A phenome-wide association study (PheWAS) to identify the health impacts of 4-cresol sulfate in the Nagahama Study.

Gut-microbiota derived metabolites are important regulators of host biology and metabolism. To understand the impacts of the microbial metabolite 4-cresol sulfate (4-CS) on four chronic diseases [type 2 diabetes mellitus, metabolic syndrome (MetS), non-alcoholic fatty liver disease, and chronic kidney disease (CKD)], we conducted association analyses of plasma 4-CS quantified by liquid chromatography coupled to mass spectrometry (LC-MS) in 3641 participants of the Nagahama study. Our results validated the elevation of 4-CS in CKD and identified a reducing trend in MetS. To delineate the holistic effects of 4-CS, we performed a phenome-wide association analysis (PheWAS) with 937 intermediate biological and behavioral traits. We detected associations between 4-CS and 39 phenotypes related to blood pressure regulation, hepatic and renal functions, hematology, sleep quality, intraocular pressure, ion regulation, ketone and fatty acid metabolisms, disease history and dietary habits. Among them, 19 PheWAS significant traits, including fatty acids and 14 blood pressure indices, were correlated with MetS, suggesting that 4-CS is a potential biomarker for MetS. Consistent associations of this gut microbial-derived metabolite on multiple endophenotypes underlying distinct etiopathogenesis support its role in the overall host health, with prospects of probiotic-based therapeutic solutions in chronic diseases.

Metabonomic Characteristics of Myocardial Diastolic Dysfunction in Type 2 Diabetic Cardiomyopathy Patients.

Diabetic cardiomyopathy (DCM) is one of the most essential cardiovascular complications in diabetic patients associated with glucose and lipid metabolism disorder, fibrosis, oxidative stress, and inflammation in cardiomyocytes. Despite increasing research on the molecular pathogenesis of DCM, it is still unclear whether metabolic pathways and alterations are probably involved in the development of DCM. This study aims to characterize the metabolites of DCM and to identify the relationship between metabolites and their biological processes or biological states through untargeted metabolic profiling. UPLC-MS/MS was applied to profile plasma metabolites from 78 patients with diabetes (39 diabetes with DCM and 39 diabetes without DCM as controls). A total of 2,806 biochemical were detected. Compared to those of DM patients, 78 differential metabolites in the positive-ion mode were identified in DCM patients, including 33 up-regulated and 45 down-regulated metabolites; however, there were only six differential metabolites identified in the negative mode including four up-regulated and two down-regulated metabolites. Alterations of several serum metabolites, including lipids and lipid-like molecules, organic acids and derivatives, organic oxygen compounds, benzenoids, phenylpropanoids and polyketides, and organoheterocyclic compounds, were associated with the development of DCM. KEGG enrichment analysis showed that there were three signaling pathways (metabolic pathways, porphyrin, chlorophyll metabolism, and lysine degradation) that were changed in both negative- and positive-ion modes. Our results demonstrated that differential metabolites and lipids have specific effects on DCM. These results expanded our understanding of the metabolic characteristics of DCM and may provide a clue in the future investigation of reducing the incidence of DCM. Furthermore, the metabolites identified here may provide clues for clinical management and the development of effective drugs.

mGWAS-Explorer: Linking SNPs, Genes, Metabolites, and Diseases for Functional Insights.

Tens of thousands of single-nucleotide polymorphisms (SNPs) have been identified to be significantly associated with metabolite abundance in over 65 genome-wide association studies with metabolomics (mGWAS) to date. Obtaining mechanistic or functional insights from these associations for translational applications has become a key research area in the mGWAS community. Here, we introduce mGWAS-Explorer, a user-friendly web-based platform to help connect SNPs, metabolites, genes, and their known disease associations via powerful network visual analytics. The application of the mGWAS-Explorer was demonstrated using a COVID-19 and a type 2 diabetes case studies.

Integrin ß4 promotes invasion and anoikis resistance of papillary thyroid carcinoma and is consistently overexpressed in lymphovascular tumor thrombus.

Although the majority of papillary thyroid cancers (PTC) are indolent, a subset of PTCs behaves aggressively due to extensive invasion and distant metastasis. Integrin ß4, a member of the integrin family, has been shown to enhance the progression in some malignancies; however, its role in PTC remains unclear. Here, we demonstrated that ß4 overexpression was associated with extrathyroid extension, lymph node metastasis, high TNM stage, and poor overall survival based on The Cancer Genome Atlas cohort. Immunohistochemistry showed that ß4 expression was significantly upregulated in the tumors with infiltrating growth pattern, as well as those with positive lymphovascular invasion. Moreover, ß4 was invariably overexpressed in the lymphovascular tumor thrombi, which has not been reported before. After shRNA-induced knockdown of ß4 in vitro, the migration, invasion and scratch repair ability of the tumor cells were significantly reduced. Furthermore, ß4 reduction decreased anchorage-independent growth and increased anoikis. The bioinformatics analysis revealed that approximately 70 pathways were significantly dysregulated in the high ß4 expression group. The MAPK pathway and propanoate metabolism were located in the network center of those pathways. Taken together, our results suggest that ß4 could promote the tumor's aggressiveness by enhancing invasion and antagonizing anoikis. The upregulated expression of ß4 in the tumor thrombi is intrinsically linked to its role in strengthening the anoikis resistance.

An in-depth analysis of glycosylated haemoglobin level, body mass index and left ventricular diastolic dysfunction in patients with type 2 diabetes.

BACKGROUND: Glycosylated hemoglobin (HbA1c) has a detrimental impact on the myocardium with left ventricular (LV) diastolic dysfunction. Obesity is a risk factor of type 2 diabetes. To understand the relationships between HbA1c, body mass index (BMI) and LV diastolic dysfunction, we performed this interaction analysis in patients with type 2 diabetes. METHODS: Total 925 type 2 diabetes patients were selected from the patients who were diagnosed and treated at the First Affiliated Hospital of Shenzhen University. Patients' BMI levels were defined as normal (BMI < 24 kg/m2) and overweight /obese (BMI ≥ 24 kg/m2). Patients' HbA1c levels were grouped as HbA1c ≥ 9%、7% ≤ HbA1c < 9% and HbA1c < 7%. Logistic regression, stratified, interaction analysis, multivariate Cox regression and curve fitting analysis were performed to investigate the correlations and interactions between HbA1c and BMI with LV diastolic dysfunction. RESULTS: The BMI levels were significantly associated with LV diastolic dysfunction in the patients with type 2 diabetes [adjusted model: 1.12 (1.05, 1.20), P = 0.001]. While HbA1c levels had association with LV diastolic dysfunction only in normal BMI group patients [adjusted model: 1.14 (1.01, 1.30), P = 0.0394] and curve correlation was observed. There was a significant interaction between BMI and HbA1c to affect LV diastolic dysfunction (P = 0.0335). Cox regression model analysis showed that the risk of LV diastolic dysfunction was a U type correlation with HbA1c levels in the normal weight group and the turning point was HbA1c at 10%. HbA1c level was not found to have a significant association with LV diastolic dysfunction in overweight/obese group. CONCLUSIONS: In patients with type 2 diabetes, correlation between LV diastolic dysfunction and HbA1c was interactively affected by BMI. Glycemic control is beneficial to the heart function in normal body weight patients. For overweight/obese patients, the risk of LV diastolic dysfunction was not determined by the HbA1c level, indicating it may be affected by other confounding factors.

[Evaluation of insulin secretion and insulin resistance by hyperglycemic clamp in Graves disease patients with impaired glucose tolerance].

OBJECTIVE: To investigate the state of insulin secretion and insulin resistance in patients of Graves disease (GD) with impaired glucose tolerance (IGT) by hyperglycemic clamp. METHODS: Six cases of Graves disease with IGT were selected as GD + IGT group and ten healthy volunteers as normal control group (NC group). All the subjects were required to fast for 12 hours and then underwent hyperglycemic clamp to assay insulin secretion and insulin sensitivity. Glutamic acid decarboxylase antibody (GAD-A) was tested in all the subjects. RESULTS: Insulin secretion in GD + IGT group was significantly higher than that in NC group. The 1st phase insulin secretion (1PH) was (636.31 +/- 105.54) mIU/L vs (233.56 +/- 21.33) mIU/L, P = 0.001. The 2nd phase insulin secretion (2PH) was (146.68 +/- 25.00) mIU/L vs (67.06 +/- 6.23) mIU/L, P = 0.03. The maximal insulin secretion during 120 - 150 minutes (Ins(120 - 150)) was (195.05 +/- 32.94) mIU/L vs (87.64 +/- 9.78) mIU/L, P = 0.04. The hyperglycemic clamp insulin sensitivity index (average glucose metabolic rate during 120 - 150 minutes/Ins(120 - 150)) was significantly lower in GD + IGT group than that in NC group (11.52 +/- 1.90 vs 21.72 +/- 3.25, P = 0.04). GAD-A was negative in all subjects. CONCLUSION: Cases of GD with IGT show significant insulin resistance with compensated elevated insulin secretion.