RESUMO
Maternal hypoxia is strongly linked to insulin resistance (IR) in adult offspring, and altered insulin signaling for muscle glucose uptake is thought to play a central role. However, whether the SIRT3/GSK-3ß/GLUT4 axis is involved in maternal hypoxia-induced skeletal muscle IR in old male rat offspring has not been investigated. Maternal hypoxia was established from Days 5 to 21 of pregnancy by continuous infusion of nitrogen and air. The biochemical parameters and levels of key insulin signaling molecules of old male rat offspring were determined through a series of experiments. Compared to the control (Ctrl) old male rat offspring group, the hypoxic (HY) group exhibited elevated fasting blood glucose (FBG) (â¼30%), fasting blood insulin (FBI) (â¼35%), total triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C), as well as results showing impairment in the glucose tolerance test (GTT) and insulin tolerance test (ITT). In addition, hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM) revealed impaired cellular structures and mitochondria in the longitudinal sections of skeletal muscle from HY group mice, which might be associated with decreased SIRT3 expression. Furthermore, the expression of insulin signaling molecules, such as GSK-3ß and GLUT4, was also altered. In conclusion, the present results indicate that the SIRT3/GSK-3ß/GLUT4 axis might be involved in maternal hypoxia-induced skeletal muscle IR in old male rat offspring.
Assuntos
Transportador de Glucose Tipo 4 , Glicogênio Sintase Quinase 3 beta , Hipóxia , Resistência à Insulina , Músculo Esquelético , Sirtuína 3 , Animais , Masculino , Glicogênio Sintase Quinase 3 beta/metabolismo , Resistência à Insulina/fisiologia , Músculo Esquelético/metabolismo , Feminino , Transportador de Glucose Tipo 4/metabolismo , Gravidez , Sirtuína 3/metabolismo , Ratos , Hipóxia/metabolismo , Transdução de Sinais , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos Sprague-Dawley , Insulina/sangue , Insulina/metabolismo , Glicemia/metabolismo , SirtuínasRESUMO
Background: Studies providing more evidence to guide adjuvant chemotherapy decisions in elderly colon cancer patients are expected. Methods: We obtained data from the Surveillance, Epidemiology and End Results (SEER) database between 2004 and 2012. Kaplan-Meier survival curves were constructed to calculate the cancer-specific survival (CSS) rate, and comparisons of survival difference between different subgroups were performed using the log-rank test. Multivariate Cox proportional hazards regression models were carried out to estimate hazard ratio (HR) and 95% confidence intervals (CIs) of different clinicopathological characteristics. Results: In stage II colon cancer patients aged 70 years or older, the Kaplan-Meier survival analysis showed that the 5-year CSS rates of no chemotherapy and chemotherapy groups were 82.0% and 72.4%, respectively (P < 0.001). In stage III colon cancer patients aged 70 years or older, the Kaplan-Meier survival analysis showed that the 5-year CSS rates of no chemotherapy and chemotherapy groups were 50.7% and 61.3%, respectively (P < 0.001). Patients with chemotherapy receipt were independently associated with a 35.8% lower cancer-specific mortality rate (HR = 0.642, 95% CI: 0.620-0.665, P < 0.001) compared with those who did not receive chemotherapy. Conclusions: Adjuvant chemotherapy should be considered during the treatment of stage III colon cancer patients aged 70 years or older, but the chemotherapy benefit in elderly stage II colon cancer is suboptimal.
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PURPOSE: To validate the prognostic value and evaluate the predictive value of response to adjuvant chemotherapy of perineural invasion (PNI) in node-negative colon cancer using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) 18 tumor registry database. METHODS: Patients diagnosed with colon cancer from the SEER database between January 1, 2010 and December 31, 2015 were identified. Chi-square analysis was performed to evaluate different demographic and clinical features of patients between PNI-negative (PNI (-)) and PNI-positive (PNI (+)) groups. Univariate and multivariate Cox proportional hazard regression models were built to examine the relationship of demographic and clinical features and survival outcomes with the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: In total, 57,255 node-negative colon cancer patients were extracted from the SEER database. The receipt of chemotherapy was not an independent prognostic factor for CSS in T3 colon cancer with or without the presence of PNI (P >0.05). The receipt of chemotherapy was independently associated with 34.0% decreased risk of cancer-specific mortality compared with those without the receipt of chemotherapy in T4 colon cancer without the presence of PNI (HR = 0.660, 95%CI = 0.559-0.779, P <0.001); the receipt of chemotherapy was independently associated with 36.0% decreased risk of cancer-specific mortality compared with those without the receipt of chemotherapy in T4 colon cancer with the presence of PNI (HR = 0.640, 95%CI = 0.438-0.935, P = 0.021). CONCLUSIONS: The present study demonstrated the poor prognosis of PNI (+) in both stage I and II colon cancer. However, the presence of PNI was not a predictive factor of response to adjuvant chemotherapy in node-negative colon cancer.
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OBJECTIVE: Accumulating evidence illustrates that sirtuins (SIRTs) regulate autophagy and apoptosis in cancer cells; however, the role of SIRT5 in gastric cancer (GC) cells remains unknown. In this study, we examined the role of SIRT5 in GC cells. METHODS: We detected SIRT5 protein levels in freshly collected samples from patients with GC. Next, we studied the function of SIRT5 in autophagy. Furthermore, the signaling pathway through which SIRT5 enhanced autophagy in GC cells was detected. In addition, we established a GC cell apoptosis model to analyze the role of SIRT5 in apoptosis. RESULTS: SIRT5 expression was downregulated in GC tissues. We discovered that SIRT5 promoted autophagy in GC cells. We demonstrated that SIRT5 enhanced autophagy in GC cells via the AMP-activated protein kinase-mammalian target of rapamycin signaling pathway. In addition, SIRT5 was degraded during apoptosis in GC cells. Meanwhile, we observed that calpains and caspase-related proteins were associated with SIRT5-related GC cell apoptosis. CONCLUSIONS: SIRT5 is a crucial regulator of autophagy and apoptosis in GC cell lines that can maintain the balance of autophagy and apoptosis.
Assuntos
Sirtuínas , Neoplasias Gástricas , Apoptose , Autofagia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Transdução de Sinais , Sirtuínas/genética , Sirtuínas/metabolismo , Neoplasias Gástricas/genéticaRESUMO
Hepatocellular carcinoma (HCC) is the most common form of liver cancer. Because of the relatively chemotherapy-refractory nature of HCC and significant potential poor hepatic reserve, chemotherapy has not been used consistently in the treatment of HCC. Effective new drugs for HCC are urgently needed. Teriflunomide, which was approved for the treatment of relapsing forms of multiple sclerosis (MS), has been identified as a potential antineoplastic drug. Long noncoding RNAs (lncRNAs) are a novel class of RNA molecules defined as transcripts longer than 200 nucleotides that lack protein coding potential. In this study, we investigated the ability of teriflunomide to act as an antineoplastic drug by examining the effects of teriflunomide treatment on HCC cells. Teriflunomide strongly inhibited the proliferation of HCC cells, induced cell apoptosis and induced cell accumulation in S phases of the cell cycle. LncRNA and mRNA expression profiles of HCC cells treated with teriflunomide compared with controls were performed by using microarray analysis. For comparison, the differentially expressed mRNAs were annotated by using gene ontology (GO) and pathway analyses. The microarray revealed that 2085 lncRNAs and 1561 mRNAs differed in the cells treated with teriflunomide compared with controls. Several GO terms including protein folding, mitochondrial outer membrane, transmembrane receptor protein phosphatase activity, negative regulation of cellular biosynthetic process, DNA packaging complex, and receptor signaling protein activity were enriched in gene lists, suggesting a potential correlation with the action mechanism of teriflunomide. Pathway analysis then demonstrated that JAK-STAT signaling pathway may play important roles in the cell apoptosis induced by teriflunomide. Co-expression network analysis indicated that a number of lncRNAs and mRNAs were included in the co-expression network, and p34710_v4 is the lncRNA with highest degree. Then the mRNAs associated with those differentially expressed lncRNAs were also annotated by using gene ontology (GO) and pathway analyses. The pathway analyses shows that teriflunomide significantly inhibited cell proliferation and promoted cell apoptosis partly by participating in Wnt signaling pathways. These findings suggest that teriflunomide could be a potential drug for chemotherapy and molecularly targeted therapies of HCC.
Assuntos
Antineoplásicos/farmacologia , Crotonatos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hidroxibutiratos/farmacologia , Imunossupressores/farmacologia , Nitrilas/farmacologia , RNA Longo não Codificante/genética , Toluidinas/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Neoplasias Hepáticas/genética , Interferência de RNA , RNA Mensageiro/genéticaRESUMO
BACKGROUND: Liver ischemia and reperfusion (I/R) is a common but severe clinical problem. Previous studies have revealed that the expression level of ß-arrestin2 affects serum deprivation (SD)-induced cell apoptosis and was involved in lipopolysaccharide (LPS) stimulated TLR4 signaling pathway. However, little is known about ß-arrestin2 in liver apoptosis and immune response induced by I/R. METHODS: A non-lethal model of segmental (70%) hepatic ischemia was utilized. Histology examination, cell apoptosis and cytokine levels were measured using H&E staining, TUNEL assay, and ELISA, respectively. Apoptosis-related protein and gene level of cytokines were respectively detected using Western blot and Real-time PCR. RESULTS: Our data showed that knockout (KO) of ß-arrestin2 gene significantly deteriorated the injury of liver caused by I/R according to liver histology, higher serum liver enzyme, and increased level of cell apoptosis. ß-arrestin2 KO could result in increased level of apoptosis related protein and decreased level of Akt phosphorylation. Furthermore, decreased levels of Bcl-2 and Bad phosphorylation, but increased level of Bax were found in ß-arrestin2 KO group. In addition, the levels of p-ERK1/2, p-p38MAPKs, and p-NF-κB in ß-arrestin2 KO group were significantly higher than that in WT group. CONCLUSIONS: ß-arrestin2 protected liver from I/R injury and this effect may be due to the regulating of Akt pathway, Bcl-2/Bax ratio, MAPKs and NF-κB pathway.
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Inflamação/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Receptor 4 Toll-Like/metabolismo , beta-Arrestina 2/uso terapêutico , Animais , Apoptose , Humanos , Hepatopatias/tratamento farmacológico , Hepatopatias/patologia , Masculino , Camundongos , Camundongos Knockout , Traumatismo por Reperfusão/patologia , Transdução de Sinais , beta-Arrestina 2/farmacologiaRESUMO
RATIONALE: Total pancreatectomy (TP) is performed in cases of multifocal and large invasive tumors of the pancreas, and is associated with high rates of mortality and morbidity. Previously, the limitations and unsatisfactory effect of this surgery rendered it rarely performed; however, with improvements in surgical techniques and blood sugar management, TP is now more frequently performed. TP has a similar long-term survival rate as that for pancreatoduodenectomy (PD). However, the application of TP plus total gastrectomy (TG) for the treatment of invasive pancreatic ductal adenocarcinoma has not been reported previously. PATIENT CONCERNS: The patient was a 64-year-old man with epigastric discomfort. Physical examination showed a hard mass. Preoperative computed tomography and magnetic resonance imaging revealed a solid mass located in the pancreatic body and involving the portal vein and stomach. DIAGNOSIS: Pancreatic cancer. INTERVENTIONS: The patient was treated with TP combined with TG and portal vein reconstruction. OUTCOMES: The patient had a smooth post-operative recovery but, regretfully, developed metastases 2 months after discharge. LESSONS: Considering the poor outcome of the present case, the validity of the operation should be reevaluated. Although a single case does not elicit a convincing conclusion, the current case might serve as a warning against performing a similar surgery.
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Carcinoma Ductal Pancreático/cirurgia , Gastrectomia , Pancreatectomia , Neoplasias Pancreáticas/cirurgia , Terapia Combinada , Gastrectomia/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatectomia/métodosRESUMO
Interleukin-24 (IL-24)/melanoma differentiation-associated gene-7 (mda-7) is a unique cytokine-tumor suppressor that displays ubiquitous antitumor properties and tumor-specific killing activity. Oncostatin M (OSM) is the most active IL-6-type cytokine and inhibits the proliferation of various solid tumor cell lines. Multigene-based combination therapy may be an effective practice in cancer gene therapy. The therapeutic potential of a combination of IL-24 and OSM in treating cancers is still elusive. In this study, we aimed to examine the enhanced antitumor activity of adenovirus-mediated IL-24/OSM tumor suppressor gene cotransfer in human melanoma cells. We constructed an IL-24/OSM bicistronic adenovirus and assessed its combined effect on A375 human melanoma cells in vitro and in vivo by detecting and comparing apoptosis in the bicistronic antioncogene group (Ad-IL-24-OSM) and in the IL-24 or OSM single antioncogene group. We also investigated the possible mechanism underlying this effect. The bicistronic adenovirus-mediated coexpression of IL-24 and OSM induced additive growth suppression and apoptosis and an overlapping effect on the upregulation of p21, p53, Bax, and cleaved caspase-3 in vitro and in vivo. Moreover, Ad-IL-24-OSM treatment additively reduced the expression of CDK4 and cyclin D1 in A375 melanoma cells and the expression of CD34 and Cox-2 in A375 xenograft tumors in athymic nude mice. The enhanced antitumor activity elicited by Ad-IL-24-OSM was closely associated with the activation of the apoptotic pathway and the additive inhibition of tumor angiogenesis. Therefore, our results indicate that cancer gene therapy combining two or more tumor suppressors, such as IL-24 and OSM, may constitute a novel and effective therapeutic strategy for treating malignant melanoma and other cancers.