Dong Zhao

Background: Diabetic cardiomyopathy (DCM) is the main cause of heart failure in diabetes patients with no effective therapies currently available. A deeper understanding of the mechanisms underlying DCM is essential for identifying novel therapeutic targets.Methods: DCM model was established in C57BL/6J mice by administering multiple low-dose intraperitoneal injections of streptozotocin (STZ) in combination with a high-fat diet (HFD). Proteomic profiling was conducted on cardiac tissues from control and DCM mice to identify differentially expressed proteins. The expression of β-hydroxybutyrate dehydrogenase 1 (BDH1, also known as 3-hydroxybutyrate dehydrogenase) in cardiac tissues and cardiomyocyte were determined by immunoblot and quantitative polymerase chain reaction. The function and mechanism of BDH1 in DCM were investigated using a cardiac-specific BDH1-overexpressing mouse model, combined with cardiomyocyte cell lines with either BDH1 overexpression or knockdown.Results: BDH1 was markedly downregulated in cardiac tissues of DCM mice, as well as in cardiomyocytes treated with high glucose and palmitic acid (HGPA). Cardiac-specific overexpression of BDH1 markedly improved cardiac dysfunction and myocardial fibrosis in DCM mice. In vitro, BDH1 overexpression attenuated mitochondrial damage and inhibited apoptosis in cardiomyocytes induced by HGPA. Conversely, BDH1 knockdown exacerbated these pathological changes under HGPA conditions. Transcriptome analysis linked BDH1 expression to the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) pathway, and we confirmed that BDH1 overexpression reversed diabetes-induced inhibition of the AKT/glycogen synthase kinase 3β (GSK3β) pathway. The protective effects of BDH1 on mitochondrial function and cardiomyocytes apoptosis were abolished following treatment with AKT inhibitor (AKTi). Cardiac-specific overexpression of BDH1 markedly decreased β-hydroxybutyric acid (BHB, the predominant ketone body) levels in cardiac tissues of DCM mice. Elevated BHB levels suppressed AKT activation in cardiomyocytes, while BDH1 overexpression effectively restored AKT/GSK3β pathway activity and ameliorated BHB-induced mitochondrial dysfunction and cardiomyocytes apoptosis.Conclusion: Our study demonstrates that BDH1 plays a protective role in DCM by regulating BHB level and activating the AKT/GSK3β pathway, thereby mitigating mitochondrial damage and cardiomyocyte apoptosis. BDH1 may be a promising therapeutic target for DCM.

Non-shivering thermogenesis contributes to increased energy expenditure and can be a potential therapy to combat obesity. Here we show that the adipose tissue N⁶-methyladenosine (m⁶A) demethylase ALKBH5 responds to cold and adrenergic stimulation to induce non-shivering thermogenesis independent of UCP1. Fat-specific Alkbh5 knockout reduces thermogenic capacity, increases susceptibility to obesity and disrupts glucose homoeostasis in both male and female mice. Conversely, Alkbh5 overexpression in thermogenic fat increases energy expenditure and improves systemic metabolism. Furthermore, fat ALKBH5 expression inversely correlates with obesity in humans. Mechanistically, ALKBH5 is transcriptionally induced by the cAMP/PKA/CREB pathway in response to thermogenic stimuli. ALKBH5 demethylates m⁶A on CKB mRNA and prevents its degradation mediated by YTHDF2, thereby enhancing creatine metabolism-mediated thermogenesis in both wild-type and Ucp1-knockout mice. These findings suggest that ALKBH5 transduces thermogenic signalling towards creatine-driven thermogenesis, serving as a potential target for the treatment of obesity.

Introduction: Hashimoto's thyroiditis (HT) is a prevalent autoimmune thyroid disorder, typically triggers localized thyroid inflammation and systemic dyslipidemia, and progression to hypothyroidism. While growth differentiation factor 15 (GDF15) is recognized for its role in lipid metabolism and inflammatory diseases, its specific involvement in HT remains elusive. Methods: We conducted plasma metabolomic profiling in HT patients and matched healthy controls to identify altered metabolic pathways. Correlation analysis was performed between serum GDF15 and clinical indicators. In vitro thyroid follicular cell models and NaI-induced in vivo thyroid inflammatory models were applied with GDF15 overexpression, knockdown, recombinant protein and siRNA treatment to explore the functional role of GDF15. Results: Plasma metabolomic profiling in HT patients revealed that differentially expressed metabolites are predominantly enriched in lipid metabolism pathways. GDF15 expression was increased by 1.98-fold in HT serum compared to controls ( p < 0.001), and serum GDF15 levels were negatively correlated with thyroid-stimulating hormone (TSH, R = −0.4943, p = 0.0040), aspartate aminotransferase (AST, R = −0.4506, p = 0.0238) and ultrasound attenuation parameter (UAP, R = −0.4894, p = 0.0071) in HT patients. Functional assays demonstrated that GDF15 overexpression tends to attenuate NaI-induced thyroid and systemic inflammation, relatively improving lipid profiles and reduces hepatic lipid deposition; however, GDF15 knockdown appeared to exacerbate these pathologies. Furthermore, recombinant GDF15 protein mitigates NaI-induced inflammatory responses in thyroid follicular cells, whereas GDF15 siRNA intensifies the inflammation. Discussion: Given the limitations of the NaI-induced model and the lack of thyroid-specific genetic manipulation, these findings suggest a significant association between GDF15 and HT, though further research is required to establish definitive causality.

Diabetic cardiomyopathy (DCM) is a common and severe major complication of diabetes, and effective treatment strategies are currently lacking. Existing research indicates that protein post-translational modifications (PTMs) play a critical role in its pathophysiological mechanisms; however, the function of the emerging lysine crotonylation modification (Kcr) in DCM remains unclear. The results of this study show that both global lysine crotonylation and histone H3K18 crotonylation (H3K18cr) levels are elevated in heart tissues of DCM models, as well as in AC16 cells induced by high glucose and palmitic acid. Supplementation with sodium crotonate (NaCr) further increased histone crotonylation and H3K18cr, and was associated with reduced cardiac inflammation, fibrosis, and injury under DCM conditions. Moreover, the NaCr‑induced H3K18cr and its protective effects were reversed by inhibiting acetyl-CoA synthetase 2 (ACSS2) in vitro. Taken together, these findings reveal an association between NaCr-enhanced H3K18cr and attenuation of DCM phenotypes. While H3K18cr may represent a potential correlate of cardioprotection, its direct causal role and the possible confounding effect of NaCr's glucose-lowering activity remain to be clarified by future studies.

Osteoporosis (OP), a metabolic bone disease characterized by low bone mineral density (BMD), has an underexplored link with the De Ritis ratio (aspartate aminotransferase/alanine aminotransferase) – a marker of metabolic and inflammatory status. This study investigated the association between the De Ritis ratio and both OP and BMD in middle-aged and older adults. BMD was assessed by dual-energy X-ray absorptiometry, and OP was diagnosed based on a T -score ≤−2.5. First, multivariate logistic regression was employed to estimate the adjusted odds ratio (95% confidence interval) for OP in relation to the De Ritis ratio, with covariates including age, sex, body mass index (BMI), hypertension, diabetes, parental OP history, and key liver markers. Second, multivariable linear regression analyzed the association between the De Ritis ratio and BMD, adjusting for age, sex, and BMI. Finally, the predictive ability of the De Ritis ratio was assessed via receiver operating characteristic curve analysis, with results expressed as the area under the curve. In 2483 subjects (233 OP cases, 9.39%), a higher De Ritis ratio was closely associated with a greater risk of OP after full adjustment. Subgroup analyses asserted this positive association in females, individuals with a BMI < 30 kg/m ² , individuals without hypertension/diabetes/parental OP, and individuals across liver marker subgroups. The multivariable linear regression suggested that participants in the highest De Ritis ratio tertile (T3) had significantly lower BMD at the total femur (β = −0.062, P = .002; P -trend = .002) and femoral neck (β = −0.049, P = .025; P -trend = .018) than those in the lowest tertile (T1). Stratified analyses consistently revealed negative correlations between the De Ritis ratio and BMD at both sites. The De Ritis ratio provided an area under the curve value of 0.644 (95% confidence interval = 0.606–0.681) for OP in middle-aged and older adults. Our findings indicate that a higher De Ritis ratio is significantly associated with an increased risk of OP and lower BMD in middle-aged and older adults, suggesting its potential utility as a useful adjunct clinical tool for OP risk stratification. However, the complex relationship underlying this association warrants further validation in large-scale prospective studies.

Background: Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and end-stage renal disease in type 2 diabetes mellitus (T2DM) patients. Recent studies have demonstrated that pregnancy zone protein (PZP), a hepatic cytokine, plays a role in regulating glucose and lipid metabolism. This retrospective study aimed to investigate the connection between plasma PZP concentrations and DKD. Materials and methods: All participants were stratified by estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). The discovery cohort included 130 participants, from whom plasma samples were collected for four-dimensional data-independent acquisition (4D-DIA) quantitative proteomics. In contrast, plasma PZP concentrations were measured using the enzyme-linked immunosorbent assay (ELISA) in a validation cohort of 283 participants. Comparisons of clinical parameters, Spearman’s rho correlation analysis, logistic regression, and receiver operating characteristic (ROC) curve analysis were performed. Data were retrieved from public databases, and plasma PZP expression was simultaneously assessed in db/db mice and in primary hepatocytes treated with high glucose and palmitic acid (HGPA). Results: 4D-DIA quantitative proteomics identified PZP as a differentially expressed protein in DKD patients. In the validation cohort, plasma PZP levels were significantly increased in DKD patients. Spearman’s rho correlation analysis revealed positive correlations between plasma PZP concentrations and systolic blood pressure (SBP), HbA1c, low-density lipoprotein (LDL), Cr, blood urea nitrogen (BUN), and UACR, as well as negative correlations with high-density lipoprotein (HDL) and eGFR. A multiple logistic regression analysis demonstrated a significant correlation between PZP and DKD progression (mild DKD: OR = 1.007; severe DKD: OR = 1.011). The ROC curve area was 0.8143. Plasma PZP levels in db/db mice were notably elevated, and a positive correlation with the UACR was observed. Moreover, PZP mRNA expression in HGPA-treated primary hepatocytes was twice as high as that in untreated cells. Conclusion: In summary, elevated plasma PZP levels are independently associated with DKD.

Aim: This study aimed to investigate effectiveness of multi-radiomics features (RFs) extracted from super-resolution MRI for predicting minor amputation in patients with Wagner 3 diabetic foot ulcers. Methods: 275 eligible patients with Wagner 3 ulcers were retrospectively included and randomly divided into a training set (n = 192) and a test set (n = 83). A deep-transfer learning network was utilized to process coronal proton density weighted images (PDWI) and generate super-resolution PDWI (SRPDWI). RFs were extracted separately from soft tissues and phalanges. Random forest models were then developed to predict minor amputation. Results: The minor amputation rate was 36.4% for the left foot and 32.2% for the right foot. All random forest models demonstrated excellent performance in the training set, achieving AUC ranging from 0.91 to 0.99. In the test set, the integrated radiomics model (combining RFs extracted from both soft tissue and phalanges) exhibited superior performance, with an AUC of 0.83, sensitivity of 0.71, and specificity of 0.79. Additionally, the inclusion of clinical indicators did not enhance the predictive performance of the integrated radiomics model. Conclusion: The multi-RFs extracted from SRPDWI demonstrated promising potential in predicting the risk of minor amputation for Wagner 3 diabetic foot ulcers.