Knockdown of UBE2I inhibits tumorigenesis and enhances chemosensitivity of cholangiocarcinoma via modulating p27kip1 nuclear export.

The asymptomatic nature of cholangiocarcinoma (CCA), particularly during its early stages, in combination with its high aggressiveness and chemoresistance, significantly compromises the efficacy of current therapeutic options, contributing to a dismal prognosis. As a tumor suppressor that inhibits the cell cycle, abnormal cytoplasmic p27kip1 localization is related to chemotherapy resistance and often occurs in various cancers, including CCA. Nevertheless, the underlying mechanism is unclear. SUMOylation, which is involved in regulating subcellular localization and the cell cycle, is a posttranslational modification that regulates p27kip1 activity. Here, we confirmed that UBE2I, as the only key enzyme for SUMOylation, was highly expressed and p27kip1 was downregulated in CCA tissues, which were associated with poor outcomes in CCA. Moreover, UBE2I silencing inhibited CCA cell proliferation, delayed xenograft tumor growth in vivo, and sensitized CCA cells to the chemotherapeutics, which may be due to cell cycle arrest induced by p27kip1 nuclear accumulation. According to the immunoprecipitation result, we found that UBE2I could bind p27kip1, and the binding amount of p27kip1 and SUMO-1 decreased after UBE2I silencing. Moreover, nuclear retention of p27kip1 was induced by UBE2I knockdown and SUMOylation or CRM1 inhibition, further suggesting that UBE2I could cooperate with CRM1 in the nuclear export of p27kip1. These data indicate that UBE2I-mediated SUMOylation is a novel regulatory mechanism that underlies p27kip1 export and controls CCA tumorigenesis, providing a therapeutic option for CCA treatment.

Typical layered structure bismuth-based photocatalysts for photocatalytic nitrogen oxides oxidation.

Traditional NOx treatment methods require external reducing reagents and harsh reaction conditions, which is not conducive to effectively eliminate NOx at low concentration, especially at ppb levels. Fortunately, low concentration NOx can be removed by photocatalytic oxidation under mild reaction conditions. Bismuth (Bi)-based photocatalysts with the layered structure have obtained considerable concerns of photocatalytic NOx oxidation. This review focused on typical layered Bi-based photocatalysts (Bi2WO6, Bi2O2CO3, BiOY (YCl, Br, and I), BiOIO3, and BiOCOOH) with the structure of [Bi2O2]2+ layer for photocatalytic NOx oxidation. The strategies (morphological control, defect engineering, heterostructure construction, etc.) to improve photocatalytic oxidation activity were summarized. Furthermore, the mechanism involving various free radicals (hydroxyl radical, superoxide radical, etc.) of photocatalytic oxidation of NOx was proposed. In addition, the non-NO2 selectivity was also illuminated. Lastly, the current drawbacks and further research directions for photocatalytic NOx oxidation were elaborated. The development of photocatalysts with high photocatalytic activity, wide light absorption range, and non-NO2 selectivity is the focus of future research. This review aims to provide a pandect and theoretical guidance for the practical application of photocatalytic oxidation of NOx.

RNF4 promotes tumorigenesis, therapy resistance of cholangiocarcinoma and affects cell cycle by regulating the ubiquitination degradation of p27kip1 in the nucleus.

Among the hallmarks of cholangiocarcinoma (CCA) progression and unresponsiveness to therapy is impaired ubiquitin-dependent degradation of nuclear tumor suppressor protein. In the previous stage, our research group found that as a key tumor suppressor, nuclear dysfunction of p27kip1 is closely related to chemotherapy resistance of CCA, but the specific mechanism is unclear. It was recently shown that p27kip1-driven tumors were strongly dependent on the SUMO pathway. RNF4, as the SUMO-targeted ubiquitin ligase (STUbL), identifies SUMOylated proteins as a substrate through sumo-interacting motifs (SIM) and causes its degradation via the ubiquitin proteasome pathway. Here we described that the expression of RNF4 was upregulated in CCA tissues and related to malignant features. Silencing RNF4 arrested human CCA cells at the G1 phase, which was associated with the upregulation of p27kip1 and the downregulation of its downstream cycle-related proteins. Silencing RNF4 inhibited cell proliferation and migration, increased cell apoptosis, and sensitized CCA cells to treatment of chemotherapeutic drugs in vitro. Immunofluorescence showed that p27kip1 and RNF4 were mainly co-located in the nucleus. Immunoprecipitation and Western blot showed that p27kip1 was a target protein for SUMOylation and high expression of RNF4 decreased the levels of nuclear p27kip1, enhanced the levels of ubiquitinated and SUMOylated p27kip1, indicating that RNF4 could regulate cell cycle progression via recognizing SUMOylated p27kip1 and facilitating its ubiquitination degradation. These data indicate that RNF4-mediated ubiquitination degradation of SUMOylated proteins is a novel regulatory mechanism of p27kip1 dysfunction and CCA tumorigenesis, which provides a potential option for therapeutic intervention of CCA.

Enhanced photocatalytic activity of 3D hierarchical RP/BP/BiOCOOH via oxygen vacancies and double heterojunctions.

A 3D hierarchical RP/BP/BiOCOOH double heterostructures with abundant oxygen vacancies (OVs) was obtained by hydrothermal process and its photocatalytic activity was investigated by degradation of TC-HCl with different light sources and various natural water. The physicochemical characteristics of RP/BP/BiOCOOH heterojunctions were systematically characterized via TEM, XPS, EPR, EIS et al. Compared with BiOCOOH, the photocatalytic activity of RP/BP/BiOCOOH was obviously enhanced. Under simulated solar light irradiation, 60.5% of TC-HCl was removed by 3%RP/BP/BiOCOOH. And the rate constant of 3%RP/BP/BiOCOOH was 2.95 times than that of BiOCOOH. Traces of small molecular organics were beneficial to improve photocatalytic efficiency. The process of photocatalytic degradation and the cytotoxicity of intermedia products of TC-HCl were discussed via HPLC-MS, 3D-EEM, and antibacterial properties test. Based on the results of trapping experiments and ESR tests, •OH and •O2- were the most significant reactive oxygen species. The enhanced photocatalytic activity was ascribed to two reasons: 1 double heterojunctions structure enhanced the separation efficiency of carriers, 2 the introduction of OVs and BP/RP expanded the response range of light. This work provides a feasible strategy that non-metallic element semiconductor is used to modify the wide band gap semiconductor to enhance the photocatalytic efficiency.

Self-assembled micro-flowers of ultrathin Au/BiOCOOH nanosheets photocatalytic degradation of tetracycline hydrochloride and reduction of CO2.

The low separation efficiency of carriers and weak light response of photocatalysts severely limit the application of photocatalysis technology. Herein, we prepared a visible light responsive self-assembled micro-flowers of ultrathin bismuth oxide formate nanosheets supported by gold nanoparticles (Au/BiOCOOH) composite photocatalyst via hydrothermal method. The physicochemical and photoelectric properties of obtained-photocatalysts were completely analyzed via a range of characterization means. Compared with bare BiOCOOH, the photocatalytic activity of Au/BiOCOOH was significantly improved. 2.0%Au/BiOCOOH possessed the highest rate constant of 0.0054 min-1 for degradation of tetracycline hydrochloride (TC-HCl), which was nearly 13.5 times higher than that of BiOCOOH. The intermediate products were analyzed by 3D EEM and HPLC/MS, and the antibacterial ability of intermediate products with 2.0%Au/BiOCOOH significantly descended. In order to explore the potential of practical applications, photocatalytic experiments were also implemented through different water sources and solar light irradiation. Furthermore, the photocatalytic activity was also investigated by photocatalytic reduction of carbon dioxide (CO2). The excellent photocatalytic activity owed to the enhanced separation of charge carriers and light absorption ability by the surface plasmon resonance (SPR) effect of Au nanoparticles. The work may provide a feasible strategy to obtain efficient BiOCOOH-based photocatalyst.