Scholarlink

Background <p>Persistent macrophage-mediated inflammation under hyperglycemic conditions is an important feature of the inflammatory microenvironment associated with diabetic wounds. α-Mangostin (α-MG), a natural xanthone derived from <i>Garcinia mangostana</i>, has been reported to exert anti-inflammatory activity in various experimental models. However, its effects on high-glucose-induced macrophage inflammation and oxidative stress remain insufficiently characterized.</p> Objective <p>This study aimed to investigate the effects of α-MG on inflammatory and oxidative responses in high-glucose-stimulated macrophages and to explore its potential molecular mechanisms using an integrative strategy combining network pharmacology, molecular docking, molecular dynamics simulation, and in vitro assessment.</p> Methods <p>Potential targets of α-MG were collected and intersected with diabetic wound-associated genes to identify candidate targets. Protein–protein interaction analysis and functional enrichment analyses were performed to identify hub targets and related biological pathways. Molecular docking was used to evaluate the binding affinity between α-MG and key targets, followed by a 110 ns MD simulation of the α-MG–TNF complex and a 50 ns supplementary MD simulation of the α-MG–PTGS2 complex. In vitro experiments were performed using high-glucose-stimulated RAW264.7 macrophages, with mannitol included as an osmotic control. The effects of α-MG on inflammatory mediators, oxidative stress markers, PTGS2/COX-2 expression, and NF-κB activation were further evaluated.</p> Results <p>A total of 24 overlapping targets between α-MG and diabetic wound-associated genes were identified. Enrichment analyses suggested that these targets were mainly associated with inflammatory and immune-related biological processes, with TNF and IL-17 signaling pathways identified as computationally predicted and potentially relevant pathways. Molecular docking showed favorable binding interactions between α-MG and several hub targets, including PTGS2, AKT1, TNF, and PARP1. The 110 ns molecular dynamics simulation further suggested that the α-MG–TNF complex remained relatively stable during the simulation period. A supplementary 50 ns MD simulation also supported the conformational stability of the α-MG–PTGS2 complex. In high-glucose-stimulated RAW264.7 macrophages, α-MG significantly reduced the mRNA expression and secretion of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. α-MG also decreased PTGS2/COX-2 expression and inhibited NF-κB p65 phosphorylation. In addition, α-MG alleviated high-glucose-induced oxidative stress, as indicated by increased GSH content and SOD activity, together with reduced MDA levels. The inclusion of the mannitol control helped distinguish glucose-associated inflammatory and oxidative responses from osmotic stress-related effects.</p> Conclusion <p>α-MG attenuated high-glucose-induced inflammatory and oxidative responses in RAW264.7 macrophages. The integrative computational analysis suggested that computationally predicted TNF- and IL-17-related pathways may be involved, whereas the in vitro experiments provided supportive evidence only for changes in inflammatory cytokines, PTGS2/COX-2, oxidative stress markers, and NF-κB activation. These findings provide preliminary experimental and computational evidence for the anti-inflammatory and antioxidant potential of α-MG under diabetic-like macrophage inflammatory conditions. However, direct pathway-specific validation and functional diabetic wound-related models are required before drawing conclusions regarding TNF/IL-17 pathway regulation or therapeutic efficacy in diabetic wound healing.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Integrative analysis and in vitro assessment of the effects of α-mangostin on high-glucose-induced inflammatory and oxidative stress responses in RAW264.7 macrophages

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月20日

查看全文
  • Peng Cao,
  • Yunwei Wang,
  • Mingfan Xi,
  • Kaituo Liu,
  • Shuoyi Hui,
  • Peng Zhao,
  • Guozhong Lyu

摘要

Background

Persistent macrophage-mediated inflammation under hyperglycemic conditions is an important feature of the inflammatory microenvironment associated with diabetic wounds. α-Mangostin (α-MG), a natural xanthone derived from Garcinia mangostana, has been reported to exert anti-inflammatory activity in various experimental models. However, its effects on high-glucose-induced macrophage inflammation and oxidative stress remain insufficiently characterized.

Objective

This study aimed to investigate the effects of α-MG on inflammatory and oxidative responses in high-glucose-stimulated macrophages and to explore its potential molecular mechanisms using an integrative strategy combining network pharmacology, molecular docking, molecular dynamics simulation, and in vitro assessment.

Methods

Potential targets of α-MG were collected and intersected with diabetic wound-associated genes to identify candidate targets. Protein–protein interaction analysis and functional enrichment analyses were performed to identify hub targets and related biological pathways. Molecular docking was used to evaluate the binding affinity between α-MG and key targets, followed by a 110 ns MD simulation of the α-MG–TNF complex and a 50 ns supplementary MD simulation of the α-MG–PTGS2 complex. In vitro experiments were performed using high-glucose-stimulated RAW264.7 macrophages, with mannitol included as an osmotic control. The effects of α-MG on inflammatory mediators, oxidative stress markers, PTGS2/COX-2 expression, and NF-κB activation were further evaluated.

Results

A total of 24 overlapping targets between α-MG and diabetic wound-associated genes were identified. Enrichment analyses suggested that these targets were mainly associated with inflammatory and immune-related biological processes, with TNF and IL-17 signaling pathways identified as computationally predicted and potentially relevant pathways. Molecular docking showed favorable binding interactions between α-MG and several hub targets, including PTGS2, AKT1, TNF, and PARP1. The 110 ns molecular dynamics simulation further suggested that the α-MG–TNF complex remained relatively stable during the simulation period. A supplementary 50 ns MD simulation also supported the conformational stability of the α-MG–PTGS2 complex. In high-glucose-stimulated RAW264.7 macrophages, α-MG significantly reduced the mRNA expression and secretion of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. α-MG also decreased PTGS2/COX-2 expression and inhibited NF-κB p65 phosphorylation. In addition, α-MG alleviated high-glucose-induced oxidative stress, as indicated by increased GSH content and SOD activity, together with reduced MDA levels. The inclusion of the mannitol control helped distinguish glucose-associated inflammatory and oxidative responses from osmotic stress-related effects.

Conclusion

α-MG attenuated high-glucose-induced inflammatory and oxidative responses in RAW264.7 macrophages. The integrative computational analysis suggested that computationally predicted TNF- and IL-17-related pathways may be involved, whereas the in vitro experiments provided supportive evidence only for changes in inflammatory cytokines, PTGS2/COX-2, oxidative stress markers, and NF-κB activation. These findings provide preliminary experimental and computational evidence for the anti-inflammatory and antioxidant potential of α-MG under diabetic-like macrophage inflammatory conditions. However, direct pathway-specific validation and functional diabetic wound-related models are required before drawing conclusions regarding TNF/IL-17 pathway regulation or therapeutic efficacy in diabetic wound healing.