Elucidating the role of liver enzymes as markers and regulators in ovarian cancer: a synergistic approach using Mendelian randomization, single-cell analysis, and clinical evidence.

OBJECTIVE: To investigate the association between liver enzymes and ovarian cancer (OC), and to validate their potential as biomarkers and their mechanisms in OC. Methods Genome-wide association studies for OC and levels of enzymes such as Alkaline phosphatase (ALP), Aspartate aminotransferase (AST), Alanine aminotransferase, and gamma-glutamyltransferase were analyzed. Univariate and multivariate Mendelian randomization (MR), complemented by the Steiger test, identified enzymes with a potential causal relationship to OC. Single-cell transcriptomics from the GSE130000 dataset pinpointed pivotal cellular clusters, enabling further examination of enzyme-encoding gene expression. Transcription factors (TFs) governing these genes were predicted to construct TF-mRNA networks. Additionally, liver enzyme levels were retrospectively analyzed in healthy individuals and OC patients, alongside the evaluation of correlations with cancer antigen 125 (CA125) and Human Epididymis Protein 4 (HE4). RESULTS: A total of 283 single nucleotide polymorphisms (SNPs) and 209 SNPs related to ALP and AST, respectively. Using the inverse-variance weighted method, univariate MR (UVMR) analysis revealed that ALP (P = 0.050, OR = 0.938) and AST (P = 0.017, OR = 0.906) were inversely associated with OC risk, suggesting their roles as protective factors. Multivariate MR (MVMR) confirmed the causal effect of ALP (P = 0.005, OR = 0.938) on OC without reverse causality. Key cellular clusters including T cells, ovarian cells, endothelial cells, macrophages, cancer-associated fibroblasts (CAFs), and epithelial cells were identified, with epithelial cells showing high expression of genes encoding AST and ALP. Notably, TFs such as TCE4 were implicated in the regulation of GOT2 and ALPL genes. OC patient samples exhibited decreased ALP levels in both blood and tumor tissues, with a negative correlation between ALP and CA125 levels observed. CONCLUSION: This study has established a causal link between AST and ALP with OC, identifying them as protective factors. The increased expression of the genes encoding these enzymes in epithelial cells provides a theoretical basis for developing novel disease markers and targeted therapies for OC.

The Role of Interferon-Induced Proteins with Tetratricopeptide Repeats 1 and 2 in Sepsis-Induced Acute Liver Injury.

Background: Sepsis refers to a life-threatening organ dysfunction which can be resulted from the infection-induced dysregulated host response. A large number of inflammatory cytokines are released to act on the liver, making the liver one of the common target organs for the development of multiple organ dysfunction syndrome (MODS) in patients with sepsis. Sepsis-induced acute liver injury (SALI) can aggravate systemic disease. As a result, it is of great clinical significance to comprehend the molecular biological mechanism of SALI and to identify the markers for evaluating SALI. Interferon-induced proteins with tetratricopeptide repeats 1 and 2 (IFIT1, IFIT2) have been recognized as the anti-inflammatory factors that are widely expressed in various organs. The present study was aimed at clarifying the roles of IFIT1 and IFIT2 in the development of SALI. Methods: A two-sample Mendelian randomization (MR) analysis was employed. Summary statistics datas were obtained from GWAS for inflammatory factors [tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6)], IFIT2, and sepsis as well as liver injury. Independent SNPs were selected as instrumental variables (IVs). Inverse variance weighted (IVW) in the MR analysis was adopted as the primary method for estimating the causal associations of inflammatory factors and IFIT2 with two diseases, and the associations of inflammatory factors with IFIT2. Additionally, weighted median method, MR-Egger and sensitivity analyses were applied in assessing the robustness of the results and ensure the result reliability. Subsequently, 119 healthy volunteers, 116 patients with sepsis and 116 SALI patients were recruited. The ELISA method was employed to quantify the expression levels of TNF-α, IL-1ß, and IL-6. Additionally, qRT-PCR was conducted to measure the expression of IFIT1 and IFIT2. Furthermore, the correlations of IFIT1 and IFIT2 with inflammatory factors, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were explored. Results: As shown by the MR analysis, the genetically predisposed sepsis was significantly associated with the risk of IL-1ß, with an odds ratio (OR) of 1.069 (95% confidence interval (CI), 1.015-1.127, p = 0.0119), and negatively associated with the risk of IL-6, with an OR of 0.880 (95% CI: 0.792-0.979, p= 0.0184). Meanwhile, there were positive causal effects of IL-6 (OR = 1.269, 95% CI: 1.032-1.561, p= 0.0238), IL-1ß (OR = 1.106, 95% CI: 1.010-1.211, p = 0.0299) and IFIT2 (OR = 1.191, 95% CI: 1.045-1.359, p = 0.0090) on liver injury. Additionally, there was a positive causal effect of IFIT2 (OR = 1.164, 95% CI: 1.035-1.309, p= 0.0110) on IL-1ß. Upon sensitivity analyses, there was weak evidence of such effects, indicating that the findings of this study were robust and reliable. Our results revealed the elevated levels of TNF-α, IL-1ß, and IL-6 in the blood samples of sepsis and SALI patients (p < 0.0001). Conversely, IFIT1 and IFIT2 demonstrated the significantly decreased levels in peripheral blood mononuclear cells (PBMCs) of SALI patients (p < 0.0001). Furthermore, the expression levels of IFIT1 and IFIT2 were both negatively correlated with ALT activity (r = -0.3426, p = 0.0002; r = -0.3069, p = 0.0008) and AST activity (r = -0.2483, p = 0.0072; r = -0.3261, p = 0.0004), respectively. Moreover, the expression of IFIT1 and IFIT2 was both negatively related to the levels of TNF-α (r = -0.5027, p < 0.0001; r = -0.4218, p < 0.0001), IL-1ß (r = -0.3349, p = 0.0002; r = -0.4070, p < 0.0001) and IL-6 (r = -0.2734, p = 0.0030; r = -0.3536, p < 0.0001), respectively. Conclusion: IFIT1 and IFIT2 can serve as the diagnostic markers for sepsis-related liver injury, and IFIT1 and IFIT2 may participate in the pathological process of sepsis-related liver injury by regulating inflammation and liver function.

Microscopic Mechanical Model Analysis and Visualization Investigation of SiO2 Nanoparticle/HPAM Polymer Foam Liquid Film Displacing Heavy Oil.

In this paper, the microscopic mechanisms and macroscopic characteristics of polymer/nanoparticle foam flooding in a heavy oil reservoir environment were studied. Sodium dodecyl sulfate (SDS) surfactant was used as the foaming agent, and the foam was prepared by a combination of partially hydrolyzed polyacrylamide (HPAM) polymer and SiO2 nanoparticles. By performing experiments with the microscopic model, the foam flooding dynamics in the heavy oil reservoir were simulated. Based on the experiments, the formula model was established to evaluate the physicochemical effects between the foam liquid film and oil surface. Finally, the macroscopic characteristics of foam flooding were studied by performing oil displacement experiments with a 2D visual model. The microscopic experiments demonstrated that the foam liquid film could exert multiple actions, such as adsorption, stretching, and cutting on the heavy oil in the reservoir pores. These actions were accompanied by force changes between the foam and heavy oil, and the addition of polymer and nanoparticles further strengthened them. The calculations of the formula model indicated that the polymer and nanoparticles amplified the force between the foam liquid film and heavy oil by 1.95 and 2.2 times, respectively. The 2D visual model experiments suggested that foam flooding could further develop heavy oil after water flooding through its liquid film effects, and the oil recovery efficiency increased from 42.43 to 57.82%. In addition, the polymer and nanoparticles further optimized the oil displacement effect of the foam liquid film, which made the oil recovery efficiency reach 64.77-68.16%.

Experimental Investigation on Microscopic Force Measurement of Foam and Heavy Oil.

This paper combined experiments with a theoretical model to simulate the behavior between a foam and heavy oil during contact pressing, separation, and adsorption. We discuss the changes in the elasticity and adsorption forces during the pressing and adsorption of the two fluids. The influence of the changes in temperature and pressure, the concentration of the sodium dodecyl sulfate surfactant, the heavy oil viscosity, and the addition of partially hydrolyzed polyacrylamide and hydrophobic SiO2 nanoparticles was studied. The results showed that the overall increase in the elasticity and adsorption forces between the foam at 1 wt % surfactant and heavy oil was more than 2 times greater than those of the foam with 0.2 wt % surfactant. The increase in viscosity of heavy oil also increased various forces. The overall improvement in the adsorption force between fluids caused by nanoparticles during separation and adsorption stages reached 1.8 times, which was better than that obtained using the polymer (1.65 times). However, the polymer showed a 1.4 times higher elastic force during the fluid pressing stage than the nanoparticles and about 4 times higher than the control foam, and the increase in temperature greatly weakened the effect of the force, while the change in pressure did not cause much impact. An analytical model was built based on fluid mechanics, and the calculation results were consistent with the experimental data with an error of about 5-12%, suggesting that this model provides a good reference value.