Genetic and inflammatory factors underlying gestational diabetes mellitus: a review.

Gestational diabetes mellitus (GDM) poses a significant global health concern, impacting both maternal and fetal well-being. Early detection and treatment are imperative to mitigate adverse outcomes during pregnancy. This review delves into the pivotal role of insulin function and the influence of genetic variants, including SLC30A8, CDKAL1, TCF7L2, IRS1, and GCK, in GDM development. These genetic variations affect beta-cell function and insulin activity in crucial tissues, such as muscle, disrupting glucose regulation during pregnancy. We propose a hypothesis that this variation may disrupt zinc transport, consequently impairing insulin production and secretion, thereby contributing to GDM onset. Furthermore, we discussed the involvement of inflammatory pathways, such as TNF-alpha and IL-6, in predisposing individuals to GDM. Genetic modulation of these pathways may exacerbate glucose metabolism dysregulation observed in GDM patients. We also discussed how GDM affects cardiovascular disease (CVD) through a direct correlation between pregnancy and cardiometabolic function, increasing atherosclerosis, decreased vascular function, dyslipidemia, and hypertension in women with GDM history. However, further research is imperative to unravel the intricate interplay between inflammatory pathways, genetics, and GDM. This understanding is pivotal for devising targeted gene therapies and pharmacological interventions to rectify genetic variations in SLC30A8, CDKAL1, TCF7L2, IRS1, GCK, and other pertinent genes. Ultimately, this review offers insights into the pathophysiological mechanisms of GDM, providing a foundation for developing strategies to mitigate its impact.

Integrated Analysis Identified TGFBI as a Biomarker of Disease Severity and Prognosis Correlated with Immune Infiltrates in Patients with Sepsis.

Background: Sepsis is a major contributor to morbidity and mortality among hospitalized patients. This study aims to identify markers associated with the severity and prognosis of sepsis, providing new approaches for its management and treatment. Methods: Data were mined from the Gene Expression Omnibus (GEO) databases and were analyzed by multiple statistical methods like the Spearman correlation coefficient, Kaplan-Meier analysis, Cox regression analysis, and functional enrichment analysis. Candidate indicator' associations with immune infiltration and roles in sepsis development were evaluated. Additionally, we employed techniques such as flow cytometry and neutral red staining to evaluate its impact on macrophage functions like polarization and phagocytosis. Results: Twenty-eight genes were identified as being closely linked to the severity of sepsis, among which transforming growth factor beta induced (TGFBI) emerged as a distinct marker for predicting clinical outcomes. Notably, reductions in TGFBI expression during sepsis correlate with poor prognosis and rapid disease progression. Elevated expression of TGFBI has been observed to mitigate abnormalities in sepsis-related immune cell infiltration that are critical to the pathogenesis and prognosis of the disease, including but not limited to type 17 T helper cells and activated CD8 T cells. Moreover, the protein-protein interaction network revealed the top ten genes that interact with TGFBI, showing significant involvement in the regulation of the actin cytoskeleton, extracellular matrix-receptor interactions, and phagosomes. These are pivotal elements in the formation of phagocytic cups by macrophages, squaring the findings of the Human Protein Atlas. Additionally, we discovered that TGFBI expression was significantly higher in M2-like macrophages, and its upregulation was found to inhibit lipopolysaccharide-induced polarization and phagocytosis in M1-like macrophages, thereby playing a role in preventing the onset of inflammation. Conclusion: TGFBI warrants additional exploration as a promising biomarker for assessing illness severity and prognosis in patients with sepsis, considering its significant association with immunological and inflammatory responses in this condition.

Association of glutamate receptor gene polymorphisms with attention-deficit hyperactivity disorder susceptibility: a systematic review and meta-analysis.

Background: There is a growing body of evidence indicating a possible association between genetic variations and attention-deficit hyperactivity disorder (ADHD), although the results have been inconsistent. The objective of this study was to evaluate the correlation between the GRIN2A, GRIN2B and GRM7 gene polymorphisms and ADHD. Methods: A comprehensive meta-analysis and subgroup evaluation was conducted using a fixed-effects model to analyze the association between ADHD and GRIN2B (rs2284411), GRIN2A (rs2229193), and GRM7 (rs3792452) in six genetic models (dominant, recessive, overdominant, homozygous, heterozygous, and allele models). Results: The meta-analysis comprised 8 studies. The overall analysis showed that the GRIN2B rs2284411 T allele and T carries were significantly associated with a decreased risk of ADHD (dominant model:TT + CT vs. CC: OR = 0.783; 95% CI: 0.627-0.980; p = 0.032, allele model:T vs. C: OR = 0.795; 95% CI: 0.656-0.964; p = 0.019), especially in the Korean subgroup (dominant model:TT + CT vs. CC: OR = 0.640; 95% CI: 0.442-0.928; p = 0.019, overdominant model: CT vs. TT + CC: OR = 0.641; 95% CI: 0.438-0.938; p = 0.022, allele model:T vs. C: OR = 0.712; 95% CI: 0.521-0.974; p = 0.034 and heterozygous model: CT vs. CC: OR = 0.630; 95% CI: 0.429-0.925; p = 0.018). However, no meaningful associations were found for rs2229193 and rs3792452. Conclusion: The results of the meta-analysis provide strong evidence that the rs2284411 T allele is significantly associated with reduced susceptibility to ADHD, particularly in the Korean population.

Non-adherent culture method affects the proliferation and apoptosis of mesenchymal stem cells through inhibiting LINC00707 to promote RNF6-mediated QKI ubiquitination.

Exploration of the molecular mechanisms of mesenchymal stem cell (MSC) growth has significant clinical benefits. Long non-coding RNAs (lncRNAs) have been reported to play vital roles in the regulation of the osteogenic differentiation of MSCs. However, the mechanism by which lncRNA affects the proliferation and apoptosis of MSCs is unclear. In this study, sequencing analysis revealed that LINC00707 was significantly decreased in non-adherent human MSCs (non-AC-hMSCs) compared to adherent human MSCs. Moreover, LINC00707 overexpression promoted non-AChMSC proliferation, cell cycle progression from the G0/G1 phase to the S phase and inhibited apoptosis, whereas LINC00707 silencing had the opposite effect. Furthermore, LINC00707 interacted directly with the quaking (QKI) protein and enhanced the E3 ubiquitin-protein ligase ring finger protein 6 (RNF6)-mediated ubiquitination of the QKI protein. Additionally, the overexpression of QKI rescued the promotive effects on proliferation and inhibitory effects on apoptosis in non-AC-hMSCs induced by the ectopic expression of LINC00707. Thus, LINC00707 contributes to the proliferation and apoptosis in non-AChMSCs by regulating the ubiquitination and degradation of the QKI protein.

Association between GLO1 variants and gestational diabetes mellitus susceptibility in a Chinese population: a preliminary study.

Background: Glyoxalase 1 (GLO1) plays a crucial role in defending against glycation. Single nucleotide polymorphism (SNP) variants in the GLO1 gene may affect gene expression and alter enzyme activity. However, there have been limited studies evaluating the association between GLO1 and diabetes, especially gestational diabetes mellitus (GDM). Therefore, this study is the first to explore the association of GLO1 SNPs and GDM risk. Methods: The study included a total of 500 GDM patients and 502 control subjects. The SNPscan™ genotyping assay was used to genotype rs1781735, rs4746 and rs1130534. To assess the disparities in genotype, allele, and haplotype distributions and their correlation with GDM risk, the independent sample t-test, logistic regression, and chi-square test were employed during the data processing phase. Furthermore, one-way ANOVA was conducted to determine the differences in genotype and blood glucose and methylglyoxal(MG) levels. Results: Significant differences were observed in prepregnancy body mass index (pre-BMI), age, systolic blood pressure (SBP), diastolic blood pressure (DBP), and parity between GDM and healthy subjects (P < 0.05). After adjusting for these factors, GLO1 rs1130534 TA remained associated with an increased risk of GDM (TA vs. TT + AA: OR = 1.320; 95% CI: 1.008-1.728; P = 0.044), especially in the pre-BMI ≥ 24 subgroup (TA vs. TT + AA: OR = 2.424; 95% CI: 1.048-5.607; P = 0.039), with fasting glucose levels being significantly elevated in the TA genotype compared to the TT genotype (P < 0.05). Conversely, the GLO1 rs4746 TG was associated with a decreased risk of GDM (TG vs. TT: OR = 0.740; 95% CI: 0.548-0.999; P = 0.049; TG vs. TT + GG: OR = 0.740; 95% CI: 0.548-0.998; P = 0.048). Additionally, the haplotype T-G-T of rs1781735, rs4746 and rs1130534 was associated with a decreased risk of GDM among individuals with a pre-BMI ≥ 24 (OR = 0.423; 95% CI: 0.188-0.955; P = 0.038). Furthermore, the rs1781735 GG genotype was found to be more closely related to maternal MG accumulation and neonatal weight gain (P < 0.05). Conclusion: Our findings suggested that GLO1 rs1130534 was associated with an increased susceptibility to GDM and higher blood glucose levels, but GLO1 rs4746 was associated with a decreased risk of GDM. The rs1781735 has been associated with the accumulation of maternal MG and subsequent weight gain in neonates.

Association of solute carrier family 30 A8 zinc transporter gene variations with gestational diabetes mellitus risk in a Chinese population.

Background: The solute carrier family 30 A8 zinc transporter (SLC30A8) plays a crucial role in insulin secretion. This study aimed to investigate the impact of SLC30A8 gene polymorphisms on gestational diabetes mellitus (GDM). Methods: The research objective was to select 500 patients with GDM and 502 control subjects. Rs13266634 and rs2466293 were genotyped using the SNPscan™ genotyping assay. Statistical tests, such as the chi-square test, t-test, logistic regression, ANOVA, and meta-analysis, were conducted to determine the differences in genotypes, alleles, and their associations with GDM risk. Results: Statistically significant differences were observed in age, pregestational BMI, SBP, DBP, and parity between individuals with GDM and healthy subjects (P < 0.05). After adjusting for these factors, rs2466293 remained significantly associated with an increased risk of GDM in overall subjects (GG+AG vs. AA: OR = 1.310; 95% CI: 1.005-1.707; P = 0.046, GG vs. AA: OR = 1.523; 95% CI: 1.010-2.298; P = 0.045 and G vs. A: OR = 1.249; 95% CI: 1.029-1.516; P = 0.024). Rs13266634 was still found to be significantly associated with a decreased risk of GDM in individuals aged ≥ 30 years (TT vs. CT+CC: OR = 0.615; 95% CI: 0.392-0.966; P = 0.035, TT vs. CC: OR = 0.503; 95% CI: 0.294-0.861; P = 0.012 and T vs. C: OR =0.723; 95% CI: 0.557-0.937; P = 0.014). Additionally, the haplotype CG was found to be associated with a higher risk of GDM (P < 0.05). Furthermore, pregnant women with the CC or CT genotype of rs13266634 exhibited significantly higher mean blood glucose levels than those with the TT genotype (P < 0.05). Our findings were further validated by the results of a meta-analysis. Conclusion: The SLC30A8 rs2466293 polymorphism was found to be associated with an increased risk of GDM, while rs13266634 was associated with a decreased risk of GDM in individuals aged ≥ 30 years. These findings provide a theoretical basis for GDM testing.

Association of miR-196a2 and miR-27a polymorphisms with gestational diabetes mellitus susceptibility in a Chinese population.

Introduction: MiR-196a2 and miR-27a play a key role in the regulation of the insulin signaling pathway. Previous studies have indicated that miR-27a rs895819 and miR-196a2 rs11614913 have a strong association with type 2 diabetes (T2DM), but very few studies have investigated their role in gestational diabetes mellitus (GDM). Methods: A total of 500 GDM patients and 502 control subjects were enrolled in this study. Using the SNPscan™ genotyping assay, rs11614913 and rs895819 were genotyped. In the data treatment process, the independent sample t test, logistic regression and chi-square test were used to evaluate the differences in genotype, allele, and haplotype distributions and their associations with GDM risk. One-way ANOVA was conducted to determine the differences in genotype and blood glucose level. Results: There were obvious differences in prepregnancy body mass index (pre-BMI), age, systolic blood pressure (SBP), diastolic blood pressure (DBP) and parity between GDM and healthy subjects (P < 0.05). After adjusting for the above factors, the miR-27a rs895819 C allele was still associated with an increased risk of GDM (C vs. T: OR=1.245; 95% CI: 1.011-1.533; P = 0.039) and the TT-CC genotype of rs11614913-rs895819 was related to an increased GDM risk (OR=3.989; 95% CI: 1.309-12.16; P = 0.015). In addition, the haplotype T-C had a positive interaction with GDM (OR=1.376; 95% CI: 1.075-1.790; P=0.018), especially in the 18.5 ≤ pre-BMI < 24 group (OR=1.403; 95% CI: 1.026-1.921; P=0.034). Moreover, the blood glucose level of the rs895819 CC genotype was significantly higher than that of the TT and TC genotypes (P < 0.05). The TT-CC genotype of rs11614913-rs895819 showed that the blood glucose level was significantly higher than that of the other genotypes. Discussion: Our findings suggest that miR-27a rs895819 is associated with increased GDM susceptibility and higher blood glucose levels.

Systematic analysis of prognostic and immunologic characteristics associated with coronavirus disease 2019 regulators in acute myeloid leukemia.

The coronavirus disease 2019 (COVID-19) pandemic has so far damaged the health of millions and has made the treatment of cancer patients more complicated, and so did acute myeloid leukemia (AML). The current problem is the lack of understanding of their interactions and suggestions of evidence-based guidelines or historical experience for the treatment of such patients. Here, we first identified the COVID-19-related differentially expressed genes (C-DEGs) in AML patients by analyzing RNA-seq from public databases and explored their enrichment pathways and candidate drugs. A total of 76 C-DEGs associated with the progress of AML and COVID-19 infection were ultimately identified, and the functional analysis suggested that there are some shared links between them. Their protein-protein interactions (PPIs) and protein-drug interactions were then recognized by multiple bioinformatics algorithms. Moreover, a COVID-19 gene-associated prognostic model (C-GPM) with riskScore was constructed, patients with a high riskScore had poor survival and apparently immune-activated phenotypes, such as stronger monocyte and neutrophil cell infiltrations and higher immunosuppressants targeting expressions, meaning which may be one of the common denominators between COVID-19 and AML and the reason what complicates the treatment of the latter. Among the study's drawbacks is that these results relied heavily on publicly available datasets rather than being clinically confirmed. Yet, these findings visualized those C-DEGs' enrichment pathways and inner associations, and the C-GPM based on them could accurately predict survival outcomes in AML patients, which will be helpful for further optimizing therapies for AML patients with COVID-19 infections.

Association of vitamin D receptor gene rs739837 polymorphism with type 2 diabetes and gestational diabetes mellitus susceptibility: a systematic review and meta-analysis.

BACKGROUND: Increasing evidence shows that genetic variants of genes in the diabetes mellitus (DM) metabolic pathway, such as the vitamin D receptor (VDR) gene rs739837 polymorphism, increase the risk of DM susceptibility. However, the findings have been inconsistent. The present study was performed to evaluate the association of VDR gene rs739837 and type 2 diabetes (T2DM) or gestational diabetes mellitus (GDM) risk. METHODS: A comprehensive meta-analysis and a subgroup analysis were conducted to assess the association between VDR rs739837 and T2DM or GDM among five genetic models (dominant, recessive, homozygote heterozygote, and allele models) using a fixed or random model. RESULTS: The meta-analysis included 9 studies. In the overall analysis, the results showed that VDR rs739837 was associated with an increased risk of T2DM or GDM in the allele model (T vs. G: OR = 1.088; 95% CI: 1.018-1.163; P = 0.012) and dominant model (TT + GT vs. GG: OR = 1.095; 95% CI: 1.001-1.197; P = 0.047). In the subgroup analysis, VDR rs739837 was also associated with an increased risk of T2DM in the allele model (T vs. G: OR = 1.159; 95% CI: 1.055-1.273; P = 0.002) and dominant model (TT + GT vs. GG: OR = 1.198; 95% CI: 1.048-1.370; P = 0.008). However, VDR rs739837 was not associated with GDM. CONCLUSIONS: Significant associations were found between the VDR rs739837 polymorphism and T2DM susceptibility, but not with GDM.

Diagnostic value of circRNAs as effective biomarkers in human cardiovascular disease: an updated meta-analysis.

Background: A growing body of literature has demonstrated that circular RNAs (circRNAs) are the potential biomarkers in human cardiovascular disease (CVD). Therefore, a meta-analysis based on current studies was accomplished to appraise the role of circRNAs in the diagnostic of CVD patients. Methods: Studies before October 30, 2021, were searched using PubMed, EMBASE, the Web of Science, and Cochrane Library. The diagnostic odds ratio (DOR) with a confidence interval (CI) of 95% was used to investigate the associations between circRNAs and CVDs. Results: A total of 27 eligible articles were selected, including 47 studies, with 6833 participants meeting the criteria standard constrain. The pooled overall sensitivity and specificity for circRNAs expression profile in differentiating CVD patients from controls (non-CVDs or healthy subjects) were 0.81 (95%CI 0.78-0.83) and 0.74 (95%CI 0.68-0.78), respectively; the overall positive likelihood ratio was 3.1 (95%CI 2.5-3.7); the negative likelihood ratio was 0.26 (95%CI 0.22-0.31); the overall diagnostic odds ratio corresponding to an area under the curve of 0.85 (95%CI 0.81-0.88) was 12 (95%CI 9-16). Subgroup analysis indicated that the serum rather than blood has higher diagnostic accuracy. Likewise, meta-regression analysis demonstrated that the specimen, detection method, sample size, and publication year were the main sources of heterogeneity. Sensitivity analysis and Deeks' funnel plot revealed that our results are relatively robust. Conclusions: Our evidence-based analysis results suggested that circRNAs provide higher diagnostic accuracy in the prediction of CVDs. Thus, circRNAs might be potential biomarkers in CVDs.

Association Between Insulin-like Growth Factor-1 rs35767 Polymorphism and Type 2 Diabetes Mellitus Susceptibility: A Meta-Analysis.

Background: Insulin-like growth factor-1 (IGF-1) has been demonstrated to increase fatty acid ß oxidation during fasting, and play an important role in regulating lipid metabolism and type 2 diabetes mellitus (T2DM). The rs35767 (T > C) polymorphism, a functional SNP was found in IGF-1 promoter, which may directly affect IGF-1 expression. However, the inconsistent findings showed on the IGF-1 rs35767 polymorphism and T2DM risk. Methods: We performed a comprehensive meta-analysis to estimate the association between the IGF-1 rs35767 and T2DM risk among four genetic models (the allele, additive, recessive and dominant models). Results: A total 49,587 T2DM cases and 97,906 NDM controls were included in the allele model, a total 2256 T2DM cases and 2228 NDM controls were included in the other three genetic models (the additive; recessive and dominant models). In overall analysis, the IGF-1 rs35767 was shown to be significantly associated with increased T2DM risk for the allele model (T vs. C: OR = 1.251, 95% CI: 1.082-1.447, p = 0.002), additive model (homozygote comparisons: TT vs. CC: OR = 2.433, 95% CI: 1.095-5.405, p = 0.029; heterozygote comparisons: TC vs. CC: OR = 1.623, 95% CI: 1.055-2.495, p = 0.027) and dominant model (TT + CT vs. CC: OR = 1.934, 95% CI: 1.148-3.257, p = 0.013) with random effects model. After omitting Gouda's study could reduce the heterogeneity, especially in the recessive model (TT vs. CC + CT: I2 = 38.7%, p = 0.163), the fixed effects model for recessive effect of the T allele (TT vs. CC + CT) produce results that were of borderline statistical significance (OR = 1.206, 95% CI: 1.004-1.448, p = 0.045). And increasing the risk of T2DM in Uyghur population of subgroup for the allele model. Conclusion: The initial analyses that included all studies showed statistically significant associations between the rs35767 SNP and type 2 diabetes, but after removing the Gouda et al. study produced results that were mostly not statistically significant. Therefore, there is not enough evidence from the results of the meta-analysis to indicate that the rs35767 SNP has a statistically significant association with type 2 diabetes.

Construction and validation of a metabolic gene-associated prognostic model for cervical carcinoma and the role on tumor microenvironment and immunity.

Metabolic reprogramming is a common feature of tumor cells and is associated with tumorigenesis and progression. In this study, a metabolic gene-associated prognostic model (MGPM) was constructed using multiple bioinformatics analysis methods in cervical carcinoma (CC) tissues from The Cancer Genome Atlas (TCGA) database, which comprised fifteen differentially expressed metabolic genes (DEMGs). Patients were divided into a high-risk group with shorter overall survival (OS) and a low-risk group with better survival. Receiver operating characteristic (ROC) curve analysis showed that the MGPM precisely predicted the 1-, 3- and 5-year survival of CC patients. As expected, MGPM exhibited a favorable prognostic significance in the training and testing datasets of TCGA. And the clinicopathological parameters including stage, tumor (T) and metastasis (M) classifications had significant differences in low- and high-risk groups, which further demonstrated the MGPM had a favorite prognostic prediction ability. Additionally, patients with low-ESTMATEScore had a shorter OS and when those combined with high-risk scores presented a worse prognosis. Through "CIBERSORT" package and Wilcoxon rank-sum test, patients in the high-risk group with a poor prognosis showed lower levels of infiltration of T cell CD8 (P < 0.001), T cells memory activated (P = 0.010) and mast cells resting (P < 0.001), and higher levels of mast cells activated (P < 0.001), and we also found these patients had a worse response for immunosuppressive therapy. These findings demonstrate that MGPM accurately predicts survival outcomes in CC patients, which will be helpful for further optimizing immunotherapies for cancer by reprogramming its cell metabolism.

Different Associations Between CDKAL1 Variants and Type 2 Diabetes Mellitus Susceptibility: A Meta-analysis.

Background: CDK5 regulatory subunit associated protein 1 like 1 (CDKAL1) is a major pathogenesis-related protein for type 2 diabetes mellitus (T2DM). Recently, some studies have investigated the association of CDKAL1 susceptibility variants, including rs4712523, rs4712524, and rs9460546 with T2DM. However, the results were inconsistent. This study aimed to evaluate the association of CDKAL1 variants and T2DM patients. Methods: A comprehensive meta-analysis was performed to assess the association between CDKAL1 SNPs and T2DM among dominant, recessive, additive, and allele models. Results: We investigated these three CDKAL1 variants to identify T2DM risk. Our findings were as follows: rs4712523 was associated with an increased risk of T2DM for the allele model (G vs A: OR = 1.172; 95% CI: 1.103-1.244; p < 0.001) and dominant model (GG + AG vs AA: OR = 1.464; 95% CI: 1.073-1.996; p = 0.016); rs4712524 was significantly associated with an increased risk of T2DM for the allele model (G vs A: OR = 1.146; 95% CI: 1.056-1.245; p = 0.001), additive model (GG vs AA: OR = 1.455; 95% CI: 1.265-1.673; p < 0.001) recessive model (GG vs AA + AG: OR = 1.343; 95% CI: 1.187-1.518; p < 0.001) and dominant model (GG + AG vs AA: OR = 1.221; 95% CI: 1.155-1.292; p < 0.001); and rs9460546 was associated with an increased risk of T2DM for the allele model (G vs T: OR = 1.215; 95% CI: 1.167-1.264; p = 0.023). The same results were found in the East Asian subgroup for the allele model. Conclusions: Our findings suggest that CDKAL1 polymorphisms (rs4712523, rs4712524, and rs9460546) are significantly associated with T2DM.

Positive Correlation Between LTA Expression and Overall Immune Activity Suggests an Increased Probability of Survival in Uterine Corpus Endometrial Carcinoma.

Mounting evidence indicates that immune status plays a crucial role in tumor progress and metastasis, while there are no effective and easily assayed biomarkers to reflect it in uterine corpus endometrial carcinoma (UCEC) patients. Here, we attempted to identify the potential biomarkers that were differentially expressed between normal and tumor tissues and involved in prognosis and immune microenvironment of UCEC patients. RNA-seq data with relevant clinical information were obtained from The Cancer Genome Atlas (TCGA). ssGSEA algorithm was applied to calculate the enrichment scores of every tumor infiltration lymphocyte (TIL) set in each sample, and patients were then divided into three clusters using multiple R packages. Cox analysis, ESTIMATE, and CIBERSORT were utilized to determine the differentially expressed immune-related genes (DEIGs) with overall survival, and to explore their roles in prognosis, immune microenvironment, and immunotherapeutic response. The TIMER and TISIDB databases were utilized to predict the effectiveness of immunotherapy in UCEC patients. LTA was finally identified to be significantly upregulated in tumor tissues and closely associated with prognosis and immunological status, which was then verified in GSE17025. In multivariate analysis, the hazard ratio of LTA was 0.42 with 95% CI (0.22-0.80) (p = 0.008). Patients with high LTA expression had better survival and apparently immune-activated phenotypes, such as more tumor mutation burden (TMB), stronger immune cell infiltrations, higher expression of immunosuppressive points, and higher immunophenoscore, meaning they had an immunotherapeutic advantage over those with low LTA expression. TIMER and TISIDB indicated that LTA was highly expressed in UCEC, and its expression was negatively correlated with stages and positively related to prognosis. Additionally, we found that LTA ectopic expression weakened the proliferation ability of RL95-2 cells. All these findings indicated that LTA could act as a novel and easily assayed biomarker to predict immunological status and clinical outcomes and even as an antioncogene to explore UCEC in depth.

Different Associations Between the IREB2 Variants and Chronic Obstructive Pulmonary Disease Susceptibility.

Background: Iron responsive element binding protein 2 (IREB2) variants may be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Recently, many studies have been performed on IREB2 susceptibility variants, including rs2568494, rs2656069, rs10851906, rs12593229, and rs13180, associated with COPD. However, inconsistent findings have been reported. The aim of our research was to determine the association of IREB2 SNPs with COPD. Methods: A comprehensive meta-analysis was performed to accurately estimate the association between IREB2 variants and COPD among four different genetic models. Results: This meta-analysis included a total of 4,096 patients and 5,870 controls. Here, we investigated the 5 IREB2 variants to identify COPD risk. Our results indicate that rs2568494 was associated with an increased risk of COPD for the dominant model (AA+GA vs. GG: OR = 1.150, 95% CI: 1.5-1.304, P = 0.029); rs2656069 was associated with a decreased risk of COPD for the recessive model (GG vs. AA+AG: OR = 0.589, 95% CI: 0.440-0.789; P = 0.000), additive model (GG vs. AA: OR =0.641, 95% CI: 0.441-0.931; P = 0.020), and allele model (G vs. A: OR = 0.812, 95% CI: 0.668-0.988; P = 0.037); and rs10851906 was associated with a decreased risk of COPD for the recessive model (GG vs. AA+AG: OR = 0.732, 95% CI: 0.560-0.958; P = 0.023) and additive model (GG vs. AA: OR = 0.777, 95% CI: 0.637-0.947; P = 0.012). Conclusion: Our findings suggest that the IREB2 rs2568494 minor alleles A may be a genetic factor in susceptibility to COPD. In addition, the minor alleles G of rs2656069 and rs10851906 appear to have a protective effect.

miR-137: A Novel Therapeutic Target for Human Glioma.

MicroRNA (miR)-137 is highly expressed in the brain and plays a crucial role in the development and prognosis of glioma. In this review, we aim to summarize the latest findings regarding miR-137 in glioma cell apoptosis, proliferation, migration, invasion, angiogenesis, drug resistance, and cancer treatment. In addition, we focus on the identified miR-137 targets and pathways in the occurrence and development of glioma. Finally, future implications for the diagnostic and therapeutic potential of miR-137 in glioma were discussed.

Inhibition of miR-186-5p contributes to high glucose-induced injury in AC16 cardiomyocytes.

A growing body of evidence has demonstrated that microRNAs (miRs) have pivotal roles in the pathophysiological development mechanisms of diabetic cardiomyopathy (DCM). Previous studies have demonstrated that miR-186-5p was significantly decreased in DCM. In addition, it has recently been reported that an imbalance of miR-186 is associated with a variety of physiological and pathological processes. Therefore, the present study was designed to investigate the role of miR-186-5p in high glucose (HG)-induced cytotoxicity and apoptosis in AC16 cardiomyocytes. Reverse transcription-polymerase chain reaction was used to demonstrate the significant decrease in the level of miR-186-5p in HG-treated AC16 cells (P<0.05). Subsequently, it was clarified that pre-transfection with miR-186-5p mimic significantly ameliorated the effects of high glucose, which induced a significant decrease in the viability of AC16 cells (P<0.05) and increases in apoptosis, as evidenced by the appearance of apoptotic nucleus and the significant upregulation of apoptosis rate in AC16 cells (P<0.05). In addition, the significantly increased expression of caspase-3 induced by HG (P<0.01) was also reversed by miR-186-5p mimic (P<0.01). Conversely, transfection with miR-186-5p inhibitor significantly reduced the viability of AC16 cells (P<0.05) and promoted apoptosis (P<0.05) as well as the expression of caspase-3 in AC16 cells (P<0.01), indicating the beneficial role of miR-186-5p in the physiological process of HG-induced damage. In conclusion, these results suggest that the distribution of miR-186-5p contributes to HG-induced cytotoxicity and apoptosis in AC16 cardiomyocytes.

Cysteinyl leukotriene receptor 1 regulates glucose-stimulated insulin secretion (GSIS).

Insulin resistance is an important pathological hallmark of type 2 diabetes mellitus. Glucose-stimulated insulin secretion (GSIS) plays a key role in maintaining blood glucose levels within normal range. Impaired GSIS has been associated with type 2 diabetes, however, the underlying molecular mechanisms remain largely unknown. Cysteinyl leukotriene receptor 1 (cysLT1R) is an important G protein-coupled receptor mediating the biological functions of cysteinyl leukotrienes (cys-LTs). Little is known about the effects of cysLT1R in insulin secretion and pathogenesis of T2DM. In the present study, we aimed to define the physiological functions of cysLT1R in GSIS in MIN6 ß-cells. Using reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis, we found that cysLT1R was expressed in pancreatic MIN6 ß-cells. We also reported that glucose increased the expression of cysLT1R in MIN6 cells. Additionally, the cysLT1R antagonist montelukast promoted GSIS in a dose dependent manner, however, the cysLT1R agonist LD4 inhibited GSIS, suggesting an antagonistic effect of cysLT1R on GSIS. Silencing of cysLT1R by transfection with cysLT1R siRNA enhanced GSIS while overexpression of cysLT1R reduced GSIS in pancreatic MIN6 ß-cells. Mechanistically, we found that the Arf6/Cdc42/Rac1 pathway was involved in this process. Collectively, our findings highlight the essential role of cysLT1R in suppressing pancreatic insulin secretion, and potentially provided a new insight into understanding the mechanical regulation of glucose homeostasis.

Long Noncoding RNA H19 Acts as a Competing Endogenous RNA to Mediate CTGF Expression by Sponging miR-455 in Cardiac Fibrosis.

Cardiac fibrosis is closely related to multiple cardiovascular system diseases, and noncoding RNAs (ncRNAs), including long noncoding RNA (lncRNA) and microRNA (miRNA), have been reported to play a vital role in fibrogenesis. The present study aims to investigate the potential regulatory mechanism of lncRNA H19 and miR-455 on fibrosis-associated protein synthesis in cardiac fibroblasts (CFs). miRNA microarray assay revealed 34 significantly dysregulated miRNAs, including 13 upregulated miRNAs and 21 downregulated miRNAs. Among these aberrantly expressed miRNAs, we paid attention to miR-455, which was significantly downregulated in diabetic mouse myocardium and Ang II-induced CFs. Loss- and gain-of-function experiments showed that miR-455 expression levels were negatively correlated with collagen I and III expression in Ang II-induced CFs. Bioinformatic prediction programs (TargetScan, miRanda, starBase) predicted that miR-455 targeted connective tissue growth factor (CTGF) and H19 with complementary binding sites at the 3'-untranslated region, which was validated by luciferase reporter assay. Functional validation assay demonstrated that H19 knockdown could enhance the antifibrotic role of miR-455 and attenuate the CTGF expression and further decrease fibrosis-associated protein synthesis (collagen I, III, and α-SMA). The present study reveals a novel function of the H19/miR-455 axis targeting CTGF in cardiac fibrosis, suggesting its potential therapeutic role in cardiac diseases.

New mechanism of lipotoxicity in diabetic cardiomyopathy: Deficiency of Endogenous H2S Production and ER stress.

OBJECTIVE: To investigate the roles and mechanisms of endogenous hydrogen sulfide (H2S) and endoplasmic reticulum (ER) stress in the development of diabetic cardiomyopathy (DCM). METHODS: Blood of DCM patients included in the study were collected. The model of DCM rats was established using streptozotocin (STZ) injection. Cardiac lipotoxicity in vitro models were established using 500µM palmitic acid (PA) treatment for 24h in AC16 cardiomyocytes. Endogenous H2S production in plasma, culture supernatant and heart was measured by sulphur ion-selective electrode assay. Cell viability was tested by using the cell counting kit-8 (CCK-8) kit. Glucose regulated protein (GRP78), CCAAT/enhancer binding protein homologous transcription factor (C/EBP) homologous protein (CHOP), caspase-3 and caspase-12 expressions were measured using western blot analysis. Lipid droplet was evaluated by Oil Red O staining. Apoptosis in hearts of DCM rats was analyzed using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. RESULTS: H2S levels in serum of DCM patients and DCM rats were significant lower, H2S contents and cystathionine-γ-lyase (CSE) expression in heart tissues of DCM rats were also markedly lower. H2S levels in supernatants of PA-treated AC16 cardiac cells were decreased. Cardiac lipotoxicity demonstrated by increase in TUNEL positive cells and lipid deposit in vivo and in vitro accompanied by a decrease of H2S levels. Pretreatment AC16 cells with 100µmol/L of NaHS (a donor of H2S) could suppress the PA-induced myocardial injury similar to the effects of 4-phenylbutyric acid (4-PBA, an endoplasmic reticulum (ER) stress inhibitor), leading to an increase in cell viability and preventing lipid deposit. Meanwhile, administration diabetic rats with NaHS or 4-PBA alleviated cardiac lipotoxicity, as evidenced by decrease in TUNEL positive cells, cleaved caspase-3 expression and lipid accumulation. CONCLUSION: Deficiency of endogenous H2S was involved in lipotoxicity-induced myocardial injury. Exogenous H2S attenuates PA-induced myocardial injury though inhibition of ER stress.