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1.
J Chin Med Assoc ; 87(7): 678-685, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38829960

RESUMEN

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) followed by MRI-targeted prostate biopsy is the current standard for diagnosing prostate cancer (PCa). However, studies evaluating the value of biomarkers, including prostate health index (PHI) and its derivatives using this method are limited. We aimed to investigate the efficacy of PHI density (PHID) in guiding MRI-targeted prostate biopsies to identify clinically significant PCas (csPCa). METHODS: The multicenter prospectively registered prostate biopsy database from three medical centers in Taiwan included patients with PHI and MRI-targeted and/or systematic prostate biopsies. We assessed the required values of prostate-specific antigen (PSA), prostate volume, PHI, PHID, and Prostate Imaging Reporting & Data System (PI-RADS) score using multivariable analyses, receiver operating characteristic curve analysis, and decision curve analyses (DCA). csPCa was defined as the International Society of Urological Pathology Gleason group ≥2 PCa, with an emphasis on reducing unwarranted biopsies. RESULTS: The study cohort comprised 420 individuals. Diagnoses of PCa and csPCa were confirmed in 62.4% and 47.9% of the participants, respectively. The csPCa diagnosis rates were increased with increasing PI-RADS scores (20.5%, 44.2%, and 73.1% for scores 3, 4, and 5, respectively). Independent predictors for csPCa detection included PHI, prostate volume, and PI-RADS scores of 4 and 5 in multivariable analyses. The area under the curve (AUC) for csPCa of PHID (0.815) or PHI (0.788) was superior to that of PSA density (0.746) and PSA (0.635) in the entire cohort, and the superiority of PHID (0.758) was observed in PI-RADS 3 lesions. DCA revealed that PHID achieved the best net clinical benefit in PI-RADS 3-5 and 4/5 cases. Among PI-RADS 3 lesions, cutoff values of PHID 0.70 and 0.43 could eliminate 51.8% and 30.4% of omitted biopsies, respectively. CONCLUSION: PHI-derived biomarkers, including PHID, performed better than other PSA-derived biomarkers in diagnosing PCa in MRI-detected lesions.


Asunto(s)
Imagen por Resonancia Magnética , Próstata , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/diagnóstico por imagen , Anciano , Persona de Mediana Edad , Próstata/patología , Próstata/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Antígeno Prostático Específico/sangre , Biopsia Guiada por Imagen/métodos
2.
Life Sci ; 327: 121863, 2023 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-37331504

RESUMEN

AIMS: The enhancement of inflammation and reactive oxygen species leads to the damage of renal tubular cells in acute kidney injury (AKI), and the upregulation of inflammation increases the risk of AKI being converted into chronic kidney disease (CKD). Hydralazine has shown renoprotective effects in multiple kidney diseases and was shown to be a potent xanthine oxidase (XO) inhibitor. This study aimed to investigate the mechanisms of hydralazine in ischemia-reperfusion (I/R)-stimulated renal proximal tubular epithelial cells in vitro and in AKI animals in vivo. MAIN METHODS: The effects of hydralazine in AKI-to-CKD transition were also evaluated. Human renal proximal tubular epithelial cells were stimulated by I/R conditions in vitro. To generate a mouse model of AKI, a right nephrectomy was performed, followed by left renal pedicle I/R using a small atraumatic clamp. KEY FINDINGS: In the in vitro part, hydralazine could protect renal proximal tubular epithelial cells against insults from the I/R injury through XO/NADPH oxidase inhibition. In the in vivo part, hydralazine preserved renal function in AKI mice and improved the AKI-to-CKD transition by decreasing renal glomerulosclerosis and fibrosis independently of blood pressure lowering. Furthermore, hydralazine exerted antioxidant, anti-inflammatory, and anti-fibrotic effects both in vitro and in vivo. SIGNIFICANCE: Hydralazine, as a XO/NADPH oxidase inhibitor, could protect renal proximal tubular epithelial cells from the insults of I/R and prevent kidney damage in AKI and AKI-to-CKD. The above experimental studies strengthen the possibility of repurposing hydralazine as a potential renoprotective agent through its antioxidative mechanisms.


Asunto(s)
Lesión Renal Aguda , Insuficiencia Renal Crónica , Daño por Reperfusión , Ratones , Humanos , Animales , Xantina Oxidasa , NADPH Oxidasas , Insuficiencia Renal Crónica/patología , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/patología , Riñón/patología , Hidralazina/farmacología , Inhibidores Enzimáticos/farmacología , Inflamación/patología , Daño por Reperfusión/patología , Fibrosis
3.
Biomed Pharmacother ; 164: 114962, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37276643

RESUMEN

Bladder cancer is known as one of the top ten most common cancer types worldwide and can be majorly divided into muscles invasive bladder cancer (MIBC) and non-muscles invasive type (NMIBC). However, the prognosis of BC remains poor under standard treatment including radical cystectomy or concurrent chemoradiotherapy. Numerous studies have reported that the prognosis of BC is associated with the activation of signal transducer and activator of transcription (STAT3) and nuclear factor kappa-B (NF-κB). Fluoxetine, a well-known anti-depressant, has been reported to against various type of cancers. However, it is unclear whether fluoxetine has the capacity to inhibit BC progression by targeting STAT3 and NF-κB-mediated signaling. Here, we used cell viability, apoptosis assay, wound healing assay, invasion/migration assay, Western blotting assay, immunofluorescence staining, as well as animal experiments, to elucidate the efficacy of fluoxetine on in vitro and in vivo BC models. We found that fluoxetine may induce cytotoxicity and intrinsic/extrinsic apoptosis in BC and enhance the potential of cisplatin. Fluoxetine promoted both caspase-dependent and caspase-independent apoptosis signaling by activating caspase-3, 8, 9, apoptosis-inducing factor (AIF), and EndG. Furthermore, fluoxetine suppressed invasion and migration ability and the expression of metastasis-associated genes. Fluoxetine was also found to inactivate the phosphorylation of STAT3 (Tyr705) and NF-κB (Ser536) and suppress the nuclear translocation of NF-κB. In MB49-bearing mice, fluoxetine effectively delayed the progression of BC without inducing general toxicity. In summary, the induction of apoptosis and the inhibition of invasion triggered by fluoxetine are associated with the inactivation of STAT3 and NF-κB.


Asunto(s)
FN-kappa B , Neoplasias de la Vejiga Urinaria , Animales , Ratones , FN-kappa B/metabolismo , Cisplatino/farmacología , Cisplatino/metabolismo , Fluoxetina/farmacología , Fluoxetina/uso terapéutico , Línea Celular Tumoral , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo , Apoptosis , Caspasas/metabolismo , Factor de Transcripción STAT3/metabolismo
5.
J Urol ; 210(1): 88-98, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37036248

RESUMEN

PURPOSE: We compare Prostate Health Index, Prostate Health Index density, and PSA density in predicting clinically significant prostate cancer in MRI-guided prostate biopsy. MATERIALS AND METHODS: This is a multicenter evaluation of prospectively maintained prostate biopsy databases at 10 urology centers. Men with Prostate Health Index and MRI-guided targeted and systematic prostate biopsy performed and without prior prostate cancer diagnosis were included. The additional value of PSA density, Prostate Health Index, and Prostate Health Index density to MRI PI-RADS (Prostate Imaging Reporting & Data System) score was evaluated with multivariable analyses, area under the curve, and decision curve analyses. The proportion of unnecessary biopsies that can be avoided are estimated for clinically significant prostate cancer (International Society of Urological Pathology group ≥2 prostate cancer). RESULTS: A total of 1,215 men were analyzed. Prostate cancer and clinically significant prostate cancer were diagnosed in 51% (617/1,215) and 35% (422/1,215) of men, respectively. Clinically significant prostate cancer was diagnosed in 4.4% (3/68), 15% (72/470), 39% (176/446), and 74% (171/231) of highest PI-RADS score of 2, 3, 4, and 5 lesions, respectively. In multivariable analyses, independent predictors for clinically significant prostate cancer detection included Prostate Health Index (OR 1.04), prostate volume (OR 0.97), and PI-RADS score 4 (OR 2.81) and 5 (OR 8.34). Area under the curve for clinically significant prostate cancer of PI-RADS + Prostate Health Index density (0.85) was superior to PI-RADS + PSA density (0.81), Prostate Health Index density (0.81), Prostate Health Index (0.78), PI-RADS (0.76), PSA density (0.72), and PSA (0.60) in the whole cohort, and the superiority of Prostate Health Index density was also observed in PI-RADS 3 lesions. Decision curve analysis showed Prostate Health Index density achieving the best net clinical benefit in PI-RADS 3 or 4 cases. Among PI-RADS 3 lesions, using cutoffs of PSA density 0.15, Prostate Health Index 38.0, and Prostate Health Index density 0.83 could reduce 58%, 67%, and 72% of unnecessary biopsies, respectively. CONCLUSIONS: Prostate Health Index density outperformed Prostate Health Index or PSA density in clinically significant prostate cancer detection in men with multiparametric MRI performed, and further reduced unnecessary biopsies in PI-RADS 3 lesions.


Asunto(s)
Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Próstata/patología , Antígeno Prostático Específico/análisis , Imagen por Resonancia Magnética/métodos , Estudios Retrospectivos , Biopsia Guiada por Imagen/métodos
7.
Biomed Pharmacother ; 151: 113139, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35623171

RESUMEN

Reactive oxygen species (ROS) and oxidative stress are associated with the progression of diabetic nephropathy (DN). Hydralazine is an antihypertensive agent and may act as a xanthine oxidase (XO) inhibitor to reduce uric acid levels in a mouse renal injury model. This study aimed to investigate the potential mechanisms of hydralazine in experimental DN. Streptozotocin-induced diabetic mice were fed a high-fat diet to generate DN. Human renal proximal tubular epithelial cells were used in vitro. Nitrendipine and allopurinol which can reduce blood pressure or XO activity levels, were used as two positive controls. Hydralazine downregulated NF-κB/p38 signaling pathways and reduced TNF-α/IL-6 expressions in high glucose-stimulated renal proximal tubular epithelial cells. Hydralazine reduced in vitro ROS production via XO inhibition and nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated heme oxygenase (HO)-1 activation. Furthermore, hydralazine reduced high glucose-induced apoptosis by downregulating PARP/caspase-3 signaling. Hydralazine and allopurinol but not nitrendipine reduced serum uric acid levels and systemic inflammation. Hydralazine and allopurinol treatment improved renal function with decreased urinary albumin-to-creatinine ratios, glomerular hypertrophy, glomerulosclerosis, and fibrosis in the kidney of DN mice. While both hydralazine and allopurinol downregulated XO and NADPH oxidase expression, only hydralazine upregulated Nrf2/HO-1 renal expression, suggesting the additional effects of hydralazine independent of XO/ NADPH oxidase inhibition. In conclusion, hydralazine protected renal proximal tubular epithelial cells against the insults of high glucose and prevented renal damage via XO/NADPH oxidase inhibition and Nrf-2/HO-1 activation, suggesting the comprehensive antioxidation and anti-inflammation mechanisms for the management of DN.


Asunto(s)
Diabetes Mellitus Experimental , Nefropatías Diabéticas , Hidralazina , Animales , Ratones , Alopurinol/farmacología , Antioxidantes/farmacología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/metabolismo , Glucosa/metabolismo , Hemo-Oxigenasa 1/metabolismo , Hidralazina/farmacología , Riñón , NADPH Oxidasas/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Ácido Úrico/metabolismo
8.
Mol Cancer Ther ; 21(6): 1010-1019, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35312783

RESUMEN

Cisplatin-based chemotherapy is the first-line therapy for bladder cancer. However, cisplatin resistance has been associated with the recurrence of bladder cancer. Previous studies have shown that activation of FGFR and HER2 signaling are involved in bladder cancer cell proliferation and drug resistance. Smoking is the most common etiologic risk factor for bladder cancer, and there is emerging evidence that smoking is associated with cisplatin resistance. However, the underlying mechanism remains elusive. Acrolein, a highly reactive aldehyde, is abundant in tobacco smoke, cooking fumes, and automobile exhaust fumes. Our previous studies have shown that acrolein contributes to bladder carcinogenesis through the induction of DNA damage and inhibition of DNA repair. In this study, we found that acrolein induced cisplatin resistance and tumor progression in both non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) cell lines RT4 and T24, respectively. Activation of HER2 and FGFR3 signaling contributes to acrolein-induced cisplatin resistance in RT4 and T24 cells, respectively. Furthermore, trastuzumab, an anti-HER2 antibody, and PD173074, an FGFR inhibitor, reversed cisplatin resistance in RT4 and T24 cells, respectively. Using a xenograft mouse model with acrolein-induced cisplatin-resistant T24 clones, we found that cisplatin combined with PD173074 significantly reduced tumor size compared with cisplatin alone. These results indicate that differential molecular alterations behind cisplatin resistance in NMIBC and MIBC significantly alter the effectiveness of targeted therapy combined with chemotherapy. This study provides valuable insights into therapeutic strategies for cisplatin-resistant bladder cancer.


Asunto(s)
Antineoplásicos , Fumar Cigarrillos , Neoplasias de la Vejiga Urinaria , Acroleína/farmacología , Acroleína/uso terapéutico , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Cisplatino/farmacología , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/genética , Humanos , Ratones , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología
9.
Front Oncol ; 11: 772182, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34869007

RESUMEN

BACKGROUND: Prostate-specific antigen (PSA) is considered neither sensitive nor specific for prostate cancer (PCa). We aimed to compare total PSA (tPSA), percentage of free PSA (%fPSA), the PSA density (PSAD), Prostate Health Index (PHI), and the PHI density (PHID) to see which one could best predict clinically significant prostate cancer (csPCa): a potentially lethal disease. METHODS: A total of 412 men with PSA of 2-20 ng/mL were prospectively included. Serum biomarkers for PCa was collected before transrectal ultrasound guided prostate biopsy. PHI was calculated by the formula: (p2PSA/fPSA) x √tPSA. PHID was calculated as PHI divided by prostate volume measured by transrectal ultrasound. RESULTS: Of the 412 men, 134 (32.5%) and 94(22.8%) were diagnosed with PCa and csPCa, respectively. We used the area under the receiver operating characteristic curve (AUC) and decision curve analyses (DCA) to compare the performance of PSA related parameters, PHI and PHID in diagnosing csPCa. AUC for tPSA, %fPSA, %p2PSA, PSAD, PHI and PHID were 0.56、0.63、0.76、0.74、0.77 and 0.82 respectively for csPCa detection. In the univariate analysis, the prostate volume, tPSA, %fPSA, %p2PSA, PHI, PSAD, and PHID were all significantly associated with csPCa, and PHID was the most important predictor (OR 1.41, 95% CI 1.15-1.72). Besides, The AUC of PHID was significantly larger than PHI in csPCa diagnosis (p=0.004). At 90% sensitivity, PHID had the highest specificity (54.1%) for csPCa and could reduce the most unnecessary biopsies (43.7%) and miss the fewest csPCa (8.5%) when PHID ≥ 0.67. In addition to AUC, DCA re-confirmed the clinical benefit of PHID over all PSA-related parameters and PHI in csPCa diagnosis. The PHID cut-off value was positively correlated with the csPCa ratio in the PHID risk table, which is useful for evaluating csPCa risk in a clinical setting. CONCLUSION: The PHID is an excellent predictor of csPCa. The PHID risk table may be used in standard clinical practice to pre-select men at the highest risk of harboring csPCa.

10.
In Vivo ; 34(6): 3217-3224, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33144426

RESUMEN

BACKGROUND: Although both chemotherapy and radiotherapy (RT) can sufficiently maintain tumor suppression of colorectal cancer (CRC), these treatments may trigger the expression of nuclear factor kappa B (NF-κB) and compromise patients' survival. Regorafenib suppresses NF-κB activity in various tumor types. However, whether regorafenib may act as a suitable radiosensitizer to enhance therapeutic efficacy of RT remains unknown. MATERIALS AND METHODS: Here, we established a CRC-bearing animal model to investigate the therapeutic efficacy of regorafenib in combination with RT, through measurement of tumor growth, body weight, whole-body computed tomography (CT) scan and immunohisto-chemistry staining. RESULTS: Smallest tumor size and weight were found in the combination treatment group. In addition, RT-induced up-regulation of NF-κB and downstream proteins were diminished by regorafenib. Moreover, the body weight and liver pathology in the treated group were similar to those of the non-treated control group. CONCLUSION: Regorafenib may enhance the anti-CRC efficacy of RT.


Asunto(s)
Apoptosis , Neoplasias Colorrectales , Animales , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Humanos , FN-kappa B/genética , Compuestos de Fenilurea , Piridinas , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Urol Oncol ; 38(5): 465-475, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32199754

RESUMEN

BACKGROUND: Urothelial carcinomas (UCs) are highly prevalent in patients with end-stage renal disease. Chronic kidney disease (CKD) is the predecessor of end-stage renal disease, and it is also associated with UC. However, the interplay between CKD and UC lacks solid evidence. Acrolein is produced by polyamines and has been suggested to be the uremic "toxin." The level of acrolein correlates well with chronic renal failure. We recently found that acrolein-induced DNA damage and inhibited DNA repair in urothelial cells, which contribute to bladder cancer. Therefore, we hypothesize that acrolein is involved in the formation of UC in patients with CKD. MATERIALS AND METHODS: A total of 62 UC patients and 43 healthy control subjects were recruited. Acrolein-DNA (Acr-dG) adducts and p53 gene mutations in UC tissues, plasma acrolein-protein conjugates (Acr-PC) and S-(3-hydroxypropyl)-N-acetylcysteine levels, and urinary Acr metabolites were analyzed in these patients. RESULTS: Acr-dG levels were statistically correlated with CKD stages in UC patients (P < 0.01). Most p53 mutations were G to A and G to T mutations in these patients, and 50% of mutations at G:C pairs occurred in CpG sites, which is similar to the mutational spectra induced by Acr-dG adducts. Acr-PC levels in the plasma of UC patients with CKD were significantly higher than those of control subjects (P < 0.001). Altered urinary S-(3-hydroxypropyl)-N-acetylcysteine was also found in UC patients with CKD compared to control subjects (P < 0.005). CONCLUSION: These results indicate that acrolein acts as an endogenous uremic toxin and contributes to UC formation in patients with CKD.


Asunto(s)
Acroleína/efectos adversos , Carcinoma de Células Transicionales/genética , Daño del ADN , Genes p53/efectos de los fármacos , Genes p53/genética , Mutación , Insuficiencia Renal Crónica/complicaciones , Neoplasias Urológicas/genética , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Células Tumorales Cultivadas
12.
Sci Rep ; 10(1): 776, 2020 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-31964956

RESUMEN

To evaluate the predictive accuracy of the %p2PSA and prostate health index (PHI) in predicting aggressive pathological outcomes in patients with prostate cancer (PCa) undergoing radical prostatectomy (RP), we enrolled 91 patients with organ-confined PCa who were treated with robot-assisted RP. p2PSA levels and the PHI were investigated for their ability to predict pathological results. The %p2PSA and PHI were both significantly higher in patients with ≥pT3 disease, high-risk disease, positive surgical margin, or seminal vesical invasion (SVI). In univariable analysis, p2PSA derivatives were significant predictors of the presence of ≥pT3 disease, high-risk disease, positive surgical margin, and SVI. To predict adverse pathological outcomes at a sensitivity of 90%, p2PSA derivatives had higher specificity than standard PSA derivatives. In multivariable analysis, additional increases in the area under the receiver operating characteristic curve (AUC) were observed with the %p2PSA and PHI for ≥pT3 disease, high-risk disease, and positive surgical margin (8.2% and 2.7%, 6.2% and 4.1%, and 8.6% and 5.4%, respectively). A PHI ≥61.26 enhanced the predictive accuracy of the model for SVI by increasing the AUC from 0.624 to 0.819 (p = 0.009). The preoperative %p2PSA and PHI accurately predict adverse pathological results and are useful for decision-making.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Antígeno Prostático Específico/metabolismo , Prostatectomía/métodos , Neoplasias de la Próstata/cirugía , Anciano , Humanos , Masculino , Persona de Mediana Edad , Periodo Preoperatorio , Pronóstico , Estudios Prospectivos , Neoplasias de la Próstata/metabolismo , Curva ROC , Resultado del Tratamiento
13.
In Vivo ; 33(6): 1865-1877, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31662514

RESUMEN

BACKGROUND/AIM: Muscle-invasive bladder cancer (MIBC) has long been recognized as a difficult to treat cancer type, thus a new treatment strategy is needed. The major purpose of the present study was to verify the anticancer effect of hyperforin and the mechanism through which it affects tumor cell growth and invasion in bladder cancer in vitro. MATERIALS AND METHODS: Bladder cancer TSGH-8301 cells were treated with different concentrations of hyperforin for different durations of time. The changes in cell viability, production of calcium and reactive oxygen species (ROS), and anti-apoptotic signaling were evaluated using MTT assay, flow cytometry, and western blot analysis. The effect of hyperforin on the expression of nuclear factor-kappaB (NF-ĸB) p65 (Ser276), tumor progression-associated proteins, as well as on cell invasion was investigated using western blotting and cell invasion assay, respectively. RESULTS: Hyperforin significantly induces apoptosis, extrinsic/intrinsic apoptotic signaling, accumulation of cytosol ROS, and calcium signalling. Hyperforin also significantly diminishes the expression of NF-ĸB p65 (Ser276), anti-apoptotic and tumor progression-associated proteins, as well as the cell invasion ability of TSGH-8301 cells. CONCLUSION: Our findings demonstrate that hyperforin triggers apoptosis depending on extrinsic/intrinsic pathways and suppresses NF-ĸB-mediated cell survival as well as the invasive properties of bladder cancer in vitro.


Asunto(s)
Apoptosis/efectos de los fármacos , FN-kappa B/metabolismo , Invasividad Neoplásica/patología , Floroglucinol/análogos & derivados , Transducción de Señal/efectos de los fármacos , Terpenos/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Floroglucinol/farmacología , Especies Reactivas de Oxígeno/metabolismo , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología
14.
Anticancer Res ; 39(7): 3641-3649, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31262890

RESUMEN

BACKGROUND/AIM: Amentoflavone has been shown to be effective against a variety of cancer cells, but its role in bladder cancer remains unclear. Thus, the aim of this study is to evaluate whether amentoflavone may induce toxicity effect of bladder cancer. MATERIALS AND METHODS: Herein, we evaluated amentoflavone effects in a human bladder cancer cell line TSGH8301 in vitro. RESULTS: Amentoflavone caused significant cytotoxicity in TSGH8301 cells at a concentration as low as 200 µM. FAS/FASL-dependent extrinsic apoptosis and mitochondria-dependent intrinsic apoptosis were observed in amentoflavone-treated cells in a dose-dependent manner. Levels of several proapoptotic proteins, such as FAS, FAS-ligand and BAX (B-cell lymphoma 2 associated X) were increased following amentoflavone treatment. Meanwhile, anti-apoptotic MCL-1 (myeloid cell leukemia sequence 1) and cellular FLICE-inhibitory protein (C-FLIP) protein levels were reduced. Additionally, angiogenesis and proliferation-related proteins, including matrix metalloproteinase (MMP)-2, -9, vascular endothelial growth factor (VEGF), urokinase-type plasminogen actvator (uPA) and cyclin D1 were diminished by amentoflavone. CONCLUSION: Amentoflavone induced toxicity of bladder cancer by inhibiting tumor progression and inducing apoptosis signaling transduction.


Asunto(s)
Antineoplásicos/farmacología , Biflavonoides/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proteína Ligando Fas/metabolismo , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Neovascularización Patológica/fisiopatología , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/fisiopatología , Receptor fas/metabolismo
15.
Environ Toxicol ; 34(6): 679-688, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30801954

RESUMEN

The aim of the present study is to investigate anticancer effect and mechanism of regorafenib in bladder cancer in vitro and in vivo. Human bladder cancer TSGH 8301 cells were treated with regorafenib, NF-κB, AKT, or mitogen-activated protein kinase (MAPK) inhibitors for different time. The changes of cell viability, NF-κB activation, apoptotic signaling transduction, and expression of tumor progression-associated proteins were evaluated with MTT, NF-κB reporter gene assay, flow cytometry, and Western blotting assay. TSGH 8301 tumor bearing mice were established and treated with vehicle (140 µL of 0.1% DMSO) or regorafenib (10 mg/kg/day by gavage) for 15 days. The changes of tumor volume, body weight, NF-κB activation, MAPK activation, and tumor progression-associated proteins (MMP-9, XIAP, VEGF, and Cyclin-D1) after regorafenib treatment were evaluated with digital caliper, digital weight, and ex vivo Western blotting assay. Our results demonstrated NF-κB activation and protein levels of MMP-9, XIAP, VEGF, and Cyclin-D1 were significantly reduced by NF-κB (QNZ), ERK (PD98059), and P38 (SB203580) inhibitors. Regorafenib also significantly induced extrinsic and intrinsic apoptotic signaling transduction in bladder cancer in vitro. In addition, regorafenib significantly inhibited tumor growth, NF-κB, p38, ERK activation and expression of tumor progression-associated proteins in bladder cancer in vitro and in vivo. Taken together, these results proved that regorafenib not only induced apoptosis through extrinsic and intrinsic pathways and but suppressed MAPK/ NF-κB-modulated tumor progression in bladder cancer.


Asunto(s)
Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Compuestos de Fenilurea/uso terapéutico , Piridinas/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Progresión de la Enfermedad , Humanos , Imidazoles/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Trasplante de Neoplasias , Piridinas/farmacología , Transducción de Señal/efectos de los fármacos , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
16.
J Formos Med Assoc ; 118(1 Pt 2): 260-267, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29779925

RESUMEN

BACKGROUND/PURPOSE: Prostate specific antigen (PSA) with low specificity that causes unnecessary prostate biopsies increases clinical morbidities, psychological stress, and medical expenses. We aimed to test the accuracy and cutoff value of Prostate Health Index (PHI) in men for prostate cancer detection. METHODS: We prospectively enrolled 213 men who underwent prostate biopsy with PSA≦10 ng/ml or abnormal findings on digital rectal examination. Total PSA (tPSA), free PSA (fPSA) and p2PSA levels were measured by serum samples before prostate biopsy. PHI was calculated as (p2PSA/fPSA) × âˆštPSA. Multivariable logistic regression analyses were used to predict the risk of cancer and detect clinically significant prostate cancer. RESULTS: 33 (27.0%) patients were confirmed with the diagnoses of prostate cancer by prostate biopsy. The levels of p2PSA, %p2PSA, and PHI showed statistically significant differences between prostate cancer patients and non-cancer patients. %p2PSA and PHI had the highest area under the receiver operating characteristic curve (AUC) of 0.723 and 0.772 (both p < 0.001), respectively, predicting cancer detection at biopsy than other predictors (tPSA, fPSA, %fPSA, and PSA density (AUC: 0.544, 0.538, 0.593, and 0.664, respectively). In multivariable logistic regression, %p2PSA had a statistical significant odds ratio 8.51 (p = 0.003) and PHI had an odds ratio with marginal significance 4.18 (p = 0.06). CONCLUSION: %p2PSA and PHI increased the diagnostic accuracy with significantly greater sensitivity and specificity than tPSA. We determined an optimal cut-off value of PHI among Taiwanese population. These findings support the usefulness in the decisional process of prostate biopsy.


Asunto(s)
Antígeno Prostático Específico/sangre , Próstata/patología , Neoplasias de la Próstata/diagnóstico , Anciano , Biomarcadores de Tumor/sangre , Biopsia/estadística & datos numéricos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Estudios Prospectivos , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Curva ROC , Taiwán
17.
Eur Urol ; 75(4): 558-561, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30396635

RESUMEN

Asians have a lower incidence of prostate cancer (PC). We compared the performance of the Prostate Health Index (PHI) for 2488 men in different ethnic groups (1688 Asian and 800 European men from 9 sites) with PSA 2-20ng/ml and PHI test and transrectal ultrasound-guided biopsy results available. Of these, 1652 men had PSA 2-10ng/ml and a normal digital rectal examination and underwent initial biopsy. The proportions of PC (Gleason ≥6) and higher-grade PC (HGPC, Gleason ≥7) across different PHI ranges were compared. The performance of PSA and PHI was compared using the area under the receiver operating characteristic curve (AUC) and decision curve analyses (DCA). Among Asian men, HGPC would be diagnosed in 1.0%, 1.9%, 13%, and 30% of men using PHI thresholds of <25, 25-35, 35-55, and >55, respectively. At 90% sensitivity for HGPC (PHI >30), 56% of biopsies and 33% of Gleason 6 PC diagnoses could have been avoided. Among European men, HGPC would be diagnosed in 4.1%, 4.3%, 30%, and 34% of men using PHI thresholds of <25, 25-35, 35-55, and >55, respectively. At 90% sensitivity for HGPC (PHI >40), 40% of biopsies and 31% of Gleason 6 PC diagnoses could have been avoided. AUC and DCA confirmed the benefit of PHI over PSA. The benefit of PHI was also seen at repeat biopsy (n=397) and for PSA 10-20ng/ml (n=439). PHI is effective in cancer risk stratification for both European and Asian men. However, population-specific PHI reference ranges should be used. PATIENT SUMMARY: The Prostate Health Index (PHI) blood test helps to identify individuals at higher risk of prostate cancer among Asian and European men, and could significantly reduce unnecessary biopsies and overdiagnosis of prostate cancer. Different PHI reference ranges should be used for different ethnic groups.


Asunto(s)
Pueblo Asiatico , Indicadores de Salud , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/etnología , Población Blanca , Asia/epidemiología , Biopsia , Tacto Rectal , Europa (Continente)/epidemiología , Estado de Salud , Humanos , Calicreínas/sangre , Masculino , Clasificación del Tumor , Valor Predictivo de las Pruebas , Prevalencia , Antígeno Prostático Específico/sangre , Valores de Referencia , Reproducibilidad de los Resultados , Medición de Riesgo , Factores de Riesgo
18.
J Chin Med Assoc ; 81(10): 871-877, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30017813

RESUMEN

BACKGROUND: Induced pluripotent stem cells (iPSCs) have a great potential for application in patient-specific therapy. The reprogramming method that does not involve c-Myc reduces tumorigenic risk, but also largely reduces the efficiency of generation of iPSCs, especially for those reprogrammed from damaged cells. Poly(ADP-ribose) polymerase 1 (Parp1) catalyzes a reaction of poly(ADP-ribosylation) and has been reported to enhance cell reprogramming. METHODS: Using Oct-4/Sox2/Klf4/Parp1 (OSKP) reprogramming method, reprogramming factors plus Parp1 were capable of generation of iPSCs from adult fibroblasts and further toward to differentiate from iPSCs status into hepatocyte-like cells. RESULTS: Our results showed that Oct-4/Sox2/Klf4/Parp1 (OSKP)-derived iPSC exhibited regular pluripotent properties, long-term passages and more stable cellular-divided period. These OSKP-derived iPSCs can effectively differentiate into hepatocyte-like cells (OSKP-iPSC-Heps), and present high mRNA levels of Sox17, HNF3b, and HNF4a in OSKP-iPSC-Heps. The mature hepatic functions, including CYP3A4, LDL uptake, glycogen synthesis and urea secretion were analyzed and well detected in OSKP-iPSC-Heps on day 14 post-differentiation. CONCLUSION: In conclusion, we demonstrated that Parp1 promoted reprogramming process to generate the high quality of iPSCs, which could be used as a high quality source of hepatocytes.


Asunto(s)
Reprogramación Celular/fisiología , Hepatocitos/citología , Células Madre Pluripotentes Inducidas/citología , Poli(ADP-Ribosa) Polimerasa-1/fisiología , Proteínas Proto-Oncogénicas c-myc/fisiología , Diferenciación Celular , Humanos , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/fisiología , Factor 3 de Transcripción de Unión a Octámeros/fisiología , Factores de Transcripción SOXB1/fisiología
19.
Anticancer Res ; 37(9): 4919-4926, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28870913

RESUMEN

The aim of the present study was to verify the effects of regorafenib on apoptosis and metastatic potential in TSGH 8301 human bladder carcinoma cells in vitro. Cells were treated with different concentration of regorafenib for different periods of time. Effects of regorafenib on cell viability, apoptosis pathways, metastatic potential, and expression of metastatic and anti-apoptotic proteins were evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay, flow cytometry, cell migration and invasion assay, and western blotting. We found regorafenib significantly reduced cell viability, cell migration and invasion, and expression of metastatic and anti-apoptotic proteins. In addition, regorafenib significantly induced accumulation of sub-G1 phase cells, loss of mitochondrial membrane potential, and expression of active caspase-3 and caspase-8. These results show that regorafenib not only induces apoptosis, but also inhibits metastatic potential in bladder cancer TSGH 8301 cells in vitro.


Asunto(s)
Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Compuestos de Fenilurea/farmacología , Piridinas/farmacología , Neoplasias de la Vejiga Urinaria/patología , Proliferación Celular/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Células Tumorales Cultivadas , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo
20.
Cell Transplant ; 24(3): 541-59, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25668102

RESUMEN

Acute hepatic failure (AHF) is a severe liver injury leading to sustained damage and complications. Induced pluripotent stem cells (iPSCs) may be an alternative option for the treatment of AHF. In this study, we reprogrammed human dental pulp-derived fibroblasts into iPSCs, which exhibited pluripotency and the capacity to differentiate into tridermal lineages, including hepatocyte-like cells (iPSC-Heps). These iPSC-Heps resembled human embryonic stem cell-derived hepatocyte-like cells in gene signature and hepatic markers/functions. To improve iPSC-Heps engraftment, we next developed an injectable carboxymethyl-hexanoyl chitosan hydrogel (CHC) with sustained hepatocyte growth factor (HGF) release (HGF-CHC) and investigated the hepatoprotective activity of HGF-CHC-delivered iPSC-Heps in vitro and in an immunocompromised AHF mouse model induced by thioacetamide (TAA). Intrahepatic delivery of HGF-CHC-iPSC-Heps reduced the TAA-induced hepatic necrotic area and rescued liver function and recipient viability. Compared with PBS-delivered iPSC-Heps, the HGF-CHC-delivered iPSC-Heps exhibited higher antioxidant and antiapoptotic activities that reduced hepatic necrotic area. Importantly, these HGF-CHC-mediated responses could be abolished by administering anti-HGF neutralizing antibodies. In conclusion, our findings demonstrated that HGF mediated the enhancement of iPSC-Hep antioxidant/antiapoptotic capacities and hepatoprotection and that HGF-CHC is as an excellent vehicle for iPSC-Hep engraftment in iPSC-based therapy against AHF.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Factor de Crecimiento de Hepatocito/farmacología , Hepatocitos/citología , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Células Madre Pluripotentes Inducidas/trasplante , Fallo Hepático Agudo/terapia , Regeneración Hepática , Alanina Transaminasa/análisis , Animales , Antioxidantes/química , Antioxidantes/metabolismo , Aspartato Aminotransferasas/análisis , Bilirrubina/análisis , Células Cultivadas , Reprogramación Celular , Quitosano/análogos & derivados , Quitosano/química , Pulpa Dental/citología , Femenino , Factor de Crecimiento de Hepatocito/química , Factor de Crecimiento de Hepatocito/metabolismo , Hepatocitos/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/citología , Hígado/metabolismo , Fallo Hepático Agudo/inducido químicamente , Fallo Hepático Agudo/patología , Masculino , Malondialdehído , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ratones Desnudos , Especies Reactivas de Oxígeno/metabolismo , Tioacetamida/toxicidad
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