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关键词： Acute respiratory distress syndrome   Endoplasmic reticulum stress   Pyroptosis   Thapsigargin   Interleukin 33  

摘要： Background: Inflammatory activation of pulmonary microvascular endothelial cells (PMVECs) initiated by endoplasmic reticulum stress (ERS) contributes to acute respiratory distress syndrome (ARDS). Interleukin 33 (IL-33) has pro-inflammatory and transcriptional regulatory effects. Therefore, this study intends to investigate the effect of IL-33 on ERS and pyroptosis in the hPMVEC. Methods: The hPMVEC-associated ARDS cell model was induced with lipopolysaccharide (LPS) and treated with 4-PBA (ERS inhibitor), thapsigargin (ERS activator), or IL-33 neutralizing antibody. Western blot and IF staining were performed to analyze the expression of cell-cell junction-associated (Cx37, Cx40, Cx43, Occludin, and Zo1), ERS-associated (ATF6, IRE1a, and p-Erk), and pyroptosis-associated (NLRP3, IL-1 beta, and IL-18) proteins. Bioinformatics identified differential expression of IL-33 in ARDS-related datasets and targets of thapsigargin. Results: IL-33 was highly expressed in serum of ARDS patients and in ARDS cohorts from multiple GEO datasets (GSE237260, GSE216635, GSE89953, GSE263867, and GSE5883), and was significantly correlated with clinical features. 4-PBA decreased permeability and IL-33 levels, and increased Cx37, Cx40 and Cx43 levels in the ARDS cell model. IL-33 neutralizing antibody effectively augmented the levels of Cx43 and Zo-1, and diminished the levels of ATF6, IRE1a, p-Erk, NLRP3, IL-1 beta, IL-18, ROS, and Ca2 +. The therapeutic effect of IL-33 neutralizing antibodies was reverted by thapsigargin. Moreover, the Swiss Target Prediction and Super-PRED databases obtained 140 and 122 thapsigargin targets, which had 14 intersections. These intersections were associated with immunity, inflammation, apoptosis, pyroptosis, and Ca2+ homeostasis. Notably, CASP8 and PTGS2 interacted with IL-33 in these intersections. Conclusion: IL-33 promotes ERS and pyroptosis, thereby contributing to barrier damage in ARDS cell models. IL- 33 is a promising therapeutic target for ARDS.

关键词： Interleukin-26   Monoclonal antibodies   T cells   Macrophages   Bacterial infection  

摘要： Interleukin-26 (IL-26) belongs to the IL-10 cytokine family and exerts diverse biological functions in regulating immune responses in vertebrates. Although IL-26 has been extensively studied in mammals, the functions of IL- 26 remain largely unexplored in lower vertebrates. In this study, we determined the tissue and cell sources of IL- 26 using a monoclonal antibody (mAb) generated against grass carp (Ctenopharyngodon idella, Ci) IL-26, and investigated the responses of IL-26 producing cells to bacterial infection. We showed that the CiIL-26 mAb specifically recognized the recombinant CiIL-26 proteins expressed in the Escherichia coli and HEK293 cells. Flow cytometry analysis revealed that the CiIL-26 mAb could detect the intracellular CiIL-26 expressed in the HEK293 cells and CIK cells stimulated with inactivated Aeromonas hydrophila (A. hydrophila). Using confocal microscopy, we analyzed IL-26+ cells in various tissues of grass carp following infection with A. hydrophila. It was shown that the IL-26+ cells were significantly increased in the gills, head kidney, posterior intestine and spleen. Remarkably, for the first time, we observed that most IL-26+ cells were CD3 gamma/delta+ T cells and MCSFR+ monocytes/macrophages, which could be induced by A. hydrophila. Our findings highlight the essential roles of CD3 gamma/delta+/IL-26+ T cells and MCSFR+/IL-26+ macrophages in the immune defense against bacterial infections in fish.

关键词： ovarian cancer   lncRNA   ZNF667-AS1   tumor necrosis factor  

摘要： Ovarian cancer (OC) is the most lethal gynecological malignancy and poses a significant public health burden. The present study explored the function and mechanism of long noncoding RNA (lncRNA) ZNF667-AS1 in OC progression. The present study conducted a multifaceted evaluation, including transcriptomic analyses, to examine the expression and prognostic value of lncRNA ZNF667-AS1 in OC via the Cancer Genome Atlas and Genotype-Tissue Expression data. In vitro experiments on OC cell lines were used to investigate the functional effect of ZNF667-AS1 via cell proliferation, migration and invasion assays and RNA sequencing and western blotting were used to explore the implicated molecular pathways. ZNF667-AS1 was significantly underexpressed in OC tissues and cell lines. Its expression levels were positively associated with improved patient prognosis and affected both tumor behavior and tumor microenvironment interactions. Functional analysis confirmed the tumor-suppressive role of ZNF667-AS1 and revealed a marked decrease in proliferation, migration and invasion in ZNF667-AS1-overexpressing cells. Additionally, ZNF667-AS1 was identified as a key regulator in the tumor necrosis factor signaling pathway, which suggests a strong link between ZNF667-AS1 expression and OC progression. The present study identified ZNF667-AS1 as a potential biomarker for OC prognosis and treatment and illustrated its significant regulatory effects on the TNF pathway and its broader implications in cancer pathobiology.

关键词： Acute transverse myelitis   COVID-19   Tumor necrosis factor-alpha inhibitor   Ulcerative colitis  

摘要： We report a case of acute transverse myelitis (ATM) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a 59-year-old man. This patient had been treated for ulcerative colitis (UC) for 4.5 years with several medications, including a tumor necrosis factor (TNF)-alpha inhibitor. Because this patient developed ATM almost concurrently with the onset of coronavirus disease 2019, SARS-CoV-2 infection was considered the likely cause of ATM, although TNF-alpha inhibitor therapy and the autoimmune condition UC might also have played a role.

关键词： Osteoarthritis (OA)   m6A methylation   Chondrocyte   WTAP   IL-33  

摘要： Osteoarthritis (OA) is a multifactorial degenerative disorder entailing cartilage loss and progressive joint failure. m6A RNA methylation could impact multiple disorders, including OA. In this study, m6A methylation regulator WTAP was down-regulated in OA cartilage, accompanied by significantly lower m6A methylation levels in OA tissues. In the DMM-induced mice OA model and IL-1 beta- or TNF-alpha-stimulated chondrocytes, WTAP and m6A methylation levels were decreased, but IL-1 beta, IL-6, and TNF-alpha cytokine expressions were elevated. In vivo and in vitro, WTAP overexpression increased m6A methylation levels but reduced proinflammatory cytokine contents. Furthermore, WTAP overexpression (OE) increased chondrocyte viability and proliferation, aggrecan and collagen II protein, and decreased cell apoptosis, MMP3, MMP13, and ADAMTS5. WTAP-mediated m6A methylation of IL-33 and impaired IL-33 mRNA stability. IL-33 OE caused no changes to WTAP expression;however, IL-33 OE partially attenuated WTAP OE-induced IL-33 downregulation. IL-33 overexpression inhibited chondrocyte viability and proliferation, decreased aggrecan and collagen II but elevated MMP3, MMP13, and ADAMTS5, and increased cell apoptosis and proinflammatory cytokine contents. More importantly, IL-33 eliminated the effects of WTAP OE on chondrocytes. Therefore, WTAP is down-regulated in OA;WTAP improves chondrocyte proliferation and function, thereby ameliorating OA through mediating m6A methylation of IL-33 and impairing IL-33 mRNA stability.

摘要： Background and ObjectivesAssociation of human leukocyte antigen (HLA) with anti-aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG NMOSD) has been reported. However, this association in the Korean population has not been previously investigated. We aimed to evaluate whether specific HLA subtypes were associated with Korean patients with AQP4-IgG NMOSD and whether the HLA genotype is associated with specific clinical *** compared the HLA subtypes of 122 patients with AQP4-IgG NMOSD with those of 485 (HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1) and 173 (HLA-DPB1) healthy controls. In addition, we compared the clinical features of patients with and without specific HLA *** most significant risk allele for AQP4-IgG NMOSD was HLA-DRB1*03:01 (24 patients [19.67%], odds ratio [OR]: 3.997, pc value = 0.0001). Susceptibility of AQP4-IgG NMOSD was significantly associated with the HLA-DRB1*03:01-DQB1*02:01 (23 patients [18.85%], OR: 3.792, pc value = 0.0002) and DRB1*12:02-DQB1*03:01 (23 patients [18.85%], OR: 3.402, pc value = 0.0009) haplotypes. Patients with the DRB1*12:02-DQB1*03:01 haplotype showed more frequent spinal involvement, a higher Expanded Disability Status Scale score at disease-onset nadir, and a shorter time to second attack than patients without this *** a Korean cohort of patients withAQP4-IgG NMOSD, the HLA-DRB1*12:02-DQB1*03:01 haplotype was associated with disease severity at onset. HLA-DRB1*03:01, broadly reported as a significant susceptibility allele across diverse ethnic groups, showed a significant risk association in Korean patients with AQP4-IgG NMOSD.

关键词： Chemotherapy   Doxorubicin   Nephrotoxicity   Oxyresveratrol   Dapagliflozin  

摘要： PurposeAmong the most undesirable effects that lead to the restriction of doxorubicin (DOX) use in chemotherapy is kidney damage. This research aimed to assess the possible defenses against DOX-induced nephrotoxicity offered by oxyresveratrol (ORES) and/or dapagliflozin (DAPA).MethodsFive groups of eight male Swiss albino rats each were created from a total of sixty-four. One intravenous injection of DOX (10 mg/kg) was given into the tail vein on the fourteenth day of the experiment;in the meantime, ORES (80 mg/kg) and DAPA (10 mg/kg) were given orally 14 days prior to the DOX injection and 2 days following the DOX *** rats given DOX, ORES and/or DAPA both successfully reduced the kidney weight, kidney/bodyweight ratio, and blood levels of creatinine, uric acid, and urea. They also increased final body weight and albumin serum levels. Additionally, lower serum concentrations of TNF-alpha and IL-6 were noted, along with a lower kidney content of caspase-3. Furthermore, the expression of the Bcl-2 gene was upregulated, as were the Nrf-2, PPAR-gamma, and HO-1 proteins, and there was a downregulation of the ATG-5, Keap-1, and NF-kappa B renal gene expression. These findings support a decrease in oxidative stress and relief of histopathological *** current study's findings suggest that ORES and/or DAPA pretreatment could be a viable therapeutic approach to ameliorate DOX-induced nephrotoxicity.

关键词： Hyperuricemia   Astragalus flavone extract   Metabolomics   JNK/AP-1/NLRP3/IL-1 beta signaling pathway   Uric acid metabolism  

摘要： Background: Hyperuricemia (HUA) is a metabolic disease disturbing human health caused by the overproduction or underexcretion of uric acid (UA). Astragalus is the root of Astragalus membranaceus (Fisch.) Bunge, has notable regulatory effect on chronic nephritis, proteinuria and spontaneous sweating, suggesting it could be a potential anti-HUA agent. However, limited research has been conducted on its anti-HUA effect and mechanism. Methods: The present study performed untargeted and plasma metabolomics of Astragalus extract to identify the main constituents that can be absorbed and exert effect in mice, and further investigated the underlying mechanism by enzyme activity assay, Western Blotting and molecular docking. Results: The results showed that Astragalus flavone extract inhibited UA synthesis by binding to XOD to hinder substrate binding and inhibiting xanthine oxidase (XOD) protein expression, inhibited JNK/AP-1/NLRP3/IL-1 beta signaling pathway to alleviate prolonged HUA-induced inflammation and abnormal UA metabolism, and protected the kidney by reducing serum renal function index and improving renal tissue atrophy, fibrosis and tubular dilatation both in vitro and in vivo. Besides, glycitein and isoformononet were identified as the main flavones in Astragalus extract absorbed into the bloodstream of mice, isoformononetin was found to inhibit UA synthesis by direct binding to XOD, and glycitein was found to interact with c-Jun to facilitate UA excretion and inhibit inflammation. Conclusion: This paper represents the pioneering investigation that firstly identifying two flavonoids of Astragalus extract that can be absorbed to fight against HUA, and elucidating their diverse molecular mechanism by targeting JNK/AP-1/NLRP3/IL-1 beta signaling pathway, UA metabolism and kidney protection.

关键词： Sjogren's disease   Integrated stress response   Type I interferons   PKR   microRNA   ISRIB  

摘要： Labial salivary glands (LSG) from Sjogren's disease (SjD) patients are characterized by increased levels of proinflammatory cytokines, such as type I interferons (IFN-I). These LSG also show activation of the integrated stress response (ISR) with overexpression of protein kinase R (PKR), a known IFN-stimulated gene. In vitro, IFN-I stimulation reproduces the downregulation of hsa-miR-145-5p, which is associated with TLR4 overexpression observed in LSG of SjD patients. MicroRNA levels depend on its biogenesis, which is a multi-step process involving several protein complexes. It is not known whether altered miRNA biogenesis is associated with the activation of the ISR induced by IFN-I in LSG from SjD. The aim of this study was to characterize the expression and localization of components of the miRNA biogenesis machinery in LSG of SjD patients, to assess the effect of pro-inflammatory cytokines on these components, and to test whether inhibition of the IFN-beta-induced ISR restores the levels of hsa-miR-145-5p. In LSG from 12 SjD patients and 11 non-SjD sicca controls, we determined mRNA fold changes, relative protein levels, and the localization of the ISR and miRNA biogenesis machinery components by RT-qPCR, Western blot, and immunofluorescence, respectively. Pro-inflammatory cytokines, the ISR inhibitor ISRIB, and the PKR inhibitor C16 were used for in vitro assays. In LSG from SjD patients, PKR and its activator PACT colocalized in the cytoplasm, whereas the PKR inhibitor TRBP was observed in the nuclei. IFN-beta activates PKR, increases p-eIF2 alpha and ATF4 levels, and increases PACT and AGO2 detection in stress granules. C16 inhibits PKR phosphorylation but increases ATF4 by activating GCN2. ISRIB restores levels of hsa-miR-145-5p and its target TLR4 mRNA upon IFN-beta stimulation. These findings suggest an association between inflammation, cellular stress, and miRNA biogenesis, where modulation of the ISR emerges as a potential strategy to

关键词： Saposhnikovia divaricata   Umbelliferae   Chromones   Inhibit proliferative activity  

摘要： Nine previously undescribed chromones, named sadivamones O-W (1-9), and five known analogues (10-14), were isolated from the roots of Saposhnikovia divaricata (Turcz.) Schischk. The detailed structural analysis of each compound was finalized by a variety of methods including NMR (1D and 2D), mass spectrometry (HR-ESI-MS) spectroscopic data, and sugar hydrolysis. The absolute configurations of compounds (4-5) were determined by CD. Moreover, compounds 1-14 were evaluated for their inhibition of IL-1/3-induced proliferative activity in SW982 cells. The results demonstrated that compounds 2-4 and 11-12 exhibited notable inhibitory effects on IL1/3-induced proliferation in a concentration-dependent manner, with the most pronounced inhibition observed at a concentration of 20 mu M.