Combination of gene/protein and metabolite multiomics to reveal biomarkers of nickel ion cytotoxicity and the underlying mechanism.

Biomarkers have been applied for toxicity assessment of biomaterials due to their advantages. However, research on biomarkers for biomaterials is still in its early stages. There is a lack of integrated analysis in biomarker research based on multiomics studies. Herein, we report a new approach for combining of gene/protein and metabolite multiomics to reveal biomarkers of nickel ion (Ni2+) cytotoxicity and the underlying mechanism. Firstly, differentially expressed genes and proteins were compared to screen gene/protein pairs exhibiting consistent differential expression within the same Ni2+-treated groups. Next, metabolic pathway analysis was carried out to reveal pathways in which gene/protein pairs and metabolites showed upstream and downstream relationships. Important networks composed of gene/protein pairs, metabolites and metabolic pathways and candidate biomarkers were subsequently identified. Through expression level and function validation, the gene/protein/metabolite biomarkers were confirmed, and the underlying mechanism was revealed: Ni2+ influenced the expression of the Rrm2 gene biomarker, which subsequently affected the expression of the RRM2 protein biomarker. These changes in turn impacted the levels of uric acid and uridine metabolite biomarkers, ultimately inhibiting DNA synthesis, suppressing cell proliferation, increasing intracellular ROS levels and reducing ATP content.

Association between the triglyceride glucose index and heart failure: NHANES 2007-2018.

Background: Patients with heart failure (HF) were compared with non-HF people to explore the relationship between the triglyceride glucose (TyG) index and HF in participants with cardiovascular and cerebrovascular diseases. Methods: TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. Multivariate logistic regression models were used to investigate the association between the TyG index and the risk of HF. Restricted cubic spline (RCS) analysis was applied to evaluate the dose-response relationship between the TyG index and the risk of HF. Results: National Health and Nutrition Examination Survey (NHANES) (2007-2018) was used to analyze the association between TyG and HF in patients. A total of 13,825 participants who had their TyG index measured were included, involving 435 individuals with HF and 13,390 individuals without HF. Those with HF had higher levels of the TyG index compared with those without HF (8.91 ± 0.74 vs. 8.57 ± 0.66, p < 0.001). The odds ratio (OR) of HF for the TyG index from logistic regression was 1.644 and 1.057 in Model 1 (without adjusting for any variables) and Model 4 (adjusted for all covariates), respectively. Compared with individuals with Q1, a higher TyG index was related to the increased risk of HF. Model 1 showed that there was a linear dose-response relationship between the TyG index and HF (p = 0.686). The TyG index predicted the area of the receiver operating characteristic (ROC) curve of 0.602 (95% CI: 0.575-0.629, p < 0.001) and the optimal cutoff value was 8.91. Conclusion: The TyG index was positively associated with the risk of HF. The TyG index may be a therapeutic target and an important predictor of HF.

Screening and validation of nickel ion cytotoxicity biomarkers based on transcriptomic and proteomic technology.

The aim of this study was to screen cytotoxicity biomarkers of nickel ions (Ni2+) using transcriptomic and proteomic approaches combined with molecular biology validation. First, the MTT method was used to evaluate cytotoxicity in L929 cells treated with Ni2+ at different concentrations. Ni2+ at both 100 µM and 200 µM affected cell proliferation. Then, transcriptomic and proteomic technology was used to study the effects of Ni2+ on the expression of genes/proteins in cells. It was found that 1490, 789, 652 and 729 genes (12, 24, 48 and 72 h, respectively) and 177, 2191 and 2095 proteins (12, 24 and 48 h, respectively) were differentially expressed after treatment with 100 µM Ni2+. In total, 1403, 963, 916 and 1230 genes (12, 24, 48 and 72 h, respectively) and 83, 1681 and 2398 proteins (12, 24 and 48 h, respectively) were differentially expressed after treatment with 200 µM Ni2+. Then, four target gene/protein biomarkers were filtered by combined screening using gene/proteomic experimental data and biological pathway analyses. Further expression level validation of all these target biomarkers and functional validation of selected gene/protein biomarkers were carried out, and a final gene/protein biomarker (UQCRB) was identified.

The role of Forkhead box O in diabetes mellitus.

FOXO(Forkhead box O) proteins are transcription factors that are involved in many physiological processes, including diabetes mellitus, which is a complex, multifactorial metabolic disorder. FOXO proteins are emerging as pivotal regulators in the progression of diabetes mellitus, mainly by inhibiting insulin or insulinlike growth factor，but little is known about their roles in diabetes mellitus. Although no targeted therapy exists to slow the development of diabetes and diabetes-related complications, several recent advances have clarified the molecular mechanisms underlying the disease. This review summarizes findings about FOXO proteins and diabetes mellitus ,and sheds new light on the roles of FOXO proteins in diabetes mellitus.

Effectiveness and safety of ertugliflozin for type 2 diabetes: A meta-analysis of data from randomized controlled trials.

AIMS/INTRODUCTION: To evaluate the effectiveness and safety of the novel sodium-glucose cotransporter inhibitor, ertugliflozin, compared with a placebo or other antihyperglycemic agents for type 2 diabetes patients. MATERIALS AND METHODS: We carried out a meta-analysis of randomized controlled trials to assess the benefits and harms of ertugliflozin. Online database searches were carried out in PubMed, EMBASE, WEB OF SCIENCE and Cochrane from inception up to 11 March 2021. Our end-points were glycated hemoglobin, fasting plasma glucose and bodyweight. We analyzed the results using a random effects model, computed weighted mean differences and risk ratios. RESULT: A total of 10 randomized controlled trials with 13,223 patients met the inclusion criteria. Compared with a placebo, the weighted mean differences in glycated hemoglobin were -0.77% (95% confidence interval [CI] -0.86 to -0.68%) for ertugliflozin 5 mg, and -0.82% (95% CI -1.01 to -0.63%) for ertugliflozin 15 mg. Ertugliflozin 5 mg daily was also associated with bodyweight loss (weighted mean difference -1.87 kg, 95% CI -2.12 to -1.6). When compared with a placebo, ertugliflozin significantly reduced fasting plasma glucose by -1.62 mmol/L (weighted mean difference, 95% CI -1.82 to -1.42 for 5 mg ertugliflozin). Yet, we observed a rising risk for genital mycotic infections (risk ratio 4.34, 95% CI 2.78-6.76). The results were similar for the 15 mg ertugliflozin group. CONCLUSION: Ertugliflozin effectively reduces glycated hemoglobin levels and provides extra clinical benefits including bodyweight and fasting plasma glucose. Common adverse effects, including genital mycotic infections and so on, were reviewed.

A high-throughput study on endothelial cell adhesion and growth mediated by adsorbed serum protein via signaling pathway PCR array.

The purpose of this paper is to utilize the signaling pathway polymerase chain reaction (PCR) arrays to investigate the activation of two important biological signaling pathways in endothelial cell adhesion and growth mediated by adsorbed serum protein on the surface of bare and titanium nitride (TiN)-coated nickel titanium (NiTi) alloys. First, the endothelial cells were cultured on the bare and TiN-coated NiTi alloys and chitosan films as control for 4 h and 24 h, respectively. Then, the total RNA of the cells was collected and the PCR arrays were performed. After that, the differentially expressed genes in the transforming growth factor beta (TGF-ß) signaling pathway and the regulation of actin cytoskeleton pathway were screened out; and the further bioinformatics analyses were performed. The results showed that both TGF-ß signaling pathway and regulation of actin cytoskeleton pathway were activated in the cells after 4 h and 24 h culturing on the surface of bare and TiN-coated NiTi alloys compared to the chitosan group. The activated TGF-ß signaling pathway promoted cell adhesion; the activated regulation of actin cytoskeleton pathway promoted cell adhesion, spreading, growth and motility. In addition, the activation of both pathways was much stronger in the cells cultured for 24 h versus 4 h, which indicated that cell adhesion and growth became more favorable with longer time on the surface of two NiTi alloy materials.