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
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
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
Chemotherapeutic drugs,such as cisplatin and phenanthriplatin(PhenPt),as STING agonists to induce DNA damage and activate the cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)signaling pathway provide...Chemotherapeutic drugs,such as cisplatin and phenanthriplatin(PhenPt),as STING agonists to induce DNA damage and activate the cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)signaling pathway provides a potential strategy for clinical chemo-immunotherapy.However,treatment with Pt-based drugs leads to irreversible ectopia of phosphatidylserine(PS),a major component of the intracellular membrane,to the surface of the cancer cells by enzymes(Xkr8).Exposed PS can bind to immune cell receptors and inhibit the presentation of tumor antigens,leading to immunosuppression and attenuation of chemotherapy.Herein,we report a novel approach to enhance chemo-immunotherapy by constructing siRNA targeted Xkr8(siXkr8)-mediated tetrahedral framework nucleic acid nanogel structure concurrently loaded with PhenPt(siXkr8-FNG/PhenPt)for co-delivery of siRNA and Pt-based drugs.The results showed that siXkr8-FNG/PhenPt can not only be used as an efficient delivery carrier to deliver siXkr8,block the expression of Xkr8,reduce the exposure of PS on the cancer cells surface,but also act as an immune stimulant to activate cGAS-STING pathway,effectively improve the immunosuppressive microenvironment,produce antitumor immune response,and inhibit tumor growth and metastasis.Overall,this new delivery system is important for improving the effect of Pt-based drug chemotherapy,inducing immune enhancement and nucleic acid drug delivery.展开更多
Nanocatalytic therapy shows great potential for therapeutic interventions.However,therapeutic efficiency is often limited by unsatisfactory enzyme activity and lack of the coordination of immune system.Therefore,engin...Nanocatalytic therapy shows great potential for therapeutic interventions.However,therapeutic efficiency is often limited by unsatisfactory enzyme activity and lack of the coordination of immune system.Therefore,engineering nanozymes activity enhancement while activating immune system will be an effective strategy to achieve efficient tumor therapy.Herein,we synthesize a DSPE-PEG-FA modified manganese dioxide-based dual-atom nanozyme(MDF),on which iridium and platinum atoms are anchored.The obtained MDF can simultaneously mimic four enzyme activities of catalase,oxidase,peroxidase,and glutathione oxidase,set off a reactive oxygen species(ROS)storm,cause tumor cell death.The enzyme activity of MDF can be enhanced by its own photothermal effect.Meanwhile,MDF can consume intracellular glutathione and release Mn^(2+),which can prevent generated ROS from consumption and further activate cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes(cGAS-STING)pathway and promote the secretion of type I interferon,which will help promote dendritic cells maturation,present antigens to T lymphocytes to help kill tumor cells.Ultimately,MDF shows excellent tumor suppressive effects.This work provides a new paradigm for the field of nanozymes and offers a new reference for involvement of cGAS-STING pathway activation in tumor catalytic therapy.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.
基金supported by the Natural Science Foundation of Shandong province(ZR2023QH204 and ZR2024ME024,China).
文摘Chemotherapeutic drugs,such as cisplatin and phenanthriplatin(PhenPt),as STING agonists to induce DNA damage and activate the cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)signaling pathway provides a potential strategy for clinical chemo-immunotherapy.However,treatment with Pt-based drugs leads to irreversible ectopia of phosphatidylserine(PS),a major component of the intracellular membrane,to the surface of the cancer cells by enzymes(Xkr8).Exposed PS can bind to immune cell receptors and inhibit the presentation of tumor antigens,leading to immunosuppression and attenuation of chemotherapy.Herein,we report a novel approach to enhance chemo-immunotherapy by constructing siRNA targeted Xkr8(siXkr8)-mediated tetrahedral framework nucleic acid nanogel structure concurrently loaded with PhenPt(siXkr8-FNG/PhenPt)for co-delivery of siRNA and Pt-based drugs.The results showed that siXkr8-FNG/PhenPt can not only be used as an efficient delivery carrier to deliver siXkr8,block the expression of Xkr8,reduce the exposure of PS on the cancer cells surface,but also act as an immune stimulant to activate cGAS-STING pathway,effectively improve the immunosuppressive microenvironment,produce antitumor immune response,and inhibit tumor growth and metastasis.Overall,this new delivery system is important for improving the effect of Pt-based drug chemotherapy,inducing immune enhancement and nucleic acid drug delivery.
基金supported by the National Natural Science Foundation of China(52371254,22020102003)the Jilin Province Youth Science and Technology Talent Support Project(QT202229)+1 种基金the Program of Science and Technology Development Plan of Jilin Province of China(YDZJ202302CXJD065)the Natural Science Foundation of Chongqing of China(cstc2021jcyj-msxmX0936)。
文摘Nanocatalytic therapy shows great potential for therapeutic interventions.However,therapeutic efficiency is often limited by unsatisfactory enzyme activity and lack of the coordination of immune system.Therefore,engineering nanozymes activity enhancement while activating immune system will be an effective strategy to achieve efficient tumor therapy.Herein,we synthesize a DSPE-PEG-FA modified manganese dioxide-based dual-atom nanozyme(MDF),on which iridium and platinum atoms are anchored.The obtained MDF can simultaneously mimic four enzyme activities of catalase,oxidase,peroxidase,and glutathione oxidase,set off a reactive oxygen species(ROS)storm,cause tumor cell death.The enzyme activity of MDF can be enhanced by its own photothermal effect.Meanwhile,MDF can consume intracellular glutathione and release Mn^(2+),which can prevent generated ROS from consumption and further activate cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes(cGAS-STING)pathway and promote the secretion of type I interferon,which will help promote dendritic cells maturation,present antigens to T lymphocytes to help kill tumor cells.Ultimately,MDF shows excellent tumor suppressive effects.This work provides a new paradigm for the field of nanozymes and offers a new reference for involvement of cGAS-STING pathway activation in tumor catalytic therapy.
