Background:Diabetic wounds pose significant clinical challenges due to impaired healing processes,often resulting in chronic,nonhealing ulcers.Asiaticoside(AC),a natural triterpene derivative from Centella asiatica,ha...Background:Diabetic wounds pose significant clinical challenges due to impaired healing processes,often resulting in chronic,nonhealing ulcers.Asiaticoside(AC),a natural triterpene derivative from Centella asiatica,has demonstrated notable anti-inflammatory and wound-healing properties.However,the synergistic effects of nitric oxide(NO)-a recognized promoter of wound healing-combined with AC in treating diabetic wounds remain inadequately explored.Methods:Ultraperformance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)was utilized to identify differential metabolites and dysregulated metabolic pathways associated with diabetic wounds.Molecular docking analyses were conducted to confirm the binding affinity of AC to key therapeutic targets.The effects of asiaticoside-nitric oxide hydrogel(ACNO)on gene and protein expression were evaluated using reverse transcription-quantitative polymerase chain reaction(RT-qPCR)and western blotting.In vitro experiments using sarcoma(SRC)agonists and inhibitors were performed to investigate the impact of ACNO therapy on the expression of SRC,STAT3,and other proteins in HaCaT cells.Results:Metabolomic profiling revealed that diabetic wounds in mice exhibited marked metabolic dysregulation,which was attenuated by ACNO treatment.Key metabolites modulated by ACNO included mandelic acid,lactic acid,and 3-hydroxyisovaleric acid.The primary metabolic pathways involved were methyl histidine metabolism and the malate-aspartate shuttle.Immunofluorescence staining confirmed that ACNO therapy enhanced angiogenesis,promoted cellular proliferation,and facilitated diabetic wound closure.RT-qPCR data demonstrated that ACNO regulated the transcription of critical genes(SRC,STAT3,EGFR,and VEGFA).Notably,ACNO attenuated SRC/STAT3 pathway activation while concurrently upregulating EGFR and VEGFA expression.Conclusions:These findings emphasize the therapeutic potential of ACNO hydrogel in diabetic wound healing through the modulation of metabolic pathways and the SRC/STAT3 signaling axis.By correlating altered metabolites with molecular targets,this study elucidates the pharmacodynamic foundation for ACNO's preclinical application and provides valuable insights into the development of targeted therapies for diabetic wound management.展开更多
Diabetic wound healing(DWH)represents a major complication of diabetes where inflammation is a key impediment to proper healing.The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)signaling pathway ...Diabetic wound healing(DWH)represents a major complication of diabetes where inflammation is a key impediment to proper healing.The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)signaling pathway has emerged as a central mediator of inflammatory responses to cell stress and damage.However,the contribution of cGAS-STING activation to impaired healing in DWH remains understudied.In this review,we examine the evidence that cGAS-STING-driven inflammation is a critical factor underlying defective DWH.We summarize studies revealing upregulation of the cGAS-STING pathway in diabetic wounds and discuss how this exacerbates inflammation and senescence and disrupts cellular metabolism to block healing.Partial pharmaceutical inhibition of cGAS-STING has shown promise in damping inflammation and improving DWH in preclinical models.We highlight key knowledge gaps regarding cGAS-STING in DWH,including its relationships with endoplasmic reticulum stress and metal-ion signaling.Elucidating these mechanisms may unveil new therapeutic targets within the cGAS-STING pathway to improve healing outcomes in DWH.This review synthesizes current understanding of how cGASSTING activation contributes to DWH pathology and proposes future research directions to exploit modulation of this pathway for therapeutic benefit.展开更多
基金supported by the National Natural Science Foundation of China(No.82160770,82460792)the Outstanding Young Scientific and Technological Talents Project of Guizhou Province(No.2021-5639)+1 种基金the Zunyi Science and Technology Talent Platform Carrier Construction Project(No.ZSKRPT2023-1)scholarships from the China Scholarship Council(No.CSC-202008520012).
文摘Background:Diabetic wounds pose significant clinical challenges due to impaired healing processes,often resulting in chronic,nonhealing ulcers.Asiaticoside(AC),a natural triterpene derivative from Centella asiatica,has demonstrated notable anti-inflammatory and wound-healing properties.However,the synergistic effects of nitric oxide(NO)-a recognized promoter of wound healing-combined with AC in treating diabetic wounds remain inadequately explored.Methods:Ultraperformance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)was utilized to identify differential metabolites and dysregulated metabolic pathways associated with diabetic wounds.Molecular docking analyses were conducted to confirm the binding affinity of AC to key therapeutic targets.The effects of asiaticoside-nitric oxide hydrogel(ACNO)on gene and protein expression were evaluated using reverse transcription-quantitative polymerase chain reaction(RT-qPCR)and western blotting.In vitro experiments using sarcoma(SRC)agonists and inhibitors were performed to investigate the impact of ACNO therapy on the expression of SRC,STAT3,and other proteins in HaCaT cells.Results:Metabolomic profiling revealed that diabetic wounds in mice exhibited marked metabolic dysregulation,which was attenuated by ACNO treatment.Key metabolites modulated by ACNO included mandelic acid,lactic acid,and 3-hydroxyisovaleric acid.The primary metabolic pathways involved were methyl histidine metabolism and the malate-aspartate shuttle.Immunofluorescence staining confirmed that ACNO therapy enhanced angiogenesis,promoted cellular proliferation,and facilitated diabetic wound closure.RT-qPCR data demonstrated that ACNO regulated the transcription of critical genes(SRC,STAT3,EGFR,and VEGFA).Notably,ACNO attenuated SRC/STAT3 pathway activation while concurrently upregulating EGFR and VEGFA expression.Conclusions:These findings emphasize the therapeutic potential of ACNO hydrogel in diabetic wound healing through the modulation of metabolic pathways and the SRC/STAT3 signaling axis.By correlating altered metabolites with molecular targets,this study elucidates the pharmacodynamic foundation for ACNO's preclinical application and provides valuable insights into the development of targeted therapies for diabetic wound management.
基金supported by the National Natural Science Foundation of China(81960741,82160770)the Guizhou Provincial Natural Science Foundation(QKH-J-2020-1Z070)+1 种基金Outstanding Young Scientific and Technological Talents Project of Guizhou Province(2021-5639)scholarships from the China Scholarship Council(No.CSC-202008520012).
文摘Diabetic wound healing(DWH)represents a major complication of diabetes where inflammation is a key impediment to proper healing.The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)signaling pathway has emerged as a central mediator of inflammatory responses to cell stress and damage.However,the contribution of cGAS-STING activation to impaired healing in DWH remains understudied.In this review,we examine the evidence that cGAS-STING-driven inflammation is a critical factor underlying defective DWH.We summarize studies revealing upregulation of the cGAS-STING pathway in diabetic wounds and discuss how this exacerbates inflammation and senescence and disrupts cellular metabolism to block healing.Partial pharmaceutical inhibition of cGAS-STING has shown promise in damping inflammation and improving DWH in preclinical models.We highlight key knowledge gaps regarding cGAS-STING in DWH,including its relationships with endoplasmic reticulum stress and metal-ion signaling.Elucidating these mechanisms may unveil new therapeutic targets within the cGAS-STING pathway to improve healing outcomes in DWH.This review synthesizes current understanding of how cGASSTING activation contributes to DWH pathology and proposes future research directions to exploit modulation of this pathway for therapeutic benefit.
