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关键词： Zebrafish   ARRDC3a   SVCV   RLR signaling pathway   Type I IFN  

摘要： Arrestin domain-containing 3 (ARRDC3), a member of the alpha-arrestins family, plays an important regulatory role in host anti-tumor and cellular metabolism by modulating the degradation and transportation of G proteincoupled receptors (GPCRs). However, the function of ARRDC3 in fish remains largely unexplored, particularly in host antiviral response. Here, we identified a paralog of ARRDC3 in teleost, zebrafish ARRDC3a, which was found to be induced by spring viremia of carp virus (SVCV) in vivo and in vitro. Overexpression of ARRDC3a significantly attenuated IFN expression and facilitated SVCV replication, whereas its knockdown inhibited viral proliferation. Furthermore, ARRDC3a overexpression markedly suppressed the IFN response triggered by retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) signaling pathway, and reduced the protein stability of TBK1, MITA, and IRF3. In summary, our findings suggest that zebrafish ARRDC3a acts as a negative regulator of type I IFN production by targeting RLR-associated signaling molecules, thereby promoting SVCV replication in the host. Our study provides novel insights into the biological function of ARRDC3a in fish.

关键词： AT1-AA   Interleukin-6   BK channel   NF-kappa B nuclear translocation  

摘要： The inflammatory phenotype of vascular smooth muscle cells (VSMCs) is an important factor in triggering vascular disease, and interleukin-6 (IL-6) is one of the earliest inflammatory cytokines upregulated in many inflammatory contexts. Angiotensin II-1 receptor autoantibody (AT1-AA) can promote the phenotypic transformation of VSMCs into macrophage-like cells, then synthesize abundant IL-6 to induce vascular inflammation. Previous studies suggested that abnormal BK channel function on the surface of VSMCs played an important role in the synthesis of IL-6, but the mechanism of abnormal BK channel involving in AT1-AA-induced IL-6 synthesis in VSMCs was unclear. In this study, the agonist NS1619 of the BK channel and the inhibitor Paxilline were used to reverse or exacerbate IL-6 synthesis in AT1-AA-induced VSMCs. It is known that NF-kappa B can enter the nucleus due to increased calcium ion concentration caused by BK channel dysfunction, thereby increasing IL-6 transcription. This study observed that Paxilline pretreatment significantly increased the residence time of AT1-AAinduced NF-kappa B in the nucleus, while NS1619 pretreatment showed the opposite trend. JSH-23 inhibiting NF-kappa B nuclear entry reversed the increase in IL-6 expression in VSMCs induced by AT1-AA. This study found that AT1AA enhanced NF-kappa B nuclear translocation by inhibiting BK channel function, which in turn promoted IL-6 transcription in VSMCs, increased IL-6 synthesis and induced vascular inflammation. This study revealed the importance of BK channel dysfunction in the process of AT1-AA increasing IL-6 synthesis and promoting vascular inflammation, and provided a new idea for alleviating vascular inflammatory diseases from the perspective of improving potassium channel function.

关键词： Sciaenops ocellatus   Vibrio harveyi   Interleukin-34   NF-kappa B   Inflammation  

摘要： Interleukin (IL)-34 belongs to the short-chain helical hematopoietic cytokine family, which binds to colony stimulating factor 1 receptor (CSF-1R) to activate several signaling pathways, and perform essential roles in immune surveillance, inflammatory responses, and cell proliferation differentiation and migration. In this study, the IL-34, CSF-1R1, and CSF-1R2 gene of Sciaenops ocellatus (named SoIL-34, SoCSF-1R1, and SoCSF-1R2) have been identified, and their evolutionary conservation among vertebrates as well as their immune function were analyzed. The bioinformatics analysis revealed that SoIL-34, SoCSF-1R1, and SoCSF-1R2 exhibited a conserved structure, indicating its evolutionary trajectory to be relatively conserved. The expression profile analysis showed that Gram-negative bacterium Vibrio harveyi and lipopolysaccharide significantly up-regulated SoIL-34, SoCSF-1R1, and SoCSF-1R2 expression. Further functional experiments demonstrated overexpression or knockdown of SoIL-34 could significantly modulate the expression of inflammatory cytokines and SoCSF-1R1 and SoCSF-1R2. Particularly, we revealed that SoIL-34 exhibited robust activation of NF-kappa B reporter activity, as well as IL-8 and IL-1 beta reporter activities. These results indicated that SoIL-34 may function as a positive regulator in S. ocellatus which will offer insights into the role of IL-34 and CSF-1R in innate immunity of teleost fish and significantly enhancing our understanding of complex host-pathogen interactions in lower vertebrates.

关键词： IL-23   IL-17   bioinformatics   cytokine   gene   inflammation   receptor  

摘要： Introduction/Objective Bioinformatic analysis is a valuable tool that allows us to collect, archive, analyze, and disseminate biological data for further interpretation. Analysis of the IL-23/IL-17A axis and its receptors will provide us with essential information about their functions, interactions, and relationships with various diseases. This review aims to identify the central genes co-expressed in the IL-23/IL-17A axis and their receptors and to understand their ontology and modifying *** We used several databases, including COXPRESdb to obtain the co-expressed genes, ShinyGO and ToppGene platforms to explore gene functional enrichment, and the NetworkAnalyst 3.0 platform for gene expression *** We found that genes encoding IL-23/IL-17A axis proteins and their receptors mainly respond to microbial components, participate in the inflammatory response, and are primarily associated with inflammatory and autoimmune diseases. In addition, we observed an association of the IL-23/IL-17 axis with Behcet's disease, Graft-versus-host disease, and Hodgkin's disease, although there is no direct evidence of their *** The IL-23/IL-17A axis is associated with several inflammatory and autoimmune pathologies. Therefore, we suggest further research to confirm its role in these pathologies and, if possible, use it as a therapeutic target.

关键词： Apoptosis   IL-17RA signaling   Salivary gland epithelial cells   SHP2   Sjögren's disease  

摘要： Salivary gland (SG) dysfunction is a hallmark manifestation of Sjögren's disease (SjD). While SHP2 has been implicated in several autoimmune diseases, its specific function in SjD remains to be elucidated. Here, we investigated the involvement of SHP2 in SjD-induced SG damage and elucidate the underlying molecular mechanisms. Our findings revealed that SHP2 is elevated in SG tissues of SjD patients and SjD-like animals, with predominant localization to salivary gland epithelial cells (SGECs) of acini and ducts. Notably, pharmacological inhibition of SHP2 with the allosteric inhibitor SHP099 significantly alleviates SG histopathological damage and reduces inflammatory cell infiltration in SjD-like animals. In vitro studies in the human SGEC line A253 revealed that SHP2 inhibition attenuated poly(I:C)-induced SGEC apoptosis and proinflammatory cytokine production. Mechanistically, SHP099 treatment disrupted the IL-17RA/ACT1/TRAF6 signaling axis, phenocopying the effects of SHP2 knockdown and direct IL-17R antagonism, which leads to downregulation of JAK/STAT3 and NF-κB pathways. Collectively, our findings highlight the significant involvement of SHP2 in the pathogenesis of SjD and suggest that targeting SHP2 or its downstream signaling pathways may represent a promising therapeutic approach for SjD treatment. © 2025 Elsevier B.V.

关键词： Anti-IL-6 receptor antibody   Microglia   Aquaporin-4   IL-6   NMOSD  

摘要： Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease characterized by periods of remission and relapse;severe relapses often lead to permanent neurological disability. Satralizumab, an anti--interleukin-6 receptor (anti-IL-6R) antibody, has been proven in previous studies to reduce the frequency and severity of relapses in patients with NMOSD. There are several reports on the mechanisms through which anti-IL-6R antibodies are thought to suppress relapse. However, the mechanisms underlying how anti-IL-6R antibodies reduce the severity of myelitis have not been elucidated. We investigated the effect of an anti-IL-6R antibody (MR16-1) on the severity of myelitis in an AQP4 peptide-immunized mice model. This mouse model exhibits NMOSD-like pathological characteristics and the production of anti-AQP4 autoantibodies. Unlike the previously reported experimental protocol where antibody and peptide are administered simultaneously, we tested delayed administration of MR16-1 (9 days after peptide immunization). We found that delayed MR16-1 administration suppressed the clinical score of AQP4 peptide-immunized mice experiencing myelitis. Mice treated with MR16-1 showed a greater percentage of CD11c+ microglia in the spinal cord, along with upregulated expression of phagocytosis-related genes. Blockade of IL-6R by anti-IL-6R antibodies may suppress the severity of myelitis by increasing CD11c+ microglia and enhancing phagocytic function in AQP4 peptide-immunized mice.

关键词： Biomass fuel   IL-17A   Neuroinflammation   Neurodegeneration   Lung-brain axis  

摘要： Biomass fuel (BMF) exposure is known to cause respiratory inflammation, but its impact on the central nervous system (CNS) and the mechanisms underlying this effect remain unclear. BMF combustion releases particulate matter (PM2.5), triggering systemic inflammation, which is linked to an increased risk of neurodegenerative diseases such as Parkinson's disease (PD). This study revealed that prolonged BMF exposure leads to dopaminergic neuron loss, increased alpha-synuclein (alpha-syn) phosphorylation, and neuroinflammation, resulting in motor and cognitive impairments in mice. Mechanistically, BMF activates the interleukin-17A (IL-17A) signalling pathway in the periphery, promoting Th cell infiltration across the blood-brain barrier, which stimulates astrocytes to release IL-17A and activates IL-17 receptor A (IL-17RA) on microglia. Transcriptomic and metabolomic analyses revealed that BMF exposure significantly disrupts immune and neurotransmitter pathways. Importantly, IL-17A knockout (IL-17A-/-) mice exhibit marked improvements in motor and cognitive functions and reduced neuroinflammation following BMF exposure. These findings identify IL-17A as a critical mediator of the lung-brain axis, orchestrating PD-related immune responses within both the CNS and peripheral nervous system. The IL-17A pathway represents a promising therapeutic target for PD and the related neuroinflammatory changes associated with environmental pollutant exposure.

关键词： Duplex recombinase polymerase amplification   Centrifugal microfluidics   Allele identification   HLA-B*58:01   Point-of-care  

摘要： We developed a fully integrated, portable centrifugal microfluidic platform to detect HLA-B*58:01 allele, a strong genetic risk factor for severe hypersensitivity reactions to allopurinol. This allele is located within the human leukocyte antigen (HLA) locus, which is characterized by its polymorphism and high GC content. The platform is capable of performing on chip lysis, duplex recombinase polymerase amplification (RPA) and realtime fluorescence detection of genomic DNA directly from buccal swab samples. A localized contact heating module was customized to enable fast and efficient sample lysis using a thermophilic proteinase, and a build-in internal control was incorporated to minimize diagnostic errors. All reagents are pre-stored in a disposable microfluidic chip and the swab samples can be added directly without any pre-treatment, achieving a fully automated, walk-away test. As a verification, our platform could simultaneously detect the HLA-B*58:01 allele and the beta-globin gene as an internal control, with a limit of detection (LOD) of 30 pg/mu L and 3 pg/mu L, respectively. Validation using buccal swabs from 12 volunteers demonstrated 100 % concordance with the gold-standard sequencing-based typing (SBT) methods. The platform demonstrated high specificity, reproducibility, and reliability. Compared to SBT, our platform significantly reduces the time-to-result (50 min vs. up to 16 h) while minimizing extensive manual labor. Its fully automated integration of sample lysis and genomic DNA analysis provides a new direction for pharmacogenetic screening, enabling personalized medicine in resource-limited settings.

关键词： Anti-IL-6 receptor antibody   Glucocorticoid   Osteoporosis   Aquaporin-4   IL-6   NMOSD  

摘要： Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease characterized by the production of autoantibodies against aquaporin-4 (AQP4). Treatment with prednisolone (PSL) or anti-IL-6 receptor (IL-6R) antibody can reduce the frequency of relapse in patients with AQP4 antibody-positive NMOSD. We previously established a mouse model of paralysis induced by intradermal immunization with AQP4 peptide. In this study, we investigated the effects of PSL and anti-IL-6R antibody treatment on paralysis and on bone fragility in this NMOSD mouse model. Prednisolone and anti-IL-6R antibody treatment each suppressed the clinical scores and incidence of paralytic symptoms in AQP4 peptide-immunized mice. High-PSL treatment induced thinning of cortical bone and reduction of tissue mineral density in the femoral shaft and a decrease in femoral bone strength, although it increased bone volume/tissue volume in the trabecular bone of the distal femur. In contrast, anti-IL-6R treatment showed no significant differences in bone strength or cortical thickness compared to the non-immunized naive group. Bone morphometric analysis showed that high-PSL treatment reduced the bone formation rate in both cortical and trabecular bone, with a predominance of bone resorption, whereas anti-IL-6R treatment demonstrated no notable effect on bone metabolism. These results suggest that anti-IL-6R antibody can prevent the development of paralytic symptoms in AQP4 peptide-immunized mice without reducing bone strength.