Background. GLP-1 receptor agonists (GLP-1RA) are common clinical agents that are clinically protective against diabetic complications, such as diabetic retinopathy (DR). Previous studies have shown that the RhoA/ROCK pathway plays an important role in the development of DR. However, the specific mechanism of action between GLP-1RA and DR remains unclear. The aim of this study was thus to investigate the main mechanism involved in the protective effect of GLP-1RA on DR. Methods. Type 2 diabetic mice were fed a high-sugar, high-fat diet. Changes in the retinal structure were observed via HE staining and transmission electron microscopy. The expression of retinal GLP-1R, blood-retinal barrier- (BRB-) related proteins, inflammatory factors, and related pathway proteins were studied via Western blot or immunohistochemistry/immunofluorescence analysis. Results. GLP-1RA treatment reduced the blood glucose and lipid levels as well as the body weight of the diabetic mice while also improving retinal thickness, morphology, and vascular ultrastructure. Moreover, restored GLP-1R expression, increased Occludin and ZO-1 levels, and decreased albumin expression led to reduced retinal leakage and improved the BRB by inhibiting the RhoA/ROCK pathway. Conclusions. We found that the protective effect of GLP-1RA on the retina may be realized through the GLP-1R-ROCK-p-MLC signaling pathway.

Objective: Thapsigargin (TG) is a natural product that exists in most parts of the plant Thapsia garganica L. and possesses potential anticancer activities against variety tumor cell lines. TG induces endoplasmic reticulum (ER) stress and apoptosis by inhibiting cancer growth. However, the antineoplastic effect of TG in human adrenocortical carcinoma (ACC) cells is still unknown. Methods: In this study, two human ACC cell lines including SW-13 and NCI-H295R were employed to explore the potential role of TG in ACC. A mouse xenograft model of SW-13 cells was established to verify the role of TG in vivo. The cell viability was tested using Cell Counting Kit-8 and Transwell assays. Flow cytometry and Hoechst 33,258 staining were employed to analyze cell apoptosis. RT-qPCR and Western blot (WB) were performed to explore the underlying mechanism of TG-induced apoptosis in ACC cells. Results: The results indicated that TG dose-dependently inhibited proliferation, migration and invasion in human ACC cells. TG significantly increased the mitochondrial rate of apoptosis and ER stress activity in ACC cells and suppressed ACC xenograft growth in vivo. In addition, the expression of Jun N-terminal kinase (JNK) signaling-related genes and proteins was upregulated by the treatment with TG. Conclusion: Our findings suggest that TG inhibits the viability of ACC cells by inducing apoptosis through the activation of JNK signaling. Thus, TG is expected to be a potential candidate for the treatment of ACC.

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus, marked by progressive renal damage. Recent evidence indicates that metabolic reprogramming is crucial to DN pathogenesis, yet its underlying mechanisms are not well understood. This study aimed to examine how metabolic reprogramming-related genes (MRRGs) are differentially expressed and to explore their potential mechanisms in the development of DN. We analyzed the datasets GSE30528 and GSE96804 from the Gene Expression Omnibus (GEO), comprising 50 DN samples and 33 controls. MRRGs were sourced from GeneCards and PubMed. Data preprocessing included batch effect correction using the R package sva, followed by normalization and differential expression analysis with limma (|logFC|> 0.5, adj.p < 0.05). Functional enrichment analyses (GO, KEGG, GSEA) were performed using clusterProfiler. Protein–protein interaction (PPI) networks were constructed via STRING, identifying hub genes through CytoHubba. Regulatory networks (mRNA-TF, mRNA-miRNA) were derived from ChIPBase and StarBase. Validation of hub genes and ROC analysis assessed diagnostic performance. ssGSEA quantified immune cell infiltration. Our analysis identified 708 differentially expressed genes (DEGs), including 119 metabolic reprogramming-related DEGs (MRRDEGs). Enrichment analyses revealed significant roles for MRRDEGs in processes such as wound healing and pathways like MAPK signaling. The PPI network identified nine hub genes: FN1, CD44, KDR, EGF, HSPG2, HGF, FGF9, IGF1, and ALB, which exhibited high diagnostic accuracy (AUC 0.7 to 0.9). Notably, FN1 and CD44 showed significant association with renal fibrosis and could serve as potential biomarkers for early diagnosis and therapeutic targets in DN. Immune infiltration analysis showed notable differences in immune cell composition between DN and control samples. This study identifies hub genes such as FN1 and CD44, with potential diagnostic value in DN. It also reveals immune cell infiltration differences between DN patients and controls, offering insights into disease progression and potential therapeutic targets.

Background: Not many large‐sample investigations are available that compare the potency of the relationship of remnant cholesterol (RC) and other lipid parameters with diabetes and prediabetes. The goals of our study are to discover the relationship between RC and prediabetes, diabetes, and insulin resistance (IR) and to investigate RC, high‐density lipoprotein cholesterol (HDL‐C), non‐HDL‐C, triglycerides (TG), low‐density lipoprotein cholesterol (LDL‐C), total cholesterol (TC), TC/HDL‐C, LDL‐C/HDL‐C, and TG/HDL‐C, which are the lipid parameters that are most positively related to diabetes, prediabetes, and IR.Methods: This research enrolled 36 684 subjects from China's eight provinces. We employed multiple logistic regression analysis for testing the relationship between lipid parameters and diabetes, prediabetes, and IR.Results: After adjusting for potential confounders, and comparing the results with other lipid parameters, the positive relationship between RC and diabetes (odds ratio [OR] 1.417, 95% confidence interval [CI]: 1.345–1.492), prediabetes (OR 1.555, 95% CI: 1.438–1.628), and IR (OR 1.488, 95% CI: 1.404–1.577) was highest. RC was still related to diabetes, prediabetes, and IR even when TG <2.3 mmol/L (diabetes: OR 1.256, 95% CI: 1.135–1.390; prediabetes: OR 1.503, 95% CI: 1.342–1.684; and IR: OR 1.278, 95% CI: 1.140–1.433), LDL‐C <2.6 mmol/L (diabetes: OR 1.306, 95% CI: 1.203–1.418; prediabetes: OR 1.597, 95% CI: 1.418–1.798; and IR: OR 1.552, 95% CI: 1.416–1.701), or HDL‐C ≥1 mmol/L (diabetes: OR 1.456, 95% CI: 1.366–1.550; prediabetes: OR 1.553, 95% CI: 1.421–1.697; and IR: OR 1.490, 95% CI: 1.389–1.598).Conclusion: RC is more positively related to diabetes, prediabetes, and IR than conventional lipids and lipid ratios in the general population, the relationships between RC and diabetes, prediabetes, and IR are stable, even if HDL‐C, LDL‐C, or TG are at appropriate levels. image

Background: Both subacute thyroiditis (SAT) and Graves’ disease (GD) can lead to thyrotoxicosis, but the methods to distinguish these two diseases are relatively complex. Therefore, it is necessary to find biomarkers which can quickly and efficiently identify the two kinds of thyrotoxicosis. Blood cell-derived indexes are widely used to evaluate systemic inflammation. We aimed to evaluate the diagnostic value of blood cell-derived indexes in SAT patients with thyrotoxicosis. Methods: Totally 139 SAT patients with thyrotoxicosis, 146 GD patients, and 100 euthyroid individuals were enrolled in the study. Complete blood cell (CBC) count, thyroid function, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR), systemic immune-inflammatory index (SII), systemic inflammation response index (SIRI), aggregate inflammation systemic index (AISI), and mean platelet volume to platelet ratio (MPR) were evaluated in all subjects. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the capacity of blood cell-derived indexes in differentiating SAT patients with thyrotoxicosis from GD patients. We also evaluated the association between blood cell-derived indexes and other laboratory indicators and clinical outcomes in SAT patients. Results: NLR, PLR, MLR, SII, SIRI, and AISI were significantly higher in the SAT group. MPR was significantly lower in the SAT group. A formula including NLR, PLR, MLR, SII, SIRI, AISI and MPR was developed. The combination formula with an optimal cutoff of 0.426 showed the better diagnostic value [area under the curve (AUC) =0.921; 95% confidence interval (CI): 0.891–0.950; P<0.001; sensitivity, 87.1%; specificity, 83.6%]. However, thyroid function, erythrocyte sedimentation rate (ESR), thyroid peroxidase antibodies (TPOAb), and blood cell-derived indexes, were not found to be significantly associated with hypothyroidism and recurrence. Conclusions: We developed a formula combining 7 blood cell-derived indexes. The combination formula could be a novel biomarker to distinguish SAT patients with thyrotoxicosis from GD patients. However, we did not find significant association between the blood cell-derived indexes and clinical outcomes in SAT patients.

Dyslipidaemia has always been regarded as the cornerstone of arteriosclerosis and is related to the pathogenesis of renal insufficiency. However, it is unclear which routinely available lipid parameter is related to urinary albumin to creatinine ratio (UACR). The purpose of this study was to examine the lipid abnormalities associated with UACR in the general population in China. The present study was nested in an ongoing Risk Evaluation of cAncers in Chinese diabetic Individuals: A lONgitudinal (REACTION) study, which was designed to demonstrate the association of abnormal glucose metabolism with the risk of cancer in the Chinese population. This cross-sectional study included 34, 569 subjects (11, 390 males and 23, 179 females) from 8 different regional community cohorts, with an average age of 57.9 years. The UACR data were divided into the < 25% group, the 25–49% group, the 50–74% group, and the ≥ 75% group according to the quartile division of the centre where the subjects visited. The lipid classes were defined according to the guidelines for the prevention and treatment of dyslipidaemia in Chinese adults. Multiple logistic regression analysis was used to evaluate the association of the lipid parameters and UACR. Multivariable regression analysis revealed that compared with the other lipid parameters, triglycerides (TG) showed an adjusted odds ratio that was significant in model 1–4. This relationship was attenuated after adjusting for Haemoglobin A1c (HbA1c) and blood pressure (BP), but TG ≥ 2.3 mmol/L was still significantly associated with UACR in total subjects and in both men and women (OR: 1.131, 95% CI 1.065–1.203, P < 0.001 in total subjects; OR: 1.134, 95% CI 1.022–1.258, P = 0.017 in men; OR: 1.129, 95% CI 1.046–1.219, P = 0.002 in women). In the stratified analysis, elevated TG was significantly associated with increased urinary albumin in subjects with eGFR ≥ 90 mL/min per 1.73 m2, 5.6 ≤ FBG < 7.0 or 7.8 ≤ PBG < 11.1 mmol/L, 24 ≤ BMI < 28 kg/m2, 120 ≤ SBP < 140 and/or 80 ≤ DBP < 90 mmHg. We conclude that high TG levels rather than total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or non-high-density lipoprotein cholesterol levels are associated with UACR in the general population in China.