A Ce-CuZn catalyst with abundant Cu/Zn-OV-Ce active sites for CO2 hydrogenation to methanol.

CO2 hydrogenation to chemicals and fuels is a significant approach for achieving carbon neutrality. It is essential to rationally design the chemical structure and catalytic active sites towards the development of efficient catalysts. Here we show a Ce-CuZn catalyst with enriched Cu/Zn-OV-Ce active sites fabricated through the atomic-level substitution of Cu and Zn into Ce-MOF precursor. The Ce-CuZn catalyst exhibits a high methanol selectivity of 71.1% and a space-time yield of methanol up to 400.3 g·kgcat-1·h-1 with excellent stability for 170 h at 260 °C, comparable to that of the state-of-the-art CuZnAl catalysts. Controlled experiments and DFT calculations confirm that the incorporation of Cu and Zn into CeO2 with abundant oxygen vacancies can facilitate H2 dissociation energetically and thus improve CO2 hydrogenation over the Ce-CuZn catalyst via formate intermediates. This work offers an atomic-level design strategy for constructing efficient multi-metal catalysts for methanol synthesis through precise control of active sites.

Boosting Low-Temperature CO2 Hydrogenation over Ni-based Catalysts by Tuning Strong Metal-Support Interactions.

Rational design of low-cost and efficient transition-metal catalysts for low-temperature CO2 activation is significant and poses great challenges. Herein, a strategy via regulating the local electron density of active sites is developed to boost CO2 methanation that normally requires >350 °C for commercial Ni catalysts. An optimal Ni/ZrO2 catalyst affords an excellent low-temperature performance hitherto, with a CO2 conversion of 84.0 %, CH4 selectivity of 98.6 % even at 230 °C and GHSV of 12,000 mL g-1 h-1 for 106 h, reflecting one of the best CO2 methanation performance to date on Ni-based catalysts. Combined a series of in situ spectroscopic characterization studies reveal that re-constructing monoclinic-ZrO2 supported Ni species with abundant oxygen vacancies can facilitate CO2 activation, owing to the enhanced local electron density of Ni induced by the strong metal-support interactions. These findings might be of great aid for construction of robust catalysts with an enhanced performance for CO2 emission abatement and beyond.

The promoting effect and mechanism of Nrf2 on cell metastasis in cervical cancer.

BACKGROUND: Cervical cancer (CC) has poor prognosis and high mortality rate for its metastasis during the disease progression. Epithelial-mesenchymal transition (EMT) and anoikis are initial and pivotal steps during the metastatic process. Although higher levels of Nrf2 are associated with aggressive tumor behaviors in cervical cancer, the detailed mechanism of Nrf2 in cervical cancer metastasis, especially EMT and anoikis, remains unclear. METHODS: Immunohistochemistry (IHC) was used to examine Nrf2 expression in CC. Wound healing assay and transwell analysis were used to evaluate the migration ability of CC cells. Western blot, qTR-PCR and immunofluorescent staining were used to verify the expression level of Nrf2, the EMT associated markers and anoikis associated proteins. Flow cytometry assays and cell counting were used to detect the apoptosis of cervical cancer cells. The lung and lymph node metastatic mouse model were established for studies in vivo. The interaction between Nrf2 and Snail1 was confirmed by rescue-of-function assay. RESULTS: When compared with cervical cancer patients without lymph node metastasis, Nrf2 was highly expressed in patients with lymph node metastasis. And Nrf2 was proved to enhance the migration ability of HeLa and SiHa cells. In addition, Nrf2 was positively correlated with EMT processes and negatively associated with anoikis in cervical cancer. In vivo, a xenograft assay also showed that Nrf2 facilitated both pulmonary and lymphatic distant metastasis of cervical cancer. Rescue-of-function assay further revealed the mechanism that Nrf2 impacted the metastasis of CC through Snail1. CONCLUSION: Our fundings established Nrf2 plays a crucial role in the metastasis of cervical cancer by enhancing EMT and resistance to anoikis by promoting the expression of Snail1, with potential value as a therapeutic candidate.

UBE2E2 enhances Snail-mediated epithelial-mesenchymal transition and Nrf2-mediated antioxidant activity in ovarian cancer.

Dissemination of ovarian cancer (OvCa) cells can lead to inoperable metastatic lesions in the bowel and omentum, which have a poor prognosis despite surgical and chemotherapeutical options. A better understanding of the mechanisms underlying metastasis is urgently needed. In this study, bioinformatics analyses revealed that UBE2E2, a less-studied ubiquitin (Ub)-conjugating enzyme (E2), was upregulated in OvCa and was associated with poor prognosis. Subsequently, we performed western blot analysis and IHC staining with 88 OvCa and 26 normal ovarian tissue samples, which further confirmed that UBE2E2 protein is highly expressed in OvCa tissue but weakly expressed in normal tissue. Furthermore, the silencing of UBE2E2 blocked OvCa cell migration, epithelial-mesenchymal transition (EMT) and metastasis in vitro, whereas UBE2E2 overexpression exerted the opposite effects. Mechanistically, UBE2E2 promoted p62 accumulation and increased the activity of the Nrf2-antioxidant response element (ARE) system, which ultimately activated the Snail signaling pathway by inhibiting the ubiquitin-mediated degradation of Snail. Additionally, co-IP and immunofluorescence demonstrated that a direct interaction exists between UBE2E2 and Nrf2, and the N-terminal of UBE2E2 (residues 1-52) is required and sufficient for its interaction with Nrf2 protein. Mutations in the active site cysteine (Cys139) impaired both the function and cellular distribution of UBE2E2. More importantly, the deletion of UBE2E2 reduced tumorigenicity and metastasis in xenograft OvCa mouse models. Taken together, our findings reveal the role of the UBE2E2-Nrf2-p62-Snail signaling axis in OvCa and thus provides novel therapeutic targets for the prevention of OvCa metastasis.

An integrated analysis of prognostic mRNA signature in early- and progressive-stage gastric adenocarcinoma.

The pathogenesis and vital factors of early and progressive stages of stomach adenocarcinoma (STAD) have not been fully elucidated. In order to discover novel and potential targets to guide effective treatment strategies, a comprehensive bioinformatics study was performed, and the representative results were then validated by quantitative polymerase chain reaction (qPCR) and immunohistochemical (IMC) staining in clinical samples. A total of 4,627, 4,715, and 3,465 differentially expressed genes (DEGs) from overall-, early-, and progressive-stage STAD were identified, respectively. Prognostic models of 5-year OS were established for overall-, early-, and progressive-stage STAD, and ROC curves demonstrated AUC values for each model were 0.73, 0.87, and 0.92, respectively. Function analysis revealed that mRNAs of early-stage STAD were enriched in chemical stimulus-related pathways, whereas remarkable enrichment of mRNAs in progressive-stage STAD mainly lay in immune-related pathways. Both qPCR and IHC data confirmed the up-regulation of IGFBP1 in the early-stage and CHAF1A in progressive-stage STAD compared with their matched normal tissues, indicating that these two representative targets could be used to predict the prognostic status of the patients in these two distinct STAD stages, respectively. In addition, seven mRNAs (F2, GRID2, TF, APOB, KIF18B, INCENP, and GCG) could be potential novel biomarkers for STAD at different stages from this study. These results contributed to identifying STAD patients at high-risk, thus guiding targeted treatment with efficacy in these patients.

Diosmetin induces apoptosis in ovarian cancer cells by activating reactive oxygen species and inhibiting the Nrf2 pathway.

The fatality rate of ovarian cancer ranks first among gynecological tumors, and the prognosis is poor. Diosmetin (Dio), a natural flavonoid obtained from citrus fruits, has been shown to have anti-tumor effects in lung, liver, and skin cancers. We aimed to investigate the effects of Dio on ovarian cancer A2780 and SKOV3 cells along with the underlying mechanisms. Our data showed that Dio inhibited the proliferation, migration, and invasion of these cells and induced their apoptosis. Moreover, Dio upregulated the levels of Bax and cleaved Caspase-3 and PARP while downregulating the level of Bcl2. Mechanistically, our results revealed that Dio inhibited Nrf2 and induced the production of reactive oxygen species (ROS). The ROS scavenger N-acetyl-L-cysteine (NAC) suppressed the inhibitory effect of Dio on the proliferation of the ovarian cancer cells. Additionally, overexpression of Nrf2 partially suppressed the Dio-induced apoptosis and proliferation inhibition in these cells. These findings indicate that Dio exerts an anti-tumor activity by upregulating ROS levels and inhibiting Nrf2, indicating that Dio is a promising chemotherapeutic candidate for the treatment of ovarian cancer.

Targeting Nrf2 may reverse the drug resistance in ovarian cancer.

BACKGROUND: Acquired resistance to therapeutic drugs has become an important issue in treating ovarian cancer. Studies have shown that the prevalent chemotherapy resistance (cisplatin, paclitaxel etc.) for ovarian cancer occurs partly because of decreased production of reactive oxygen species within the mitochondria of ovarian cancer cells. MAIN BODY: Nuclear erythroid-related factor-2 (Nrf2) mainly controls the regulation of transcription of genes through the Keap1-Nrf2-ARE signaling pathway and protects cells by fighting oxidative stress and defending against harmful substances. This protective effect is reflected in the promotion of tumor cell growth and their resistance to chemotherapy drugs. Therefore, inhibition of the Nrf2 pathway may reverse drug resistance. In this review, we describe the functions of Nrf2 in drug resistance based on Nrf2-associated signaling pathways determined in previous studies. CONCLUSIONS: Further studies on the relevant mechanisms of Nrf2 may help improve the outcomes of ovarian cancer therapy.

Bioinformatics Analysis of Prognostic miRNA Signature and Potential Critical Genes in Colon Cancer.

This study aims to lay a foundation for studying the regulation of microRNAs (miRNAs) in colon cancer by applying bioinformatics methods to identify miRNAs and their potential critical target genes associated with colon cancer and prognosis. Data of differentially expressed miRNAs (DEMs) and genes (DEGs) downloaded from two independent databases (TCGA and GEO) and analyzed by R software resulted in 472 DEMs and 565 DEGs in colon cancers, respectively. Next, we developed an 8-miRNA (hsa-mir-6854, hsa-mir-4437, hsa-mir-216a, hsa-mir-3677, hsa-mir-887, hsa-mir-4999, hsa-mir-34b, and hsa-mir-3189) prognostic signature for patients with colon cancer by Cox proportional hazards regression analysis. To predict the target genes of these miRNAs, we used TargetScan and miRDB. The intersection of DEGs with the target genes predicted for these eight miRNAs retrieved 112 consensus genes. GO and KEGG pathway enrichment analyses showed these 112 genes were mainly involved in protein binding, one-carbon metabolic process, nitrogen metabolism, proteoglycans in cancer, and chemokine signaling pathways. The protein-protein interaction network of the consensus genes, constructed using the STRING database and imported into Cytoscape, identified 14 critical genes in the pathogenesis of colon cancer (CEP55, DTL, FANCI, HMMR, KIF15, MCM6, MKI67, NCAPG2, NEK2, RACGAP1, RRM2, TOP2A, UBE2C, and ZWILCH). Finally, we verified the critical genes by weighted gene co-expression network analysis (WGCNA) of the GEO data, and further mined the core genes involved in colon cancer. In summary, this study identified an 8-miRNA model that can effectively predict the prognosis of colon cancer patients and 14 critical genes with vital roles in colon cancer carcinogenesis. Our findings contribute new ideas for elucidating the molecular mechanisms of colon cancer carcinogenesis and provide new therapeutic targets and biomarkers for future treatment and prognosis.

Ubiquitination of the HPV Oncoprotein E6 Is Critical for E6/E6AP-Mediated p53 Degradation.

High-risk Human papillomaviruses (HPVs) types are associated with more than 90% of premalignant and malignant squamous lesions of the uterine cervix. The E6 oncoprotein of high-risk HPVs is a key determinant in cell transformation because it induces the degradation of the host pro-apoptotic tumor suppressor p53. E6 recruits the intracellular ubiquitin ligase E6AP and subsequently induces proteasome-dependent p53 degradation. Neither E6 nor E6AP alone interact with p53; however, the precise mechanism of the functional regulation of the E6/E6AP/p53 complex is unclear. Here, we showed that the high-risk HPV E6 proteins are ubiquitinated during E6/E6AP/p53 complex assembly and degraded by the proteasome system. Increasing p53 expression enhanced E6/E6AP/p53 assembly and facilitated E6 ubiquitination and degradation. The dominant negative mutant of p53 R175H, which does not efficiently bind E6, decreased E6 ubiquitination and increased stability. Furthermore, we showed that the ubiquitin ligase E6AP is essential for E6 ubiquitination, and downregulation of E6AP expression increased E6 stability. We also showed that p53 R175H inhibited E6-mediated p53 degradation. Consistently, the host deubiquitinating enzyme USP15 removed ubiquitin chains from E6 proteins and inhibited E6-mediated p53 degradation. Crucially, ectopic expression of either p53 R175H or USP15 promoted p53-triggered apoptosis in human cervical cancer cells. Considering the importance of ubiquitinated E6 on p53 degradation, the disruption of E6 ubiquitination represents an attractive pharmacological intervention against HPV-positive human cervical cancer. IMPORTANCE: Virtually 100% of cervical cancers are linked to HPV infection. Commercial HPV vaccines are estimated to prevent up to 90% of HPV-associated cancers, while they do not eliminate persistent HPV infections and have no effect on the progression to malignancy. Hence, the development of novel therapeutic interventions against HPV is urgently required. The HPV oncoprotein E6 binds to the intracellular E3 ubiquitin ligase E6AP and p53 resulting in the degradation of p53. In this study, we demonstrate that HPV E6 is ubiquitinated by E6AP in presence of p53. Crucially, ubiquitination of E6 is important for p53 degradation and blockage of E6 ubiquitination negatively interferes with E6-mediated p53 degradation and enhances the apoptotic effects of p53 and the cytotoxicity of DNA damage in HPV-positive cervical cancer cells. Importantly, our data suggest that the HPV oncogene E6 might be an optimal pharmacologic.

Disruption of protein neddylation with MLN4924 attenuates paclitaxel-induced apoptosis and microtubule polymerization in ovarian cancer cells.

Surgery and chemotherapy are the gold-standard treatments for ovarian cancer. The major cause of treatment failure in patients with ovarian cancer is tumoral heterogeneity and drug resistance. Paclitaxel (PTX) is one of the most commonly used first-line drugs for ovarian cancer chemotherapy. Unfortunately, the mechanisms of PTX chemoresistance remain unclear. Here, we examined the effects of post-translational neddylation on the sensitivity of ovarian cancer cells (OCCs) to PTX-induced apoptosis. Disruption of protein neddylation with the first-in-class inhibitor MLN4924 dramatically neutralized PTX-mediated antiproliferative, antimigration, and apoptotic effects in human OCCs. Moreover, MLN4924 treatment interrupted PTX-induced microtubule polymerization. Importantly, two neddylation conjugating E2 enzymes, UBE2M and UBE2F, were found to play essential roles in PTX-induced cytotoxicity and tubulin polymerization in OCCs. In summary, our findings demonstrated that disruption of protein neddylation by MLN4924 conferred resistance to PTX and provided insights into the potential mechanisms of PTX chemoresistance in ovarian cancer.