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关键词： 康艾注射液   人参-黄芪提取物   苦参素   肺癌   抗肿瘤   免疫功能   T淋巴细胞   调节性T细胞  

摘要： 目的:通过体内实验,探究康艾注射液及其组分对肺癌荷瘤小鼠的抗肿瘤和免疫调节作用。方法:取雄性C57BL/6J小鼠,随机分为空白组、模型组、低剂量组、中剂量组、高剂量组,除空白组外均建立肺癌皮下荷瘤模型。各组小鼠均腹腔注射给药,每日1次,低剂量组、中剂量组、高剂量组分别予康艾注射液25 mg/（kg·d）、50 mg/（kg·d）和75 mg/（kg·d）,连续给药28 d。每3天测量各组体质量和肿瘤大小,在模型建立第17天和第27天,小动物活体成像观测肿瘤情况。第29天处死小鼠,苏木精-伊红（HE）染色观察小鼠肺部的转移灶,流式细胞术检测白细胞分化抗原3（CD3）+、白细胞分化抗原4（CD4）+、白细胞分化抗原8（CD8）+淋巴细胞亚群和调节性T细胞（Treg）比例,免疫组织化学法检测肿瘤组织Treg细比例。同时进一步选取康艾注射最佳治疗剂量并根据其组成成分为人参-黄芪提取物组和苦参素组,给药方式及检测同前,流式荧光法（CBA）检测血清白细胞介素-10（IL-10）、白细胞介素-12（IL-12）、γ干扰素（IFN-γ）含量。结果:康艾注射液低剂量组、中剂量组、高剂量组和人参-黄芪组瘤质量和肺重均低于模型组（P<0.05）,切片显示肺转移灶减少,中剂量组抑瘤率最高。与模型组相比,中药各剂量组的CD3+、CD4+均显著升高（P<0.05）。中药各剂量组脾脏和肿瘤微环境Treg比例则明显低于模型组（P<0.05）。苦参素组IL-10水平降低,同时人参-黄芪组IFN-γ水平升高,康艾注射液中剂量组IL-12水平升高（P <0.05）。结论:康艾注射液可抑制小鼠肺癌的生长和转移,并改善小鼠免疫功能,此作用与调节肿瘤微环境中Treg比例有关,其中扶正药物人参黄芪-提取物在免疫调节中发挥重要的作用。

关键词： Gastric cancer   Gene polymorphism   HLA-G   HLA-G 14pb Ins/Del   HLA-G + 3142C/G   sHLA-G  

摘要： BACKGROUND:Gastric cancer (GC) remains a serious health concern and is characterized by a multifactorial etiology involving both genetic and epigenetic factors. The aim of the current study was to examine the relationship between Human leukocyte antigen (HLA)-G 3'UTR polymorphisms and the expression of HLA-G in both tumor tissues and plasma samples from patients with GC in the Tunisian population. METHODS:HLA-G 3'UTR polymorphisms (14pb Insertion/deletion and + 3142C/G) were identified by polymerase chain reaction (PCR) or Sanger sequencing. Plasma levels of sHLA-G (total sHLA-G, shed HLA-G1 and HLA-G5) were determined. Immunohistochemistry was used to evaluate the expression of HLA-G in tumor tissues. RESULTS:The Del/Del genotype and Del allele frequencies were different between GC patients and healthy donors (HD) (OR [95 % CI] = 2.483 [1.070-5.410], p = 0.025 vs. OR [95 % CI] = 1.537 [0.924-2.584], p = 0.099; respectively). The C/C genotype and C allele frequencies were significantly greater in GC patients than in HD (OR [95 % CI] = 2.269[0.1.070-4.904], p = 0.033 vs. OR [95 % CI] = 1.746[1.045-2.878], p = 0.034; respectively). Interestingly, the Del/Del genotype and Del allele were significantly associated with an increased risk of GC in patients aged ≥55 years at diagnosis. HLA-G was highly expressed in GC tissues, particularly in tissues with advanced tumor invasion (T3 + T4). Compared with HD, GC patients had higher soluble HLA-G, shed HLA-G1 and HLA-G5 levels (Mann-Whitney: p = 0.001, p = 0.001 and p = 0.643, respectively). Assessment of patients' survival by Kaplan-Meier analysis indicated that the Del allele was significantly associated with reduced overall survival (OS) in GC patients at advanced stages III + IV (p = 0.043). CONCLUSIONS:These results suggest that HLA-G 3'UTR polymorphisms are associated with GC susceptibility in Tunisian population. The expression of HLA-G in both the tissue and plasma may play an important role in the development and prog

关键词： breeding geese during the laying period   intestinal morphology   nutrient apparent utilization rates   reproductive performance   serum immunoglobulins   vitamin B12  

摘要： The purpose of this study was to study the effects of vitamin B₁₂ on reproductive performance, serum reproductive hormone and immunoglobulin contents, nutrient apparent utilization rates and intestinal morphology of breeding geese during laying period. A total of 180 thirty-four-week-old Wulong breeding geese were randomly divided into 6 groups with 6 replicates in each group and 5 geese (1 male and 4 females) in each replicate. The dietary vitamin B₁₂ supplemental levels in 6 groups were 0 (control group), 12.5, 25.0, 37.5, 50.0 and 62.5 μg/ kg, respectively. The pre-experimental period lasted for 1 week, and the experimental period lasted for 16 weeks. The results showed that compared with the control group: 1) the hatchability rate of 25.0, 37.5, 50.0 and 62.5 μg/ kg groups was significantly increased (P<0.05);2) the serum follicle-stimulating hormone content of 25.0 and 62.5 μg/ kg groups was significantly increased (P<0.05), and the serum prolactin content of 37.5 μg/ kg group was significantly decreased (P<0.05);3) the serum immunoglobulin G content of 25.0, 37.5, 50.0 and 62.5 μg/ kg groups was significantly increased (P<0.05);4) the ether extract apparent utilization rate of 25.0 and 37.5 μg/ kg groups was significantly increased (P<0.05);5) the duodenal villi height of 25.0 and 37.5 μg/ kg groups was significantly increased (P<0.05), and the duodenal villi height/ crypt depth and jejunal villi height and villi height/ crypt depth of 25.0, 37.5, 50.0 and 62.5 μg/ kg groups were significantly increased (P<0.05). In conclusion, the appropriate supplemental level of vitamin B₁₂ can improve the hatching rate of breeding geese during the laying period, regulate the reproductive hormone contents, increase the serum immunoglobulin contents and nutrient apparent utilization rates, and improve intestinal morphology. Under the conditions of this experiment, the appropriate supplemental levels of vitamin B₁₂ for breeding gees

关键词： airway remodeling   dupilumab   severe asthma  

摘要： Rationale: The role of IL-13 on the airway epithelium in severe asthma leading to airway remodeling remains poorly understood. Objectives: To study IL-13–induced airway remodeling on goblet cells and cilia in the airway epithelium in severe asthma and the impact of an anti-IL4Ra antibody, dupilumab, in vitro. Methods: Quantitative computed tomography of the lungs and endobronchial biopsies and brushings were obtained in 51 participants (22 with severe asthma, 11 with nonsevere asthma, and 18 healthy participants) in SARPIII (Severe Asthma Research Program III) and measured for mucin and cilia-related proteins. Epithelial cells were differentiated at air–liquid interface (ALI) with IL-13 with or without dupilumab and assessed for mucin, cilia, cilia beat frequency (CBF), and epithelial integrity (transepithelial electrical resistance [TEER]). Measurements and Main Results: Increased Muc5AC (mucin 5AC) (D 1 263.2 6 92.7 luminosity/epithelial area) and decreased ciliated cells (D 2 0.07 6 0.03 Foxj1¹ cells/epithelial area) were observed in biopsies from patients with severe asthma when compared with healthy control subjects (P, 0.01 and P = 0.047, respectively). RNA sequencing of endobronchial cell brushings confirmed a Muc5AC increase with a decrease in a five-gene cilia-related mean in patients with severe asthma compared with healthy subjects (all P, 0.05). IL-13 (5 ng/ml)–differentiated ALI cultures of healthy and asthmatic samples (from participants with severe and nonsevere asthma) increased Muc5AC, decreased cilia (a-aceytl-tubulin) in samples from healthy participants (D 1 6.5% 6 1.5%, D 2 14.1% 6 2.7%;all P, 0.001 respectively) and participants with asthma (D 1 4.4% 6 2.5%, D 2 13.1% 6 2.7%;P = 0.084, P, 0.001 respectively), and decreased epithelial integrity (TEER) in samples from healthy participants (2140.9 6 21.3 [ohms], P, 0.001), while decreasing CBF in samples from participants with asthma (D 2 4.4 6 1.7 [Hz], P, 0.01). When dupilumab was add

摘要： IL-33 plays an important role in the early programming of CD8 T cells;however, its contribution to the differentiation of tissue- resident memory T cells in vivo remains poorly defined. After infection of mice with Yersinia pseudotuberculosis, IL-33 expression was increased in the intestinal tissue, and this coincided with the expression of ST2 on T cells infiltrating the intestinal epithelium and lamina propria. Blocking IL-33 signaling after T cell infiltration of the intestinal tissue did not significantly impact the number or phenotype of tissue-resident memory T cells generated. However, overexpression of ST2 on T cells was able to increase expression of TCF1 and T cell number in the intestine compared with the lymphoid organs during infection. We also observed that enhanced accumulation and maintenance of ST2-overexpressing cells in the intestine postinfection were resolved. This points to a role for IL-33 in increasing the number of T cells that commit to intestinal tissue residency in vivo. The Journal of Immunology, 2024, 213: 1884-1892.

关键词： Exosomes   Ferroptosis   HSPA5/GPX4 axis   Intracerebral hemorrhage  

摘要： Background: Neuronal cell ferroptosis following intracerebral hemorrhage (ICH) is a crucial factor contributing to the poor prognosis of ICH patients. The objective of this investigation was to investigate the molecular mechanism of IL-1β-induced mesenchymal stem cell-derived exosomes (IL-1β-Exo) in mitigating ICH injury. Methods: Exo and IL-1β-Exo were obtained and identified. Hemin was used to induce an ICH model, and an ICH mouse model was established using Collagenase. Exo and IL-1β-Exo interventions were conducted to study their impact and molecular mechanisms on neuronal ferroptosis in ICH. Results: Vesicular structure Exo and IL-1β-Exo, with an average particle size of 141.7 ± 38.8 nm and 138.8 ± 37.5 nm, respectively, showed high expression of CD63, CD9 and CD81 could be taken up by SH-SY5Y cells. These Exos reversed Hemin-induced abnormalities in neuronal cells, including elevated iron, Fe²⁺, ROS, MDA, 4-HNE, and decreased SOD, GSH-Px, GSH, FTH1 levels, and cell vitality. The RNA content of IL-1β-Exo was linked to its ability to reduce iron accumulation. There was an interaction between HSPA5 and GPX4. Exo and IL-1β-Exo reversed Hemin-induced downregulation of HSPA5 and GPX4 expression. Overexpression and knockdown of HSPA5 respectively potentiate or counteract the impacts of Exo and IL-1β-Exo. IL-1β-Exo was more effective than Exo. These findings were further validated in ICH mice. Moreover, both Exo and IL-1β-Exo reduced the modified neurological severity score and brain water content, as well as alleviated pathological damage in ICH mice. Conclusion: IL-1β-Exo inhibited neuronal ferroptosis in ICH through the HSPA5/GPX4 axis. © 2024 Elsevier B.V.

摘要： Chimeric Ag receptor T cells derived from universal donors are susceptible to recipient immunologic rejection, which may limit their in vivo persistence and compromise treatment efficacy. In this study, we generated HLA class Ideficient T cells by disrupting b 2-microglobulin to evade recognition by HLA-mismatched CD8+ T cells, and then restored NK cell tolerance by forced expression of an HLA-E single-chain receptor. We specifically report on an optimized hypoimmunogenic disulfide trap HLA-E4 (dtHLA-E4) molecule that exhibited increased surface expression, enhanced NK cell inhibitory potential, and abrogated CD8-dependent T cell recognition. Our dtHLA-E4 molecule comprised the CD4 (4) transmembrane domain and truncated cytoplasmic region, as well as disulfide trap mutations to anchor an HLA class I signal sequence-derived peptide. Functional comparison of dtHLA-E4 molecules fused to different VL9 epitopes showed that peptides derived from HLA-A and HLA-C allotypes maximized NK cell inhibition and minimized NKG2C+ NK cell activation. Furthermore, incorporation of mutations into the a 3 domain of HLA-E diminished the immunogenicity of dtHLA-E4 by reducing CD8+ T cell recognition, but crucially, these mutations left NK cell inhibitory function intact. These findings demonstrate the systematic construction of a hypoimmunogenic dtHLA-E4 molecule, which promises to facilitate persistence of allogeneic HLA class Ideficient chimeric Ag receptor T cells by overcoming NK cell missing-self recognition.

摘要： IFN-(3 is a potent antiviral cytokine and the first member of the type I IFN family of cytokines to be induced during the antiviral response. IFN-(3 plays an essential protective role in host defense against virus infections, as well as a pathogenic role in numerous autoimmune and autoinflammatory disorders. However, contemporary tools to study the induction, kinetics, and behavior of IFN-(3 are lacking. In this study, we describe a knockin Ifnb-IRES-TdTomato-Cre reporter mouse to track IFN-(3-expressing cells. We demonstrate pathway-specific induction of the TdTomato reporter and show that the linked Cre lung epithelial cells following Sendai virus infection in vivo. Finally, we find that activation of RNase L in macrophages by RNA ligands of the RIG-I-like receptors prevents protein translation of IFN-(3 and the TdTomato reporter. Our mouse model provides a powerful tool to study the biology of type I IFN induction and the antiviral response.

摘要： Dysregulation of lipid homeostasis causes the deposition of lipids in the form of tiny droplets within foamy macrophages (FMs). In FMs, host-derived lipids aid in survival of various intracellular pathogens leading to sustained infection. In several infectious diseases, the transformation of macrophages into a foamy phenotype is linked to the presence of high IL-10, a potent immune- modulatory cytokine. This review aims to understand the role of IL-10 in the signaling events that are crucial in generation of FMs and highlights how various intracellular pathogens targets the IL-10- FM axis for successful establishment of infections. The review also briefly discusses how the IL-10- FM axis can be a target for developing novel therapeutic strategies to prevent intracellular infections. The Journal of Immunology, 2024, 213: 1729-1737.