Integrating bioinformatic prediction and the "gut microbiota-inflammation-skin axis" to decipher the mechanisms of quercetin (from Evodia rutaecarpa) in diabetic wound healing.

Quercetin was identified as a principal active component of Evodia rutaecarpa with predicted binding affinity for key targets involved in inflammatory and hypoxic responses.

• Bioinformatic prediction was used to identify quercetin as a core bioactive flavonoid of E. rutaecarpa.
• Predicted targets were involved in both inflammatory and hypoxic response pathways.
• Quercetin's therapeutic potential in diabetic wound healing was described as previously underexplored.

Quercetin directly bound to and stabilized HIF1α protein in vitro, as assessed by cellular thermal shift assay.

• The direct interaction between quercetin and HIF1α was assessed using cellular thermal shift assay (CETSA).
• Quercetin stabilized HIF1α protein upon binding.
• Experiments were conducted in a lipopolysaccharide-induced RAW264.7/HUVEC co-culture system.

Quercetin upregulated the expression of both HIF1α and VEGF in HUVECs under inflammatory co-culture conditions.

• HIF1α and VEGF expression were evaluated in a lipopolysaccharide-induced RAW264.7/HUVEC co-culture system.
• Upregulation of both HIF1α and VEGF was observed following quercetin treatment.
• This finding supports the functional effect of quercetin on the HIF1α/VEGF pathway.

Quercetin treatment significantly accelerated wound closure in streptozotocin-induced diabetic rats with full-thickness dorsal wounds.

• A streptozotocin-induced diabetic rat model with full-thickness dorsal wounds was used for in vivo assessment.
• Wound healing rates were measured as an outcome in Que-treated versus control diabetic rats.
• Quercetin treatment produced significant acceleration of wound closure compared to untreated diabetic controls.

Quercetin treatment improved systemic glucose and lipid metabolism and reduced serum levels of pro-inflammatory cytokines TNF-α and IL-1β in diabetic rats.

• Metabolic parameters including systemic glucose and lipid metabolism were analyzed in Que-treated diabetic rats.
• Serum levels of TNF-α and IL-1β were significantly reduced following quercetin treatment.
• These effects were observed in the streptozotocin-induced diabetic rat model.

Quercetin treatment modulated gut microbiota structure in diabetic rats.

• Gut microbiota composition was analyzed in Que-treated versus untreated diabetic rats.
• Quercetin produced changes in gut microbiota structure as part of its therapeutic mechanism.
• This modulation was proposed as a component of the 'gut microbiota-inflammation-skin axis'.

Fecal microbiota transplantation (FMT) from quercetin-treated donor rats replicated pro-healing effects in diabetic recipient rats, including enhanced angiogenesis, increased collagen deposition, and reduced tissue inflammation.

• FMT was performed from Que-treated donors to diabetic recipient rats to test the causal role of gut microbiota.
• FMT from Que-treated donors enhanced angiogenesis and collagen deposition in wounds of recipient rats.
• FMT from Que-treated donors reduced tissue inflammation in recipient diabetic rats.
• This experiment provided evidence for a causal role of gut microbiota in quercetin's wound-healing effects.

Serum derived from FMT-Que group rats promoted HUVEC migration and tube formation and attenuated pro-inflammatory cytokine expression in RAW264.7 cells in vitro.

• Drug-containing serum from the FMT-Que group was assessed in HUVEC and RAW264.7 cell cultures.
• FMT-Que serum promoted HUVEC migration and tube formation, indicating pro-angiogenic activity.
• FMT-Que serum attenuated pro-inflammatory cytokine expression in RAW264.7 macrophage cells.
• These in vitro findings were consistent with the in vivo pro-healing effects observed after FMT.