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关键词： Psoriasis   AURKA   Keratinocytes   IL-22  

摘要： Circular RNAs (circRNAs) are demonstrated to be involved in psoriasis progression. CircRNAs can act as RNA-binding protein (RBP) sponges. Here, we investigated the action of circAKR1B10 in psoriasis, and explored the potential proteins interacted with circAKR1B10. Levels of genes and proteins were assayed by qRT-PCR and western blotting analyses. Keratinocytes in functional groups were treated with interleukin (IL)-22. Functional analysis were conducted using MTT, 5-ethynyl-2'-deoxyuridine (EdU), and transwell assays, respectively. Interaction analysis among circAKR1B10, Eukaryotic initiation factor 4 A-III (EIF4A3) and Aurora Kinase A (AURKA) was conducted using bioinformatics analysis, RNA pull-down assay, and RNA immunoprecipitation (RIP) assay. CircAKR1B10 was highly expressed in psoriasis patients and IL-22-induced keratinocytes. Functionally, knockdown of circAKR1B10 abolished IL-22-induced proliferation, migration and invasion in keratinocytes. AURKA expression was also higher in psoriasis patients and IL-22-induced keratinocytes, and was negatively correlated with circAKR1B10 expression. Moreover, AURKA silencing reduced the proliferative, migratory and invasive abilities of IL-22-induced keratinocytes. Mechanistically, circAKR1B10 interacted with EIF4A3 protein to stabilize and regulate AURKA expression. CircAKR1B10 contributes to IL-22-induced proliferation, migration and invasion in keratinocytes via up-regulating AURKA expression through interacting with EIF4A3 protein.

关键词： Hughes-Stovin syndrome (HSS)   Vasculitis   Thrombosis   Pulmonary artery aneurysm   Tumour necrosis factor-alpha inhibitor   Case report  

摘要： Background Hughes-Stovin syndrome (HSS) is a rare vasculitis characterized by the association of thrombophlebitis with pulmonary artery aneurysms (PAAs). Because it is rarely reported, there are currently no established diagnostic criteria or standardized treatment guidelines for HSS. While conventional immunosuppressants are generally effective as first-line treatment, relapsing and refractory cases urge the need to investigate alternative therapies, such as TNF-alpha inhibitors. However, with only five cases published in the literature, knowledge of their efficacy in HSS is very *** summary A 28-year-old man, with no past medical history, presented with haemoptysis, chest pain, and dyspnoea on exertion. Physical examination found bilateral leg swelling, with no associated lesions. CT angiography showed multiple bilateral PAA, proximal pulmonary artery thrombosis (PAT), and deep venous thrombosis (DVT) in the superior mesenteric vein and spleno-mesaraic confluence. Echocardiography was performed, identifying right intracardiac thrombosis (ICT). Initial management included high-dose corticosteroids and monthly cyclophosphamide cycles, followed by maintenance treatment with oral azathioprine. Eighteen months later, the patient presented with haemoptysis revealing a relapse of ICT and two new PAA. Infliximab was initiated, allowing complete and sustained remission after one year of *** We report the challenging case of an HSS patient presenting with multiple PAA, proximal PAT, right ICT, and extended abdominal DVT. The positive response of our patient to infliximab, following a relapse under conventional immunosuppressants, supports the efficacy of TNF-alpha inhibitors as second-line treatment in relapsing/refractory HSS.

关键词： Cartilage   Osteoarthritis   Knee joints   Knees   Inflammation   Chondrocytes   Mouse models   Antibody therapy  

摘要： Introduction Osteoarthritis (OA) is a chronic inflammatory disease where pro-inflammatory cytokines, damage-associated molecular patterns and macrophages play a crucial role. However, the interaction of these mediators, the exact cause, and the treatment of knee osteoarthritis (KOA) are still unclear. Moreover, the interaction of interleukin (IL)-33, platelet-derived growth factor-BB (PDGF-BB), and matrix metalloproteinase-9 (MMP-9) with other factors in the pathogenesis of KOA has not been elaborately *** Therefore, in this study, we analyzed the expression of IL-33, PDGF-BB, and MMP-9 in the knee cartilage tissue of model mice, murine KOA was induced by using the destabilization of the medial meniscus (DMM) *** Compared with the sham operation control group, the expression levels of PDGF-BB, IL-33, and MMP-9 were increased significantly, and the pathological sections showed obvious cartilage damage. Additionally, we assessed the levels of IL-33 and MMP-9 expression in the knee joint of KOA model mice following intervention with PDGF-BB antibody, and we found that the expression level of MMP-9 was reduced following intervention with IL-33 antibody. When the effects of the three antibodies were compared in a mouse disease model, it was discovered that the IL-33 antibody could dramatically lower the relative expression level of MMP-9, resulting in the least amount of cartilage damage and improved protection. In conclusion, inhibiting IL-33 can significantly lower inflammatory factor levels in the knee joint, including IL-33 and MMP-9, and it can improve cartilage breakdown in osteoarthritis of the *** Overall, the results indicate that IL-33 has a therapeutic function in the treatment of knee osteoarthritis and may be a novel target for treatment of the underlying causes of KOA. Additionally, PDGF-BB might be an upstream pathway of IL-33, and KOA's MMP-9 is an downstream pathway of IL-33.

关键词： Autoimmunity   Rheumatology   T cell receptor   T cells  

摘要： HLA-B*27 was one of the first HLA alleles associated with an autoimmune disease, i.e., axial spondyloarthritis (axSpA) and acute anterior uveitis (B27AAU), which cause joint and eye inflammation, respectively. Gastrointestinal inflammation has been suggested as a trigger of axSpA. We recently identified a bacterial peptide (YeiH) that can be presented by HLA-B*27 to expanded public T cell receptors in the joint in axSpA and the eye in B27AAU. While YeiH is present in enteric microbiota and pathogens, additional evidence that pathogenic T cells in HLA-B*27- associated autoimmunity may have had a prior antigenic encounter within the gastrointestinal tract remains lacking. Here, we analyzed ocular, synovial, and blood T cells in B27AAU and axSpA, showing that YeiH-specific CD8+ T cells express a mucosal gene set and surface proteins consistent with intestinal differentiation, including CD161, integrin alpha 4 beta 7, and CCR6. In addition, we found an expansion of YeiH-specific CD8+ T cells in axSpA and B27AAU blood compared with that from across groups. Finally, we demonstrated the dispensability of TRBV9 for antigen recognition. Collectively, our data suggest that, in HLA-B27-associated autoimmunity, early antigen exposure and differentiation of pathogenic CD8+ T cells may occur in enteric organs.

关键词： Protein sequencing   Language   Physicochemical properties   Decision tree learning   COVID 19   Cytokines   Forecasting   Machine learning  

摘要： Interleukin (IL)-13 has emerged as one of the recently identified cytokine. Since IL-13 causes the severity of COVID-19 and alters crucial biological processes, it is urgent to explore novel molecules or peptides capable of including IL-13. Computational prediction has received attention as a complementary method to in-vivo and in-vitro experimental identification of IL-13 inducing peptides, because experimental identification is time-consuming, laborious, and expensive. A few computational tools have been presented, including the IL13Pred and iIL13Pred. To increase prediction capability, we have developed PredIL13, a cutting-edge ensemble learning method with the latest ESM-2 protein language model. This method stacked the probability scores outputted by 168 single-feature machine/deep learning models, and then trained a logistic regression-based meta-classifier with the stacked probability score vectors. The key technology was to implement ESM-2 and to select the optimal single-feature models according to their absolute weight coefficient for logistic regression (AWCLR), an indicator of the importance of each single-feature model. Especially, the sequential deletion of single-feature models based on the iterative AWCLR ranking (SDIWC) method constructed the meta-classifier consisting of the top 16 single-feature models, named PredIL13, while considering the model's accuracy. The PredIL13 greatly outperformed the-state-of-the-art predictors, thus is an invaluable tool for accelerating the detection of IL13-inducing peptide within the human genome.

关键词： 膝骨性关节炎   臭氧水   关节腔冲洗   穴位注射   疼痛   炎性因子  

摘要： 目的探索臭氧水联合疗法治疗老年性膝关节骨性关节炎患者疼痛的临床疗效及相关因子水平影响的研究。方法选取2023年6月至2023年12月门诊老年KOA患者，将其随机分为2组，每组32例。对照组为臭氧水穴位注射，观察组在对照组基础上联合臭氧水腔内冲洗，两组均每周治疗1次，连续治疗4次。每组治疗前后均采取视觉模拟评分法（VAS)评分、Lysholm膝关节评分评价两组疾病的疼痛变化，相关因子研究采用酶联免疫吸附法（ELISA)检测治疗前后关节液中相关疼痛因子前列腺素E2（PGE2）、白介素-1β（IL-1β）及IL-6水平变化。结果治疗后两组患者VAS评分、Lysholm评分、PGE2、IL-1β及IL-6水平较治疗前均有明显改善（P<0.01）。组间比较发现，观察组VAS评分、PGE2、IL-1β及IL-6水平均显著低于对照组（P<0.01），Lysholm评分趋势显著上升（P<0.01），总优良率优于对照组，差异具有统计学意义（P<0.05)。多重线性回归分析示VAS评分与PGE2水平相关（P<0.001）。结论臭氧水联合疗法对KOA镇痛效应可能是通过调控疼痛相关因子的表达，减少致痛因子和炎症因子水平，从而改善疼痛症状，提高老年患者生活质量，临床疗效优于单纯穴位注射组，更值得临床推广。

关键词： antibodies   tumor necrosis factor inhibitors   methotrexate   arthritis, rheumatoid   antirheumatic agents  

摘要： Objectives This study aimed to evaluate the long-term safety and efficacy profiles of ozoralizumab in patients with rheumatoid arthritis (RA) from the OHZORA, NATSUZORA and HOSHIZORA *** This study conducted an integrated analysis of the three trials. Patients who completed the OHZORA trial with concomitant treatment of ozoralizumab and methotrexate (MTX) or the NATSUZORA trial without MTX were eligible to participate in the long-term extension HOSHIZORA trial. Safety assessment was performed in the safety analysis set, and the incidence rate per 100 person-year (PY) was calculated for a summary of adverse events (AEs) and AEs of special interests (AESIs). The efficacy was analysed in terms of disease activity index response rates and functional *** The OHZORA and NATSUZORA trials enrolled 521 patients, of whom 401 patients entered the HOSHIZORA trial and 279 completed the long-term extension treatment with a mean treatment duration of 200 weeks and total exposure of 1419.34 PY in all enrolled patients. Of the patients, 96.9% demonstrated >= 1 AEs, which is mostly mild to moderate. One death was observed, but no conspicuous AEs emerged and no specific concerns in AESIs were found through the long-term administration. The efficacy assessment revealed the maintained American College of Rheumatology response rates of 20%, 50%, and 70% during the *** This integrated analysis revealed no new safety concerns, and the efficacy was maintained in patients with RA under long-term ozoralizumab *** registration number jRCT2080223971, jRCT2080223973, NCT04077567.

关键词： Acute myeloid leukemia   AML   leukemia stem cells   LSC   Th1-differentiation   histone methylation   IFN-ɣ   TNF-α  

摘要： In acute myeloid leukemia (AML), leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) interact with various cell types in the bone marrow (BM) microenvironment, regulating their expansion and differentiation. To study the interaction of CD4+ + and CD8+ + T cells in the BM with LSCs and LPCs, we analyzed their transcriptome and predicted cell- cell interactions by unbiased high-throughput correlation network analysis. We found that CD4+ + T cells in the BM of patients with AML were activated and skewed toward T-helper (Th)1 polarization, whereas interleukin-9 (IL-9)-producing - producing (Th9) CD4+ + T cells were absent. In contrast to normal hematopoietic stem cells, LSCs produced IL-9, and the correlation modeling predicted IL9 in LSCs as a main hub gene that activates CD4+ + T cells in AML. Functional validation revealed that IL-9 receptor signaling in CD4+ + T cells leads to activation of the JAK-STAT pathway that induces the upregulation of KMT2A and KMT2C genes, resulting in methylation on histone H3 at lysine 4 to promote genome accessibility and transcriptional activation. This induced Th1-skewing, proliferation, and effector cytokine secretion, including interferon gamma (IFN-gamma) gamma ) and tumor necrosis factor alpha (TNF-alpha). alpha ). IFN-gamma gamma and, to a lesser extent, TNF-alpha alpha produced by activated CD4+ + T cells induced the expansion of LSCs. In accordance with our fi ndings, high IL9 expression in LSCs and high IL9R, , TNF, , and IFNG expression in BM-infiltrating - in fi ltrating CD4+ + T cells correlated with worse overall survival in AML. Thus, IL-9 secreted by AML LSCs shapes a Th1-skewed immune environment that promotes their expansion by secreting IFN-gamma gamma and TNF-alpha. alpha.

关键词： skin   respiratory system   infections  

摘要： A toddler presented with recurrent subcutaneous abscesses, otitis media and pneumonia, requiring frequent hospitalisations and intravenous antimicrobials. He also had oral thrush and difficulty in gaining weight;hence, an underlying inborn error of immunity (IEI) was strongly suspected. The complete haemogram showed leucocytosis with neutrophilic predominance. Both erythrocyte sedimentation rate and C reactive protein were elevated. Klebsiella pneumoniae was isolated from blood culture. The dihydrorhodamine-123 assay was negative, and the immunoglobulin profile showed an increased IgG level. Whole exome sequencing revealed a novel homozygous pathogenic variation in the IL-17RA gene (c.2563G>A, p. Asp855Asn). He showed remarkable improvement following intravenous colistin and fluconazole with complete resolution of abscesses. Thus, it is prudent to consider the possibility of IL-17RA deficiency in children with a history of recurrent abscesses, skin ulcerations and pneumonia after excluding the common groups of IEI.

关键词： IL-6   Cytokine storm   Suppressive effect   Isofraxidin   MAPK/ERK pathway  

摘要： Interleukin-6 (IL-6) is a pleiotropic cytokine that has many biological activities, including inflammation, hematopoiesis, bone metabolism, embryonic development, and other fundamental processes. Recently, IL-6 has been widely recognized as an important pro-inflammatory cytokine involved in cytokine storm pathogenesis during severe inflammatory diseases, such as coronavirus disease 2019 (COVID-19). Therefore, IL-6 is considered to be a therapeutic target for inhibiting cytokine storm. In the present study, we investigated the suppressive effect of isofraxidin, a major coumarin compound of Acanthopanax senticosus, on the overexpression of IL-6 and its molecular mechanism. The expression of IL-6 mRNA was measured using quantitative real-time PCR, and intracellular signaling molecules were detected using western blotting. When the HuH-7 human hepatocellular carcinoma cell line and HepG2 human hepatoblastoma cell line were treated with 12-O-tetradecanoylphorbol 13-acetate (TPA), a marked induction of IL-6 mRNA expression was observed in HuH-7 cells compared with HepG2 cells. Isofraxidin significantly suppressed TPA-induced IL-6 mRNA expression in HuH-7 cells in a dose-dependent manner. Furthermore, isofraxidin inhibited TPA-induced phosphorylation of ERK1/2 in a dose-dependent manner. Similarly, the MAPK/ERK inhibitor U0126 suppressed TPA-induced IL-6 mRNA expression. However, isofraxidin had no effects on TPA-induced phosphorylation of SAPK/JNK, Akt (Ser473), and STAT3 (Tyr705), nuclear translocation of NF-kappa B p65, and degradation of I kappa B. Taken together, isofraxidin suppresses TPA-induced overexpression of IL-6 mRNA by selectively inhibiting the activation of the MAPK/ERK pathway in HuH-7 cells, indicating that isofraxidin may be an effective anti-inflammatory agent for treating cytokine storm.