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1.
Anticancer Res ; 40(1): 221-227, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892570

RESUMO

BACKGROUND/AIM: Autophagy can be either tumor promotive or suppressive. We previously identified an autophagy-inducing activity in the 30-100 kDa fraction of areca-nut-extract (ANE 30-100K) and showed that several tumor cells subjected to chronic ANE 30-100K stimulation (CAS) exhibited higher resistance against stressed environments including serum-free (SF) conditions in vitro. Herein, we aimed to assess whether CAS can also provide growth advantages for tumor cells in vivo and the therapeutic effect of autophagy inhibition on CAS-treated tumors. MATERIALS AND METHODS: Esophageal CE81T/VGH cells and nude mice were used as experimental models. Autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ), as well as another anticancer drug cisplatin (DDP), were chosen to challenge CAS-treated CE81T/VGH cells in vitro and in vivo. RESULTS: CAS-treated CE81T/VGH cells expressed higher levels of microtubule-associated protein 1 light chain 3A/B-II (LC3-II) and beclin 1 proteins, and showed stronger resistance to SF and hypoxia conditions, that were mitigated by CQ or 3-MA in vitro. Furthermore, CAS-treated CE81T/VGH cells induced significantly larger tumors in mice, which were also attenuated by single 3-MA or CQ treatment. Finally, the combined treatment of 3-MA or CQ with DDP further up-regulated DDP-induced caspase-3 activity in vitro and exhibited synergistic anti-tumor effects on mice. CONCLUSION: CAS may up-regulate tumoral autophagy and provide growth advantage for tumors both in vitro and in vivo. Furthermore, autophagy inhibition alone or in combination with DDP may achieve positive therapy for tumors encountered with CAS.


Assuntos
Areca/química , Autofagia , Neoplasias/patologia , Nozes/química , Regulação para Cima , Animais , Autofagia/genética , Hipóxia Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus
2.
Anticancer Res ; 40(1): 323-333, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892583

RESUMO

BACKGROUND/AIM: Despite the Warburg effect, mitochondria play an essential role in the survival and maintenance of cancer cells. Thus, mitochondria have been considered a target for anticancer agents. Here, we identified a mitochondria-targeting anticancer agent from natural products. MATERIALS AND METHODS: Morphological and functional changes in mitochondria were determined by a fluorescence-based High Content Imaging System. Using human non-small cell lung cancer (NSCLC) cell lines (H1299, H226B, and A549), cell viability and colony formation assays, cell cycle analysis, and immunoblotting were performed to determine cytotoxic and proapoptotic effects of papuamine. RESULTS: Using a natural product chemical library, we identified papuamine as an active compound to inhibit viability and ATP production of NSCLC cells. Papuamine depleted intracellular ATP by causing mitochondrial dysfunction, as indicated by the loss of the mitochondrial membrane potential and increased mitochondrial superoxide generation. Papuamine significantly inhibited viability and colony formation of NSCLC cells by inducing apoptosis. CONCLUSION: Papuamine has a potential as a novel mitochondria-targeting anticancer agent.


Assuntos
Alcaloides/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mitocôndrias/patologia , Células A549 , Trifosfato de Adenosina/metabolismo , Adenilato Quinase/metabolismo , Alcaloides/química , Alcaloides/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia , Mitocôndrias/efeitos dos fármacos , Ensaio Tumoral de Célula-Tronco , Regulação para Cima/efeitos dos fármacos
3.
Medicine (Baltimore) ; 99(1): e18445, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31895772

RESUMO

BACKGROUNDS: HER-2 positive breast cancer is a subtype of breast cancer with poor clinical outcome. The aim of this study was to identify differentially expressed genes (DEGs) for HER-2 positive breast cancer and elucidate the potential interactions among them. MATERIAL AND METHODS: Three gene expression profiles (GSE29431, GSE45827, and GSE65194) were derived from the Gene Expression Omnibus (GEO) database. GEO2R tool was applied to obtain DEGs between HER-2 positive breast cancer and normal breast tissues. Gene ontology (GO) annotation analysis and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analysis was performed by the Database for Annotation, Visualization and Integrated Discovery (David) online tool. Protein-protein interaction (PPI) network, hub gene identification and module analysis was conducted by Cytoscape software. Online Kaplan-Meier plotter survival analysis tool was also used to investigate the prognostic values of hub genes in HER-2 positive breast cancer patients. RESULTS: A total of 54 upregulated DEGs and 269 downregulated DEGs were identified. Among them, 10 hub genes including CCNB1, RAC1, TOP2A, KIF20A, RRM2, ASPM, NUSAP1, BIRC5, BUB1B, and CEP55 demonstrated by connectivity degree in the PPI network were screened out. In Kaplan-Meier plotter survival analysis, the overexpression of RAC1 and RRM2 were shown to be associated with an unfavorable prognosis in HER-2 positive breast cancer patients. CONCLUSIONS: This present study identified a number of potential target genes and pathways which might impact the oncogenesis and progression of HER-2 positive breast cancer. These findings could provide new insights into the detection of novel diagnostic and therapeutic biomarkers for this disease.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica/genética , Ribonucleosídeo Difosfato Redutase/genética , Proteínas rac1 de Ligação ao GTP/genética , Estudos de Casos e Controles , Biologia Computacional , Regulação para Baixo , Feminino , Humanos , Receptor ErbB-2 , Transcriptoma/genética , Regulação para Cima
4.
Food Microbiol ; 85: 103301, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31500710

RESUMO

Lactobacillus paracasei is able to persist in a variety of natural and technological environments despite physico-chemical perturbations, in particular alternations between desiccation and rehydration. However, the way in which it adapts to hydric fluctuations and the genetic determinants involved are not clearly understood. To identify the genes involved in adaptation to desiccation, an annotated library of L. paracasei random transposon mutants was screened for viability after desiccation (25% relative humidity, 25 °C). We found 16 genes that have not been described as being involved in this response. Most of them are linked to either the transport of molecules or to cell wall structure and function. Our screening also identified genes encoding DNA related enzymes and an alarmone necessary for L. paracasei survival. Subsequently, the expression of the identified genes was measured at five stages of the dehydration-rehydration process to decipher the chronology of genetic mechanisms. They were classified into four different transcriptional profiles: genes upregulated during both desiccation and rehydration phases, genes upregulated during the desiccation phase only, genes downregulated during both desiccation and rehydration and genes downregulated only during the rehydration stage. Thus, genetic response to hydric fluctuations seems to occur during desiccation and can continue or not during rehydration. The genes identified should contribute to improve the stabilization of Lactobacillus starters in dry state.


Assuntos
Dessecação , Hidratação , Lactobacillus paracasei/genética , Adaptação Fisiológica , Regulação para Baixo , Perfilação da Expressão Gênica , Lactobacillus paracasei/fisiologia , Regulação para Cima , Água
5.
Chemosphere ; 240: 124905, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31563103

RESUMO

Microcystin-LR (MCLR) was commonly regarded as a potent hepatotoxin and has been reported to cause neurotoxicity. This study was aimed to investigate how maternal MCLR exposure during pregnancy alters behavioral responses in offspring mice and the possible molecular mechanism involved in this procedure. Three doses of MCLR solutions (0, 3 or 15 µg/kg body weight) were administered subcutaneously to pregnant C57bl/6 from gestation day (GD) 6-19. Our results showed that MCLR prenatal exposure led to the impairment of learning and memory function in offspring on postnatal days (PND) 35, accompanied by endoplasmic reticulum (ER) stress and neuronal apoptosis in hippocampal CA1 regions of mice. Sixteen miRNAs in hippocampus of pups on PND 35 were significantly affected by MCLR exposure with the markedly decreased transcription of miR-181a-5p. We then found that miR-181a-5p was down-regulated, accompanied by activation of ER stress after prenatal exposure to MCLR using qPCR analysis. Furthermore, glucose-regulated protein, 78kDa/binding immunoglobulin protein (Grp78/BIP), a major ER chaperone and signaling regulator, was identified as a target of miR-181a-5p. Our study showed that miR-181a could lead to a decrease in the mRNA expression and protein levels of Grp78 by directly binding to its 3'-untranslated region (3'-UTR) in primary hippocampal neurons. Our findings indicate that the up-regulation of Grp78 mediated by inhibition of miR-181a-5p is a possible mechanism resulting in ER stress and cognitive impairment in pups following prenatal MCLR exposure.


Assuntos
Estresse do Retículo Endoplasmático/fisiologia , MicroRNAs/metabolismo , Microcistinas/toxicidade , Animais , Apoptose , Regulação para Baixo , Feminino , Hipocampo/metabolismo , Masculino , Memória , Camundongos , MicroRNAs/genética , Gravidez , Regulação para Cima
6.
Gene ; 725: 144167, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31639434

RESUMO

Osteoporosis in advanced cholestatic and end-stage liver disease is related to low bone formation. Previous studies have demonstrated the deleterious consequences of lithocholic acid (LCA) and bilirubin on osteoblastic cells. These effects are partially or completely neutralized by ursodeoxycholic acid (UDCA). We have assessed the differential gene expression of osteoblastic cells under different culture conditions. The experiments were performed in human osteosarcoma cells (Saos-2) cultured with LCA (10 µM), bilirubin (50 µM) or UDCA (10 and 100 µM) at 2 and 24 h. Expression of 87 genes related to bone metabolism and other signalling pathways were assessed by TaqMan micro fluidic cards. Several genes were up-regulated by LCA, most of them pro-apoptotic (BAX, BCL10, BCL2L13, BCL2L14), but also MGP (matrix Gla protein), BGLAP (osteocalcin), SPP1 (osteopontin) and CYP24A1, and down-regulated bone morphogenic protein genes (BMP3 and BMP4) and DKK1 (Dickkopf-related protein 1). Parallel effects were observed with bilirubin, which up-regulated apoptotic genes and CSF2 (colony-stimulating factor 2) and down-regulated antiapoptotic genes (BCL2 and BCL2L1), BMP3, BMP4 and RUNX2. UDCA 100 µM had specific consequences since differential expression was observed, up-regulating BMP2, BMP4, BMP7, CALCR (calcitonin receptor), SPOCK3 (osteonectin), BGLAP (osteocalcin) and SPP1 (osteopontin), and down-regulating pro-apoptotic genes. Furthermore, most of the differential expression changes induced by both LCA and bilirubin were partially or completely neutralized by UDCA. Conclusion: Our observations reveal novel target genes, whose regulation by retained substances of cholestasis may provide additional insights into the pathogenesis of osteoporosis in cholestatic and end-stage liver diseases.


Assuntos
Bilirrubina/metabolismo , Osteoblastos/metabolismo , Osteoporose/genética , Apoptose/efeitos dos fármacos , Ácidos e Sais Biliares/metabolismo , Linhagem Celular Tumoral , Colestase/genética , Regulação para Baixo/efeitos dos fármacos , Perfil Genético , Humanos , Ácido Litocólico/farmacologia , Fígado/metabolismo , Fígado/fisiologia , Hepatopatias/genética , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Osteoporose/metabolismo , Osteossarcoma/genética , Osteossarcoma/metabolismo , Regulação para Cima/efeitos dos fármacos , Ácido Ursodesoxicólico/farmacologia
7.
Gene ; 725: 144191, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31654705

RESUMO

Caloric restriction (CR) has long been known to increase median and maximal lifespans and to decrease mortality and morbidity in short-lived animal models, likely by altering fundamental biological processes that regulate aging and longevity. However, the detailed mechanisms of immunomodulation by CR remain unclear. In this study, we established a mouse model for CR and analyzed the changes of immune cells in these mice. The CR mice fed a calorie-restricted diet for 4 weeks had lower body weight and fat mass compared with control mice. The proportions of CD4+, CD8+, and naïve CD4+ T cells in spleen cells from CR mice were higher than those in of control mice. Additionally, the proportion of CD8+ T cells was significantly decreased and the mRNA expression of proinflammatory cytokines in the colon of CR mice was significantly decreased compared with those of control mice. To determine the effect of CR on microRNA (miRNA) expression, serum and tissues were collected from mice and the expression level of miRNA was analyzed by real-time RT-PCR. As a result, the expressions of miR-16-5p, miR-196b-5p, and miR-218-5p in serum from CR mice were higher than those in control mice. The expression of miR-16-5p increased in the spleen, thymus, colon, and stomach of CR mice compared with expression in control mice. Furthermore, RAW264 cells transfected with a miR-16-5p mimic significantly decreased the mRNA expression of IL-1ß, IL-6, and TNF-α under LPS stimulation. These results suggested that miR-16-5p might be a critical factor involving the anti-inflammatory effects of calorie-restricted feeding.


Assuntos
Macrófagos/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Envelhecimento/metabolismo , Animais , Restrição Calórica/métodos , Citocinas/genética , Citocinas/metabolismo , Dietoterapia , Inflamação/metabolismo , Interleucina-1beta/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Células RAW 264.7 , Ativação Transcricional , Fator de Necrose Tumoral alfa/genética , Regulação para Cima
8.
Food Chem ; 307: 125515, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31648177

RESUMO

This study evaluated the polyphenol profile and the antioxidative properties of Plinia trunciflora (O. Berg) Kausel fruits. Folin-Ciocalteau and pH-jumping methods indicated that these berries are a major source of antioxidant polyphenols (1201.05 mg GAE/100 g FW), particularly anthocyanins. HPLC-DAD-ESI-MS/MS analysis identified cyanidine glycosides as the main components. Flavon-3-ols and hydrolysable-tannins were also found. CAA assay showed that extracts of P. trunciflora fruits prevent lipid peroxidation in HepG2 cells with higher efficacy than other colourful fruits (CAA50 935.25 mg FW/mL cell medium). Moreover, our results suggested that the observed antioxidant protection involve both redox active properties of P. trunciflora components, as measured by ABTS, DPPH and FRAP assays, and upregulation of the genes coding for the antioxidant enzymes MnSOD and GPx, as evaluated by qRT-PCR. Collectively, our data provided evidence on the potential of P. trunciflora fruit as a very rich source of natural antioxidant molecules.


Assuntos
Antioxidantes/metabolismo , Suplementos Nutricionais/análise , Myrtaceae/química , Compostos Fitoquímicos/química , Cromatografia Líquida de Alta Pressão , Frutas/química , Frutas/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Células Hep G2 , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Myrtaceae/metabolismo , Compostos Fitoquímicos/análise , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/análise , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Espectrometria de Massas em Tandem , Regulação para Cima/efeitos dos fármacos
9.
Medicine (Baltimore) ; 98(51): e18487, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31861032

RESUMO

Pancreatic cancer is one of the most malignant tumors worldwide. DNA replication plays a critical role in the occurrence and development of pancreatic cancer. TYMS encodes thymidylate synthase, which is important for DNA synthesis. The TYMS gene has been assessed in some tumors. However, the specific role of TYMS in pancreatic cancer has not been identified. This study was designed to clarify the diagnostic and prognostic significance of TYMS in pancreatic cancer.The Cancer Genome Atlas (TCGA) database was used to compare TYMS expression in pancreatic cancer, and ROC curve analysis was used to investigate its diagnostic value. The correlation between clinical characteristics and TYMS expression was analyzed, and the prognostic value of TYMS expression in the patients with pancreatic cancer was assessed by Kaplan-Meier curves and Cox analysis.TYMS was upregulated in pancreatic cancer and associated with poor overall survival (OS) and recurrence-free survival (RFS). Univariate and multivariate survival analysis demonstrated that TYMS is an independent risk factor for OS and RFS in patients with pancreatic cancer.The upregulation of TYMS in pancreatic cancer leads to unfavorable OS and RFS in patients, and represents a diagnostic and prognostic biomarker for patients with pancreatic cancer.


Assuntos
Neoplasias Pancreáticas/metabolismo , Timidilato Sintase/metabolismo , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidade , Prognóstico , Regulação para Cima
10.
Medicine (Baltimore) ; 98(45): e17529, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702612

RESUMO

BACKGROUND: A number of studies have attempted to determine the prognostic value of T-cell lymphoma invasion and metastasis-inducing factor 1 (Tiam1) in patients with solid cancers, but the reported results were of inconsistency. Thus, we performed a systematic review and meta-analysis to exhaustively evaluate the prognostic role of Tiam1 expression in patients with solid cancers. METHODS: We retrieved literature published in between 1994 and April 22th, 2019 through searching PubMed, Web of Science and China national knowledge infrastructure (CNKI). Hazard ratios (HRs) coupled with 95% confidence intervals (95% CIs) were used to assess the relationship of Tiam1 expression and overall survival (OS), and disease-free survival (DFS). RESULTS: A total of 2647 patients with solid cancers in 20 studies were enrolled in our meta-analysis eventually. The pooled results showed that Tiam1 high expression was closely correlated with poor OS (HR = 2.17, 95% CI: 1.80-2.61, P = .000) and DFS (pooled HR = 1.95, 95% CI = 1.58-2.40, P = .000). Moreover, our subgroup analysis and sensitivity analysis demonstrated the reliability and stability of our pooled results. CONCLUSION: In conclusion, this meta-analysis confirmed that Tiam1 higher expression positively correlated with OS and DFS, suggesting that Tiam1 may act as a valuable prognostic predictor and therapeutic target for patients with solid cancers. Nevertheless, in future more homogeneous and prospective studies should be performed to further support our findings.


Assuntos
Neoplasias/metabolismo , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T/metabolismo , Regulação para Cima , Biomarcadores Tumorais/metabolismo , Intervalo Livre de Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico , Estudos Prospectivos
11.
Medicine (Baltimore) ; 98(45): e17583, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702614

RESUMO

BACKGROUND: Long noncoding RNA paternally expressed 10 (lncRNA PEG10) is highly expressed in a variety of human cancers and related to the clinical prognosis of patients. However, to date there has been no previous study evaluating the prognostic significance of lncRNA PEG10 in gliomas. In the present study, we investigated the expression levels of lncRNA PEG10 to determine the prognostic value of this oncogene in human gliomas. METHODS: Expression levels of lncRNA PEG10 were detected by real-time polymerase chain reaction in a hospital-based study cohort of 147 glioma patients and 23 cases of patients with craniocerebral trauma tissues. Associations of lncRNA PEG10 expression with clinicopathological variables and clinical outcome of glioma patients were investigated. RESULTS: The results indicated that expression levels of lncRNA PEG10 were significantly increased in human gliomas compared to normal control brain tissues. In addition, lncRNA PEG10 expression was progressively increased from pathologic grade I to IV (P = .009) and correlated with the Karnofsky performance status (P = .018) in glioma patients. Furthermore, we also found that glioma patients with increased expression of lncRNA PEG10 had a higher risk to relapse and a statistically significant shorter overall survival (OS) than patients with reduced expression of lncRNA PEG10. In multivariate analysis, expression level of lncRNA PEG10 was found to be an independent prognostic factor for both progression-free survival and OS in glioma patients. CONCLUSIONS: LncRNA PEG10 served as an oncogene and played crucial roles in the progression of glioma. Molecular therapy targeted on lncRNA PEG10 might bring significant benefits to the clinical outcome of malignant glioma.


Assuntos
Neoplasias Encefálicas/patologia , Glioma/patologia , RNA Longo não Codificante/genética , Regulação para Cima , Adulto , Idoso , Neoplasias Encefálicas/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Análise de Sobrevida , Adulto Jovem
12.
Medicine (Baltimore) ; 98(45): e17799, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702632

RESUMO

Alpha-B crystallin (CRYAB), as a small heat shock protein, has been found to be highly expressed in various human cancers and significantly associated with the unfavorable prognosis of these tumor. Nevertheless, the clinical significance of CRYAB in gastric cancer (GC) angiogenesis remains to be elucidated. In this study, we evaluated the expression of CRYAB and CD34 in GC tissues and corresponding normal gastric specimens to explore whether high level CRYAB is related with the angiogenesis and the poor prognosis in GC.In this study, the expression of CRYAB and CD34 were detected in GC tissues and corresponding normal gastric tissues by immunohistochemical (IHC) technique. Furthermore, the relationship of CRYAB with CD34-evaluated microvessel density (MVD) and poor prognosis was also investigated.CRYAB expression level was significantly higher in GC tissue than in normal gastric mucosa tissue, and clearly mean higher MVD was observed in tumor tissues compared with non-cancerous tissues. Besides, higher MVD value was observed in positive CRYAB expression group than in negative CRYAB expression group. Statistical analysis showed that CRYAB and MVD are associated with clinicopathological features including lymph node metastasis (LNM), tumor differentiation, invasion depth, and TNM stages. Kaplan-Meier method and multivariate survival analysis indicated that high expression of CRYAB, MVD, invasion depth, TNM stages, and tumor differentiation, as well as LNM significantly correlate with poor prognosis of GC patients.High expression of CRYAB may contribute to angiogenesis, invasion and metastasis of GC. These results indicated that CRYAB was expected to be a promising molecular marker for poor prognosis and potential therapeutic target in patients with GC.


Assuntos
Antígenos CD34/metabolismo , Neoplasias Gástricas/patologia , Regulação para Cima , Cadeia B de alfa-Cristalina/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Neoplasias Gástricas/metabolismo , Análise de Sobrevida
13.
Medicine (Baltimore) ; 98(45): e17827, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702637

RESUMO

This study was designed to analyze the clinical characteristics and prognostic value of c-MYC and BCL-2 proteins expression in patients with primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL).82 patients newly diagnosed with PCNS-DLBCL, from January 2008 to November 2018, were enrolled in this study. Clinical characteristics, immunohistochemical features, laboratory examinations, and treatment outcome were analyzed among these patients.Among these 82 cases, 45 were males (54.9%) and 37 were females (45.1%). Age ranged from 16 to 78 years old, and 29 patients (35.4%) were elder than 60 years old, with median age at 57 years old. According to Hans classification, 25 were accounted for origin of germinal center B-cell (GCB) subtype (30.5%) and 49 were accounted for non-GCB subtype (59.8%), respectively. Eight patients were unclassified due to lack of detailed pathological results. The median survival of these 82 patients was 30 months, and 1-year, 3-year, and 5-year overall survival (OS) rate was 59.7%, 44.6%, and 34.1%, respectively. Patients treated with sequential HD-MTX based chemotherapies showed a superior prognosis than those without. In combination with rituximab, the outcome was further improved. The median OS was 55 months in HD-MTX + R group, 27 months in HD-MTX group, and 9 months in other groups, respectively. Univariate analysis identified age ≥60, ECOG score ≥ 2 points, and overexpression of BCL-2 protein (≥85%) were adverse prognostic factors for OS. Co-expression of c-MYC (≥40%) and BCL-2 (≥50%) proteins was associated with poor ECOG score, high Ki-67 expression, and trended towards an inferior outcome. Gender, lesion location, number of lesions, lactic dehydrogenase (LDH), cell of origin, BCL-6 protein expression, expression of c-MYC protein alone and Ki-67 ≥85% had no significant impact on OS.In patients with PCNS-DLBCL, age ≥60 years old, ECOG score ≥2 points, and overexpression of BCL-2 protein (≥85%) were associated with a poor survival. HD-MTX based chemotherapies in combination with rituximab could improve the prognosis.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias do Sistema Nervoso Central/mortalidade , Linfoma Difuso de Grandes Células B/mortalidade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Regulação para Cima , Adolescente , Adulto , Idoso , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/metabolismo , Tratamento Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
14.
Cell Physiol Biochem ; 53(5): 832-850, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31703162

RESUMO

BACKGROUND/AIMS: Runt-related transcription factor 2 (Runx2) is a master regulator of osteogenic differentiation, but most of the direct downstream targets of RUNX2 during osteogenesis are unknown. Likewise, High-temperature requirement factor A1 (HTRA1) is a serine protease expressed in bone, yet the role of Htra1 during osteoblast differentiation remains elusive. We investigated the role of Htra1 in osteogenic differentiation and the transcriptional regulation of Htra1 by RUNX2 in primary mouse mesenchymal progenitor cells. METHODS: Overexpression of Htra1 was carried out in primary mouse mesenchymal progenitor cells to evaluate the extent of osteoblast differentiation. Streptavidin agarose pulldown assay, chromatin immunoprecipitation assay, and dual luciferase assay were carried out to investigate the interaction of RUNX2 protein at the Htra1 promoter during osteoblast differentiation. RESULTS: Overexpression of Htra1 increased the production of mineralized bone matrix, upregulating several osteoblast genes, such as Sp7 transcription factor (Sp7) and Alkaline phosphatase, liver/bone/kidney (Alpl). In addition, Htra1 upregulated osteogenesis-related signalling genes, such as Fibroblast growth factor 9 (Fgf9) and Vascular endothelial growth factor A (Vegfa). A series of experiments confirmed Htra1 as a direct RUNX2 transcriptional target. Overexpression of Runx2 resulted in the upregulation of Htra1 mRNA and protein. Chromatin immunoprecipitation and streptavidin agarose pull-down assays showed that RUNX2 binds a proximal -400 bp region of the Htra1 promoter during osteogenic differentiation. Dual luciferase assays confirmed that RUNX2 activates the proximal Htra1 promoter during osteogenic differentiation. Mutation of putative RUNX2 binding sites revealed that RUNX2 interacts with the Htra1 promoter at -252 bp and -84 bp to induce Htra1 expression. CONCLUSION: We demonstrate that Htra1 is a positive regulator of osteogenic differentiation, showing for the first time that Htra1 is a direct downstream target of RUNX2.


Assuntos
Diferenciação Celular , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo , Animais , Sítios de Ligação , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Fator 9 de Crescimento de Fibroblastos/metabolismo , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Osteogênese , Regiões Promotoras Genéticas , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismo
15.
J Photochem Photobiol B ; 201: 111637, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31706086

RESUMO

Plants are considered to be a leading source for possible human therapeutic agents. This holistic study has investigated the anti-quorum sensing (anti-QS), anti-infection, antioxidant and anti-photoaging properties of neglected plant Diplocyclos palmatus. The results showed that D. palmatus methanolic leaf extract (DPME) effectively inhibited the quorum sensing (QS) regulated virulence factor production as well as biofilm formation in Serratia marcescens. The transcriptomic analysis revealed that DPME significantly downed the expression of QS-regulated genes such as fimA, fimC, flhC, bsmB, pigP and shlA in S. marcescens, which supports the outcome of in vitro bioassays. Further, the docking study revealed that the presence of active compounds, namely tocopherols and phytol, DPME exhibited its anti-QS activity against S. marcescens. In addition, DPME treatment extended the lifespan of S. marcescens infected C. elegans by the action of dropping the internal accumulation. Further, qPCR analysis clearly revealed that DPME treatment significantly up-regulated the expression of the lifespan-related gene (daf-16) and immune-related genes (clec-60, clec-87, lys-7 and bec-1) in S. marcescens infected C.elegans. On the other hand, DPME extensively reduced the UV-A induced ROS stress, thereby, extended the lifespan in UV-A photoaged C. elegans. Further, the qPCR analysis also confirmed the up-regulation of daf-16, clec-60, clec-87 and col-19 genes which advocated the improvement of the lifespan, healthspan and collagen production in UV-A photoaged C. elegans. Further bioassays evidenced that that the lifespan extension of photoaged C. elegans was accomplished by the actions of antioxidants such as tocopherols and phytol in DPME.


Assuntos
Envelhecimento/efeitos dos fármacos , Caenorhabditis elegans/efeitos da radiação , Cucurbitaceae/química , Extratos Vegetais/farmacologia , Percepção de Quorum/efeitos dos fármacos , Serratia marcescens/fisiologia , Raios Ultravioleta , Envelhecimento/efeitos da radiação , Animais , Antioxidantes/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biofilmes/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Colágeno/metabolismo , Cucurbitaceae/metabolismo , Longevidade/efeitos dos fármacos , Extratos Vegetais/química , Folhas de Planta/química , Folhas de Planta/metabolismo , Infecções por Serratia/patologia , Infecções por Serratia/veterinária , Regulação para Cima/efeitos dos fármacos
16.
Indian J Dent Res ; 30(4): 634-638, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31745065

RESUMO

Masseter traumatic myositis chondro-ossificans (TMCO) is a rare pathological condition that causes severe mandibular function restriction. The aim of the present study is to report a TMCO case after direct masseter muscle injury and correlate it to bone and cartilage biomarkers up-regulation. Caucasian male patient, 38 years old, seeks treatment nine days after trauma with severe mouth opening limitation. Physical examination revealed a circumscribed hardened area connected to masseter muscle on the left side. Cone beam tomography and ultrasonography of masseter region were requested. There was incomplete fracture between the posterior board of inferior jaw and coronoid process as well as calcification within masseter muscle. The proposed treatment was excisional biopsy of calcification, coronoid process removal to enhance mouth opening as well as incomplete condyle fracture monitoring. Material removed was sent for histological analysis in order to confirm diagnosis. Immuhistochemistry was conducted and it was found that chondro-ossification biomarkers such as TGF-b1, Indian Hegdehog (IHH), BMP2, osteopontin (OP) and osteocalcin (OC) were up-regulated. One-year follow-up showed that the patient is stable with increased mouth opening and satisfactory jaw movements. Pathologists and maxillofacial surgeons must be aware of differential diagnosis of TMCO. Understanding cellular mechanisms of muscle tissue after trauma is also important once cellular pathway modifications leads to clinical features that differ from previously described in literature.


Assuntos
Miosite Ossificante , Miosite , Adulto , Proteína Morfogenética Óssea 2 , Humanos , Masculino , Músculo Masseter , Osteocalcina , Osteopontina , Fator de Crescimento Transformador beta1 , Regulação para Cima
17.
Medicine (Baltimore) ; 98(44): e17743, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689825

RESUMO

BACKGROUND: Polyphyllin I has been reported to possess anticancer properties in various cancer types, including prostate cancer. However, little is known about the potential of Polyphyllin I in induction of prostate cancer cell cycle arrest and its underlying mechanisms. METHODS: The anti-proliferation activity of Polyphyllin I was tested using cell counting kit-8 assay. The cell cycle arrest effects of Polyphyllin I were confirmed by flow cytometry. Western blot was used to test the effect of Polyphyllin I on cell cycle-related protein expression. Reverse transcription-polymerase chain reaction was used to test the expression of genes regulating P21 expression. RESULTS: Polyphyllin I induced prostate cancer cell cycle arrest in G0/G1 phase in concentration-dependent manner. Polyphyllin I induced cell cycle arrest by upregulating the expression of P21. Further studies showed that the upregulation of p21 expression induced by Polyphyllin I via the upregulation of IL6 expression. CONCLUSION: Polyphyllin I could induce cell cycle arrest in G0/G1 phase in prostate cancer cells by upregulating the expression of P21 and IL6.


Assuntos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Diosgenina/análogos & derivados , Interleucina-6/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Regulação para Cima/efeitos dos fármacos , Linhagem Celular Tumoral , Diosgenina/farmacologia , Humanos , Masculino
18.
Protein Pept Lett ; 26(10): 751-757, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618170

RESUMO

BACKGROUND: NMAAP1 plays a role in regulating macrophage differentiation to the M1 type and exerting antitumoral functions. It is not clear what role and mechanism NMAAP1 does play in the reversal of macrophages from M1 to M2. METHODS: We detected the typing of macrophages with high or low expression of NMAAP1 by QPCR and ELISA, and detected the colocalization of NMAAP1 and endogenous IP3R by laser confocal microscopy, and detected the protein expression in cells by Western-blotting. RESULTS: Our study found that knockdown NMAAP1 in RAW264.7 cells induced macrophage polarization to the M2 type and up-regulation of NMAAP1 in RAW264.7 cells maintain M1 Phenotype even in the presence of IL-4, a stronger inducer of the M2 type. Additionally, Coimmunoprecipitation revealed a protein-protein interaction between NMAAP1 and IP3R and then activates key molecules in the PKC-dependent Raf/MEK/ERK and Ca2+/CaM/CaMKII signaling pathways. Activation of PKC (Thr638/641), ERK1/2 (Thr202/Tyr204) and CaMKII (Thr286) is involved in the regulation of cell differentiation. CONCLUSION: NMAAP1 interacts with IP3R, which in turn activates the PKC-dependent Raf/MEK/ERK and Ca2+/CaM/CaMKII signaling pathways. These results provide a new explanation of the mechanism underlying M1 differentiation.


Assuntos
Cálcio/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais , Animais , Diferenciação Celular , Citocinas/metabolismo , Regulação da Expressão Gênica , Humanos , Macrófagos/citologia , Proteínas de Membrana/genética , Camundongos , Fenótipo , Ligação Proteica , Células RAW 264.7 , RNA Interferente Pequeno/metabolismo , Regulação para Cima
19.
Cell Physiol Biochem ; 53(5): 747-759, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31622062

RESUMO

BACKGROUND/AIMS: Angiotensin II (Ang II) induces podocyte injury resulting in apoptosis in vitro and in vivo. However, the relationship between autophagy and apoptosis in Ang II-induced podocyte injury is unknown and the role of Ang II-induced autophagy in podocyte survival or death remains unclear. We investigated the sequential relationship between autophagy and apoptosis in Ang II-induced podocytes as well as the role of phosphatidylinositide 3-kinase (PI3-kinase). METHODS: Mouse podocytes were incubated in media containing various concentrations of Ang II and at different incubation times. The changes of podocyte autophagy and apoptosis were observed by electron microscopy, confocal imaging, western blotting, and FACS assay according to the presence of Ang II. RESULTS: Ang II enhanced the podocyte expression of the autophagic proteins, LC3A/B-II and beclin-1, and also increased the number of autophagosomes compared with control cells at early phase of 12 hours in a dose-dependent manner. This effect was inhibited by pretreatment with 3-methyladenine (3-MA), a PI3-kinase class III inhibitor. Thereafter, the Ang II-induced enhancement in autophagy decreased, whereas, podocyte apoptosis appeared later at 24 hours in concentration- and time-dependent manners in FACS and TUNEL assays. 3-MA and LY294002, a pan PI3-kinase inhibitor, further increased Ang II-induced podocyte apoptosis. Suppression of autophagy by Atg5 siRNA could induce podocyte apoptosis and further augment high-dose Ang II-induced podocyte apoptosis. CONCLUSION: These findings suggest that Ang II promotes autophagy in podocytes before apoptosis as an early adaptive cytoprotective mechanism for podocyte survival after Ang II treatment, and the transitional imbalance between autophagy and apoptosis causes podocyte injury.


Assuntos
Angiotensina II/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Autofagossomos/metabolismo , Proteína 5 Relacionada à Autofagia/antagonistas & inibidores , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/metabolismo , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Podócitos/citologia , Podócitos/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Regulação para Cima/efeitos dos fármacos
20.
Anticancer Res ; 39(10): 5311-5327, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570425

RESUMO

BACKGROUND/AIM: MiR-221, often described both as an oncogenic microRNA and as a tumour suppressor, targets mRNAs involved in carcinogenesis. While other oncogenic microRNAs showed correlations with prostate cancer cell lines' aggressiveness, miR-221 showed an unusual overexpression in PC3. MATERIALS AND METHODS: CRISPR was used to delete miR-221 from PC3 cells. Analysing the characteristics of PC3miR-221del cells, a reduced growth rate and expression of cell-cycle genes was observed. In global gene expression/ontology analysis of PC3miR-221del cells, cell-cell and cell-substrate adhesion pathways were found to be greatly affected. In addition, reduced levels of adhesion, invasion and motility for PC3miR-221del cells, a change in F-actin localisation and a reduction of EMT markers were observed. RESULTS: The tumour suppressor gene, DIRAS3, was a predicted target of miR-221. In PC3miR-221del cells DIRAS3 was up-regulated at the gene and protein level. Ectopic expression of DIRAS3 in PC3wt cells recapitulated the cellular morphology changes seen in PC3miR-221del cells. DIRAS3 3'UTR was more stable in PC3miR-221del cells, as measured by semi-quantitative PCR and luciferase fusion reporter assays. CONCLUSION: MiR-221 promotes aggressiveness of PC3 cells by down-regulating DIRAS3, and promoting epithelial-to-mesenchymal transition.


Assuntos
Adesão Celular/genética , Movimento Celular/genética , Proliferação de Células/genética , MicroRNAs/genética , Deleção de Sequência/genética , Regiões 3' não Traduzidas/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Oncogenes/genética , Células PC-3 , Neoplasias da Próstata/genética , Regulação para Cima/genética , Proteínas rho de Ligação ao GTP/genética
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