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Based on the use of quercetin for treating diabetes and H2 S for promoting wound healing, a series of three quercetin-linker-H2 S donor conjugates was designed, synthesized and characterized by 1 H-NMR, 13 C-NMR and MS. Meanwhile, inâ vitro evaluation of these compounds was also researched by IR-HepG2 treatment experiment, MTT assay, scratch test and tubule formation experiment. The three compounds could be used to treat insulin resistance induced by high glucose and promote the proliferation of human umbilical vein endothelial cells, wound healing, and the formation of tubules inâ vitro under a high-glucose environment. Our results illustrate that these compounds could be used to treat diabetes and promote wound healing at the same time. Furthermore, molecular docking study results of the compounds were consistent with the evaluated biological activity. Inâ vivo research of compounds is underway.
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Diabetes Mellitus , Quercetina , Humanos , Quercetina/farmacologia , Simulação de Acoplamento Molecular , Cicatrização , Diabetes Mellitus/tratamento farmacológico , Células Endoteliais da Veia Umbilical Humana , GlucoseRESUMO
N6-methyladenosine (m6A) is the most common mRNA modification and it plays a critical role in tumor progression, prognoses and therapeutic response. In recent years, more and more studies have shown that m6A modifications play an important role in bladder carcinogenesis and development. However, the regulatory mechanisms of m6A modifications are complex. Whether the m6A reading protein YTHDF1 is involved in the development of bladder cancer remains to be elucidated. The aims of this study were to determine the association between METTL3/YTHDF1 and bladder cancer cell proliferation and cisplatin resistance to explore the downstream target genes of METTL3/YTHDF1 and to explore the therapeutic implications for bladder cancer patients. The results showed that the reduced expression of METTL3/YTHDF1 could lead to decreased bladder cancer cell proliferation and cisplatin sensitivity. Meanwhile, overexpression of the downstream target gene, RPN2, could rescue the effect of reduced METTL3/YTHDF1 expression on bladder cancer cells. In conclusion, this study proposes a novel METTL3/YTHDF1-RPN2-PI3K/AKT/mTOR regulatory axis that affects bladder cancer cell proliferation and cisplatin sensitivity.
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Hexosiltransferases , Neoplasias da Bexiga Urinária , Humanos , Proliferação de Células , Cisplatino/farmacologia , Cisplatino/metabolismo , Hexosiltransferases/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Ligação a RNA/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Neoplasias da Bexiga Urinária/metabolismoRESUMO
BACKGROUND: Previous studies projecting future temperature-related mortality under climate change have mostly used short-term temperature-mortality associations based on daily time series data. The present study aimed to project mortality under different Representative Concentration Pathways (RCPs) in 21st century in Hong Kong by using analysis of annual data during 1976-2018. METHODS: We employed a degree-days approach, calculating the sum of daily degrees above or below certain temperature threshold within a relevant historical year. The yearly age-standardized mortality rates (ASMRs) were regressed on annual hot and cold degree-days in quasi-Poisson generalized additive models to assess the exposure-response function that was subsequently used to calculate future changes in ASMR. The projection was performed without and with certain human adaptation assumed. RESULTS: ASMRs were projected to have net increases under RCPs 4.5, 6.0, and 8.5, with increased mortality attributable to excess hot days exceeding decreases attributable to excess cold days. The average net changes under RCP8.5 was estimated to be 0.12%, 12.44%, 38.99%, and 89.25% during 2030s, 2050s, 2070s, and 2090s, respectively. Higher projected ASMRs were estimated for those aged over 75 years and for cardiovascular deaths. When human adaptation was considered, slope reduction alone under RCP4.5 and 6.0 and all adaptation assumptions under RCP8.5 might still not offset its corresponding adverse impact. CONCLUSIONS: The projected decreases in cold-related mortality do not compensate for projected increases in heat-related mortality in Hong Kong. Better public adaptations strategies are warranted for coping with the adverse health impacts of climate change on a local scale.
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Mudança Climática , Temperatura Alta , Idoso , Hong Kong/epidemiologia , Humanos , Mortalidade , Temperatura , Fatores de TempoRESUMO
In this work, a series of 7-azaindole analogs were designed by the bioisosteric principle based on the pharmacodynamic parent nucleus. Moreover, 5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}pyrimidin-2-amine (compound P1) with the strongest interaction with colony-stimulating factorâ 1 receptor (CSF-1R) was screened by molecular docking. Compound P1 was successfully prepared by the six-step reaction with HPLC purity of 99.26 % and characterized by 1 H-NMR and ESI-MS spectra. Inâ vitro bioactivity study showed that compound P1 appeared the cytotoxicity to MCF-7 and A549 cells, especially to HOS cells (IC50 =88.79±8.07â nM), while it had lower toxicity to normal L929 cells (IC50 =140.49±8.03â µM). In addition, compound P1 could induce HOS cell death by apoptosis and blocking the G0/G1 phase at nanomolar concentrations. The obtained results indicated that compound P1 might be a promising candidate compound for anticancer drug.
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Antineoplásicos , Fator Estimulador de Colônias de Macrófagos , Simulação de Acoplamento Molecular , Fator Estimulador de Colônias de Macrófagos/farmacologia , Antineoplásicos/química , Aminas/farmacologia , Relação Estrutura-Atividade , Estrutura Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células , Linhagem Celular TumoralRESUMO
BACKGROUND: Aberrant autophagy and preternatural elevated glycolysis are prevalent in bladder cancer (BLCA) and are both related to malignant progression. However, the regulatory relationship between autophagy and glycolytic metabolism remains largely unknown. We imitated starvation conditions in the tumour microenvironment and found significantly increased levels of autophagy and aerobic glycolysis, which both regulated the progression of BLCA cells. We further explored the regulatory relationships and mechanisms between them. METHODS: We used immunoblotting, immunofluorescence and transmission electron microscopy to detect autophagy levels in BLCA cells under different treatments. Lactate and glucose concentration detection demonstrated changes in glycolysis. The expression of lactate dehydrogenase A (LDHA) was detected at the transcriptional and translational levels and was also silenced by small interfering RNA, and the effects on malignant progression were further tested. The underlying mechanisms of signalling pathways were evaluated by western blot, immunofluorescence and immunoprecipitation assays. RESULTS: Starvation induced autophagy, regulated glycolysis by upregulating the expression of LDHA and caused progressive changes in BLCA cells. Mechanistically, after starvation, the ubiquitination modification of Axin1 increased, and Axin1 combined with P62 was further degraded by the autophagy-lysosome pathway. Liberated ß-catenin nuclear translocation increased, binding with LEF1/TCF4 and promoting LDHA transcriptional expression. Additionally, high expression of LDHA was observed in cancer tissues and was positively related to progression. CONCLUSION: Our study demonstrated that starvation-induced autophagy modulates glucose metabolic reprogramming by enhancing Axin1 degradation and ß-catenin nuclear translocation in BLCA, which promotes the transcriptional expression of LDHA and further malignant progression.
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The biological characteristics of bladder cancer include enhanced invasion and migration, which are the main causes of death in patients. Starvation is a typical feature of the bladder cancer microenvironment and can induce autophagy. Autophagy has an important relationship with the invasion and migration of tumors. However, the role of autophagy in the invasion and migration of bladder cancer cells remains unclear. Hence, the aim of the current study was to clarify this role and underlying mechanism. In this study, we found that starvation enhanced the epithelial-mesenchymal transition (EMT)-mediated invasion and migration of T24 and 5637 cells while inducing autophagy. The inhibition of autophagy with chloroquine (CQ) or 3-methyladenine (3MA) decreased EMT-mediated invasion and migration. In addition, the expression of transforming growth factor 1 (TGF-ß1) and phosphorylated Smad3 (p-Smad3) increased after starvation. The inhibition of autophagy with CQ or 3MA also decreased the expression of TGF-ß1 and p-Smad3. The inhibitor of TGF-ß receptor sb431542 also inhibited the invasion, migration, and EMT of T24 and 5637 cells during starvation. Furthermore, recombinant TGF-ß1 induced autophagy and inhibition of the TGF-ß/Smad signaling pathway with sb431542 suppressed autophagy. In summary, our results suggested that autophagy promotes the invasion and migration of bladder cancer cells by inducing EMT through the TGF-ß1/Smad3 signaling pathway. Moreover, autophagy and TGF-ß1 can form a positive feedback loop to synergistically promote invasion and migration. Thus, our findings may provide a theoretical basis for the prevention of invasion and migration in bladder cancer.
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Autofagia , Movimento Celular , Transição Epitelial-Mesenquimal , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Linhagem Celular Tumoral , Humanos , Invasividade Neoplásica , Transdução de SinaisRESUMO
Cystadenomas of the seminal vesicles are extremely rare. Here, we report a large seminal vesicle cystadenoma. A 37-year-old man presented a 6-month history of haemospermia, 10 days of Lower Urinary Tract symptoms (LUTSs) and gross haematuria. Transabdominal ultrasonography, computed tomography and magnetic resonance imaging were performed and revealed a large solid-cystic pelvic mass morphometrically measured 7.0 cm × 11.9 cm × 8.6 cm on the right seminal vesicle, which caused hydronephrosis of the right kidney. The prostate-specific antigen of the patient was 27.860 ng/dl. Laparoscopic exploration found the capsule of tumour was complete and the tumour came from the right seminal vesicle, in addition, the mass had a certain space with the bladder and prostate, which could be separated. So a nerve-sparing Laparoscopic Vesiculectomy was performed at last, even though the intraoperative frozen section analysis could not make sure the nature of the tumour either. The postoperative pathology revealed cystadenoma of the seminal vesicle.
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Cistadenoma/cirurgia , Neoplasias dos Genitais Masculinos/cirurgia , Laparoscopia/métodos , Glândulas Seminais/cirurgia , Procedimentos Cirúrgicos Urogenitais/métodos , Cistadenoma/diagnóstico por imagem , Neoplasias dos Genitais Masculinos/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Glândulas Seminais/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento , UltrassonografiaRESUMO
With the continuous development of educational informatization, more and more emerging technologies are applied in teaching activities. These technologies provide massive and multidimensional information for teaching research, but at the same time, the information obtained by teachers and students presents an explosive increase. Extracting the core content of the class record text through text summarization technology to generate concise class minutes can significantly improve the efficiency of teachers and students to obtain information. This article proposes a hybrid-view class minutes automatic generation model (HVCMM). The HVCMM model uses a multilevel encoding strategy to encode the long text of the input class records to avoid memory overflow in the calculation after the long text is input into the single-level encoder. The HVCMM model uses the method of coreference resolution and adds role vectors to solve the problem that the excessive number of participants in the class may lead to confusion about the referential logic. Machine learning algorithms are used to analyze the topic and section of the sentence to capture structural information. We test the HVCMM model on the Chinese class minutes dataset (CCM) and the augmented multiparty interaction (AMI) dataset, and the results show that the HVCMM model outperforms other baseline models on the ROUGE metric. With the help of the HVCMM model, teachers can improve the efficiency of reflection after class and improve the teaching level. Students can review the key content to strengthen their understanding of what they have learned with the help of the class minutes automatically generated by the model.
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BACKGROUND: Renal cell carcinoma is the most common aggressive tumor of the genitourinary system. The main pathological subtype is clear cell renal cell carcinoma (ccRCC), and its treatment options are very limited. Therefore, identifying specific biomarkers of ccRCC is of great significance for diagnosis and prognosis. METHODS: First, we obtained transcriptome data and clinical data of 611 patients with renal clear cell carcinoma to analyze the relationship between hypoxia-related lncRNAs and overall survival (OS). We screened hypoxia-related lncRNAs through Pearson correlation and Cox regression analysis. Univariate and multivariate regression analysis were applied to assess survival-related risk factors. According to the median risk score, patients were divided into two groups. Next, a nomogram map was built, and GSEA was used for gene function annotation. RT-qPCR, Western Blot, and Flow Cytometry were used to determine the role of SNHG19 in RCC cells. RESULTS: By analyzing the co-expression of hypoxia genes and lncRNAs, 310 hypoxia-related genes were obtained. Four sHRlncRs (AC011445.2, PTOV1-AS2, AP004609.3, and SNHG19) with the highest prognostic values were included in the group to construct the HRRS model. The high-risk group had a shorter OS than the low-risk group. HRRS was considered to be an independent prognostic factor and associated with OS. The two groups showed different pathways in GSEA. Experiments showed that SNHG19 plays essential roles in the autophagy and apoptosis of RCC cells. CONCLUSION: We constructed and validated a hypoxia-related lncRNA model for ccRCC patients. This study also provides new biomarkers for the poor prognosis of ccRCC patients.
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Autophagy-dependent cisplatin resistance poses a challenge in bladder cancer treatment. SIRT1, a protein deacetylase, is involved in autophagy regulation. However, the precise mechanism through which SIRT1 mediates cisplatin resistance in bladder cancer via autophagy remains unclear. In this study, we developed a cisplatin-resistant T24/DDP cell line to investigate this mechanism. The apoptosis rate and cell viability were assessed using flow cytometry and the CCK8 method. The expression levels of the relevant RNA and protein were determined using RT-qPCR and a Western blot analysis, respectively. Immunoprecipitation was utilized to validate the interaction between SIRT1 and Beclin1, as well as to determine the acetylation level of Beclin1. The findings indicated the successful construction of the T24/DDP cell line, which exhibited autophagy-dependent cisplatin resistance. Inhibiting autophagy significantly reduced the drug resistance index of these cells. The T24/DDP cell line showed a high SIRT1 expression level. The overexpression of SIRT1 activated autophagy, thereby further promoting cisplatin resistance in the T24/DDP cell line. Conversely, inhibiting autophagy counteracted the cisplatin-resistance-promoting effects of SIRT1. Silencing SIRT1 led to increased acetylation of Beclin1, the inhibition of autophagy, and a reduction in the cisplatin resistance of the T24/DDP cell line. Introducing a double mutation (lysine 430 and 437 to arginine, 2KR) in Beclin-1 inhibited acetylation and activated autophagy, effectively reversing the decreased cisplatin resistance resulting from SIRT1 silencing. In summary, our study elucidated that SIRT1 promotes cisplatin resistance in human bladder cancer T24 cells through Beclin1-deacetylation-mediated autophagy activation. These findings suggest a potential new strategy for reversing cisplatin resistance in bladder cancer.
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ABSTRACT: Genetic risk factors have been shown to contribute to the development of sexual dysfunction. However, the role of methylenetetrahydrofolate reductase (MTHFR) gene variants in the risk of erectile dysfunction (ED) remains unclear. In this study, we recruited 1254 participants who underwent ED assessed by the International Index of Erectile Function-5. The MTHFR c.677C>T variant was also measured by fluorescence polymerase chain reaction (PCR). No significant difference in the genotypic frequency of the MTHFR C677T polymorphism (CC, CT, and TT) was observed between men from the ED and non-ED groups. In addition, on binary logistic regression analysis, both crude and adjusted models showed that the risk of ED was not significantly associated with the C677T polymorphism. Interestingly, a significantly higher frequency of the 677TT polymorphism was found in severe and moderate ED (P = 0.02). The positive correlation between the MTHFR 677TT polymorphism and severe ED was confirmed by logistic regression analysis, even after adjusting for potential confounders (odds ratio [OR] = 2.46, 95% confidence interval [CI]: 1.15-5.50, P = 0.02). These findings suggest a positive correlation between the MTHFR 677TT polymorphism and the risk of severe ED. Identification of MTHFR gene polymorphisms may provide complementary information for ED patients during routine clinical diagnosis.
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OBJECTIVE: To explore the feasibility of ultra-rapid freezing of human spermatozoa in the cryogenic vial with different concentrations of sucrose solution. METHODS: We divided 40 normal semen samples prepared with the routine swim-up technique into 6 aliquots, 1 as the control and the other 5 cryopreserved with sucrose solution at the concentrations of 0.15, 0.20, 0.25 and 0.30 mol/L, respectively. After thawing, we determined and compared the motility, progressive motility and plasma membrane integrity of the sperm among the 6 groups. RESULTS: The motility, progressive motility and plasma membrane integrity of the sperm were significantly lower after thawing than before cryopreservation ([96.2 +/- 1.8]%, [93.8 +/- 2.8]% and [99.0 +/- 0.8 ]%) (P<0.05). Post-thawing sperm motility was (55.5 +/- 6.3)% in the 0.20 mol/L sucrose group, significantly higher than in the 0.15, 0.25 and 0.30 mol/L groups ([45.9 +/- 6.6]%, [50.4 +/- 9.4]% and [45.5 +/- 11.2]%) (P<0.05), and it was (53.6 +/- 5.0)% in the conventional freezing group, with no statistically significant difference from the 0.20 and 0.25 mol/L sucrose cryopreservation groups (P> 0.05), but remarkably higher than in the 0.15 and 0.30 mol/L groups (P<0.05). Post-thawing progressive sperm motility exhibited no statistically significant differences between the 0.20 mol/L sucrose and conventional freezing groups ([44.4 +/- 7.4]% vs [42.3 +/- 8.1]%, P>0.05), but markedly higher in both than in the 0.15, 0.25 and 0.30 mol/L sucrose groups ([37.1 +/- 8.3 ]%, [33.1 +/- 9.2]% and [22.0 +/- 9.1]%) (P<0.05). Post-thawing plasma membrane integrity was significantly higher in the 0.20 mol/L sucrose cryopreservation group ( [70.1 +/- 6.9]%) than in either the conventional freezing group ([63.1 +/- 6.8]%) or the 0.15, 0.25 and 0.30 mol/L sucrose groups ([57.7 +/- 8.3]%, [63.5 +/- 10.7]% and [57.8 +/- 12.9]%) (P<0.05). CONCLUSION: As a simple, safe and effective method, ultra-rapid freezing with sucrose solution at the final concentration of 0.20 mol/L can be used for the cryopreservation of human spermatozoa.
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Preservação do Sêmen/métodos , Sacarose/administração & dosagem , Sacarose/farmacologia , Membrana Celular/efeitos dos fármacos , Criopreservação/métodos , Humanos , Masculino , Motilidade dos Espermatozoides/efeitos dos fármacosRESUMO
[This corrects the article DOI: 10.1155/2021/9884297.].
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Serine/threonine protein phosphatase 2A (PP2A) is a protein that has a wide range of biological functions. As prostate cancer progresses from hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC), the expression level of PP2A has been found to decrease. The present study aimed to determine the roles that PP2A may play in prostate cancer and its association with the downstream factor, X-linked inhibitor of apoptosis (XIAP). First, the mRNA and protein expression levels of PP2A in LNCaP, DU145 and PC-3 prostate cancer cell lines were measured. Next, the population of PP2A heterodimers was increased using a PP2A agonist, DT061, in the DU145 and PC-3 cell lines. PP2A expression was then knocked down in the LNCaP cell line. Western blot analysis was performed to determine the association between PP2A, phosphorylated (p)-eukaryotic initiation factor 4B (eIF4B) and XIAP. The results revealed that following the increase in PP2A expression, the DU145 and PC-3 cell lines were more sensitive to docetaxel according to Cell Counting Kit-8 assays and had an increased apoptotic rate as assessed by flow cytometry. Conversely, following the transfection of small interfering (si)PP2A into the LNCaP cell line, the sensitivity to docetaxel decreased, as well as the apoptotic rate. In addition, following treatment with the PP2A agonist, DT061, PP2A expression was found to be significantly upregulated, while p-eIF4B and XIAP protein expression levels were significantly downregulated. By contrast, following the transfection of siPP2A into the LNCaP cell line, PP2A protein expression levels were found to be downregulated, while p-eIF4B and XIAP expression levels were significantly upregulated. In conclusion, by affecting the downstream factor XIAP, PP2A may play a key role in promoting apoptosis and facilitating docetaxel sensitivity in prostate cancer cell lines.
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Most of the existing chest X-ray datasets include labels from a list of findings without specifying their locations on the radiographs. This limits the development of machine learning algorithms for the detection and localization of chest abnormalities. In this work, we describe a dataset of more than 100,000 chest X-ray scans that were retrospectively collected from two major hospitals in Vietnam. Out of this raw data, we release 18,000 images that were manually annotated by a total of 17 experienced radiologists with 22 local labels of rectangles surrounding abnormalities and 6 global labels of suspected diseases. The released dataset is divided into a training set of 15,000 and a test set of 3,000. Each scan in the training set was independently labeled by 3 radiologists, while each scan in the test set was labeled by the consensus of 5 radiologists. We designed and built a labeling platform for DICOM images to facilitate these annotation procedures. All images are made publicly available in DICOM format along with the labels of both the training set and the test set.
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Algoritmos , Radiografia Pulmonar de Massa , Humanos , Radiografia , Radiologistas , Estudos RetrospectivosRESUMO
We performed in vitro and in vivo experiments to explore the role of protein kinase C-binding protein 1 (PICK1), an intracellular transporter involved in oxidative stress-related neuronal diseases, in sepsis-related acute kidney injury (AKI). Firstly, PCR, western blotting, and immunohistochemistry were used to observe the expression of PICK1 after lipopolysaccharide- (LPS-) induced AKI. Secondly, by inhibiting PICK1 in vivo and silencing PICK1 in vitro, we further explored the effect of PICK1 on AKI. Finally, the relationship between PICK1 and oxidative stress and the related mechanisms were explored. We found that the expression of PICK1 was increased in LPS-induced AKI models both in vitro and in vivo. PICK1 silencing significantly aggravated LPS-induced apoptosis, accompanied by ROS production in renal tubular epithelial cells. FSC231, a PICK1-specific inhibitor, aggravated LPS-induced kidney injury. Besides, NAC (N-acetylcysteine), a potent ROS scavenger, significantly inhibited the PICK1-silencing-induced apoptosis. In conclusion, PICK1 might protect renal tubular epithelial cells from LPS-induced apoptosis by reducing excessive ROS, making PICK1 a promising preventive target in LPS-induced AKI.
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Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/deficiência , Proteínas Nucleares/metabolismo , Sepse/complicações , Acetilcisteína/farmacologia , Injúria Renal Aguda/patologia , Animais , Apoptose , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Túbulos Renais Proximais/patologia , Lipopolissacarídeos , MAP Quinase Quinase Quinase 5/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Peróxidos/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
To explore the role of metastasis-related long noncoding RNA (lncRNA) signature for predicting the prognosis of clear cell renal cell carcinoma (ccRCC) patients. Firstly, metastasis-associated genes were identified to establish a metastasis-related lncRNA signature by statistical analysis. Secondly, the ccRCC patients were grouped into high-risk or low-risk group according to the established signature, and the different pathways between the 2 groups were identified by gene set enrichment analysis (GSEA). Finally, investigations involving PCR, transwell migration and invasion assay were carried out to further confirm our findings. The metastasis-related lncRNA signature was successfully constructed according to 7-metastasis-related genes (ADAM12, CD44, IL6, TFPI2, TGF-ß1, THBS2, TIMP3). The diagnostic efficacy and the clinically predictive capacity of the signature were evaluated. Most of the values of the area under the time-dependent receiver-operating characteristic (ROC) were greater than 0.70. The nomogram constructed by integrating clinical data and risk scores confirmed that the risk score calculated from our signature was a good prognosis predictor. GSEA analysis showed that some tumor-related pathways were enriched in the high-risk group, while metabolism-related pathways were enriched in the low-risk group. In carcinoma tissues, the SSR3-6, WISP1-2 were highly expressed, but the expression of UBAC2-6 was low there. Knocking down SSR3-6 decreased the ability of migration and invasion in ccRCC cells. In conclusion, we successfully constructed a metastasis-related lncRNA signature, which could accurately predict the survival and prognosis of ccRCC patients.
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Sphingosine1phosphate (S1P) serves an important role in various physiological and pathophysiological processes, including the regulation of cell apoptosis, proliferation and survival. Sphingosine kinase 1 (SPHK1) is a lipid kinase that phosphorylates sphingosine to generate S1P. S1P has been proven to be positively correlated with chemotherapy resistance in breast cancer, colorectal carcinoma and nonsmall cell lung cancer. However, whether SPHK1 is involved in the development of cisplatin resistance remains to be elucidated. The present study aimed to identify the association between SPHK1 and chemoresistance in bladder cancer cells and to explore the therapeutic implications in patients with bladder cancer. Bladder cancer cell proliferation and apoptosis were determined using Cell Counting Kit8 assays and flow cytometry, respectively. Apoptosisrelated proteins were detected via western blotting. The results revealed that SPHK1 was positively correlated with cisplatin resistance in bladder cancer cells, exhibiting an antiapoptotic effect that was reflected by the downregulation of apoptosisrelated proteins (Bax and cleaved caspase3) and the upregulation of an antiapoptotic protein (Bcl2) in SPHK1overexpression cell lines. Suppression of SPHK1 by small interfering RNA or FTY720 significantly reversed the antiapoptotic effect. A potential mechanism underlying SPHK1induced cisplatin resistance and apoptosis inhibition may be activation of STAT3 via binding nonPOU domain containing octamer binding. In conclusion, the present study suggested that SPHK1 displayed significant antiapoptotic effects in cisplatinbased treatment, thus may serve as a potential novel therapeutic target for the treatment for bladder cancer.
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Cisplatino/farmacologia , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Proteínas de Ligação a RNA/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Neoplasias da Bexiga Urinária/metabolismo , Idoso , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Ligação Proteica/efeitos dos fármacos , Neoplasias da Bexiga Urinária/patologiaRESUMO
Bladder cancer is a common malignant tumour worldwide. Epithelial-mesenchymal transition (EMT)-related biomarkers can be used for early diagnosis and prognosis of cancer patients. To explore, accurate prediction models are essential to the diagnosis and treatment for bladder cancer. In the present study, an EMT-related long noncoding RNA (lncRNA) model was developed to predict the prognosis of patients with bladder cancer. Firstly, the EMT-related lncRNAs were identified by Pearson correlation analysis, and a prognostic EMT-related lncRNA signature was constructed through univariate and multivariate Cox regression analyses. Then, the diagnostic efficacy and the clinically predictive capacity of the signature were assessed. Finally, Gene set enrichment analysis (GSEA) and functional enrichment analysis were carried out with bioinformatics. An EMT-related lncRNA signature consisting of TTC28-AS1, LINC02446, AL662844.4, AC105942.1, AL049840.3, SNHG26, USP30-AS1, PSMB8-AS1, AL031775.1, AC073534.1, U62317.2, C5orf56, AJ271736.1, and AL139385.1 was constructed. The diagnostic efficacy of the signature was evaluated by the time-dependent receiver-operating characteristic (ROC) curves, in which all the values of the area under the ROC (AUC) were more than 0.73. A nomogram established by integrating clinical variables and the risk score confirmed that the signature had a good clinically predict capacity. GSEA analysis revealed that some cancer-related and EMT-related pathways were enriched in high-risk groups, while immune-related pathways were enriched in low-risk groups. Functional enrichment analysis showed that EMT was associated with abundant GO terms or signaling pathways. In short, our research showed that the 14 EMT-related lncRNA signature may predict the prognosis and progression of patients with bladder cancer.
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Transição Epitelial-Mesenquimal/genética , RNA Longo não Codificante/genética , Neoplasias da Bexiga Urinária/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico , Neoplasias da Bexiga Urinária/genéticaRESUMO
The clear cell renal cell carcinoma (ccRCC) is not only a malignant disease but also an energy metabolic disease, we aimed to identify a novel prognostic model based on glycolysis-related long non-coding RNA (lncRNAs) and explore its mechanisms. With the use of Pearson correlation analysis between the glycolysis-related differentially expressed genes and lncRNAs from The Cancer Genome Atlas (TCGA) dataset, we identified three glycolysis-related lncRNAs and successfully constructed a prognostic model based on their expression. The diagnostic efficacy and the clinically predictive capacity of the signature were evaluated by univariate and multivariate Cox analyses, Kaplan-Meier survival analysis, and principal component analysis (PCA). The glycolysis-related lncRNA signature was constructed based on the expressions of AC009084.1, AC156455.1, and LINC00342. Patients were grouped into high- or low-risk groups according to risk score demonstrated significant differences in overall survival (OS) period, which were validated by patients with ccRCC from the International Cancer Genome Consortium (ICGC) database. Univariate Cox analyses, multivariate Cox analyses, and constructed nomogram-confirmed risk score based on our signature were independent prognosis predictors. The CIBERSORT algorithms demonstrated significant correlations between three-glycolysis-related lncRNAs and the tumor microenvironment (TME) components. Functional enrichment analysis demonstrated potential pathways and processes correlated with the risk model. Clinical samples validated expression levels of three-glycolysis-related lncRNAs, and LINC00342 demonstrated the most significant aberrant expression. in vitro, the general overexpression of LINC00342 was detected in ccRCC cells. After silencing LINC00342, the aberrant glycolytic levels and migration abilities in 786-O cells were decreased significantly, which might be explained by suppressed Wnt/ß-catenin signaling pathway and reversed Epithelial mesenchymal transformation (EMT) process. Collectively, our research identified a novel three-glycolysis-related lncRNA signature as a promising model for generating accurate prognoses for patients with ccRCC, and silencing lncRNA LINC00342 from the signature could partly inhibit the glycolysis level and migration of ccRCC cells.