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@#Abstract: Upon monitoring cytoplasmic aberrant double-stranded DNA, cGAS-STING signaling pathway induces the expression of type I interferons and pro-inflammatory cytokines, which activates the host immune response and enhances anti-tumor immune response and resistance to pathogen infection. However, sustained activation of the cGAS-STING signaling pathway drives diseases such as autoimmune diseases, aging-associated inflammation, and neurodegenerative pathologies. Herein, we describe the mechanism by which cGAS-STING signaling pathway participates in regulating the development of various immune-related diseases, with a particular review of the research and development progress of STING agonists, cGAS inhibitors, and STING inhibitors, aiming to provide some theoretical reference for the future development of cGAS-STING modulators.
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Objective To investigate the mechanism of naringenin resisting lower extremity deep venous thrombosis(LEDVT)in rats.Methods Sixty rats were randomly divided into 6 groups,i.e.,sham-operation group,model group,naringenin low-,medium-,and high-dose groups,and naringenin high-dose + STING agonist 2.5 hexamethylene cacodylate(DMXAA)group,with 10 rats in each group.The coagulation indexes[D-dimer,thrombin time(TT),activated partial thromboplastin time(APTT),prothrombin time(PT)],inflammation indexes[interleukin 1β(IL-1β),interleukin 6(IL-6),tumor necrosis factor α(TNF-α)]and oxidative stress indexes[malondialdehyde(MDA),glutathione peroxidase(GSH-Px),superoxide dismutase(SOD)];Hematoxylin-eosin(HE)staining to detect thrombus formation in venous tissues;wet and dry mass of thrombus were detected;ultrastructure of venous thrombus was detected by transmission electron microscope(TEM);protein expressions of cyclic GMP-AMP synthase(cGAS)and stimulator of interferon genes(STING)in venous thrombus tissue were detected by Western Blot.Results(1)Compared with the sham-operation group,rats in the model group showed an increase in D-dimer levels,IL-1β,IL-6,TNF-α levels,MDA content,thrombus wet and dry mass,and a decrease in TT,APTT,PT,SOD activity,and GSH-Px activity(all P＜0.05);and compared with the model group,rats in naringen's low-,medium-,and high-dose groups showed a decrease in D-dimer levels,IL-1β,IL-6,TNF-α levels,MDA content,thrombus wet and dry mass,TT,APTT and PT,SOD activity and GSH-Px activity were increased(P＜0.05)in a dose-dependent manner compared with the model group;compared with the naringenin high-dose group,rats in the naringenin high-dose + DMXAA group,D-dimer levels,IL-1β,IL-6,TNF-α levels,MDA content,thrombus wet and dry mass were elevated,TT,APTT and PT,SOD activity and GSH-Px activity were decreased(P＜0.05).(2)Compared with the sham-operation group,the expression levels of cGAS and STING proteins in the venous thrombus tissues of rats in the model group were elevated(P＜0.05);compared with the model group,the expression levels of cGAS and STING proteins in the venous thrombus tissues of rats in the naringeno low-,medium-and high-dose groups were significantly reduced(P＜0.05);cGAS and STING protein expression levels in the naringenin high-dose + DMXAA group were significantly higher than those in the naringenin high-dose group(P＜0.05).Conclusion Naringenin can inhibit the activation of cGAS/STING signalling pathway,thereby inhibiting the inflammatory response and resisting oxidative stress,and thus alleviating the LEDVT.
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BACKGROUND:Nucleus pulposus cell apoptosis is the main pathological basis for intervertebral disc degeneration,and inflammation and peroxidation are important factors leading to apoptosis in the nucleus pulposus.Studies have shown that matrine has antioxidant,senescent,inflammatory and apoptotic effects,and may be a potential drug for the treatment of disc degeneration. OBJECTIVE:To investigate the effect of matrine on apoptosis of nucleus pulposus cells in rats with intervertebral disc degeneration by regulating the cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)signaling pathway. METHODS:(1)Nucleus pulposus cells of rats at a logarithmic phase were randomly separated into a control group,a model group,a low-dose matrine group,a high-dose matrine group,an empty group,and a high-dose matrine+cGAS overexpression group.Except for the control group,cell models of intervertebral disc degeneration were established in the other groups through oxygen-glucose deprivation.At the same time of modeling,the low-dose and high-dose groups were treated with 0.4 and 0.8 mmol/L matrine,respectively,and the empty group was transfected with the empty plasmid,while the high-dose+cGAS overexpression group was treated with 0.8 mmol/L matrine with the transfection of the cGAS overexpression plasmid.After 24 hours of treatment,cell activity and apoptosis,intracellular levels of reactive oxygen species,superoxide dismutase,tumor necrosis factor α and interleukin 1β,and intracellular expression of apoptotic proteins and cGAS-STING pathway proteins were detected.(2)Sixty Sprague-Dawley rats were randomized into six groups(n=10 per group):control group,model group,low-dose matrine group,high-dose matrine group,empty group,and high-dose+cGAS overexpression group.After 12 weeks of modeling,60 and 120 mg/kg matrine were given by gavage in the low-dose and high-dose matrine groups,respectively(once a day),and the empty plasmid was injected into the tail vein in the empty group(2 times/week),while the high-dose+cGAS overexpression group was given 120 mg/kg matrine by gavage and injected with cGAS overexpression plasmid to the tail vein.Treatment in each group was given consecutively for 3 weeks.Samples were taken after drug administration and assayed for apoptosis,levels of reactive oxygen species,superoxide dismutase,tumor necrosis factor α and interleukin 1β,as well as apoptotic protein and cGAS-STING pathway protein expression. RESULTS AND CONCLUSION:Compared with the control group,in the model group,cell activity and superoxide dismutase levels were decreased(P<0.05),and apoptosis rate,levels of reactive oxygen species,tumor necrosis factor α and interleukin 1β,and the expression of cGAS,STING,cleaved caspase-3 and Bax proteins were elevated(P<0.05).Matrine dose-dependently ameliorated the above changes in each index due to cellular modeling(P<0.05),whereas cGAS overexpression partially antagonized the ameliorative effect of high-dose matrine.Similar results to the in vitro cellular experiments were obtained in animal experiments.These results indicate that matrine could inhibit inflammation and oxidative stress by blocking the cGAS-STING signaling,which in turn attenuates apoptosis and elevates the activity of nucleus pulposus cells in rats with intervertebral disc degeneration.
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Objective:To investigate whether tetrandrine could be used as an agonist of cGAMP to enhance the activation of cGAS-STING signaling pathway and analyze the antiviral function of tetrandrine.Methods:THP1-Lucia-ISRE and RAW-Lucia-ISRE cells were incubated with different doses of tetrandrine in combination with cGAMP, respectively. IRF3 reporter activity was analyzed by luciferase reporter assay. Western blot was used to detect the activation of cGAS-STING signaling pathway. The expression of IFN-β, CXCL10 and CCL5 at mRNA level was quantified by real-time quantitative PCR. The expression of IFN-β at protein level was assessed by ELISA. HeLa cells stably expressing STING-GFP gene (HeLa-STNG-GFP cells) were constructed and stimulated with tetrandrine and cGAMP, then puncta-like structures were imaged by ZEISS LSM780. THP1-Lucia-ISRE cells were infected with herpes simplex virus type 1 (HSV-1) in the presence or absence of tetrandrine or cGAMP. The antiviral function of tetrandrine was analyzed by Western blot and fluorescence intensity assay.Results:Tetrandrine enhanced cGAMP-mediated IRF3 responses and activated cGAS-STING signaling pathway in combination with cGAMP. Tetrandrine combined with cGAMP triggered STING translocation and the formation of puncta-like structures in HeLa-STNG-GFP cells. The titer of HSV-1, the expression of HSV-glycoprotein D/UL30 and the fluorescence intensity of HSV-GFP were all decline after treating HSV-1-infected THP1-Lucia-ISRE cells with tetrandrine and cGAMP.Conclusions:Tetrandrine combined with cGAMP activates cGAS-STING signaling pathway, thus enhancing the host antiviral response.
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According to the latest global cancer statistics， the incidence and mortality of lung cancer rank first in China. Classical therapies remain the most common cancer treatment options， such as surgical resection， radiotherapy， and chemotherapy， but not all cancer patients respond to classical therapies， which require new lung cancer treatment strategies. After decades of research and development， cancer immunotherapy has achieved certain curative effect， which provides new possibilities for cancer treatment. Cyclic guanosine monophosphate-adenosine monophosphate synthase （cGAS） is a cytosolic DNA sensor. It can induce protective immune defense responses against various DNA-containing pathogens and provide anti-tumor immunity by activating the interferon （IFN） gene stimulator （STING） protein. At present， relevant researchers in China and abroad have done a lot of research on the occurrence and development of lung cancer and the pathophysiological mechanism of drug intervention in the treatment of lung cancer. The results show that cGAS/STING signaling pathway plays an important role in the development of the disease， and traditional Chinese medicine monomers or compounds can intervene in lung cancer cells by regulating the cGAS/STING signaling pathway， induce their autophagy and death， regulate their cycle operation， promote senescence， inhibit their proliferation and tumor angiogenesis， promote their invasion and metastasis， and promote the immune activation of anti-lung cancer cells， so as to inhibit or delay the occurrence and development of lung cancer. In recent years， the related research results have been updated rapidly， and the previous literature has not included the latest research results in time， which causes a lot of inconvenience for many scholars to search the literature. Based on this， this paper mainly summarized the mechanism of cGAS/STING signaling pathway intervention in lung cancer in China and abroad in recent years， as well as the research progress of related traditional Chinese medicine intervention， so as to provide new ideas for the development of lung cancer in molecular biology， drug treatment research， and clinical new drug research and provide a reference for further mechanism research.
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cGAS-STING signaling is a significant component of the innate immune system and functions as a vital sentinel mechanism to monitor cellular and tissue aberrations in microbial invasion and organ injury. cGAS, a cytosolic DNA sensor, is specialized in recognizing abnormally localized cytoplasmic double-stranded DNA (dsDNA) and catalytically synthesizes the second messenger cyclic-GMP-AMP (cGAMP), which initiates a cascade of type I interferon and inflammatory responses mediated by STING. Micronucleus, a byproduct of chromosomal missegregation during anaphase, are also significant contributors to cytoplasmic dsDNA. These unstable subcellular structures are susceptible to irreversible nuclear envelope rupture, exposing genomic dsDNA to the cytoplasm, which potently recruits cGAS and activates STING-mediated innate immune signaling and its downstream activities, including type I interferon and classical nuclear factor-κB (NF-κB) signaling pathways lead to senescence, apoptosis, autophagy activating anti-cancer immunity or directly killing tumor cells. However, sustained STING activation-induced endoplasmic reticulum stress, activated chronic type I interferon and nonclassical NF-κB signaling pathways remodel immunosuppressive tumor microenvironment, leading to immune evasion and facilitating tumor metastasis. Therefore, activated cGAS-STING signaling plays a dual role of suppressing or facilitating tumor growth in tumorigenesis and therapy. This review elaborates on research advances in mechanisms of micronucleus inducing activation of cGAS-STING signaling and its implications in tumorigenesis and therapeutic strategies of malignant tumors.
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Objective To study the cGAS/STING signaling pathway and investigate the potential effect of emodin(EMD)on autophagy of human rheumatoid arthritis fibroblast synovial cells(MH7A).Methods CCK-8 method was used to detect MH7A cell proliferation,and the experimental concentration of EMD was screened according to cell survival rate.Then,autophagy inhibitor 3-MA was added to further verify the effect of EMD on autophagy.Autophagy of MH7A cells was detected via the monodansylcadaverine staining method.Protein expression levels of cGAS,STING,p-STING,LC3-Ⅰ,LC3-Ⅱ,P62 and Beclin-1 were detected by Western blot.Results Monodansylcadaverine staining indicated that EMD enhanced the autophagy of MH7A cells.Western blot indicated that EMD decreased the expression of autophagy related proteins cGAS,STING,p-STING and P62,and increased that of LC3-Ⅱ and Beclin-1 in MH7A cells.After addition of the autophagy inhibitor 3-MA,the expression of P62 protein in MH7A cells increased,while that of LC3-Ⅱ and Beclin-1 decreased.Conclusions EMD may accelerate autophagy and inhibit MH7A cell proliferation by down-regulating cGAS/STING signaling pathway proteins.
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OBJECTIVE To investigate the improvement effect and mechanism of triptolide （TP） on sciatica rats. METHODS Sciatica rat model was prepared and then randomly divided into model group （normal saline）， indomethacin group （positive control， 7.5 mg/kg）， TP low-dose and high-dose groups （TP-L group and TP-H group， 50， 100 μg/kg TP）， and high-dose TP+ stimulator of interferon gene （STING） activator group （TP-H+DMXAA group， 100 μg/kg TP+25 mg/kg DMXAA）， with 12 rats in each group. Another 12 unligated rats were selected as sham operation group （normal saline）. After 14 days of intraperitoneal administration， the paw mechanical withdrawal threshold （PWT） and paw withdrawal thermal latency （PWL） were detected； the pathological changes， morphology of sciatic nerve and the number of microglia in sciatic nerve were observed. The levels of interleukin-1β （IL-1β） and tumor necrosis factor-α （TNF-α）， mRNA and protein expression levels of cyclic guanosine monophosphate- adenosine monophosphate synthase （cGAS） and STING in sciatic nerve were detected. RESULTS Compared with sham operation group， PWT and PWL of rats in model group were obviously reduced and shortened， the number of Nissl bodies was obviously decreased， while the number of microglia， sciatic neuropathology score， the levels of IL-1β and TNF-α， mRNA and protein expressions of cGAS and STING were obviously increased （P＜0.05）， and sciatic nerve injury was serious. Compared with model group， the changes of various indexes in indomethacin group， TP-L group and TP-H group were opposite to the above （P＜0.05）， and sciatic nerve injury was reduced. STING activator DMXAA weakened the inhibitory effect of TP on the activity of microglia and inflammatory response in sciatica rats （P＜0.05）. CONCLUSIONS TP may reduce the activity of microglia and inflammatory response by down-regulating the cGAS/STING signaling pathway， thus alleviating sciatica in rats.
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Bee stings usually result in mild allergic reactions; however, mass envenomation can cause severe complications such as rhabdomyolysis, hemolysis, shock, or multi-organ damage. Rhabdomyolysis can result in acute renal failure either by tubular obstruction by myoglobin casts or by direct cytotoxic injury. We present a case of a 12-year-old female child who presented with sudden onset anuria and hypertension following mass envenomation by bees. A renal biopsy was performed, the microscopic evaluation of which revealed tubular injury, with associated intratubular pigmented casts. The casts stained positive for myoglobin immunohistochemical stain, thus confirming a diagnosis of myoglobin cast nephropathy. The patient was given IV steroids and underwent seven sessions of hemodialysis, following which there was complete recovery of renal function.
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Kounis syndrome, also known as “allergic angina syndrome” or “allergic myocardial infarction”, refers to acute coronary syndrome secondary to hypersensitivity reaction as a result of exposure to various allergens. Signs and symptoms may include chest pain, with or without raised troponins and cardiac enzymes, vomiting, syncope, hypotension or acute renal failure. A 60-year-old male, farmer by occupation, was bitten by multiple bees over head, neck region and bilateral upper limbs in the afternoon on 04/03/2022. On presentation, vitals were stable. After 2 hours, patient developed severe chest pain, palpitations, and dizziness. ECG showed inferior wall ST elevation MI. Subsequently CPK, CK-MB, troponin I were done, which were found to be elevated. Echocardiography was done, which showed regional wall motion abnormality in the inferior wall. Patient was treated with anticoagulants and antiplatelets. CT coronary angiography showed healthy coronaries. In literature, we had few cases of myocardial infarction following bee sting. In acute myocardial infarction after bee stings, it has been suggested that vasoconstriction secondary to mediators released after the sting, aggravated by exogenous adrenaline and platelet aggregation contributes to myocardial ischemia. Cardiac complications can accompany bee sting. Intensive supportive treatment in intensive or coronary care facilities with administration of drugs to treat complications early in the course of the illness will improve the outcome.
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Lipid-formulated RNA vaccines have been widely used for disease prevention and treatment, yet their mechanism of action and individual components contributing to such actions remain to be delineated. Here, we show that a therapeutic cancer vaccine composed of a protamine/mRNA core and a lipid shell is highly potent in promoting cytotoxic CD8+ T cell responses and mediating anti-tumor immunity. Mechanistically, both the mRNA core and lipid shell are needed to fully stimulate the expression of type I interferons and inflammatory cytokines in dendritic cells. Stimulation of interferon-β expression is exclusively dependent on STING, and antitumor activity from the mRNA vaccine is significantly compromised in mice with a defective Sting gene. Thus, the mRNA vaccine elicits STING-dependent antitumor immunity.
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@#ObjectiveTo investigate the anti-tumor effect of agonist MnCl_2of a novel cyclic guanosine monophosphate-adenosine monophosphate synthase(c GAS)/stimulator of interferon genes(STING)pathway collaborated with tumor cell lysate(Lysate)and the neo-antigen 10K-Adpgk of mouse colon cancer MC38 cell line.MethodsBone marrow-derived dendritic cells(BMDCs)were extracted from mouse bone marrow and divided into three groups:PBS,1 μmol/L MnCl_2and 10 μmol/L MnCl_2,which were analyzed for the maturation by flow cytometry,determined for the concentration of IL-6 in supernatant by ELISA,and detected for the transcription levels of IL-6,IFN-α,IFN β and CXCL9 genes by q PCR.Mouse tumor model was established by using MC38 cell line.When the tumor volume reached 100 mm3,the mice were randomly divided into two groups for administration,PBS,Lysate,MnCl_2,10K-Adpgk,Lysate + MnCl_2group and Lysate +10K-Adpgk + MnCl_2combined treatment group,which were administered subcutaneously through the tail for 3 times,with each interval of 1 week,and measured for the tumor volume every 2 days.One week after the last dose,serum samples were collected and determined for the concentrations of IFNγ and TNFα by ELISA.The tumor and spleen were isolated.The proportions of tumor infiltrating T cells and T cells in peripheral blood mononuclear cells(PBMCs)and the ratio of T cells to memory T cells in spleen were detected by flow cytometry,and the proportion of antigen specific T cells in spleen was detected by ELISPOT.Results10 μmol/L MnCl_2stimulated the maturation of BMDCs and activated the subsequent immune process.The tumor volumes of mice in the combined treatment group were considerably smaller than those in PBS group,the contents of IFNγ and TNF-α in serum were higher than those in other groups,and the proportions of tumor infiltrating T cells,T cells in PBMCs and ratio of T cells to memory T cells in spleen were also significantly higher than those in PBS group.Combined therapy caused strong antigen-specific T cell immune response.ConclusionThe addition of the novel adjuvant MnCl_2significantly enhanced the treatment effect of tumor cell lysate and neo-antigen,which provided an experimental basis for the development of the combination tumor treatment method based on MnCl_2and tumor antigens.
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【Objective】 To explore the expression and role of stimulator of interferon gene (STING)-TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3) signaling pathway in the brain of chronic stress mice. 【Methods】 Mice were divided into control (CON) group and chronic restraint stress (RST) group. Mice in the RST group were given chronic restraint stress stimulation (6 hours per day, 14 days). After 14 days, the mRNA expressions of pro-inflammatory cytokines CCL2, CXCL10, IL-1β, IL-6, IL-10, and TNFα in the brain were detected and analyzed by qRT-PCR; protein expression of STING, TBK1, p-TBK1, IRF3, and p-IRF3 were detected and analyzed by immunofluorescence staining and Western blotting. 【Results】 Compared to the CON group, the mRNA expressions of pro-inflammatory cytokines in the RST group were significantly increased (P<0.05). STING and microglia marker Iba-1 were highly co-located and the expression of STING was decreased as detected by immunofluorescence staining. Moreover, the protein expressions of STING, p-TBK1, and p-IRF3 were significantly decreased (all P<0.01). 【Conclusion】 Chronic restraint stress triggers a neuroinflammatory response and the STING-TBK1-IRF3 pathway in the brain of the RST mice is significantly inhibited.
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ObjectiveThis study aims to investigate the effect of modified Baitouwengtang （MBTWD） on tumor growth and the number of tumor-associated macrophages （TAMs） in tumor tissue of MC38 cell tumor-bearing mice with colorectal cancer and explores whether MBTWD mediates the remodeling of TAM phenotype to play an immunologically antitumor effect. MethodFirstly， The C57BL/6 mouse tumor model grafted subcutaneously was established， and then model mice were classified into a model group， positive control group（3 mg·kg-1）， and MBTWD groups with high and low dosages（23.43、46.86 g·kg-1）， with 10 mice in each group. In addition， 10 healthy mice were set as the blank group， and the changes in body weight， tumor volume， and survival status of mice in each group were observed. Tumor tissue， spleen， and peripheral blood were collected to calculate the tumor volume change， tumor inhibition rate， and spleen mass. Hematoxylin-eosin （HE） staining was used to observe the morphological changes of tumor tissue， and an immunofluorescence assay was used to detect the expression levels of CD4， CD8， and CD206 in tumor tissues of tumor-bearing mice. The secretion levels of transforming growth factor （TGF）-β， interleukin （IL）-6， and chemokine （C-C Motif） ligand 2 （CCL2） in peripheral serum were measured by using enzyme-linked immunosorbent assay （ELISA）. Secondly， a co-culture model induced by IL-4 in vitro of MC38 cells and murine monocytic macrophage RAW264.7 cells was established. Cell proliferation and activity assay （CCK-8） was used to detect the inhibitory effect of MBTWD containing serum on cell proliferation. A transwell experiment was used to detect the effect of IL-4-induced M2 macrophages on the invasion of MC38 cells. Flow cytometry was used to detect the expression of CD86 on the membrane of M2 macrophages induced by IL-4 with MBTWD containing serum. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to detect the effect of MBTWD containing serum on the mRNA expression levels of M1 macrophage-related polarization factors CD86， nitric oxide synthase （iNOS）， and IL-12， as well as M2 macrophage-related polarization factors CD206， CD163， and IL-10 after co-cultivation. Finally， the protein expression levels of colony-stimulating factor 1 receptor （CSF1R）， stimulator of interferon genes （STING）， and TANK binding kinase 1 （TBK1） in tumor tissues of tumor-bearing mice were detected by Western blot. ResultIn vivo experimental results show that compared with the model group， the MBTWD can significantly inhibit the tumor growth of tumor-bearing mice. Immunofluorescence experiments show that the MBTWD can increase the number of CD8+ T cell infiltration in tumor tissue of tumor-bearing mice， reduce the number of CD206+ TAMs infiltration， and down-regulate the secretion levels of cytokines IL-6， TGF-β， and CCL2 in peripheral blood of tumor-bearing mice. The results of in vitro experiments show that the MBTWD containing serum has no obvious inhibitory effect on cell proliferation， but the cell supernatant after co-cultivation with RAW264.7 cells can inhibit the proliferation activity of MC38 cells， and the invasion ability of MC38 cells is enhanced by IL-4-induced M2 macrophages. However， this effect can be inhibited in a concentration-dependent manner by the MBTWD containing serum. At the same time， the results of Real-time PCR show that the MBTWD containing serum can up-regulate the mRNA expression levels of M1 macrophage-related polarization factors CD86， iNOS， and IL-12 and down-regulate those of M2 macrophage-related polarization factors CD206， CD163， and IL-10. Flow cytometry results also confirm that the MBTWD containing serum can increase the number of repolarized CD86+ M1 macrophages， indicating that MBTWD can induce M2 macrophages to repolarized M1 macrophages to play an anti-tumor growth role. Finally， Western blot results show that MBTWD can down-regulate the expression of CSF1R protein and up-regulate that of STING and TBK1 proteins in tumor tissue of tumor-bearing mice. ConclusionMBTWD can down-regulate the infiltration number of CD206+ TAMs and increase the infiltration of CD8+ T cells， thereby playing an immunologically antitumor effect on the growth inhibition of colorectal cancer， which may be related to regulating CSF1R signaling and then activating STING/TBK1 signaling pathway to induce phenotypic remodeling of TAMs.
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This study was performed to investigate the impact of nobiletin(NOB)on fracture healing in osteoporosis(OP)rats through the stimulator of interferon gene(STING)/nuclear transcription factor kappa B(NF-κB)signal pathway.A rat model of OP fracture was established by ovariectomy and right femoral shaft fracture intramedullary fixation;the rats after modeling were randomly grouped into model group,high dose(NOB-H,30 mg/kg NOB),medium dose(NOB-M,20 mg/kg NOB),low dose(NOB-L,10 mg/kg NOB)NOB group and NOB-H+ STING activator(DMXAA)group(30 mg/kg NOB+25 mg/kg DMXAA),and 18 rats experienced only ovaries expose were used as sham operation group.After the intervention,the fracture healing status of rats were measured;Micro-CT was used to detect the changes of bone trabecular microstructure in rats;commercial kits were used to detect the serum levels of bone metabolism related indicators(alkaline phosphatase(ALP),calcium,phosphorus)and inflammatory factors(tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β));HE was used to detect the morphological changes and trabecular area of femur,while Western blot was applied to detect the expression of STING/NF-κB pathway related proteins.Compared with the control group,the fracture line in the model group was clear,the trabecular structure was disordered and the gap was large,furthermore,the levels of TNF-α and IL-1β,the expression of STING and p-NF-κB p65/NF-κB p65 were significantly increased,the trabecular area,the levels of ALP,calcium,phosphorus,and bone mineral density(BMD),bone volume fraction(BV/TV),bone trabecular number(Tb.N)and bone trabecular thickness(Tb.Th)were significantly decreased(P<0.05);compared with the model group,the fracture line of NOB-L group,NOB-M group and NOB-H group gradually blurred,the trabecular structure arranged orderly,and the gap gradually decreased,and the trend of the index changes mentioned above were opposite to that of the model group(P<0.05).STING activators attenuated the promotion of fracture healing by NOB in OP rats and increased the inflammatory responses.In conclusion,NOB can reduce inflammatory reaction and promote fracture healing in OP rats,which may be related to the inhibition of STING/NF-κB signal pathway.
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This study was performed to analyze the impact of neferine on airway inflammation in young rats with asthma,and its effect on cGAS-STING signal pathway.Total of 50 SD rats were randomly grouped into control group,model group,low-dose neferine group(20 mg/kg),high-dose neferine group(40 mg/kg),high-dose neferine+ 2'3'-cGAMP group(40 mg/kg neferine+500 μg/kg 2'3'-cGAMP).In addition to the control group,asthma models were established in all other groups.ELISA was used to measure the levels of CysLTs and CysLTR1 in the bronchoalveolar lavage fluid of rats;HE staining and PAS staining were performed on the lung tissue of rats to evaluate the formation of goblet cells and the inflammatory infiltration around the bronchus and blood vessels;the levels of IL-4 and IFN-γ in lung tissue were measured with ELISA kits;the levels of cGAS-STING pathway related proteins in lung tissue were detected by Western blotting.Compared with the control group,a large number of inflammatory cells infiltrated into the inner wall of bronchi and blood vessels,and goblet cells proliferated obviously in the model group;the airway inflammation of rats in the two neferine groups were reduced;compared with the high-dose neferine group,the airway inflammation of rats in the high-dose neferine+2'3'-cGAMP group was aggravated.Compared with the control group,the levels of CysLTs and CysLTR1 in the alveolar lavage fluid,lung inflammation score,mucus score,IL-4 level,and the expression of cGAS and STING proteins in lung tissue of the model group were increased,while the level of IFN-γ in lung tissue was decreased(P<0.05).Neferine(both low-dose and high-dose)could reverse these changes mentioned above in model rats(P<0.05),in a dose-dependent manner.While 2'3'-cGAMP could suppress these effects of neferine(P<0.05).Taken together,neferine may alleviate airway inflammation in neonatal asthmatic rats by inhibiting the activation of cGAS-STING pathway.
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Objective:To compare the effect and safety of continuous veno-venous hemofiltration (CVVH)+double plasma molecular absorption (DPMA)+hemoperfusion (HP), CVVH+HP, and CVVH+plasma exchange (PE) in treatment of patient with severe wasp stings injury.Methods:Multicenter, historical cohort study and superiority test were used. From July 2020 to October 2022, patients with wasp sting injury and multiple organ damage admitted to the intensive care units (ICU) of five hospitals were consecutively screened and recruited into the CVVH+DPMA+HP group (intervention group). Propensity score matching was used to establish historical cohorts. Patients with severe wasp sting injury who hospitalized from January 2016 to June 2020 in each ICU were collected and matched 1∶1 with the intervention group, and divided into CVVH+HP group and CVVH+PE group according to their actual hemopurification protocols (historical control groups). The primary outcome was the acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score on days 3 and 7 after initiation of treatment. Secondary outcomes included complications, length of ICU and hospital stays, and all-cause mortality. Multivariate Cox proportional risk regression was used to analyze the prognosis of patients.Results:After propensity score matching, 56 patients in intervention group and each of the two historical control groups were matched successfully. There were no significant differences in age, gender, comorbidities, biochemical test indices and critical illness scores among the groups. After treatment, APACHE Ⅱ score markedly declined in all groups, and the decrease was faster in the intervention group; treatment with DPMA [hazard ratio ( HR) = 1.04, 95% confidence interval (95% CI) was 1.02-1.08, P = 0.00], the decreased levels of body temperature ( HR = 1.02, 95% CI was 1.00-1.03, P = 0.02), serum creatine kinase (CK; HR = 0.98, 95% CI was 0.96-1.00, P = 0.05) and myoglobin (MYO; HR = 2.88, 95% CI was 1.24-6.69, P = 0.01) were independent risk factors for APACHE Ⅱ score decline to the target value (15 scores). There were no significant differences in the incidence of bleeding complications, filter or perfusion thrombosis, blood pressure reduction, catheter-related infection and anaphylaxis among the groups. Conclusion:CVVH+DPMA+HP regimen can significantly reduce the APACHE Ⅱ score of patients with severe wasp sting injury, and the efficacy is superior to CVVH+HP and CVVH+PE regimens, with safety.
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OBJECTIVE To investigate the effects of pharmacological inhibition of STING by C-176,a STING selective inhibitor,in experimental model of Parkinson's disease.METHODS The acute and sub-acute mice mod-els of Parkinson's disease(PD)were established by in-traperitoneal injection of 1-methyl-4-(2′-methylphenyl)-1,2,3,6-tetrahydrophine(MPTP).The selective STING inhibitor C-176 was administered by intraperitoneal injec-tion.The potential neuroprotective effects of C-176 were evaluated by behavioral test,tyrosine hydroxylase(TH)immunostaining,Nissl staining,Western blotting,qPCR and immunofluorescence.For in vitro study,the effects of C-176 on LPS/MPP+-induced inflammatory responses in BV2 microglial cells were determined by real time RT-PCR and Western blotting analysis.RESULTS Our study revealed that C-176 significantly inhibited STING signaling activation,ameliorated MPTP-induced dopami-nergic neurotoxicity,motor deficit and associated neuroin-flammation.Furthermore,pharmacological inhibition of STING in BV2 microglia treated with LPS/MPP+ exhibited decreased inflammatory responses.More importantly,C176 also reduced NLRP3 inflammasome activation both in vitro and in vivo.CONCLUSION The results of our study suggest that pharmacologic inhibition of STING protects against neuroinflammation that may act at least in part through suppressing NLRP3 inflammasome acti-vation and thus ameliorated dopaminergic neurodegener-ation.STING signaling may holds great promise for the development of new treatment strategy for PD as an effective therapeutic target.
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OBJECTIVE Alzheimer's disease(AD)is the most common neurodegenerative disease worldwide.Neuroinflammation is a potential target for the patients with AD.It is attributed to activated microglia and the release of various inflammatory mediators from infec-tion,ischemia and toxin accumulation.Accumulating evi-dence has indicated that the cGAS-STING pathway driven neuroinflammation in neurological disease.TSG is a main natural active ingredient that derived from polyg-onum multiflorum.Previous research from our group found that TSG has beneficial effects of anti-aging,anti-inflammatory action and improving memory function in APP/PS1 transgenic AD mice.Here,we investigated the effects of TSG on cognitive impairment and neuroinflam-mation in APP/PS1-AD mice and explore the underly-ing mechanism by which TSG ameliorates memory func-tion in the cGAS-STING-mediated inflammatory response.METHODS The Morris water mace test and the novel object recognition test were performed to test the effects of TSG on spatial learning and cognitive and memory abil-ity in APP/PS1 double transgenic AD mice model.In addi-tion,real-time quantitative PCR,Western blotting,ELISA analysis,and flow cytometry to examine gene and pro-tein expression of cGAS-STING related pro-inflammatory cytokines and chemokines.Statistical analyses were ana-lyzed using the SPSS 25.0 package by analysis of vari-ance(ANOVA).Neuman-Keuls or Tukey's multiple-com-parisons test were conducted as ANOVA justified post hoc comparisons between group means.RESULTS We demonstrated that AD transgenic mice exhibited cognitive deficits accompanied by the elevated serum and brain inflammation.The expressions of serum inflammatory cytokines and the activation of microglia in cerebral cor-tex and hippocampus were suppressed after TSG treat-ment,which was probably attributable to the decrease of cyclic GMP-AMP synthase(cGAS)and stimulator of interferon genes(STING)triggered immune response.Additionally,the data showed that TSG treatment reduced the expression level of inflammatory cytokines(IL-1β,TNF-α,IFN-β,IFN-α)in microglial cells BV2 primed with LPS and IFN-γ.CONCLUSION TSG implicated the health benefits in preventing cognitive disorders by inhib-iting neuroinflammation via cGAS-STING signalling path-way in AD.
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Wasp sting is a common emergency in mountainous areas of China, with rapid onset and progression, high mortality rate, and serious harm to public health. Wasp sting can cause mild local reactions in mild cases, and Anaphylaxis or even multiple organ dysfunction in severe cases, of which Acute kidney injury (AKI) is the most common and serious. Blood purification treatment is commonly used for wasp sting patients to maintain renal function, eliminate toxins, and maintain Internal environment stability. The commonly used clinical methods are Hemoperfusion (HP), plasma exchange (PE), and continuous renal replacement therapy (CRRT). At present, there is no clear recommendation for the blood purification treatment mode of wasp sting in China, and there is no clear guidance for its combined treatment mode. This article will review the single and combined use of blood purification treatment models for wasp stings, based on the latest clinical research.