BMC Veterinary Research
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2024
·Vol. 20
·期 1
·1-11
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IF 2.3
Yang Yuxin,Hu XianWang,Wang Shuangshuang,Tian Yongxiang,Yang Keli,Li Chang,Wu Qiong,Liu Wei,Gao Ting,Yuan Fangyan,Guo Rui,Liu Zewen,Yang Yuying,Zhou Danna
Background Japanese encephalitis virus (JEV) is a mosquito-borne zoonotic pathogen that causes encephalitis in humans and reproductive failure in pigs. The transmission of JEV between humans and animals poses a significant public health threat and results in substantial economic losses. Excessive inflammation in the central nervous system of JEV-infected patients is a major cause of mortality and disability. Rosmarinic acid (RA), a polyhydroxyphenolic compound isolated from medicinal herbs, has been preliminarily shown to possess anti-inflammatory properties and significantly inhibit JEV-induced neuroinflammation in mice. Results This study investigated the antiviral capacity and potential mechanisms of RA in JEV-infected cells. The results demonstrated that RA could inhibit JEV replication in vitro. Furthermore, the expression levels of inflammatory cytokines (including IL-6, IL-1β, CCL-2, and TNF-α), membrane receptors (including RIG-I, TLR3, TLR4, TLR7, and TLR8), NF-κB complex and p62/SQSTM1 were assessed using qPCR, ELISA, and Western blot, respectively. The findings indicated that RA significantly suppressed the expression of IL-6, IL-1α, TNF-α, and CCL-2 in JEV-infected BV-2 cells in a dose-dependent manner. Additionally, RA treatment downregulated the expression levels of RIG-I and p62, while p62 silencing inhibited the upregulation of inflammatory cytokines in JEV-infected BV-2 cells. Conclusion Our present study highlights the important role of RA-mediated reduction of RIG-I and p62 in microglia, conferring resistance to Japanese encephalitis virus-induced inflammation.
研究领域:
病毒学
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免疫学
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药理学
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高影响因子
NUCLEIC ACIDS RESEARCH
·
2022
·Vol. 50
·期 10
·5850-5863
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IF 19.16
Lei Yixuan,Fei Panyu,Song Bin,Shi Wenjia,Luo Cheng,Luo Dahai,Li Dan,Chen Wei,Zheng Jie
DDX58 encodes RIG-I, a cytosolic RNA sensor that ensures immune surveillance of nonself RNAs. Individuals with RIG-IE510V and RIG-IQ517H mutations have increased susceptibility to Singleton-Merten syndrome (SMS) defects, resulting in tissue-specific (mild) and classic (severe) phenotypes. The coupling between RNA recognition and conformational changes is central to RIG-I RNA proofreading, but the molecular determinants leading to dissociated disease phenotypes remain unknown. Herein, we employed hydrogen/deuterium exchange mass spectrometry (HDX-MS) and single molecule magnetic tweezers (MT) to precisely examine how subtle conformational changes in the helicase insertion domain (HEL2i) promote impaired ATPase and erroneous RNA proofreading activities. We showed that the mutations cause a loosened latch-gate engagement in apo RIG-I, which in turn gradually dampens its self RNA (Cap2 moiety:m7G cap and N1-2-2′-O-methylation RNA) proofreading ability, leading to increased immunopathy. These results reveal HEL2i as a unique checkpoint directing two specialized functions, i.e. stabilizing the CARD2-HEL2i interface and gating the helicase from incoming self RNAs; thus, these findings add new insights into the role of HEL2i in the control of antiviral innate immunity and autoimmunity diseases.
研究领域:
免疫学
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分子生物学
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遗传学
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生物化学
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PubMed
高影响因子
NATURE CELL BIOLOGY
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2025
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IF 19.1
Wang Bin,Wang Yongqiang,Pan Ting,Zhou Lili,Ran Yu,Zou Jing,Yan Xiaohua,Wen Zhenke,Lin Shixian,Ren Aiming,Wang Fangwei,Liu Zhuang,Liu Ting,Lu Huasong,Yang Bing,Zhou Fangfang,Zhang Long
Maintaining innate immune homeostasis is critical for preventing infections and autoimmune diseases but effective interventions are lacking. Here we identified C864–C869-mediated intermolecular disulfide-linkage formation as a critical step for human RIG-I activation that can be bidirectionally regulated to control innate immune homeostasis. The viral-stimulated C864–C869 disulfide linkage mediates conjugation of an SDS-resistant RIG-I oligomer, which prevents RIG-I degradation by E3 ubiquitin-ligase MIB2 and is necessary for RIG-I to perform liquid–liquid phase separation to compartmentalize downstream signalsome, thereby stimulating type I interferon signalling. The corresponding C865S ‘knock-in’ caused an oligomerization defect and liquid–liquid phase separation in mouse RIG-I, which inhibited innate immunity, resulting in increased viral load and mortality in mice. Using unnatural amino acids to generate covalent C864–C869 linkage and the development of an interfering peptide to block C864–C869 residues, we bidirectionally regulated RIG-I activities in human diseases. These findings provide in-depth insights on mechanism of RIG-I activation, allowing for the development of methodologies that hold promising implications in clinics.
研究领域:
免疫学
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分子生物学
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病毒学
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Journal of Translational Medicine
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2025
·Vol. 23
·期 1
·1-19
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IF 7.5
Xing Chunyang,Hu Wei,Zhao Liyuan
Background Osteosarcoma (OS) is one of the most common malignancies arising in bone. Hypoxia and immune regulation are pivotal in tumor biology. However, their combined effects and mechanisms in OS remain understudied. This study aimed to explore the role and mechanism of hypoxic-induced M2 macrophages in promoting the progression of OS.Methods Differentially expressed proteins in hypoxic macrophage supernatants were detected by antibody array. Cell functional experiments, siRNA-mediated gene silencing, and overexpression transfection were used to study osteopontin (OPN) and its supernatant effect. Bioinformatics analysis was applied to investigate downstream targets and pathways, and a xenograft model was established to assess in vivo effects.Results Our data revealed that hypoxic M2 macrophage supernatant enhanced OS malignancy and epithelial-mesenchymal transition, activating cancer pathways. Hypoxia upregulated OPN in M2 macrophages, and OPN inhibition reduced its tumor-promoting effect. Early growth response 3 (EGR3) was differentially expressed in OS cells treated with the supernatant, and its overexpression inhibited OS cell migration, reversing tumor promotion. Interferon-stimulated gene 15 (ISG15), a key differentially expressed gene related to OPN and EGR3 overexpression, inhibited OS cell proliferation and migration. Additionally, OPN increased retinoic acid-inducible gene I (RIG-I) expression and enhanced signal transducer and activator of transcription 3, nuclear factor kappa B, and extracellular signal-regulated kinase signaling, while EGR3 and ISG15 overexpression inhibited these effects. Silencing ISG15 restored pathway activation and reversed the inhibitory effect of EGR3 on OS cell migration. Dual-Luciferase reporter gene assay confirmed that EGR3 activates ISG15 transcription. OPN treatment upregulated DNA (cytosine-5)-methyltransferase 1 (DNMT1) expression, and ChIP assays demonstrated that EGR3 overexpression enhanced DNMT1 binding to the EGR3 promoter. These findings suggest that OPN promotes OS malignancy by downregulating EGR3 and ISG15, and by enhancing RIG-I expression, as validated in a xenograft model of OS.Conclusion Our findings demonstrate that hypoxic-induced M2 macrophages promote OS progression through OPN-dependent mechanisms, including inhibition of EGR3 and ISG15 expression and upregulation of RIG-I.Graphical abstract
研究领域:
癌症生物学
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免疫学
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分子生物学
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细胞生物学
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肿瘤微环境
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信号转导
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PHYTOMEDICINE
·
2021
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IF 5.34
Yajie Cai,Bing Xu,Fei Zhou,Jianzhi Wu,Shuo Li,Qi Zheng,Yajing Li,Xiaojiaoyang Li,Feng Gao,Shifen Dong,Runping Liu
Background Ulcerative colitis (UC) is a chronic relapsing inflammatory disease that markedly elevates the risk of colon cancers and results in disability. The disrupted immune homeostasis has been recognized as a predominant player in the pathogenesis of UC. However, the overall remission rate of current therapies based on immunoregulation is still unsatisfactory. Si-Ni-San (SNS) has been found effective in relieving UC through thousands of years of clinical practice, yet the specific mechanisms of the protective effect of SNS were not fully elucidated. Purpose We aim to investigate the therapeutic effects of SNS against the development of chronic colitis and the underlying mechanisms. Methods We established a DSS-induced chronic experimental colitis mouse model to evaluate the effect of SNS. RNA-sequencing, bioinformatic analysis, and in vitro studies were performed to investigate the underlying mechanisms. Results Our data demonstrated that SNS significantly ameliorated chronic experimental colitis via inhibiting the expression of genes associated with inflammatory responses. Interestingly, SNS significantly suppressed DSS-induced type I interferon (IFN) responses instead of directly downregulating the production of pro-inflammatory cytokines, such as Il-6. In vitro study further found that SNS selectively inhibited STING and RIG-I pathway-induced type I IFN responses by modulating TBK1- and IRF3-dependent signaling transduction. SNS also suppressed the expression of IFN-stimulated genes by directly inhibiting STAT1 and STAT2 activation. Conclusion Our study not only provides novel insights into the pathogenic role of type I IFN responses in colitis but also suggested that SNS or bioactive compounds derived from SNS may serve as novel therapeutic strategies for the treatment of UC via interfering type I IFN-mediated inflammation.
研究领域:
药理学
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免疫学
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胃肠病学
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分子生物学
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高影响因子
Cell Reports
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2023
·Vol. 42
·期 11
·113388-113388
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IF 8.8
Song J,Liu Y,Yin Y,Wang H,Zhang X,Li Y,Zhao X,Zhang G,Meng X,Jin Y,Lu D
Cancer evades host immune surveillance by virtue of poor immunogenicity. Here, we report an immune suppressor, designated as PTIR1, that acts as a promotor of tumor immune resistance. PTIR1 is selectively induced in human cancers via alternative splicing of DDX58 (RIG-I), and its induction is closely related to poor outcome in patients with cancer. Through blocking the recruitment of leukocytes, PTIR1 facilitates cancer immune escape and tumor-intrinsic resistance to immunotherapeutic treatments. Unlike RIG-I, PTIR1 is capable of binding to the C terminus of UCHL5 and activates its ubiquitinating function, which in turn inhibits immunoproteasome activity and limits neoantigen processing and presentation, consequently blocking T cell recognition and attack against cancer. Moreover, we find that the adenosine deaminase ADAR1 induces A-to-I RNA editing on DDX58 transcript, thus triggering PTIR1 production. Collectively, our data uncover the immunosuppressive role of PTIR1 in tumorigenesis and propose that ADAR1-PTIR1-UCHL5 signaling is a potential cancer immunotherapeutic target.
研究领域:
癌症生物学
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免疫学
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分子生物学
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细胞生物学
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高影响因子
FISH & SHELLFISH IMMUNOLOGY
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2023
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IF 4.7
Yan Zhou,Tian-Xiu Qiu,Huan Wang,Ling Hu,Lei Liu,Jiong Chen
In recent years, the exploration of natural compounds possessing both immunostimulatory and antiviral activities has attracted growing attention in aquaculture research. Consequently, the pursuit of identifying natural products exhibiting anti-SVCV potential as immunostimulants holds significant promise, offering a pathway to mitigate the economic ramifications inflicted by SVCV outbreaks in aquaculture settings. Among them, rhein emerges as a particularly compelling contender. Boasting a widespread distribution, well-established extraction methods, and multiple biological activities, it has exhibited the capacity to enhance the antiviral activity of host cells in vitro by blocking the viral internalization process, with a peak inhibition rate of 44.0%. Based on this intervention, rhein inhibited apoptosis and mitochondrial damage triggered by SVCV infection, ultimately producing a significant antiviral effect. Moving beyond the laboratory setting, rhein's efficacy translates effectively into in vivo scenarios. It has demonstrated substantial antiviral potency by increasing the expression of antiviral-related genes, most notably, retinoic acid-inducible gene I ( RIG-I ), interferon-φ ( IFN-φ ) and IFN-stimulated gene product 15 ( ISG15 ). In concert with this genetic modulation, rhein efficiently reduces the viral load, precipitating a consequential enhancement in the survival rate of SVCV-infected fish, elevating it to an encouraging 16%. In conclusion, the outcomes of our investigation offer a compelling testament to rhein's potential as a valuable immunomodulator in the battle against SVCV infections in aquaculture, and the remarkable attributes exhibited by rhein underscore its viability for future commercial deployment.
研究领域:
水产养殖
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免疫学
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病毒学
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药理学
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PubMed
高影响因子
Pharmaceuticals
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2026
·Vol. 19
·期 4
·640
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IF 5.7
Zeting Tan,Rongshun Liang,Adam Junka,Haoxuan Sun,Jie Jiang,Haojia Ma,Shisong Fang,Yanfang Sun
Background: Respiratory syncytial virus (RSV) is a leading global pathogen of acute lower respiratory tract infection, posing significant risks to infants, the elderly, and immunocompromised patients.Artemisia argyiLevl.et Vant Extract (AALE) and its active components have a variety of pharmacological effects, but their anti-RSV potential remains unclear. The aim of this study is to investigate the anti-RSV activity of AALE and parthenolide and its underlying mechanisms.Methods: Cell counting kit-8 (CCK-8) assay was used to determine the anti-RSV activities of AALE and parthenolide. Time-of-addition assay and phase of action analysis were used to explore the effect of drugs on the viral replication cycle. Quantitative polymerase chain reaction (qRCR), immunofluorescence (IF) and Western blot (WB) were used to investigate the effects of AALE and parthenolide on RSV-F gene and protein and on RIG-I/TLR-3 pathway related molecules in vitro. In vivo antiviral efficacy was verified by hematoxylin–eosin (HE) staining for lung histopathology, quantitative real-time PCR (qPCR) quantification of RSV-F, RIG-I, TLR-3, IRF3, IL-6, and IFN-β gene expression in lung tissues, and enzyme-linked immunosorbent assay (ELISA) for serum IL-6 and IFN-β levels.Results: AALE exhibited the strongest anti-RSV activity among the extracts (SI = 27.6), while parthenolide was the most potent monomeric compound (SI = 8.19). In vitro, both AALE and parthenolide were effective in the co-treatment and post-treatment models, reducing RSV-F gene and F protein levels in infected cells. Furthermore, they alleviated RSV infection by regulating RIG-I and TLR-3 pathway-related genes and proteins. In vivo, AALE and parthenolide suppressed lung index and RSV proliferation, attenuated lung injury, and down-regulated RIG-I, TLR-3, IRF3, IL-6, and IFN-β expression in the lungs of RSV-infected mice.Conclusions: AALE and its component parthenolide can inhibit the invasion and replication of RSV, making it a potential candidate for the treatment of RSV-related diseases.
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FISH & SHELLFISH IMMUNOLOGY
·
2026
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IF 4.2
Yujun Liu,Gengrong Zhang,Haozhe Qu,Ziyu Hu,Maosheng He,Fei Ling,Gaoxue Wang,Tianqiang Liu
The mRNA vaccine can induce specific antibodies in Largemouth bass. • mRNA Cap (1) and poly (A) mRNA reduce RIG-I recognition of foreign mRNA in Largemouth bass. • The mRNA vaccine triggered a rapid immune response in bony fish. • Improved the survival rate of largemouth bass to 57% in LMBV infection. Largemouth bass virus (LMBV) infection poses a significant threat to largemouth bass farming in China, yet effective and safe vaccines remain scarce. In this study, we designed and evaluated four mRNA vaccine candidates against LMBV, all encoding the viral major capsid protein (MCP). The fully configured construct (LMUM) contained a 5′ cap1, untranslated regions (UTRs), and a poly(A) tail, and was produced by in vitro transcription. Each mRNA was encapsulated into lipid nanoparticles (LNPs), yielding homogeneous particles (∼110 nm diameter, ∼54 mV zeta potential) with >96% encapsulation efficiency that provided substantial protection against RNase degradation (43% of mRNA remained intact in LNP-encapsulated groups versus 10% in unprotected controls). Intramuscular immunization of largemouth bass with LNP-encapsulated LMUM (0.2 μg/g body weight) induced MCP-specific serum antibodies after primary immunization, with a strong booster response after the second dose. In the LMUM-immunized group, spleen mRNA levels of IgM and CD4 were upregulated 3.4-fold and 3.2-fold, respectively, by day 14, while the groups lacking UTR or cap/poly(A) tail failed to induce these adaptive immune markers. Interestingly, the incomplete constructs triggered stronger activation of the RIG-I pathway (RIG-I, MAVS, TBK1) than the fully modified LMUM, suggesting that the combination of cap1, UTR, and poly(A) tail helps dampen excessive innate sensing. Following a lethal LMBV challenge, the LMUM vaccine conferred 45–50% relative survival after primary immunization, which increased to 53–57% after the booster dose. In contrast, the incomplete vaccine constructs and naked mRNA gave only 10–15% survival, and control groups experienced nearly complete mortality. These results demonstrate that a fully modified mRNA-LNP vaccine against LMBV induces robust humoral and cellular immune responses and provides significant protective efficacy in largemouth bass.
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CARBOHYDRATE POLYMERS
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2025
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IF 12.5
Qingchi Wang,Yuhang Luo,Yi Xin,Yuanxiang Jin,Guiling Yang,Quanbin Zhang,Zhengshun Wen
Marine polysaccharides have emerged as promising immunomodulators. However, conventional analytical approaches have failed to elucidate their activation mechanisms from a global perspective. In this study, we isolated a highly branched glycogen (GCEP2a) from eggs of the sea urchin Glyptocidaris crenularis . Structural characterization revealed that GCEP2a possesses a backbone composed of →4)-α-D-Glc p -(1 → residues, with one C6-branch per five residues, and a molecular weight of 8.06 × 10 3 kDa. Employing nascent-proteome bioorthogonal non-canonical amino acid tagging (BONCAT) enrichment followed by DIA-FAIMS, we unraveled the global immunostimulatory mechanisms of GCEP2a in RAW264.7 macrophages. This advanced approach enabled dynamic profiling of nascent protein synthesis, uncovering a multi-receptor and multi-pathway regulatory network. Specifically, GCEP2a activates signaling consistent with engagement of the toll-like receptors (TLRs), C-type lectin receptors (CLRs), and RIG-I-like receptors (RLRs), thereby triggering downstream signaling cascades including the NF-κB, MAPK, and PI3K-AKT pathways. Additionally, GCEP2a downregulates the biosynthesis of lacto- and neolacto-series glycosphingolipids, indicating metabolic reprogramming associated with M1 polarization. These findings not only suggest that GCEP2a exhibits potential as an immune adjuvant, but also provide initial insights into the application of BONCAT-based nascent proteomics for investigating the multi-modal immunostimulatory mechanisms of marine polysaccharides.
研究领域:
免疫学
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海洋生物化学
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糖生物学
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蛋白质组学
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分子免疫学
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细胞信号转导
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高影响因子
ENVIRONMENTAL POLLUTION
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2024
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IF 7.6
Dengdiao Yao,Jian Shao,Dantong Jia,Weiling Sun
Hexafluoropropylene oxide dimer acid (HFPO-DA) and perfluoroethylcyclohexane sulfonate (PFECHS) are increasingly used as alternatives for perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). However, their immunotoxicity and underlying molecular mechanisms remain poorly understood. Here, to assess immunotoxic effects, zebrafish embryos were exposed to environmentally relevant concentrations of PFOA, PFOS, HFPO-DA, and PFECHS for four days. Results revealed that all four per- and polyfluoroalkyl substances (PFAS) resulted in decreased heart rate and spontaneous movement, and induced oxidative stress in zebrafish larvae. Notably, HFPO-DA exhibited more severe oxidative stress than PFOA. Immune dysfunction was observed, characterized by elevated cytokine, complement factor, nitric oxide, and neutrophil content, along with a significant decrease in lysozyme content. Transcriptomic analysis revealed the activation of Toll-like receptor (TLR)/NOD-like receptor (NLR)/RIG-I-like receptor (RLR) and associated downstream genes, indicating their pivotal role in PFAS-induced immunomodulation. Molecular docking simulations demonstrated stable interactions between PFAS and key receptors (TLR2, NOD2 and RIG-I). Overall, HFPO-DA and PFECHS exhibited immunotoxic effects in zebrafish larvae similar to legacy PFAS, providing important information for understanding the toxic mode of action of these emerging alternatives.
研究领域:
环境毒理学
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免疫学
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分子生物学
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PubMed
高影响因子
危险品化学品经营许可证（带存储）