Decabromodiphenyl ether(BDE-209)has been recognized for its adverse effects on the male reproductive system.The specific negative effects and underlying mechanisms through which BDE-209 impacts the reproductive functi...Decabromodiphenyl ether(BDE-209)has been recognized for its adverse effects on the male reproductive system.The specific negative effects and underlying mechanisms through which BDE-209 impacts the reproductive function of offspring are not yet fully understood.The present study classified institute of cancer research(ICR)mice into control and BDE-209 treatment groups,administering doses of 0 and 75 mg/(kg·day),respectively.After 50 days of exposure,normal female mice were co-housed with the male mice,and their male offspring were sacrificed at 2 and 12 months of age.Paternal BDE-209 exposure reduced both sperm quantity and quality in offspring.Furthermore,exposure to BDE-209 resulted in DNA damage and the upregulation of the cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)DNA-sensing and inflammatory signaling pathways.The activation resulted in Z-DNA binding protein 1(ZBP1)binding to the mitochondrial antiviral signaling protein(MAVS),subsequently activating mitochondrial apoptosis in the testes.The activation of the cGAS-STING pathway inhibited mitophagy,leading to senescence in the testes of male offspring.In vitro studies indicated that the cGAS inhibitor RU320521(RU.521)effectively reversed the cGAS-STING pathway activation,alleviated the mitophagy inhibition,and decreased apoptosis and senescence in mouse spermatocyte line GC-2spd cells treated with BDE-209.The results showed that paternal BDE-209 exposure might disrupt spermatogenesis in mouse offspring by activating the cGAS-STING pathway and inhibiting mitophagy.This study provides essential data on the toxicity of BDE-209 to male reproduction and have important scientific and practical implications for maintaining biodiversity and population health in general.展开更多
Deoxynivalenol(DON),a toxic mycotoxin produced by Fusarium Fungi,poses substantial risks to both human and animal health.Although its male reproductive toxicity has been reported,the underlying molecular mechanisms an...Deoxynivalenol(DON),a toxic mycotoxin produced by Fusarium Fungi,poses substantial risks to both human and animal health.Although its male reproductive toxicity has been reported,the underlying molecular mechanisms and potential therapeutic strategies remain insufficiently elucidated.In this study,we investigated the effects of DON on testicular injury in mice and explored the associated molecular pathways.DON exposure markedly reduced testicular sperm count,impaired spermatogenesis,and caused structural damage to the seminiferous tubules.Furthermore,DON elicited pronounced inflammatory responses in both testicular tissues and TM4 mouse Sertoli cells.Mechanistically,DON induced mitochondrial damage,resulting in mitochondrial DNA(mtDNA)leakage into the cytoplasm.The cytosolic mtDNA subsequently activated the cyclic GMP-AMP(cGAS)-stimulator of interferon genes(STING)signaling pathway,promoting TANK-binding kinase 1(TBK1)and interferon regulatory factor 3(IRF3)phosphorylation and enhancing the expression of pro-inflammatory cyto-kines,including IL-6 and TNF-α,via NF-κB activation.Notably,depletion of mtDNA with ethidium bromide(EtBr)or pharmacological inhibition of STING with H151 attenuated DON-induced inflammation,whereas mtDNA transfection further amplified cGAS-STING activation.Collectively,these findings demonstrate that mtDNA leakage-mediated activation of the cGAS-STING pathway plays a central role in DON-induced testicular inflammation and identify potential therapeutic targets for mitigating DON-associated male reproductive toxicity.展开更多
The impaired function of periodontal ligament stem cells(PDLSCs)impedes restoration of periodontal tissues.The cGAS-cGAMP-STING pathway is an innate immune pathway that sensing cytosolic double-stranded DNA(dsDNA),but...The impaired function of periodontal ligament stem cells(PDLSCs)impedes restoration of periodontal tissues.The cGAS-cGAMP-STING pathway is an innate immune pathway that sensing cytosolic double-stranded DNA(dsDNA),but its role in regulating the function of PDLSCs is still unclear.In this study,we found that mito-chondrial DNA(mtDNA)was released into the cytoplasm through the mitochondrial permeability transition pore(mPTP)in PDLSCs upon inflammation,which binds to cGAS and activated the STING pathway by promoting the production of cGAMP,and ultimately impaired the osteogenic differentiation of PDLSCs.Additionally,it is first found that inflammation can down-regulate the level of the ATP-binding cassette membrane subfamily member C1(ABCC1,a cGAMP exocellular transporter)and ectonucleotide pyrophosphatase/phosphodiesterase 1(ENPP1,a cGAMP hydrolase),which further aggravated the accumulation of intracellular cGAMP,leading to the persistent activation of the cGAS-STING pathway and thus the impaired the differentiation capacity of PDLSCs.Furthermore,we designed a hydrogel system loaded with a mPTP blocker,an ABCC1 agonist and ENPP1 to promote periodontal tissue regeneration by modulating the production,exocytosis,and clearance of cGAMP.In conclusion,our results highlight the profound effects,and specific mechanisms,of the cGAS-STING pathway on the function of stem cells and propose a new strategy to promote periodontal tissue restoration based on the reestablishment of cGAMP homeostasis.展开更多
The aim of this study was to examine whether pasteurized Akkermansia muciniphila(pAkk)could protect mice from chemotherapy-induced mucositis(CIM)in tumor-bearing mice.Mice were pretreated with pAkk and then treated wi...The aim of this study was to examine whether pasteurized Akkermansia muciniphila(pAkk)could protect mice from chemotherapy-induced mucositis(CIM)in tumor-bearing mice.Mice were pretreated with pAkk and then treated with 5-fluorouracil(5-FU).pAkk mitigates symptoms of 5-FU-induced CIM,including slowing the rate of weight loss(14.2%)and increasing the villus height to crypt depth ratio(1.54%)in the ileum,while not impacting the antitumor efficacy of 5-FU.Furthermore,pAkk diminished the levels of proteins associated with apoptosis,including Bax,caspase-3,and Bcl-2,both in vivo and in vitro,and decreased the number of TUNEL-positive cells.pAkk further alleviated the disruption of cell barrier function and inflammation induced by 5-FU in a Caco-2/RAW264.7 co-culture model.Further exploration revealed that the cGAS-STING signaling pathway plays a crucial role in improving CIM by pAkk,with the expression of its related proteins being reversed upon pAkk treatment.The protective effect of pAkk was partially nullified after using a STING activator,further confirming that pAkk exerts its function at least partly through cGAS-STING signaling pathway.These findings provide support for developing Akkermansia muciniphila-based strategies to mitigate chemotherapy-related in-testinal toxicity for patients with cancer.展开更多
Three multifunctional ruthenium(Ⅱ)complexes(Ru1–Ru3)modified with cholic acid were synthesized,which exhibited excellent singlet oxygen-generating ability and near-infrared(NIR)aggregation-induced emission(AIE)phosp...Three multifunctional ruthenium(Ⅱ)complexes(Ru1–Ru3)modified with cholic acid were synthesized,which exhibited excellent singlet oxygen-generating ability and near-infrared(NIR)aggregation-induced emission(AIE)phosphorescence activity.Cellular toxicity assays revealed that Ru1 displayed pronounced phototoxicity against both human breast cancer cells(MDA-MB-231)and murine breast cancer cells(4T1),achieving a maximum phototoxicity index(PI)of 83.3.Mechanistic studies indicated that Ru1 exhibited superior targeting affinity for the endoplasmic reticulum(ER).Upon irradiation at 450 nm,it stimulated the production of reactive oxygen species(ROS)and initiated ER stress.This stress activated the interferon gene stimulator(STING)pathway’s signaling cascade within the ER,prompting a Golgi apparatus response.The consequent activation induced pyroptosis and sequentially engaged the downstream proteins p-TBK1 and p-IRF3 within the STING pathway,thus promoting the secretion of antitumor cytokines and the elicitation of tumor immune responses.In vivo experiments conducted on Balb/c mice have demonstrated significant anti-tumor immune effects exhibited by Ru1.In summary,the immune modulation and targeted intervention by metal complexes represent an innovative and promising therapeutic strategy for cancer.This approach is anticipated to yield new perspectives for the development of metal complexes that augment tumor immunotherapy.展开更多
An increasing amount of evidence shows that type I interferon response,which is induced by cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)and stimulator of interferon genes(STING)is closely assoc...An increasing amount of evidence shows that type I interferon response,which is induced by cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)and stimulator of interferon genes(STING)is closely associated with health and neuroinflammatory diseases.Abnormal activation or loss of control of the cGAS-STING axis affects the development of neuroinflammation.Thus,we examined its role in major neurological diseases,including traumatic brain injury,Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,multiple sclerosis,herpes simplex encephalitis,and ataxia-telangiectasia.Additionally,targeted intervention of the cGAS-STING axis to control neuroinflammation and treat related diseases has become the focus of current clinical research.This article describes the development of cGAS inhibitors and small molecules that target the cGAS-STING axis and explores the potential applications of STING inhibitors and agonists in clinical research.In summary,the cGAS-STING axis may impact neurological diseases more than a single protein or gene.Future studies should focus on elucidating the functional dynamics and regulatory networks of this axis and delineating its crosstalk with other signaling cascades.These investigations will provide mechanistic insights for developing targeted therapeutic strategies for associated disorders and potentially facilitate drug repurposing across diverse disease contexts.展开更多
Since its discovery,the cyclic GMP-AMPsynthase(cGAS)-stimulator of the interferon gene(STING)signaling pathway has been considered a pivotal component of innate immunity and a promising target for cancer immunotherapy...Since its discovery,the cyclic GMP-AMPsynthase(cGAS)-stimulator of the interferon gene(STING)signaling pathway has been considered a pivotal component of innate immunity and a promising target for cancer immunotherapy.Beyond its canonical role in pathogen defense,accumulating evidence has demonstrated that the cGAS-STING pathway critically regulates diverse cellular processes,including cellular senescence,autophagy,cell death,and tumor immunosurveillance;therefore,dysregulation of this pathway correlates with the pathogenesis and progression of various human diseases,ranging from autoimmune and inflammatory disorders to cancer.Herein,we reviewed the regulatory mechanisms and cellular functions of the cGAS-STING pathway,highlighting its essential role in maintaining immune homeostasis.We systematically discussed the dual roles of the cGAS-STING pathway in cancer immunity,in which it triggers both antitumor and immunosuppressive effects.Finally,we summarized the recent advances and challenges in therapeutic strategies targeting the cGAS-STING pathway and discussed the next generation of therapies,including nanomaterials,antibody-drug conjugates,engineered bacteria,alternative strategies,optogenetic approaches,and combination strategies.We hope that our efforts will advance the understanding of the fundamental principles of innate immune recognition and response,and provide novel directions for improving the clinical outcomes of cGAS-STING-targeted therapies.展开更多
基金supported by the National Natural Science Foundation of China(No.32171492)。
文摘Decabromodiphenyl ether(BDE-209)has been recognized for its adverse effects on the male reproductive system.The specific negative effects and underlying mechanisms through which BDE-209 impacts the reproductive function of offspring are not yet fully understood.The present study classified institute of cancer research(ICR)mice into control and BDE-209 treatment groups,administering doses of 0 and 75 mg/(kg·day),respectively.After 50 days of exposure,normal female mice were co-housed with the male mice,and their male offspring were sacrificed at 2 and 12 months of age.Paternal BDE-209 exposure reduced both sperm quantity and quality in offspring.Furthermore,exposure to BDE-209 resulted in DNA damage and the upregulation of the cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)DNA-sensing and inflammatory signaling pathways.The activation resulted in Z-DNA binding protein 1(ZBP1)binding to the mitochondrial antiviral signaling protein(MAVS),subsequently activating mitochondrial apoptosis in the testes.The activation of the cGAS-STING pathway inhibited mitophagy,leading to senescence in the testes of male offspring.In vitro studies indicated that the cGAS inhibitor RU320521(RU.521)effectively reversed the cGAS-STING pathway activation,alleviated the mitophagy inhibition,and decreased apoptosis and senescence in mouse spermatocyte line GC-2spd cells treated with BDE-209.The results showed that paternal BDE-209 exposure might disrupt spermatogenesis in mouse offspring by activating the cGAS-STING pathway and inhibiting mitophagy.This study provides essential data on the toxicity of BDE-209 to male reproduction and have important scientific and practical implications for maintaining biodiversity and population health in general.
基金supported by the Joint Funds of the National Natural Science Foundation of China(U23A20240)the National Natural Science Foundation of China(32172770)+4 种基金the Science and Technology Program of Guangdong(2022B0202160011)department of Agriculture and Rural Affairs of Guangdong Province(2024-WPY-00-012)the Science and Technology Program of Guangzhou(2023B03J1390)Guangdong Feed Industry Technology System(2024CXTD14)Guangdong Basic and Applied Basic Research Foundation(2024A1515013195,2022B1515130003).
文摘Deoxynivalenol(DON),a toxic mycotoxin produced by Fusarium Fungi,poses substantial risks to both human and animal health.Although its male reproductive toxicity has been reported,the underlying molecular mechanisms and potential therapeutic strategies remain insufficiently elucidated.In this study,we investigated the effects of DON on testicular injury in mice and explored the associated molecular pathways.DON exposure markedly reduced testicular sperm count,impaired spermatogenesis,and caused structural damage to the seminiferous tubules.Furthermore,DON elicited pronounced inflammatory responses in both testicular tissues and TM4 mouse Sertoli cells.Mechanistically,DON induced mitochondrial damage,resulting in mitochondrial DNA(mtDNA)leakage into the cytoplasm.The cytosolic mtDNA subsequently activated the cyclic GMP-AMP(cGAS)-stimulator of interferon genes(STING)signaling pathway,promoting TANK-binding kinase 1(TBK1)and interferon regulatory factor 3(IRF3)phosphorylation and enhancing the expression of pro-inflammatory cyto-kines,including IL-6 and TNF-α,via NF-κB activation.Notably,depletion of mtDNA with ethidium bromide(EtBr)or pharmacological inhibition of STING with H151 attenuated DON-induced inflammation,whereas mtDNA transfection further amplified cGAS-STING activation.Collectively,these findings demonstrate that mtDNA leakage-mediated activation of the cGAS-STING pathway plays a central role in DON-induced testicular inflammation and identify potential therapeutic targets for mitigating DON-associated male reproductive toxicity.
基金the National Natural Science Founda-tion of China(82220108019 to P.Ji and 82201059 to Q.M.Zhai)the Chongqing Postdoctoral Science Special Foundation(2021XM1031 to Q.M.Zhai)+1 种基金China Postdoctoral Science Foundation(2022M720599 to Q.M.Zhai)Haobo medical technology(Shanghai)limited company helped us synthesize the PEGA materials.
文摘The impaired function of periodontal ligament stem cells(PDLSCs)impedes restoration of periodontal tissues.The cGAS-cGAMP-STING pathway is an innate immune pathway that sensing cytosolic double-stranded DNA(dsDNA),but its role in regulating the function of PDLSCs is still unclear.In this study,we found that mito-chondrial DNA(mtDNA)was released into the cytoplasm through the mitochondrial permeability transition pore(mPTP)in PDLSCs upon inflammation,which binds to cGAS and activated the STING pathway by promoting the production of cGAMP,and ultimately impaired the osteogenic differentiation of PDLSCs.Additionally,it is first found that inflammation can down-regulate the level of the ATP-binding cassette membrane subfamily member C1(ABCC1,a cGAMP exocellular transporter)and ectonucleotide pyrophosphatase/phosphodiesterase 1(ENPP1,a cGAMP hydrolase),which further aggravated the accumulation of intracellular cGAMP,leading to the persistent activation of the cGAS-STING pathway and thus the impaired the differentiation capacity of PDLSCs.Furthermore,we designed a hydrogel system loaded with a mPTP blocker,an ABCC1 agonist and ENPP1 to promote periodontal tissue regeneration by modulating the production,exocytosis,and clearance of cGAMP.In conclusion,our results highlight the profound effects,and specific mechanisms,of the cGAS-STING pathway on the function of stem cells and propose a new strategy to promote periodontal tissue restoration based on the reestablishment of cGAMP homeostasis.
基金supported in part by Dalian Jinshiwan Laboratory Project(Dljswgj202403)National Key Research and Development Program of China(2022YFD2100104).
文摘The aim of this study was to examine whether pasteurized Akkermansia muciniphila(pAkk)could protect mice from chemotherapy-induced mucositis(CIM)in tumor-bearing mice.Mice were pretreated with pAkk and then treated with 5-fluorouracil(5-FU).pAkk mitigates symptoms of 5-FU-induced CIM,including slowing the rate of weight loss(14.2%)and increasing the villus height to crypt depth ratio(1.54%)in the ileum,while not impacting the antitumor efficacy of 5-FU.Furthermore,pAkk diminished the levels of proteins associated with apoptosis,including Bax,caspase-3,and Bcl-2,both in vivo and in vitro,and decreased the number of TUNEL-positive cells.pAkk further alleviated the disruption of cell barrier function and inflammation induced by 5-FU in a Caco-2/RAW264.7 co-culture model.Further exploration revealed that the cGAS-STING signaling pathway plays a crucial role in improving CIM by pAkk,with the expression of its related proteins being reversed upon pAkk treatment.The protective effect of pAkk was partially nullified after using a STING activator,further confirming that pAkk exerts its function at least partly through cGAS-STING signaling pathway.These findings provide support for developing Akkermansia muciniphila-based strategies to mitigate chemotherapy-related in-testinal toxicity for patients with cancer.
基金supported by the National Natural Science Foundation of China(22477081 and 22107074)the Guangdong Basic and Applied Basic Research Foundation(2024A1515030157,2022A1515011356,and 2021A1515110211)+4 种基金the Innovation Team Project of the Guangdong Provincial Department of Education(2024KCXTD012)the Shenzhen Natural Science Fund(the Stable Support Plan Program 20220811110339002)the Shenzhen Science and Technology Innovation Program(JCYJ20230808105913028)the Shenzhen Longgang District Science and Technology Innovation Bureau(LGKCYLWS2021000001)the Natural Science Foundation of Top Talent of SZTU(GDRC202416)。
文摘Three multifunctional ruthenium(Ⅱ)complexes(Ru1–Ru3)modified with cholic acid were synthesized,which exhibited excellent singlet oxygen-generating ability and near-infrared(NIR)aggregation-induced emission(AIE)phosphorescence activity.Cellular toxicity assays revealed that Ru1 displayed pronounced phototoxicity against both human breast cancer cells(MDA-MB-231)and murine breast cancer cells(4T1),achieving a maximum phototoxicity index(PI)of 83.3.Mechanistic studies indicated that Ru1 exhibited superior targeting affinity for the endoplasmic reticulum(ER).Upon irradiation at 450 nm,it stimulated the production of reactive oxygen species(ROS)and initiated ER stress.This stress activated the interferon gene stimulator(STING)pathway’s signaling cascade within the ER,prompting a Golgi apparatus response.The consequent activation induced pyroptosis and sequentially engaged the downstream proteins p-TBK1 and p-IRF3 within the STING pathway,thus promoting the secretion of antitumor cytokines and the elicitation of tumor immune responses.In vivo experiments conducted on Balb/c mice have demonstrated significant anti-tumor immune effects exhibited by Ru1.In summary,the immune modulation and targeted intervention by metal complexes represent an innovative and promising therapeutic strategy for cancer.This approach is anticipated to yield new perspectives for the development of metal complexes that augment tumor immunotherapy.
基金supported by the National Natural Science Foundation of China,No.82301382the Natural Science Foundation of Hebei Province,No.H2022316001+1 种基金Government Funded Clinical Medicine Excellent Talents Project,No.ZF2023126the Postdoctoral Research Support Program for Clinical Medicine of Hebei Medical University,No.PD2023004(all to QZ).
文摘An increasing amount of evidence shows that type I interferon response,which is induced by cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)and stimulator of interferon genes(STING)is closely associated with health and neuroinflammatory diseases.Abnormal activation or loss of control of the cGAS-STING axis affects the development of neuroinflammation.Thus,we examined its role in major neurological diseases,including traumatic brain injury,Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,multiple sclerosis,herpes simplex encephalitis,and ataxia-telangiectasia.Additionally,targeted intervention of the cGAS-STING axis to control neuroinflammation and treat related diseases has become the focus of current clinical research.This article describes the development of cGAS inhibitors and small molecules that target the cGAS-STING axis and explores the potential applications of STING inhibitors and agonists in clinical research.In summary,the cGAS-STING axis may impact neurological diseases more than a single protein or gene.Future studies should focus on elucidating the functional dynamics and regulatory networks of this axis and delineating its crosstalk with other signaling cascades.These investigations will provide mechanistic insights for developing targeted therapeutic strategies for associated disorders and potentially facilitate drug repurposing across diverse disease contexts.
基金the National Natural Science Foundation of China,Grant/Award Numbers:82272794,82573178,82472969Research and Innovation Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital,Grant/Award Number:2024AOXIANG04。
文摘Since its discovery,the cyclic GMP-AMPsynthase(cGAS)-stimulator of the interferon gene(STING)signaling pathway has been considered a pivotal component of innate immunity and a promising target for cancer immunotherapy.Beyond its canonical role in pathogen defense,accumulating evidence has demonstrated that the cGAS-STING pathway critically regulates diverse cellular processes,including cellular senescence,autophagy,cell death,and tumor immunosurveillance;therefore,dysregulation of this pathway correlates with the pathogenesis and progression of various human diseases,ranging from autoimmune and inflammatory disorders to cancer.Herein,we reviewed the regulatory mechanisms and cellular functions of the cGAS-STING pathway,highlighting its essential role in maintaining immune homeostasis.We systematically discussed the dual roles of the cGAS-STING pathway in cancer immunity,in which it triggers both antitumor and immunosuppressive effects.Finally,we summarized the recent advances and challenges in therapeutic strategies targeting the cGAS-STING pathway and discussed the next generation of therapies,including nanomaterials,antibody-drug conjugates,engineered bacteria,alternative strategies,optogenetic approaches,and combination strategies.We hope that our efforts will advance the understanding of the fundamental principles of innate immune recognition and response,and provide novel directions for improving the clinical outcomes of cGAS-STING-targeted therapies.
