Diabetic foot, one of the most severe chronic complications of diabetes mellitus, arises from complex interactions among neuropathy, vascular ischemia, and inflammatory dysregulation. This review systematically explores the inflammatory regulatory network centered on NF-κB and the interleukin (IL) family in the diabetic foot microenvironment and examines their roles in promoting tissue damage. Under hyperglycemic conditions, the AGE-RAGE axis potently activates the NF-κB signaling pathway, leading to upregulation of pro-inflammatory factors and suppression of anti-inflammatory mediators, thereby forming a vicious cycle of “inflammation-oxidative stress-tissue damage.” Charcot foot, a distinct subtype characterized by neurogenic osteoarthropathy, is strongly linked to abnormal IL-6/RANKL pathway activation and impaired anti-inflammatory neuropeptide signaling. We further assess the diagnostic utility of inflammatory biomarkers, including procalcitonin (PCT), high-sensitivity C-reactive protein (hs-CRP), and the neutrophil-to-lymphocyte ratio (NLR), and summarize current therapeutic challenges along with emerging targeted strategies, such as NF-κB inhibition via salicylates. This review underscores the importance of spatiotemporal heterogeneity and dynamic equilibrium within inflammatory networks for clinical stratification and proposes that integrating multi-omics data with artificial intelligence models holds promise for developing personalized interventions. This approach offers novel theoretical insights to overcome therapeutic bottlenecks in diabetic foot management.

Cardiac dysfunction is a prevalent comorbidity of disrupted inflammatory homeostasis observed in conditions such as sepsis (acute) or obesity (chronic). Secreted and transmembrane protein 1a (Sectm1a) has previously been implicated to regulate inflammatory responses, yet its role in inflammation-associated cardiac dysfunction is virtually unknown. Using the CRISPR/Cas9 system, we generated a global Sectm1a-knockout (KO) mouse model and observed significantly increased mortality and cardiac injury after lipopolysaccharide (LPS) injection, when compared with wild-type (WT) control. Further analysis revealed significantly increased accumulation of inflammatory macrophages in hearts of LPS-treated KO mice. Accordingly, ablation of Sectm1a remarkably increased inflammatory cytokines levels both in vitro [from bone marrow-derived macrophages (BMDMs)] and in vivo (in serum and myocardium) after LPS challenge. RNA-sequencing results and bioinformatics analyses showed that the most significantly down-regulated genes in KO-BMDMs were modulated by LXRα, a nuclear receptor with robust anti-inflammatory activity in macrophages. Indeed, we identified that the nuclear translocation of LXRα was disrupted in KO-BMDMs when treated with GW3965 (LXR agonist), resulting in higher levels of inflammatory cytokines, compared to GW3965-treated WT-cells. Furthermore, using chronic inflammation model of high-fat diet (HFD) feeding, we observed that infiltration of inflammatory monocytes/macrophages into KO-hearts were greatly increased and accordingly, worsened cardiac function, compared to WT-HFD controls. This study defines Sectm1a as a new regulator of inflammatory-induced cardiac dysfunction through modulation of LXRα signalling in macrophages. Our data suggest that augmenting Sectm1a activity may be a potential therapeutic approach to resolve inflammation and associated cardiac dysfunction.

Postaxial polydactyly (PAP) is a common abnormality characterized by extra digits on hands and/or feet. To date, sequence variants in seven genes have been identified in non-syndromic PAP. In the present study, a fetus manifesting non-syndromic postaxial polydactyly type A (PAPA) was found by fetal ultrasonography. To better evaluate fetal prognosis, SNP array analysis and trio whole-exome sequencing (trio-WES) were performed to identify the underlying etiology. Although SNP array analysis revealed no abnormality, trio-WES identified compound heterozygous splice site variants in KIAA0825, c.-1-2A>T and c.2247-2A>G in intron 2 and intron 12, respectively. These two splice site variants were absent in control databases and were predicted to influence splicing by in silico analysis. To confirm the potential pathogenicity of the variants, in vitro splicing assays using minigene and RNA from peripheral leukocytes of the heterozygous parents were conducted. Minigene and RT-PCR assays demonstrated that the c.-1-2A>T variant led to the loss of the initiation codon, and the c.2247-2A>G variant mainly resulted in exon 13 skipping. Prenatal WES and subsequent functional studies are important approaches for defining the genetic etiology of fetuses with PAPA and are also essential for accurate genetic counseling and decision making. Taken together, this study expands the spectrum of KIAA0825 variations in PAPA patients and increases the knowledge of the molecular consequences of KIAA0825 splice site variants.

The relationship between heavy metal exposure and heart failure is complex and poorly understood. This study employs machine learning techniques to model these associations in a population aged 50 years and older from the National Health and Nutrition Examination Survey (NHANES). Our findings emphasize the need for continued investigation into the mechanisms of these associations and highlight the importance of monitoring and regulatory measures to mitigate heavy metal exposure in populations at risk. Five machine learning models were evaluated, with Gradient Boosting Decision Trees (GBDT) selected as the optimal model based on accuracy, interpretability, and ability to capture nonlinear relationships. Model performance was assessed through various metrics, and interpretability was enhanced using SHAP (SHapley Additive exPlanations), permuted Feature Importance, Individual Conditional Expectation (ICE), and Partial Dependence Plots (PDP). The GBDT model achieved an accuracy of 0.78, with a sensitivity of 0.93 and an AUC of 0.92. Our analysis revealed that higher levels of urinary iodine, blood cadmium, urinary cobalt, urinary tungsten, and urinary arsenic acid were significantly associated with heart failure. Synergistic effects involving age and body mass index (BMI) were also observed, further strengthening these associations.

Cardiac cells can adapt to pathological stress-induced energy crisis by shifting from fatty acid oxidation to glycolysis. However, the use of glucose-insulin-potassium (GIK) solution in patients undergoing cardiac surgery does not alleviate ischemia/reperfusion (I/R)-induced energy shortage. This indicates that insulin-mediated translocation of glucose transporter-4 (Glut-4) is impaired in ischemic hearts. Indeed, cardiac myocytes contain two intracellular populations of Glut-4: an insulin-dependent non-endosomal pool (also referred to as Glut-4 storage vesicles, GSVs) and an insulin-independent endosomal pool. Tumor susceptibility gene 101 (Tsg101) has been implicated in the endosomal recycling of membrane proteins. In this study, we aimed to examine whether Tsg101 regulated the sorting and re-distribution of Glut-4 to the sarcolemma membrane of cardiomyocytes under basal and ischemic conditions, using gain- and loss-of-function approaches. Forced overexpression of Tsg101 in mouse hearts and isolated cardiomyocytes could promote Glut-4 re-distribution to the sarcolemma, leading to enhanced glucose entry and adenosine triphosphate (ATP) generation in I/R hearts which in turn, attenuation of I/R-induced cardiac dysfunction. Conversely, knockdown of Tsg101 in cardiac myocytes exhibited opposite effects. Mechanistically, we identified that Tsg101 could interact and co-localize with Glut-4 in the sarcolemma membrane of cardiomyocytes. Our findings define Tsg101 as a novel regulator of cardiac Glut-4 trafficking, which may provide a new therapeutic strategy for the treatment of ischemic heart disease.