Comprehensive investigation in oncogenic functions and immunological roles of NCBP2 and its validation in prostate cancer.

BACKGROUND: Nuclear cap-binding protein 2 (NCBP2), as the component of the cap-binding complex, participates in a number of biological processes, including pre-mRNA splicing, transcript export, translation regulation and other gene expression steps. However, the role of NCBP2 on the tumor cells and immune microenvironment remains unclear. To systematically analyze and validate functions of NCBP2, we performed a pan-cancer analysis using multiple approaches. METHODS: The data in this study were derived from sequencing, mutation, and methylation data in the TCGA cohort, normal sample sequencing data in the GTEx project, and cell line expression profile data in the CCLE database. RESULTS: Survival analyses including the Cox proportional-hazards model and log-rank test revealed the poor prognostic role of NCBP2 in multiple tumors. We further validated the oncogenic ability of NCBP2 in prostate cancer cell lines, organoids and tumor-bearing mice. A negative correlation was observed between NCBP2 expression and immune score by the ESTIMATE algorithm. Simultaneously, the NCBP2-induced immunosuppressive microenvironment might be related to the decline in CD8+T cells and the increase in regulatory T cells and neutrophils, examined by flow cytometry experiments for NCBP2 overexpressed tumor-bearing mice. CONCLUSION: This research offered strong proof supporting NCBP2 as the prognostic marker and the therapeutic target in the future.

Bioconjugation and Reaction-Induced Tumor Therapy via Alkynamide-Based Thiol-Yne Click Reaction.

Ferroptosis is associated with the occurrence and development of many diseases, which is the result of an imbalance in cellular metabolism and oxidation-reduction balance. Therefore, it is an effective therapeutic strategy that simultaneously regulating the intracellular oxidation-reduction system. Herein, a click reaction of alkynylamide with thiol groups in the presence of amine or in PBS (pH = 7.4) is developed, which can react efficiently with thiol substances, such as cysteine (Cys), glutathione (GSH), and bovine serum albumin (BSA). Notably, MBTB-PA, an aggregation-induced emission (AIE) photosensitizer with an alkynylamide unit, is synthesized and its intracellular behavior is visualized in situ by fluorescence imaging, demonstrating its excellent ability to target the endoplasmic reticulum. Furthermore, MBTB-PA reacted with proteins in tumor cells, consumed reducing substances, and triggered intracellular oxidative stress, resulting in cell death. Based on this reaction therapy strategy, click reaction is combined with photodynamic therapy to achieve effective killing of tumor cells by simultaneously raising the intracellular oxidative state and reducing the reductive state. This work not only develops an application of click reaction of alkynamide with thiol in bioconjugation and anti-tumor therapy, but also provides feasible ideas for organic reactions in the exploration of organisms.

Click-Reaction-Mediated Chemotherapy and Photothermal Therapy Synergistically Inhibit Breast Cancer in Mice.

The development of functional materials for tumor immunogenicity enhancement is desirable for overcoming the low therapeutic efficiency and easy metastasis during tumor treatments. Herein, the thermoresponsive nanoparticles composed of photothermal agent (PTA) and click reactive reagent are developed for enhanced immunotherapy application. A Ni-bis(dithiolene)-containing PTA with intense near-infrared absorption and efficient photothermal conversion is developed for thermoresponsive nanoparticles construction. The generated heat by encapsulated PTA further induces the phase transition of thermoresponsive nanoparticles with the release of chemotherapy reagent to react with the amino groups on functional proteins, realizing PTT and chemotherapy simultaneously. Moreover, the immunogenic cell death (ICD) of cancer cells evoked by PTT could be further enhanced by the released reactive reagent. As a result, the synergistic effect of photothermal treatment and reaction-mediated chemotherapy can suppress the growth of a primary tumor, and the evoked ICD could further activate the immune response with the suppression of a distant tumor. This synergistic treatment strategy provides a reliable and promising approach for cancer immunotherapy in clinic.

NIR luminogen for low-temperature photothermal therapy by triggering HSP90α down-regulation.

A near-infrared (NIR) luminogen TST was designed and used to efficiently trigger HSP90α protein knockdown through photo-thermal conversion based on a gene interference strategy, by which in vitro and in vivo tumor ablation were significantly acquired at low-temperature.

Aggregation Effect on Multiperformance Improvement in Aryl-Armed Phenazine-Based Emitters.

The concept of aggregate science was proposed to explain changes in materials performance that accompany the generation of aggregates, but aggregation-triggered multifunction improvements in a class of materials have rarely been reported. Herein, we present the first report of a new class of multifunctional aggregation-induced emission (AIE) luminogens (AIEgens) based on 5,10-diarylphenazine (DPZ) derivates with full-wavelength emission. Intriguingly, multiple properties, such as fluorescence intensity and free radical and type I reactive oxygen species (ROS) efficiencies, could be simultaneously activated from the unimolecular level to the aggregate state. The mechanisms of this multiple performance improvement are discussed in detail based on sufficient performance characterization, and some of the newly prepared AIEgens exhibited toxicity to cancer cells during photodynamic therapy. This work systematically demonstrates the positive effect of aggregation on improving multiple functions of materials, which is expected to promote the development of aggregate science theory for the design of multifunctional materials.

Referential modification strategy based on phenolic hydroxyl-containing KSA luminogens for ER-targeting probe construction.

The endoplasmic reticulum (ER) plays essential roles in various physiological processes and is intimately connected to kinds of diseases. The development of ER-targeting theranostic agents is highly demanded for precise treatments, however, the effective and referential strategies for the construction of ER-targeting probes are limited. Herein, we developed series of ER-targeting luminogens based on keto-salicylaldehyde azine (KSA) framework by introducing phenolic hydroxyl group, which present good theranostic performance with selective enrichment in ER. Under systematical structure modulation, the key role of phenolic hydroxyl group at K-terminal in ER-targeting was experimentally confirmed. Besides, the cyanobenzyl moiety at S-terminal can enhance the luminous efficiency and improve cellular uptake ability. Moreover, the generated reactive oxygen species (ROS) of these KSA derivatives can efficiently trigger ER stress to induce the apoptosis of cancer cells, resulting in the effective inhibition of tumor cells both in vitro and in vivo. Therefore, this feasible modification strategy of inserting phenolic hydroxyl group to common multi-aryl-based luminogens provides a reliable and referential approach for ER-targeting probe establishment.

Photo-Enhanced Chemotherapy Performance in Bladder Cancer Treatment via Albumin Coated AIE Aggregates.

The implementation of cisplatin-based neoadjuvant chemotherapy (NAC) plays a key role in conjunction with surgical resection in preventing bladder cancer progression and recurrence. However, the significant dose-dependent toxic side effects of NAC are still a major challenge. To solve this problem, we developed a photoenhanced cancer chemotherapy (PECC) strategy based on AIEgen ((E)-3-(2-(2-(5-(4-(diphenylamino)phenyl)thiophen-2-yl)vinyl)-1,1-dimethyl-1H-3λ4-benzo[e]indol-3-yl)propane-1-sulfonate), which is abbreviated as BITT. Multifunctional BITT@BSA-DSP nanoparticles (NPs) were employed with an albumin-based nanocarrier decorated with the cisplatin(IV) prodrug and loaded to produce strong near-infrared fluorescence imaging (NIR FLI), and they exhibited good photoenhancement performance via photodynamic therapy (PDT) and photothermal therapy (PTT). In vitro results demonstrated that BITT@BSA-DSP NPs could be efficiently taken up by bladder cancer cells and reduced to release Pt (II) under reductase, ensuring the chemotherapy effect. Furthermore, both in vitro and in vivo evaluation verified that the integration of NIR FL imaging-guided PECC efficiently promoted the sensitivity of bladder cancer to cisplatin chemotherapy with negligible side effects. This work provides a promising strategy to enhance the sensitivity of multiple cancers to chemotherapy drugs and even achieve effective treatments for drug-resistant cancers.

miR-129-5p restores cardiac function in rats with chronic heart failure by targeting the E3 ubiquitin ligase Smurf1 and promoting PTEN expression.

Chronic heart failure (CHF) is a prevalent health concern with complex pathogenesis. This current study set out to estimate the function of the miR-129-5p/Smurf1/PTEN axis on cardiac function injury in CHF. The model of CHF in rats was established. The cardiac function indexes, myocardial tissue damage, and oxidative stress-related factors in CHF rats were evaluated after the interference of Smurf1/miR-129-5p/PTEN. The targeting relationships between miR-129-5p and Smurf1 and between PTEN and Smurf1 were verified. It was found that that after modeling, cardiac functions were impaired, heart/left ventricular/lung weight and the myocardial structure was destroyed, and the degree of fibrosis of myocardial tissue was increased. After Smurf1 knockdown, the cardiac function, myocardial structure, and oxidative stress were improved, and the fibrosis in myocardial tissue was decreased. Smurf1 was a target of miR-129-5p. miR-129-5p could annul the protective effect of Smurf1 silencing on CHF rats. Smurf1 inhibited PTEN expression by promoting PTEN ubiquitination, while miR-129-5p enhanced PTEN expression by inhibiting Smurf1. Meanwhile, overexpression of PTEN annulled the cardiac dysfunction in CHF rats induced by Smurf1. In conclusion, miR-129-5p targeted Smurf1 and repressed the ubiquitination of PTEN, and promoted PTEN expression, thus improving the cardiac function of CHF rats.

LncRNA PVT1 accelerates malignant phenotypes of bladder cancer cells by modulating miR-194-5p/BCLAF1 axis as a ceRNA.

BACKGROUND: Numerous studies proved that long non-coding RNA (lncRNA) is involved in the progression of multifarious diseases, especially in some carcinomas. As a potential tumor biomarker, plasmacytoma variant translocation 1 gene (PVT1) is involved in the development and progression of multifarious cancers. Nevertheless, the intrinsic and concrete molecular mechanism of PVT1 in bladder cancer still remained unclear, which is also the dilemma faced in many non-coding RNA studies. RESULTS: Our research revealed that PVT1 was significantly higher expression in bladder carcinoma specimens and cell lines. Further experiments indicated that knockdown or overexpression of PVT1 restrained or promoted the malignant phenotype and WNT/ß-catenin signaling in bladder cancer cells. Meanwhile miR-194-5p was in contrast and miR-194-5p could partially reverse the function of PVT1 in malignant bladder tumor cells. As a microRNA sponge, PVT1 actively promotes the expression of b-cells lymphoma-2-associated transcription factor 1 (BCLAF1) to sponge miR-194-5p and subsequently increases malignant phenotypes of bladder cancer cells. Therefore, it performs a carcinogenic effect and miR-194-5p as the opposite function, and serves as an antioncogene in the bladder carcinomas pathogenesis. CONCLUSION: PVT1-miR-194-5p-BCLAF1 axis is involved in the malignant progression and development of bladder carcinomas. Experiments revealed that PVT1 has a significant regulatory effect on bladder cancer (BC) and can be used as a clinical diagnostic marker and a therapeutic molecular marker for patients suffering from BC. METHODS: In urothelial bladder carcinoma specimens and cell lines, the relative expression levels of PVT1 and miR-194-5p were detected by quantitative reverse transcription PCR (RT-qPCR). Through experiments such as loss-function and over-expression, the biological effects of PVT1 and miR-194-5p on the proliferation, migration, apoptosis and tumorigenicity were explored in bladder cancer cells. Co-immunoprecipitation, proteomics experiments, dual luciferase reporter gene analysis, western blot and other methods were adopted to investigate the PVT1 potential mechanism in bladder carcinomas.

MiR-24-3p as a prognostic indicator for multiple cancers: from a meta-analysis view.

A growing number of researches suggest that microRNAs (miRNAs) as oncogene or tumor suppressor genes play a fundamental role in various kinds of cancers. Among them, miR-24-3p, as a star molecule, is widely studied. However, the prognostic value of miR-24-3p is unclear and controversial. We conducted this meta-analysis to evaluate the prognostic value of miR-24-3p in a variety of cancers by integrated existing articles from four databases. PubMed, Embase, Web of Science, and Cochrane Library (last update in March 2020) were searched for approach literature. Hazard ratios (HRs) and odds ratios (ORs) were used to evaluate the association between miR-24-3p expression levels and prognostic value or clinicopathological characteristics, respectively. A total of 15 studies from 14 literature were finally qualified and concluded in the present meta-analysis. A significantly worse overall survival was observed in higher expression of miR-24-3p cancer group for OS (overall survival) of log-rank tests and Cox multivariate regression by fixed effects model. Also, we found a significant correlation between elevated miR-24-3p levels to RFS (recurrence-free survival) and DFS (disease-free survival). In addition, the pooled odds ratios (ORs) showed that evaluated miR-24-3p was also associated with the larger tumor size (≥5 cm) and advanced TNM stage (III and IV). Built on the above findings, elevated expression levels of miR-24-3p may serve as a promising biomarker used to predict the worse prognosis of cancer patients.

[Intrarectal local anesthesia versus periprostatic nerve block in transrectal prostate biopsy for patients with different prostate volumes: A prospective randomized controlled trial].

OBJECTIVE: To evaluate the analgesic effect of intrarectal local anesthesia (IRLA) versus that of periprostatic nerve block anesthesia (PPNB) in initial transrectal ultrasound-guided prostate biopsy (TRUS-PB) for patients with different prostate volumes (PV). METHODS: A total of 253 patients undergoing initial TRUS-PB in our hospital from January 2014 to November 2017 were divided into three PV groups (<50 ml, 50－100 ml, and >100 ml), each again randomized into three subgroups (control, IRLA, and PPNB) with the random number table method. The pain during the procedure was assessed based on the Visual Analogue Scale (VAS) scores and the blind method was used by the biopsy operator, VAS valuator and data analyst. RESULTS: Among the patients with PV <50 ml, the VAS scores in the blank control, IRLA, and PPNB subgroups were 4.39±0.87, 3.51±0.84 and 3.43±1.07, respectively, remarkably higher in the control than in the IRLA and PPNB groups (P<0.05), but with no statistically significant differences between the latter two (P>0.05). Among those with PV of 50－100 ml, the VAS scores in the three subgroups were 4.50±1.05, 4.38±1.13 and 3.38±1.44, respectively, markedly higher in the control and IRLA than in the PPNB group (P<0.05), but with no statistically significant differences between the former two groups (P>0.05). Among those with PV >100 ml, the VAS scores in the three subgroups were 5.19±1.05, 5.00±1.25 and 4.19±0.91, respectively, remarkably higher in the former two groups than in the latter (P<0.05), but with no statistically significant differences between the former two groups (P>0.05). CONCLUSIONS: Either IRLA or PPNB can be recommended for initial TRUS-PB in patients with PV <50 ml, PPNB for those with PV of 50－100 ml, and PPNB with other painkillers for those with PV >100 ml.

Involvement of JNK1/2-NF-κBp65 in the regulation of HMGB2 in myocardial ischemia/reperfusion-induced apoptosis in human AC16 cardiomyocytes.

JNK1/2 and NF-κB signal are essential signaling pathways that mediate a variety of cellular processes, including cell survival, apoptosis, inflammation and angiogenesis. JNK1/2 activation and NF-κBp65 nuclear translocation have been found in ischemia/reperfusion (I/R)-induced injury. However, the regulation of JNK1/2-NF-κBp65 signaling pathway remains unclear. To examine the function and possible mechanism of HMGB2 in I/R-induced cell injury, human AC16 cardiomyocytes transfected with pLVX-Puro-HMGB2 were treated with SP600125 (JNK1/2 inhibitor) or PDTC (NF-κB inhibitor) and that following I/R injury were transfected with HMGB2-shRNA. The cell proliferation and apoptosis were measured by CCK-8, flow cytometry and TUNEL, respectively. The expression of HMGB2, Cleaved PARP and Caspase-3, Bax and Bcl-2 and activity of MAPKs and NF-κBp65 were measured by Western blot. Here, we found that I/R time-dependently induced the increase in the expression of HMGB2 in AC16 cardiomyocytes. HMGB2 silencing significantly inhibited I/R-induced the cell proliferation reduction, cell apoptosis, activation of ERK1/2, JNK1/2 and NF-κBp65, increased Bax, Cleaved PARP and Caspase-3 and decreased Bcl-2 expression. HMBG2 overexpression mimicked the effect of I/R-induced injury in AC16 cardiomyocytes, which was reversed by treatment with SP600125 or PDTC. Moreover, PDTC treatment in rats following I/R injury also showed decreases in the cell apoptosis, HMGB2, Cleaved PARP and Caspase-3 and Bax expression, and JNK1/2 activation. Taken together, our findings suggest that HMBG2 overexpression promotes I/R-induced cell apoptosis through activating the JNK1/2-NF-κBp65 signaling in AC16 cardiomyocytes.

In vitro and in silico investigations of the binary-mixture toxicity of phthalate esters and cadmium (II) to Vibrio qinghaiensis sp.-Q67.

Phthalate esters (PAEs) are widely used as plasticizers and have become one of the emerging contaminants with an increasing public concern. The residues of PAEs frequently co-exist with heavy metals such as cadmium (Cd) in waters; however, their joint ecotoxicity remains largely unknown. We herein investigated the single and joint toxicity of commonly used PAEs and Cd using freshwater luminescent bacteria Vibrio qinghaiensis sp.-Q67. The median effective concentration (EC50) of benzyl butyl phthalate (BBP), dibutyl phthalate (DBP), diethyl phthalate (DEP), dimethyl phthalate (DMP), diisooctyl phthalate (DIOP) and di-n-octyl phthalate (DOP) were determined to be in the range from 134.4mg/L to as high as 1000mg/L, indicating very weak toxicity to Vibrio qinghaiensis sp.-Q67. The toxicity of single PAEs showed a significant linear relationship with Log Kow, indicating the dependence of the elevated toxicity on the increasing hydrophilicity. The toxicity of binary mixture of PAEs was further evaluated in silico using the independent action (IA) model and concentration addition (CA) model. DMP-DEP, DEP-DBP or DMP-DBP exhibited antagonistic effects with the toxic unit value higher than 1.2. The CA and IA models poorly predicted the joint toxicity of DMP-DEP, DEP-DBP or DMP-DBP. The joint toxicity of the binary mixtures of DMP, DEP or DBP with Cd was simple additive as predicted by the CA and IA models. Our results indicated the potentially higher risk of PAEs in the presence of Cd, emphasizing the importance of determining the impact of their joint effects on aquatic organisms. The integrated in vitro and in silico methods employed in this study will be beneficial to study the joint toxicity and better assess the aquatic ecological risk of PAEs.