The canonical signaling of interferon gamma(IFN-γ)through the Janus kinase 1 and 2–signal transducer and activator of transcription 1(STAT1)axis leads to the expression of several interferon-stimulated genes(ISGs),w...The canonical signaling of interferon gamma(IFN-γ)through the Janus kinase 1 and 2–signal transducer and activator of transcription 1(STAT1)axis leads to the expression of several interferon-stimulated genes(ISGs),which have diverse effects depending on the cellular context.In glioblastoma,a highly aggressive primary brain tumor in adults,elements of IFN-γcanonical signaling are deregulated,resulting in the overexpression of STAT1-target ISGs associated with tumor progression.This mini-review highlights key ISGs,including STAT1,interferon regulatory factor 1,programmed death-ligand 1,indoleamine 2,3-dioxygenase 1,and interferon-stimulated gene 15,involved in the pathology of glioblastoma.These genes may serve as valuable biomarkers and have therapeutic potential for targeting IFN-γsignaling in this malignancy.展开更多
Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report...Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells.Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype.In addition,si RNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase,tumor necrosis factorα,CD16,CD32,and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1.Taken together,our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)ranks as the fourth leading cause of cancerrelated deaths in China,and the treatment options are limited.The cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS...BACKGROUND Hepatocellular carcinoma(HCC)ranks as the fourth leading cause of cancerrelated deaths in China,and the treatment options are limited.The cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)activates the stimulator of interferon gene(STING)signaling pathway as a crucial immune response pathway in the cytoplasm,which detects cytoplasmic DNA to regulate innate and adaptive immune responses.As a potential therapeutic target,cGASSTING pathway markedly inhibits tumor cell proliferation and metastasis,with its activation being particularly relevant in HCC.However,prolonged pathway activation may lead to an immunosuppressive tumor microenvironment,which fostering the invasion or metastasis of liver tumor cells.AIM To investigate the dual-regulation mechanism of cGAS-STING in HCC.METHODS This review was conducted according to the PRISMA guidelines.The study conducted a comprehensive search for articles related to HCC on PubMed and Web of Science databases.Through rigorous screening and meticulous analysis of the retrieved literature,the research aimed to summarize and elucidate the impact of the cGAS-STING pathway on HCC tumors.RESULTS All authors collaboratively selected studies for inclusion,extracted data,and the initial search of online databases yielded 1445 studies.After removing duplicates,remaining 964 records were screened.Ultimately,55 articles met the inclusion criteria and were included in this review.CONCLUSION Acute inflammation can have a few inhibitory effects on cancer,while chronic inflammation generally promotes its progression.Extended cGAS-STING pathway activation will result in a suppressive tumor microenvironment.展开更多
The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)signaling pathway has emerged as a key mediator of neuroinflammation.While current studies primarily attribute its effects to neurons and glial ce...The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)signaling pathway has emerged as a key mediator of neuroinflammation.While current studies primarily attribute its effects to neurons and glial cells,emerging research suggests that cGAS-STING signaling may play a critical role in cerebral vasculature,particularly in brain endothelial cells.Therefore,studying the role 7of inflammation caused by the cGAS-STING pathway in brain endothelial cells could provide a more comprehensive understanding of neuroinflammatory disease and new avenues for therapeutic interventions.Here,we review the multifaceted role of global cGAS-STING signaling in various neurological and neuroinflammatory diseases and the potential contribution of cGAS-STING in brain endothelial cells.展开更多
OBJECTIVE:To examine the effects of the Jianpi Yifei Tongluo recipe(健脾益肺通络方剂,JYTR)on chronic obstructive pulmonary disease(COPD)within an animal model and to elucidate its anti-inflammatory mechanisms.METHODS:...OBJECTIVE:To examine the effects of the Jianpi Yifei Tongluo recipe(健脾益肺通络方剂,JYTR)on chronic obstructive pulmonary disease(COPD)within an animal model and to elucidate its anti-inflammatory mechanisms.METHODS:In this study,we utilized cigarette smoke(CS)exposure and lipopolysaccharide(LPS)-induced models of COPD in rats to evaluate the effects of the JYTR on airway inflammation.Sprague-Dawley rats were randomly assigned to various groups:control,model,budesonide,synbiotics,and low,medium,and high JYTR.Pulmonary function was gauged using an animal volumetric tracer.Pathological alterations in lung tissue were examined under a light microscope.To ascertain cytokine production,we conducted enzyme-linked immunosorbent assay tests,and we employed Western blotting to measure the expression levels of interferon regulatory factor 4(IRF4),arginase 1(Arg1),inducible nitric oxide synthase(iNOS),nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor,alpha(IKB-α),and P65.RESULTS:Compared to the control group,rats in the COPD model group exhibited significantly compromised pulmonary function and severe inflammatory pathology in the lungs.Treatment with budesonide,synbiotics,and the JYTR markedly improved pulmonary function and diminished the production of inflammatory cytokines transforming growth factor-beta(TGF-β),tumor necrosis factor-alpha(TNF-α),and interleukin-6(IL-6).These improvements were particularly notable in the budesonide group and the high-dose JYTR group.Additionally,the JYTR increased the expression of IRF4 and upregulated the protein expression of Arg1,while concurrently downregulating the protein expression of iNOS,phosphorylated IKB-α,and phosphorylated P65.CONCLUSION:Our current study reveals that JYTR can mitigate inflammatory lung injury,enhance lung function,and lower levels of inflammatory cytokines induced by CS or LPS exposure in COPD model rats.The mechanism behind its anti-inflammatory effect likely involves the regulation of IRF4 expression and M2 polarization through the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway.展开更多
BACKGROUND Chronic hepatitis B(CHB)patients rarely achieve functional cure with initial pegylated interferon alpha-2b(Peg-IFNα-2b)therapy.Validated tools to guide retreatment candidates are lacking.We hypothesized th...BACKGROUND Chronic hepatitis B(CHB)patients rarely achieve functional cure with initial pegylated interferon alpha-2b(Peg-IFNα-2b)therapy.Validated tools to guide retreatment candidates are lacking.We hypothesized that clinical indicators predict hepatitis B surface antigen(HBsAg)clearance during retreatment.AIM To develop a prediction model for HBsAg clearance in Peg-IFNα-2b retreatment.METHODS In this retrospective cohort study,we enrolled 135 CHB/compensated cirrhosis patients receiving Peg-IFNα-2b retreatment after initial non-clearance at Tianjin University Central Hospital(2017-2025).Predictors were identified through univariate Cox,least absolute shrinkage and selection operator,and multivariate Cox regression.Model performance was assessed via receiver operating characteristic analysis and Harrell’s C-index,with risk stratification by X-tile optimization.RESULTS HBsAg clearance rate was 20.74%(28/135).Independent predictors included:Combination nucleos(t)ide analogue(NA)therapy during initial treatment[hazard ratio(HR)=0.276,95%confidence interval(CI):0.092-0.833],baseline HBsAg at retreatment(HR=0.571,95%CI:0.410-0.795),HBsAg decline after initial treatment(HR=2.050,95%CI:1.108-3.793),and treatment interval(HR=1.013/week,95%CI:1.008-1.018).The retreatment HBsAg clearance prediction score(RHCP-S)demonstrated area under the curve of 0.920(95%CI:0.863-0.946),sensitivity of 92.3%,specificity of 79.3%.Clearance rates differed significantly:RHCP-S challenge group(≤74 points):3.45%,RHCP-S probable group(74-110 points):29.63%,RHCP-S dominant group(≥110 points):80.95%(P<0.001).CONCLUSION The overall HBsAg clearance rate with Peg-IFNα-2b retreatment was 20.74%(28/135).The RHCP-S model identifies optimal retreatment candidates(≥110 points)with 80.95%clearance probability,associated with the absence of combination NA therapy during initial treatment,greater initial HBsAg decline,longer intervals,and lower retreatment HBsAg.展开更多
AIM:To investigate the expression of interferon regulatory factors(IRFs)in peripheral blood mononuclear cells(PBMCs)of patients with Sjögren’s syndrome-related dry eye(SSDE)and to explore their correlation with ...AIM:To investigate the expression of interferon regulatory factors(IRFs)in peripheral blood mononuclear cells(PBMCs)of patients with Sjögren’s syndrome-related dry eye(SSDE)and to explore their correlation with clinical features,dendritic cell activation,and serological indicators.METHODS:A total of 53 SSDE patients and 62 non-Sjögren’s syndrome dry eye(NSSDE)patients were enrolled.Demographic and clinical data were collected,and comprehensive ophthalmic examinations were performed,including the ocular surface disease index(OSDI)questionnaires,Schirmer I test(SIT),tear break-up time(TBUT),corneal fluorescein staining score(CFS),and in vivo confocal microscopy(IVCM).PBMCs were isolated,and IRFs expression levels were analyzed using Western blotting(WB)and quantitative real-time polymerase chain reaction(qRT-PCR).Serological indicators,including antinuclear antibodies(ANA)and anti-Ro60,anti-Ro52,and anti-La autoantibodies,were detected.Statistical analyses evaluated correlations between IRFs expression and clinical parameters.RESULTS:Compared to NSSDE,the relative mRNA and protein expression of the IRF-8 was significantly upregulated in patients with SSDE(P<0.001),whereas no significant differences were observed in IRF-1,IRF-3,IRF-5,and IRF-7(P=0.12,P=0.10,P=0.66,P=0.96).Correlation analysis revealed that IRF-8 expression was positively associated with CFS and OSDI scores(r=0.57,r=0.38,both P<0.05).Moreover,IRF-8 expression correlated with corneal dendritic cell(DC)density and size,and the number of dendrites(r=0.43,r=0.40,r=0.65,all P<0.05).IRF-8 expression was significantly elevated in patients positive for anti-Ro60,anti-Ro52 and anti-La autoantibodies(P<0.05).CONCLUSION:In SSDE,IRF-8 is upregulated and associated with clinical features,DC activation,and serological indicators.These findings suggest that IRF-8 plays a critical role in SSDE pathogenesis and may serve as a potential therapeutic target for diagnosis and treatment.展开更多
Hepatitis C virus(HCV)is a major cause of liver disease worldwide.HCV is able to evade host defense mechanisms,including both innate and acquired immune responses,to establish persistent infection,which results in a b...Hepatitis C virus(HCV)is a major cause of liver disease worldwide.HCV is able to evade host defense mechanisms,including both innate and acquired immune responses,to establish persistent infection,which results in a broad spectrum of pathogenicity,such as lipid and glucose metabolism disorders and hepatocellular carcinoma development.The HCV genome is characterized by a high degree of genetic diversity,which can be associated with viral sensitivity or resistance(reflected by different virological responses)to interferon(IFN)-based therapy.In this regard,it is of importance to note that polymorphisms in certain HCV genomic regions have shown a close correlation with treatment outcome.In particular,among the HCV proteins,the core and nonstructural proteins(NS)5A have been extensively studied for their correlation with responses to IFN-based treatment.This review aims to cover updated information on the impact of major HCV genetic factors,including HCV genotype,mutations in amino acids 70 and91 of the core protein and sequence heterogeneity in the IFN sensitivity-determining region and IFN/ribavirin resistance-determining region of NS5A,on virological responses to IFN-based therapy.展开更多
Ischemic brain injury triggers an inflammatory response. tissue but can also exacerbate brain injury. Microglia are This response is necessary to clear damaged brain the innate immune cells of the brain that execute t...Ischemic brain injury triggers an inflammatory response. tissue but can also exacerbate brain injury. Microglia are This response is necessary to clear damaged brain the innate immune cells of the brain that execute this critical function. In healthy brain, microglia perform a housekeeping function, pruning unused syn- apses between neurons. However, microglia become activated to an inflammatory phenotype upon brain injury. Interferon regulatory factors modulate microglial activation and their production of inflammatory cytokines. This review briefly discusses recent findings pertaining to these regulatory mechanisms in the context of stroke recovery.展开更多
AIM To assess the effects of hepatitis E virus(HEV) on the production of type Ⅰ interferons(IFNs) and determine the underlying mechanisms.METHODS We measured the production of interferon(IFN)-alpha and-beta(-α/β) i...AIM To assess the effects of hepatitis E virus(HEV) on the production of type Ⅰ interferons(IFNs) and determine the underlying mechanisms.METHODS We measured the production of interferon(IFN)-alpha and-beta(-α/β) in genotype 3 HEV-infected C3 A cells at different time points(0, 8, 12, 24, 48, 72 and 120 h) by enzyme-linked immunosorbent assay(ELISA). The expression levels of IFN-stimulated gene(ISG)15 in HEVinfected C3A cells at different time points were tested by western blotting. The plasmid-expressing open reading frame 3(ORF3) or control plasmids(green fluorescent protein-expressing) were transfected into C3A cells, and the levels of IFN-α/β and ISG15 were evaluated, respectively. Furthermore, the plasmid-expressing ISG15 or small interfering RNA-inhibiting ISG15 was transfected into infected C3A cells. Then, the production of IFN-α/β was also measured by ELISA.RESULTS We showed that genotype 3 HEV could enhance the production of IFN-α/β and induce elevation of ISG15 in C3A cells. HEV ORF3 protein could enhance the production of IFN-α/β and the expression of ISG15. Additionally, ISG15 silencing enhanced the production of IFN-α/β. Overexpression of ISG15 resulted in the reduction of IFN-α/β.CONCLUSION HEV may promote production of IFN-α/β and expression of ISG15 via ORF3 in the early stages, and increased ISG15 subsequently inhibited the production of IFN-α/β.展开更多
Diabetic retinopathy(DR)is one of the major causes of visual impairment and irreversible blindness in developed regions.Aside from abnormal angiogenesis,inflammation is the most specific and might be the initiating fa...Diabetic retinopathy(DR)is one of the major causes of visual impairment and irreversible blindness in developed regions.Aside from abnormal angiogenesis,inflammation is the most specific and might be the initiating factor of DR.As a key participant in inflammation,interferon-gamma(IFN-γ)can be detected in different parts of the eye and is responsible for the breakdown of the blood-retina barrier and activation of inflammatory cells and other cytokines,which accelerate neovascularization and neuroglial degeneration.In addition,IFN-γis involved in other vascular complications of diabetes mellitus and angiogenesis-dependent diseases,such as diabetic nephropathy,cerebral microbleeds,and age-related macular degeneration.Traditional treatments,such as anti-vascular endothelial growth factor agents,vitrectomy,and laser photocoagulation therapy,are more effective for angiogenesis and not tolerable for every patient.Many ongoing clinical trials are exploring effective drugs that target inflammation.For instance,IFN-αacts against viruses and angiogenesis and is commonly used to treat malignant tumors.Moreover,IFN-αhas been shown to contribute to alleviating the progression of DR and other ocular diseases.In this review,we emphasize the roles that IFNs play in the pathogenesis of DR and discuss potential clinical applications of IFNs in DR,such as diagnosis,prognosis,and therapeutic treatment.展开更多
Hepatitis B virus (HBV) infection is one of the major causes of liver diseases, affecting more than 350 million people worldwide. The interferon (IFN)-mediated innate immune responses could restrict HBV replication at...Hepatitis B virus (HBV) infection is one of the major causes of liver diseases, affecting more than 350 million people worldwide. The interferon (IFN)-mediated innate immune responses could restrict HBV replication at the different steps of viral life cycle. Indeed, IFN-α has been successfully used for treatment of patients with chronic hepatitis B. However, the role of the innate immune response in HBV replication and the mechanism of the anti-HBV effect of IFN-α are not completely explored. In this review, we summarized the currently available knowledge about the IFN-mediated anti-HBV effect in the HBV life cycle and the possible effectors downstream the IFN signaling pathway. The antiviral effect of Toll-like receptors (TLRs) in HBV replication is briefly discussed. The strategies exploited by HBV to evade the IFN- and TLR-mediated antiviral actions are summarized.展开更多
AIM: To assess systematically the spectrum and extent of depressive symptoms comparing patient groups receiving peginterferon or conventional interferon.METHODS: Ninety-eight patients with chronic hepatitis C and inte...AIM: To assess systematically the spectrum and extent of depressive symptoms comparing patient groups receiving peginterferon or conventional interferon.METHODS: Ninety-eight patients with chronic hepatitis C and interferon-based therapy (+ribavirin) were consecutively enrolled in a longitudinal study. Patients were treated with conventional interferon alfa-2b (48/98patients; 5 MIU interferon alfa-2b thrice weekly) or peginterferon alfa-2b (50/98 patients; 80-150 μgpeginterferon alfa-2b) in combination with weight-adapted ribavirin (800-1 200 mg/d). Repeated psychometric testing was performed before, three times during and once after antiviral therapy: Depression was evaluated by the Hospital Anxiety and Depression Scale (HADS), anger/hostility by the Symptom Checklist-90 Items Revised (SCL-90-R).RESULTS: Therapy with pegylated interferon alfa-2bproduces comparable scores for depression (ANOVA:P = 0.875) as compared to conventional interferon.Maximums of depression scores were even higher and cases of clinically relevant depression were frequent during therapy with peginterferon. Scores for anger/hostility were comparable for both therapy subgroups.CONCLUSION: Our findings suggest that the extent and frequency of depressive symptoms in total are not reduced by peginterferon. Monitoring and management of neuropsychiatric toxicity especially depression have to be considered as much as in antiviral therapy with unmodified interferon.展开更多
Host interferon-stimulated gene 20(ISG20)exerts antiviral effects on viruses by degrading viral RNA or by enhancing IFN signaling.Here,we examined the role of ISG20 during pseudorabies virus(PRV)proliferation.We found...Host interferon-stimulated gene 20(ISG20)exerts antiviral effects on viruses by degrading viral RNA or by enhancing IFN signaling.Here,we examined the role of ISG20 during pseudorabies virus(PRV)proliferation.We found that ISG20 modulates PRV replication by enhancing IFN signaling.Further,ISG20 expression was upregulated following PRV infection and poly(I:C)treatment.Ectopic expression of ISG20 inhibited PRV proliferation in PK15 cells,whereas knockdown of ISG20 promoted PRV proliferation.In addition,ISG20 expression upregulated IFN-βexpression and enhanced IFN downstream signaling during PRV infection.Notably,PRV UL24 suppressed the transcription of ISG20,thus antagonizing its antiviral effect.Further domain mapping analysis showed that the N terminus(amino acids 1-90)of UL24 was responsible for the inhibition of ISG20 transcription.Collectively,these findings characterize the role of ISG20 in suppressing PRV replication and increase the understanding of host-PRV interplay.展开更多
AIM: To investigate the association of hypertension and diabetes mellitus (DM) with interferon-associated retinopathy (IAR) risk in chronic hepatitis C (CHC).
AIM: To examine the association between interferon(IFN) therapy and loss of hepatitis B surface antigen(HBs Ag) in inactive HBs Ag carriers. METHODS: This was a retrospective cohort study in inactive HBs Ag carriers, ...AIM: To examine the association between interferon(IFN) therapy and loss of hepatitis B surface antigen(HBs Ag) in inactive HBs Ag carriers. METHODS: This was a retrospective cohort study in inactive HBs Ag carriers, who were treatment-naive, with a serum HBs Ag level < 100 IU/m L and an undetectable hepatitis B virus(HBV) DNA level(< 100 IU/m L). All the 20 treated patients received subcutaneous PEG-IFN alfa-2a 180 μg/wk for 72 wk and were then followed for 24 wk. There were 40 untreated controls matched with 96 wk of observation. Serum HBs Ag, HBV DNA, and alanine aminotransferases were monitored every 3 mo in the treatment group and every 3-6 mo in the control group. RESULTS: Thirteen(65.0%) of 20 treated patients achieved HBs Ag loss, 12 of whom achieved HBs Ag seroconversion. Mean HBs Ag level in treated patients decreased to 6.69 ± 13.04 IU/m L after 24 wk of treatment from a baseline level of 26.22 ± 33.00 IU/m L. Serum HBV DNA level remained undetectable(< 100 IU/m L) in all treated patients during the study. HBs Ag level of the control group decreased from 25.72 ± 25.58 IU/m L at baseline to 17.11 ± 21.62 IU/m L at week 96(P = 0.108). In the control group, no patient experienced HBs Ag loss/seroconversion, and two(5.0%) developed HBV reactivation.CONCLUSION: IFN treatment results in HBs Ag loss and seroconversion in a considerable proportion of inactive HBs Ag carriers with low HBs Ag concentrations.展开更多
AIM： To investigate whether DNA-dependent activator of interferon-regulatory factors （DAI） inhibits hepatitis B virus （HBV） replication and what the mechanism is. METHODS： After the human hepatoma cell line Huh7...AIM： To investigate whether DNA-dependent activator of interferon-regulatory factors （DAI） inhibits hepatitis B virus （HBV） replication and what the mechanism is. METHODS： After the human hepatoma cell line Huh7 was cotransfected with DAI and HBV expressing plas- mid, viral protein （HBV surface antigen and HBV e an- tigen） secretion was detected by enzyme-linked immu- nosorbent assay, and HBV RNA was analyzed by real- time polymerase chain reaction and Northern blotting, and viral DNA replicative intermediates were examined by Southern blotting. Interferon regulatory factor 3 （IRF3） phosphorylation and nuclear translocation were analyzed via Western blotting and immunofluorescence staining respectively. Nuclear factor-KB （NF-KB） activity induced by DAI was detected by immunofluorescence staining of P65 and dual luciferase reporter assay. Tran- swell co-culture experiment was performed in order to investigate whether the antiviral effects of DAI were dependent on the secreted cytokines. RESULTS： Viral protein secretion was significantly re- duced by 57% （P 〈 0.05）, and the level of total HBV RNA was reduced by 67% （P 〈 0.05）. The viral core particle-associated DNA was also dramatically down- regulated in DAI-expressing Huh7 cells. Analysis of involved signaling pathways revealed that activation of NF-KB signaling was essential for DAI to elicit antivi- ral response in Huh7 cells. When the NF-KB signaling pathway was blocked by a NF-KB signaling suppressor （I~：B^-SR）, the anti-HBV activity of DAI was remarkably abrogated. The inhibitory effect of DAI was indepen- dent of IRF3 signaling and secreted cytokines. CONCLUSION： This study demonstrates that DAI can inhibit HBV replication and the inhibitory effect is asso- ciated with activation of NF-KB but independent of IRF3 and secreted cytokines.展开更多
Objective This work explores the impact of electroacupuncture(EA)on acute postoperative pain(APP)and the role of stimulator of interferon genes/type-1 interferon(STING/IFN-1)signaling pathway modulation in the analges...Objective This work explores the impact of electroacupuncture(EA)on acute postoperative pain(APP)and the role of stimulator of interferon genes/type-1 interferon(STING/IFN-1)signaling pathway modulation in the analgesic effect of EA in APP rats.Methods The APP rat model was initiated through abdominal surgery and the animals received two 30 min sessions of EA at bilateral ST36(Zusanli)and SP6(Sanyinjiao)acupoints.Mechanical,thermal and cold sensitivity tests were performed to measure the pain threshold,and electroencephalograms were recorded in the primary somatosensory cortex to identify the effects of EA treatment on APP.Western blotting and immunofluorescence were used to examine the expression and distribution of proteins in the STING/IFN-1 pathway as well as neuroinflammation.A STING inhibitor(C-176)was administered intrathecally to verify its role in EA.Results APP rats displayed mechanical and thermal hypersensitivities compared to the control group(P<0.05).APP significantly reduced the amplitude ofθ,αandγoscillations compared to their baseline values(P<0.05).Interestingly,expression levels of proteins in the STING/IFN-1 pathway were downregulated after inducing APP(P<0.05).Further,APP increased pro-inflammatory factors,including interleukin-6,tumor necrosis factor-αand inducible nitric oxide synthase,and downregulated anti-inflammatory factors,including interleukin-10 and arginase-1(P<0.05).EA effectively attenuated APP-induced painful hypersensitivities(P<0.05)and restored theθ,αandγpower in APP rats(P<0.05).Meanwhile,EA distinctly activated the STING/IFN-1 pathway and mitigated the neuroinflammatory response(P<0.05).Furthermore,STING/IFN-1 was predominantly expressed in isolectin-B4-or calcitonin-gene-related-peptide-labeled dorsal root ganglion neurons and superficial laminae of the spinal dorsal horn.Inhibition of the STING/IFN-1 pathway by intrathecal injection of C-176 weakened the analgesic and anti-inflammatory effects of EA on APP(P<0.05).Conclusion EA can generate robust analgesic and anti-inflammatory effects on APP,and these effects may be linked to activating the STING/IFN-1 pathway,suggesting that STING/IFN-1 may be a target for relieving APP.展开更多
Hepatitis C virus(HCV) infection is a major health concern worldwide. Interferon-α(IFN-α) therapy has been the main antiviral treatment for more than 20 years. Because of its established antitumor effects, IFNbased ...Hepatitis C virus(HCV) infection is a major health concern worldwide. Interferon-α(IFN-α) therapy has been the main antiviral treatment for more than 20 years. Because of its established antitumor effects, IFNbased treatments for chronic HCV infection still have a clinical impact, particularly for patients with high risk conditions of developing hepatocellular carcinoma, such as older age and advanced liver fibrosis. As a result of exhaustive research, several viral factors, including NS5 A amino acid mutations such as the IFN sensitivitydetermining region and the IFN/ribavirin resistancedetermining region, and mutations of amino acids in the core protein region(core 70 and 91) were shown to be associated with the response to IFN-α treatment. In addition, among the host factors related to the response to IFN-α treatment, polymorphisms of the interleukin-28 B gene were identified to be the most important factor. In this article, we review the factors associated with the efficacy of IFN-α treatment for chronic HCV infection. In addition, our recent findings regarding the possible involvement of anti-IFN-α neutralizing antibodies in a non-response to pegylated-IFN-α treatment are also described.展开更多
基金Supported by Colegio de Ciencia y Tecnología de la Universidad Autónoma de la Ciudad de México,No.CCYT-2025-CON-11.
文摘The canonical signaling of interferon gamma(IFN-γ)through the Janus kinase 1 and 2–signal transducer and activator of transcription 1(STAT1)axis leads to the expression of several interferon-stimulated genes(ISGs),which have diverse effects depending on the cellular context.In glioblastoma,a highly aggressive primary brain tumor in adults,elements of IFN-γcanonical signaling are deregulated,resulting in the overexpression of STAT1-target ISGs associated with tumor progression.This mini-review highlights key ISGs,including STAT1,interferon regulatory factor 1,programmed death-ligand 1,indoleamine 2,3-dioxygenase 1,and interferon-stimulated gene 15,involved in the pathology of glioblastoma.These genes may serve as valuable biomarkers and have therapeutic potential for targeting IFN-γsignaling in this malignancy.
基金supported by the National Natural Science Foundation of China,Nos.82171429,81771384a grant from Wuxi Municipal Health Commission,No.1286010241190480(all to YS)。
文摘Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells.Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype.In addition,si RNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase,tumor necrosis factorα,CD16,CD32,and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1.Taken together,our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.
基金Supported by the National Natural Science Foundation of China,No.81973840the Sichuan Provincial Administration of Traditional Chinese Medicine Major Science and Technology projects,No.2021XYCZ004。
文摘BACKGROUND Hepatocellular carcinoma(HCC)ranks as the fourth leading cause of cancerrelated deaths in China,and the treatment options are limited.The cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)activates the stimulator of interferon gene(STING)signaling pathway as a crucial immune response pathway in the cytoplasm,which detects cytoplasmic DNA to regulate innate and adaptive immune responses.As a potential therapeutic target,cGASSTING pathway markedly inhibits tumor cell proliferation and metastasis,with its activation being particularly relevant in HCC.However,prolonged pathway activation may lead to an immunosuppressive tumor microenvironment,which fostering the invasion or metastasis of liver tumor cells.AIM To investigate the dual-regulation mechanism of cGAS-STING in HCC.METHODS This review was conducted according to the PRISMA guidelines.The study conducted a comprehensive search for articles related to HCC on PubMed and Web of Science databases.Through rigorous screening and meticulous analysis of the retrieved literature,the research aimed to summarize and elucidate the impact of the cGAS-STING pathway on HCC tumors.RESULTS All authors collaboratively selected studies for inclusion,extracted data,and the initial search of online databases yielded 1445 studies.After removing duplicates,remaining 964 records were screened.Ultimately,55 articles met the inclusion criteria and were included in this review.CONCLUSION Acute inflammation can have a few inhibitory effects on cancer,while chronic inflammation generally promotes its progression.Extended cGAS-STING pathway activation will result in a suppressive tumor microenvironment.
基金partially supported by a grant(RF1AG059694)from the U.S.National Institutes of Healthby Polytrauma System of Care,VAPAHCS(to JL)。
文摘The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)signaling pathway has emerged as a key mediator of neuroinflammation.While current studies primarily attribute its effects to neurons and glial cells,emerging research suggests that cGAS-STING signaling may play a critical role in cerebral vasculature,particularly in brain endothelial cells.Therefore,studying the role 7of inflammation caused by the cGAS-STING pathway in brain endothelial cells could provide a more comprehensive understanding of neuroinflammatory disease and new avenues for therapeutic interventions.Here,we review the multifaceted role of global cGAS-STING signaling in various neurological and neuroinflammatory diseases and the potential contribution of cGAS-STING in brain endothelial cells.
基金Supported by the National Science Foundation for Distinguished Young Scholars of China to Intestinal Microflora-Mediated Regulation of Breast Regression Protein 39/chitinase-3-like Protein 1 Signaling pathway in the Intervention of Chronic Obstructive Pulmonary Disease by Invigorating Spleen Supplementing Lung and Relaxing Collaterals Method (No. 81804074)
文摘OBJECTIVE:To examine the effects of the Jianpi Yifei Tongluo recipe(健脾益肺通络方剂,JYTR)on chronic obstructive pulmonary disease(COPD)within an animal model and to elucidate its anti-inflammatory mechanisms.METHODS:In this study,we utilized cigarette smoke(CS)exposure and lipopolysaccharide(LPS)-induced models of COPD in rats to evaluate the effects of the JYTR on airway inflammation.Sprague-Dawley rats were randomly assigned to various groups:control,model,budesonide,synbiotics,and low,medium,and high JYTR.Pulmonary function was gauged using an animal volumetric tracer.Pathological alterations in lung tissue were examined under a light microscope.To ascertain cytokine production,we conducted enzyme-linked immunosorbent assay tests,and we employed Western blotting to measure the expression levels of interferon regulatory factor 4(IRF4),arginase 1(Arg1),inducible nitric oxide synthase(iNOS),nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor,alpha(IKB-α),and P65.RESULTS:Compared to the control group,rats in the COPD model group exhibited significantly compromised pulmonary function and severe inflammatory pathology in the lungs.Treatment with budesonide,synbiotics,and the JYTR markedly improved pulmonary function and diminished the production of inflammatory cytokines transforming growth factor-beta(TGF-β),tumor necrosis factor-alpha(TNF-α),and interleukin-6(IL-6).These improvements were particularly notable in the budesonide group and the high-dose JYTR group.Additionally,the JYTR increased the expression of IRF4 and upregulated the protein expression of Arg1,while concurrently downregulating the protein expression of iNOS,phosphorylated IKB-α,and phosphorylated P65.CONCLUSION:Our current study reveals that JYTR can mitigate inflammatory lung injury,enhance lung function,and lower levels of inflammatory cytokines induced by CS or LPS exposure in COPD model rats.The mechanism behind its anti-inflammatory effect likely involves the regulation of IRF4 expression and M2 polarization through the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway.
基金Supported by the Tianjin Health Research Project(Key Project),No.TJWJ2024ZD004Tianjin Key Medical Discipline(Specialty)Construction Project,No.TJYXZDXK-034A.
文摘BACKGROUND Chronic hepatitis B(CHB)patients rarely achieve functional cure with initial pegylated interferon alpha-2b(Peg-IFNα-2b)therapy.Validated tools to guide retreatment candidates are lacking.We hypothesized that clinical indicators predict hepatitis B surface antigen(HBsAg)clearance during retreatment.AIM To develop a prediction model for HBsAg clearance in Peg-IFNα-2b retreatment.METHODS In this retrospective cohort study,we enrolled 135 CHB/compensated cirrhosis patients receiving Peg-IFNα-2b retreatment after initial non-clearance at Tianjin University Central Hospital(2017-2025).Predictors were identified through univariate Cox,least absolute shrinkage and selection operator,and multivariate Cox regression.Model performance was assessed via receiver operating characteristic analysis and Harrell’s C-index,with risk stratification by X-tile optimization.RESULTS HBsAg clearance rate was 20.74%(28/135).Independent predictors included:Combination nucleos(t)ide analogue(NA)therapy during initial treatment[hazard ratio(HR)=0.276,95%confidence interval(CI):0.092-0.833],baseline HBsAg at retreatment(HR=0.571,95%CI:0.410-0.795),HBsAg decline after initial treatment(HR=2.050,95%CI:1.108-3.793),and treatment interval(HR=1.013/week,95%CI:1.008-1.018).The retreatment HBsAg clearance prediction score(RHCP-S)demonstrated area under the curve of 0.920(95%CI:0.863-0.946),sensitivity of 92.3%,specificity of 79.3%.Clearance rates differed significantly:RHCP-S challenge group(≤74 points):3.45%,RHCP-S probable group(74-110 points):29.63%,RHCP-S dominant group(≥110 points):80.95%(P<0.001).CONCLUSION The overall HBsAg clearance rate with Peg-IFNα-2b retreatment was 20.74%(28/135).The RHCP-S model identifies optimal retreatment candidates(≥110 points)with 80.95%clearance probability,associated with the absence of combination NA therapy during initial treatment,greater initial HBsAg decline,longer intervals,and lower retreatment HBsAg.
基金Supported by National Natural Science Foundation of China(No.82471046)the Joint Medical Research Project of Chongqing Health Commission and Science and Technology Bureau(No.2023GDRC004)the Program for Youth Innovation in Future Medicine of Chongqing Medical University(No.W0185).
文摘AIM:To investigate the expression of interferon regulatory factors(IRFs)in peripheral blood mononuclear cells(PBMCs)of patients with Sjögren’s syndrome-related dry eye(SSDE)and to explore their correlation with clinical features,dendritic cell activation,and serological indicators.METHODS:A total of 53 SSDE patients and 62 non-Sjögren’s syndrome dry eye(NSSDE)patients were enrolled.Demographic and clinical data were collected,and comprehensive ophthalmic examinations were performed,including the ocular surface disease index(OSDI)questionnaires,Schirmer I test(SIT),tear break-up time(TBUT),corneal fluorescein staining score(CFS),and in vivo confocal microscopy(IVCM).PBMCs were isolated,and IRFs expression levels were analyzed using Western blotting(WB)and quantitative real-time polymerase chain reaction(qRT-PCR).Serological indicators,including antinuclear antibodies(ANA)and anti-Ro60,anti-Ro52,and anti-La autoantibodies,were detected.Statistical analyses evaluated correlations between IRFs expression and clinical parameters.RESULTS:Compared to NSSDE,the relative mRNA and protein expression of the IRF-8 was significantly upregulated in patients with SSDE(P<0.001),whereas no significant differences were observed in IRF-1,IRF-3,IRF-5,and IRF-7(P=0.12,P=0.10,P=0.66,P=0.96).Correlation analysis revealed that IRF-8 expression was positively associated with CFS and OSDI scores(r=0.57,r=0.38,both P<0.05).Moreover,IRF-8 expression correlated with corneal dendritic cell(DC)density and size,and the number of dendrites(r=0.43,r=0.40,r=0.65,all P<0.05).IRF-8 expression was significantly elevated in patients positive for anti-Ro60,anti-Ro52 and anti-La autoantibodies(P<0.05).CONCLUSION:In SSDE,IRF-8 is upregulated and associated with clinical features,DC activation,and serological indicators.These findings suggest that IRF-8 plays a critical role in SSDE pathogenesis and may serve as a potential therapeutic target for diagnosis and treatment.
基金Supported by A Health and Labour Sciences Research Grant from the Ministry of Health,Labour and Welfare,Japan,a SATREPS Grant from Japan Science and Technology Agency and Japan International Cooperation Agencythe Japan Initiative for Global Research Network on Infectious Diseases(J-GRID)program from the Ministry of Education,Culture,Sports,Science and Technology,Japan
文摘Hepatitis C virus(HCV)is a major cause of liver disease worldwide.HCV is able to evade host defense mechanisms,including both innate and acquired immune responses,to establish persistent infection,which results in a broad spectrum of pathogenicity,such as lipid and glucose metabolism disorders and hepatocellular carcinoma development.The HCV genome is characterized by a high degree of genetic diversity,which can be associated with viral sensitivity or resistance(reflected by different virological responses)to interferon(IFN)-based therapy.In this regard,it is of importance to note that polymorphisms in certain HCV genomic regions have shown a close correlation with treatment outcome.In particular,among the HCV proteins,the core and nonstructural proteins(NS)5A have been extensively studied for their correlation with responses to IFN-based treatment.This review aims to cover updated information on the impact of major HCV genetic factors,including HCV genotype,mutations in amino acids 70 and91 of the core protein and sequence heterogeneity in the IFN sensitivity-determining region and IFN/ribavirin resistance-determining region of NS5A,on virological responses to IFN-based therapy.
基金supported by a grant from the Heart and Stroke Foundation of Canada(HHC,AFRS)a grant from the Natural Science&Engineering Research Council of Canada(HHC,AFRS)a Mid-Career Investigator Award from the Heart and Stroke Foundation of Ontario,Canada(HHC)
文摘Ischemic brain injury triggers an inflammatory response. tissue but can also exacerbate brain injury. Microglia are This response is necessary to clear damaged brain the innate immune cells of the brain that execute this critical function. In healthy brain, microglia perform a housekeeping function, pruning unused syn- apses between neurons. However, microglia become activated to an inflammatory phenotype upon brain injury. Interferon regulatory factors modulate microglial activation and their production of inflammatory cytokines. This review briefly discusses recent findings pertaining to these regulatory mechanisms in the context of stroke recovery.
基金Supported by the National Natural Science Foundation of China,No.81570540
文摘AIM To assess the effects of hepatitis E virus(HEV) on the production of type Ⅰ interferons(IFNs) and determine the underlying mechanisms.METHODS We measured the production of interferon(IFN)-alpha and-beta(-α/β) in genotype 3 HEV-infected C3 A cells at different time points(0, 8, 12, 24, 48, 72 and 120 h) by enzyme-linked immunosorbent assay(ELISA). The expression levels of IFN-stimulated gene(ISG)15 in HEVinfected C3A cells at different time points were tested by western blotting. The plasmid-expressing open reading frame 3(ORF3) or control plasmids(green fluorescent protein-expressing) were transfected into C3A cells, and the levels of IFN-α/β and ISG15 were evaluated, respectively. Furthermore, the plasmid-expressing ISG15 or small interfering RNA-inhibiting ISG15 was transfected into infected C3A cells. Then, the production of IFN-α/β was also measured by ELISA.RESULTS We showed that genotype 3 HEV could enhance the production of IFN-α/β and induce elevation of ISG15 in C3A cells. HEV ORF3 protein could enhance the production of IFN-α/β and the expression of ISG15. Additionally, ISG15 silencing enhanced the production of IFN-α/β. Overexpression of ISG15 resulted in the reduction of IFN-α/β.CONCLUSION HEV may promote production of IFN-α/β and expression of ISG15 via ORF3 in the early stages, and increased ISG15 subsequently inhibited the production of IFN-α/β.
基金Supported by National Natural Science Foundation of China,No.81800855 and No.82070967Natural Science Foundation of Hunan Province,No.2018JJ3765.
文摘Diabetic retinopathy(DR)is one of the major causes of visual impairment and irreversible blindness in developed regions.Aside from abnormal angiogenesis,inflammation is the most specific and might be the initiating factor of DR.As a key participant in inflammation,interferon-gamma(IFN-γ)can be detected in different parts of the eye and is responsible for the breakdown of the blood-retina barrier and activation of inflammatory cells and other cytokines,which accelerate neovascularization and neuroglial degeneration.In addition,IFN-γis involved in other vascular complications of diabetes mellitus and angiogenesis-dependent diseases,such as diabetic nephropathy,cerebral microbleeds,and age-related macular degeneration.Traditional treatments,such as anti-vascular endothelial growth factor agents,vitrectomy,and laser photocoagulation therapy,are more effective for angiogenesis and not tolerable for every patient.Many ongoing clinical trials are exploring effective drugs that target inflammation.For instance,IFN-αacts against viruses and angiogenesis and is commonly used to treat malignant tumors.Moreover,IFN-αhas been shown to contribute to alleviating the progression of DR and other ocular diseases.In this review,we emphasize the roles that IFNs play in the pathogenesis of DR and discuss potential clinical applications of IFNs in DR,such as diagnosis,prognosis,and therapeutic treatment.
基金Supported by National Natural Science Foundation of China to Pei RJ and Chen XC,Nos.31200135 and 31200699German Research Foundation to Lu MG,Nos.TRR60,GK1045/2 and GK1949
文摘Hepatitis B virus (HBV) infection is one of the major causes of liver diseases, affecting more than 350 million people worldwide. The interferon (IFN)-mediated innate immune responses could restrict HBV replication at the different steps of viral life cycle. Indeed, IFN-α has been successfully used for treatment of patients with chronic hepatitis B. However, the role of the innate immune response in HBV replication and the mechanism of the anti-HBV effect of IFN-α are not completely explored. In this review, we summarized the currently available knowledge about the IFN-mediated anti-HBV effect in the HBV life cycle and the possible effectors downstream the IFN signaling pathway. The antiviral effect of Toll-like receptors (TLRs) in HBV replication is briefly discussed. The strategies exploited by HBV to evade the IFN- and TLR-mediated antiviral actions are summarized.
基金Supported by an Unrestricted Grant From Essex Pharma (Munich, Germany), a subsidiary of Schering-Plough (Kenilworth NJ, USA)
文摘AIM: To assess systematically the spectrum and extent of depressive symptoms comparing patient groups receiving peginterferon or conventional interferon.METHODS: Ninety-eight patients with chronic hepatitis C and interferon-based therapy (+ribavirin) were consecutively enrolled in a longitudinal study. Patients were treated with conventional interferon alfa-2b (48/98patients; 5 MIU interferon alfa-2b thrice weekly) or peginterferon alfa-2b (50/98 patients; 80-150 μgpeginterferon alfa-2b) in combination with weight-adapted ribavirin (800-1 200 mg/d). Repeated psychometric testing was performed before, three times during and once after antiviral therapy: Depression was evaluated by the Hospital Anxiety and Depression Scale (HADS), anger/hostility by the Symptom Checklist-90 Items Revised (SCL-90-R).RESULTS: Therapy with pegylated interferon alfa-2bproduces comparable scores for depression (ANOVA:P = 0.875) as compared to conventional interferon.Maximums of depression scores were even higher and cases of clinically relevant depression were frequent during therapy with peginterferon. Scores for anger/hostility were comparable for both therapy subgroups.CONCLUSION: Our findings suggest that the extent and frequency of depressive symptoms in total are not reduced by peginterferon. Monitoring and management of neuropsychiatric toxicity especially depression have to be considered as much as in antiviral therapy with unmodified interferon.
基金supports from the National Key Research and Development Program of China(2016YFD0500100)Shanghai Science and Technology Innovation Action Plan(17391901900)Shanghai Municipal Agriculture Science and Technology Key Project(2016,4-2)。
文摘Host interferon-stimulated gene 20(ISG20)exerts antiviral effects on viruses by degrading viral RNA or by enhancing IFN signaling.Here,we examined the role of ISG20 during pseudorabies virus(PRV)proliferation.We found that ISG20 modulates PRV replication by enhancing IFN signaling.Further,ISG20 expression was upregulated following PRV infection and poly(I:C)treatment.Ectopic expression of ISG20 inhibited PRV proliferation in PK15 cells,whereas knockdown of ISG20 promoted PRV proliferation.In addition,ISG20 expression upregulated IFN-βexpression and enhanced IFN downstream signaling during PRV infection.Notably,PRV UL24 suppressed the transcription of ISG20,thus antagonizing its antiviral effect.Further domain mapping analysis showed that the N terminus(amino acids 1-90)of UL24 was responsible for the inhibition of ISG20 transcription.Collectively,these findings characterize the role of ISG20 in suppressing PRV replication and increase the understanding of host-PRV interplay.
基金Supported by National Natural Science Foundation of China,No.81201291National Science and Technology Major Project,No.2012ZX10002003Science and Technology Major Projects of Zhejiang Province,No.2009C03011-2
文摘AIM: To investigate the association of hypertension and diabetes mellitus (DM) with interferon-associated retinopathy (IAR) risk in chronic hepatitis C (CHC).
文摘AIM: To examine the association between interferon(IFN) therapy and loss of hepatitis B surface antigen(HBs Ag) in inactive HBs Ag carriers. METHODS: This was a retrospective cohort study in inactive HBs Ag carriers, who were treatment-naive, with a serum HBs Ag level < 100 IU/m L and an undetectable hepatitis B virus(HBV) DNA level(< 100 IU/m L). All the 20 treated patients received subcutaneous PEG-IFN alfa-2a 180 μg/wk for 72 wk and were then followed for 24 wk. There were 40 untreated controls matched with 96 wk of observation. Serum HBs Ag, HBV DNA, and alanine aminotransferases were monitored every 3 mo in the treatment group and every 3-6 mo in the control group. RESULTS: Thirteen(65.0%) of 20 treated patients achieved HBs Ag loss, 12 of whom achieved HBs Ag seroconversion. Mean HBs Ag level in treated patients decreased to 6.69 ± 13.04 IU/m L after 24 wk of treatment from a baseline level of 26.22 ± 33.00 IU/m L. Serum HBV DNA level remained undetectable(< 100 IU/m L) in all treated patients during the study. HBs Ag level of the control group decreased from 25.72 ± 25.58 IU/m L at baseline to 17.11 ± 21.62 IU/m L at week 96(P = 0.108). In the control group, no patient experienced HBs Ag loss/seroconversion, and two(5.0%) developed HBV reactivation.CONCLUSION: IFN treatment results in HBs Ag loss and seroconversion in a considerable proportion of inactive HBs Ag carriers with low HBs Ag concentrations.
基金Supported by Grants of The Chinese State Basic Research, No.2009CB522504National Mega Projects for Infectious Diseases, No. 2008ZX10203
文摘AIM： To investigate whether DNA-dependent activator of interferon-regulatory factors （DAI） inhibits hepatitis B virus （HBV） replication and what the mechanism is. METHODS： After the human hepatoma cell line Huh7 was cotransfected with DAI and HBV expressing plas- mid, viral protein （HBV surface antigen and HBV e an- tigen） secretion was detected by enzyme-linked immu- nosorbent assay, and HBV RNA was analyzed by real- time polymerase chain reaction and Northern blotting, and viral DNA replicative intermediates were examined by Southern blotting. Interferon regulatory factor 3 （IRF3） phosphorylation and nuclear translocation were analyzed via Western blotting and immunofluorescence staining respectively. Nuclear factor-KB （NF-KB） activity induced by DAI was detected by immunofluorescence staining of P65 and dual luciferase reporter assay. Tran- swell co-culture experiment was performed in order to investigate whether the antiviral effects of DAI were dependent on the secreted cytokines. RESULTS： Viral protein secretion was significantly re- duced by 57% （P 〈 0.05）, and the level of total HBV RNA was reduced by 67% （P 〈 0.05）. The viral core particle-associated DNA was also dramatically down- regulated in DAI-expressing Huh7 cells. Analysis of involved signaling pathways revealed that activation of NF-KB signaling was essential for DAI to elicit antivi- ral response in Huh7 cells. When the NF-KB signaling pathway was blocked by a NF-KB signaling suppressor （I~：B^-SR）, the anti-HBV activity of DAI was remarkably abrogated. The inhibitory effect of DAI was indepen- dent of IRF3 signaling and secreted cytokines. CONCLUSION： This study demonstrates that DAI can inhibit HBV replication and the inhibitory effect is asso- ciated with activation of NF-KB but independent of IRF3 and secreted cytokines.
基金This work was supported by the National Natural Science Foundation of China(Grant No.82071251)National Key Research and Development Program of China(Grant No.2018YFC2001802)Hubei Province Key Research and Development Program(Grant No.2021BCA145).
文摘Objective This work explores the impact of electroacupuncture(EA)on acute postoperative pain(APP)and the role of stimulator of interferon genes/type-1 interferon(STING/IFN-1)signaling pathway modulation in the analgesic effect of EA in APP rats.Methods The APP rat model was initiated through abdominal surgery and the animals received two 30 min sessions of EA at bilateral ST36(Zusanli)and SP6(Sanyinjiao)acupoints.Mechanical,thermal and cold sensitivity tests were performed to measure the pain threshold,and electroencephalograms were recorded in the primary somatosensory cortex to identify the effects of EA treatment on APP.Western blotting and immunofluorescence were used to examine the expression and distribution of proteins in the STING/IFN-1 pathway as well as neuroinflammation.A STING inhibitor(C-176)was administered intrathecally to verify its role in EA.Results APP rats displayed mechanical and thermal hypersensitivities compared to the control group(P<0.05).APP significantly reduced the amplitude ofθ,αandγoscillations compared to their baseline values(P<0.05).Interestingly,expression levels of proteins in the STING/IFN-1 pathway were downregulated after inducing APP(P<0.05).Further,APP increased pro-inflammatory factors,including interleukin-6,tumor necrosis factor-αand inducible nitric oxide synthase,and downregulated anti-inflammatory factors,including interleukin-10 and arginase-1(P<0.05).EA effectively attenuated APP-induced painful hypersensitivities(P<0.05)and restored theθ,αandγpower in APP rats(P<0.05).Meanwhile,EA distinctly activated the STING/IFN-1 pathway and mitigated the neuroinflammatory response(P<0.05).Furthermore,STING/IFN-1 was predominantly expressed in isolectin-B4-or calcitonin-gene-related-peptide-labeled dorsal root ganglion neurons and superficial laminae of the spinal dorsal horn.Inhibition of the STING/IFN-1 pathway by intrathecal injection of C-176 weakened the analgesic and anti-inflammatory effects of EA on APP(P<0.05).Conclusion EA can generate robust analgesic and anti-inflammatory effects on APP,and these effects may be linked to activating the STING/IFN-1 pathway,suggesting that STING/IFN-1 may be a target for relieving APP.
文摘Hepatitis C virus(HCV) infection is a major health concern worldwide. Interferon-α(IFN-α) therapy has been the main antiviral treatment for more than 20 years. Because of its established antitumor effects, IFNbased treatments for chronic HCV infection still have a clinical impact, particularly for patients with high risk conditions of developing hepatocellular carcinoma, such as older age and advanced liver fibrosis. As a result of exhaustive research, several viral factors, including NS5 A amino acid mutations such as the IFN sensitivitydetermining region and the IFN/ribavirin resistancedetermining region, and mutations of amino acids in the core protein region(core 70 and 91) were shown to be associated with the response to IFN-α treatment. In addition, among the host factors related to the response to IFN-α treatment, polymorphisms of the interleukin-28 B gene were identified to be the most important factor. In this article, we review the factors associated with the efficacy of IFN-α treatment for chronic HCV infection. In addition, our recent findings regarding the possible involvement of anti-IFN-α neutralizing antibodies in a non-response to pegylated-IFN-α treatment are also described.
