Identification of potential immunotherapeutic targets and prognostic biomarkers in Graves' disease using weighted gene co-expression network analysis.

Graves' disease (GD) is an autoimmune disorder characterized by hyperthyroidism resulting from autoantibody-induced stimulation of the thyroid gland. Despite recent advancements in understanding GD's pathogenesis, the molecular processes driving disease progression and treatment response remain poorly understood. In this study, we aimed to identify crucial immunogenic factors associated with GD prognosis and immunotherapeutic response. To achieve this, we implemented a comprehensive screening strategy that combined computational immunogenicity-potential scoring with multi-parametric cluster analysis to assess the immunomodulatory genes in GD-related subtypes involving stromal and immune cells. Utilizing weighted gene co-expression network analysis (WGCNA), we identified co-expressed gene modules linked to cellular senescence and immune infiltration in CD4+ and CD8+ GD samples. Additionally, gene set enrichment analysis enabled the identification of hallmark pathways distinguishing high- and low-immune subtypes. Our WGCNA analysis revealed 21 gene co-expression modules comprising 1,541 genes associated with immune infiltration components in various stages of GD, including T cells, M1 and M2 macrophages, NK cells, and Tregs. These genes primarily participated in T cell proliferation through purinergic signaling pathways, particularly neuroactive ligand-receptor interactions, and DNA binding transcription factor activity. Three genes, namely PRSS1, HCRTR1, and P2RY4, exhibited robustness in GD patients across multiple stages and were involved in immune cell infiltration during the late stage of GD (p < 0.05). Importantly, HCRTR1 and P2RY4 emerged as potential prognostic signatures for predicting overall survival in high-immunocore GD patients (p < 0.05). Overall, our study provides novel insights into the molecular mechanisms driving GD progression and highlights potential key immunogens for further investigation. These findings underscore the significance of immune infiltration-related cellular senescence in GD therapy and present promising targets for the development of new immunotherapeutic strategies.

Potential effects of biomaterials on macrophage function and their signalling pathways.

The use of biomaterials in biomedicine and healthcare has increased in recent years. Macrophages are the primary immune cells that induce inflammation and tissue repair after implantation of biomaterials. Given that macrophages exhibit high heterogeneity and plasticity, the influence of biomaterials on macrophage phenotype should be considered a crucial evaluation criterion during the development of novel biomaterials. This review provides a comprehensive summary of the physicochemical, biological, and dynamic characteristics of biomaterials that drive the regulation of immune responses in macrophages. The mechanisms involved in the interaction between macrophages and biomaterials, including endocytosis, receptors, signalling pathways, integrins, inflammasomes and long non-coding RNAs, are summarised in this review. In addition, research prospects of the interaction between macrophages and biomaterials are discussed. An in-depth understanding of mechanisms underlying the spatiotemporal changes in macrophage phenotype induced by biomaterials and their impact on macrophage polarization can facilitate the identification and development of novel biomaterials with superior performance. These biomaterials may be used for tissue repair and regeneration, vaccine or drug delivery and immunotherapy.

Comparison of twelve single-drug regimens for the treatment of type 2 diabetes mellitus.

We performed a network meta-analysis to compare the efficacy of 12 single-drug regimens (Glibenclamide, Glimepiride, Pioglitazone, Rosiglitazone, Repaglinide, Metformin, Sitaglitin, Exenatide, Liraglutide, Acarbose, Benfluorex, and Glipizide) in the treatment of type 2 diabetes mellitus (T2DM). Fifteen relevant randomized controlled trials (RCTs) were included; direct and indirect evidence from these studies was combined, and weighted mean difference (WMD) and surface under the cumulative ranking curves (SUCRAs) were examined to evaluate the monotherapies. Liraglutide was more effective than Glimepiride, Pioglitazone, Sitaglitin, Exenatide, and Glipizide at reducing glycated hemoglobin (HbA1c) levels. In contrast, Acarbose was less effective than Glibenclamide, Glimepiride, Pioglitazone, Rosiglitazone, Repaglinide, Metformin, and Liraglutide at decreasing HbA1c levels. Reductions in fasting plasma glucose (FPG) levels were similar after all treatments. Rosiglitazone was less effective than Glibenclamide and Repaglinide at reducing total cholesterol (TC) levels. High density lipoprotein (HDL), low density lipoprotein (LDL), and triglyceride levels did not differ after treatment with any of the monotherapies. HbA1c and FPG SUCRA values were highest for Liraglutide, while HbA1c and FPG values were lowest for Acarbose, and TC and LDL values were lowest for Rosiglitazone. These results suggest that Liraglutide may be most effective, and Acarbose least effective, at reducing blood glucose levels, while Glibenclamide, Repaglinide, and Metformin may be most effective, and Rosiglitazone least effective, at reducing lipoidemia, in T2DM patients.

Effect of simvastatin on the expression of farnesoid X receptor in diabetic animal models of altered glucose homeostasis.

BACKGROUND: Statin therapy has affected glucose homoeostasis of type 2 diabetes patients, which could be related with bile acids metabolism. Whether bile acid metabolism and the expression of farnesoid X receptor (FXR), liver X receptor-α (LXR-α) and sterol regulatory element-binding protein (Srebp)-1c is regulated by hyperglycemia, or whether simvastatin therapy led to higher glucose is related with down-regulated expression of FXR in diabetic rats remained unclear. METHODS: Forty male Wistar rats were randomly divided into four groups: normal control rats, insulin resistance rats, diabetic model rats, and the late simvastatin induced diabetic rats. Normal control rats were fed with standard diet, others were fed with high-fat diet. Diabetic model rats were induced by a single intraperitoneal injection of streptozotocin (STZ). The late simvastatin induced diabetic rats started simvastatin administration after STZ induced diabetic model rats. Characteristics of fasting blood glucose (FPG), lipid files and total bile acids (TBAs) were measured and the oral glucose tolerance test (OGTT) was performed after overnight fasting at the eighth weekend. RNA and protein levels of FXR, LXR-α and Srebp-1c were tested by Western blotting and reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The insulin resistance rats showed higher glucose, lipid files and lower expression of FXR compared with normal control rats (P > 0.05). The diabetic model rats showed significantly higher glucose, lipid files, TBA and lower expression of FXR compared with insulin resistance rats (P < 0.05). The late simvastatin induced diabetic rats displayed higher glucose and TBA and lower expression of FXR compared with diabetic model rats (P < 0.05). CONCLUSIONS: Changes in bile acid homeostasis, including the alterations of bile acid levels and bile acid receptors, are either a cause or a consequence of the metabolic disturbances observed during diabetic models. Statin therapy induced hyperglycemia may be related with FXR, SHP, LXR-α and Srebp-1 pathways.

Serum 25(OH)D is inversely associated with metabolic syndrome risk profile among urban middle-aged Chinese population.

BACKGROUND: Vitamin D deficiency is associated with a variety of chronic metabolic diseases. Limited evidence regarding vitamin D deficiency exists within the Chinese population. The present study aims to examine the association between serum vitamin D concentrations and cardiometabolic risk factors in the young and middle-aged, urban Chinese population METHODS: The cross-sectional relationships between serum 25-hydroxyvitamin D [25(OH)D] concentrations and indices of adiposity and cardiometabolic risk factors (e.g., body mass index, waist circumference, fasting plasma glucose, etc.) were evaluated in 601 non-diabetic adults. RESULT: Vitamin D deficiency or insufficiency was present in 66% of the tested population, and serum 25(OH)D levels were lower in patients who were overweight/obese or suffered metabolic syndrome when compared to individuals of healthy weight without metabolic syndrome (24.08 ± 8.08 vs 31.70 ± 11.77 ng/ml, 21.52 ± 6.9 vs 31.74 ± 10.21 ng/ml respectively). 25(OH)D was inversely associated with waist circumference, fasting glucose, fasting insulin, triglycerides and LDL-cholesterol, and it was positively associated with HDL-cholesterol in a multivariable-adjusted regression model. CONCLUSION: Vitamin D deficiency is common in the young and middle-aged, urban Chinese population, with high prevalence in overweight/obese individuals and patients with metabolic syndrome. Low vitamin D concentration was associated with indices of adiposity and cardiometabolic risk factors. Further studies are warranted to elucidate the cause-effect relation between vitamin D status, obesity and related metabolic disorders.