Valtrate Suppresses TNFSF14-Mediated Arrhythmia After Myocardial Ischemia-Reperfusion by Inducing N-linked Glycosylation of LTßR to Regulate MGA/MAX/c-Myc/Cx43.

ABSTRACT: Myocardial ischemia-reperfusion (MIR)-induced arrhythmia remains a major cause of death in patients with cardiovascular diseases. The reduction of Cx43 has been known as a major inducer of arrhythmias after MIR, but the reason for the reduction of Cx43 remains largely unknown. The aim of this study was to find the key mechanism underlying the reduction of Cx43 after MIR and to screen out an herbal extract to attenuate arrhythmia after MIR. The differentially expressed genes in the peripheral blood mononuclear cell (PBMCs) after MIR were analyzed using the data from several gene expression omnibus data sets, followed by the identification in PBMCs and the serum of patients with myocardial infarction. Tumor necrosis factor superfamily protein 14 (TNFSF14) was increased in PBMCs and the serum of patients, which might be associated with the injury after MIR. The toxic effects of TNFSF14 on cardiomyocytes were investigated in vitro . Valtrate was screened out from several herbal extracts. Its protection against TNFSF14-induced injury was evaluated in cardiomyocytes and animal models with MIR. Recombinant TNFSF14 protein not only suppressed the viability of cardiomyocytes but also decreased Cx43 by stimulating the receptor LTßR. LTßR induces the competitive binding of MAX to MGA rather than the transcriptional factor c-Myc, thereby suppressing c-Myc-mediated transcription of Cx43. Valtrate promoted the N-linked glycosylation modification of LTßR, which reversed TNFSF14-induced reduction of Cx43 and attenuated arrhythmia after MIR. In all, valtrate suppresses TNFSF14-induced reduction of Cx43, thereby attenuating arrhythmia after MIR.

Association between basal metabolic rate and cardio-metabolic risk factors: Evidence from a Mendelian Randomization study.

Background: Cardio-metabolic risk factors play a crucial role in the development of cardiovascular and metabolic diseases. Basal metabolic rate (BMR) is a fundamental physiological parameter that affects energy expenditure and might contribute to variations in these risk factors. However, the exact relationship between BMR and cardio-metabolic risk factors has remained unclear. Methods: We employed Mendelian Randomization (MR) analysis to explore the association between BMR (N: 534,045) and various cardio-metabolic risk factors, including body mass index (BMI, N: 681,275), fasting glucose (N: 200,622), high-density lipoprotein (HDL) cholesterol (N = 403,943), low-density lipoprotein (LDL) cholesterol (N = 431,167), total cholesterol (N: 344,278), and triglycerides (N: 441,016), C-reactive protein (N: 436,939), waist circumference (N: 232,101), systolic blood pressure (N: 810,865), diastolic blood pressure (N: 810,865), glycated haemoglobin (N: 389,889), and N-terminal prohormone brain natriuretic peptide (N: 21,758). We leveraged genetic variants strongly associated with BMR as instrumental variables to investigate potential causal relationships, with the primary analysis using the Inverse Variance Weighted (IVW) method. Results: Our MR analysis revealed compelling evidence of a causal link between BMR and specific cardio-metabolic risk factors. Specifically, genetically determined higher BMR was associated with an increased BMI (ß = 0.7538, 95% confidence interval [CI]: 0.6418 to 0.8659, p < 0.001), lower levels of HDL cholesterol (ß = -0.3293, 95% CI: 0.4474 to -0.2111, p < 0.001), higher levels of triglycerides (ß = 0.1472, 95% CI: 0.0370 to 0.2574, p = 0.0088), waist circumference (ß = 0.4416, 95% CI: 0.2949 to 0.5883, p < 0.001), and glycated haemoglobin (ß = 0.1037, 95% CI: 0.0080 to 0.1995, p = 0.0377). However, we did not observe any significant association between BMR and fasting glucose, LDL cholesterol, total cholesterol, C-reactive protein, systolic blood pressure, diastolic blood pressure, or N-terminal prohormone brain natriuretic peptide (all p-values>0.05). Conclusion: This MR study provides valuable insights into the relationship between BMR and cardio-metabolic risk factors. Understanding the causal links between BMR and these factors could have important implications for the development of targeted interventions and therapies.

Single-cell insights: pioneering an integrated atlas of chromatin accessibility and transcriptomic landscapes in diabetic cardiomyopathy.

BACKGROUND: Diabetic cardiomyopathy (DCM) poses a growing health threat, elevating heart failure risk in diabetic individuals. Understanding DCM is crucial, with fibroblasts and endothelial cells playing pivotal roles in driving myocardial fibrosis and contributing to cardiac dysfunction. Advances in Multimodal single-cell profiling, such as scRNA-seq and scATAC-seq, provide deeper insights into DCM's unique cell states and molecular landscape for targeted therapeutic interventions. METHODS: Single-cell RNA and ATAC data from 10x Multiome libraries were processed using Cell Ranger ARC v2.0.1. Gene expression and ATAC data underwent Seurat and Signac filtration. Differential gene expression and accessible chromatin regions were identified. Transcription factor activity was estimated with chromVAR, and Cis-coaccessibility networks were calculated using Cicero. Coaccessibility connections were compared to the GeneHancer database. Gene Ontology analysis, biological process scoring, cell-cell communication analysis, and gene-motif correlation was performed to reveal intricate molecular changes. Immunofluorescent staining utilized various antibodies on paraffin-embedded tissues to verify the findings. RESULTS: This study integrated scRNA-seq and scATAC-seq data obtained from hearts of WT and DCM mice, elucidating molecular changes at the single-cell level throughout the diabetic cardiomyopathy progression. Robust and accurate clustering analysis of the integrated data revealed altered cell proportions, showcasing decreased endothelial cells and macrophages, coupled with increased fibroblasts and myocardial cells in the DCM group, indicating enhanced fibrosis and endothelial damage. Chromatin accessibility analysis unveiled unique patterns in cell types, with heightened transcriptional activity in myocardial cells. Subpopulation analysis highlighted distinct changes in cardiomyocytes and fibroblasts, emphasizing pathways related to fatty acid metabolism and cardiac contraction. Fibroblast-centered communication analysis identified interactions with endothelial cells, implicating VEGF receptors. Endothelial cell subpopulations exhibited altered gene expressions, emphasizing contraction and growth-related pathways. Candidate regulators, including Tcf21, Arnt, Stat5a, and Stat5b, were identified, suggesting their pivotal roles in DCM development. Immunofluorescence staining validated marker genes of cell subpopulations, confirming PDK4, PPARγ and Tpm1 as markers for metabolic pattern-altered cardiomyocytes, activated fibroblasts and endothelial cells with compromised proliferation. CONCLUSION: Our integrated scRNA-seq and scATAC-seq analysis unveils intricate cell states and molecular alterations in diabetic cardiomyopathy. Identified cell type-specific changes, transcription factors, and marker genes offer valuable insights. The study sheds light on potential therapeutic targets for DCM.

Plasma metabolites and risk of myocardial infarction: a bidirectional Mendelian randomization study.

BACKGROUND: Myocardial infarction (MI) is a critical cardiovascular event with multifaceted etiology, involving several genetic and environmental factors. It is essential to understand the function of plasma metabolites in the development of MI and unravel its complex pathogenesis. METHODS: This study employed a bidirectional Mendelian randomization (MR) approach to investigate the causal relationships between plasma metabolites and MI risk. We used genetic instruments as proxies for plasma metabolites and MI and conducted MR analyses in both directions to assess the impact of metabolites on MI risk and vice versa. In addition, the large-scale genome-wide association studies datasets was used to identify genetic variants associated with plasma metabolite (1400 metabolites) and MI (20,917 individuals with MI and 440,906 individuals without MI) susceptibility. Inverse variance weighted was the primary method for estimating causal effects. MR estimates are expressed as beta coefficients or odds ratio (OR) with 95% CI. RESULTS: We identified 14 plasma metabolites associated with the occurrence of MI (P < 0.05), among which 8 plasma metabolites [propionylglycine levels (OR = 0.922, 95% CI: 0.881-0.965, P < 0.001), gamma-glutamylglycine levels (OR = 0.903, 95% CI: 0.861-0.948, P < 0.001), hexadecanedioate (C16-DC) levels (OR = 0.941, 95% CI: 0.911-0.973, P < 0.001), pentose acid levels (OR = 0.923, 95% CI: 0.877-0.972, P = 0.002), X-24546 levels (OR = 0.936, 95% CI: 0.902-0.971, P < 0.001), glycine levels (OR = 0.936, 95% CI: 0.909-0.964, P < 0.001), glycine to serine ratio (OR = 0.930, 95% CI: 0.888-0.974, P = 0.002), and mannose to trans-4-hydroxyproline ratio (OR = 0.912, 95% CI: 0.869-0.958, P < 0.001)] were correlated with a decreased risk of MI, whereas the remaining 6 plasma metabolites [1-palmitoyl-2-arachidonoyl-GPE (16:0/20:4) levels (OR = 1.051, 95% CI: 1.018-1.084, P = 0.002), behenoyl dihydrosphingomyelin (d18:0/22:0) levels (OR = 1.076, 95% CI: 1.027-1.128, P = 0.002), 1-stearoyl-2-docosahexaenoyl-GPE (18:0/22:6) levels (OR = 1.067, 95% CI: 1.027-1.109, P = 0.001), alpha-ketobutyrate levels (OR = 1.108, 95% CI: 1.041-1.180, P = 0.001), 5-acetylamino-6-formylamino-3-methyluracil levels (OR = 1.047, 95% CI: 1.019-1.076, P < 0.001), and N-acetylputrescine to (N (1) + N (8))-acetylspermidine ratio (OR = 1.045, 95% CI: 1.018-1.073, P < 0.001)] were associated with an increased risk of MI. Furthermore, we also observed that the mentioned relationships were unaffected by horizontal pleiotropy (P > 0.05). On the contrary, MI did not lead to significant alterations in the levels of the aforementioned 14 plasma metabolites (P > 0.05 for each comparison). CONCLUSIONS: Our bidirectional MR study identified 14 plasma metabolites associated with the occurrence of MI, among which 13 plasma metabolites have not been reported previously. These findings provide valuable insights for the early diagnosis of MI and potential therapeutic targets.

Systolic blood pressure is associated with abnormal alterations in brain cortical structure: Evidence from a Mendelian randomization study.

BACKGROUND: Hypertension has been recognized as a significant risk factor for cerebrovascular diseases and cognitive decline. However, the specific impact of hypertension, systolic/diastolic blood pressure, pulse pressure (PP) and mean arterial pressure (MAP) on brain cortical structure remains unclear. Mendelian randomization (MR) provides a robust approach to investigate the causal relationship between blood pressure components and brain cortical changes. METHODS: In this MR study, data from large-scale genome-wide association studies for blood pressure components and neuroimaging were utilized to conduct our analyses. We leveraged genetic variants associated specifically with hypertension (122,620 cases and 332,683 controls), systolic (469,767 individuals), diastolic (490,469 individuals) blood pressure, PP (810,865 individuals) and MAP (over 1 million individuals) to evaluate their effects on brain cortex surficial area (51,665 individuals) and cortex thickness (51,665 individuals). RESULTS: Our findings revealed a significant correlation between systolic blood pressure and abnormal reduction in brain cortex surficial area (ß=-1330.69, 95% confident interval [CI]: -2655.35 to -6.02, p = 0.0489); however, no significant relationship was found between systolic blood pressure and brain cortex thickness (ß=-0.0078, 95% CI: -0.0178 to 0.0022, p = 0.1287). Additionally, no significant associations were observed between hypertension (ß=-200.05, p = 0.6884; ß=-0.0051, p = 0.1179, respectively), diastolic blood pressure (ß=-460.63, p = 0.5160; ß=0.0047, p = 0.2448, respectively), PP (ß=1041.84, p = 0.3725; ß=-0.0112, p = 0.2212, respectively), MAP (ß=-18.84, p = 0.8841; ß=0.0002, p = 0.7654, respectively) and both brain cortex surficial area and brain cortex thickness. CONCLUSION: Our MR study provides evidence supporting the hypothesis that systolic blood pressure, rather than diastolic blood pressure, PP or MAP, is associated with abnormal changes in brain cortical structure.

Causal association between serum 25-hydroxyvitamin D levels and right ventricular structure and function: A Mendelian randomization study.

BACKGROUND AND AIM: Deficient concentrations of vitamin D have been linked to several cardiovascular conditions, but the causal relationship between serum 25-hydroxyvitamin D (25(OH)D) levels and right ventricular structure and function remains unclear. Mendelian randomization (MR) was employed to inspect this association. METHODS AND RESULTS: Genetic instrumental variables associated with 25(OH)D levels were acquired from genome-wide association studies (GWAS) analyses. Summary statistics for right ventricular structure and function, including right ventricular end diastolic volume, right ventricular end systolic volume, right ventricular stroke volume, and right ventricular ejection fraction, were acquired from publicly available GWAS datasets. For the primary analysis, the inverse variance weighted (IVW) method was utilized in performing the MR analysis. Additionally, secondly analyses were conducted to estimate the robustness and consistency of the attained conclusions. The MR analysis did not reveal a considerable causal association between serum 25(OH)D levels and right ventricular end diastolic volume (ß: 0.112, 95% confident interval [CI]: -0.006 to 0.230, p = 0.063), right ventricular end systolic volume (ß: 0.102, 95% CI: -0.021 to 0.226, p = 0.105), right ventricular stroke volume (ß: 0.095, 95% CI: -0.018 to 0.207, p = 0.099), or right ventricular ejection fraction (ß: -0.005, 95% CI: -0.123 to 0.112, p = 0.928). CONCLUSIONS: Our findings did not reveal any substantial evidence supporting a causal relationship between serum 25(OH)D levels and the structure and function of the right ventricle. These findings suggest that serum 25(OH)D levels may not directly influence right ventricular parameters assessed.

lncRNA SNHG15 Promotes Ovarian Cancer Progression through Regulated CDK6 via Sponging miR-370-3p.

Ovarian cancer is a kind of cancer from the female genital tract; the molecular mechanism still needs to be explored. lncRNA plays a vital role in tumorigenesis and development. Our aim was to identify oncogenic lncRNAs in ovarian cancer and explore the potential molecular mechanism. SNHG15 was initially identified by using GEO datasets (GSE135886 and GSE119054) and validated by tumor tissues and the cell line, identifying that SNHG15 was upregulated in ovarian cancer. Besides, high SNHG15 indicated poor prognosis in ovarian cancer. Furthermore, knockdown SNHG15 suppresses ovarian cancer proliferation and promotes apoptosis. Mechanistically, SNHG15 promotes proliferation through upregulated CDK6 via sponging miR-370-3p. Taken together, our findings emphasize the important role of SNHG15 in ovarian cancer, suggesting that SNHG15 may be a promising target for ovarian cancer.

[Extrapulmonary small cell carcinoma in 52 patients].

BACKGROUND & OBJECTIVE: The majority of small cell carcinoma occurs in the lung. Extrapulmonary small cell carcinoma (ESCC) has been recognized as a clinicopathologic entity distinct from small cell carcinoma of the lung. The study was to investigate the clinical characteristics, therapy, and prognosis of ESCC. METHODS: The medical records, from Jan. 1985 to Dec. 2005, of 53 patients with pathologically proved ESCC were analyzed retrospectively. RESULTS: Of the 53 patients, 39 were men and 14 were women, with the median age of 53 years (range, 27-76 years). Of the 53 cases of ESCC, 33 (62.3%) were detected in the esophagus, 5 in the cervix, 4 in the larynx, 3 in the pharynx, 2 in the upper sinus, 2 in the rectum and sublingual gland, 1 in the thyroid gland, 1 in the pleura, and 1 in the liver. Forty patients (75.5%) had limited disease (LD) and 13 (24.5%) had extensive disease (ED). Patients with ED mostly received platinum-based chemotherapy, for which the response rate was 69.2%. Patients with LD were treated with a variety of therapeutic modalities: 7 were treated with surgery plus radiochemotherapy, 3 with surgery plus radiotherapy, 18 with surgery plus chemotherapy, 6 with radiotherapy plus chemotherapy, 4 with radiotherapy alone, and 2 with chemotherapy alone. The median survival time (MST) was 20 months for all patients, and the 1-and 3-year survival rates were 41.3% and 31.4%. MST for patients with ED and LD were 15 months and 26 months, respectively, and 1-and 3-year survival rates were 51.1% vs. 14.4%, and 42.5% vs. 0% (P=0.017 ). CONCLUSIONS: ESCC is identified in various sites, with the most common primary site being the esophagus. Multimodality therapy has become increasingly used for the majority of patients with LD-ESCC. Combination chemotherapy has been a major treatment for patients with ED-ESCC. Generally, the prognosis of LD-ESCC is significantly superior to ED-ESCC.