Study of high-pressure thermophysical properties of orthocarbonate Sr3CO5 using deep learning molecular dynamics simulations.

The exploration of the physical attributes of the recently discovered orthocarbonate Sr3CO5 is significant for comprehending the carbon cycle and storage mechanisms within the Earth's interior. In this study, first-principles calculations are initially used to examine the structural phase transitions of Sr3CO5 polymorphs within the range of lower mantle pressures. The results suggest that Sr3CO5 with the Cmcm phase exhibits a minimal enthalpy between 8.3 and 30.3 GPa. As the pressure exceeds 30.3 GPa, the Cmcm phase undergoes a transition to the I4/mcm phase, while the experimentally observed Pnma phase remains metastable under our studied pressure. Furthermore, the structural data of SrO, SrCO3, and Sr3CO5 polymorphs are utilized to develop a deep learning potential model suitable for the Sr-C-O system, and the pressure-volume relationship and elastic constants calculated using the potential model are in line with the available results. Subsequently, the elastic properties of Cmcm and I4/mcm phases in Sr3CO5 at high temperature and pressure are calculated using the molecular dynamics method. The results indicate that the I4/mcm phase exhibits higher temperature sensitivity in terms of elastic moduli and wave velocities compared to the Cmcm phase. Finally, the thermodynamic properties of the Cmcm and I4/mcm phases are predicted in the range of 0-2000 K and 10-120 GPa, revealing that the heat capacity and bulk thermal expansion coefficient of both phases increase with temperature, with the constant volume heat capacity gradually approaching the Dulong-Petit limit as the temperature rises.

CRISPR/Cas9-HPV-liposome enhances antitumor immunity and treatment of HPV infection-associated cervical cancer.

Increasing evidence shows that human papillomavirus (HPV) E6/E7 deletion in cervical cancer cells may be related to the immunosuppressive tumor microenvironment and adverse reactions or resistance to immune checkpoint blockade. Here, we demonstrate that liposome delivery of CRISPR/cas9 can effectively knock out HPV, which, in turn, induces autophagy and triggers cell death-related immune activation by releasing damage-related molecular patterns. The results of in vivo experiments showed that HPV-targeting guide RNA-liposomes could promote CD8+ T cell infiltration in tumor tissues; enhance the expression of proinflammatory cytokines, such as interleukin-12, tumor necrosis factor-α, and interferon-γ, and reduce regulatory T cells and myeloid suppressor cells. The combination of HPV-targeting guide RNA-liposomes with immune checkpoint inhibitors and antiprogrammed death-1 antibodies produced highly effective antitumor effects. In addition, combination therapy induced immune memory in the cervical cancer model.

Intravaginal delivery for CRISPR-Cas9 technology: For example, the treatment of HPV infection.

The increasing incidence of sexually transmitted diseases in women, including human papillomavirus (HPV) infection, has led to the need to develop user-friendly potential prevention methods. At present, although there are several therapeutic parts, none of them has a preventive effect, but they are only limited to providing patients with symptom relief. Researchers have now recognized the need to find effective local preventive agents. One of the potential undiscovered local fungicides is the vaginal delivery of CRISPR/Cas9. CRISPR/Cas9 delivery involves silencing gene expression in a sequence-specific manner in the pathogenic agent, thus showing microbicidal activity. However, vaginal mucosal barrier and physiological changes (such as pH value and variable epithelial thickness in the menstrual cycle) are the main obstacles to effective delivery and cell uptake of CRISPR/Cas9. To enhance the vaginal delivery of CRISPR/Cas9, so far, nano-carrier systems such as lipid delivery systems, macromolecular systems, polymer nanoparticles, aptamers, and cell-penetrating peptides have been extensively studied. In this paper, various nano-carriers and their prospects in the preclinical stage are described, as well as the future significance of CRISPR/Cas9 vaginal delivery based on nano-carriers.

Adsorption of CO32-/HCO3- on a quartz surface: cluster formation, pH effects, and mechanistic aspects.

Soluble inorganic carbon is an important component of a soil carbon pool, and its fate in soils, sediments, and underground water environments has great effects on many physiochemical and geological processes. However, the dynamical processes, behaviors and mechanism of their adsorption by soil active components, such as quartz, are still unclear. The aim of this work is to systematically address the anchoring mechanism of CO32- and HCO3- on a quartz surface at different pH values. Three pH values (pH 7.5, pH 9.5 and pH 11) and three carbonate salt concentrations (0.07, 0.14 and 0.28 M) are considered, and molecular dynamics methods are used. The results indicate that the pH value regulates the adsorption behavior of CO32- and HCO3- on the quartz surface by affecting the CO32-/HCO3- ratio and the surface charge of quartz. In general, both HCO3- and CO32- ions were able to adsorb on the quartz surface and the adsorption capacity of CO32- is higher than that of HCO3-. HCO3- ions tended to uniformly distribute in an aqueous solution and contact the quartz surface in the form of single molecules instead of clusters. In contrast, CO32- ions were mainly adsorbed as clusters which became larger as the concentration increased. Na+ ions were essential for the adsorption of HCO3- and CO32-, because some of the Na+ and CO32- ions spontaneously associated together to form clusters, promoting the clusters to be adsorbed on the quartz surface through cationic bridges. The local structures and dynamics trajectory of CO32- and HCO3- showed that the anchoring mechanism of carbonate solvates on quartz involved H-bonds and cationic bridges, which changed in relation to the concentration and pH values. However, the HCO3- ions mainly adsorbed on the quartz surface via H-bonds while the CO32- ions tended to be adsorbed through cationic bridges. These results may help in understanding the geochemical behavior of soil inorganic carbon and further the processes of the Earth's carbon chemical cycle.

Association between postoperative thrombocytopenia and outcomes after traumatic brain injury surgery: A cohort study.

BACKGROUND: It is well known that thrombocytopenia occurs in patients with traumatic brain injury (TBI), and its incidence increases with the severity of injury. We aimed to determine whether postoperative thrombocytopenia in patients with TBI is associated with poor clinical outcomes. METHODS: This was a retrospective cohort study of a large international database called the Medical Information Mart for Intensive Care III (MIMIC-III), which included 1093 patients who underwent TBI surgery. Hospital mortality was the primary endpoint of this study. RESULTS: Multivariate logistic regression analysis revealed non-thrombocytopenia was significantly associated with a decreased hospital mortality (adjusted odds ratio [OR] 0.49; 95% confidence interval [CI] 0.33-0.75; p = .01). In addition, platelet counts increased over time in both survivors and non-survivors, according to generalized additive mixed model (GAMM). However, the platelet count increased more noticeably in the survivors than in the non-survivors and the difference in platelet count between the two groups showed a trend toward increasing within 7 days after surgery. This difference increased by 7.97 per day on average. CONCLUSIONS: Patients with TBI who experienced postoperative thrombocytopenia were more likely to have a poor short-term prognosis. In addition, we found that the rate of platelet growth over time varied significantly between the survival and non-survival groups. Patients with TBI who experienced a greater early increase in platelet count had a lower mortality rate.

Obesity is associated with postoperative outcomes in patients undergoing cardiac surgery: a cohort study.

BACKGROUND: The purpose of present study was to determine whether obesity was associated with increased adverse outcomes after cardiac surgery. METHODS: This is a retrospective cohort study from a large international database called the Medical Information Mart for Intensive Care III (MIMIC-III). Patients who underwent cardiac surgery and greater than 18 years old were divided into either nonobese (BMI < 30 kg/m2) or obese (BMI ≥ 30 kg/m2). The primary outcome of this study was 28-day mortality from the date of operation. Secondary outcomes included ICU mortality, 1-year mortality, incidence of postoperative atrial fibrillation (POAF), hospital length of stay (HOS_LOS) and ventilation-free days within 28 days (VFD_28). RESULTS: Multivariate logistic regression analysis revealed a negative effect of obesity on 28-day mortality, with an adjusted odds ratio (OR) of 1.57 (95% CI 1.14-2.16; p = 0.005). The association remained significant when PSM analysis and double robust analysis with all covariates were performed. In terms of 28-day mortality, the mediating effect of longer ventilation duration on obese patients was noticeable, and the proportion of the effect mediated was 8.2% (95% CI 2.1-25.5%; p = 0.012). CONCLUSIONS: Among patients with cardiac surgery, obesity is associated with higher 28-day mortality. The longer ventilation duration may have mediated this effect. In future, considering the elevated incidence of the obese patients undergoing cardiac surgery, obesity stat should be included as one of the predictive variables for stratification of perioperative death risk.

Mechanical power of ventilation is associated with mortality in neurocritical patients: a cohort study.

This study aimed to determine the predictive relevance of mechanical power in the clinical outcomes (such as ICU mortality, hospital mortality, 90-day mortality, length of ICU stay, and number of ventilator-free days at day 28) of neurocritical patients. This is a retrospective cohort analysis of an open-access clinical database known as MIMIC-III. The study included patients who had sustained an acute brain injury and required invasive ventilation for at least 24 h. Demographic parameters, disease severity scores (Glasgow coma scale), comorbidities, vital signs, laboratory parameters and ventilator parameters were collected within the first 24 h of ICU admission. The main outcome was the relationship between MP and ICU mortality. A total of 529 patients were selected for the study. The critical value of MP was 12.16 J/min, with the area under the curve (AUC) of the MP was 0.678 (95% CI 0.637-0.718), and compared to the GCS scores, the MP performed significantly better in discrimination (DeLong's test: p < 0.001). Among these patients elevated MP was associated to higher ICU mortality (OR 1.11; 95% CI 1.06-1.17; p < 0.001), enhanced the risk of hospital mortality, prolonged ICU stay, and decreased the number of ventilator-free days. In the subgroup analysis, high MP was associated with ICU mortality regardless of ARDS (OR 1.01, 95% CI 1.00-1.02, p = 0.009; OR 1.01, 95% CI 1.00-1.02, p = 0.018, respectively) or obesity (OR 1.01, 95% CI 1.00-1.02, p = 0.012; OR 1.01, 95% CI 1.01-1.02, p < 0.001, respectively). In neurocritical care patients undergoing invasive ventilation, elevated MP is linked to higher ICU mortality and a variety of other clinical outcomes.

In Situ Inhibitor Synthesis and Screening by Fluorescence Polarization: An Efficient Approach for Accelerating Drug Discovery.

Target-directed dynamic combinatorial chemistry has emerged as a useful tool for hit identification, but has not been widely used, in part due to challenges associated with analyses involving complex mixtures. We describe an operationally simple alternative: in situ inhibitor synthesis and screening (ISISS), which links high-throughput bioorthogonal synthesis with screening for target binding by fluorescence. We exemplify the ISISS method by showing how coupling screening for target binding by fluorescence polarization with the reaction of acyl-hydrazides and aldehydes led to the efficient discovery of a potent and novel acylhydrazone-based inhibitor of human prolyl hydroxylase 2 (PHD2), a target for anemia treatment, with equivalent in vivo potency to an approved medicine.

Postoperative Neutrophil-to-Lymphocyte Ratio Is Associated with Mortality in Adult Patients After Cardiopulmonary Bypass Surgery: A Cohort Study.

BACKGROUND Cardiopulmonary bypass (CPB) contributes to the development of systemic inflammatory response after cardiothoracic surgery. As a measure of inflammation and immune reaction, the neutrophil-to-lymphocyte ratio (NLR) has been linked to poor outcomes in a variety of diseases. However, it remains to be seen whether postoperative NLR is associated with CPB patient mortality. The purpose of this research was to explore the prognostic role of the postoperative NLR in adult patients undergoing cardiothoracic surgery with cardiopulmonary bypass. MATERIAL AND METHODS This is an analysis of data stored in the databases of the MIMIC-III, which contains data of critically ill patients for over 50,000. The exposure of interest was postoperative NLR. The primary outcomeaThis study incorporates data from the MIMIC III database, which includes more than 50 000 critically ill patients. The variable of interest was postoperative NLR. The primary outcome was 30-day mortality and the secondary outcomes were 90-day mortality, length of intensive care unit stay, and length of hospital stay. was 30-day mortality, the secondary outcome was 90-day mortality, length of hospital stay and length of ICU stay. RESULTS We enrolled 575 CPB patients. The ROC curve for the postoperative NLR to estimate mortality was 0.741 (95% confidence interval [CI]: 0.636-0.847, P<0.001), and the critical value was 7.48. There was a significant difference between different postoperative NLR levels in the Kaplan-Meier curve (P=0.045). Furthermore, elevated postoperative NLR was associated with increased hospital mortality (hazard ratio [HR]: 1.1, 95% CI: 1.0-1.1, P=0.021). However, there was no important relationship in these patients between the postoperative NLR levels and 90-day mortality (HR: 1.1, 95% CI: 1.0-1.5, P=0.465). CONCLUSIONS Our findings suggest that higher postoperative NLR is associated with greater hospital mortality in adult patients undergoing cardiopulmonary bypass surgery.

Mechanical power normalized to predicted body weight is associated with mortality in critically ill patients: a cohort study.

BACKGROUND: Mechanical power (MP), defined as the amount of energy produced by mechanical ventilation and released into the respiratory system, was reportedly a determining factor in the pathogenesis of ventilator-induced lung injury. However, previous studies suggest that the effects of MP were proportional to their involvement in the total lung function size. Therefore, MP normalized to the predicted body weight (norMP) should outperform the absolute MP value. The objective of this research is to determine the connection between norMP and mortality in critically ill patients who have been on invasive ventilation for at least 48 h. METHODS: This is a study of data stored in the databases of the MIMIC-III, which contains data of critically ill patients for over 50,000. The study involved critically ill patients who had been on invasive ventilation for at least 48 h. norMP was the relevant exposure. The major endpoint was ICU mortality, the secondary endpoints were 30-day, 90-day mortality; ICU length of stay, the number of ventilator-free days at day 28. RESULT: The study involved a total of 1301 critically ill patients. This study revealed that norMP was correlated with ICU mortality [OR per quartile increase 1.33 (95% CI 1.16-1.52), p <  0.001]. Similarly, norMP was correlated with ventilator-free days at day 28, ICU length of stay. In the subgroup analysis, high norMP was associated with ICU mortality whether low or high Vt (OR 1.31, 95% CI 1.09-1.57, p = 0.004; OR 1.32, 95% CI 1.08-1.62, p = 0.008, respectively). But high norMP was associated with ICU mortality only in low PIP (OR 1.18, 95% CI 1.01-1.38, p = 0.034). CONCLUSION: Our findings indicate that higher norMP is independently linked with elevated ICU mortality and various other clinical findings in critically ill patients with a minimum of 48 h of invasive ventilation.

miR-603 targeted hexokinase-2 to inhibit the malignancy of ovarian cancer cells.

The Warburg effect, characterized by energy production through a high rate of aerobic glycolysis, is a metabolic hallmark of cancer cells. We previously found that ginsenoside 20(S)-Rg3 upregulated miR-603 and impaired the malignancy of ovarian cancer cells by inhibiting the Warburg effect. However, the precise functional role of miR-603 in ovarian cancer progression remains poorly defined. Here, we report that the level of miR-603 in ovarian cancer tissues is significantly lower than that in para-tumor tissues. Overexpression of miR-603 in ovarian cancer cells inhibits the Warburg effect as evidenced by a decrease in glucose consumption, lactate production and hexokinase-2 (HK2) expression, reduces cell proliferation in vitro, and weakens their migration and invasion. Further, miR-603 directly targets HK2 as indicated in a luciferase reporter assay. In contrast to agomiR-NC, agomiR-603 treatment significantly inhibits tumor growth in vivo and the Warburg effect, which is illustrated by a decreased uptake of 18F-FDG in subcutaneous xenografts and HK2 downregulation. Finally, miR-603 is negatively regulated by DNMT3A-mediated DNA methylation in the promoter region of its precursor gene, suggesting that 20(S)-Rg3 antagonizes DNMT3A-mediated DNA methylation to impair growth, migration and invasion of ovarian cancer cells. In conclusion, miR-603 is a tumor suppressor targeting HK2 in ovarian cancer and its low level may result from DNMT3A-mediated methylation.

WITHDRAWN: CRISPR/Cas9 mediated HPV and PD1 inhibition produces a synergistic anti-tumor effect on cervical cancer.

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Oncogenic Human Papillomavirus: Application of CRISPR/Cas9 Therapeutic Strategies for Cervical Cancer.

Oncogenic human papillomaviruses (HPVs) cause different types of cancer especially cervical cancer. HPV-associated carcinogenesis provides a classical model system for clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) based cancer therapies since the viral oncogenes E6 and E7 are exclusively expressed in cancerous cells. Sequence-specific gene knockdown/knockout using CRISPR/Cas9 shows promise as a novel therapeutic approach for the treatment of a variety of diseases that currently lack effective treatments. However, CRISPR/Cas9-based targeting therapy requires further validation of its efficacy in vitro and in vivo to eliminate the potential off-target effects, necessitates verification of the delivery vehicles and the combinatory use of conventional therapies with CRISPR/Cas9 to ensure the feasibility and safety. In this review we discuss the potential of combining CRISPR/Cas9 with other treatment options as therapies for oncogenic HPVs-associated carcinogenesis. and present our assessment of the promising path to the development of CRISPR/Cas9 therapeutic strategies for clinical settings.

A Feedback Loop Between miR-30a/c-5p and DNMT1 Mediates Cisplatin Resistance in Ovarian Cancer Cells.

BACKGROUND: Many microRNAs (miRs) are dysregulated in cancers, and aberrant miR expression patterns have been suggested to correlate with chemo-resistance of cancer cells. We aim to study the role of miR-30 family members in cisplatin-resistance of ovarian cancer cells. METHODS: qRT-PCR was used to compare differential expression levels of miR-30 family members in ovarian cancer cell line A2780 and its cisplatin-resistant derivative CP70. Changes of cisplatin-sensitivity in miR-30a-5p- and miR-30c-5p-overexpressed-CP70 cells and miR-30a-5p- and miR-30c-5p-inhibited-A2780 cells were examined by CCK8 assay and apoptosis analysis using flow cytometry; targets of miR-30a/c-5p were analyzed by western blotting and luciferase reporter assay; methylation regulation of pre-miR-30a/c-5p was examined by methylation specific PCR. RESULTS: miR-30a-5p and miR-30c-5p, in contrast to other miR-30 family members, dramatically decreased in cisplatin-resistant CP70 cells due to overexpressed-DNMT1 induced aberrant methylation. miR-30a/c-5p in turn directly inhibited DNMT1 as well as Snail. Forced expression of miR-30a/c-5p or knocking down of DNMT1 and Snail promoted cisplatin susceptibility and partially reversed epithelial-mesenchymal transition (EMT) in CP70 cells, while inhibition of miR-30a/c-5p or ectopic expression of DNMT1 and Snail induced cisplatin resistance and partial EMT in cisplatin-sensitive A2780 cells. CONCLUSIONS: A feedback loop between miR-30a/c-5p and DNMT1 is a potent signature for cisplatin-resistance and EMT in ovarian cancer, promising a potential target for improved anti-cancer treatment.

In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by CRISPR/Cas9.

Deregulated expression of high-risk human papillomavirus oncogenes (E6 and E7) is a pivotal event for pathogenesis and progression in cervical cancer. Both viral oncogenes are therefore regarded as ideal therapeutic targets. In the hope of developing a gene-specific therapy for HPV-related cancer, we established CRISPR/Cas9 targeting promoter of HPV 16 E6/E7 and targeting E6, E7 transcript, transduced the CRISPR/Cas9 into cervical HPV-16-positive cell line SiHa. The results showed that CRISPR/Cas9 targeting promoter, as well as targeting E6 and E7 resulted in accumulation of p53 and p21 protein, and consequently remarkably reduced the abilities of proliferation of cervical cancer cells in vitro. Then we inoculated subcutaneously cells into nude mice to establish the transplanted tumor animal models, and found dramatically inhibited tumorigenesis and growth of mice incubated by cells with CRISPR/Cas9 targeting (promoter+E6+E7)-transcript. Our results may provide evidence for application of CRISPR/Cas9 targeting HR-HPV key oncogenes, as a new treatment strategy, in cervical and other HPV-associated cancer therapy.

CYP1A1 polymorphism interactions with smoking status in oral cancer risk: evidence from epidemiological studies.

The cytochrome CYP1A1 gene has been implicated in the etiology of oral cancer. However, the results have been inconsistent. In this study, a meta-analysis was performed to clarify the associations of polymorphisms in CYP1A1 gene with oral cancer risk. Published literatures from PubMed, MEDLINE, EMBASE, and China National Knowledge infrastructure (CNKI) databases were retrieved. A total of 12 studies were included in this meta-analysis. We found that significant positive associations between CYP1A1*2A polymorphism and oral cancer risk in recessive model (CC vs. TC + TT, OR = 1.93), dominant model (CC + TC vs. TT, OR = 1.33), and additive model (CC vs. TT, OR = 1.97). In subgroup analysis based on the ethnicity of study population, significant associations were found in all three genetic models for Asians (recessive OR = 2.29, 95% CI = .42-3.71; dominant OR = 1.54, 95% CI = 1.03-2.31; additive OR 2.39, 95% CI = 1.47-3.88) but not non-Asians. For the smoking stratification, the result indicated a significant association between CYP1A1*2A polymorphism and oral cancer among the smoking subjects (OR = 1.83, 95% CI = 1.47-2.26). This meta-analysis indicated a marked association of CYP1A1*2A polymorphisms with oral cancer risk, particularly among Asians, whereas there were significant interactions between the polymorphisms and cigarette smoking on oral cancer risk.

Expression and biochemical characterization of recombinant human epididymis protein 4.

Whey acidic proteins (WAP) belong to a large gene family of antibacterial peptides that perform critical immune system functions. The function of human epididymis protein 4 (HE4), a 124-amino acid long polypeptide that has two whey acidic protein four-disulfide core (WFDC) domains, is not well studied. Here, a fusion gene encoding the HE4 protein fused to an IgG1 Fc domain was constructed. The recombinant HE4 protein was expressed as a secretory protein in Pichia pastoris and mammalian HEK293-F cells and was subsequently purified. Our data suggested that the HE4 protein produced by these two expression systems bound to both gram-negative and gram-positive bacteria, but demonstrated slightly inhibitory activity towards the growth of Staphylococcus aureus. Moreover, HE4 exhibited proteinase inhibitory activity towards trypsin, elastase, matrix metallopeptidase 9, and the secretory proteinases from Bacillus subtilis. The effects of glycosylation on the biochemical characterization of HE4 were also investigated. LC-ESI-MS glycosylation analysis showed that the high-mannose glycosylated form of HE4 expressed by P. pastoris has lower biological activity when compared to its complex-glycosylated form produced from HEK293-F cells. The implications of this are discussed, which may be provide theoretical basis for its important role in the development of cancer and innate immune system.

CRISPR/Cas9 for hepatitis B virus infection treatment.

Hepatitis B virus (HBV) infection remains a global health challenge. Despite the availability of effective preventive vaccines, millions of people are at risk of cirrhosis and hepatocellular carcinoma. Current drug therapies inhibit viral replication, slow the progression of liver fibrosis and reduce infectivity, but they rarely remove the covalently sealed circular DNA (cccDNA) of the virus that causes HBV persistence. Alternative treatment strategies, including those based on CRISPR/cas9 knockout virus gene, can effectively inhibit HBV replication, so it has a good prospect. During chronic infection, some virus gene knockouts based on CRISPR/cas9 may even lead to cccDNA inactivation. This paper reviews the progress of different HBV CRISPR/cas9, vectors for delivering to the liver, and the current situation of preclinical and clinical research.

TGF-ß1-based CRISPR/Cas9 Gene Therapy Attenuates Radiation-induced Lung Injury.

BACKGROUND: Radiation-induced lung injury (RILI) is lacking effective therapeutic strategies. In this study, we conducted TGF-ß1-based CRISPR/Cas9 gene therapy for RILI. OBJECTIVE: Mouse lungs were irradiated with a single-dose of 20-Gy gamma rays followed by intravenous administration of Ad-CRISPR-TGF-ß1 or Ad- CRISPR-Null. METHODS: Haematoxylin and eosin staining, as well as Masson staining, were performed to observe lung morphology. Albumin and IgM concentrations in bronchoalveolar lavage fluid were measured by ELISA. Cytokine levels were measured using ELISA and/or real-time PCR with terminal deoxynucleotidyl transferase-mediated nick-end labelling. RESULTS: Ad-CRISPR-TTGF-ß1 improved histopathological and biochemical markers of lung injury, reduced secretion and expression of inflammatory cytokines, and inhibited progression of fibrosis. Importantly, the SK1/S1P axis, which is known to play a key role via S1P1 in TGF-ß1-dependent S1PR pattern remodelling, is responsible for promoting fibrosis. CONCLUSION: Our results indicate novel insights for RILI therapy.

Downregulation of DNMT3A Attenuates the Warburg Effect, Proliferation, and Invasion via Promoting the Inhibition of miR-603 on HK2 in Ovarian Cancer.

Background: Ovarian cancer is a highly malignant gynecological cancer. Aerobic glycolysis is one of the features of cancer cell metabolism. Studying the molecular modulation of the Warburg effect in ovarian cancer is significantly valuable for understanding the progression mechanism of ovarian cancer. Materials and Methods: The expression level and prognostic significance of DNMT3A were analyzed using public databases. DNMT3A was overexpressed by plasmid transfection, and DNMT3A was interfered with specific siRNAs transfection. miR-603 was overexpressed by mimic transfection or inhibited by inhibitor transfection. The expression of the molecules was detected by qPCR or western blotting. CCK-8 and transwell assays were used to determine the cell proliferation, migration, and invasion abilities of ovarian cancer. Results: We found that the DNMT3A protein level was higher in ovarian cancer tissues than in normal ovary tissues, but the mRNA level had no significant difference in ovarian cancer tissues and normal ovary tissues. The higher the RNA level of DNMT3A, the poorer prognosis of patients. DNMT3A knocking down impeded the Warburg effect, cell proliferation, migration, and invasion of ovarian cancer cells. Further investigations discovered that DNMT3A promoted ovarian cancer cell malignancy via silencing miR-603. Conclusion: We found that patients who overexpressed DNMT3A showed a poor prognosis. DNMT3A was found to promote the Warburg effect, cell proliferation, migration, and invasion of ovarian cancer by inhibiting the expression of miR-603. As a result, the research revealed that DNMT3A/miR-603/HK2 axis contributed to the Warburg effect of ovarian cancer and DNMT3A may be a potential therapeutic target for ovarian cancer.