Interactions between miRNAs and the Wnt/ß-catenin signaling pathway in endometriosis.

Endometriosis is a disease characterized by the ectopic growth of endometrial tissue (glands and stroma) outside the confines of the uterus and often involves vital organs such as the intestines and urinary system. Endometriosis is considered a refractory disease owing to its enigmatic etiology, propensity for recurrence following conservative or surgical interventions, and the absence of radical treatment and long-term management. In recent years, the incidence of endometriosis has gradually increased, rendering it a pressing concern among women of childbearing age. A more profound understanding of its pathogenesis can significantly improve prognosis. Recent research endeavors have spotlighted the molecular mechanisms by which microRNAs (miRNAs) regulate the occurrence and progression of endometriosis. Many miRNAs have been reported to be aberrantly expressed in the affected tissues of both patients and animal models. These miRNAs actively participate in the regulation of inflammatory reactions, cellular proliferation, angiogenesis, and tissue remodeling. Their capacity to modulate crucial signaling pathways, such as the Wnt/ß-catenin signaling pathway, reinforces their potential utility as diagnostic markers or therapeutic agents for endometriosis. In this review, we provide the latest insights into the role of miRNAs that interact with the Wnt/ß-catenin pathway to regulate the biological behaviors of endometriosis cells and disease-related symptoms, such as pain and infertility. We hope that this review will provide novel insights and promising targets for innovative therapies addressing endometriosis.

A retrospective analysis of robot-assisted total hysterectomy by transvaginal natural orifice transluminal endoscopic surgery.

Objective: The present study aimed to explore the feasibility and safety of robot-assisted total hysterectomy by transvaginal natural orifice transluminal endoscopic surgery (vNOTES). Methods: In this study, the clinical data of 37 patients who underwent da Vinci robot-assisted total hysterectomy by vNOTES between September 1, 2019 and March 31, 2022 at the Department of Gynecology, the First Affiliated Hospital of Zhengzhou University, China were retrospectively analyzed. Clinical characteristics, operative postoperative complications, surgical outcomes, and postoperative pain scores were collected and analyzed. Results: The average age of the patients included in the study was 47.43 ± 4.44 years. The body mass index (BMI) was calculated using the formula BMI = body weight (kg)/height2 (m2). The average BMI was 23.16 ± 2.72 kg/m2. Among the 37 patients, 30 patients underwent total hysterectomy and bilateral salpingectomy, of which 11 patients underwent ovarian cystectomy simultaneously. Among these 11 patients, three had bilateral ovarian cysts and eight had unilateral ovarian cysts, with the largest cyst diameter measuring 8 cm. The remaining seven patients underwent total hysterectomy and bilateral salpingo-oophorectomy. The average operative time was 86.19 ± 17.83 min, and the estimated intraoperative blood loss was 24.46 ± 15.40 mL, with no intraoperative complications reported. The time to the first postoperative exhaust was 18.51 ± 6.63 h, and the average postoperative length of hospital stay was 3.81 ± 1.05 days. The postoperative visual analog scale (VAS) pain scores were 5.30 ± 0.91 at 24 h after surgery, 3.30 ± 0.70 at 36 h after surgery, and 1.14 ± 0.92 at 48 h after surgery. Only one patient experienced a fever exceeding 38.5 °C, which resolved after receiving antibiotic treatment. Conclusion: The use of the da Vinci robot-assisted total hysterectomy by vNOTES demonstrated safety and offers several advantages. These include reduced surgical trauma, an aesthetic incision, decreased pain, and shorter duration of postoperative exhaust time and hospital stay. These benefits contribute to accelerated postoperative rehabilitation.

FBXO16-mediated hnRNPL ubiquitination and degradation plays a tumor suppressor role in ovarian cancer.

Heterogeneous nuclear ribonucleoprotein L (hnRNPL) is a type of RNA binding protein that highly expressed in a variety of tumors and plays a vital role in tumor progression. However, its post-translational regulation through ubiquitin-mediated proteolysis and the cellular mechanism responsible for its proteasomal degradation remains unclear. F-box proteins (FBPs) function as the substrate recognition subunits of SCF ubiquitin ligase complexes and directly bind to substrates. The aberrant expression or mutation of FBPs will lead to the accumulation of its substrate proteins that often involved in tumorigenesis. Here we discover FBXO16, an E3 ubiquitin ligase, to be a tumor suppressor in ovarian cancer, and patients with the relatively high expression level of FBXO16 have a better prognosis. Silencing or depleting FBXO16 significantly enhanced ovarian cancer cell proliferation, clonogenic survival, and cell invasion by activating multiple oncogenic pathways. This function requires the F-box domain of FBXO16, through which FBXO16 assembles a canonical SCF ubiquitin ligase complex that constitutively targets hnRNPL for degradation. Depletion of hnRNPL is sufficient to inactive multiple oncogenic signaling regulated by FBXO16 and prevent the malignant behavior of ovarian cancer cells caused by FBXO16 deficiency. FBXO16 interacted with the RRM3 domain of hnRNPL via its C-terminal region to trigger the proteasomal degradation of hnRNPL. Failure to degrade hnRNPL promoted ovarian cancer cell proliferation in vitro and tumor growth vivo, phenocopying the deficiency of FBXO16 in ovarian cancer.

Unveiling the High Catalytic Activity of a Dinuclear Iron Complex for the Oxygen Evolution Reaction.

The dinuclear iron complex [(H2O)-FeIII-(ppq)-O-(ppq)-FeIII-Cl]3+ (FeIII(ppq), ppq = 2-(pyrid-2'-yl)-8-(1″,10″-phenanthrolin-2″-yl)-quinoline) demonstrates a catalytic activity about one order of magnitude higher than the mononuclear iron complex [Cl-FeIII(dpa)-Cl]+ (FeIII(dpa), dpa = N,N-di(1,10-phenanthrolin-2-yl)-N-isopentylamine) for the oxygen evolution reaction (OER). However, the mechanism behind such an unusually high activity has remained largely unclear. To solve this puzzle, a decomposition-and-reaction mechanism is proposed for the OER with the dinuclear FeIII(ppq) complex as the initial state of the catalytic agent. In this mechanism, the high-valent dinuclear iron complex first dissociates into two mononuclear moieties, and the oxidized mononuclear iron complexes directly catalyze the formation of an O-O bond through a nitrate attack pathway with nitrate functioning as a cocatalyst. Density functional theory calculations reveal that it is the electron-deficient microenvironment around the iron center that gives rise to the remarkable catalytic activity observed experimentally. Therefore, the outstanding performance of the FeIII(ppq) catalyst can be ascribed to the high reactivity of its mononuclear moieties in a high oxidation state, which is concomitant with the structural stability of the low-valent dinuclear complex. The theoretical insights provided by this study could be useful for the optimization and design of novel iron-based water oxidation catalysts.

FBXO6-mediated RNASET2 ubiquitination and degradation governs the development of ovarian cancer.

RNASET2 (Ribonuclease T2) functions as a tumor suppressor in preventing ovarian tumorigenesis. However, the mechanisms underlying the regulation of RNASET2 protein are completely unknown. Here we identified the F-box protein FBXO6, a substrate recognition subunit of an SCF (Skp1-Cul1-F-box protein) complex, as the ubiquitin E3 ligase for RNASET2. We found that the interaction between FBXO6 and RNASET2 induced RNASET2 instability through the ubiquitin-mediated proteasome degradation pathway. FBXO6 promoted K48-dependent ubiquitination of RNASET2 via its FBA domain. Through analysis of the TCGA dataset, we found that FBXO6 was significantly increased in ovarian cancer tissues and the high expression of FBXO6 was related to the poor overall survival (OS) of ovarian cancer patients at advanced stages. An inverse correlation between the protein levels of FBXO6 and RNASET2 was observed in clinic ovarian cancer samples. Depletion of FBXO6 promoted ovarian cancer cells proliferation, migration, and invasion, which could be partially reversed by RNASET2 silencing. Thus, our data revealed a novel FBXO6-RNASET2 axis, which might contribute to the development of ovarian cancer. We propose that inhibition of FBXO6 might represent an effective therapeutic strategy for ovarian cancer treatment.

E2F1 mediated DDX11 transcriptional activation promotes hepatocellular carcinoma progression through PI3K/AKT/mTOR pathway.

The DEAD/DEAH box helicase 11 (DDX11) plays vital roles in regulating the initiation of DNA replication. However, its precise function and regulation in hepatocellular carcinoma (HCC) have never been reported yet. In the current study, we found that DDX11 was overexpressed in HCC tissues. High DDX11 expression was positively correlated with large tumor size, tumor multiplicity, late tumor-node-metastasis (TNM) stage and poor prognosis. Additional, gain-of-function and loss-of-function experimental results revealed that DDX11 overexpression promoted HCC cell proliferation, migration, invasion and inhibited cell apoptosis in vitro. Overexpression of DDX11 also enhanced HCC tumorigenicity in vivo. Furthermore, DDX11 was transcriptionally regulated by transcription factor E2F1 in HCC, as demonstrated by chromatin immunoprecipitation (Ch-IP) and luciferase reporter assays. Mechanistically, E2F1/DDX11 axis promoted HCC cell proliferation, migration and invasion, at least in part, through activating PI3K/AKT/mTOR signaling pathway. Conclusively, our study demonstrates that E2F1-enhanced DDX11 expression promotes HCC progression through PI3K/AKT/mTOR pathway and DDX11 might be a potential therapeutic and prognostic target for HCC treatment.

UBQLN4 promotes progression of HCC via activating wnt-ß-catenin pathway and is regulated by miR-370.

BACKGROUND: Ubiquilin-4 (UBQLN4) is a member of the ubiquitin-proteasome system that is usually upregulated in many tumor cells. Its overexpression has been associated with poor disease outcomes in various cancer diseases. However, the underlying mechanism of UBQLN4 in the development of hepatocellular carcinoma (HCC) has not been elucidated. METHODS: Immunochemistry, real-time PCR, and western blotting were used to evaluate the expression levels of UBQLN4 in cancer tissues. Univariate, Cox-regression, and Kaplan-Meier analyses were performed to determine the association between UBQLN4 expression and HCC prognosis. Cell Counting Kit-8 (CCK-8), transwell, EDU and colony formation assays were conducted to evaluate the role of UBQLN4 in HCC cell progression. The gene set enrichment analysis and luciferase reporter experiments were conducted to find the mechanism of UBQLN4 in HCC. RESULTS: Ubiquilin-4 (UBQLN4) was overexpressed in HCC tissues. Besides, overexpression of UBQLN4 was associated with poor overall survival and disease-free survival rate of HCC patients. The loss-of-function analysis revealed that suppression of UBQLN4 inhibited the proliferation and invasion of HCC cells in vivo and in vitro. The KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis showed that UBQLN4 could regulate activation of the wnt-ß-catenin pathway in HCC cells. Furthermore, our results showed that UBQLN4 was downregulated by miR-370, which acted as a tumor suppressor gene in HCC progression. CONCLUSION: The results of the present study suggest that the miR-370/UBQLN4 axis may play a critical role in the progression of HCC. These findings may inform future strategies for the development of therapeutic agents against HCC.

The Role of Upregulated DDX11 as A Potential Prognostic and Diagnostic Biomarker in Lung Adenocarcinoma.

Background: Lung adenocarcinoma (ADC) is the main cause of cancer-related mortality in lung cancer patients. DEAD/DEAH box helicase 11 (DDX11) was previously shown to be dysregulated and to exert oncogenic activity in cancer. However, the diagnostic value and clinical significance of DDX11 in ADC remain unknown. Methods: A total of 513 ADC and 59 normal tissue samples were obtained from The Cancer Genome Atlas (TCGA) database, and the mRNA expression level of DDX11 in ADC was evaluated. Additionally, a meta-analysis of 7 ADC cohorts from the Gene Expression Omnibus (GEO) database was conducted to validate the DDX11 expression pattern. Moreover, receiver operating characteristic (ROC) curve analysis was used to identify the diagnostic power of DDX11 in ADC. A tissue microarray (TMA) comprising 86 ADC specimens and their adjacent normal specimens was applied to indicate DDX11 protein expression status. In addition, Kaplan-Meier and Cox regression analyses were conducted to validate the prognostic value of DDX11 in ADC. Finally, the molecular mechanism of DDX11 action in ADC was predicted by gene set enrichment analysis (GSEA). Results: DDX11 was upregulated in ADC tissues and was associated with worse overall survival (OS). ROC curves of DDX11 showed high values for diagnosis. Additionally, DDX11 expression has remarkable correlations with DNA replication and the cell cycle G1-S phase pathway. Consistently, it was associated with cell cycle genes, such as CCNA2, CCNB1, CCNC, CCND1, CCNE1, CDK2, CDK4 and CDK6. Moreover, high CCNA2, CCNB1, CCNE1 and CDK6 expression in ADC patients predicted worse OS and progression-free survival (PFS). Conclusion: DDX11 was significantly upregulated and predicted poor prognosis in ADC. This gene might serve as a potential novel prognostic and diagnostic biomarker for ADC.

Theoretical insights into the reactivity of Fe-based catalysts for water oxidation: the role of electron-withdrawing groups.

Recent experiments have shown that complex (1), [Fe(OTf)2(Pytacn)] (OTf = CF3SO3-, Pytacn = 1-(2'-pyridylmethyl)-4,7-dimethyl-1,4,7-triazacyclononane), is a promising artificial photosynthetic catalyst because of its distinct capability in water oxidation. Experimentalists have also synthesized several derivatives, e.g., [Fe(OTf)2(E,HPytacn)] (E = -Cl (2), -CO2Et (3) and -NO2 (4)) and [Fe(OTf)2 (E,RPytacn)] (R = -F (5) and R = -Me (6)), and proposed that the E-substituted electron-withdrawing groups could improve the catalytic efficiency. However, the mechanism remains somewhat unclear, especially on the relative catalytic efficiency of these complexes. In this work, we propose an oxygen radical mechanism based on density functional theory (DFT) calculations for the six complexes. The crucial O-O bond-formation step is elucidated. Our calculations reveal that the FeIV-oxyl radical is the active species during the reaction, and the catalytic activities follow the sequence of (4) > (3) > (2) > (1) > (5) > (6), which agrees consistently with the experimental findings. Furthermore, we propose a simple charge-pair interaction model to characterize the effect of electron-withdrawing groups on the catalytic efficiency. It is clearly demonstrated that an electron-withdrawing group with a higher electronegativity is associated with a lower Gibbs free energy barrier for the O-O bond formation, which then leads to a more active catalyst. We also emphasize that the accurate description of dispersive interactions in DFT calculations is crucially important to retrieve the correct sequence of the catalytic efficiency. The theoretical insights provided in this work could be useful for the design of highly efficient Fe-based water oxidation catalysts.

Rational Ligand Design for an Efficient Biomimetic Water Splitting Complex.

Being an important biomimetic model catalyst for water oxidation, the dimanganese molecular complex [H2O(terpy)MnIII(µ-O)2MnIV(terpy)OH2]3+ (complex 1, terpy = 2,2':6',2″-terpyridine) has been investigated extensively by experimentalists. By carrying out density functional theory calculations, we explore theoretically the oxygen evolution mechanisms of complex 1. On the basis of understandings of the geometric and electronic structural features of complex 1, we explore the possibility of improving its catalytic efficiency through a rational design of ligands coordinated to the manganese ions. Recognizing that the rate-determining step of oxygen evolution is the formation of an O-O bond at a high-valent manganese center, we design a new complex, [H2O(2-bpnp)MnIII(µ-O)2MnIV(2-bpnp)OH2]3+ (complex 2, 2-bpnp = 2-([2,2'-bipyridin]-6-yl)-1,8-naphthyridine). It is verified that the proton-accepting 2-bpnp ligand leads to stabilized hydrogen bonding with surrounding water molecules, and hence, the barrier height associated with O-O bond formation is substantially reduced. Moreover, despite its larger size, the 2-bpnp ligand does not cause steric hindrance for the release of molecular oxygen. Consequently, the proposed complex 2 is expected to outperform the existing complex 1 regarding catalytic efficiency. This work highlights the potential usefulness of rational design toward reaching the high efficiency of the oxygen evolution center in photosystem II.