Nootka rose (</span><i><span style="font-family:Verdana;">Rosa nutkana </span></i><span style="font-family:Verdana;">C. Presl) and stinging nettle (</span>...Nootka rose (</span><i><span style="font-family:Verdana;">Rosa nutkana </span></i><span style="font-family:Verdana;">C. Presl) and stinging nettle (</span></span><i><span style="font-family:Verdana;">Urtica dioica </span></i><span style="font-family:Verdana;">L.</span><span style="font-family:""><span style="font-family:Verdana;">) have been traditionally used in the treatment of skin infection by Indigenous peoples of Vancouver Island, British Columbia, Canada. The main objective of this study was to examine the antibacterial efficacy of extracts of Nootka </span><span style="font-family:Verdana;">rose and stinging nettle against the common pathogenic skin bacteria</span> </span><i><span style="font-family:Verdana;">Staphylococcus aureus</span></i><span style="font-family:""><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Micrococcus luteus</span></i><span style="font-family:Verdana;">, and </span><i><span style="font-family:Verdana;">Pseudomonas aeruginosa</span></i> </span><span style="font-family:Verdana;">using </span><span style="font-family:Verdana;">Indigenous science and standard methods of analysis. The Indigenous science method of plant extraction by steeping as advised by the Traditional Knowledge keeper</span><span style="font-family:Verdana;"> was performed to examine minimum inhibitory concentration </span><span style="font-family:Verdana;">(MIC) </span><span style="font-family:Verdana;">values and minimum bactericidal concentrations </span><span style="font-family:Verdana;">(MBC) by serial dilution and bacterial population counts. </span><span style="font-family:Verdana;">Soxhlet extractions and Kirby Bauer disc sensitivity testing showed that Nootka rose </span><span style="font-family:Verdana;">extracts possessed antibacterial effectiveness against all three bacterial species while stinging nettle extracts were effective against </span><i><span style="font-family:Verdana;">M. luteus</span></i><span style="font-family:""><span style="font-family:Verdana;">. Results for MIC and MBC indicated antibacterial activity against </span><i><span style="font-family:Verdana;">M. luteus</span></i><span style="font-family:Verdana;"> and </span><i><span style="font-family:Verdana;">S. aureus</span></i><span style="font-family:Verdana;"> for the </span></span><span style="font-family:Verdana;">Nootka rose when using </span><span style="font-family:""><span style="font-family:Verdana;">full-strength solutions;all three bacterial species exhibited growth when undiluted stinging nettle treatments were used. When considering bacterial population counts for</span><b> </b><i><span style="font-family:Verdana;">S. aureus,</span></i><span style="font-family:Verdana;"> results indicated</span><b> </b><span style="font-family:Verdana;">that only the Nootka rose treatment offered effective inhibition. Chemical analysis showed that alkaloid percentage was greater in the stinging nettle (0.17%) than </span></span><span style="font-family:Verdana;">Nootka rose </span><span style="font-family:Verdana;">(0.07%), while saponin percentage was greater in the </span><span style="font-family:Verdana;">Nootka rose </span><span style="font-family:Verdana;">(0.87%) than stinging nettle (0.17%). Overall, </span><span style="font-family:""><span style="font-family:Verdana;">Nootka rose showed a greater level of</span><b> </b><span style="font-family:Verdana;">antibacterial effectiveness than </span></span><span style="font-family:Verdana;">stinging nettle by Indigenous and Western scientific methods of plant extract preparation.展开更多
该文主要探究汉黄芩素(WOG)调控STING/NF-κB通路对M5诱导的银屑病样HaCaT细胞模型炎症反应的影响。将HaCaT细胞随机分为NC组、五联因子(M5)组、M5+WOG组、M5+STING抑制剂(H-151)组、M5+WOG+STING激动剂(SR-717)组。采用CCK-8、EdU染色...该文主要探究汉黄芩素(WOG)调控STING/NF-κB通路对M5诱导的银屑病样HaCaT细胞模型炎症反应的影响。将HaCaT细胞随机分为NC组、五联因子(M5)组、M5+WOG组、M5+STING抑制剂(H-151)组、M5+WOG+STING激动剂(SR-717)组。采用CCK-8、EdU染色法和流式细胞仪分别检测细胞增殖和凋亡情况;免疫荧光法检测细胞屏障功能损伤相关指标;qPCR和ELISA分别检测炎症反应和银屑病特征性因子表达情况;Western blot检测STING/NF-κB信号通路相关蛋白表达情况。与NC组比较,M5组Ha Ca T细胞增殖活性,增殖率,IL-6、IL-8及TNF-αmRNA相对表达量,S100A7、S100A8及DEFB4含量,以及p-STING/STING、p-TBK1/TBK1、p-p65/p65值均上调,凋亡率以及ZO-1、Occludin及E-cadherin的阳性率均下调(P<0.05)。而WOG或STING抑制剂H-151的处理则有效逆转了上述M5诱导的效应(P<0.05)。值得注意的是,STING激动剂SR-717可部分抵消WOG的保护作用,表明WOG的疗效依赖于对STING/NF-κB通路的抑制(P<0.05)。WOG通过抑制STING/NF-κB信号通路有效抑制M5诱导的银屑病样Ha Ca T细胞增殖,促进其凋亡,修复屏障功能损伤,并减轻炎症反应。展开更多
The aim of this experiment was to evaluate the effects of dietary supplementation of stinging nettle powder(SNP) on laying performance,egg quality,and some selected serum biochemical parameters of quails.One hundred a...The aim of this experiment was to evaluate the effects of dietary supplementation of stinging nettle powder(SNP) on laying performance,egg quality,and some selected serum biochemical parameters of quails.One hundred and forty-four 10-wk-old Japanese quails(initial body weight=199±18 g) were divided into 3 dietary treatment groups(basic diet without SNP [SNPO],SNPO with 3% SNP [SNP3],SNPO with 6% SNP [SNP6]) with 4 replicates of 12 quails for a rearing period of 12 wk.At 22 wk of age,the final body weights of the SNP3 and SNP6 groups were significantly(P=0.001) reduced compared to that of the SNPO group.Daily feed intake was not statistically different among the groups.The mean number of eggs laid ranged from 65 to 69 with laying rates from 76.8% to 82.1%.The percentage of cracked eggs was not significantly different among the groups and ranged from 1.6% to 1.9%.The egg weight was similar and the feed conversion ratio was closer among the groups.The egg yolk cholesterol,serum cholesterol and serum triglyceride levels in the SNP6 group were significantly reduced(P <0.001) compared to those of the SNPO group.Serum Ca,P and Mg were not significantly influenced by the supplementation.In conclusion,the results demonstrated that the supplementation of SNP to the quail diet at the level of 6%reduced quail egg yolk cholesterol,serum total cholesterol and serum triglyceride levels and did not negatively influence quail performance.展开更多
目的:探讨干扰素基因刺激因子(stimulator of interferon genes,STING)介导的铁死亡在有氧运动改善高脂饮食小鼠心肌损伤中的作用及机制。方法:雄性C57BL/6J小鼠采用高脂饮食喂养,进行8周有氧跑台运动,通过腹腔注射diABZI药理学激活STIN...目的:探讨干扰素基因刺激因子(stimulator of interferon genes,STING)介导的铁死亡在有氧运动改善高脂饮食小鼠心肌损伤中的作用及机制。方法:雄性C57BL/6J小鼠采用高脂饮食喂养,进行8周有氧跑台运动,通过腹腔注射diABZI药理学激活STING、尾静脉注射腺相关病毒9型敲低心肌STING。体外实验中,采用棕榈酸(palmitic acid,PA)处理大鼠H9C2心肌细胞,模拟体外高脂诱导的心肌细胞损伤,通过小干扰RNA敲低STING,小分子抑制剂RSL3干预抑制谷胱甘肽过氧化物酶4(glutathione Peroxidase 4,GPX4)表达。小动物超声成像系统检测小鼠心功能;组织学染色分析心肌组织病理变化;透射电镜观察心肌线粒体形态结构;试剂盒检测小鼠心肌组织和H9C2细胞亚铁离子(Fe2+)、丙二醛(malondialdehyde,MDA)、总超氧化物歧化酶(total superoxide dismutase,T-SOD)、谷胱甘肽(glutathione,GSH)和氧化型谷胱甘肽(oxidized glutathione,GSSG)水平;二氢乙啶(dihydroethidium,DHE)染色评估活性氧(reative oxygen species,ROS)水平;JC-1染色检测线粒体膜电位变化;Western blot检测STING、GPX4、溶质载体家族7成员11(solute carrier family 7 member 11,SLC7A11)和酰基辅酶A合成酶长链家族成员4(acyl-CoA synthetase long-chain family member 4,ACSL4)蛋白表达。结果:(1)有氧运动显著抑制高脂饮食小鼠心肌STING表达。(2)STING激动剂di ABZI显著削弱有氧运动对高脂饮食小鼠心肌损伤的改善作用和对铁死亡的抑制作用。(3)敲低STING显著改善高脂饮食小鼠心脏功能和结构损伤,抑制心肌铁死亡。(4)敲低STING显著抑制PA诱导的H9C2细胞铁死亡,而GPX4抑制剂RSL3则削弱STING敲低对铁死亡的抑制作用。结论:STING-GPX4轴在高脂诱导的心肌细胞铁死亡中发挥着重要作用。有氧运动可通过下调STING表达,抑制铁死亡,改善高脂饮食小鼠心肌损伤。展开更多
Intensive fish farming has an excessive prevalence of infection and is typically controlled by the administration of antibiotics.Although amalgamated antibiotics are a relatively novel therapeutic idea and more effect...Intensive fish farming has an excessive prevalence of infection and is typically controlled by the administration of antibiotics.Although amalgamated antibiotics are a relatively novel therapeutic idea and more effective than traditional antibiotic monotherapy,they can also have a toxic effect on the fish body when it is administered abruptly.This study investigated the cyto-genotoxic effects on erythrocytes and histo-architectural malformations in the liver and kidneys of stinging catfish(Heteropneustes fossilis)in relation to Enrocip plus use as an amalgamated antibiotic agent.The experimental fish with an initial average weight of 17.38±1.94 g were divided into four treatment groups with antibiotic doses:according to the recommendation of the manufacturer 0.167 mg/ml Enrocip plus was used as a standard dose(x)and it was treated as T3,while 0%of the standard dose(0×mg/ml),1/2×(0.083 mg/ml),and 2×(0.333 mg/ml)were treated as T1,T2 and T4,respectively for a period of 30 days.The observed erythrocyte cellular deformities(ECD)were twin,tear-drop,serrated,tail budded and de-membranated cells,whereas the erythrocyte nuclear deformities(END)were a nuclear bridge,bi-nucleus,nuclear termination,karyopyknosis,and micronucleus at different concentrations of Enrocip plus.Both ECD and END percentages experienced the interaction of antibiotic dose and exposure time,and were significantly different(P<0.01).Significant changes in hepatocytes,mild to severe necrosis,vacuole formation,and hepatopancreas damage were also observed in the liver of the treated fish whereas highly degraded renal tubules and hematopoietic tissue,glomerular occlusion,and vacuolation were evident in the kidneys.The current investigation fully emphasizes the adverse effects of amalgamated antibiotics on the cytogenotoxicity and the histomorphology of the kidneys and liver of fish.Thus,the use of an amalgamated antibiotic in aquaculture must be carefully evaluated.展开更多
Background:The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation.Methods:We analyzed the DNA of an index patient with early-onset systemic inflammation,cuta...Background:The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation.Methods:We analyzed the DNA of an index patient with early-onset systemic inflammation,cutaneous vasculopathy,and pulmonary inflammation.We sequenced a candidate gene,TMEM173,encoding the stimulator of interferon genes(STING),in this patient and in five unrelated children with similar clinical phenotypes.Four children were evaluated clinically and immunologically.With the STING ligand cyclic guanosine monophosphate-adenosine monophosphate(cGAMP),we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls,as well as commercially obtained endothelial cells,and then assayed transcription of IFNB1,the gene encoding interferon-β,in the stimulated cells.We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs.Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1(STAT1),so we tested the effect of Janus kinase(JAK)inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls.展开更多
Background:The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation.Methods:We analyzed the DNA of an index patient with early-onset systemic inflammation,cuta...Background:The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation.Methods:We analyzed the DNA of an index patient with early-onset systemic inflammation,cutaneous vasculopathy,and pulmonary inflammation.We sequenced a candidate gene,TMEM173,encoding the stimulator of interferon genes(STING),in this patient and in five unrelated children with similar clinical phenotypes.展开更多
Inflammation plays a key role in driving the secondary brain injury that follows ischemic stroke.Melatonin is an endogenous neuroendocrine hormone that regulates mitochondrial homeostasis.However,the role and mechanis...Inflammation plays a key role in driving the secondary brain injury that follows ischemic stroke.Melatonin is an endogenous neuroendocrine hormone that regulates mitochondrial homeostasis.However,the role and mechanisms by which melatonin regulates microglial pyroptosis and the inflammatory cascade through double-stranded DNA(dsDNA)-sensing cyclic GMP-AMP synthase(cGAS)signaling warrant further study.Using middle cerebral artery occlusion mice,we investigated the effects of melatonin on cGAS-mediated pyroptosis and neuroinflammation.Middle cerebral artery occlusion model mice exhibited significantly increased DNA damage and cytoplasmic dsDNA release,as reflected byγH2AX staining,as well as heightened activation of the cytosolic dsDNA-sensing cGAS-STING pathway,both of which were notably suppressed by melatonin treatment.Melatonin also mitigated NOD-like receptor family pyrin domain-containing protein 3(NLRP3)inflammasome activation and nuclear factor(NF)-κB/gasdermin D-mediated pyroptosis in microglia following ischemic stroke,while exhibiting the capacity to attenuate the immune response to ischemia in mice.This led to reduced infiltration of peripheral neutrophils and monocytes/macrophages in the ischemic brain.Specifically,melatonin administration resulted in reductions in the numbers of ionized calcium-binding adapter molecule 1-positive cells and production of interleukin-6 and tumor necrosis factor-αby microglia.Regarding neurological outcomes,melatonin significantly reduced cerebral infarct volume and ameliorated neurological deficits in mice.Notably,the neuroprotective effect of melatonin was correlated with the inhibition of cGAS activity.We also developed and tested melatonin co-loaded macrophage membrane-biomimetic reactive oxygen species-responsive nanoparticles(Mф-MLT@FNGs),which exhibited therapeutic properties in middle cerebral artery occlusion mice.Our findings suggest that melatonin acts on microglial pyroptosis to inhibit neuroinflammation and reshape the immune microenvironment through regulation of the cGAS-STING-NF-κB signaling pathway.By doing so,melatonin rescues damaged brain tissue and protects neurological function,highlighting its potential as a neuroprotective treatment for ischemic stroke.展开更多
Objective:Clinical use of stimulator of interferon genes(STING)agonists has challenges due to poor responsiveness and variable efficacy.Therefore,identifying tumor types that are sensitive to these agents and clarifyi...Objective:Clinical use of stimulator of interferon genes(STING)agonists has challenges due to poor responsiveness and variable efficacy.Therefore,identifying tumor types that are sensitive to these agents and clarifying the underlying mechanisms are essential.Methods:In vitro screening was performed to identify tumor types that are sensitive to STING agonists.The non-nucleotide agonist,SR-717,and the macrocyclic agonist,E7766,were compared for efficacy.Complementary in vivo and in vitro studies,including gene-knockout models,HMGN2-knockout Neuro-2A and CT-2A cells apoptosis assays,and murine tumor models,were then performed.These experiments focused on the mechanism by which SR-717 mediates antitumor effects and emphasized the role of STING signaling-induced high-mobility group nucleosome-binding protein 2(HMGN2).In addition,the potential of HMGN2 as a prognostic biomarker was assessed.Results:Neuroblastomas and glioblastomas,two nervous system tumors,were shown to be sensitive to STING agonists.SR-717 exhibited greater antitumor efficacy compared to E7766.Mechanistic studies indicated that STING agonists promote apoptosis through activation of the intrinsic STING-signal transducer and activator of transcription 1(STAT1)-HMGN2 axis within tumor cells.Ectopic expression of HMGN2 in melanoma cells,which naturally lack HMGN2,led to significant apoptosis.Furthermore,analysis of The Cancer Genome Atlas and Gene Expression Omnibus databases revealed positive correlation between elevated HMGN2 expression and patient survival,supporting the utility of HMGN2 as a prognostic biomarker.Conclusions:This study clarified the mechanism underlying the potent antitumor activity of SR-717 in nervous system tumors through activation of the STING-STAT1-HMGN2 signaling pathway and demonstrated that SR-717 has superior efficacy compared to E7766.In addition,HMGN2 was shown to exhibit translational potential as a prognostic biomarker for patient survival.展开更多
This report presents a forensic evaluation of a case involving blindness(visual acuity grade 5)following a bee/wasp sting to the left eye.Through systematic analysis of the patient’s multiple hospital admissions,post...This report presents a forensic evaluation of a case involving blindness(visual acuity grade 5)following a bee/wasp sting to the left eye.Through systematic analysis of the patient’s multiple hospital admissions,postoperative follow-up data,and a review of the pathological mechanisms of ocular injury caused by bee venom,this study comprehensively assesses the injury characteristics,treatment course,and visual outcomes.Bee venom induces severe complications such as corneal damage,uveitis,cataract,and secondary glaucoma through multiple mechanisms including direct cytotoxicity,immune-inflammatory responses,and enzymatic hydrolysis.Despite interventions including anterior chamber irrigation,phacoemulsification with intraocular lens implantation,and antiglaucoma surgery,the affected eye ultimately lost light perception.Forensic examination confirmed the absence of light perception in the left eye and abnormal visual pathway function,consistent with clinical observations.According to the relevant Chinese disability assessment standard(JR/T 0083-2013,Article 4.2.2),the injury was classified as grade 7 disability.This study provides an in-depth discussion of the mechanisms and key forensic identification points in bee-sting-induced blindness,offering a scientific reference for similar forensic clinical cases.展开更多
Objectives:This study aimed to determine the role and mechanism underlying migration and invasion inhibitory protein(MIIP)modulation in M2 macrophages within the tumor microenvironment and the potential of targeting t...Objectives:This study aimed to determine the role and mechanism underlying migration and invasion inhibitory protein(MIIP)modulation in M2 macrophages within the tumor microenvironment and the potential of targeting the MIIP-stimulator of interferon genes(STING)pathway in colorectal cancer(CRC)therapy.Methods:MIIP expression was analyzed for associations with the STING pathway and M2 macrophage infiltration using public datasets and clinical CRC samples.CRC cells were genetically modified using lentiviral vectors to overexpress or silence MIIP and STING.The interactions of genetically modified CRC cells with macrophages were studied in co-culture systems.Techniques,including immunofluorescence staining,RT‒qPCR,western blot,ELISA,flow cytometry,and Transwell migration and invasion assays,were used to evaluate the crosstalk between CRC cells and macrophages.An orthotopic mouse CRC model was developed to study the effects of MIIP on M2 macrophage polarization and tumor metastasis through the STING-NFκB2-IL10 axis.The therapeutic significance of a STING antagonist was also assessed in vivo.Results:Analyses of The Cancer Genome Atlas(TCGA)cohort and our CRC cohort revealed low MIIP expression is associated with STING pathway activation,increased M2 macrophage infiltration,and poor clinical outcomes.The results of functional experiments demonstrated that MIIP inhibits IL10 production via the STING-TRAF3-NFκB2 axis in CRC cells,suppressing M2 macrophage polarization in co-culture systems.Conversely,M2 macrophages promoted CRC cell migration and invasion in an IL10-dependent manner.In vitro and in vivo studies confirmed that the MIIP-mediated feedback loop between CRC cells and macrophages depends on the STING-NFκB2-IL10 axis.Furthermore,inhibition of STING expression in a mouse model reduced M2 macrophage polarization and tumor metastasis.Conclusions:This study established MIIP as a crucial regulator of macrophage polarization in the CRC tumor microenvironment,providing new insights into the role in suppressing CRC progression and immune-tumor crosstalk.These findings highlight the potential of targeting the STING pathway as a therapeutic strategy for CRC patients who respond poorly to immune checkpoint inhibitors.展开更多
Dear Editor,Systemic sclerosis(SSc)is an autoimmune connective tissue disease in which there are vascular abnormalities,inflammation,and fibrosis[1].These three characteristics primarily affect the skin and lungs.Of a...Dear Editor,Systemic sclerosis(SSc)is an autoimmune connective tissue disease in which there are vascular abnormalities,inflammation,and fibrosis[1].These three characteristics primarily affect the skin and lungs.Of all the autoimmune rheumatic diseases,SSc has the highest all-cause mortality rate,and the underlying pathogenic processes that mediate disease are still obscure,with wide diff erences in presentation and progression[2,3].展开更多
文摘Nootka rose (</span><i><span style="font-family:Verdana;">Rosa nutkana </span></i><span style="font-family:Verdana;">C. Presl) and stinging nettle (</span></span><i><span style="font-family:Verdana;">Urtica dioica </span></i><span style="font-family:Verdana;">L.</span><span style="font-family:""><span style="font-family:Verdana;">) have been traditionally used in the treatment of skin infection by Indigenous peoples of Vancouver Island, British Columbia, Canada. The main objective of this study was to examine the antibacterial efficacy of extracts of Nootka </span><span style="font-family:Verdana;">rose and stinging nettle against the common pathogenic skin bacteria</span> </span><i><span style="font-family:Verdana;">Staphylococcus aureus</span></i><span style="font-family:""><span style="font-family:Verdana;">,</span><i><span style="font-family:Verdana;"> Micrococcus luteus</span></i><span style="font-family:Verdana;">, and </span><i><span style="font-family:Verdana;">Pseudomonas aeruginosa</span></i> </span><span style="font-family:Verdana;">using </span><span style="font-family:Verdana;">Indigenous science and standard methods of analysis. The Indigenous science method of plant extraction by steeping as advised by the Traditional Knowledge keeper</span><span style="font-family:Verdana;"> was performed to examine minimum inhibitory concentration </span><span style="font-family:Verdana;">(MIC) </span><span style="font-family:Verdana;">values and minimum bactericidal concentrations </span><span style="font-family:Verdana;">(MBC) by serial dilution and bacterial population counts. </span><span style="font-family:Verdana;">Soxhlet extractions and Kirby Bauer disc sensitivity testing showed that Nootka rose </span><span style="font-family:Verdana;">extracts possessed antibacterial effectiveness against all three bacterial species while stinging nettle extracts were effective against </span><i><span style="font-family:Verdana;">M. luteus</span></i><span style="font-family:""><span style="font-family:Verdana;">. Results for MIC and MBC indicated antibacterial activity against </span><i><span style="font-family:Verdana;">M. luteus</span></i><span style="font-family:Verdana;"> and </span><i><span style="font-family:Verdana;">S. aureus</span></i><span style="font-family:Verdana;"> for the </span></span><span style="font-family:Verdana;">Nootka rose when using </span><span style="font-family:""><span style="font-family:Verdana;">full-strength solutions;all three bacterial species exhibited growth when undiluted stinging nettle treatments were used. When considering bacterial population counts for</span><b> </b><i><span style="font-family:Verdana;">S. aureus,</span></i><span style="font-family:Verdana;"> results indicated</span><b> </b><span style="font-family:Verdana;">that only the Nootka rose treatment offered effective inhibition. Chemical analysis showed that alkaloid percentage was greater in the stinging nettle (0.17%) than </span></span><span style="font-family:Verdana;">Nootka rose </span><span style="font-family:Verdana;">(0.07%), while saponin percentage was greater in the </span><span style="font-family:Verdana;">Nootka rose </span><span style="font-family:Verdana;">(0.87%) than stinging nettle (0.17%). Overall, </span><span style="font-family:""><span style="font-family:Verdana;">Nootka rose showed a greater level of</span><b> </b><span style="font-family:Verdana;">antibacterial effectiveness than </span></span><span style="font-family:Verdana;">stinging nettle by Indigenous and Western scientific methods of plant extract preparation.
文摘该文主要探究汉黄芩素(WOG)调控STING/NF-κB通路对M5诱导的银屑病样HaCaT细胞模型炎症反应的影响。将HaCaT细胞随机分为NC组、五联因子(M5)组、M5+WOG组、M5+STING抑制剂(H-151)组、M5+WOG+STING激动剂(SR-717)组。采用CCK-8、EdU染色法和流式细胞仪分别检测细胞增殖和凋亡情况;免疫荧光法检测细胞屏障功能损伤相关指标;qPCR和ELISA分别检测炎症反应和银屑病特征性因子表达情况;Western blot检测STING/NF-κB信号通路相关蛋白表达情况。与NC组比较,M5组Ha Ca T细胞增殖活性,增殖率,IL-6、IL-8及TNF-αmRNA相对表达量,S100A7、S100A8及DEFB4含量,以及p-STING/STING、p-TBK1/TBK1、p-p65/p65值均上调,凋亡率以及ZO-1、Occludin及E-cadherin的阳性率均下调(P<0.05)。而WOG或STING抑制剂H-151的处理则有效逆转了上述M5诱导的效应(P<0.05)。值得注意的是,STING激动剂SR-717可部分抵消WOG的保护作用,表明WOG的疗效依赖于对STING/NF-κB通路的抑制(P<0.05)。WOG通过抑制STING/NF-κB信号通路有效抑制M5诱导的银屑病样Ha Ca T细胞增殖,促进其凋亡,修复屏障功能损伤,并减轻炎症反应。
文摘The aim of this experiment was to evaluate the effects of dietary supplementation of stinging nettle powder(SNP) on laying performance,egg quality,and some selected serum biochemical parameters of quails.One hundred and forty-four 10-wk-old Japanese quails(initial body weight=199±18 g) were divided into 3 dietary treatment groups(basic diet without SNP [SNPO],SNPO with 3% SNP [SNP3],SNPO with 6% SNP [SNP6]) with 4 replicates of 12 quails for a rearing period of 12 wk.At 22 wk of age,the final body weights of the SNP3 and SNP6 groups were significantly(P=0.001) reduced compared to that of the SNPO group.Daily feed intake was not statistically different among the groups.The mean number of eggs laid ranged from 65 to 69 with laying rates from 76.8% to 82.1%.The percentage of cracked eggs was not significantly different among the groups and ranged from 1.6% to 1.9%.The egg weight was similar and the feed conversion ratio was closer among the groups.The egg yolk cholesterol,serum cholesterol and serum triglyceride levels in the SNP6 group were significantly reduced(P <0.001) compared to those of the SNPO group.Serum Ca,P and Mg were not significantly influenced by the supplementation.In conclusion,the results demonstrated that the supplementation of SNP to the quail diet at the level of 6%reduced quail egg yolk cholesterol,serum total cholesterol and serum triglyceride levels and did not negatively influence quail performance.
文摘目的:探讨干扰素基因刺激因子(stimulator of interferon genes,STING)介导的铁死亡在有氧运动改善高脂饮食小鼠心肌损伤中的作用及机制。方法:雄性C57BL/6J小鼠采用高脂饮食喂养,进行8周有氧跑台运动,通过腹腔注射diABZI药理学激活STING、尾静脉注射腺相关病毒9型敲低心肌STING。体外实验中,采用棕榈酸(palmitic acid,PA)处理大鼠H9C2心肌细胞,模拟体外高脂诱导的心肌细胞损伤,通过小干扰RNA敲低STING,小分子抑制剂RSL3干预抑制谷胱甘肽过氧化物酶4(glutathione Peroxidase 4,GPX4)表达。小动物超声成像系统检测小鼠心功能;组织学染色分析心肌组织病理变化;透射电镜观察心肌线粒体形态结构;试剂盒检测小鼠心肌组织和H9C2细胞亚铁离子(Fe2+)、丙二醛(malondialdehyde,MDA)、总超氧化物歧化酶(total superoxide dismutase,T-SOD)、谷胱甘肽(glutathione,GSH)和氧化型谷胱甘肽(oxidized glutathione,GSSG)水平;二氢乙啶(dihydroethidium,DHE)染色评估活性氧(reative oxygen species,ROS)水平;JC-1染色检测线粒体膜电位变化;Western blot检测STING、GPX4、溶质载体家族7成员11(solute carrier family 7 member 11,SLC7A11)和酰基辅酶A合成酶长链家族成员4(acyl-CoA synthetase long-chain family member 4,ACSL4)蛋白表达。结果:(1)有氧运动显著抑制高脂饮食小鼠心肌STING表达。(2)STING激动剂di ABZI显著削弱有氧运动对高脂饮食小鼠心肌损伤的改善作用和对铁死亡的抑制作用。(3)敲低STING显著改善高脂饮食小鼠心脏功能和结构损伤,抑制心肌铁死亡。(4)敲低STING显著抑制PA诱导的H9C2细胞铁死亡,而GPX4抑制剂RSL3则削弱STING敲低对铁死亡的抑制作用。结论:STING-GPX4轴在高脂诱导的心肌细胞铁死亡中发挥着重要作用。有氧运动可通过下调STING表达,抑制铁死亡,改善高脂饮食小鼠心肌损伤。
文摘Intensive fish farming has an excessive prevalence of infection and is typically controlled by the administration of antibiotics.Although amalgamated antibiotics are a relatively novel therapeutic idea and more effective than traditional antibiotic monotherapy,they can also have a toxic effect on the fish body when it is administered abruptly.This study investigated the cyto-genotoxic effects on erythrocytes and histo-architectural malformations in the liver and kidneys of stinging catfish(Heteropneustes fossilis)in relation to Enrocip plus use as an amalgamated antibiotic agent.The experimental fish with an initial average weight of 17.38±1.94 g were divided into four treatment groups with antibiotic doses:according to the recommendation of the manufacturer 0.167 mg/ml Enrocip plus was used as a standard dose(x)and it was treated as T3,while 0%of the standard dose(0×mg/ml),1/2×(0.083 mg/ml),and 2×(0.333 mg/ml)were treated as T1,T2 and T4,respectively for a period of 30 days.The observed erythrocyte cellular deformities(ECD)were twin,tear-drop,serrated,tail budded and de-membranated cells,whereas the erythrocyte nuclear deformities(END)were a nuclear bridge,bi-nucleus,nuclear termination,karyopyknosis,and micronucleus at different concentrations of Enrocip plus.Both ECD and END percentages experienced the interaction of antibiotic dose and exposure time,and were significantly different(P<0.01).Significant changes in hepatocytes,mild to severe necrosis,vacuole formation,and hepatopancreas damage were also observed in the liver of the treated fish whereas highly degraded renal tubules and hematopoietic tissue,glomerular occlusion,and vacuolation were evident in the kidneys.The current investigation fully emphasizes the adverse effects of amalgamated antibiotics on the cytogenotoxicity and the histomorphology of the kidneys and liver of fish.Thus,the use of an amalgamated antibiotic in aquaculture must be carefully evaluated.
文摘Background:The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation.Methods:We analyzed the DNA of an index patient with early-onset systemic inflammation,cutaneous vasculopathy,and pulmonary inflammation.We sequenced a candidate gene,TMEM173,encoding the stimulator of interferon genes(STING),in this patient and in five unrelated children with similar clinical phenotypes.Four children were evaluated clinically and immunologically.With the STING ligand cyclic guanosine monophosphate-adenosine monophosphate(cGAMP),we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls,as well as commercially obtained endothelial cells,and then assayed transcription of IFNB1,the gene encoding interferon-β,in the stimulated cells.We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs.Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1(STAT1),so we tested the effect of Janus kinase(JAK)inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls.
文摘Background:The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation.Methods:We analyzed the DNA of an index patient with early-onset systemic inflammation,cutaneous vasculopathy,and pulmonary inflammation.We sequenced a candidate gene,TMEM173,encoding the stimulator of interferon genes(STING),in this patient and in five unrelated children with similar clinical phenotypes.
基金supported by the Natural Science Foundation of Heilongjiang Province,No.YQ2021H011(to QL)China Postdoctoral Science Foundation,Nos.2020M670925,2022T150172(to QL)+2 种基金Postdoctoral Foundation of Heilongjiang Province,Nos.LBH‐Z19027,LBH‐TZ2019(to QL)Institute Cultivation Fund,No.PYMS2023-1(to QL)Natural Science Foundation of Jiangsu Province,No.BK20241233(to YL).
文摘Inflammation plays a key role in driving the secondary brain injury that follows ischemic stroke.Melatonin is an endogenous neuroendocrine hormone that regulates mitochondrial homeostasis.However,the role and mechanisms by which melatonin regulates microglial pyroptosis and the inflammatory cascade through double-stranded DNA(dsDNA)-sensing cyclic GMP-AMP synthase(cGAS)signaling warrant further study.Using middle cerebral artery occlusion mice,we investigated the effects of melatonin on cGAS-mediated pyroptosis and neuroinflammation.Middle cerebral artery occlusion model mice exhibited significantly increased DNA damage and cytoplasmic dsDNA release,as reflected byγH2AX staining,as well as heightened activation of the cytosolic dsDNA-sensing cGAS-STING pathway,both of which were notably suppressed by melatonin treatment.Melatonin also mitigated NOD-like receptor family pyrin domain-containing protein 3(NLRP3)inflammasome activation and nuclear factor(NF)-κB/gasdermin D-mediated pyroptosis in microglia following ischemic stroke,while exhibiting the capacity to attenuate the immune response to ischemia in mice.This led to reduced infiltration of peripheral neutrophils and monocytes/macrophages in the ischemic brain.Specifically,melatonin administration resulted in reductions in the numbers of ionized calcium-binding adapter molecule 1-positive cells and production of interleukin-6 and tumor necrosis factor-αby microglia.Regarding neurological outcomes,melatonin significantly reduced cerebral infarct volume and ameliorated neurological deficits in mice.Notably,the neuroprotective effect of melatonin was correlated with the inhibition of cGAS activity.We also developed and tested melatonin co-loaded macrophage membrane-biomimetic reactive oxygen species-responsive nanoparticles(Mф-MLT@FNGs),which exhibited therapeutic properties in middle cerebral artery occlusion mice.Our findings suggest that melatonin acts on microglial pyroptosis to inhibit neuroinflammation and reshape the immune microenvironment through regulation of the cGAS-STING-NF-κB signaling pathway.By doing so,melatonin rescues damaged brain tissue and protects neurological function,highlighting its potential as a neuroprotective treatment for ischemic stroke.
文摘Objective:Clinical use of stimulator of interferon genes(STING)agonists has challenges due to poor responsiveness and variable efficacy.Therefore,identifying tumor types that are sensitive to these agents and clarifying the underlying mechanisms are essential.Methods:In vitro screening was performed to identify tumor types that are sensitive to STING agonists.The non-nucleotide agonist,SR-717,and the macrocyclic agonist,E7766,were compared for efficacy.Complementary in vivo and in vitro studies,including gene-knockout models,HMGN2-knockout Neuro-2A and CT-2A cells apoptosis assays,and murine tumor models,were then performed.These experiments focused on the mechanism by which SR-717 mediates antitumor effects and emphasized the role of STING signaling-induced high-mobility group nucleosome-binding protein 2(HMGN2).In addition,the potential of HMGN2 as a prognostic biomarker was assessed.Results:Neuroblastomas and glioblastomas,two nervous system tumors,were shown to be sensitive to STING agonists.SR-717 exhibited greater antitumor efficacy compared to E7766.Mechanistic studies indicated that STING agonists promote apoptosis through activation of the intrinsic STING-signal transducer and activator of transcription 1(STAT1)-HMGN2 axis within tumor cells.Ectopic expression of HMGN2 in melanoma cells,which naturally lack HMGN2,led to significant apoptosis.Furthermore,analysis of The Cancer Genome Atlas and Gene Expression Omnibus databases revealed positive correlation between elevated HMGN2 expression and patient survival,supporting the utility of HMGN2 as a prognostic biomarker.Conclusions:This study clarified the mechanism underlying the potent antitumor activity of SR-717 in nervous system tumors through activation of the STING-STAT1-HMGN2 signaling pathway and demonstrated that SR-717 has superior efficacy compared to E7766.In addition,HMGN2 was shown to exhibit translational potential as a prognostic biomarker for patient survival.
文摘This report presents a forensic evaluation of a case involving blindness(visual acuity grade 5)following a bee/wasp sting to the left eye.Through systematic analysis of the patient’s multiple hospital admissions,postoperative follow-up data,and a review of the pathological mechanisms of ocular injury caused by bee venom,this study comprehensively assesses the injury characteristics,treatment course,and visual outcomes.Bee venom induces severe complications such as corneal damage,uveitis,cataract,and secondary glaucoma through multiple mechanisms including direct cytotoxicity,immune-inflammatory responses,and enzymatic hydrolysis.Despite interventions including anterior chamber irrigation,phacoemulsification with intraocular lens implantation,and antiglaucoma surgery,the affected eye ultimately lost light perception.Forensic examination confirmed the absence of light perception in the left eye and abnormal visual pathway function,consistent with clinical observations.According to the relevant Chinese disability assessment standard(JR/T 0083-2013,Article 4.2.2),the injury was classified as grade 7 disability.This study provides an in-depth discussion of the mechanisms and key forensic identification points in bee-sting-induced blindness,offering a scientific reference for similar forensic clinical cases.
文摘Objectives:This study aimed to determine the role and mechanism underlying migration and invasion inhibitory protein(MIIP)modulation in M2 macrophages within the tumor microenvironment and the potential of targeting the MIIP-stimulator of interferon genes(STING)pathway in colorectal cancer(CRC)therapy.Methods:MIIP expression was analyzed for associations with the STING pathway and M2 macrophage infiltration using public datasets and clinical CRC samples.CRC cells were genetically modified using lentiviral vectors to overexpress or silence MIIP and STING.The interactions of genetically modified CRC cells with macrophages were studied in co-culture systems.Techniques,including immunofluorescence staining,RT‒qPCR,western blot,ELISA,flow cytometry,and Transwell migration and invasion assays,were used to evaluate the crosstalk between CRC cells and macrophages.An orthotopic mouse CRC model was developed to study the effects of MIIP on M2 macrophage polarization and tumor metastasis through the STING-NFκB2-IL10 axis.The therapeutic significance of a STING antagonist was also assessed in vivo.Results:Analyses of The Cancer Genome Atlas(TCGA)cohort and our CRC cohort revealed low MIIP expression is associated with STING pathway activation,increased M2 macrophage infiltration,and poor clinical outcomes.The results of functional experiments demonstrated that MIIP inhibits IL10 production via the STING-TRAF3-NFκB2 axis in CRC cells,suppressing M2 macrophage polarization in co-culture systems.Conversely,M2 macrophages promoted CRC cell migration and invasion in an IL10-dependent manner.In vitro and in vivo studies confirmed that the MIIP-mediated feedback loop between CRC cells and macrophages depends on the STING-NFκB2-IL10 axis.Furthermore,inhibition of STING expression in a mouse model reduced M2 macrophage polarization and tumor metastasis.Conclusions:This study established MIIP as a crucial regulator of macrophage polarization in the CRC tumor microenvironment,providing new insights into the role in suppressing CRC progression and immune-tumor crosstalk.These findings highlight the potential of targeting the STING pathway as a therapeutic strategy for CRC patients who respond poorly to immune checkpoint inhibitors.
文摘Dear Editor,Systemic sclerosis(SSc)is an autoimmune connective tissue disease in which there are vascular abnormalities,inflammation,and fibrosis[1].These three characteristics primarily affect the skin and lungs.Of all the autoimmune rheumatic diseases,SSc has the highest all-cause mortality rate,and the underlying pathogenic processes that mediate disease are still obscure,with wide diff erences in presentation and progression[2,3].
