G protein-coupled receptors and traditional Chinese medicine: new thinks for the development of traditional Chinese medicine.

G protein-coupled receptors (GPCRs) widely exist in vivo and participate in many physiological processes, thus emerging as important targets for drug development. Approximately 30% of the Food and Drug Administration (FDA)-approved drugs target GPCRs. To date, the 'one disease, one target, one molecule' strategy no longer meets the demands of drug development. Meanwhile, small-molecule drugs account for 60% of FDA-approved drugs. Traditional Chinese medicine (TCM) has garnered widespread attention for its unique theoretical system and treatment methods. TCM involves multiple components, targets and pathways. Centered on GPCRs and TCM, this paper discusses the similarities and differences between TCM and GPCRs from the perspectives of syndrome of TCM, the consistency of TCM's multi-component and multi-target approaches and the potential of GPCRs and TCM in the development of novel drugs. A novel strategy, 'simultaneous screening of drugs and targets', was proposed and applied to the study of GPCRs. We combine GPCRs with TCM to facilitate the modernisation of TCM, provide valuable insights into the rational application of TCM and facilitate the research and development of novel drugs. This study offers theoretical support for the modernisation of TCM and introduces novel ideas for development of safe and effective drugs.

Au/Doc/Quer@PDA/A10-3.2 Nanoparticles for targeted treatment of docetaxel-resistant prostate cancer.

Docetaxel (Doc), as a first-line chemotherapy drug for prostate cancer (PC), often loses its therapeutic efficacy due to acquired resistance and lack of targeting specificity. Therefore, there is a need to develop a novel drug that can overcome Doc resistance and enhance its targeting ability to inhibit PC progression. In this study, we prepared Au/Doc/Quer@PDA/A10-3.2 nanoparticles (NPs) composite drug by encapsulating Doc and quercetin (Quer) within polydopamine (PDA)-coated Au NPs and further modifying them with RNA oligonucleotide aptamer A10-3.2. A10-3.2 was used for specific targeting of prostate-specific membrane antigen (PSMA)-positive PC cells (LNCaP). Quer was employed to reverse the resistance of Doc-resistant cell line (LNCaP/R) to Doc. Physical characterization using ultraviolet-visible spectroscopy (UV-vis), transmission electron microscopy (TEM), dynamic light scattering (DLS), X-ray photoelectron spectroscopy (XPS), and Fourier-transform infrared spectroscopy (FTIR) confirmed the successful preparation of Au/Doc/Quer@PDA/A10-3.2 NPs. Fluorescence imaging and flow cytometry experiments demonstrated the targeting ability of Au/Doc/Quer@PDA/A10-3.2 NPs towards PSMA-positive LNCaP/R cells. Cell proliferation, apoptosis, invasion, and migration experiments revealed that Quer reversed the resistance of LNCaP/R cells to Doc. Immunoblotting experiments further confirmed the mechanism behind sensitization of chemotherapy by Quer. Finally, we evaluated the therapeutic efficacy of Au/Doc/Quer@PDA/A10-3.2 NPs in a mouse model of PC. In conclusion, this study synthesized and validated a novel nano-composite drug (Au/Doc/Quer@PDA/A10-3.2 NPs) for combating Doc-resistant PC, which could potentially be applied in clinical treatment of PC.

Identifying spatiotemporal trends of SARS-CoV-2 RNA in wastewater: from the perspective of upstream and downstream wastewater-based epidemiology (WBE).

Recently, many efforts have been made to address the rapid spread of newly identified COVID-19 virus variants. Wastewater-based epidemiology (WBE) is considered a potential early warning tool for identifying the rapid spread of this virus. This study investigated the occurrence of SARS-CoV-2 in eight wastewater treatment plants (WWTPs) and their sewerage systems which serve most of the population in Taoyuan City, Taiwan. Across the entire study period, the wastewater viral concentrations were correlated with the number of COVID-19 cases in each WWTP (Spearman's r = 0.23-0.76). In addition, it is confirmed that several treatment technologies could effectively eliminate the virus RNA from WWTP influent (> 90%). On the other hand, further results revealed that an inverse distance weighted (IDW) interpolation and hotspot model combined with the geographic information system (GIS) method could be applied to analyze the spatiotemporal variations of SARS-CoV-2 in wastewater from the sewer system. In addition, socio-economic factors, namely, population density, land use, and income tax were successfully identified as the potential drivers which substantially affected the onset of the COVID-19 outbreak in Taiwan. Finally, the data obtained from this study can provide a powerful tool in public health decision-making not only in response to the current epidemic situation but also to other epidemic issues in the future.

A review on medical waste treatment in COVID-19 pandemics: Technologies, managements and future strategies.

Since the outbreak of COVID-19 few years ago, the increasing of the number of medical waste has become a huge issue because of their harmful impact to environment. A major concern associated to the limitation of technologies for dealing with medical waste, especially conventional technologies, are overcapacities since pandemic occurs. Moreover, the outbreak of new viruses from post COVID-19 should become a serious attention to be prevented not only environmental issues but also the spreading of viruses to new pandemic near the future. The high possibility of an outbreak of new viruses and mutation near the future should be prevented based on the experience associated with the SARS-CoV-2 virus in the last 3 yr. This review presented information and strategies for handling medical waste during the outbreak of COVID-19 and post-COVID-19, and also information on the current issues related to technologies, such as incineration, pyrolysis/gasification, autoclaves and microwave treatment for the dealing with high numbers of medical waste in COVID-19 to prevent the transmission of SARS-CoV-2 virus, their advantages and disadvantages. Plasma technology can be considered to be implemented as an alternative technology to deal with medical waste since incinerator is usually over capacities during the pandemic situation. Proper treatment of specific medical waste in pandemics, namely face masks, vaccine vials, syringes, and dead bodies, are necessary because those medical wastes are mediums for transmission of the SARS-CoV-2 virus. Furthermore, emission controls from incinerator and plasma are necessary to be implemented to reduce the high concentration of CO2, NOx, and VOCs during the treatment. Finally, future strategies of medical waste treatment in the perspective of potential outbreak pandemic from new mutation viruses are discussed in this review paper.Implications: Journal of the air and waste management association may consider our review paper to be published. In this review, we give important information related to the technologies, managements and strategies for handling the medical waste and control the transmission of SARS-CoV-2 virus, starting from proper technology to control the high number of medical waste, their pollutants and many strategies for controlling the spreading of SARS-CoV-2 virus. Moreover, this review also describes some strategies associated with control the transmission not only the SARS-CoV-2 virus but also the outbreak of new viruses near the future.

SlERF.G3-Like mediates a hierarchical transcriptional cascade to regulate ripening and metabolic changes in tomato fruit.

The tomato ripening process contains complex changes, including ethylene signalling, cell wall softening and numerous metabolic changes. So far, much is still unknown about how tomato plants precisely coordinate fruit maturation and metabolic regulation. In this paper, the ERF family transcription factor SlERF.G3-Like in tomato was found to be involved in the regulation of ethylene synthesis, cell wall degradation and the flavonoid pathway. We show that the master ripening regulator SlRIN was found to directly bind to the promoter region of SlERF.G3-Like to activate its expression. In addition, we managed to increase the production of resveratrol derivatives from ~1.44 mg/g DW in E8:VvStSy line to ~2.43 mg/g DW by crossing p35S: SlERF.G3-Like with the E8:VvStSy line. Our data provide direct evidence that SlERF.G3-Like, a hierarchical transcriptional factor, can directly manipulate pathways in which tomatoes can coordinate fruit maturation and metabolic changes. We also attest that SlERF.G3-Like can be used as an effective tool for phenylpropanoid metabolic engineering.

NEDD4L inhibits migration, invasion, cisplatin resistance and promotes apoptosis of bladder cancer cells by inactivating the p62/Keap1/Nrf2 pathway.

PURPOSE: This study identified the function of neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L) on bladder cancer (BLCA). METHODS: NEDD4L expression in BLCA patients was scrutinized. The function of NEDD4L on the viability, apoptosis, migration and invasion of BLCA cells was evaluated by cell counting kit-8, flow cytometry and Transwell assays. The effect of NEDD4L on the cisplatin (DDP) resistance of the DDP-resistant BLCA cells was explored. The influence of NEDD4L on the p62/Keap1/Nrf2 pathway activity in BLCA cells was tested by Western blot. Rescue experiments were implemented to verify whether NEDD4L regulated BLCA cell malignant behavior by mediating the Keap1/Nrf2 pathway activity via p62. The effect of NEDD4L on the growth and the p62/Keap1/Nrf2 pathway activity in vivo was researched in xenograft tumor nude mice models. RESULTS: The down-regulated NEDD4L in BLCA patients was associated with unfavorable survival. NEDD4L suppressed the viability (inhibition rate 57.1%/49.0%), migration (inhibition rate 49.7%/77.1%), invasion (inhibition rate 50.6%/75.7%), promoted the apoptosis of T24/5637 cells (promotion rate 243.8%/201.9%), reduced IC 50 of DDP-resistant T24/5637 cells from 132.2/101.8 to 57.81/59.71 µM, respectively, and inactivated the p62/Keap1/Nrf2 pathway in T24/5637 cells. p62 up-regulation partially abrogated the inhibition of NEDD4L on the Keap1/Nrf2 pathway activity, the malignant behavior of BLCA cells, and the DDP resistance of DDP-resistant BLCA cells. NEDD4L overexpression inhibited the tumor growth and the p62/Keap1/Nrf2 pathway activity in vivo in BLCA. CONCLUSION: NEDD4L inhibits the progression of BLCA by inactivating the p62/Keap1/Nrf2 pathway. It may be an effective target for BLCA treatment.

MiR-24-1-5p Hinders Malignant Phenotypes of Clear Cell Renal Cell Carcinoma by Targeting SHOX2.

MiRNAs are essential epigenetic modulators that can regulate protein expression. According to the principle of base complementary pairing, miRNA is partially or completely complementary to the 3'-UTR region of its target gene, by which it inhibits the translation of the targeted gene. This study investigated the role of miR-24-1-5p in clear cell renal cell carcinoma (ccRCC). Data in TCGA-KIRC denoted that miR-24-1-5p was under-expressed in ccRCC. Bioinformatics analysis predicted that its target gene was SHOX2, which was significantly expressed in cancer tissues. Dual luciferase assay verified the targeting relationship between miR-24-1-5p and SHOX2. Cell function experiments demonstrated that overexpression of miR-24-1-5p significantly inhibited SHOX2 level and the malignant phenotypes of ccRCC cells. The above results illustrated that miR-24-1-5p/SHOX2 axis was critical for the oncogenesis and development of ccRCC, which might be helpful for us to understand the mechanism and novel therapeutic methods of ccRCC.

Antifouling catalytic mixed-matrix membranes based on polyethersulfone and composition-optimized Zn-Cu-Fe-O CWAO catalyst under dark ambient conditions.

Besides photocatalysts, novel catalytic wet-air oxidation (CWAO) catalysts capable of operating under mild conditions are a potential candidate to fabricate antifouling filtration membranes. This study optimized the CWAO catalyst consisting of three metal oxide components (ZnO, CuO, and Fe3O4) and used it to fabricate composite membranes with PES (polyethersulfone). The catalyst was characterized by methods such as FTIR, BET, XRD, UV-Vis DRS, XPS, ESR. The activity of the catalyst and the composite membranes was tested by the Acid Yellow 42 (AY42) degradation experiments in both cases with and without hydrogen peroxide at room conditions with air aeration. The pure water fluxes of composite membranes were also investigated based on a vacuum filtration system. The major degradation pathways of AY42 by the catalyst were proposed from the DFT (Density Functional Theory) and NBO (Natural Bond Orbital) calculations. The results showed that the optimal catalyst has molar ratios of Zn, Cu, and Fe metal ions of 0.05, 0.588, and 0.362, respectively, with AY42 decomposition efficiency of 88% in 3 h. The main factors affecting the catalytic efficiency of the CWAO catalyst determined from the trapping experiment were e- and O2. The results from different materials characterization methods have demonstrated the successful synthesis of the catalyst with a high surface area (103.5 m2/g) and small pore diameters (∼10 nm). The AY42 degradation of composite membranes was stable over five repeated cycles with over 70% efficiency. The pure water fluxes of composite membranes have also been significantly improved and are proportional to catalyst contents.

Antifouling CuO@TiO2 coating on plasma-grafted PAA/PES membrane based on photocatalysis and hydrogen peroxide activation.

Because of the small size effect leading to the high bandgap of TiO2 P25, the photocatalytic membrane using this photocatalyst has low antifouling efficiency. This study prepared CuO@TiO2 composite photocatalyst with a lower bandgap than TiO2 P25 and used it as antifouling coatings on the PES membrane with PAA intermediate adhesive layer. PAA was grafted onto the surface of the PES membranes through free radicals generated by the cold plasma treatment of the PES membrane. The composite photocatalysts were characterized by FTIR, SEM-EDS, TEM-EDS, XRD, BET, UV-Vis DRS, XPS, and ESR methods demonstrating high surface area (51.0 m2/g), decreased bandgap, and the formation of active free radicals under UV light irradiation. Under photocatalysis and hydrogen peroxide activation, the degradation of AB260 (acid blue 260) catalyzed by 10%CuO@TiO2 reached about 92% after 60 min. Besides, the photocatalytic and antifouling activities of CuO@TiO2/PAA/PES membranes are high and stable over five continuous cycles. The water flux of the modified membrane was not significantly influenced and only decreased about 10% compared to the pristine membrane. In addition, the flux recovery ratios (FRR) of fouled membranes treated by photocatalysis were almost 100%.

SMAR1 inhibits proliferation, EMT and Warburg effect of bladder cancer cells by suppressing the activity of the Wnt/ß-catenin signaling pathway.

This study aimed to investigate the effects of scaffold matrix attachment region binding protein 1 (SMAR1) on the development of bladder cancer (BCa). SMAR1 expression in paired tumor and corresponding adjacent normal tissues from 55 BCa patients was detected by quantitative reverse transcription-polymerase chain reaction. BCa cells were transfected to regulate SMAR1 expression. BCa cells were treated with XAV-939, LiCl and 2-deoxyglucose. The effect of SMAR1 on the viability, proliferation, migration, invasion and Warburg effect of BCa cells was researched by counting kit-8, colony formation assay, Transwell and aerobic glycolysis assays. Western blot was performed to detect protein expression. BCa cell growth in vivo was recorded in nude mice. Immunohistochemical staining was performed for clinical and xenografted tumor tissue specimens. SMAR1 expression was down-regulated in BCa patients, associating with worse prognoses. SMAR1 knockdown enhanced the viability, proliferation, migration, invasion, EMT and Warburg effect of BCa cells. The opposite effect was found in the SMAR1 overexpression BCa cells. XAV-939 treatment reversed the elevation of ß-catenin, c-Myc and Cyclin D1 proteins expression and Warburg effect in Bca cells post-SMAR1 knockdown. LiCl treatment abrogated the inhibition of ß-catenin, c-Myc and Cyclin D1 proteins expression and Warburg effect proteins due to SMAR1 overexpression in BCa cells. SMAR1 overexpression inhibited the growth of BCa cells in vivo. SMAR1 might suppress the Wnt/ß-catenin signaling pathway activity to inhibit the progression of BCa. It might be an effective treatment target for BCa.

Rapid fabrication of MgO@g-C3N4 heterojunctions for photocatalytic nitric oxide removal.

Nitric oxide (NO) is an air pollutant impacting the environment, human health, and other biotas. Among the technologies to treat NO pollution, photocatalytic oxidation under visible light is considered an effective means. This study describes photocatalytic oxidation to degrade NO under visible light with the support of a photocatalyst. MgO@g-C3N4 heterojunction photocatalysts were synthesized by one-step pyrolysis of MgO and urea at 550 °C for two hours. The photocatalytic NO removal efficiency of the MgO@g-C3N4 heterojunctions was significantly improved and reached a maximum value of 75.4% under visible light irradiation. Differential reflectance spectroscopy (DRS) was used to determine the optical properties and bandgap energies of the material. The bandgap of the material decreases with increasing amounts of MgO. The photoluminescence spectra indicate that the recombination of electron-hole pairs is hindered by doping MgO onto g-C3N4. Also, NO conversion, DeNOx index, apparent quantum efficiency, trapping tests, and electron spin resonance measurements were carried out to understand the photocatalytic mechanism of the materials. The high reusability of the MgO@g-C3N4 heterojunction was shown by a five-cycle recycling test. This study provides a simple way to synthesize photocatalytic heterojunction materials with high reusability and the potential of heterojunction photocatalysts in the field of environmental remediation.

Influence of C/N ratios on treatment performance and biomass production during co-culture of microalgae and activated sludge.

Novel phycosphere associated bacteria processes are being regarded as a potential and cost-effective strategy for controlling anthropogenic contaminants in wastewater treatment. However, the underlying concern with the process is its vulnerability to improper organic or nutrient intake. This study established a synergistic interaction between microalgae and activated sludge in a three-photobioreactor system (without external aeration) to understand how pollutants could be mitigated whilst simultaneously yielding biomass under different C/N ratios of 1:1, 5:1 and 10:1. The result showed that the superior biomass productivity was facilitated at a C/N ratio of 5:1 (106 mg L-1 d-1), and the high degradation rate constants (kCOD = 0.25 d-1, kTN = 0.29 d-1, kTP = 0.35 d-1) was approximated using a first-order kinetic model. The removal of pollutants was remarkably high, exceeding 90% (COD), 93% (TN), and 96% (TP). Nevertheless, the C/N ratio of 1:1 resulted in a threefold drop in biomass-specific growth rate (µ = 0.07 d-1). Microalgal assimilation, followed by bacterial denitrification, is the major pathway of removing total nitrogen when the C/N ratio exceeds 5:1. Activated sludge plays an important role in improving microalgae tolerance to high concentration of ammonia nitrogen and boosting nitrification (light phase) and denitrification (dark phase). The use of phycosphere associated bacteria could be a promising strategy for controlling nutrients pollution and other environmental considerations in wastewater.

A review on vitrification technologies of hazardous waste.

Vitrification technology provides a solution for the issue of safe disposal of hazardous waste containing harmful chemical composition and organic pollutants. This review discusses application of vitrification technologies to treat hazardous waste including, asbestos, fly ash, electronic sludge, nuclear waste, medical waste and radioactive waste. Vitrification processes via Joule heating, microwave heating, plasma technology, electric arc furnaces and incinerators are compared herein. Stabilization of hazardous waste can be achieved by vitrification with the addition of flux agents/additives. Furthermore, crystalline structures, containing the silicate-glass network, are formed as a result of vitrification, depending on the type of flux agents/additives used. In addition, the concentration of heavy metals can be degraded in the final residue and leaching resistance can be achieved. Moreover, energy consumption, pollution prevention and the foreground of the practical application of vitrification are discussed. Vitrification with the advantage of encapsulating pollutants from the hazardous waste is proven to be a promising approach for hazardous waste treatment.

Comparison of degradation kinetics of tannery wastewater treatment using a nonlinear model by salt-tolerant Nitrosomonas sp. and Nitrobacter sp.

Conventional biological treatment has been reported to be ineffective for pollutant removal in tannery wastewater due to high salinity. To overcome it, this work used salt-tolerant bacteria (STB) isolated from a membrane bioreactor to evaluate the organic and nutrient removal through a series of batch experiments. Compared with the control, the STB reactor enhanced the reduction of persistent organics by 11% based on the double exponential decay model. Besides, the removal of NH4+-N is 26% higher, satisfying the first-order decay model. The nitrification was inhibited entirely in control during 48 h, whilst the assimilation process involved 55% of total nitrogen removal. In the STB reactor, nitrification occurred after 12 h, resulting in significantly increased NO2--N and NO3--N concentrations according to the logistic function. Although nitrification was successfully activated, C/N ratios and free ammonia were identified as limiting factors for STB activity, requiring mitigation strategies in further studies.

Score for the Risk and Overall Survival of Lung Metastasis in Patients First Diagnosed With Soft Tissue Sarcoma: A Novel Nomogram-Based Risk Assessment System.

Background: Metastatic soft tissue sarcoma (STS) patients have a poor prognosis with a 3-year survival rate of 25%. About 30% of them present lung metastases (LM). This study aimed to construct 2 nomograms to predict the risk of LM and overall survival of STS patients with LM. Materials and Methods: The data of patients were derived from the Surveillance, Epidemiology, and End Results database during the period of 2010 to 2015. Logistic and Cox analysis was performed to determine the independent risk factors and prognostic factors of STS patients with LM, respectively. Afterward, 2 nomograms were, respectively, established based on these factors. The performance of the developed nomogram was evaluated with receiver operating characteristic curves, area under the curve (AUC) calibration curves, and decision curve analysis (DCA). Results: A total of 7643 patients with STS were included in this study. The independent predictors of LM in first-diagnosed STS patients were N stage, grade, histologic type, and tumor size. The independent prognostic factors for STS patients with LM were age, N stage, surgery, and chemotherapy. The AUCs of the diagnostic nomogram were 0.806 in the training set and 0.799 in the testing set. For the prognostic nomogram, the time-dependent AUC values of the training and testing set suggested a favorable performance and discrimination of the nomogram. The 1-, 2-, and 3-year AUC values were 0.698, 0.718, and 0.715 in the training set, and 0.669, 0.612, and 0717 in the testing set, respectively. Furthermore, for the 2 nomograms, calibration curves indicated satisfactory agreement between prediction and actual survival, and DCA indicated its clinical usefulness. Conclusion: In this study, grade, histology, N stage, and tumor size were identified as independent risk factors of LM in STS patients, age, chemotherapy surgery, and N stage were identified as independent prognostic factors of STS patients with LM, these developed nomograms may be an effective tool for accurately predicting the risk and prognosis of newly diagnosed patients with LM.

Impact of climatic and non-climatic stressors on ocean life and human health: A review.

Ocean life forms are fundamentally well adapted to natural environmental variations, and they can even tolerate extreme conditions for a short time. However, several anthropogenic stressors are causing such drastic changes in the ocean ecosystem. First, the review attempts to outline the impact of climatic and non-climatic stressors on ocean life, and it also outlines the synergistic impact of both stressors. Then the impact on human health caused by the damage of the marine ecosystem has been discussed. Furthermore, the type of prior studies and current mitigation adaptation programs have been presented. Finally, some perspectives about future research and mitigation adaptation are offered.

Degradation of contaminants in plasma technology: An overview.

The information of plasma technologies applications for environmental clean-up on treating and degrading metals, metalloids, dyes, biomass, antibiotics, pesticides, volatile organic compounds (VOCs), bacteria, virus and fungi is compiled and organized in the review article. Different reactor configurations of plasma technology have been applied for reactive species generation, responsible for the pollutants removal, hydrogen and methane production and microorganism inactivation. Therefore, in this review article, the reactive species from discharge plasma are presented here to provide the insight into the environmental applications. The combinations of plasma technology with flux agent and photocatalytic are also given in this review paper associated with the setup of the plasma system on the removal process of metals, VOCs, and microorganisms. Furthermore, the potential of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inactivation via plasma technology is also described in this review paper. Detailed information of plasma parameter configuration is given to support the influence of the critical process in the plasma system to deal with contaminants.

Literature review and report of three cases of Dubin-Johnson syndrome related to ABCC2 gene mutations in children.

OBJECTIVE: The aim of the present study was to analyze the clinical features of Dubin-Johnson syndrome (DJS) related to ABCC2 gene mutations in children and to review the relevant literature to improve understanding of this type of genetic disease and reduce misdiagnosis. METHODS: Three children with clinically suspected DJS who were treated at Beijing Children's Hospital of Capital Medical University between 2017 and 2020 were enrolled in the study. The target genes were captured and sequenced using GenCap target gene capture technology and a new generation of high-throughput sequencing technology (Beijing Mykino Company). The clinical and genetic characteristics were analyzed and summarized. RESULTS: Two of the cases were female and one was male. All three cases were in early infancy and in good general health. Case 1 was complicated with unilateral hypertrophy, Case 2 was complicated with pneumonia, anemia, myocardial injury, and bilateral inguinal hernia, and Case 3 was complicated with patent foramen ovale and a ventricular septal defect. In all three cases, total bilirubin was elevated, with the main increase being in direct bilirubin (DBIL) and varying degrees of elevated alanine aminotransferase (ALT), γ-glutamyl transferase (GGT), and total bile (TBA). Genetic testing indicated that there were seven gene mutations in ABCC2, two mutation sites of which had not been reported previously. CONCLUSION: The clinical manifestations of DJS are non-specific and are mainly characterized by elevated DBIL. Some children might have different degrees of hepatic function abnormality and cholestasis. Due to the lack of serological markers, the diagnosis of DJS is difficult, but genetic testing, along with the formation of pedigree analysis and verification, could be used for accurate diagnosis. Novel mutations might enrich the spectrum of ABCC2 gene mutation.

ROC1 promotes the malignant progression of bladder cancer by regulating p-IκBα/NF-κB signaling.

BACKGROUND: Regulator of cullins 1 (ROC1) is an important catalytic subunit of cullin-RING E3 ligase. Nuclear factor-kappa B (NF-κB) signaling is closely related to tumor invasion and metastasis. Earlier, we reported that ROC1 was associated with a poor prognosis in patients with bladder cancer (BCa). However, it is unclear whether ROC1 is involved in the NF-κB signaling associated with malignant BCa progression. METHODS: The expression of ROC1 and p65 in bladder cancer and paracancerous tissues were detected by immunohistochemistry (IHC). Pearson correlation was used to assess correlation between ROC1 and p65 protein expressions. The wound-healing and transwell assays were used to monitor cell invasion and migration. The effect of ROC1 on the expression of key proteins in the NF-κB signaling was determined by immunofluorescence and western blot (WB). Cycloheximide (CHX), MG132 and immunoprecipitation assays were used to evaluate the effect of ROC1 on the ubiquitination of phosphorylated inhibitor of kappa B alpha (p-IκBα). A lung metastasis mouse model was generated to detect the role of ROC1 in tumor metastasis. RESULTS: We found that ROC1 was up-regulated in BCa tissues and cell lines, and high ROC1 levels were positively correlated with higher tumour grade, lymph node metastasis, distant metastasis and poor prognosis. Linear-regression analysis showed significant a Pearson correlation between ROC1 and nuclear p65 expression in BCa tissue microarray (TMA) samples. Functional studies demonstrated that ROC1 promoted BCa cell invasion and migration. In vitro and in vivo experiments showed that ROC1 activated NF-κB signaling by enhancing the ubiquitination of p-IκBα, which caused p65 nuclear translocation and promoted the transcription of some metastasis-related target genes, such as urokinase-type plasminogen activator receptor (uPAR), intracellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), and matrix metalloproteinase 9 (MMP9), resulting in promoting BCa metastasis. CONCLUSION: ROC1 plays an important role in the progression of BCa and serves as a potential diagnostic and therapeutic target for patients with BCa.