Jumonji domain-containing protein RIOX2 is overexpressed and associated with worse survival outcomes in prostate cancers

BackgroundHistone demethylase RIOX2 was cloned as a c-Myc downstream gene involved in cell proliferation and has been implicated as an oncogenic factor in multiple tumor types. Its expression profiles and correlation with disease progression in prostate cancers are unknown.MethodsTranscriptomic profiles of Jumanji domain-containing protein genes were assessed using multiple public expression datasets generated from RNA-seq and cDNA microarray assays. RIOX2 protein expression was assessed using an immunohistochemistry approach on a tissue section array from benign and malignant prostate tissues. Gene expression profiles were analyzed using the bioinformatics software R package. Western blot assay examined androgen stimulation on RIOX2 protein expression in LNCaP cells.ResultsAmong 35 Jumanji domain-containing protein genes, 12 genes were significantly upregulated in prostate cancers compared to benign compartments. COX regression analysis identified that the ribosomal oxygenase 2 (RIOX2) gene was the only one significantly associated with disease-specific survival outcomes in prostate cancer patients. RIOX2 upregulation was confirmed at the protein levels using immunohistochemical assays on prostate cancer tissue sections. Meanwhile, RIOX2 upregulation was associated with clinicopathological features, including late-stage diseases, adverse Gleason scores, TP53 gene mutation, and disease-free status. In castration-resistant prostate cancers (CRPC), RIOX2 expression was positively correlated with AR signaling index but negatively correlated with the neuroendocrinal progression index. However, androgen treatment had no significant stimulatory effect on RIOX2 expression, indicating a parallel but not a causative effect of androgen signaling on RIOX2 gene expression. Further analysis discovered that RIOX2 expression was tightly correlated with its promoter hypomethylation and MYC gene expression, consistent with the notion that RIOX2 was a c-Myc target gene.ConclusionThe Jumanji domain-containing protein RIOX2 was significantly overexpressed in prostate cancer, possibly due to c-Myc upregulation. RIOX2 upregulation was identified as an independent prognostic factor for disease-specific survival

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ABSTRACT Response surface methodology(RSM) was employed to optimize conditions for ultrasound-assisted extraction(UAE) of antioxidantive components from Arundinagraminifolia. 1,1-diphenyl-2-picryl-hydrazyl(DPPH) free radical scavenging assay was used to evaluate the activity of antioxidative components. Based on the single-factor test, we identified extraction time, ethanol volume fraction, extraction temperature and liquid-solid ratio as the main variables that influence DPPH free radical scavenging activity of A. graminifolia extract. The optimal conditions to achieve the maximum activity were determined as follows: extraction time 35 min, extraction temperature46ºC, ethanol volume fraction 74%and liquid-solidratio27 mL.g -1 . The scavenging rateof 78.71%was achieved under the optimal extraction conditions, which was well in agreement with the optimal predicted values (79.16%). This extraction method was simple and efficient and provided a method of sample preparation to determine DPPH radical scavenging activity of total antioxidative components from A. graminifolia. The research also provided a reference for full utilization of A. graminifolia and identified a technique to extract antioxidative components

Prostate-targeted biodegradable nanoparticles loaded with androgen receptor silencing constructs eradicate xenograft tumors in mice

BACKGROUND: Prostate cancer is the major cause of cancer death in men and the androgen receptor (AR) has been shown to play a critical role in the progression of the disease. Our previous reports showed that knocking down the expression of the AR gene using a siRNA-based approach in prostate cancer cells led to apoptotic cell death and xenograft tumor eradication. In this study, we utilized a biodegradable nanoparticle to deliver the therapeutic AR shRNA construct specifically to prostate cancer cells. MATERIALS & METHODS: The biodegradable nanoparticles were fabricated using a poly(dl-lactic-co-glycolic acid) polymer and the AR shRNA constructs were loaded inside the particles. The surface of the nanoparticles were then conjugated with prostate-specific membrane antigen aptamer A10 for prostate cancer cell-specific targeting. RESULTS: A10-conjugation largely enhanced cellular uptake of nanoparticles in both cell culture- and xenograft-based models. The efficacy of AR shRNA encapsulated in nanoparticles on AR gene silencing was confirmed in PC-3/AR-derived xenografts in nude mice. The therapeutic property of A10-conjugated AR shRNA-loaded nanoparticles was evaluated in xenograft models with different prostate cancer cell lines: 22RV1, LAPC-4 and LNCaP. Upon two injections of the AR shRNA-loaded nanoparticles, rapid tumor regression was observed over 2 weeks. Consistent with previous reports, A10 aptamer conjugation significantly enhanced xenograft tumor regression compared with nonconjugated nanoparticles. DISCUSSION: These data demonstrated that tissue-specific delivery of AR shRNA using a biodegradable nanoparticle approach represents a novel therapy for life-threatening prostate cancers

The calcimimetic R-568 induces apoptotic cell death in prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Increased serum level of parathyroid hormone (PTH) was found in metastatic prostate cancers. Calcimimetic R-568 was reported to reduce PTH expression, to suppress cell proliferation and to induce apoptosis in parathyroid cells. In this study, we investigated the effect of R-568 on cellular survival of prostate cancer cells.</p> <p>Methods</p> <p>Prostate cancer cell lines LNCaP and PC-3 were used in this study. Cellular survival was determined with MTT, trypan blue exclusion and fluorescent Live/Death assays. Western blot assay was utilized to assess apoptotic events induced by R-568 treatment. JC-1 staining was used to evaluate mitochondrial membrane potential.</p> <p>Results</p> <p>In cultured prostate cancer LNCaP and PC-3 cells, R-568 treatment significantly reduced cellular survival in a dose- and time-dependent manner. R-568-induced cell death was an apoptotic event, as evidenced by caspase-3 processing and PARP cleavage, as well as JC-1 color change in mitochondria. Knocking down calcium sensing receptor (CaSR) significantly reduced R-568-induced cytotoxicity. Enforced expression of Bcl-xL gene abolished R-568-induced cell death, while loss of Bcl-xL expression led to increased cell death in R-568-treated LNCaP cells,.</p> <p>Conclusion</p> <p>Taken together, our data demonstrated that calcimimetic R-568 triggers an intrinsic mitochondria-related apoptotic pathway, which is dependent on the CaSR and is modulated by Bcl-xL anti-apoptotic pathway.</p

Prodrug Strategy for PSMA-targeted Delivery of TGX-221 to Prostate Cancer Cells

TGX-221 is a potent, selective, and cell membrane permeable inhibitor of the PI3K p110β catalytic subunit. Recent studies showed that TGX-221 has anti-proliferative activity against PTEN-deficient tumor cell lines including prostate cancers. The objective of this study was to develop an encapsulation system for parenterally delivering TGX-221 to the target tissue through a prostate-specific membrane aptamer (PSMAa10) with little or no side effects. In this study, PEG-PCL micelles were formulated to encapsulate the drug, and a prodrug strategy was pursued to improve the stability of the carrier system. Fluorescence imaging studies demonstrated that the cellular uptake of both drug and nanoparticles were significantly improved by targeted micelles in a PSMA positive cell line. The area under the plasma concentration time curve of the micelle formulation in nude mice was 2.27-fold greater than the naked drug, and the drug clearance rate was 17.5-fold slower. These findings suggest a novel formulation approach for improving site-specific drug delivery of a molecular-targeted prostate cancer treatment

Bax degradation involvement in tumor survival and progression

According to the present invention, there is provided an assay for determining Bax degradation activity in a patient sample. The assay includes a labeled Bax protein which is incubated with a protein extract from the sample and a detector for detecting a signal from the labeled Bax protein, whereby decreased signals compared to a control indicates Bax degradation activity. Also provided by the present invention is a method for assaying a tissue for Bax degradation activity for determining aggressiveness of a tumor, for screening compounds for inhibitors of Bax degradation activity and for determining efficacy of proteasome inhibitors to prevent Bax degradation including the steps of incubating the sample with a labeled Bax protein and detecting the presence of a label generated signal whereby decrease signal compared to a control indicates Bax degradation activity. A method for screening potential proteasome inhibitors and anticancer drugs for efficacy in preventing Bax degradation activity. A method of determining tumor grade by measuring the Bax protein level and Bax degradation activity level whereby low or moderate levels of Bax protein and high levels of Bax degradation activity indicate a high-grade tumor is also provided

Comparative study of clinical and MRI features of TMD patients with or without joint effusion: a retrospective study

Abstract Background The relationship between joint effusion and temporomandibular disorders (TMD) remains unclear. The purpose of this study was to investigate the correlation among joint effusion, clinical features and MRI imaging features of TMD. Methods A total of 1532 temporomandibular joints (TMJs) from 766 patients (605 females and 161 males) with the mean age of 31.68 ± 13.71 years from January 2022 to June 2023 were included in the study. Clinical and MRI features were collected and analyzed. Chi-Square test, Spearman correlation coefficient and binary logistic regression analysis were performed. Results Patients with joint effusion were significantly older and had smaller value of MIO (p < 0.001). There were significant differences in the distribution of joint sounds (with or without), joint pain (with or without), disc morphology (biconcave, contracture, irregular and lengthened) and disc position between joint effusion group (JE) and non-joint effusion group (NA) (P < 0.05).The odds of having joint effusion were 1.726 higher in patients with joint sounds when compared to those without joint sounds. The odds of having joint effusion were 8.463 higher in patients with joint pain when compared to those without joint pain. The odds of having joint effusion were 2.277 higher in patients with contracture when compared to those with biconcave. The odds of having joint effusion were 1.740 higher in patients with anterior disc displacement with reduction (ADDWR) when compared to those with normal disc position. The prediction accuracy of this model is 74.9%, and the area under curve (AUC) is 79.5%, indicating that it can be used for the prediction and the judgment effect is average. Conclusions The results demonstrated that joint sounds, joint pain, contracture, and ADDWR are high risk factors for joint effusion, especially joint pain. Trial registration This study was retrospectively registered on 28/03/2022 and endorsed by the Ethics Committee of Affiliated Stomatology Hospital of Guangzhou Medical University (LCYJ2022014)

PI-3 kinase p110 β : a therapeutic target in advanced prostate cancers

Abstract: Prostate cancers in the castration-resistant stage are life-threatening because they are not curable in clinic. The novel androgen receptor inhibitor Xandi (Enzalutamide) and the new CYP17 inhibitor Zytiga (Abiraterone) prolonged patient survival only a few months in advanced prostate cancers. Therefore, novel therapeutic agents for advanced prostate cancers are urgently needed. PI-3 kinases are major intracellular signaling molecules that regulate multiple signal pathways related to cellular metabolism, cytokinesis, growth and survival. Accumulating evidence in the literature indicates that some isoforms of this kinase family are oncogenic and abnormally expressed in various human cancers, including prostate cancers. Recent extensive studies from our group and others showed that PI-3 kinase p110β is aberrantly overexpressed in advanced prostate cancers and is critical for prostate cancer development and progression as demonstrated in cell-based and animal models. Importantly, novel p110β-specific inhibitors have been developed and are currently been testing in clinical trials. In this article, we will briefly summarize recent developments in this regard