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关键词： Baculoviruses   gene therapy   inflammation   proliferation   superoxide dismutase 3   tumor necrosis factor-alpha  

摘要： Background Superoxide dismutase 3 (SOD3), recognized as a potent free radical scavenger, exhibits antioxidant, anti-inflammatory, and anti-angiogenic properties. However, the molecular mechanisms underlying the protective effects of SOD3 on the vascular smooth muscle cell during atherosclerosis remain *** This study aimed to investigate the efficacy of the baculovirus expressing SOD3 gene delivery to vascular smooth muscle cells (VSMCs) and investigate whether the overexpression of SOD3 mitigates cell proliferation and migration induced by tumor necrosis factor-alpha (TNF-alpha).Methods A baculoviral vector containing SOD3 cDNA (vAcMBac-CMV-IE-SOD3) was constructed and utilized to deliver the SOD3 gene into primary rat VSMCs. Cells were stimulated with recombinant TNF-alpha, and then cell proliferation and migration were evaluated using the bromodeoxyuridine and wound healing assay. Western blot was used to verify the expression of cell cycle regulators, cellular mediators, and proliferative biomarkers. Zymography, immunofluorescence staining, and ELISA assay were conducted to assess the expression levels of matrix *** The results demonstrated efficient and non-cytotoxic transduction of vAcMBac-CMV-IE-SOD3 in VSMCs. SOD3 overexpression significantly suppressed cell proliferation and motility by inhibiting cell cycle regulators in TNF-alpha-induced cells. TNF-alpha elevated protein levels of phospho-ERK and phospho-Akt were reduced markedly by SOD3-overexpressing. Additionally, SOD3 overexpression attenuated the elevation of MMP-2 and MMP-9, the pro-inflammatory and proliferative biomarkers. Overall, the SOD3 gene delivery exhibited potent anti-proliferation and anti-inflammation effects on TNF-alpha-induced *** An effective SOD3 gene delivery using a recombinant baculoviral vector has been successfully established and is useful for overexpression of the SOD gene family. This approach provides new therapeutic strateg

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： immune-related adverse events   IL-6   therapeutic potential   immune checkpoint inhibitor-induced inflammatory arthritis  

摘要： The incorporation of immune checkpoint inhibitors (ICIs) into cancer treatment has revolutionized oncology, providing marked advantages in managing various types of cancer. Nevertheless, the increasing use of ICIs has led to the emergence of immune-related side effects, including autoimmune diseases such as inflammatory arthritis. IL-6 signaling is crucial in the development of inflammatory arthritis and is linked to both the benefits and adverse effects of ICIs. The present review summarizes the latest progress in the IL-6 pathway in inflammatory arthritis and discusses the therapeutic potential of IL-6 pathway inhibitors for ICI-induced inflammatory arthritis.

关键词： A2BR   adenosine A2B receptor   ABCA1   ATP-binding cassette subfamily A member 1   ADME   absorption, distribution, metabolism, and excretion   AKAP9   A-kinase anchoring protein 9   AGEs   advanced glycation end-products   AMD   age-related macular disease   AM-ester   acetoxymethyl ester   ANF   anfibatide   Ang II   angiotensin II   ANP   atrial natriuretic peptide   AT-1R   Ang II type 1 receptor   BBB   blood-brain barrier   bFGF   basic fibroblast growth factor   BKCa   Ca2+-activated large conductance K+ channel   BRB   blood-retinal barrier   CaMKII   Ca2+/calmodulin-dependent protein kinase II   cAMP   cyclic adenosine monophosphate   CBD   cAMP-binding domain   CDC25-HD   CDC25 homology domain   CD36   cluster of differentiation 36   CICR   Ca2+-induced Ca2+ release   CI/R   cerebral ischemia/reperfusion   CNG   the cyclic nucleotide-gated channels   CNS   central nervous system   CRIS   cyclic nucleotide receptor involved in sperm function   DEP   Dishevelled/EGL-10/Pleckstrin domain   DP1   prostaglandin D2 receptor 1   DPP   dipeptidyl peptidase   DR   diabetic retinopathy   ECM   extracellular matrix   ECs   endothelial cells   eNOS   endothelial nitric oxide synthase   EP2   E prostanoid receptor 2   EPACs   exchange proteins directly activated by cAMP   ESIs   EPAC-specific inhibitors   FGF2   fibroblast growth factor 2   GEPs   guanine nucleotide exchange factors   GGTase I   geranylgeranyltransferase I   GIP   gastric inhibitory polypeptide   GLP-1   glucagon-like peptide-1   GP   glyco-protein   GPCRs   G-protein coupled receptors   HA   hyaluronan   HCN   the hyperpolarization-activated cyclic nucleotide-gated channels   HDX-MS   hydrogen-deuterium exchange mass spectrometry   HFD   high-fat diet   HIF-1α   hypoxia-inducible factor 1α   HIV   human immunodeficiency virus   HMGB1   high-mobility group box 1   HMPV   human metapneumovirus   HSCs   hematopoietic stem cells   HS   heparan sulfate   HSQC   15N, 1H Heteronuclear Single Quantum Coherence   HTS   high-throughput screening   HUVECs   human umbilical vein endothelial cells   Id1   inhibitor of differentiation 1   iECs   induced endothelial cells   IGFBP-3   insulin-like growth factor binding protein 3   IL   interleukin   iPSC   induced pluripotent stem cell   ISO   isopre  

摘要： Vascular remodeling is a complex process involving the coordinated actions of multiple cellular signaling pathways in various cell types, leading to structural and functional changes in blood vessels. These changes can be adaptive, as in wound healing, or maladaptive, as seen in chronic vascular diseases such as atherosclerosis, hypertension, and retinopathy. Exchange proteins directly activated by cAMP (EPACs) are key players in cAMP-mediated cell signaling, distinct from the more traditionally studied protein kinase A pathway. EPAC proteins are guanine nucleotide exchange factors for the small G pro-teins Rap1 and Rap2. Recent studies have also revealed noncanonical functions of EPAC1 involving the formation of biomolecular condensates. EPAC proteins regulate various cellular processes, including cell adhesion, migration, proliferation, and differentiation. In this review, we discuss the roles of EPACs in vascular remodeling and diseases associated with the process, as well as the potential of EPACs as therapeutic targets for proliferative vascular diseases. Significance Statement: Vascular remodeling is associated with various human diseases, such as atherosclerosis, stroke, and retinopathy. Understanding the roles of exchange proteins directly activated by cAMP signaling in vascular remodeling provides insights into the mechanisms underlying vascular diseases and facilitates the development of targeted therapies. (c) 2025 American Society for Pharmacology and Experimental Therapeutics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.