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关键词： 原发性高血压   左室几何构型   超声心动描记术   二维应变   白细胞介素-10   白细胞介素-18  

摘要： 目的 探讨原发性高血压（PHT）患者IL-10和IL-18与左室几何构型（LVG）及左室功能的相关性。方法 选取2023年7月至2024年5月就诊于山西医科大学第一医院确诊为PHT患者224例，分为4组：正常构型（NG）组127例、向心性重构（CR）组51例、离心性肥厚（EH）组27例和向心性肥厚（CH）组19例。另选取同期本院健康体检中心招募的年龄、性别匹配，且无高血压、心血管疾病及代谢性疾病的健康者25例作为对照组。比较5组间一般资料、血清IL-10、IL-18水平及左室参数[左室舒张末期内径（LVEDD）、室间隔厚度（IVST）、左室后壁厚度（LVPWT）、左房收缩末期前后径（LAD）、左室质量指数（LVMI）、相对室壁厚度（RWT）；二尖瓣口舒张早期血流峰值速度（E）、二尖瓣口舒张晚期血流峰值速度（A）、E/A、二尖瓣环舒张早期心肌运动速度（e′）、E/e′、左室射血分数（LVEF）、左室整体纵向应变（GLS）]。采用Pearson相关及多因素Logistic回归分析IL-10、IL-18与LVG和左室功能的关系。结果 与对照组相比，PHT组患者血清IL-10水平降低（P<0.05）,IL-18水平升高（P<0.05），其中EH组和CH组变化显著（均P<0.05）。Pearson相关分析显示，IL-10与LVEDD、IVST、LVPWT、A、E/e′呈负相关（P<0.05），与e′、E/A、LVEF、GLS呈正相关（P<0.05）;IL-18与LVEDD、IVST、LVPWT、A、E/e′呈正相关（P<0.05），与e′、E/A、LVEF、GLS呈负相关（P<0.05）。多因素Logistic回归显示，IL-10是CR、EH及CH的独立保护因素（P<0.05）;IL-18是CR、EH及CH的独立风险因素（P<0.05）。结论 IL-10和IL-18与PHT患者左室结构及功能密切相关，可能参与PHT患者左室结构和功能异常的过程。

摘要： Protein kinase R (PKR) expression is induced by interferons. This protein is activated by double-stranded (ds) RNAs or RNAs containing duplex regions, produced after different stimuli, such as after viral infections, leading to the phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α), and subsequently inhibiting cellular and viral protein translation. This function may lead to different effects such as to impairing the replication of RNA viruses by inhibiting viral protein translation, and to modulating the innate immune responses after viral infections by affecting the translation of effector proteins. In this work, we identify, for the first time, an interaction of IFN alpha inducible protein 27 (IFI27) with PKR-activating protein (PACT or PRKRA) and with PKR, showing that the interaction of IFI27 with PACT is likely mediated by dsRNAs or RNAs containing duplex regions, and that the interaction of IFI27 with PKR is PACT-dependent. Interestingly, using IFI27 knocked-down, knocked-out and overexpressing tumour-derived, established cells, we show that these interactions trigger a potentiation of the activity of PKR and, therefore, a decrease in protein translation. Moreover, we find that IFI27 increases PKR function in cells infected with different RNA viruses such as Severe Acute Respiratory virus 2 (SARS-CoV-2), and Vesicular Stomatitis virus (VSV), and in cells transfected with the dsRNA analog poly(I:C), suggesting a broad effect of IFI27 on PKR activation. Moreover, we show that IFI27 expression increases the formation of stress granules (SGs) at the cell cytoplasm, correlating with the increased PKR activation mediated by IFI27, as it has been shown that the translational arrest induced by activated PKR leads to the formation of SGs. Mechanistically, we describe that this ability of IFI27 to activate PKR is dependent on its interaction with PACT. Further understanding of the regulation of PKR activity will allow us to develop new antiviral

摘要： Metastatic colorectal cancer (CRC) has the dismal 5-year survival rate of only 14%, and immunotherapies fail to improve the patient outcome. One reason for the poor response rate is the slightly acidic (~ 6.5) immunosuppressive microenvironment. Interleukin 12 (IL-12) is a highly potent pro-inflammatory cytokine that can stimulate tumor immune cells and reverse immunosuppression by inducing interferon gamma (IFN-γ) expression. However, its clinical applications are hindered by systemic side effects. In this study, we developed pH-responsive polymeric nanoparticles (NPs) encapsulating IL-12 to enhance its therapeutic efficacy into the tumor microenvironment (TME). IL-12-loaded pH-responsive NPs induced antitumoral pro-inflammatory response in macrophages at pH ~ 6.5, determined by increased IFN-γ levels and nitric oxide (NO) release, without affecting metabolic activity. In contrast, IL-12-loaded pH non-responsive PLGA NPs showed much lower macrophage activation. To validate the specificity and efficacy in a complex immune-rich microenvironment, we developed a novel CRC 3D immuno-spheroid by incorporating human monocyte-derived macrophages with tumor cells in collagen, mimicking CRC spatial organization and extracellular matrix. The interaction of IL-12 pH-responsive NPs induced macrophage polarization, by providing a reduction of M2-like markers (CD14 + CD163+) while increasing pro-inflammatory M1-like counterparts (CD14 + CD86+). Moreover, IL-12 pH-responsive NPs increased IFN-γ levels and reduced anti-inflammatory IL-10 secretion. Overall, this study provides two major findings (1) a pH-responsive NP system to effectively deliver IL-12 to the TME and reprogram local macrophages into pro-inflammatory phenotype; (2) a macrophage-enriched human 3D immuno-spheroid in vitro system as a tool to test the effectivity of immunomodulatory NPs.

关键词： Chemokine   Chikungunya   Chronic chikungunya arthritis   Cytokine  

摘要： BACKGROUND:Cytokines and chemokines play a crucial role in orchestrating the immune response to chikungunya virus (CHIKV) infection, influencing disease course and outcome. Although significant efforts have been made to understand the cytokine signatures associated with CHIKV infection, the identification of specific cytokine biomarkers across different disease stages remains incomplete. MATERIAL AND METHOD:We have assessed CHIKV-specific cytokine, chemokine profiles of 17 analytes in 50 acute chikungunya patients, 31 chronic chikungunya arthritis patients, 30 recovered individuals, and 23 healthy controls. The cytokine and chemokines were measured in the supernatant of PBMCs stimulated in vitro with inactivated chikungunya virus. RESULTS:It was observed that chronic chikungunya arthritis patients exhibited significantly higher levels of IL-1β, IL-6, and GM-CSF compared to all other groups. MCP-1 levels were elevated in patient groups compared to recovered and control individuals. IL-1β emerged as a potential biomarker for chronic chikungunya arthritis based on ROC analysis. A negative correlation between IFN-γ levels and CHIKV load was observed in acute patients, suggesting its antiviral role. IL-12 levels were higher in recovered individuals compared to all other groups, while IFN-γ levels were elevated in recovered individuals compared to acute patients. CONCLUSION:Our findings highlight IL-1β as a potential biomarker for chronic chikungunya arthritis and suggest that GM-CSF inhibition could serve as a therapeutic intervention for disease-associated chronic inflammation. The observed co-regulation of IL-12 and IFN-γ in recovered individuals needs further investigation into their role in disease resolution. These insights provide a deeper understanding of the immunopathogenesis of CHIKV infection and may contribute in future diagnostic and therapeutic strategies.

关键词： IL‐33   Leydig cells   aging   mesenchymal cells   steroidogenesis  

摘要： BACKGROUND:Serum testosterone (T) concentration declines with aging in men, potentially affecting reproduction, mental and physical well-beings. A role of immune factors in Leydig cell (LC) function is well-known, but the specific factors involved, especially these playing roles in LC aging, are still unclear. This study investigated effects of interleukin 33 (IL-33) on LC function and its expression during testicular aging. METHODS:Immunohistochemistry and Western blotting were used to determine IL-33 and its receptor IL1RL1 expressions in testes of young (3-month-old) and old (19-24-month-old) Wistar rats. In vitro, the effects of IL-33 on sex steroid hormone productions were evaluated in primary and MLTC-1 LCs over 2-24 h. Different steroidogenic stimulators or signaling molecules (luteinizing hormone [LH], 8-Br-cAMP, Forskolin, pertussis toxin, and MAPK activators) were compared with elucidate mechanisms. Steroidogenic pathway proteins and potential signaling molecules were explored by Western blotting. RESULTS:IL-33 is expressed by mesenchymal cells, with the number increasing significantly with aging. IL1RL1, its receptor, is expressed by LCs and remains unchanged. In vitro, IL-33 acutely inhibited LC steroidogenesis in a dose-dependent manner (1-100 ng/mL) within 2-24 h. The effect was LH-dependent; replacing LH with either 8-Br-cAMP or Forskolin abolished the inhibition. IL-33 mainly affected STAR in the steroidogenic pathway. Signaling molecules involving STAR regulation (AKT and MAPK) were down-regulated while PKA phosphorylation was increased. P38 MAPK involvement was confirmed as increased Tyr182 phosphorylation of P38 by SB203580 partly reversed the IL-33-induced steroidogenesis inhibition. CONCLUSION:Testicular mesenchymal cells can synthesize IL-33, and LCs express the receptor IL1RL1. IL-33 inhibits LC steroidogenesis in vitro, partially via inhibiting P38 MAPK phosphorylation. As IL-33-expressing cell numbers rise significantly with aging, its role

关键词： Anti-IL23   Psoriasis   biologic treatment   efficacy   guselkumab   risankizumab   tildrakizumab  

摘要： INTRODUCTION:Psoriasis is a chronic, systemic inflammatory disease with significant physical and psychosocial burden. Advances in understanding the pathogenesis of psoriasis, particularly the role of interleukin (IL)23/Th17 axis, have led to the development of selective drugs targeting these cytokines. Among these, IL23 inhibitors (guselkumab, risankizumab, and tildrakizumab), represent the most recent class of biologic drugs approved for the management of moderate-to-severe plaque psoriasis. Since their approval, real-life data on the use of anti-IL23 have confirmed their high efficacy, durability, and favorable safety profile. AREAS COVERED:This narrative review summarizes real-world data on the effectiveness, also in difficult-to-treat areas, safety, and drug survival of IL23 inhibitors in psoriasis. EXPERT OPINION:Real-world evidence consistently confirms the strong efficacy, favorable safety profile, and long-term treatment durability of IL23 inhibitors across various patient subgroups, including those with comorbidities, prior biologic failures, and the involvement of difficult-to-treat areas. IL23 inhibitors have become key components of the therapeutic arsenal in psoriasis, and their performance in real-world settings continues to support their widespread adoption in clinical practice.

关键词： biofilm‐infected diabetic ulcers   core‐shell microneedle   macrophage polarization   spatiotemporal immunomodulatory  

摘要： Macrophage phenotypic dysregulation, spatially by biofilm and dynamically in time, impedes the healing of diabetic ulcers (DUs). Effective treatment requires enabling spatiotemporal regulation of macrophage polarization, balancing the M1 pro-inflammatory antimicrobial response with the M2 anti-inflammatory tissue-regeneration response. Here, a core-shell microneedle system (LM-MG@MN) is proposed with spatiotemporal immunomodulation features, designed to spatially disrupt biofilm barriers and sequentially induce macrophage polarization from M0 to M1 and subsequently to M2 by regulating the NLRP3/IL-1β pathway. Glucose oxidase (GOX)-loaded 2D MXene nanosheets (MG) are encapsulated in a hyaluronic acid-β-cyclodextrin (HA-β-CD) matrix as the MN shell layer. The rapid dissolution of this shell triggers MG to induce pro-inflammatory polarization of macrophages from M0 to M1, aiding in clearing biofilm infections. Liposomes (LM) carrying the NLRP3 inflammasome inhibitor MCC950 are embedded within a methacrylate hyaluronic acid (HAMA) matrix in the MN core. In the later stages of wound healing, LM is released gradually from the core, promoting the anti-inflammatory polarization of macrophages from M1 to M2 and accelerating tissue regeneration by enhancing crosstalk with fibroblasts and endothelial cells. Additionally, RNA sequencing indicates that LM-MG@MN regulates macrophage metabolic reprogramming to enhance DUs healing. This spatiotemporal immunomodulation strategy offers a promising approach for clinical DUs treatment.

关键词： HLA‐B27   uveitis   vitamin D  

摘要： Hybrid solid-state electrolytes, which combine ionic liquids with metal-organic frameworks, offer a promising approach to enhancing the safety and energy density of next-generation batteries. A thorough understanding of the interplay between the solid and liquid phases in hybrid solid-state electrolytes is crucial for optimizing their performance as battery electrolytes. This study investigates how interactions between different ionic liquid-based electrolytes and the metal-organic framework ZIF-8 influence the coordination and dynamics of Li in confinement. To this end, we examine five different ionic liquids, varying the chemical nature of the cation. Raman spectroscopy, supported by 2D solid-state NMR and simulations, are used to elucidate Li coordination and ion-wall interactions. The impact of these interactions on local Li dynamics and charge transport in the ionic liquid-ZIF-8 hybrid system is investigated using Li spin relaxation, impedance spectroscopy, and simulations. The results reveal a competitive interaction between Li and the ionic liquid cation with the ZIF-8 framework, which can be fine-tuned by modifying the molecular structure of the ionic liquid cation. As a consequence, local Li dynamics is enhanced, depending on the ionic liquid cation. The beneficial interactions in the confined system can even make Li the fastest diffusing species, in contrast to bulk electrolyte, where Li transport is limited by strong Li-anion clusters. Thus, blocking Li-framework interactions through other competitive interactions might be an effective strategy to enhance Li dynamics and increase Li conductivity in a hybrid solid-state electrolyte. Although confinement within the ZIF-8 model system leads to an overall decrease in conductivity, this study provides valuable insights into the design of hybrid electrolytes for next-generation battery applications.

关键词： 抗Claudin18.2单抗   抗体依赖性细胞吞噬作用   生物学活性   转基因细胞   报告基因   优化   验证  

摘要： 目的 建立抗Claudin18.2单抗（mAb）的抗体依赖性细胞吞噬作用（ADCP）生物学活性检测方法。方法 以Jurkat/NFAT/CD32a-FcεRIγ转基因细胞系作为效应细胞，HEK293T-Claudin18.2细胞系作为靶细胞，通过萤光素酶检测系统(OneGloTMLuciferase Assay System)检测抗Claudin18.2单抗的ADCP生物学活性，并进行实验参数优化与方法学验证。结果 抗Claudin18.2单抗在该报告基因法中存在量效关系，且符合四参数方程：y=（A-D）/[1+（x/C）B]+D。方法经多个实验参数筛选和优化，确定抗体工作浓度为0.02～200 000 ng/mL，靶细胞和效应细胞的接种量均为每孔5×10～4个，诱导时间为6 h。该方法具有良好的专属性；5个不同稀释组回收率样本经3次检测，相对效价分别为（48.90±2.36）%、（71.87±2.62）%、（99.64±2.12）%、（135.42±1.12）%和（151.16±6.91）%；回收率为96%～108%,RSD均小于6%，线性检测范围为50%～150%。结论 本研究成功建立基于报告基因的抗Claudin18.2单抗ADCP生物学活性测定方法，该方法具有良好的专属性、重复性和准确性，可作为抗Claudin18.2单抗ADCP生物学活性的评价方法。