Chondrosarcoma is a malignant primary bone tumor. Sirtuin-1 (SIRT1), which is a member of sirtuin family, plays a dual role either in cancer promotion or suppression. There is no report about the ...role of SIRT1 in the human chondrosarcoma cells. Resveratrol is a potent activator of SIRT1. However, its effects on chondrosarcoma have not been extensively studied. Here, we investigated the role of SIRT1 induction by resveratrol in human chondrosarcoma cell growth and tumor progression. Resveratrol significantly decreased cell viability and induced cell apoptosis in human chondrosarcoma cells in a dose-dependent manner. The protein expression and activity of SIRT1 were activated after treatment with resveratrol. Resveratrol significantly inhibited NF-κB signaling by deacetylating the p65 subunit of NF-κB complex, which could be reversed by siRNA-SIRT1 transfection or deacetylation inhibitor MS-275. Resveratrol induced-apoptosis involved a caspase-3-mediated mechanism. Both siRNA-SIRT1 transfection and MS-275 significantly inhibited the resveratrol-induced caspase-3 cleavage and activity in human chondrosarcoma cells. Moreover, in vivo chondrosarcoma xenograft study revealed a dramatic reduction in tumor volume and the increased SIRT1 and cleaved caspase-3 expressions in tumors by resveratrol treatment. These results suggest that resveratrol induces chondrosarcoma cell apoptosis via a SIRT1-activated NF-κB deacetylation and exhibits anti-chondrosarcoma activity in vivo.
The MicroRNA Spectrum in 12 Body Fluids WEBER, Jessica A; BAXTER, David H; SHILE ZHANG ...
Clinical chemistry (Baltimore, Md.),
11/2010, Letnik:
56, Številka:
11
Journal Article
Recenzirano
Odprti dostop
MicroRNAs (miRNAs) are small, noncoding RNAs that play an important role in regulating various biological processes through their interaction with cellular messenger RNAs. Extracellular miRNAs in ...serum, plasma, saliva, and urine have recently been shown to be associated with various pathological conditions including cancer.
With the goal of assessing the distribution of miRNAs and demonstrating the potential use of miRNAs as biomarkers, we examined the presence of miRNAs in 12 human body fluids and urine samples from women in different stages of pregnancy or patients with different urothelial cancers. Using quantitative PCR, we conducted a global survey of the miRNA distribution in these fluids.
miRNAs were present in all fluids tested and showed distinct compositions in different fluid types. Several of the highly abundant miRNAs in these fluids were common among multiple fluid types, and some of the miRNAs were enriched in specific fluids. We also observed distinct miRNA patterns in the urine samples obtained from individuals with different physiopathological conditions.
MicroRNAs are ubiquitous in all the body fluid types tested. Fluid type-specific miRNAs may have functional roles associated with the surrounding tissues. In addition, the changes in miRNA spectra observed in the urine samples from patients with different urothelial conditions demonstrates the potential for using concentrations of specific miRNAs in body fluids as biomarkers for detecting and monitoring various physiopathological conditions.
Microvascular complications eventually affect nearly all patients with diabetes. Advanced glycation end-products (AGEs) resulting from hyperglycemia are a complex and heterogeneous group of compounds ...that accumulate in the plasma and tissues in diabetic patients. They are responsible for both endothelial dysfunction and diabetic vasculopathy. The aim of this study was to investigate the cytotoxicity of AGEs on pancreatic islet microvascular endothelial cells. The mechanism underlying the apoptotic effect of AGEs in pancreatic islet endothelial cell line MS1 was explored. The results showed that AGEs significantly decreased MS1 cell viability and induced MS1 cell apoptosis in a dose-dependent manner. AGEs dose-dependently increased the expressions of cleaved caspase-3, and cleaved poly (ADP-ribose) polymerase in MS1 cells. Treatment of MS1 cells with AGEs also resulted in increased nuclear factor (NF)-κB-p65 phosphorylation and cyclooxygenase (COX)-2 expression. However, AGEs did not affect the expressions of endoplasmic reticulum (ER) stress-related molecules in MS1 cells. Pretreatment with NS398 (a COX-2 inhibitor) to inhibit prostaglandin E2 (PGE2) production reversed the induction of cleaved caspase-3, cleaved PARP, and MS1 cell viability. Moreover, AGEs significantly increased the receptor for AGEs (RAGE) protein expression in MS1 cells, which could be reversed by RAGE neutralizing antibody. RAGE Neutralizing antibody could also reverse the induction of cleaved caspase-3 and cleaved PARP and decreased cell viability induced by AGEs. These results implicate the involvement of NF-κB-activated COX-2/PGE2 up-regulation in AGEs/RAGE-induced islet endothelial cell apoptosis and cytotoxicity. These findings may provide insight into the pathological processes within the pancreatic islet microvasculature induced by AGEs accumulation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aristolochic acid (AA), a component of all Aristolochia‐based herbal medicines, is a potent nephrotoxin and human carcinogen associated with upper urinary tract urothelial carcinoma (UUC). To ...investigate the clinical and pathological characteristics of AA‐induced UUC, this study included 152 UUC patients, 93 of whom had been exposed to AA based on the presence of aristolactam‐DNA adducts in the renal cortex. Gene sequencing was used to identify tumors with A:T‐to‐T:A transversions in TP53, a mutational signature associated with AA. Cases with both aristolactam‐DNA adducts and A:T‐to‐T:A transversions in TP53 were defined as AA‐UUC, whereas patients lacking both of these biomarkers were classified as non‐AA‐UUC. Cases with either biomarker were classified as possible‐AA‐UUC. Forty (26%), 60 (40%), and 52 (34%) patients were classified as AA‐UUC, possible‐AA‐UUC and non‐AA‐UUC, respectively. AA‐UUC patients were younger (median ages: 64, 68, 68 years, respectively; p=0.189), predominately female (65%, 42%, 35%, respectively; p=0.011), had more end‐stage renal disease (28%, 10%, 12%, respectively; p=0.055), and were infrequent smokers (5%, 22%, 33%, respectively; p=0.07) compared to possible‐AA‐UUC and non‐AA‐UUC patients. All 14 patients who developed contralateral UUC had aristolactam‐DNA adducts; ten of these also had signature mutations. The contralateral UUC‐free survival period was shorter in AA‐UUC compared to possible‐ or non‐AA‐UUC (p=0.019 and 0.002, respectively), whereas no differences among groups were observed for bladder cancer recurrence. In conclusion, AA‐UUC patients tend to be younger and female, and have more advanced renal disease. Notably, AA exposure was associated with an increased risk for developing synchronous bilateral and metachronous contralateral UUC.
What's new?
Aristolochic acid, a component of all Aristolochia‐based herbal medicines, is a potent nephrotoxin and human carcinogen associated with upper urinary tract urothelial carcinoma (UUC). This is the first clinical study to characterize aristolochic acid‐induced UUC using two newly developed biomarkers, aristolactam‐DNA adducts in renal cortex and a signature TP53 mutation. Aristolochic acid‐induced UUC patients tended to be younger than other UUC patients and predominantly female and had more advanced renal disease. AA exposure was associated with an increased risk for developing synchronous bilateral and metachronous contralateral UUC. This pattern distinguishes AA from other carcinogens involved in the etiology of UUC.
Cisplatin-based chemotherapy is the standard treatment for bladder urothelial carcinoma (UC). Most patients experience chemoresistance, the primary cause of treatment failure, which leads to disease ...relapse. The underlying mechanism of chemoresistance involves reduced apoptosis. In this study, we investigated the antitumor effect of the deubiquitylating enzyme inhibitor PR-619 in cisplatin-resistant bladder UC. Deubiquitinase (ubiquitin-specific protease 14 (USP14) and USP21) immunohistochemical staining demonstrated that deubiquitination is related to chemoresistance in patients with metastatic UC and may be a target for overcoming chemoresistance. Cytotoxicity and apoptosis were assessed using fluorescence-activated flow cytometry and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay, and PR-619 was found to enhance the cytotoxic and apoptotic effects of cisplatin in cisplatin-resistant T24/R cells. Mitigated cisplatin chemoresistance was associated with the concurrent suppression of c-Myc expression in T24/R cells. Moreover, the expression of c-Myc was upregulated in human bladder UC specimens from patients with chemoresistance. Experiments in a xenograft nude mouse model confirmed that PR-619 enhanced the antitumor effects of cisplatin. These results are promising for the development of therapeutic strategies to prevent UC chemoresistance through the combined use of chemotherapeutic agents/deubiquitination inhibitors (PR-619) by targeting the c-Myc pathway.
The clinical characteristics and outcomes in patients with clinical aldosterone-producing adenomas harboring KCNJ5 mutations with or without subclinical hypercortisolism remain unclear. This ...prospective study is aimed at determining factors associated with subclinical hypercortisolism in patients with clinical aldosterone-producing adenomas. Totally, 82 patients were recruited from November 2016 to March 2018 and underwent unilateral laparoscopic adrenalectomy with at least a 12-month follow-up postoperatively. Standard subclinical hypercortisolism (defined as cortisol >1.8 μg/dL after 1 mg dexamethasone suppression test DST) was detected in 22 (26.8%) of the 82 patients. Intriguingly, a generalized additive model identified the clinical aldosterone-producing adenoma patients with 1 mg DST>1.5 μg/dL had significantly larger tumors (P=0.02) than those with 1 mg DST<1.5 μg/dL. Multivariable logistic regression showed that the presence of KCNJ5 mutations (odds ratio, 0.22, P=0.010) and body mass index (odds ratio, 0.87, P=0.046) were negatively associated with 1 mg DST>1.5 μg/dL, whereas tumor size was positively associated with it (odds ratio, 2.85, P=0.014). Immunohistochemistry revealed a higher degree of immunoreactivity for CYP11B1 in adenomas with wild-type KCNJ5 (P=0.018), whereas CYP11B2 was more commonly detected in adenomas with KCNJ5 mutation (P=0.007). Patients with wild-type KCNJ5 and 1 mg DST>1.5 μg/dL exhibited the lowest complete clinical success rate (36.8%) after adrenalectomy. In conclusion, subclinical hypercortisolism is common in clinical aldosterone-producing adenoma patients without KCNJ5 mutation or with a relatively larger adrenal tumor. The presence of serum cortisol levels >1.5 μg/dL after 1 mg DST may be linked to a lower clinical complete success rate.
Objectives
Decreased glomerular filtration rate has been reported in patients with primary aldosteronism after unilateral adrenalectomy. Glomerular hyperfiltration has been assumed to mask the ...preoperative subtle renal impairment. In this study, we investigated predictors for decreased estimated glomerular filtration rate after adrenalectomy in patients with primary aldosteronism.
Methods
From January 2006 through September 2018, 328 patients with confirmatory diagnoses of primary aldosteronism received unilateral laparoscopic adrenalectomy and subsequent follow‐up for 12 months. We prospectively collected related parameters of the clinical outcomes and renal function to identify predictors of renal function impairment at 12 months after surgery.
Results
Patients were stratified into three groups by preoperative estimated glomerular filtration rate level: 144 (43.9%) with estimated glomerular filtration rate ≥90, 130 (39.6%) with estimated glomerular filtration rate within 60–89.9, and 54 (16.5%) with estimated glomerular filtration rate <60 mL/min/1.73 m2. The estimated glomerular filtration rate decreased significantly at the 6th month and remained stable at the 12th month, postoperatively. Patients with estimated glomerular filtration rate ≥90 had better clinical outcome with 59.6% success rate (P = 0.006) among three groups. Multivariate logistic regression analysis indicated that preoperative estimated glomerular filtration rate (odds ratio 1.012, P = 0.02) and hypokalemia (odds ratio 2.018, P = 0.024) were associated with renal impairment at 12th month after adrenalectomy. Multivariate linear regression analysis revealed high preoperative estimated glomerular filtration rate (β = 0.261, P < 0.001), high preoperative systolic blood pressure (β = 0.168, P = 0.003), high level of microalbuminuria (β = 0.024, P = 0.001), and low level of serum potassium (β = −4.883, P = 0.007) were associated with estimated glomerular filtration rate percentage decline at 12th month after adrenalectomy.
Conclusions
Estimated glomerular filtration rate declined significantly after adrenalectomy in patients with estimated glomerular filtration rate ≥90. The study provided important information to identify primary aldosteronism patients with higher risk of estimated glomerular filtration rate decline after adrenalectomy and might help to adopt early interventions to improve the outcomes.
Cisplatin-based chemotherapy is the primary treatment for metastatic bladder urothelial carcinoma (UC). Most patients inevitably encounter drug resistance and resultant disease relapse. Reduced ...apoptosis plays a critical role in chemoresistance. Trifluoperazine (TFP), an antipsychotic agent, has demonstrated antitumor effects on various cancers. This study investigated the efficacy of TFP in inhibiting cisplatin-resistant bladder UC and explored the underlying mechanism. Our results revealed that cisplatin-resistant UC cells (T24/R) upregulated the antiapoptotic factor, B-cell lymphoma-extra large (Bcl-xL). Knockdown of Bcl-xL by siRNA resensitized cisplatin-resistant cells to the cisplatin cytotoxic effect. TFP (10-45 μM) alone elicited dose-dependent cytotoxicity, apoptosis, and G0/G1 arrest on T24/R cells. Co-treatment of TFP potentiated cisplatin-induced cytotoxicity in T24/R cells. The phenomenon that TFP alleviated cisplatin resistance to T24/R was accompanied with concurrent suppression of Bcl-xL. In vivo models confirmed that TFP alone effectively suppressed the T24/R xenograft in nude mice. TFP co-treatment enhanced the antitumor effect of cisplatin on the T24/R xenograft. Our results demonstrated that TFP effectively inhibited cisplatin-resistant UCs and circumvented cisplatin resistance with concurrent Bcl-xL downregulation. These findings provide a promising insight to develop a therapeutic strategy for chemoresistant UCs.
Objectives
To compare the performance of on-site quick cortisol assay (QCA) and C-arm computed tomography (CT) assistance on adrenal venous sampling (AVS) without adrenocorticotropic hormone ...stimulation.
Methods
The institutional review board at our hospital approved this retrospective study, which included 178 consecutive patients with primary aldosteronism. During AVS, we used C-arm CT to confirm right adrenal cannulation between May 2012 and June 2015 (n = 100) and QCA for bilateral adrenal cannulation between July 2015 and September 2016 (n = 78). Successful AVS required a selectivity index (cortisol
adrenal vein
/cortisol
peripheral
) of ≥ 2.0 bilaterally.
Results
The overall success rate of C-arm CT-assisted AVS was 87%, which increased to 97.4% under QCA (
P
= .013). The procedure time (C-arm CT, 49.5 ± 21.3 min; QCA, 37.5 ± 15.6 min;
P
< .001) and radiation dose (C-arm CT, 673.9 ± 613.8 mGy; QCA, 346.4 ± 387.8 mGy;
P
< .001) were also improved. The resampling rate was 16% and 21.8% for C-arm CT and QCA, respectively. The initial success rate of the performing radiologist remained stable during the study period (C-arm CT 75%; QCA, 82.1%,
P
= .259).
Conclusions
QCA might be superior to C-arm CT for improving the performance of AVS.
Key Points
• Adrenal venous sampling (AVS) is a technically challenging procedure.
• C-arm CT and quick cortisol assay (QCA) are efficient for assisting AVS.
• QCA might outperform C-arm CT in enhancing AVS performance.
Trichostatin A (TSA), an antifungal antibiotic derived from
, inhibits mammalian histone deacetylases, and especially, selectively inhibits class I and II histone deacetylase (HDAC) families of ...enzymes. TSA reportedly elicits an antiproliferative response in multifarious tumors. This study investigated the antitumor effects of TSA alone and in combination with paclitaxel when applied to two high-grade urothelial carcinoma (UC) cell lines (BFTC-905 and BFTC-909). Fluorescence-activated cell sorting, flow cytometry, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay were used to assess TSA's cytotoxicity and effects on apoptosis induction. TSA induced synergistic cytotoxicity, when combined with paclitaxel (combination index < 1), resulted in concomitant suppression of paclitaxel-induced activation of phospho-extracellular signal-regulated kinase (ERK) 1/2. A xenograft nude mouse model confirmed that TSA enhances the antitumor effects of paclitaxel. These findings demonstrate that the administration of TSA in combination with paclitaxel elicits a synergistic cytotoxic response. The results of this study indicate that the chemoresistance of UC could be circumvented by combining HDAC inhibitors to target the ERK pathway.
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