cancer were significantly represented. In the PPI network, the top ten hub genes ranked by degree were GNG7, PLCB1, CALML5, FGFR4, GRB2, JAK3, ADCY7, ADCY9, GNAS and KDR. Five DEGs, including ANTXR1, EFNA5, GAMT, E2F2 and NRCAM, were associated with relapse-free survival and overall survival. CONCLUSION: ANTXR1, EFNA5, GAMT, E2F2 and NRCAM are potential biomarkers and therapeutic targets for DCS treatment in GC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Cisplatino/administração & dosagem , Biologia Computacional/métodos , Docetaxel/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/genética , Ácido Oxônico/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Tegafur/administração & dosagem , Transcriptoma , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/efeitos adversos , Tomada de Decisão Clínica , Bases de Dados Genéticas , Docetaxel/efeitos adversos , Combinação de Medicamentos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Ácido Oxônico/efeitos adversos , Medicina de Precisão , Mapas de Interação de Proteínas , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Tegafur/efeitos adversos , Resultado do Tratamento
9.
Front Pharmacol ; 10: 1505, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32038231

RESUMO

Objective: Indoleamin-2,3-dioxygenase-1 (IDO) has been identified as a checkpoint protein involved in generating the immunosuppressive tumor microenvironment that supports tumor growth. It has been reported that atractylenolide III (ATLIII) has anticancer and immune modulatory effects. This study is to determine the anticancer effects of ATLIII with the Jak3/Stat3-dependent IDO inactivation. Methods: We assessed the cytotoxicity of ATLIII and IFN-γ on lung cancer cells by MTT. We determined the efficacy of ATLIII on IFN-γ-induced IDO expression by RT-PCR and Western blot. We also determined the efficacy of ATLIII on Jak3/Stat3 pathway expression induced by IFN-γ and Jak3/Stat3-dependent IDO activation. Further molecular docking assay predicted the binding activity and site of ATLIII to Jak3 protein. Additional immunofluorescence staining was used to measure the Stat3 intracellular localization. Finally, we performed mouse animal experiments to observe changes in the expression of IDO, p-Jak3, p-Stat3, and tryptophan/kynurenine after ATLIII administration. Results: ATLIII showed no cytotoxicity at a wide of dosage range. ATLIII reduced the phosphorylation level of Jak3 and Stat3 in response to IFN-γ stimulation, then remarkably reduced the nuclear translocation of p-Stat3 by IFN-γ. Lastly, ATLIII significantly downregulated the expression level of IDO at a wide dosage range. Molecular docking assay showed that the oxygen atom on the five-membered ring of ATLIII was capable of forming a hydrogen bond with Leu905-NH2 site of Jak3 protein. Further evidence showed that though IFN-γ had normal capacity to trigger Stat3 phosphorylation, nuclear translocation, and promoter luciferase activity, ATLIII failed to trigger efficacy on reducing these changes under forced Jak3-Leu905 mutant expression condition. Finally, we confirmed this view in in vivo experiments. Conclusion: ATLIII has shown significant efficacy to inhibit IFN-γ-triggered Jak3/Stat3 pathway-dependent IDO activation, and do so through a direct binding to Jak3 protein. This study elucidated a new mechanism for the anticancer effect of ATLIII, which may provide a feasible target for the clinical immunotherapy of malignant tumors.

10.
Onco Targets Ther ; 12: 101-111, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30588034

RESUMO

Objective: This study aims to investigate the functional role of long noncoding RNA SNHG15 in epithelial ovarian cancer (EOC). Materials and methods: The expression of SNHG15 was measured in EOC cells and tissues using qRT-PCR. The correlation of SNHG15 expression and the clinicopathological characters was statistically analyzed. The prognosis of patients with different clinical features in the high/low SNHG15 expression groups were calculated. Moreover, univariate and multivariate Cox regression analyses were performed to identify the risk factors for poor overall survival (OS) and progression-free survival (PFS). The effect of SNHG15 on the migration and invasion was evaluated using Transwell and Matrigel, respectively. The proliferation ability of EOC cells was tested using colony formation and MTT assay. The influence of SNHG15 on the cisplatin resistance was detected by measuring cell inhibition rate and cell viability. Results: SNHG15 was upegulated in EOC cells and tissues. High SNHG15 expression was correlated with EOC progression and predicted poor OS and PFS in different subgroups of EOC patients. Moreover, multivariate Cox regression analysis defined high SNHG15 expression as an independent risk factor for poor OS and PFS. Furthermore, functional assays showed that the overexpression of SNHG15 promoted migration and invasion, while the loss of SNHG15 suppressed migration and invasion. Furthermore, the proliferation of EOC cells was improved after the ectopic expression of SNHG15, which was suppressed with SNHG15 deficiency. In addition, cisplatin-resistant EOC cells were established for detecting the effect of SNHG15 on EOC chemoresistance. The results showed that cisplatin-resistant EOC cells exhibited much higher levels of SNHG15 expression than controls, and SNHG15 contributed to the chemoresistance of EOC cells. Conclusion: This study confirms that SNHG15 contributes to the migration, invasion, proliferation, and chemoresistance of EOC. SNHG15 may serve as a potential therapeutic target and prognostic biomarker of EOC patients.

11.
Cell Physiol Biochem ; 50(1): 277-287, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30282070

RESUMO

BACKGROUND/AIMS: Aberrant localization and over-expression of Ezrin have been reported to be implicated in cervical cancer (CC). Aberrant promoter methylation of some gene families may serve as potential diagnostic biomarkers for CC. In this study, we explored the correlation of promoter methylation of the Ezrin gene with the incidence and prognosis of CC. METHODS: Cervical tissues from a total of 483 patients with CC were collected from the China-Japan Union Hospital of Jilin University. Samples were assigned into four groups accordingly to pathological diagnosis, namely the control group, the cervical intraepithelial neoplasia (CIN) I group, the CIN II-III group and the CC group. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed to detect the mRNA expression of Ezrin. Methylation-specific polymerase chain reaction (MSP) was used to detect the promoter methylation of the Ezrin gene. The Kaplan-Meier product-limit method and the log-rank analysis were used for survival analysis, the Cox regression analysis for the prognostic factors for CC, and the logistic regression analysis for the risk factors for the occurrence of CC. RESULTS: The methylation rate of the Ezrin gene was correspondingly increased from the control, the CIN I, the CIN II-III to the CC groups. Over-expressed mRNA of Ezrin was determined in CC tissues. The mRNA expression of Ezrin was correlated with tumor size, lymphatic metastasis, pathological grade and clinical stage (FIGO). The risk factors for the occurrence of CC were the number of abortions and the promoter methylation of the Ezrin gene. Poor prognosis of CC correlated to lymphatic metastasis, higher pathological grade, higher FIGO stage and positive Ezrin promoter methylation. CONCLUSION: These findings indicate that promoter methylation of the Ezrin gene may play a crucial role in carcinogenesis, progression and prognosis of CC.


Assuntos
Proteínas do Citoesqueleto/genética , Metilação de DNA , Neoplasias do Colo do Útero/patologia , Adulto , China/epidemiologia , Proteínas do Citoesqueleto/metabolismo , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Metástase Linfática , Ciclo Menstrual , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Regiões Promotoras Genéticas , Modelos de Riscos Proporcionais , Fatores de Risco , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/mortalidade
12.
Sci Rep ; 8(1): 12968, 2018 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-30154488

RESUMO

Chemotherapy induces tumor cell death by directly damaging DNA or hindering cell mitosis. Some of the drawbacks of most chemotherapy are lack of target selectivity to tumor cells, and adverse drug reaction, which limit the treatment intensity and frequency. Herein, we synthesized the prodrug of triptolide (TP) coupled to vitamin E (VE) using dithiodiglycolic acid and co-dissolved with PEG2000- linoleic acid (MPEG200-LD) in ethanol. The PEGylated TP prodrug self-assembly nanoparticles (PTPPSN) were prepared via nanoprecipitation method. Besides, characterization, stability and in vitro release of the PEGylated nanometer prodrug were investigated. Furthermore, in vitro and in vivo antitumor efficacy of PTPPSN explored showed that the cytotoxicity of triptolide was significantly reduced in vitro preparation. However, in vitro and in vivo antitumor effect of PTPPSN was significantly improved compared to the original triptolide. In summary, the PEGylated nanoparticle successfully encapsulated triptolide yielded suitable cell microenvironment, and nanotechnology-related achievements. This study, therefore, provides a new method for antitumor research as well as an innovative technology for clinical treatment of malignant tumor.


Assuntos
Diterpenos , Portadores de Fármacos , Nanopartículas , Neoplasias Experimentais/tratamento farmacológico , Fenantrenos , Polietilenoglicóis , Pró-Fármacos , Animais , Linhagem Celular Tumoral , Diterpenos/química , Diterpenos/farmacocinética , Diterpenos/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Compostos de Epóxi/química , Compostos de Epóxi/farmacocinética , Compostos de Epóxi/farmacologia , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Fenantrenos/química , Fenantrenos/farmacocinética , Fenantrenos/farmacologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia
13.
Biochem Biophys Res Commun ; 501(4): 1034-1040, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29777711

RESUMO

Increasing evidence has demonstrated the involvement of dysregulated long non-coding RNAs (lncRNAs) in chemoresistance acting as potential oncogenes or tumor suppressors in various cancers. Nevertheless, the profound molecular mechanisms of lncRNAs in ovarian cancer (OC) chemoresistance is not well elucidated. The objective of this work was to investigate the role and molecular mechanisms of urothelial carcinoma associated 1 (UCA1) in paclitaxel (PTX) resistance in OC. Our results indicated that UCA1 was significantly up-regulated in PTX-resistant OC cells (SKOV3/PTX and HeyA-8/PTX) compared with their parental cells (SKOV3 and HeyA-8). Functionally, UCA1 knockdown sensitized SKOV3/PTX and HeyA-8/PTX cells to PTX through enhancing PTX-induced apoptosis. Mechanistically, UCA1 silencing induced PTX sensitivity of SKOV3/PTX and HeyA-8/PTX cells by de-repressing ABCB1 through sponging miR-129. Collectively, our study elaborated a novel UCA1/miR-129/ABCB1 regulatory axis underlying PTX resistance of OC cells, providing a potential therapeutic target for OC.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Paclitaxel/uso terapêutico , RNA Longo não Codificante/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Sequência de Bases , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , MicroRNAs/metabolismo , Paclitaxel/farmacologia , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
14.
J Tradit Chin Med ; 38(6): 890-895, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-32186136

RESUMO

OBJECTIVE: To examine the effects of Cuzhi liquid on learning and memory abilities in a mouse model of Alzheimer's disease (AD). METHODS: One hundred mice were divided into the normal, AD model, piracetam group, Cuzhi liquid low dose and Cuzhi liquid high dose, each group 20 mice. The AD mouse model was induced by daily intraperitoneal injection of D-galactose and sodium nitrite. AD mice then received intragastric administration of piracetam or Cuzhi liquid for 60 d, and changes in learning and memory abilities were assessed using the water maze test. The activity of acetylcholinsterase (AchE) and monamine oxidase (MAO), and the levels of nitrogen monoxidum (NO) and malonaldehyde (MDA), were measured in brain tissues. Amyloid protein deposition was assessed by methyl violet staining, and B-cell lymphoma-2 (Bcl-2) expression in the hippocampal cornus ammonis 1 region was detected by immunohistochemistry. RESULTS: In the water maze test, the escape latency of the model group was longer than that of the normal group (P < 0.01). The escape latency of the three using drug treatment groups was significantly less than that of the normal group (P < 0.05). The activity of AchE and MAO, and the levels of NO and MDA, in the brain of the model group were significantly higher than that of the normal group (P < 0.01), but significantly reduced in the three drug treatment groups compared with the model group (P < 0.05). AchE activity showed a greater reduction in the two Cuzhi liquid groups compared with the piracetam group (P < 0.01), to levels similar to the normal group. There were no differences in MAO activity or NO levels between the three drug treatment groups, while MDA levels were reduced more in the high-dose Cuzhi liquid group compared with the other treatment groups (P < 0.01). Hippocampal Bcl-2 expression was significantly reduced in the model group compared with the normal group (P < 0.01), but significantly improved in the three drug treatment groups (P < 0.05). The high-dose Cuzhi liquid group showed a significantly greater recovery in Bcl-2 expression compared with the other treatment groups. CONCLUSION: Cuzhi liquid can improve learning and memory impairment in an AD mouse model. The mechanism of action may relate to reduced AchE and MAO activity, and reduced NO and MDA levels, in the brain, and improved Bcl-2 expression, an inhibitor of apoptosis.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Medicamentos de Ervas Chinesas/administração & dosagem , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Masculino , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
15.
Cancer Med ; 7(2): 471-484, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29282893

RESUMO

In eukaryotic cells, autophagy is a process associated with programmed cell death. During this process, cytoplasmic proteins and organelles are engulfed by double-membrane autophagosomes, which then fuse with lysosomes to form autolysosomes. These autolysosomes then degrade their contents to recycle the cellular components. Autophagy has been implicated in a wide variety of physiological and pathological processes that are closely related to tumorigenesis. In recent years, an increasing number of studies have indicated that nonsteroidal anti-inflammatory drugs, such as celecoxib, meloxicam, sulindac, aspirin, sildenafil, rofecoxib, and sodium salicylate, have diverse effects in cancer that are mediated by the autophagy pathway. These nonsteroidal anti-inflammatory drugs can modulate tumor autophagy through the PI3K/Akt/mTOR, MAPK/ERK1/2, P53/DRAM, AMPK/mTOR, Bip/GRP78, CHOP/ GADD153, and HGF/MET signaling pathways and inhibit lysosome function, leading to p53-dependent G1 cell-cycle arrest. In this review, we summarize the research progress in autophagy induced by nonsteroidal anti-inflammatory drugs and the molecular mechanisms of autophagy in cancer cells to provide a reference for the potential benefits of nonsteroidal anti-inflammatory drugs in cancer chemotherapy.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
16.
Oncol Lett ; 12(5): 4231-4237, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27895797

RESUMO

Irinotecan-induced severe neutropenia and diarrhea, which remain unpredictable, has restrained the dose and clinical efficiency of irinotecan administration. In the present study, a total of 70 irinotecan-treated patients with histologically confirmed metastatic gastrointestinal cancer were enrolled. Despite genotyping well-reported alleles, direct sequencing was specifically adopted to avoid ethnic heterogeneity and to identify novel variations. The promoter (-1000 bp) and exon 1 regions of UDP glucuronosyltransferase family 1 member A complex locus (UGT1A1) gene family members UGT1A1, UGT1A7 and UGT1A9 were sequenced, and comprehensive analysis of their genetic polymorphisms was performed to determine the association between inherited genetic variations and irinotecan-induced toxicity. A total of 23 different genetic variants were detected in the present study, including 2 novel polymorphisms. The results of the present study revealed that UGT1A1*6 and UGT1A7*3 are risk factors for irinotecan-induced severe neutropenia, and UGT1A9*1b is associated with severe diarrhea. These results may provide biomarkers for the selection of the optimal chemotherapy for Chinese patients with metastatic gastrointestinal cancer.

17.
Biomed Pharmacother ; 83: 1286-1294, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27567588

RESUMO

BACKGROUND: MicroRNAs are important cancer regulators. In this work, we examined the expression pattern and mechanistic implications of microRNA-383 (miR-383) in human epithelial ovarian cancer (EOC). METHODS: Gene expression level of miR-383 was compared by qRT-PCR between EOC cell lines and normal ovarian epithelial cell line, and between clinical EOC tumors and adjacent non-tumor ovarian epithelial tissues. Endogenous miR-383 was downregulated through lentiviral infection. Its effects on regulating EOC proliferation, cell cycle, invasion and in vivo explant development were assessed. Possible downstream target of miR-383 in EOC, human caspase-2 gene (CASP2), was evaluated by luciferase assay and qRT-PCR. CASP2 was then genetically knocked down by siRNA to assess its functional relationship with miR-383 in regulating EOC development both in vitro and in vivo. RESULTS: MiR-383 was overexpressed in both immortal EOC cell lines and human EOC tumors. In stably miR-383-downregulated EOC cell lines, cancer proliferation, cell cycle progression, invasion and in vivo explant development were significantly suppressed. CASP2 was confirmed to be downstream of miR-383 in EOC. SiRNA-mediated CASP2 downregulation had reverse relationship with miR-383 downregulation in regulating EOC development both in vitro and in vivo. CONCLUSION: Inhibition of miR-383 has profound tumor suppressing effect on EOC development. And the functional regulation of miR-383 in EOC is very likely inversely associated with CASP2 gene.


Assuntos
Caspase 2/genética , Cisteína Endopeptidases/genética , Genes Supressores de Tumor/fisiologia , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/prevenção & controle , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle , Carcinoma Epitelial do Ovário , Caspase 2/biossíntese , Linhagem Celular Transformada , Linhagem Celular Tumoral , Cisteína Endopeptidases/biossíntese , Feminino , Humanos , MicroRNAs/biossíntese , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/metabolismo
18.
PLoS One ; 10(6): e0129474, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26058041

RESUMO

Cancer is a serious disease responsible for many deaths every year in both developed and developing countries. One reason is that the mechanisms underlying most types of cancer are still mysterious, creating a great block for the design of effective treatments. In this study, we attempted to clarify the mechanism underlying esophageal cancer by searching for novel genes and chemicals. To this end, we constructed a hybrid network containing both proteins and chemicals, and generalized an existing computational method previously used to identify disease genes to identify new candidate genes and chemicals simultaneously. Based on jackknife test, our generalized method outperforms or at least performs at the same level as those obtained by a widely used method--the Random Walk with Restart (RWR). The analysis results of the final obtained genes and chemicals demonstrated that they highly shared gene ontology (GO) terms and KEGG pathways with direct and indirect associations with esophageal cancer. In addition, we also discussed the likelihood of selected candidate genes and chemicals being novel genes and chemicals related to esophageal cancer.


Assuntos
Neoplasias Esofágicas/genética , Proteínas/genética , Algoritmos , Biologia Computacional/métodos , Bases de Dados Genéticas , Ontologia Genética , Humanos
19.
Int J Clin Exp Pathol ; 8(1): 252-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25755712

RESUMO

Betulinic acid selectively inhibits the growth of ovarian carcinoma cell lines without affecting the normal cells. In the present study, the effect of 5-fluorouracil (5-FU) and betulinic acid (BA) combination on ovarian carcinoma cells was studied. The results demonstrated that ovarian carcinoma cells on concurrent or 5-FU followed by BA treatment show increased Sub-G1 cell population, increased rate of cell apoptosis and morphological changes in mitochondrial membrane. In OVCAR 432 cells treatment with sequential combination of 5-FU and BA increased the Sub-G1 cell population to 51.3% and growth inhibition rate of > 72%. However, exposure to BA before 5-FU treatment caused a decrease in rate of inhibition to < 35%. Treatment with combination of 5 µM of 5-FU and 1 µM of BA for 48 h, led to an induction of apoptosis in 79.7% and induced morphological changes in OVCAR 432 cells. The Western blot results showed high concentration of cytochrome c in the cell cytosol after 24 h of 5-FU and BA combination treatment. Treatment of BA-responsive RMS-13 cells with 5-FU and BA combination resulted in inhibition of GLI1, GLI2, PTCH1, and IGF2 genes. In addition, we found a significant reduction in hedgehog activity of RMS-13 cells after 5-FU and BA combination treatment by means of a hedgehog-responsive reporter assay. Therefore, 5-FU and BA combination can be a promising regimen for the treatment of ovarian carcinoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma/patologia , Neoplasias Ovarianas/patologia , Western Blotting , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Citometria de Fluxo , Fluoruracila/administração & dosagem , Proteínas Hedgehog/metabolismo , Humanos , Triterpenos Pentacíclicos , Triterpenos/administração & dosagem
20.
Asian Pac J Cancer Prev ; 15(22): 9791-5, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25520106

RESUMO

To study the gene expression change and possible signal pathway during androgen-dependent prostate cancer (ADPC) becoming androgen-independent prostate cancer (AIPC), an LNCaP cell model of AIPC was established using flutamide in combination with androgen-free environment inducement, and differential expression genes were screened by microarray. Then the biological process, molecular function and KEGG pathway of differential expression genes are analyzed by Molecule Annotation System (MAS). By comparison of 12,207 expression genes, 347 expression genes were acquired, of which 156 were up-ragulated and 191 down-regulated. After analyzing the biological process and molecule function of differential expression genes, these genes are found to play crucial roles in cell proliferation, differntiation, cell cycle control, protein metabolism and modification and other biological process, serve as signal molecules, enzymes, peptide hormones, cytokines, cytoskeletal proteins and adhesion molecules. The analysis of KEGG show that the relevant genes of AIPC transformation participate in glutathione metabolism, cell cycle, P53 signal pathway, cytochrome P450 metabolism, Hedgehog signal pathway, MAPK signal pathway, adipocytokines signal pathway, PPAR signal pathway, TGF-ß signal pathway and JAK-STAT signal pathway. In conclusion, during the process of ADPC becoming AIPC, it is not only one specific gene or pathway, but multiple genes and pathways that change. The findings above lay the foundation for study of AIPC mechanism and development of AIPC targeting drugs.


Assuntos
Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Neoplasias Hormônio-Dependentes/genética , Neoplasias da Próstata/genética , Transdução de Sinais , Antagonistas de Androgênios/farmacologia , Apoptose , Movimento Celular , Proliferação de Células , Flutamida/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias Hormônio-Dependentes/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas
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