Tongxinluo promotes endothelium-dependent arteriogenesis to attenuate diabetic peripheral arterial disease

Diabetic foot has become one of the leading causes of disability and death in diabetic patients. Restoring blood supply to the lower limbs, especially by increasing collateral vessels, is currently the most effective strategy. We report a 70-year-old female patient diagnosed with diabetic foot who was treated with integrated traditional Chinese and Western medicine. Western medicine treatment includes blood glucose control, lipid regulation, plaque stabilization, antiplatelet coagulation and anti-inflammation. Traditional Chinese medicine (TCM) treatment is based on the principles of promoting blood circulation and relieving pain, benefiting Qi and activating blood circulation, including oral Chinese medicine Tongxinluo and electro-acupuncture treatment. The vascular morphology of the patient's lower limbs and the levels of glucolipid metabolism were evaluated before and after treatment. The results showed that after treatment, the patient had increased blood flow in the lower limbs, reduced plaque in the femoral arteries, and improved levels of glucolipid metabolism.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease (ESRD), necessitating novel therapies beyond conventional approaches. Emerging evidence indicates that gut microbiota dysbiosis promotes DKD progression through metabolite-mediated renal injury. Jinlida (JLD) is a clinically validated traditional Chinese medicine with antidiabetic activity, but its microbiota-mediated renoprotective mechanism remains unclear. This study investigates whether JLD alleviates DKD by modulating gut microbiota and vitamin B6 metabolism, and elucidates the renoprotective mechanism of its key metabolite, pyridoxamine (PM). To assess JLD's microbiota-dependent effects, we employed antibiotic-induced pseudo-germ-free mice and fecal microbiota transplantation (FMT). Metagenomics and untargeted metabolomics delineated gut microbiota and metabolite compositional changes. Renal PM levels were quantified by LC-MS/MS. The renoprotective effects and mechanisms of direct PM supplementation against DKD were further evaluated in vivo and in vitro. JLD's therapeutic effects on proteinuria and glomerulosclerosis were shown to partially depend on microbiota homeostasis. Metabolomic analysis demonstrated that JLD significantly upregulated the vitamin B6 metabolic pathway and increased levels of related metabolites, including PM and pyridoxine (PN). Metagenomic analyses indicated that JLD remodeled the gut microbiota composition and enriched pathways related to cofactor biosynthesis, and markedly increased the relative abundance of key enzyme genes involved in the de novo (DXP-dependent) vitamin B6 biosynthesis pathway - namely pdxJ, pdxB, dxs and dxr. Genes related to vitamin B6 activation and conversion (pdxH, aldH) showed no significant changes, suggesting that JLD may promote PM accumulation by enhancing the microbiota's capacity for vitamin B6 biosynthesis rather than its subsequent activation/conversion. Source-tracking pinpointed Paramuribaculum intestinale as the core functional species. In vitro culture experiments showed that JLD markedly promoted the growth of this strain and elevated PM production, and that the strain's conditioned culture medium effectively inhibited formation of advanced glycation end-products (AGEs). Notably, direct supplementation with PM recapitulated the renoprotective effects of JLD in vivo. Mechanistically, PM inhibited the AGEs-RAGE-NF-κB-AP-1 axis and TGF-β receptor signaling, thereby suppressing NF-κB-driven inflammation and Smad2-mediated fibrosis. JLD remodels the gut microbiota and enhances its de novo vitamin B6 biosynthetic capacity, leading to accumulation of PM. Gut-derived PM enters the circulation and functions as an effector molecule targeting the kidney; through PM's direct carbonyl-trapping activity it scavenges AGEs and suppresses the AGEs-RAGE axis as well as downstream inflammatory and profibrotic signaling, thereby exerting renoprotective effects. This study reveals PM as a microbially derived metabolite with therapeutic potential in DKD and offers a new metabolism-directed strategy for DKD treatment.

Aims: We aimed to construct a prediction model of type 2 diabetes mellitus (T2DM) in a Han Chinese cohort using a genetic risk score (GRS) and a nongenetic risk score (NGRS).Methods: A total of 297 Han Chinese subjects who were free from type 2 diabetes mellitus were selected from the Tianjin Medical University Chronic Disease Cohort for a prospective cohort study. Clinical characteristics were collected at baseline and subsequently tracked for a duration of 9 years. Genome-wide association studies (GWASs) were performed for T2DM-related phenotypes. The GRS was constructed using 13 T2DM-related quantitative trait single nucleotide polymorphisms (SNPs) loci derived from GWASs, and NGRS was calculated from 4 biochemical indicators of independent risk that screened by multifactorial Cox regressions.Results: We found that HOMA-IR, uric acid, and low HDL were independent risk factors for T2DM (HR &gt;1; P&lt;0.05), and the NGRS model was created using these three nongenetic risk factors, with an area under the ROC curve (AUC) of 0.678; high fasting glucose (FPG >5 mmol/L) was a key risk factor for T2DM (HR = 7.174, P< 0.001), and its addition to the NGRS model caused a significant improvement in AUC (from 0.678 to 0.764). By adding 13 SNPs associated with T2DM to the GRS prediction model, the AUC increased to 0.892. The final combined prediction model was created by taking the arithmetic sum of the two models, which had an AUC of 0.908, a sensitivity of 0.845, and a specificity of 0.839.Conclusions: We constructed a comprehensive prediction model for type 2 diabetes out of a Han Chinese cohort. Along with independent risk factors, GRS is a crucial element to predicting the risk of type 2 diabetes mellitus.

The research of standardization and normalization of syndromes in traditional Chinese medicine (TCM) is the focal and difficult points of TCM, but always fails to make some breakthroughs. In this paper, we try to apply a new analysis method (entropy-based partition method for complex system) to conduct a standardized and normalized study on the TCM syndromes of "deficiency of Yin" syndrome in vascular endothelial dysfunction (ED). Firstly, we carried out a clinical epidemiology survey, chose 400 ED patients, and collected corresponding symptoms information. Then we reached the symptoms combination and the diagnostic threshold of "deficiency of Yin" in ED objectively. Finally, we conducted an examination on this diagnostic criterion through three indexes: sensitivity, specificity and agreement rate. The result shows that the diagnostic criterion of "deficiency of Yin" in ED has a favourable diagnostic effect and the entropy-based partition method for complex system is suitable for study on the diagnostic criterion of syndromes in TCM. It paves a new way for the research of standardization and normalization of syndromes in TCM.