The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury.Regulation of shifting microglia ...The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury.Regulation of shifting microglia polarization from M1(neurotoxic and proinflammatory type)to M2(neuroprotective and anti-inflammatory type)after spinal cord injury appears to be crucial.Tryptanthrin possesses an anti-inflammatory biological function.However,its roles and the underlying molecular mechanisms in spinal cord injury remain unknown.In this study,we found that tryptanthrin inhibited microglia-derived inflammation by promoting polarization to the M2 phenotype in vitro.Tryptanthrin promoted M2 polarization through inactivating the cGAS/STING/NF-κB pathway.Additionally,we found that targeting the cGAS/STING/NF-κB pathway with tryptanthrin shifted microglia from the M1 to M2 phenotype after spinal cord injury,inhibited neuronal loss,and promoted tissue repair and functional recovery in a mouse model of spinal cord injury.Finally,using a conditional co-culture system,we found that microglia treated with tryptanthrin suppressed endoplasmic reticulum stress-related neuronal apoptosis.Taken together,these results suggest that by targeting the cGAS/STING/NF-κB axis,tryptanthrin attenuates microglia-derived neuroinflammation and promotes functional recovery after spinal cord injury through shifting microglia polarization to the M2 phenotype.展开更多
目的:探讨加味四逆理中汤通过调控cGAS/STING信号通路干预脾虚肝郁型盆腔炎性疾病后遗症(SPID)的免疫新机制。方法:选取2023年4月至2023年12月就诊于成都中医药大学附属医院且符合纳入和排除标准的脾虚肝郁型SPID患者20例,采用加味四逆...目的:探讨加味四逆理中汤通过调控cGAS/STING信号通路干预脾虚肝郁型盆腔炎性疾病后遗症(SPID)的免疫新机制。方法:选取2023年4月至2023年12月就诊于成都中医药大学附属医院且符合纳入和排除标准的脾虚肝郁型SPID患者20例,采用加味四逆理中汤治疗8周,同时设置健康对照组20例,不予任何处理。采用qRT-PCR和ELISA法检测,观察前后外周血清cGAS mRNA、STING mRNA以及下游效应分子(IFN-α, IFN-β, IL-6, TNF-α, TBK1, IRF3)的表达水平,比较组内及组间差异。结果:观察前,治疗组外周血清STING mRNA、IFN-β、IL-6、TBK1、IRF3的表达高于对照组(P P P > 0.05);观察后,治疗组STING mRNA、IFN-α、TNF-α、TBK1、IRF3的表达下降(P P P α、IFN-β、IL-6、TNF-α、TBK1、IRF3的表达均无统计学差异(P > 0.05)。结论:cGAS/STING信号通路相关因子的表达失调参与了SPID的发病进程。加味四逆理中汤可能通过调控cGAS/STING信号通路,下调炎症因子表达,恢复免疫稳态,从而有效干预SPID的发生发展。Objective: To investigate the novel immune mechanism of modified Sini Lizhong Decoction (MSLD) in treating spleen deficiency and liver stagnation syndrome sequelae of pelvic inflammatory disease (SPID) through the regulation of the cGAS/STING signaling pathway. Methods: Twenty SPID patients diagnosed with spleen deficiency and liver stagnation syndrome were selected from the Affiliated Hospital of Chengdu University of Traditional Chinese Medicine between April 2023 and December 2023 and treated with MSLD for 8 weeks. A healthy control group of 20 individuals received no treatment. The expression levels of cGAS mRNA, STING mRNA, and downstream effector molecules (IFN-α, IFN-β, IL-6, TNF-α, TBK1, IRF3) in peripheral serum were measured using qRT-PCR and ELISA before and after treatment, and differences within and between groups were compared. Results: Before treatment, the expression levels of STING mRNA, IFN-β, IL-6, TBK1, and IRF3 were significantly higher in the treatment group than in the control group (P P P > 0.05). After treatment, the expression levels of STING mRNA, IFN-α, TNF-α, TBK1, and IRF3 in the treatment group decreased significantly (P P α, IFN-β, IL-6, TNF-α, TBK1, or IRF3 (P > 0.05). Conclusion: Dysregulation of factors related to the cGAS/STING signaling pathway is involved in the pathogenesis of SPID. MSLD may effectively intervene in the development and progression of SPID by regulating the cGAS/STING signaling pathway, downregulating inflammatory factors, and restoring immune homeostasis.展开更多
Age-related macular degeneration(AMD)is a disease that affects the vision of elderly individuals worldwide.Although current therapeutics have shown effectiveness against AMD,some patients may remain unresponsive and c...Age-related macular degeneration(AMD)is a disease that affects the vision of elderly individuals worldwide.Although current therapeutics have shown effectiveness against AMD,some patients may remain unresponsive and continue to experience disease progression.Therefore,in-depth knowledge of the mechanism underlying AMD pathogenesis is urgently required to identify potential drug targets for AMD treatment.Recently,studies have suggested that dysfunction of mitochondria can lead to the aggregation of reactive oxygen species(ROS)and activation of the cyclic GMP-AMP synthase(cGAS)/stimulator of interferon genes(STING)innate immunity pathways,ultimately resulting in sterile inflammation and cell death in various cells,such as cardiomyocytes and macrophages.Therefore,combining strategies targeting mitochondrial dysfunction and inflammatory mediators may hold great potential in facilitating AMD management.Notably,emerging evidence indicates that natural products targeting mitochondrial quality control(MQC)and the cGAS/STING innate immunity pathways exhibit promise in treating AMD.Here,we summarize phytochemicals that could directly or indirectly influence the MQC and the cGAS/STING innate immunity pathways,as well as their interconnected mediators,which have the potential to mitigate oxidative stress and suppress excessive inflammatory responses,thereby hoping to offer new insights into therapeutic interventions for AMD treatment.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82071387(to HT),81971172(to YW)the Natural Science Foundation of Zhejiang Province,China,No.LY22H090012(to HT)the Basic Research Project of Wenzhou City,China,No.Y20220923(to MZ)。
文摘The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury.Regulation of shifting microglia polarization from M1(neurotoxic and proinflammatory type)to M2(neuroprotective and anti-inflammatory type)after spinal cord injury appears to be crucial.Tryptanthrin possesses an anti-inflammatory biological function.However,its roles and the underlying molecular mechanisms in spinal cord injury remain unknown.In this study,we found that tryptanthrin inhibited microglia-derived inflammation by promoting polarization to the M2 phenotype in vitro.Tryptanthrin promoted M2 polarization through inactivating the cGAS/STING/NF-κB pathway.Additionally,we found that targeting the cGAS/STING/NF-κB pathway with tryptanthrin shifted microglia from the M1 to M2 phenotype after spinal cord injury,inhibited neuronal loss,and promoted tissue repair and functional recovery in a mouse model of spinal cord injury.Finally,using a conditional co-culture system,we found that microglia treated with tryptanthrin suppressed endoplasmic reticulum stress-related neuronal apoptosis.Taken together,these results suggest that by targeting the cGAS/STING/NF-κB axis,tryptanthrin attenuates microglia-derived neuroinflammation and promotes functional recovery after spinal cord injury through shifting microglia polarization to the M2 phenotype.
文摘目的:探讨加味四逆理中汤通过调控cGAS/STING信号通路干预脾虚肝郁型盆腔炎性疾病后遗症(SPID)的免疫新机制。方法:选取2023年4月至2023年12月就诊于成都中医药大学附属医院且符合纳入和排除标准的脾虚肝郁型SPID患者20例,采用加味四逆理中汤治疗8周,同时设置健康对照组20例,不予任何处理。采用qRT-PCR和ELISA法检测,观察前后外周血清cGAS mRNA、STING mRNA以及下游效应分子(IFN-α, IFN-β, IL-6, TNF-α, TBK1, IRF3)的表达水平,比较组内及组间差异。结果:观察前,治疗组外周血清STING mRNA、IFN-β、IL-6、TBK1、IRF3的表达高于对照组(P P P > 0.05);观察后,治疗组STING mRNA、IFN-α、TNF-α、TBK1、IRF3的表达下降(P P P α、IFN-β、IL-6、TNF-α、TBK1、IRF3的表达均无统计学差异(P > 0.05)。结论:cGAS/STING信号通路相关因子的表达失调参与了SPID的发病进程。加味四逆理中汤可能通过调控cGAS/STING信号通路,下调炎症因子表达,恢复免疫稳态,从而有效干预SPID的发生发展。Objective: To investigate the novel immune mechanism of modified Sini Lizhong Decoction (MSLD) in treating spleen deficiency and liver stagnation syndrome sequelae of pelvic inflammatory disease (SPID) through the regulation of the cGAS/STING signaling pathway. Methods: Twenty SPID patients diagnosed with spleen deficiency and liver stagnation syndrome were selected from the Affiliated Hospital of Chengdu University of Traditional Chinese Medicine between April 2023 and December 2023 and treated with MSLD for 8 weeks. A healthy control group of 20 individuals received no treatment. The expression levels of cGAS mRNA, STING mRNA, and downstream effector molecules (IFN-α, IFN-β, IL-6, TNF-α, TBK1, IRF3) in peripheral serum were measured using qRT-PCR and ELISA before and after treatment, and differences within and between groups were compared. Results: Before treatment, the expression levels of STING mRNA, IFN-β, IL-6, TBK1, and IRF3 were significantly higher in the treatment group than in the control group (P P P > 0.05). After treatment, the expression levels of STING mRNA, IFN-α, TNF-α, TBK1, and IRF3 in the treatment group decreased significantly (P P α, IFN-β, IL-6, TNF-α, TBK1, or IRF3 (P > 0.05). Conclusion: Dysregulation of factors related to the cGAS/STING signaling pathway is involved in the pathogenesis of SPID. MSLD may effectively intervene in the development and progression of SPID by regulating the cGAS/STING signaling pathway, downregulating inflammatory factors, and restoring immune homeostasis.
基金funded by Chinese NSFC(Grant Nos.:82373336,82303238,and U22A20311,Sichuan Science and Technology Department,China(GrantNos.:2024NSFSC1945,,and 2023NSFSC0667)the Third People's Hospital of Chengdu Clinical Research Program,China(Grant Nos.:CSY-YN-01-2023-013,CSYYN-01-2023-005,and CSY-YN-03-2024-003)+1 种基金Sichuan University“From O to 1”Innovative Research Project,China(Project No.:2023SCUH0024)Health Commission of Chengdu,China(Grant No.:2024291).
文摘Age-related macular degeneration(AMD)is a disease that affects the vision of elderly individuals worldwide.Although current therapeutics have shown effectiveness against AMD,some patients may remain unresponsive and continue to experience disease progression.Therefore,in-depth knowledge of the mechanism underlying AMD pathogenesis is urgently required to identify potential drug targets for AMD treatment.Recently,studies have suggested that dysfunction of mitochondria can lead to the aggregation of reactive oxygen species(ROS)and activation of the cyclic GMP-AMP synthase(cGAS)/stimulator of interferon genes(STING)innate immunity pathways,ultimately resulting in sterile inflammation and cell death in various cells,such as cardiomyocytes and macrophages.Therefore,combining strategies targeting mitochondrial dysfunction and inflammatory mediators may hold great potential in facilitating AMD management.Notably,emerging evidence indicates that natural products targeting mitochondrial quality control(MQC)and the cGAS/STING innate immunity pathways exhibit promise in treating AMD.Here,we summarize phytochemicals that could directly or indirectly influence the MQC and the cGAS/STING innate immunity pathways,as well as their interconnected mediators,which have the potential to mitigate oxidative stress and suppress excessive inflammatory responses,thereby hoping to offer new insights into therapeutic interventions for AMD treatment.
