Inflammatory cytokines are key indicators affecting the development of ulcers of lower limb. The causal role of inflammatory cytokines in ulcers of lower limb and whether this can be mediated by metabolites remain unknown. We conducted a two-step, two-sample Mendelian randomization (MR) study to investigate the causal effect of inflammatory cytokines on ulcers of lower limb and the mediating role of metabolites in the association between inflammatory cytokines and ulcers of lower limb. MR analysis identified seven inflammatory cytokines (CCL19, IL-12β, MCP4, MIP1a, SCF, sirtuin2, and TNFSF9) that promote ulcers of lower limb. Additionally, 56 metabolites were found to be associated with ulcers of lower limb. Mediation MR indicated that the causal effect of sirtuin2 on ulcers of lower limb (total effect Inverse Variance Weighted [IVW]: odds ratio [OR] = 1.162, 95% confidence interval [CI] [1.051, 1.285], p = 0.003) is largely mediated by 4-hydroxyphenylacetate (0.0185, 95% CI [-0.00278, 0.0397], accounting for 11.1% of the total effect).

BACKGROUND:Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and joint destruction. Although the roles of inflammatory cytokines and metabolites in RA pathogenesis have caught a lot of attention, there is a lack of systematic studies, and their causal relationships remain unclear. METHODS:We conducted a two-step mendelian randomization analysis utilizing genetic data from genome-wide association studies (GWAS) of inflammatory cytokines, metabolites, and RA. The first step assessed the causal effect of 91 inflammatory cytokines and 1400 metabolites on RA risk using inverse variance weighted method, complemented by MR-Egger, weighted median, simple mode and MR-PRESSO to ensure robustness and assess pleiotropy. The second step evaluated the mediation effects of selected metabolites on the relationship between cytokines and RA. RESULTS:The analysis identified 9 inflammatory cytokines, including IL-1α and IL-10, which significantly increase RA risk, while TNF-β exhibited a protective effect. Additionally, 6 metabolites were associated with increased RA risk, including 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPE and arachidonate (20:4n6). Conversely, 5 metabolites, such as docosatrienoate (22:3n3) and Cholesterol, were found to reduce RA risk. The mediation analysis revealed that TNF-β may exerts its protective effect through its influence on specific metabolites, and X-24949, which accounted for a -2.58% mediated effect in the TNF-β-RA causal pathway. CONCLUSION:This study explores the complex interplay between inflammatory cytokines, metabolites, and RA. The findings suggest potential biomarkers for early diagnosis and novel therapeutic targets, particularly those related to lipid metabolites and specific cytokines like TNF-β. Key message What is already known on this topic  Inflammatory factors and metabolites are considered to be related to the onset and progression of RA. What this study adds  We conducted a MR analysis to identify all inflammatory factors and metabolites associated with RA and calculated the mediation effect of inflammatory cytokines on RA through metabolites. This study contributes to a comprehensive understanding of the pathophysiological processes of RA. How this study might affect research, practice or policy  This has laid the groundwork for developing early diagnosis methods and future treatments.

Tibial Cortex Transverse Transport (TTT) represents an innovative surgical method for treating lower extremity diabetic foot ulcers (DFUs), yet its underlying mechanisms remain elusive. Establishing an animal model that closely mirrors clinical scenarios is both critical and novel for elucidating the mechanisms of TTT. We established a diabetic rat model with induced hindlimb ischemia to mimic the clinical manifestation of DFUs. TTT was applied using an external fixator for regulated bone movement. Treatment efficacy was evaluated through wound healing assessments, histological analyses, and immunohistochemical techniques to elucidate biological processes. The TTT group demonstrated expedited wound healing, improved skin tissue regeneration, and diminished inflammation relative to controls. Marked neovascularization and upregulation of angiogenic factors were observed, with the HIF-1α/SDF-1/CXCR4 pathway and an increase in EPCs being pivotal in these processes. A transition toward anti-inflammatory M2 macrophages indicated TTT's immunomodulatory capacity. Our innovative rat model effectively demonstrates the therapeutic potential of TTT in treating DFUs. We identified TTT's roles in promoting angiogenesis and modulating the immune system. This paves the way for further in-depth research and potential clinical applications to improve DFU management strategies.

OBJECTIVE:To study the effect of local application of different concentrations of nerve growth factor (NGF) on fracture healing, and to further search for the appropriate concentration gradient of NGF to promote fracture healing.METHODS:Seventy-five adult male Sprague Dawley rats, weighing (220.0 +/- 2.5) g, were made the right tibia fracture model at 1 cm distal from the tibial tubercle and randomly divided into 5 groups (groups A, B, C, D, and E, n=15). Fractures were treated with 0.3 mL normal saline containing different concentration of NGF (0.00648 x 10(-2), 0.032 40 x 10(-1), 0.16200 x 10(-2), and 0.81000 x 10(-2) microg/g) in groups A, B, C, and D, respectively, and the same amount of normal saline in group E. After 2, 4, and 6 weeks, the specimens were harvested from 5 rats of each group to perform the biochemical test and histological observation. Before the rats were sacrificed, the arteriovenous blood was taken from the eye-ball to test the alkaline phosphatase (ALP) activity.RESULTS:After 2, 4, and 6 weeks, the gross observation showed that the size and hardness of bone tissue and callus tissue growth gradually increased in groups A, B, C, and D, and group D was higher than groups A, B, C, and E. The X-ray films showed that the calcified area gradually increased in groups A, B, C, and D, and group D was higher than groups A, B, C, and E. The histological observation showed that the trabecular quality and maturity in group D were better than those in groups A, B, C, and E. Group D was significantly higher than groups A, B, C, and E (P < 0.05) in the gray values of callus tissue and the calcium content of callus tissue at 4 and 6 weeks, in the wet weight of callus tissue at 2 and 4 weeks, and in the ALP content of serum at 2 weeks. The trabecula surface index of osteoblast, the trabecular volume, and the trabecular width decreased as time in the order of groups A, B, C, and D, which were higher than those of group E; group D was the highest, showing significant differences when compared with the other groups (P < 0.05).CONCLUSION:The local application of NGF can promote fracture healing in rats. The high concentration gradient of NGF (0.81000 x 10(-2) microg/g) has an obvious promotion role on fracture healing.