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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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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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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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BACKGROUND: Nonalcoholic fatty pancreatitis (NAFP) is one of the metabolic syndrome manifestations that need further studies to determine its molecular determinants and find effective medications. We aimed to investigate the potential effect of benzyl propylene glycoside on NAFP management via targeting the pancreatic cGAS-STING pathway-related genes (DDX58, NFκB1 & CHUK) and their upstream regulator miRNA (miR-1976) that were retrieved from bioinformatics analysis. METHODS: The rats were fed either normal chow or a high-fat high-sucrose diet (HFHS), as a nutritional model for NAFP. After 8 weeks, the HFHS-fed rats were subdivided randomly into 4 groups; untreated HFHS group (NAFP model group) and three treated groups which received 3 doses of benzyl propylene glycoside (10, 20, and 30 mg/kg) daily for 4 weeks, parallel with HFHS feeding. RESULTS: The molecular analysis revealed that benzyl propylene glycoside could modulate the expression of the pancreatic cGAS-STING pathway-related through the downregulation of the expression of DDX58, NFκB1, and CHUK mRNAs and upregulation of miR-1976 expression. Moreover, the applied treatment reversed insulin resistance, inflammation, and fibrosis observed in the untreated NAFP group, as evidenced by improved lipid panel, decreased body weight and the serum level of lipase and amylase, reduced protein levels of NFκB1 and caspase-3 with a significant reduction in area % of collagen fibers in the pancreatic sections of treated animals. CONCLUSION: benzyl propylene glycoside showed a potential ability to attenuate NAFP development, inhibit pancreatic inflammation and fibrosis and reduce the pathological and metabolic disturbances monitored in the applied NAFP animal model. The detected effect was correlated with modulation of the expression of pancreatic (DDX58, NFκB1, and CHUK mRNAs and miR-1976) panel.
Subject(s)
Animals , Rats , Pancreatic Diseases , MicroRNAs , Glycosides/pharmacology , Pancreas/pathology , Fibrosis , Signal Transduction , Models, Animal , Inflammation , Nucleotidyltransferases/metabolismABSTRACT
Objective:To investigate epidemiological characteristics of Mycobacterium marinum infection cases in the Dermatology Hospital of Shandong First Medical University from January 2019 to December 2021. Methods:Data were collected from patients with Mycobacterium marinum infection in the Dermatology Hospital of Shandong First Medical University from January 2019 to December 2021. Demographic characteristics, clinical features and prognosis of patients were retrospectively analyzed. Differences between groups were analyzed using t test, Chi-square test and Fisher′s exact test; factors influencing the time to diagnosis (the time from the first appearance of skin manifestations to the diagnosis of Mycobacterium marinum infection in the hospital) longer than 12 months were analyzed using Chi-square test and multivariate logistic regression model, and the odds ratio ( OR) and 95% confidence interval (95% CI) were calculated. Results:From 2019 to 2021, a total of 373 cases of Mycobacterium marinum infection were diagnosed in the hospital, and the number of cases in 2021 was 4.06 times that in 2019; the male-to-female ratio was 1∶1.49, and their age was 54.24 ± 14.04 years. Among the 373 patients, 211 (56.57%) had a history of trauma caused by aquatic products (e.g., fishes, shrimps), of which 51 (24.17%) were stung by sea perch. Skin lesions involved unilateral limbs in 327 (87.67%) patients, only involved the hands or wrists in 188 (50.40%) patients, and 258 (69.17%) had multiple skin lesions. Among the 341 patients with treatment information, 105 (30.79%) were given one antibiotic, 214 (62.76%) received combination treatment with two antibiotics, and 15 (4.40%) were treated with three antibiotics. The response rate was 98.77% (321/325), and the time to diagnosis [ M ( Q1, Q3) ] was 5.03 (3.00, 8.37) months. Multivariate logistic regression analysis indicated higher proportions of males ( OR [95% CI]: 1.95[1.11 - 3.41], P = 0.02), patients aged > 55 years ( OR [95% CI]: 1.82[1.04 - 3.18], P = 0.04), patients with skin lesions only involving hands, arms or lower limbs ( OR [95% CI]: 3.48[1.83 - 6.61], P<0.001) among the patients whose time to diagnosis was longer than 12 months. Conclusions:The number of patients with Mycobacterium marinum infection was increased in the Dermatology Hospital of Shandong First Medical University year by year from 2019 to 2021, and fish sting wounds were the main cause of infection. The most common treatment regimen was the combination of two antibiotics, with a high efficacy profile.
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Radiotherapy is widely used in the treatment of primary and metastatic malignant tumors. It is traditionally believed that the killing effect of radiotherapy on tumor is based on the direct or indirect damage of ionizing radiation to DNA. In recent years, the anti-tumor role and mechanism of anti-tumor immune response induced by ionizing radiation have captivated widespread attention and achieved significant progress. Among them, Cyclic GMP-AMP synthase (cGAS)-stimulator of interference genes (STING) pathway is considered to be one of the key regulatory hubs. cGAS is a cytoplasmic DNA receptor that can bind to tumor-derived double-stranded DNA and activate the downstream STING, thereby activating anti-tumor immune response of the host. In view of the latest progress in this field, the important role and potential mechanism of cGAS-STING pathway in radiotherapy immune effect were mainly summarized, and the application prospect of targeting cGAS-STING pathway in radiotherapy sensitization was explored.
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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.
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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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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: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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This study aimed to explore the mechanism of how African swine fever virus (ASFV) I226R protein inhibits the cGAS-STING signaling pathway. We observed that I226R protein (pI226R) significantly inhibited the cGAS-STING-mediated type Ⅰ interferons and the interferon-stimulated genes production by dual-luciferase reporter assay system and real-time quantitative PCR. The results of co-immunoprecipitation assay and confocal microscopy showed that pI226R interacted with cGAS. Furthermore, pI226R promoted cGAS degradation through autophagy-lysosome pathway. Moreover, we found that pI226R decreased the binding of cGAS to E3 ligase tripartite motif protein 56 (TRIM56), resulting in the weakened monoubiquitination of cGAS, thus inhibiting the activation of cGAS and cGAS-STING signaling. In conclusion, ASFV pI226R suppresses the antiviral innate immune response by antagonizing cGAS, which contributes to an in-depth understanding of the immune escape mechanism of ASFV and provides a theoretical basis for the development of vaccines.
Subject(s)
Animals , Swine , African Swine Fever Virus/metabolism , Membrane Proteins/metabolism , Immunity, Innate , Nucleotidyltransferases/metabolism , Signal Transduction/geneticsABSTRACT
【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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Inflammation-driven endothelial dysfunction is the major initiating factor in atherosclerosis, while the underlying mechanism remains elusive. Here, we report that the non-canonical stimulator of interferon genes (STING)-PKR-like ER kinase (PERK) pathway was significantly activated in both human and mice atherosclerotic arteries. Typically, STING activation leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor-kappa B (NF-κB)/p65, thereby facilitating IFN signals and inflammation. In contrast, our study reveals the activated non-canonical STING-PERK pathway increases scaffold protein bromodomain protein 4 (BRD4) expression, which encourages the formation of super-enhancers on the proximal promoter regions of the proinflammatory cytokines, thereby enabling the transactivation of these cytokines by integrating activated IRF3 and NF-κB via a condensation process. Endothelium-specific STING and BRD4 deficiency significantly decreased the plaque area and inflammation. Mechanistically, this pathway is triggered by leaked mitochondrial DNA (mtDNA) via mitochondrial permeability transition pore (mPTP), formed by voltage-dependent anion channel 1 (VDAC1) oligomer interaction with oxidized mtDNA upon cholesterol oxidation stimulation. Especially, compared to macrophages, endothelial STING activation plays a more pronounced role in atherosclerosis. We propose a non-canonical STING-PERK pathway-dependent epigenetic paradigm in atherosclerosis that integrates IRF3, NF-κB and BRD4 in inflammatory responses, which provides emerging therapeutic modalities for vascular endothelial dysfunction.
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Biomolecular condensates formed by phase separation are widespread and play critical roles in many physiological and pathological processes. cGAS-STING signaling functions to detect aberrant DNA signals to initiate anti-infection defense and antitumor immunity. At the same time, cGAS-STING signaling must be carefully regulated to maintain immune homeostasis. Interestingly, exciting recent studies have reported that biomolecular phase separation exists and plays important roles in different steps of cGAS-STING signaling, including cGAS condensates, STING condensates, and IRF3 condensates. In addition, several intracellular and extracellular factors have been proposed to modulate the condensates in cGAS-STING signaling. These studies reveal novel activation and regulation mechanisms of cGAS-STING signaling and provide new opportunities for drug discovery. Here, we summarize recent advances in the phase separation of cGAS-STING signaling and the development of potential drugs targeting these innate immune condensates.
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Humans , Nucleotidyltransferases/chemistry , Signal Transduction/physiology , Membrane Proteins/chemistry , Phase SeparationABSTRACT
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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@#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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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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Acute lung injury (ALI), as a common clinical emergency, is pulmonary edema and diffuse lung infiltration caused by inflammation. The lack of non-invasive alert strategy, resulting in failure to carry out preventive treatment, means high mortality and poor prognosis. Stimulator of interferon genes (STING) is a key molecular biomarker of innate immunity in response to inflammation, but there is still a lack of STING-targeted strategy. In this study, a novel STING-targeted PET tracer, [18F]FBTA, was labeled with high radiochemical yield (79.7 ± 4.3%) and molar activity (32.5 ± 2.9 GBq/μmol). We confirmed that [18F]FBTA has a strong STING binding affinity (Kd = 26.86 ± 6.79 nmol/L) and can be used for PET imaging in ALI mice to alert early lung inflammation and to assess the efficacy of drug therapy. Our STING-targeted strategy also reveals that [18F]FBTA can trace ALI before reaching the computed tomography (CT) diagnostic criteria, and demonstrates its better specificity and distribution than [18F]fluorodeoxyglucose ([18F]FDG).
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Introducción. El emponzoñamiento por Tityus carrilloi n. sp. representa una amenaza para la vida. Según las manifestaciones clínicas, se clasifica en leve, moderado y grave. Objetivo. Comparar las características epidemiológicas y bioquímicas en niños con escorpionismo leve, moderado y grave. Población y métodos. Estudio descriptivo, transversal y retrospectivo. Se analizaron las consultas de menores de 15 años picados por Tityus carrilloi n. sp. entre enero de 2017 y diciembre de 2018 en un hospital pediátrico de tercer nivel en Santa Fe (Argentina). Resultados. Se incluyeron 524 niños, el 81 % (421) con dolor local y el 19 % (103) con manifestaciones sistémicas. Los niños con síntomas sistémicos de escorpionismo fueron más pequeños en edad que los que presentaron manifestaciones locales (p <0,001). En el invierno los niños desarrollaron 8 veces más manifestaciones sistémicas de escorpionismo y durante la primavera, 2,4 veces más que durante el verano. De los 103 niños internados, 80 fueron casos moderados y 23, graves. No hubo diferencias entre grupos en edad (p = 0,29) ni en la demora en recibir suero antiescorpiónico (p = 0,81). El tiempo de internación fue mayor en los graves (p <0,001). Los valores de glóbulos blancos o glucemia mayores a 30 000 cel/ml y 300 mg/dl respectivamente estuvieron presentes casi exclusivamente en escorpionismos graves. Conclusión. En niños picados por el escorpión Tityus carrilloi n. sp., el riesgo de desarrollar manifestaciones sistémicas fue mayor cuanto menor fue la edad y durante el invierno y la primavera. Los valores de glóbulos blancos y de glucemia fueron mayores en niños con escorpionismo grave.
Introduction. Scorpion envenomation by Tityus carrilloi n. sp. represents a threat to life. Depending on its clinical manifestations, it is classified as mild, moderate or severe. Objective. To compare the epidemiological and biochemical characteristics among children with mild, moderate, and severe scorpionism. Population and methods. Descriptive, crosssectional, and retrospective study. The consultations at a tertiary care children's hospital in Santa Fe (Argentina) of children under 15 years of age stung by Tityus carrilloi n. sp. between January 2017 and December 2018 were analyzed. Results. In total, 524 children were included, 81% (421) with local pain and 19% (103) with systemic manifestations. Children with systemic symptoms of scorpionism were younger in age than those with local manifestations (p < 0.001). In the winter, children developed 8 times more systemic manifestations of scorpionism; during the spring, 2.4 times more than during the summer. Out of the 103 hospitalized children, 80 were moderate cases and 23 severe cases. There were no differences between age groups (p = 0.29) or in the delay in receiving the anti-scorpion serum (p = 0.81). The length of hospital stay was longer among severe cases (p < 0.001). WBC and blood glucose levels higher than 30 000 cell/mL and 300 mg/dL, respectively, were present almost exclusively in severe scorpionism cases. Conclusion. In children stung by the scorpion Tityus carrilloi n. sp., the younger the age and during winter and spring, the higher the risk for systemic manifestations. WBC and blood glucose levels were higher in children with severe scorpionism.
Subject(s)
Humans , Animals , Child , Scorpion Stings/diagnosis , Scorpion Stings/epidemiology , Scorpions , Blood Glucose , Cross-Sectional Studies , Retrospective StudiesABSTRACT
Introduction: Minas Gerais is the Brazilian state with the highest rate of scorpionism, 223,033 cases were recorded between 2010-2017, so reflections on how to reduce this public health problem are necessary. Objective: to describe the epidemiological profile of accidents with scorpions that occurred in the municipality of Patos de Minas (MG), from 2013 to 2017, and to develop an intervention project based on it. Methods: First, the number of accidents by venomous animals in Patos de Minas (MG) was analyzed using the variables included in the SINAN notification and investigation form, available on DATASUS. Additionally, two databases, CAFE and Pubmed, were used for the theoretical framework, with the following descriptors: "escorpião", "Minas Gerais", "envenenamento", "prevenção", and their respective translations into English: "scorpion", "Minas Gerais", "envenomation" and "prevention". Results: Scorpion sting accidents were the most recorded among venomous animals, and were increased annually during the study period, reaching, in 2017, the number of 274 reported cases. In addition, the frequency of accidents was recorded in greater numbers in males (51.18%) and the most affected age group was between 20 and 39 years of age (32.64%). It is also observed that most of the victims were classified as mild cases and treated in the first hour of the sting (97.92%), with no deaths in the period. The results found are in agreement with the references used, being more common, in studies, the registration of mild cases, in male adults. For the basis of the intervention proposal, five articles were used, and based on them, preventive, corrective environmental and educational actions are proposed. Conclusion: The study allowed to identify the target audience of the intervention proposals and when they should be intensified, to try to contain, thus, the constant increase in cases of scorpionism in the analyzed municipality (AU)
Introdução: Minas Gerais é o estado brasileiro com a maior taxa de escorpionismo, foram registrados 223.033 casos entre 2010-2017, dessa forma se faz necessária reflexões sobre como reduzir esse problema de saúde pública. Objetivo: O presente estudo visa descrever o perfil epidemiológico de acidentes oriundos do escorpionismo ocorridos no município de Patos de Minas (MG) no período de 2013 a 2017 e desenvolver um projeto de intervenção a partir do mesmo. Métodos: Primeiramente, o número de acidentes por animais peçonhentos em Patos de Minas (MG) foi analisado utilizando-se as variáveis que contemplam a ficha de notificação e investigação do SINAN, disponíveis no DATASUS. Além disso, foram utilizadas duas bases de dados, CAFE e PUBMED, para o referencial teórico, com os seguintes descritores: escorpião, Minas Gerais, envenenamento e prevenção e suas respectivas traduções para o inglês. Resultados: Acidentes por picada de escorpião foram os mais registrados dentre os animais peçonhentos, além de terem aumentado anualmente no período de estudo, atingindo, em 2017, o número de 274 casos notificados. Ademais, a frequência dos acidentes foi registrada em maior número no sexo masculino (51,18%) e a faixa etária mais atingida foi entre 20 a 39 anos (32,64%). Observa-se também que os acidentados foram classificados como casos leves e atendidos na primeira hora da picada (97,92%), com nenhum óbito no período. Os resultados encontrados estão em concordância com as referências utilizadas, sendo mais comum, em estudos, o registro de casos leves, em adultos, do sexo masculino. Para o embasamento da proposta de intervenção, foram utilizados cinco artigos e baseado neles propõem-se o desenvolvimento de ações preventivas, corretivas do ambiente e educacionais. Conclusão:Com o estudo, foi possível identificar o público-alvo das propostas de intervenção e quando elas deveriam ser intensificadas, para tentar conter, assim, o aumento constante dos casos de escorpionismo no município analisado (AU)