Schematic illustration of the protective effect of apple polyphenols on bone loss in obese mice induced by a high-fat-diet.

Punicalagin supplementation protects against obesity-induced impairment of the skeletal muscle function via regulating the protein stability of TET2 and the enzymatic activity of TET2 demethylation.

To investigate the causal relationship between mitochondrial genes and the pathogenesis of carotid plaque (CP), a multiomics-integrated Mendelian randomization (MR) analysis was performed in this study. Leveraging data from the McRae study, UK Biobank, eQTLGen Consortium, and decode database, we extracted mitochondrial gene QTLs at methylation, gene expression, and protein abundance levels as instrumental variables for MR and summary data-based Mendelian randomization (SMR) analyses. Multiomics evidence was classified by integrating MR, SMR, and colocalization results to investigate associations between mitochondria-related genes and CP. Integration of multiomics data across mQTL, eQTL, and pQTL levels revealed 16 genes (GATM, CBR4, PGS1, PTPMT1, SDSL, SLC25A28, SPRYD4, TARS2, ACAT1, GRHPR, METAP1D, NIT2, ACSM2A, AGXT, TOP1MT, and CKMT2) that passed MR and SMR analyses. Among these, GATM demonstrated Tier 1 evidence, showing consistent causal associations with CP across all three levels. Specifically, methylation of cg10760299 in GATM was associated with lower GATM expression, increased protein levels, and a greater risk of CP. However, mtDNA copy number was not significantly associated with CP risk according to MR analysis. This study identifies 16 mitochondrial genes with multiomics evidence linked to CP pathogenesis across genetic, methylation, and protein levels, highlighting the potential role of mitochondrial dysfunction in CP development and the potential of mitochondrial genes as biomarkers and therapeutic targets.

Objective: β-cell dysfunction and loss are major pathological determinants of impaired islet function and hyperglycemia in diabetes. Given the inability of current therapies to restore β-cell viability or glucose-responsive insulin secretion, this study aimed to investigate whether a cell-permeable PBX1 fusion protein (TAT-PBX1) could rescue streptozotocin (STZ)-induced β-cell injury and restore β-cell functional integrity. Methods: A TAT-PBX1 recombinant fusion protein was produced using a prokaryotic expression system. Its protective effects were assessed in STZ-treated MIN6 β cells and in a mouse model of STZ-induced diabetes, with the glucokinase (GK) activator dorzagliatin included as a positive control. We evaluated β-cell apoptosis, DNA damage, ATP and NAD⁺/NADH levels, insulin signaling (IRS1/PI3K/Akt), and the expression of PDX1 and GK. Glucose-stimulated insulin secretion (GSIS), glucose tolerance, islet morphology, and β-cell proliferation were also examined in vivo. Results: TAT-PBX1 was detectable and significantly enriched in pancreatic tissue and mitigated STZ-induced cytotoxicity by reducing DNA damage, PARP1-associated energy depletion, and β-cell apoptosis. It restored intracellular ATP and NAD⁺/NADH ratios and reactivated IRS1/PI3K/Akt signaling. TAT-PBX1 further enhanced PDX1 protein levels and upregulated GK, resulting in improved glucose uptake and GSIS. In addition, it increased Ki67⁺ β-cell proliferation. In diabetic mice, TAT-PBX1 improved glucose tolerance, preserved islet morphology and number, and improved insulin signaling responsiveness. Conclusions: TAT-PBX1 restores β-cell function through coordinated protection of cellular metabolism and insulin signaling, leading to improved β-cell survival, glucose responsiveness, and regenerative capacity. These findings support TAT-PBX1 as a promising molecular strategy for β-cell-protective and β-cell-restorative diabetes therapy.