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1.
J Am Heart Assoc ; : e023053, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34984916

RESUMO

Background cGMP-hydrolyzing phosphodiesterase type 5 (PDE5) regulates vascular smooth muscle cell (SMC) contraction by antagonizing cGMP-dependent protein kinase I (PKGI)-dependent SMC relaxation. SMC contractile dysfunction is implicated in the pathogenesis of aortic aneurysm. PDE5 inhibitors have been used for treating erectile dysfunction, such as drug Viagra (sildenafil). However, a few clinical cases have reported the association of Viagra usage with aortic dissection, and reduced PDE5A expression was found in human aortic aneurysm tissues. Therefore, we aimed to investigate the effect of sildenafil on experimental abdominal aortic aneurysm (AAA), the most common form of aortic aneurysm in elderly men. Methods and Results AAA was induced in C57BL/6J male mice by periaortic elastase in combination with blocking elastin/collagen formation via 3-aminopropionitrile fumarate salt for 35 days. PDE5A protein levels detected by immunostaining were significantly reduced in mouse AAA. Sildenafil application in drinking water significantly aggravated aortic wall dilation and elastin degradation with pre-existing moderate AAA. The phosphorylation level of myosin light chain 2 at Ser19, a biochemical marker of SMC contraction, was significantly reduced by sildenafil in AAA. Proximity ligation assay further revealed that the interaction between cGMP and PKGI was significantly increased by sildenafil in AAA, suggesting an elevation of PKGI activation in AAA. Conclusions Sildenafil treatment aggravated the degradation of elastin fibers and progression of experimental AAA by dysregulating cGMP and contractile signaling in SMCs. Our findings may raise the caution of clinical usage of Viagra in aneurysmal patients.

2.
Cancer Lett ; 524: 15-28, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34461182

RESUMO

Sunitinib is the first-line drug for treating renal cell carcinoma (RCC), and it functions mainly through inhibition of tumor angiogenesis. However, the patients may become insensitive or develop resistance toward sunitinib treatment, but the underlying mechanisms have not yet been fully elucidated. Herein, it was found that sunitinib could have adverse effects of promoting RCC progression by increasing vascular mimicry (VM) formation of RCC cells. Mechanism dissection revealed that sunitinib can increase the expression of a long non-coding RNA (lncRNA), lncRNA-ECVSR, thereby enhancing the stability of estrogen receptor ß (ERß) mRNA. Subsequently, the increased ERß expression can then function via transcriptional up-regulation of Hif2-α. Notably, sunitinib-increased lncRNA-ECVSR/ERß/Hif2-α signaling resulted in an increased cancer stem cell (CSC) phenotype, thereby promoting VM formation. Furthermore, the sunitinib/lncRNA-ECVSR-increased ERß expression can transcriptionally regulate lncRNA-ECVSR expression via a positive-feedback loop. Supportively, preclinical studies using RCC mouse xenografts demonstrated that combining sunitinib with the small molecule anti-estrogen PHTPP can increase sunitinib efficacy with reduced VM formation. Collectively, the findings of this study may aid in the development of potential biomarker(s) and novel therapies to better monitor and suppress RCC progression.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma de Células Renais/tratamento farmacológico , Receptor beta de Estrogênio/genética , RNA Longo não Codificante/genética , Sunitinibe/farmacologia , Animais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
BMC Genomics ; 22(1): 790, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34732130

RESUMO

BACKGROUND: The complexity of physical activity (PA) and DNA methylation interaction in the development of cardiovascular disease (CVD) is rarely simultaneously investigated in one study. We examined the role of DNA methylation on the association between PA and CVD. RESULTS: The Multi-Ethnic Study of Atherosclerosis (MESA) cohort Exam 5 data with 1065 participants free of CVD were used for final analysis. The quartile categorical total PA variable was created by activity intensity (METs/week). During a median follow-up of 4.0 years, 69 participants developed CVD. Illumina HumanMethylation450 BeadChip was used to provide genome-wide DNA methylation profiles in purified human monocytes (CD14+). We identified 23 candidate DNA methylation loci to be associated with both PA and CVD. We used the structural equation modeling (SEM) approach to test the complex relationships among multiple variables and the roles of mediators. Three of the 23 identified loci (corresponding to genes VPS13D, PIK3CD and VPS45) remained as significant mediators in the final SEM model along with other covariates. Bridged by the three genes, the 2nd PA quartile (ß = - 0.959; 95%CI: - 1.554 to - 0.449) and the 3rd PA quartile (ß = - 0.944; 95%CI: - 1.628 to - 0.413) showed the greatest inverse associations with CVD development, while the 4th PA quartile had a relatively weaker inverse association (ß = - 0.355; 95%CI: - 0.713 to - 0.124). CONCLUSIONS: The current study is among the first to simultaneously examine the relationships among PA, DNA methylation, and CVD in a large cohort with long-term exposure. We identified three DNA methylation loci bridged the association between PA and CVD. The function of the identified genes warrants further investigation in the pathogenesis of CVD.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Aterosclerose/genética , Doenças Cardiovasculares/genética , Metilação de DNA , Exercício Físico , Humanos , Fatores de Risco
4.
Circ Res ; 129(Suppl_1): AMP265, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34735298

RESUMO

Cyclic nucleotide phosphodiesterases (PDEs), through the degradation of cyclic nucleotides, play critical roles in cardiovascular biology and disease. PDE10A is able to hydrolyze both cAMP and cGMP. Its high expression in medium spiny neurons of the human striatum has led to the development of several PDE10A inhibitors with the intent to treat various psychiatric/neurodegenerative disorders, such as schizophrenia and Huntington's disease. Our previous study has reported the upregulation of PDE10A expression in failing hearts and demonstrated the protective effects of PDE10A deficiency/inhibition against cardiac hypertrophy, fibrosis, and dysfunction in mouse models of heart failure. Doxorubicin (DOX) is an effective chemotherapeutic agent against a variety of cancers. While its therapeutic utility is limited by the development of dose-dependent cardiotoxicity. In the current study, we aim to determine the role of PDE10A in cancer and cardiotoxicity induced by DOX. We found that PDE10A inhibition or deficiency alleviated DOX-induced cardiotoxicity in vivo, as well as cardiac myocyte (CM) death and atrophy in vitro. In ovarian cancer cells, PDE10A inhibition induced cell death and reduced cell proliferation; as well as potentiated the effect of DOX on antagonizing cancer cells. Interestingly, in nude mice with ovarian cancer xenografts, PDE10A inhibition attenuated ovarian tumor growth while protected DOX-induced cardiotoxicity. RNAseq and bioinformatics analysis uncovered a number of PDE10A-regulated signaling pathways and cellular processes involved in DOX-induced cardiotoxicity. Mechanistic studies further revealed that PDE10A regulates CM death and atrophy via different mechanistic actions: regulating CM death via a cGMP-dependent while cAMP-independent mechanism; and regulating CM atrophy via a mechanism dependent on both cGMP and cAMP. Several PDE10A inhibitors have been tested in humans and successfully passed phase I clinical trials for safety. Thus, our findings suggest that PDE10A may be a safe "druggable" target for cancer therapy by simultaneously preventing DOX-induced cardiotoxicity and antagonizing tumor growth.

5.
Proc Natl Acad Sci U S A ; 118(31)2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34312235

RESUMO

Abdominal aortic aneurysm (AAA) is characterized by aorta dilation due to wall degeneration, which mostly occurs in elderly males. Vascular aging is implicated in degenerative vascular pathologies, including AAA. Cyclic nucleotide phosphodiesterases, by hydrolyzing cyclic nucleotides, play critical roles in regulating vascular structure remodeling and function. Cyclic nucleotide phosphodiesterase 1C (PDE1C) expression is induced in dedifferentiated and aging vascular smooth muscle cells (SMCs), while little is known about the role of PDE1C in aneurysm. We observed that PDE1C was not expressed in normal aorta but highly induced in SMC-like cells in human and murine AAA. In mouse AAA models induced by Angiotensin II or periaortic elastase, PDE1C deficiency significantly decreased AAA incidence, aortic dilation, and elastin degradation, which supported a causative role of PDE1C in AAA development in vivo. Pharmacological inhibition of PDE1C also significantly suppressed preestablished AAA. We showed that PDE1C depletion antagonized SMC senescence in vitro and/or in vivo, as assessed by multiple senescence biomarkers, including senescence-associated ß-galactosidase activity, γ-H2AX foci number, and p21 protein level. Interestingly, the role of PDE1C in SMC senescence in vitro and in vivo was dependent on Sirtuin 1 (SIRT1). Mechanistic studies further showed that cAMP derived from PDE1C inhibition stimulated SIRT1 activation, likely through a direct interaction between cAMP and SIRT1, which leads to subsequent up-regulation of SIRT1 expression. Our findings provide evidence that PDE1C elevation links SMC senescence to AAA development in both experimental animal models and human AAA, suggesting therapeutical significance of PDE1C as a potential target against aortic aneurysms.

6.
Toxics ; 9(3)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803457

RESUMO

Following their introduction a decade ago, electronic cigarettes (e-cigarettes) have grown in popularity. Given their novelty, knowledge of the health consequences of e-cigarette use remains limited. Epidemiologic studies have not comprehensively explored associations between e-cigarette use and hypertension, a highly prevalent health condition and major contributor to cardiovascular disease burden. In this study, cross-sectional associations of cigarette smoking and e-cigarette use (vaping) with self-reported diagnosed hypertension were evaluated among 19,147 18-55 year old respondents in Wave 3 (2015-2016) of the Population Assessment of Tobacco and Health Study. Multivariable analyses first modeled smoking and vaping as separate 2-category variables, then as a 6-category composite variable accounting for former smoking. After adjusting for potential confounders, current vaping (aOR = 1.31; 95%CI: 1.05-1.63) and current smoking (aOR = 1.27; 95%CI: 1.10-1.47) were both associated with higher odds of hypertension. In analyses modeling smoking and vaping compositely, respondents who were concurrently smoking and vaping had the highest odds of hypertension (aOR = 1.77; 95%CI: 1.32-2.39 [referent: never smokers]). These results differ somewhat from prior epidemiologic studies of vaping and respiratory outcomes, which consistently report smaller point estimates for current vaping than for current smoking. Our findings reinforce the uncertainty surrounding long-term health consequences of vaping, as well as highlight important distinctions between respiratory and cardiovascular outcomes when considering the harm reduction potential of e-cigarettes.

7.
Clin Sci (Lond) ; 134(22): 2959-2976, 2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33111936

RESUMO

Abdominal aortic aneurysm (AAA), commonly occurring in the aged population, is a degenerative disease that dilate and weaken infrarenal aorta due to progressive degeneration of aortic wall integrity. Vinpocetine, a derivative of alkaloid vincamine, has long been used for cerebrovascular disorders and cognitive impairment in the aged population. Recent studies have indicated that vinpocetine antagonizes occlusive vascular disorders such as intimal hyperplasia and atherosclerosis. However, its role in vascular degenerative disease AAA remains unexplored. Herein, we determined the effect of vinpocetine on the formation of AAA as well as the intervention of pre-existing moderate AAA. AAA was induced by periaortic elastase application in C57BL/6J mice. Systemic vinpocetine treatment was applied daily via intraperitoneal injection. We showed that vinpocetine pre-treatment remarkably attenuated aneurysmal dilation assessed by diameter and volume. More importantly, vinpocetine also significantly suppressed the progression of pre-existing moderate AAA in a post-intervention model. Vinpocetine improved multiple cellular and molecular changes associated with AAA, such as elastin degradation, media smooth muscle cell depletion, collagen fibers remodeling and macrophage infiltration in aneurysmal tissues. Vinpocetine potently suppressed tumor necrosis factor-α-induced nuclear factor kappa-light-chain-enhancer of activated B cells activation and proinflammatory mediator expression in primary cultured macrophages in vitro, as well as in the aorta wall in vivo, suggesting vinpocetine conferred anti-AAA effect at least partially via the inhibition of inflammation. Taken together, our findings reveal a novel role of vinpocetine in AAA formation, development and progression. Given the excellent safety profile of vinpocetine, the present study suggests vinpocetine may be a novel therapeutic agent for AAA prevention and treatment.


Assuntos
Aneurisma da Aorta Abdominal/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Alcaloides de Vinca/uso terapêutico , Animais , Aneurisma da Aorta Abdominal/patologia , Células Cultivadas , Dilatação Patológica , Progressão da Doença , Elastina/metabolismo , Inflamação/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Substâncias Protetoras/farmacologia , Proteoglicanas/metabolismo , Proteólise/efeitos dos fármacos , Alcaloides de Vinca/farmacologia
8.
Tob Induc Dis ; 18: 82, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33082739

RESUMO

INTRODUCTION: Flavors other than tobacco flavor have been identified as a major reason for electronic nicotine delivery system (ENDS) initiation in youth and are thought to contribute to the continued use of ENDS in users of all ages. Our previous research showed a significant association between overall ENDS use and COPD. This study aims to identify the association of ENDS flavor categories with self-reported COPD. METHODS: The data analysis included 4909 adults from Population Assessment of Tobacco and Health (PATH) Wave 4 data who were ever established ENDS users and responded to an item about diagnosis of COPD. Weighted multivariable logistic regression models were used to examine the association between different ENDS flavors and self-reported COPD considering complex sampling design. RESULTS: Among 4909 ever established ENDS users, 418 adults (weighted percentage 9.8%) had self-reported COPD. Self-reported COPD prevalence differed between different ENDS flavor categories, with the highest (weighted percentage 19.9%) occurring among tobacco flavor users. Compared to non-tobacco flavor categories, tobacco flavor category showed significantly higher association with self-reported COPD (AOR=2.05; 95% CI: 1.20-3.53), after adjusting for potential confounding variables. No significant associations with self-reported COPD were found for other examined ENDS flavor categories including menthol/mint, fruit, candy/ desserts/other-sweets, and other flavors, compared to their corresponding non-users. CONCLUSIONS: Tobacco flavored ENDS use was significantly associated with self-reported COPD. Future studies are needed to confirm the biological and epidemiological association of flavored ENDS use with COPD.

9.
J Cancer Res Ther ; 16(5): 990-1001, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33004739

RESUMO

Background and Aims: CYP17 inhibitors can block androgen production both intratumorally and systemically, thus attenuating the progression of prostate cancer (PCa). Many randomized controlled trials (RCTs) showed promising results that men with metastatic castration-resistant PCa (mCRPC) might benefit from treatment with CYP17 inhibitors such as abiraterone acetate and orteronel. The goal of this study was to evaluate the efficacy of CYP17 inhibitors for the prognosis in patients with mCRPC. Materials and Methods: Studies were identified in PubMed/MEDLINE, the Cochrane Library, and the Web of Science. The RCTs with mCRPC patients focusing on the efficacy of CYP17 inhibitors were involved. Then, we analyzed the patients' prognosis such as overall survival (OS) and radiographic progression-free survival (RPFS). Results: A meta-analysis of the pooled data from seven randomized Phase III clinical trials was performed to compare 5516 mCRPC patients with CYP17 inhibitors versus that with placebo. Compared to placebo, the CYP17 inhibitors significantly increased the OS (pooled hazard ratios [HR]: 0.816, 95% confidence interval [CI]: 0.750-0.887), RPFS (pooled HR: 0.647, 95% CI: 0.557-0.752), and time to prostate-specific antigen (PSA) progression (pooled HR: 0.599, 95% CI: 0.517-0.693). Additional endpoints such as PSA response rate, objective response assessed by Response Evaluation Criteria in Solid Tumors, and time to initiation of chemotherapy were included in this study and were found having significant improvement with CYP17 inhibitors compared to placebo. Conclusion: This research showed that CYP17 inhibitors had a significant improvement on prognosis of patients with mCRPC within a relative safety profile both in pre- and post-chemotherapy trials. These expected results provide evidence for the use of CYP17 inhibitors to treat mCRPCs.


Assuntos
Acetato de Abiraterona/uso terapêutico , Inibidores das Enzimas do Citocromo P-450/uso terapêutico , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Ensaios Clínicos Fase III como Assunto , Humanos , Masculino , Prognóstico , Neoplasias de Próstata Resistentes à Castração/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida
10.
Prev Med ; 139: 106215, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32693178

RESUMO

We examined the prevalence of home smoking and vaping restrictions among US adults, and compared home policy differences for smoking and vaping among vapers, smokers, and dual users. Secondary data from the Population Assessment of Tobacco and Health (PATH) Study Wave 3 (2015-2016) with 28,148 adults were analyzed using weighted multivariable logistic regression models that account for complex sampling design to compare differences in home policies among non-users, vapers only, smokers only, and dual users. Compared to never-users, current vapers who were ex-smokers and dual users were more likely to allow home vaping (aOR = 11.06, 95% CI: 8.04-15.21; aOR = 6.44, 95% CI: 5.01-8.28) and smoking (aOR = 1.62, 95% CI: 1.19-2.22; aOR = 3.58, 95% CI: 2.88-4.45). Current smokers were more likely to allow vaping (aOR = 3.53, 95% CI: 3.06-4.06) and smoking (aOR = 4.27, 95% CI: 3.73-4.89) inside the home than never-users. Current vapers who never smoked were more likely to allow vaping inside the home than never-users (aOR = 2.45, 95% CI: 1.53-3.93). Vapers reported much lower rates of vape-free home policies relative to both their smoke-free home policies and to vape-free home policies among smokers. Vapers may be using e-cigarettes in hopes of harm reduction, but interpreting "harm reduction" as safe, thus exposing non-users in their homes to second- and thirdhand aerosols. This underscores the need to healthcare providers to extend intervention with vapers to include implementing vape-free home policies.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Política Antifumo , Vaping , Adulto , Humanos , Fumantes , Tabaco
11.
Oncogene ; 39(3): 530-545, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31501521

RESUMO

Renal cell carcinoma (RCC) is one of the most lethal urological tumors. Using sunitinib to improve the survival has become the first-line therapy for metastatic RCC patients. However, the occurrence of sunitinib resistance in the clinical application has curtailed its efficacy. Here we found TR4 nuclear receptor might alter the sunitinib resistance to RCC via altering the TR4/lncTASR/AXL signaling. Mechanism dissection revealed that TR4 could modulate lncTASR (ENST00000600671.1) expression via transcriptional regulation, which might then increase AXL protein expression via enhancing the stability of AXL mRNA to increase the sunitinib resistance in RCC. Human clinical surveys also linked the expression of TR4, lncTASR, and AXL to the RCC survival, and results from multiple RCC cell lines revealed that targeting this newly identified TR4-mediated signaling with small molecules, including tretinoin, metformin, or TR4-shRNAs, all led to increase the sunitinib sensitivity to better suppress the RCC progression, and our preclinical study using the in vivo mouse model further proved tretinoin had a better synergistic effect to increase sunitinib sensitivity to suppress RCC progression. Future successful clinical trials may help in the development of a novel therapy to better suppress the RCC progression.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Proteínas Proto-Oncogênicas/genética , RNA Longo não Codificante/genética , Receptores Proteína Tirosina Quinases/genética , Receptores de Esteroides/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Sunitinibe/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Hipóxia Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores de Esteroides/genética , Receptores dos Hormônios Tireóideos/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sunitinibe/uso terapêutico , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Qual Life Res ; 27(11): 2759-2775, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29926345

RESUMO

PURPOSE: The question of whether orthotopic neobladder (ONB) reconstruction is superior to ileal conduit diversion (ICD) with respect to health-related quality of life (HRQoL) remains controversial. The goal of this study is to perform a meta-analysis to compare post-ICD and post-ONB HRQoL in patients with bladder cancer. METHODS: A systematic search of Medline, Embase, the Cochrane Central Register of Controlled Trials, and the annual congress abstracts of the European Association of Urology (EAU), the American Urological Association (AUA) and the Société Internationale d'Urologie (SIU) up to June 2017 was conducted to identify all relevant clinical trials using validated questionnaires to assess HRQoL. A systematic review and meta-analysis were then performed. RESULTS: A total of 2507 patients from 26 eligible studies were included. Meta-analyses showed significant differences favouring ONB patients in global health status (WMD + 9.13, p = 0.004), physical functioning (WMD + 11.57, p = 0.0001), role functioning (WMD + 9.64, p = 0.002), and social functioning (WMD + 6.81, p = 0.03) based on the EORTC-QLQ-C30 questionnaire and in the total score of FACT questionnaire (WMD + 6.80, p = 0.001). However, ONB patients were more likely to have postoperative urinary symptoms than ICD patients (WMD - 22.19, p = 0.0001). CONCLUSIONS: ONB patients are more likely to have a better global health status than ICD patients. Regardless of the type of urinary diversion (UD) surgery, a gradual improvement in HRQoL over preoperative status tended to stabilise after 12 months postoperatively.


Assuntos
Nível de Saúde , Qualidade de Vida , Neoplasias da Bexiga Urinária/cirurgia , Bexiga Urinária/cirurgia , Derivação Urinária/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Resultado do Tratamento , Coletores de Urina
13.
BMC Cancer ; 18(1): 88, 2018 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-29357836

RESUMO

BACKGROUND: Scavenger receptor class B type I (SR-BI) has been reported to be involved in carcinogenesis of several human cancers. However, it is currently unknown whether SR-BI plays a role in clear cell renal cell carcinoma (ccRCC). Here, we aimed to evaluate a tumor promotive mechanism for SR-BI in ccRCC. METHODS: The expression of SR-BI was evaluated by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot and immunohistochemistry (IHC) in ccRCC tissues and cell lines. Lipid droplets in ccRCC tissues and normal kidney tissues were examined by Oil Red O (ORO) and hematoxylin-eosin (HE) staining. The correlation between SR-BI mRNA levels and clinicopathological features was analyzed by Pearson's chi-square test or Fisher's exact test. Kaplan-Meier analysis and Cox model were used to evaluate the difference in progression-free survival (PFS) associated with expression of SR-BI. Inhibition of SR-BI was conducted by using small interfering RNA (siRNA). In vitro assays were performed to assess the impact of SR-BI knockdown on cell biological behaviors. High density lipoprotein (HDL)-cholesterol content in ccRCC cells and extracellular media was also measured after transfection with siRNA. RESULTS: The expression of SR-BI was markedly up-regulated in ccRCC tissues and tumor cell lines. ORO and HE staining revealed huge amounts of lipid droplets accumulation in ccRCC. Clinical analysis showed that over-expression of SR-BI was positively associated with tumor size, grade, distant metastasis and inversely correlated with PFS. Furthermore, SR-BI was proved to be an independent prognostic marker in ccRCC patients. The inhibition of SR-BI attenuated the tumorous behaviors of ccRCC cells, expression of metastasis and AKT pathway related proteins. The content of HDL-cholesterol was reduced in cells while increased in extracellular media after transfection with si-SR-BI. CONCLUSIONS: Our results demonstrate that SR-BI functions as an oncogene and promotes progression of ccRCC. SR-BI may serve as a potential prognostic biomarker and therapeutic target for ccRCC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Prognóstico , Receptores Depuradores Classe B/genética , Adulto , Idoso , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , HDL-Colesterol/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , RNA Mensageiro/genética
14.
Tumour Biol ; 39(5): 1010428317699110, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28466781

RESUMO

Aberrant expression of scavenger receptor class B type 1 has been reported in several human cancers. Nevertheless, the roles of scavenger receptor class B type 1 in clear cell renal cell carcinoma remain unclear. The aim of this study was to evaluate the diagnostic and prognostic value of scavenger receptor class B type 1 in clear cell renal cell carcinoma. The messenger RNA level of scavenger receptor class B type 1 in clear cell renal cell carcinoma tissues was detected by quantitative reverse transcription polymerase chain reaction, while protein level was determined by western blot and immunohistochemistry. The lipid content between clear cell renal cell carcinoma tissues and normal kidney tissues was differentiated by Oil Red O and hematoxylin-eosin staining. The diagnostic value of scavenger receptor class B type 1 was determined by receiver operating characteristic curve. The prognostic significance of scavenger receptor class B type 1 was assessed by Kaplan-Meier analysis and Cox regression analysis. Our results showed that the expression of scavenger receptor class B type 1 in clear cell renal cell carcinoma tissues at both messenger RNA and protein level was much higher than that in normal kidney tissues. Receiver operating characteristic curve analysis exhibited a significant value of area under the curve (0.8486, 95% confidence interval: 0.7926-0.9045) with strong sensitivity (0.75, 95% confidence interval: 0.6535-0.8312) and specificity (0.90, 95% confidence interval: 0.8238-0.9510). Kaplan-Meier analysis revealed that patients with higher scavenger receptor class B type 1 expression had shorter progression-free survival time. Cox analysis indicated that scavenger receptor class B type 1 was an independent prognostic biomarker. In conclusion, our findings implied that scavenger receptor class B type 1 might serve as a diagnostic and independent prognostic biomarker in clear cell renal cell carcinoma.


Assuntos
Biomarcadores Tumorais/biossíntese , Carcinoma de Células Renais/genética , Prognóstico , Receptores Depuradores Classe B/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Receptores Depuradores Classe B/genética
15.
Urol Oncol ; 35(1): 36.e7-36.e14, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27633984

RESUMO

OBJECTIVES: Clear cell renal cell carcinoma (ccRCC) is the most frequent and lethal subtype of renal cell carcinoma, whose most effective measure of curing remains diagnosis and nephrectomy in its early phase. However, there is no feasible and recognized plasma biomarker for the clinical diagnosis of ccRCC. The objective of this study is to identify a novel plasma microRNA (miRNA) acting as an efficient diagnostic plasma biomarker in ccRCC. METHODS AND MATERIALS: The plasma miRNA expression profile was quantified by miRNA microarray. Validation of miRNA levels of plasmas and tissues were performed by quantitative reverse transcription polymerase chain reaction in 106 ccRCC, 28 renal angiomyolipomas (AML), and 123 healthy control plasmas and in 110 ccRCC tissues. RESULTS: We found that plasma miR-144-3p levels in 106 ccRCC plasmas were remarkably up-regulated compared with that in healthy individuals and in patients with AML. miR-144-3p served as a promising plasma biomarker for yielding an area under the receiver operating characteristic curve of 0.91 with 87.10% sensitivity and 83.02% specificity in discriminating ccRCC from healthy individuals, and an area under the curve of 0.82 with 75.00% sensitivity and 71.70% specificity in discriminating ccRCC from patients with AML. In addition, plasma miR-144-3p levels were significantly decreased after surgery in 106 patients with ccRCC. Next, we examined miR-144-3p levels in 110 human ccRCC tissues, and found that miR-144-3p levels in ccRCC tissues were increased compared with adjacent normal tissues. Pearson correlation analysis revealed that miR-144-3p levels in tumor tissues were positively correlated with preoperative plasma miR-144-3p levels in the matched samples from patients with ccRCC. In addition, the miR-144-3p levels in ccRCC plasmas and tissues were increased in patients with advanced pT stage. CONCLUSIONS: Our data indicate that miR-144-3p, which is significantly up-regulated in ccRCC plasmas and tissues, particularly with advanced pT stage, is a novel and excellent plasma biomarker for the diagnosis of ccRCC.


Assuntos
Angiomiolipoma/diagnóstico , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/diagnóstico , Neoplasias Renais/metabolismo , MicroRNAs/sangue , Angiomiolipoma/sangue , Área Sob a Curva , Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Feminino , Humanos , Rim/metabolismo , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nefrectomia , Análise de Sequência com Séries de Oligonucleotídeos , Curva ROC , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para Cima
16.
Biomarkers ; 21(7): 578-88, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27133288

RESUMO

Bladder cancer (BC) is latent in its early stage and lethal in its late stage. Therefore, early diagnosis and intervention are essential for successful BC treatment. Considering the limitations of current diagnostic tools, noninvasive biomarkers that are both highly sensitive and specific are needed to improve the overall survival and quality of life of patients. With the advent of systems biology, "-omics" technologies have been developed over the past few decades. As a promising member, global metabolomics has increasingly been found to have clear potential for biomarker discovery. However, urinary metabolomics studies related to BC have lagged behind those of other urinary cancers, and major findings have not been systematically reported. The objective of this review is to comprehensively list the currently identified potential urinary metabolite biomarkers for BC.


Assuntos
Biomarcadores Tumorais , Metabolômica/métodos , Neoplasias da Bexiga Urinária/diagnóstico , Humanos , Masculino , Metaboloma , Sensibilidade e Especificidade
17.
Clin Cancer Res ; 20(10): 2617-30, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24647573

RESUMO

PURPOSE: Although microRNAs (miRNA) have been revealed as crucial modulators of tumorigenesis, our understanding of their roles in renal cell carcinoma (RCC) is limited. Here we sought to identify human miRNAs that act as key regulators of renal carcinogenesis. EXPERIMENTAL DESIGN: We performed microarray-based miRNA profiling of clear cell RCC (ccRCC) and adjacent normal tissues and then explored the roles of miR-141 both in vitro and in vivo, which was the most significantly downregulated in ccRCC tissues. RESULTS: A total of 74 miRNAs were dysregulated in ccRCC compared with normal tissues. miR-141 was remarkably downregulated in 92.6% (63/68) ccRCC tissues and would serve as a promising biomarker for discriminating ccRCC from normal tissues with an area under the receiver operating characteristics curve of 0.93. Overexpression of miR-141 robustly impaired ccRCC cell migratory and invasive properties and suppressed cell proliferation by arresting cells at G0-G1 phase in vitro and in human RCC orthotopic xenografts. Significantly, the antitumor activities of miR-141 were mediated by its reversal regulation of erythropoietin-producing hepatocellular (Eph) A2 (EphA2), which then relayed a signaling transduction cascade to attenuate the functions of focal adhesion kinase (FAK), AKT, and MMP2/9. In addition, a specific and inverse correlation between miR-141 and EphA2 expression was obtained in human ccRCC samples. Finally, miR-141 could be secreted from the ccRCC donor cells, and be taken up and function moderately in the ccRCC recipient cells. CONCLUSION: miR-141 serves as a potential biomarker for discriminating ccRCC from normal tissues and a crucial suppressor of ccRCC cell proliferation and metastasis by modulating the EphA2/p-FAK/p-AKT/MMPs signaling cascade.


Assuntos
Carcinoma de Células Renais/genética , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , MicroRNAs/genética , Receptor EphA2/genética , Regiões 3' não Traduzidas/genética , Adulto , Idoso , Animais , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Feminino , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , Metaloproteinases da Matriz/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Metástase Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Receptor EphA2/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Heterólogo
18.
Biochem Biophys Res Commun ; 418(1): 74-80, 2012 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-22252295

RESUMO

BACKGROUND: Prevailing data suggest that ATP-sensitive potassium channels (K(ATP)) contribute to a surprising resistance to hypoxia in mammalian embryos, thus we aimed to characterize the developmental changes of K(ATP) channels in murine fetal ventricular cardiomyocytes. METHODS: Patch clamp was applied to investigate the functions of K(ATP). RT-PCR, Western blot were used to further characterize the molecular properties of K(ATP) channels. RESULTS: Similar K(ATP) current density was detected in ventricular cardiomyocytes of late development stage (LDS) and early development stage (EDS). Molecular-biological study revealed the upregulation of Kir6.1/SUR2A in membrane and Kir6.2 remained constant during development. Kir6.1, Kir6.2, and SUR1 were detectable in the mitochondria without marked difference between EDS and LDS. Acute hypoxia-ischemia led to cessation of APs in 62.5% of tested EDS cells and no APs cessation was observed in LDS cells. SarcK(ATP) blocker glibenclamide rescued 47% of EDS cells but converted 42.8% of LDS cells to APs cessations under hypoxia-ischemic condition. MitoK(ATP) blocker 5-HD did not significantly influence the response to acute hypoxia-ischemia at either EDS or LDS. In summary, sarcK(ATP) played distinct functional roles under acute hypoxia-ischemic condition in EDS and LDS fetal ventricular cardiomyocytes, with developmental changes in sarcK(ATP) subunits. MitoK(ATP) were not significantly involved in the response of fetal cardiomyocytes to acute hypoxia-ischemia and no developmental changes of K(ATP) subunits were found in mitochondria.


Assuntos
Ventrículos do Coração/embriologia , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/fisiologia , Canais de Potássio/metabolismo , Transportadores de Cassetes de Ligação de ATP/agonistas , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Hipóxia Celular , Ventrículos do Coração/metabolismo , Canais KATP/agonistas , Canais KATP/genética , Canais KATP/metabolismo , Moduladores de Transporte de Membrana/farmacologia , Camundongos , Camundongos Endogâmicos , Miócitos Cardíacos/metabolismo , Pinacidil/farmacologia , Canais de Potássio/agonistas , Canais de Potássio/genética , Canais de Potássio Corretores do Fluxo de Internalização/agonistas , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Receptores de Droga/agonistas , Receptores de Droga/genética , Receptores de Droga/metabolismo , Receptores de Sulfonilureias
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