AIM： To analyze and to compare the effects of interferon （IFN）-α, IFN-β, and IFN-γ on pancreatic stellate cell （PSC） activation/n vitro and to elucidate the molecular basis of IFN action. METHODS： PSCs were i...AIM： To analyze and to compare the effects of interferon （IFN）-α, IFN-β, and IFN-γ on pancreatic stellate cell （PSC） activation/n vitro and to elucidate the molecular basis of IFN action. METHODS： PSCs were isolated from rat＇s pancreatic tissue, cultured and stimulated with recombinant rat IFNs. Cell proliferation and collagen synthesis were assessed by measuring the incorporation of 5-bromo-2＇ -deoxyuridine （BrdU） into DNA and [^3H]-proline into acetic acid-soluble proteins, respectively. Apoptotic ceils were determined by FACS analysis （sub-G1 peak method）. Exhibition of the myofibroblastic PSC phenotype was monitored by immunoblot analysis of （α-smooth muscle actin （α-SMA） expression. To assess the activation of signal transducer and activator of transcription （STAT）, Western blots using phospho- STAT-specific antibodies were performed. In studies on STAT1 function, expression of the protein was inhibited by siRNA. RESULTS： IFN-β and IFN-γ, but not IFN-α significantly diminished PSC proliferation and collagen synthesis. IFN-γ, was the only IFN that clearly inhibited α-SMA expression. Under the experimental conditions used, no enhanced rate of apoptotic cell death was observed in response to any IFN treatment. IFN-β and IFN-γ, induced a strong increase of STAT1 and STAT3 tyrosine phosphorylation, while the effect of IFN-α was much weaker. Inhibition of STAT1 expression with siRNA was associated with a significantly reduced growth-inhibitory effect of IFN-γ. CONCLUSION： IFN-β and particularly IFN-γ, display inhibitory effects on PSC activation in vitro and should be tested regarding their in vitro efficiency. Growth inhibition by IFN-γ action requires STAT1.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
Viruses are obligatory intracellular parasites. Most of the cells in animaland human body possess the innate ability to fight viruses. Innate immune function restrictsinfection at the early stage and delay spread of v...Viruses are obligatory intracellular parasites. Most of the cells in animaland human body possess the innate ability to fight viruses. Innate immune function restrictsinfection at the early stage and delay spread of virus. The early stage of infection is the stage ofinteraction between the virus and the host's defence system. Once the latter is breached, the earlynon-specific or innate immune components such as interferon (IFN), natural killer (NK) cells andmacrophages become active. As the infection proceeds, the adaptive (specific) immune responsedevelops, with the appearance of cytotoxic T cells, helper T cells and antiviral antibodies.Antibodies provide a major barrier to virus spread between cells and cells and are particularlyimportant in restriction of virus spread in the blood stream. Virus infection directly activates thetranscription of type Ⅰ IFN (IFN-alfa/beta) genes in infected cells, while the type Ⅱ IFN(IFN-gamma) plays an essential role in the regulation of an adaptive immune response rather thaninnate immune response. Therefore, Type Ⅰ IFN is the first defence for host and neighbouring cellsto resist virus infection.展开更多
Objective：To investigate the effects and mechanisms of interferon in combination with alltrans retinoic acid （ATRA） on proliferation and differentiation of ATRA-resistent APL cell. Methods ：After MR2 cells （ATRA-...Objective：To investigate the effects and mechanisms of interferon in combination with alltrans retinoic acid （ATRA） on proliferation and differentiation of ATRA-resistent APL cell. Methods ：After MR2 cells （ATRA-resistance cell line） were treated with IFN-α, IFN-γ and ATRA alone or IFN-α and IFN-γ in combination with ATRA respectively. The cell proliferation was tested by MTT test and the cell differentiation was tested through light microscope by NBT test and flow cytometry （FCM）. The expres sion of promyelocytic leukemia （PML） protein was observed by indirect immune fluorescent method. Results： Both IFN-α and IFN-γ could inhibit the proliferation and induce the differentiation of MR2 cells to some extent. The effects were more obvious after both interferons in combination with ATRA respectively （P〈0.05）. Moreover, the maturation of MR2 cells induced by IFN-γ＋ATRA group was more higher than that by IFN-α＋ATRA group （P〈0. 05）. Both interferons could induce the expressions of PML protein. Conclusion：Both interferons can inhibit MR2 cells proliferation, which may be related to the expression of PML protein induced by both interferons. The inducing differentiation effects of IFN-γ＋ATRA group on MR2 cells are more powerful than those of IFN-aq-ATRA group, which may be related to the different signal transduction pathway of both interferons.展开更多
Sirtuin 2 is a member of the sirtuin family nicotinamide adenine dinucleotide(NAD~+)-dependent deacetylases, known for its regulatory role in different processes, including inflammation. In this context, sirtuin 2 has...Sirtuin 2 is a member of the sirtuin family nicotinamide adenine dinucleotide(NAD~+)-dependent deacetylases, known for its regulatory role in different processes, including inflammation. In this context, sirtuin 2 has been involved in the modulation of key inflammatory signaling pathways and transcription factors by deacetylating specific targets, such as nuclear factor κB and nucleotide-binding oligomerization domain-leucine-rich-repeat and pyrin domain-containing protein 3(NLRP3). However, whether sirtuin 2-mediated pathways induce a pro-or an anti-inflammatory response remains controversial. Sirtuin 2 has been implicated in promoting inflammation in conditions such as asthma and neurodegenerative diseases, suggesting that its inhibition in these conditions could be a potential therapeutic strategy. Conversely, arthritis and type 2 diabetes mellitus studies suggest that sirtuin 2 is essential at the peripheral level and, thus, its inhibition in these pathologies would not be recommended. Overall, the precise role of sirtuin 2 in inflammation appears to be context-dependent, and further investigation is needed to determine the specific molecular mechanisms and downstream targets through which sirtuin 2 influences inflammatory processes in various tissues and pathological conditions. The present review explores the involvement of sirtuin 2 in the inflammation associated with different pathologies to elucidate whether its pharmacological modulation could serve as an effective strategy for treating this prevalent symptom across various diseases.展开更多
A hallmark of systemic lupus erythematosus(SLE)is the breaking of B-cell tolerance with the generation of high-affinity autoantibodies;however,the antibody-independent features of the B-cell compartment in SLE are les...A hallmark of systemic lupus erythematosus(SLE)is the breaking of B-cell tolerance with the generation of high-affinity autoantibodies;however,the antibody-independent features of the B-cell compartment in SLE are less understood.In this study,we performed an extensive examination of B-cell subsets and their proinflammatory properties in a Chinese cohort of new-onset SLE patients.We observed that SLE patients exhibited an increased frequency of transitional B cells compared with healthy donors and rheumatoid arthritis patients.Plasma from SLE patients potently promoted the survival of transitional B cells in a type I IFN-dependent manner,which can be recapitulated by direct IFN-αtreatment.Furthermore,the effect of IFN-αon enhanced survival of transitional B cells was associated with NF-κB pathway activation and reduced expression of the pro-apoptotic molecule Bax.Transitional B cells from SLE patients harbored a higher capacity to produce proinflammatory cytokine IL-6,which was also linked to the overactivated type I IFN pathway.In addition,the frequency of IL-6-producing transitional B cells was positively correlated with disease activity in SLE patients,and these cells were significantly reduced after short-term standard therapies.Thus,the current study provides a direct link between type I IFN pathway overactivation and the abnormally high frequency and proinflammatory properties of transitional B cells in active SLE patients,which contributes to the understanding of the roles of type I IFNs and B cells in the pathogenesis of SLE.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
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
Humans and other vertebrates are safeguarded from invading pathogenic microbes by the immune system.Black seed,scientifically known as Nigella sativa,has garnered attention for its potential immunomodulatory effects i...Humans and other vertebrates are safeguarded from invading pathogenic microbes by the immune system.Black seed,scientifically known as Nigella sativa,has garnered attention for its potential immunomodulatory effects in both clinical and preclinical studies.This comprehensive review aims to consolidate and analyze the existing body of evidence surrounding the immunological impact of black seeds.In this review,we analyze the immunomodulatory potentials of black seeds(N.sativa).For the purpose of finding pertinent publications,the literatures was searched in web-based databases,including Web of Science,Medline/PMC/PubMed,Embase,EBSCO,Google Scholar,Science Direct,and reference lists.Several clinical,in vivo,and in vitro studies have demonstrated that supplementation with black seeds(N.sativa)has potential immunomodulatory activity.Black seeds(N.sativa)may influence immune responses through a variety of mechanisms.By synthesizing and critically assessing the current state of knowledge on the immunomodulatory effects of black seeds,this review aims to provide valuable insights into the potential therapeutic uses and future research directions for harnessing the immunological benefits of this natural remedy.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
Ring finger protein 122(RNF122),an E3 ubiquitin ligase,orchestrates antiviral immune responses in mammals by targeting retinoic acid-inducible gene 1 and melanoma differentiation-associated gene 5 for ubiquitination.H...Ring finger protein 122(RNF122),an E3 ubiquitin ligase,orchestrates antiviral immune responses in mammals by targeting retinoic acid-inducible gene 1 and melanoma differentiation-associated gene 5 for ubiquitination.However,its functional relevance in teleosts has yet to be clearly defined,particularly regarding the identification of substrate-specific regulatory sites.This study characterized RNF122 from mandarin fish(Siniperca chuatsi),termed scRNF122,and investigated its regulatory impact on stimulator of interferon genes(STING)-mediated antiviral signaling.Results showed that scRNF122 expression was up-regulated in response to mandarin fish ranavirus(MRV)infection,and its overexpression suppressed scSTING-mediated interferon(IFN)production and enhanced MRV replication.Co-immunoprecipitation confirmed a direct interaction between scRNF122 and scSTING.Functional assays demonstrated that scRNF122 facilitated scSTING degradation through the ubiquitin-proteasome pathway,a process impeded by MG132 treatment.Ubiquitination analyses of various scSTING mutants revealed that scRNF122 catalyzed scSTING ubiquitination at K95,K117,and K155 residues.Moreover,scRNF122 significantly impaired scSTING-dependent antiviral responses by engaging negative regulatory elements within the signaling cascade.Overall,scRNF122 was identified as a negative modulator of STING-mediated IFN signaling in mandarin fish,diminishing STING-dependent antiviral activity and promoting its degradation via the ubiquitin-proteasome pathway at lysine residues K95,K117,and K155.These findings provide mechanistic insight into the post-translational control of STING in teleosts and establish a foundation for future investigations into antiviral immune regulation.展开更多
Chronic hepatitis delta virus(HDV)represents a rare but important co-infection in approximately 5%of patients with chronic hepatitis B virus(HBV)infection,and is associated with significant morbidity and mortality due...Chronic hepatitis delta virus(HDV)represents a rare but important co-infection in approximately 5%of patients with chronic hepatitis B virus(HBV)infection,and is associated with significant morbidity and mortality due to an increased risk for liver cirrhosis,liver failure,and hepatocellular carcinoma relative to HBV monoinfected individuals.The current treatment of chronic HDV infection includes the off-label use of pegylated interferon(IFN),which is limited by poor safety,tolerability,and efficacy.Guidelines of the major international liver organizations such as the American Association for the Study of Liver Diseases,European Association for the Study of the Liver,and Asian Pacific Association for the Study of the Liver provide recommendations for contemporary diagnosis and management of chronic HDV infection,including the incorporation of bulevirtide,a newly licensed antiviral agent in Europe.Significant unmet medical needs remain in the treatment of HDV,and recent advances in drug development offer hope for meaningful advances in drug therapy which may improve virologic response rates and clinical outcomes.This review summarizes trial design and available efficacy data from key phase 2 and 3 trials for investigational therapies including entry inhibitors(bulevirtide),prenylation inhibitors(lonafarnib),novel IFNs(peginterferon lambda),RNA interference molecules(JNJ-3989,elebsiran),monoclonal antibodies(tobevibart),and nucleic acid polymers(REP2139),and addresses future directions in HDV pharmacotherapy.展开更多
Current treatment options for hepatitis D are limited,with pegylated interferonalpha(PEG-IFNα)being the only therapy available in the Asia-Pacific region.However,PEG-IFNαhas limited efficacy and significant side eff...Current treatment options for hepatitis D are limited,with pegylated interferonalpha(PEG-IFNα)being the only therapy available in the Asia-Pacific region.However,PEG-IFNαhas limited efficacy and significant side effects.Pegylated interferon lambda acts on interferon-lambda(Type III)receptors predominantly expressed in hepatocytes.In 2023,bulevirtide was approved in the European Union and Russia for treating chronic hepatitis D.This drug works by binding to and inhibiting the sodium taurocholate co-transporting polypeptide receptor on liver cells,which is the primary entry point for the virus.Recently,several new drugs have entered various stages of development,offering hope for improved hepatitis D virus(HDV)management.Two more viral entry inhibitors are HH003 and tobevibart.Other agents include nucleic acid polymers(REP 2139-Mg),prenylation inhibitors(lonafarnib),and RNA interference-based therapies(elebsiran).Emerging trials are now considering combination therapies,such as SOLSTICE,a Phase 2 clinical trial evaluating tobevibart alone or combined with elebsiran.The combination dosed monthly achieved>50%virologic and biochemical response at 24 weeks of therapy.The efficacy and safety of these drugs will further be evaluated in ECLIPSE 1,2,and 3 trials.With these new treatments on the horizon,the prospects for improved HDV patient outcomes are promising.展开更多
To investigate the risk and influencing factors of long-term liver adverse events in chronic hepatitis B patients achieving hepatitis B surface antigen(HBsAg)clearance after pegylated interferonα(Peg-IFNα)treatment,...To investigate the risk and influencing factors of long-term liver adverse events in chronic hepatitis B patients achieving hepatitis B surface antigen(HBsAg)clearance after pegylated interferonα(Peg-IFNα)treatment,a retrospective analysis was conducted on 456 patients at Beijing Ditan Hospital from 2008 to 2023 who achieved HBsAg clearance and discontinued Peg-IFNαtreatment.The baseline was defined as the time of HBsAg clearance and treatment cessation.The endpoint was the first occurrence of liver adverse events(hepatocellular carcinoma or ascites)or last follow-up.Subsequently,we evaluated the incidence and risk factors of liver adverse events,along with changes in liver fibrosis,cirrhosis,and liver function indicators.During a median follow-up of 70 months,the incidence of liver adverse events was 2.30%,hepatocellular carcinoma 1.76%,and ascites 0.55%.Older age and cirrhosis were significant risk factors(HR 1.075 and 41.393,both P<0.01).The APRI score significantly improved at follow-up compared to baseline(0.53 vs.0.25,P<0.001),and cirrhosis prevalence decreased from 5.70%to 0.88%(P<0.001).In conclusion,patients who achieved HBsAg clearance and discontinued Peg-IFNαtreatment have a low risk of liver adverse events,while advanced age and cirrhosis remain major risk factors.展开更多
Peyronie’s disease(PD)presents a multifaceted challenge in contemporary urological practice,marked by penile deformity,pain,and the potential for erectile dysfunction.We meticulously explored the existing literature ...Peyronie’s disease(PD)presents a multifaceted challenge in contemporary urological practice,marked by penile deformity,pain,and the potential for erectile dysfunction.We meticulously explored the existing literature of intralesional/topical interventions,aiming to provide clinicians with a nuanced understanding of available options for comprehensive PD management.To conduct this review,we performed a systematic search using the PubMed,Scopus,and ScienceDirect databases,including the keywords of combination of the“Peyronie’s disease/plastic induration of the penis(PIP)and intralesional/topical treatments”.The study selection was based on adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)guidelines,resulting in the inclusion of 16 articles.We delve into the effectiveness and safety profiles of collagenase Clostridium histolyticum(CCH),interferon,platelet-rich plasma(PRP),hyaluronic acid,botulinum toxin,stem cell,extracorporeal shock wave therapy(ESWT),and traction therapy,assessing their impact on penile curvature,length improvement,and patient-reported symptoms and outcomes.The best options evaluated are intralesional injections of CCH and penile traction devices,alone or in combination.Despite PD remains a challenge for urologists,the objective of this review is to contribute to the evolving landscape of PD management,fostering informed decision-making,and personalized care for individuals grappling with this challenging condition.展开更多
Topical chemotherapy is increasingly used to treat ocular surface tumors as a primary therapy and an adjuvant treatment after surgical excision.The most employed topical agents include mitomycin C(MMC),5-fluorouracil(...Topical chemotherapy is increasingly used to treat ocular surface tumors as a primary therapy and an adjuvant treatment after surgical excision.The most employed topical agents include mitomycin C(MMC),5-fluorouracil(5-FU),and interferon alpha-2b(IFNα2b),each with distinctmechanisms of action,efficacy profiles,and toxicity risks.Although these agents offer effective tumor control and allow for a non-invasive approach in many cases,ocular surface complications requiring medical or surgical management can occur.This summarizes the adverse effect and outilines practical strategies for their prevention and treatment.MMC is the most potent agent but also the most toxic,with reported complications such as limbal stemcell deficiency,punctal stenosis,and persistent epithelial defects.5-FU demonstrates a more favorable safety profile,although rare cases of corneal ulceration have been described.IFNα2b is well tolerated and associated primarily with mild,reversible reactions.The choice of the proper agent should be tailored according to patient’s clinical presentation,ocular surface status,and ability to adhere to therapy and followup.Timely recognition and management of complications are essential to minimize long-term sequelae.Reliance on compounded formulations highlights the need for stable,standardized,and commercially available topical agents specifically designed for ocular use to ensure safety,reproducibility,and global accessibility.展开更多
TypeⅠinterferon(IFN)-mediated innate immune responses represent the first line of host defense against viral infection.However,the molecular mechanisms by which avian infuenza virus(AIV)inhibits typeⅠIFN production ...TypeⅠinterferon(IFN)-mediated innate immune responses represent the first line of host defense against viral infection.However,the molecular mechanisms by which avian infuenza virus(AIV)inhibits typeⅠIFN production in ducks are not well understood.Here,we frst found that the polymerase basic 2(PB2)protein of H5N1 subtype AIV inhibited the typeⅠIFN responses by targeting duck mitochondrial antiviral signaling protein(MAVS).We further demonstrated that H5N1-PB2 bound to theΔtransmembrane(ΔTM)domain of duck MAVS,and the polymerase basic 1(PB1)binding domain(PBD)and RNA binding nuclear import domain(RND)of H5N1-PB2 interacted with MAVS to inhibit typeⅠIFN expression in ducks.Collectively,our fndings contribute to understanding the molecular mechanism by which AIV proteins regulate the retinoic acid-inducible geneⅠ(RIG-Ⅰ)-like receptor(RLR)signaling pathway to evade host antiviral immune responses in ducks.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
Background:Expression of mRNA is widely regulated by N6-methyladenosine(m6A).An increasing number of studies have shown that m6A methylation,facilitated by methyltransferase 3(METTL3),is crucial in the progression of ...Background:Expression of mRNA is widely regulated by N6-methyladenosine(m6A).An increasing number of studies have shown that m6A methylation,facilitated by methyltransferase 3(METTL3),is crucial in the progression of tumors.Previous reports have indicated the involvement of both METTL3 and c-Src kinase in the evolution of liver cancer.However,the potential connection between c-Src and the METTL3-mediated mechanism in liver cancer progression remains elusive.Methods:The correlation expression between c-Src and METTL3 between liver cancer patients and the control group was analyzed using the TCGA database,and was further demonstrated by Western blot and RT-qPCR.The functional roles of c-Src in METTL3-regulated liver cancer progression were investigated by cell proliferation assays and colony formation assays.The regulatory mechanism of METTL3 in c-Src expression was accessed by RNA-immunoprecipitation(RIP)-qPCR.Results:We demonstrated that c-Src kinase promoted liver cancer development,and the expression of SRC(encodes c-Src kinase)was positively correlated with METTL3 in liver cancer cases.We showed that SRC mRNA could be m6A-modified,and METTL3 regulated the transcription of SRC mRNA through interferon regulatory factor 1(IRF1).We revealed that IRF1,the expression of which was positively regulated byMETTL3,was a novel transcription factor of c-Src.Lastly,The pro-proliferative effect of METTL3 on hepatocellular carcinoma was mechanistically linked to IRF1/c-Src axis activation,as evidenced by our experimental data.Conclusion:Results suggested that the METTL3/IRF1/c-Src axis played potential oncogenic roles in liver cancer development and the axis may be a promising therapeutic target in the disease.展开更多
基金Supported by a grant from the Bundesministerium für Bildung und Forschung,No.FKZ 01ZZ0108
文摘AIM： To analyze and to compare the effects of interferon （IFN）-α, IFN-β, and IFN-γ on pancreatic stellate cell （PSC） activation/n vitro and to elucidate the molecular basis of IFN action. METHODS： PSCs were isolated from rat＇s pancreatic tissue, cultured and stimulated with recombinant rat IFNs. Cell proliferation and collagen synthesis were assessed by measuring the incorporation of 5-bromo-2＇ -deoxyuridine （BrdU） into DNA and [^3H]-proline into acetic acid-soluble proteins, respectively. Apoptotic ceils were determined by FACS analysis （sub-G1 peak method）. Exhibition of the myofibroblastic PSC phenotype was monitored by immunoblot analysis of （α-smooth muscle actin （α-SMA） expression. To assess the activation of signal transducer and activator of transcription （STAT）, Western blots using phospho- STAT-specific antibodies were performed. In studies on STAT1 function, expression of the protein was inhibited by siRNA. RESULTS： IFN-β and IFN-γ, but not IFN-α significantly diminished PSC proliferation and collagen synthesis. IFN-γ, was the only IFN that clearly inhibited α-SMA expression. Under the experimental conditions used, no enhanced rate of apoptotic cell death was observed in response to any IFN treatment. IFN-β and IFN-γ, induced a strong increase of STAT1 and STAT3 tyrosine phosphorylation, while the effect of IFN-α was much weaker. Inhibition of STAT1 expression with siRNA was associated with a significantly reduced growth-inhibitory effect of IFN-γ. CONCLUSION： IFN-β and particularly IFN-γ, display inhibitory effects on PSC activation in vitro and should be tested regarding their in vitro efficiency. Growth inhibition by IFN-γ action requires STAT1.
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.
文摘Viruses are obligatory intracellular parasites. Most of the cells in animaland human body possess the innate ability to fight viruses. Innate immune function restrictsinfection at the early stage and delay spread of virus. The early stage of infection is the stage ofinteraction between the virus and the host's defence system. Once the latter is breached, the earlynon-specific or innate immune components such as interferon (IFN), natural killer (NK) cells andmacrophages become active. As the infection proceeds, the adaptive (specific) immune responsedevelops, with the appearance of cytotoxic T cells, helper T cells and antiviral antibodies.Antibodies provide a major barrier to virus spread between cells and cells and are particularlyimportant in restriction of virus spread in the blood stream. Virus infection directly activates thetranscription of type Ⅰ IFN (IFN-alfa/beta) genes in infected cells, while the type Ⅱ IFN(IFN-gamma) plays an essential role in the regulation of an adaptive immune response rather thaninnate immune response. Therefore, Type Ⅰ IFN is the first defence for host and neighbouring cellsto resist virus infection.
文摘Objective：To investigate the effects and mechanisms of interferon in combination with alltrans retinoic acid （ATRA） on proliferation and differentiation of ATRA-resistent APL cell. Methods ：After MR2 cells （ATRA-resistance cell line） were treated with IFN-α, IFN-γ and ATRA alone or IFN-α and IFN-γ in combination with ATRA respectively. The cell proliferation was tested by MTT test and the cell differentiation was tested through light microscope by NBT test and flow cytometry （FCM）. The expres sion of promyelocytic leukemia （PML） protein was observed by indirect immune fluorescent method. Results： Both IFN-α and IFN-γ could inhibit the proliferation and induce the differentiation of MR2 cells to some extent. The effects were more obvious after both interferons in combination with ATRA respectively （P〈0.05）. Moreover, the maturation of MR2 cells induced by IFN-γ＋ATRA group was more higher than that by IFN-α＋ATRA group （P〈0. 05）. Both interferons could induce the expressions of PML protein. Conclusion：Both interferons can inhibit MR2 cells proliferation, which may be related to the expression of PML protein induced by both interferons. The inducing differentiation effects of IFN-γ＋ATRA group on MR2 cells are more powerful than those of IFN-aq-ATRA group, which may be related to the different signal transduction pathway of both interferons.
基金funded by FEDER/Ministerio de Ciencia,Innovación y Universidades Agencia Estatal de Investigación/Project(PID2020-119729GB-100,REF/AEI/10.13039/501100011033)(to EP)a predoctoral fellowship from the Spanish Ministry of Universities(FPU)and Amigos de la Universidad de Navarra(to NSS)“Programa MRR Investigo 2023”(to MGB and MMD)。
文摘Sirtuin 2 is a member of the sirtuin family nicotinamide adenine dinucleotide(NAD~+)-dependent deacetylases, known for its regulatory role in different processes, including inflammation. In this context, sirtuin 2 has been involved in the modulation of key inflammatory signaling pathways and transcription factors by deacetylating specific targets, such as nuclear factor κB and nucleotide-binding oligomerization domain-leucine-rich-repeat and pyrin domain-containing protein 3(NLRP3). However, whether sirtuin 2-mediated pathways induce a pro-or an anti-inflammatory response remains controversial. Sirtuin 2 has been implicated in promoting inflammation in conditions such as asthma and neurodegenerative diseases, suggesting that its inhibition in these conditions could be a potential therapeutic strategy. Conversely, arthritis and type 2 diabetes mellitus studies suggest that sirtuin 2 is essential at the peripheral level and, thus, its inhibition in these pathologies would not be recommended. Overall, the precise role of sirtuin 2 in inflammation appears to be context-dependent, and further investigation is needed to determine the specific molecular mechanisms and downstream targets through which sirtuin 2 influences inflammatory processes in various tissues and pathological conditions. The present review explores the involvement of sirtuin 2 in the inflammation associated with different pathologies to elucidate whether its pharmacological modulation could serve as an effective strategy for treating this prevalent symptom across various diseases.
基金This work was supported by the National Basic Research Program of China(No.2014CB541904)the National Natural Science Foundation of China(Nos.31470879 81571575 8171101311 and 31770960)+2 种基金the Interdisciplinary Innovation Team,External Cooperation Program(No.GJHZ201312)Key Project QYZDB-SSW-SMC036the Strategic Priority Research Program(No.XDPB0303),Chinese Academy of Sciences.
文摘A hallmark of systemic lupus erythematosus(SLE)is the breaking of B-cell tolerance with the generation of high-affinity autoantibodies;however,the antibody-independent features of the B-cell compartment in SLE are less understood.In this study,we performed an extensive examination of B-cell subsets and their proinflammatory properties in a Chinese cohort of new-onset SLE patients.We observed that SLE patients exhibited an increased frequency of transitional B cells compared with healthy donors and rheumatoid arthritis patients.Plasma from SLE patients potently promoted the survival of transitional B cells in a type I IFN-dependent manner,which can be recapitulated by direct IFN-αtreatment.Furthermore,the effect of IFN-αon enhanced survival of transitional B cells was associated with NF-κB pathway activation and reduced expression of the pro-apoptotic molecule Bax.Transitional B cells from SLE patients harbored a higher capacity to produce proinflammatory cytokine IL-6,which was also linked to the overactivated type I IFN pathway.In addition,the frequency of IL-6-producing transitional B cells was positively correlated with disease activity in SLE patients,and these cells were significantly reduced after short-term standard therapies.Thus,the current study provides a direct link between type I IFN pathway overactivation and the abnormally high frequency and proinflammatory properties of transitional B cells in active SLE patients,which contributes to the understanding of the roles of type I IFNs and B cells in the pathogenesis of SLE.
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.
文摘Humans and other vertebrates are safeguarded from invading pathogenic microbes by the immune system.Black seed,scientifically known as Nigella sativa,has garnered attention for its potential immunomodulatory effects in both clinical and preclinical studies.This comprehensive review aims to consolidate and analyze the existing body of evidence surrounding the immunological impact of black seeds.In this review,we analyze the immunomodulatory potentials of black seeds(N.sativa).For the purpose of finding pertinent publications,the literatures was searched in web-based databases,including Web of Science,Medline/PMC/PubMed,Embase,EBSCO,Google Scholar,Science Direct,and reference lists.Several clinical,in vivo,and in vitro studies have demonstrated that supplementation with black seeds(N.sativa)has potential immunomodulatory activity.Black seeds(N.sativa)may influence immune responses through a variety of mechanisms.By synthesizing and critically assessing the current state of knowledge on the immunomodulatory effects of black seeds,this review aims to provide valuable insights into the potential therapeutic uses and future research directions for harnessing the immunological benefits of this natural remedy.
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supported by the National Key Research and Development Program of China(2022YFE0203900,2024YFD2401101)China Agriculture Research System(CARS-46)+1 种基金National Natural Science Foundation of China(32473201)Guangdong S&T Program(2022B1111030001,2024B1212040007)。
文摘Ring finger protein 122(RNF122),an E3 ubiquitin ligase,orchestrates antiviral immune responses in mammals by targeting retinoic acid-inducible gene 1 and melanoma differentiation-associated gene 5 for ubiquitination.However,its functional relevance in teleosts has yet to be clearly defined,particularly regarding the identification of substrate-specific regulatory sites.This study characterized RNF122 from mandarin fish(Siniperca chuatsi),termed scRNF122,and investigated its regulatory impact on stimulator of interferon genes(STING)-mediated antiviral signaling.Results showed that scRNF122 expression was up-regulated in response to mandarin fish ranavirus(MRV)infection,and its overexpression suppressed scSTING-mediated interferon(IFN)production and enhanced MRV replication.Co-immunoprecipitation confirmed a direct interaction between scRNF122 and scSTING.Functional assays demonstrated that scRNF122 facilitated scSTING degradation through the ubiquitin-proteasome pathway,a process impeded by MG132 treatment.Ubiquitination analyses of various scSTING mutants revealed that scRNF122 catalyzed scSTING ubiquitination at K95,K117,and K155 residues.Moreover,scRNF122 significantly impaired scSTING-dependent antiviral responses by engaging negative regulatory elements within the signaling cascade.Overall,scRNF122 was identified as a negative modulator of STING-mediated IFN signaling in mandarin fish,diminishing STING-dependent antiviral activity and promoting its degradation via the ubiquitin-proteasome pathway at lysine residues K95,K117,and K155.These findings provide mechanistic insight into the post-translational control of STING in teleosts and establish a foundation for future investigations into antiviral immune regulation.
文摘Chronic hepatitis delta virus(HDV)represents a rare but important co-infection in approximately 5%of patients with chronic hepatitis B virus(HBV)infection,and is associated with significant morbidity and mortality due to an increased risk for liver cirrhosis,liver failure,and hepatocellular carcinoma relative to HBV monoinfected individuals.The current treatment of chronic HDV infection includes the off-label use of pegylated interferon(IFN),which is limited by poor safety,tolerability,and efficacy.Guidelines of the major international liver organizations such as the American Association for the Study of Liver Diseases,European Association for the Study of the Liver,and Asian Pacific Association for the Study of the Liver provide recommendations for contemporary diagnosis and management of chronic HDV infection,including the incorporation of bulevirtide,a newly licensed antiviral agent in Europe.Significant unmet medical needs remain in the treatment of HDV,and recent advances in drug development offer hope for meaningful advances in drug therapy which may improve virologic response rates and clinical outcomes.This review summarizes trial design and available efficacy data from key phase 2 and 3 trials for investigational therapies including entry inhibitors(bulevirtide),prenylation inhibitors(lonafarnib),novel IFNs(peginterferon lambda),RNA interference molecules(JNJ-3989,elebsiran),monoclonal antibodies(tobevibart),and nucleic acid polymers(REP2139),and addresses future directions in HDV pharmacotherapy.
文摘Current treatment options for hepatitis D are limited,with pegylated interferonalpha(PEG-IFNα)being the only therapy available in the Asia-Pacific region.However,PEG-IFNαhas limited efficacy and significant side effects.Pegylated interferon lambda acts on interferon-lambda(Type III)receptors predominantly expressed in hepatocytes.In 2023,bulevirtide was approved in the European Union and Russia for treating chronic hepatitis D.This drug works by binding to and inhibiting the sodium taurocholate co-transporting polypeptide receptor on liver cells,which is the primary entry point for the virus.Recently,several new drugs have entered various stages of development,offering hope for improved hepatitis D virus(HDV)management.Two more viral entry inhibitors are HH003 and tobevibart.Other agents include nucleic acid polymers(REP 2139-Mg),prenylation inhibitors(lonafarnib),and RNA interference-based therapies(elebsiran).Emerging trials are now considering combination therapies,such as SOLSTICE,a Phase 2 clinical trial evaluating tobevibart alone or combined with elebsiran.The combination dosed monthly achieved>50%virologic and biochemical response at 24 weeks of therapy.The efficacy and safety of these drugs will further be evaluated in ECLIPSE 1,2,and 3 trials.With these new treatments on the horizon,the prospects for improved HDV patient outcomes are promising.
基金funded by the Beijing Research Ward Ecxellence Program,BRWEP(BRWEP2024W102170101)the capital health research and development of special public health project(2022-1-2172)+3 种基金the National Key Research and Development Program(2022YFC2603500,2022YFC2603505,2023YFC2306901,2023YFC2308105,2023YFC2308105)the Beijing Municipal Health Commission high-level public health technical personnel construction project,discipline leader-03-26Beijing Hospitals Authority"peak"talent training program(DFL20241803)the Beijing Hospitals Authority Clinical medicine Development of special funding support(ZLRK202301).
文摘To investigate the risk and influencing factors of long-term liver adverse events in chronic hepatitis B patients achieving hepatitis B surface antigen(HBsAg)clearance after pegylated interferonα(Peg-IFNα)treatment,a retrospective analysis was conducted on 456 patients at Beijing Ditan Hospital from 2008 to 2023 who achieved HBsAg clearance and discontinued Peg-IFNαtreatment.The baseline was defined as the time of HBsAg clearance and treatment cessation.The endpoint was the first occurrence of liver adverse events(hepatocellular carcinoma or ascites)or last follow-up.Subsequently,we evaluated the incidence and risk factors of liver adverse events,along with changes in liver fibrosis,cirrhosis,and liver function indicators.During a median follow-up of 70 months,the incidence of liver adverse events was 2.30%,hepatocellular carcinoma 1.76%,and ascites 0.55%.Older age and cirrhosis were significant risk factors(HR 1.075 and 41.393,both P<0.01).The APRI score significantly improved at follow-up compared to baseline(0.53 vs.0.25,P<0.001),and cirrhosis prevalence decreased from 5.70%to 0.88%(P<0.001).In conclusion,patients who achieved HBsAg clearance and discontinued Peg-IFNαtreatment have a low risk of liver adverse events,while advanced age and cirrhosis remain major risk factors.
文摘Peyronie’s disease(PD)presents a multifaceted challenge in contemporary urological practice,marked by penile deformity,pain,and the potential for erectile dysfunction.We meticulously explored the existing literature of intralesional/topical interventions,aiming to provide clinicians with a nuanced understanding of available options for comprehensive PD management.To conduct this review,we performed a systematic search using the PubMed,Scopus,and ScienceDirect databases,including the keywords of combination of the“Peyronie’s disease/plastic induration of the penis(PIP)and intralesional/topical treatments”.The study selection was based on adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)guidelines,resulting in the inclusion of 16 articles.We delve into the effectiveness and safety profiles of collagenase Clostridium histolyticum(CCH),interferon,platelet-rich plasma(PRP),hyaluronic acid,botulinum toxin,stem cell,extracorporeal shock wave therapy(ESWT),and traction therapy,assessing their impact on penile curvature,length improvement,and patient-reported symptoms and outcomes.The best options evaluated are intralesional injections of CCH and penile traction devices,alone or in combination.Despite PD remains a challenge for urologists,the objective of this review is to contribute to the evolving landscape of PD management,fostering informed decision-making,and personalized care for individuals grappling with this challenging condition.
文摘Topical chemotherapy is increasingly used to treat ocular surface tumors as a primary therapy and an adjuvant treatment after surgical excision.The most employed topical agents include mitomycin C(MMC),5-fluorouracil(5-FU),and interferon alpha-2b(IFNα2b),each with distinctmechanisms of action,efficacy profiles,and toxicity risks.Although these agents offer effective tumor control and allow for a non-invasive approach in many cases,ocular surface complications requiring medical or surgical management can occur.This summarizes the adverse effect and outilines practical strategies for their prevention and treatment.MMC is the most potent agent but also the most toxic,with reported complications such as limbal stemcell deficiency,punctal stenosis,and persistent epithelial defects.5-FU demonstrates a more favorable safety profile,although rare cases of corneal ulceration have been described.IFNα2b is well tolerated and associated primarily with mild,reversible reactions.The choice of the proper agent should be tailored according to patient’s clinical presentation,ocular surface status,and ability to adhere to therapy and followup.Timely recognition and management of complications are essential to minimize long-term sequelae.Reliance on compounded formulations highlights the need for stable,standardized,and commercially available topical agents specifically designed for ocular use to ensure safety,reproducibility,and global accessibility.
基金supported by the grants from the National Natural Science Foundation of China(31872497 and 32072844)the National Key Research and Development Program of China(2021YFD1800200 and 2016YFD0500207)the Laboratory of Lingnan Modern Agriculture Project,China(NT2021007)。
文摘TypeⅠinterferon(IFN)-mediated innate immune responses represent the first line of host defense against viral infection.However,the molecular mechanisms by which avian infuenza virus(AIV)inhibits typeⅠIFN production in ducks are not well understood.Here,we frst found that the polymerase basic 2(PB2)protein of H5N1 subtype AIV inhibited the typeⅠIFN responses by targeting duck mitochondrial antiviral signaling protein(MAVS).We further demonstrated that H5N1-PB2 bound to theΔtransmembrane(ΔTM)domain of duck MAVS,and the polymerase basic 1(PB1)binding domain(PBD)and RNA binding nuclear import domain(RND)of H5N1-PB2 interacted with MAVS to inhibit typeⅠIFN expression in ducks.Collectively,our fndings contribute to understanding the molecular mechanism by which AIV proteins regulate the retinoic acid-inducible geneⅠ(RIG-Ⅰ)-like receptor(RLR)signaling pathway to evade host antiviral immune responses in ducks.
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 Natural Science Foundation of Hunan Province of China(project No.2022JJ40413)Outstanding Youth Project of Hunan Provincial Department of Education(project No.22B0814)+1 种基金Regional Consolidated Foundation ofHunan Province of China(project No.2023JJ50065)Natural Science Foundation of Hunan Province of China(project No.2023JJ50412).
文摘Background:Expression of mRNA is widely regulated by N6-methyladenosine(m6A).An increasing number of studies have shown that m6A methylation,facilitated by methyltransferase 3(METTL3),is crucial in the progression of tumors.Previous reports have indicated the involvement of both METTL3 and c-Src kinase in the evolution of liver cancer.However,the potential connection between c-Src and the METTL3-mediated mechanism in liver cancer progression remains elusive.Methods:The correlation expression between c-Src and METTL3 between liver cancer patients and the control group was analyzed using the TCGA database,and was further demonstrated by Western blot and RT-qPCR.The functional roles of c-Src in METTL3-regulated liver cancer progression were investigated by cell proliferation assays and colony formation assays.The regulatory mechanism of METTL3 in c-Src expression was accessed by RNA-immunoprecipitation(RIP)-qPCR.Results:We demonstrated that c-Src kinase promoted liver cancer development,and the expression of SRC(encodes c-Src kinase)was positively correlated with METTL3 in liver cancer cases.We showed that SRC mRNA could be m6A-modified,and METTL3 regulated the transcription of SRC mRNA through interferon regulatory factor 1(IRF1).We revealed that IRF1,the expression of which was positively regulated byMETTL3,was a novel transcription factor of c-Src.Lastly,The pro-proliferative effect of METTL3 on hepatocellular carcinoma was mechanistically linked to IRF1/c-Src axis activation,as evidenced by our experimental data.Conclusion:Results suggested that the METTL3/IRF1/c-Src axis played potential oncogenic roles in liver cancer development and the axis may be a promising therapeutic target in the disease.
