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关键词： T -helper cell 9   Interleukin-9   Autoimmune disease   Rheumatoid arthritis   Multiple sclerosis   Systemic lupus erythematosus  

摘要： Autoimmune diseases (AIDs), such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, are caused by abnormal immune response that targets the body's own tissues. T-helper cell 9 (Th9) is a recently discovered subpopulation of T cells that primarily participates in inflammatory responses and immune regulation by secreting interleukin-9 (IL-9). IL-9 is a multifunctional cytokine that regulates the function of T and B cells, and also affects the activation and response of mast cells, macrophages, and other cells. Studies have shown that Th9 cells significantly affect the development of autoimmune diseases and are closely related to disease activity and pathological processes. Exploring drugs targeting Th9 cells or IL-9 and elucidating the regulatory mechanisms of Th9 and IL-9 in various AIDs will provide important insights for the development of novel therapeutic strategies.

关键词： Asthma exacerbation   IL-33   Immune homeostasis   Oxidative stress   Ozone  

摘要： Short-term exposure to ozone is linked to the onset and exacerbation of asthma, yet the underlying mechanisms remain unclear. This study aims to elucidate the molecular pathways and key mediators involved in ozone-induced asthma exacerbation. In a longitudinal epidemiological study, each 10 mu g/m3 increase in ozone is associated with decreases in forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and peak expiratory flow (PEF) of 26.24 ml (95 % confidence interval [CI]: 11.16 ml, 41.33 ml), 19.10 ml (95 % CI: 6.96 ml, 31.24 ml), and 41.65 ml/s (95 % CI: 3.87 ml/s, 79.43 ml/s), respectively. In asthmatic mice, ozone exposure induces oxidative stress and worsens pulmonary dysfunction, lung tissue damage, and inflammation, disrupting the balance of type 2 innate lymphoid cells (ILC2s), T helper type 2 (Th2), and T helper type 17 (Th17) cells. These effects are partially mitigated by N-acetylcysteine (NAC). Furthermore, ozone exposure significantly increases the interleukin (IL)-33 level, while treatment with an IL-33 neutralizing antibody markedly improves lung dysfunction, inflammatory cell infiltration, and immune response dysregulation. In conclusion, this study highlights that short-term exposure to ozone has deleterious effects on asthmatic patients and animals by inducing oxidative stress in lungs and disrupting immune function via IL-33.

关键词： 异基因造血干细胞移植   新鲜脐血移植   β重型地中海贫血   移植物抗宿主病   儿童  

摘要： 背景:异基因造血干细胞移植是目前根治重型地中海贫血最有效的方法,然而仅有不到一半的患者能找到相合的骨髓或外周血干细胞。同胞来源脐血干细胞与骨髓和外周血干细胞具有不同的特征,是重型地中海贫血患者移植治疗的一种潜在造血干细胞替代来源。目的:探讨应用人类白细胞抗原相合同胞新鲜脐血移植治疗儿童β重型地中海贫血的疗效。方法:选择2010年6月至2020年6月南方医科大学南方医院收治的β重型地中海贫血患儿48例,男28例,女20例,中位年龄4岁,均接受人类白细胞抗原相合同胞新鲜脐血移植治疗,脐血移植前均采用清髓性不含抗胸腺细胞球蛋白的预处理方案,脐血移植后均采用环孢素A+吗替麦考酚酯+/-短程甲氨蝶呤预防移植物抗宿主病。结果与结论:(1)48例患儿输注的总有核细胞中位数为8.17×10^(7)/kg,输注的CD34^(+)细胞中位数为2.40×10^(5)/kg,脐血移植后中位随访时间98个月,44例植入成功,粒细胞和血小板植入中位时间分别为28 d和31 d,其中37例移植后植入证据检测为供者型完全嵌合,7例移植后早期检测为供受者稳定混合嵌合;(2)44例植入成功患儿中,4例发生急性移植物抗宿主病,分别为Ⅰ级(n=2)和Ⅱ级(n=2),受累器官均为皮肤,均未发生慢性移植物抗宿主病;(3)脐血移植后,48例患儿中5例发生巨细胞病毒感染及激活,12例发生败血症,3例发生侵袭性真菌病,21例发生口腔炎,8例发生出血性膀胱炎,1例发生肝静脉闭塞;(4)48例患儿中,47例存活,1例在移植后28 d因重症肺炎合并急性心力衰竭死亡,43例无病存活,3例发生原发性植入失败,1例发生移植后全血细胞减少,5年总生存率和无病生存率分别为98%和89%,1年时移植相关死亡的累计发病率为2.1%;(5)结果显示,人类白细胞抗原相合同胞新鲜脐血移植治疗儿童β重型地中海贫血的效果良好,移植物抗宿主病的发生风险低。

关键词： Kinsenoside   Pain   Anti-inflammation   ER stress   Glutamatergic transmission  

摘要： Neuro-inflammation contributes to neuropathic pain by sensitizing ionic channels. Kinsenoside, a traditional Chinese medicine, has recognized anti-inflammatory properties. However, it remains unclear whether kinsenoside can be used for pain therapy. Network pharmacology analysis revealed that 57 % of its targets are associated with pain, including inflammation and synaptic transmission. The analgesic effects of kinsenoside were confirmed in SNL and formalin rat models, with ED50 values of 47.99 mu g and 36.80 mu g, respectively. Transcriptome and WGCNA analyses indicated the involvement of cytokine release, anti-inflammatory activity, and synapse enrichment in the blue module. Furthermore, we confirmed that kinsenoside's efficacy was mainly mediated by IL-10 induction, phosphorylation of STAT3, and SOCS3 expression. Pretreatment with kinsenoside significantly inhibited the release of TNF-alpha, IL-1 beta, and IL-6. Kinsenoside also attenuated ER stress in both microglia and neural cells. Molecular docking analysis demonstrated significantly high binding energies of IL-10, STAT3, and SOCS3 with MHC. Additionally, whole-cell recordings revealed that bath application of kinsenoside reduced the frequency and amplitude of spinal glutamatergic transmission in a dose-dependent manner. In summary, pharmacological prediction and biological validation collectively indicate that kinsenoside significantly exerts significant analgesic effects by attenuating ER stress and inhibiting inflammatory responses via the IL-10/p-STAT3/SOCS3 axis, precisely regulating spinal glutamatergic transmission for pain relief.

关键词： Plasma proteome   Mendelian randomization   Ankylosing spondylitis   Potential drug targets   Causal inference  

摘要： Background: Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily affecting the spine and pelvis, leading to ankylosis, stiffness, and reduced quality of life. Despite therapeutic advances, identifying novel drug targets remains critical. Methods: This Mendelian randomization (MR) study leveraged proteome-wide analysis, utilizing data from five genome-wide association studies (GWAS) for proteomics exposure. Outcome data included 3162 European ancestry cases and 294,770 controls from FinnGen R10, and replication analyses used two plasma proteomic datasets (ARIC: 4657 proteins in 7213 individuals;UK Biobank: 4907 proteins in 35,559 participants) and UK Biobank AS GWAS (1344 cases, 324,074 controls). Sensitivity analyses, including Bayesian co-localization and Steiger's direction test, were conducted to ensure robust findings. Protein-protein interaction (PPI) networks were constructed to explore interactions between identified proteins and known AS drug targets. Results: After FDR adjustment, circulating ERAP1 (OR = 1.30, 95 % CI: 1.21-1.39, P = 8.18 x 10(-14)) and IL23R (OR = 2.21, 95 % CI: 1.61-3.03, P = 9.47 x 10(-7)) were genetically linked to increased AS risk, while IL1RL2 showed a protective effect (OR = 0.70, 95 % CI: 0.58-0.85, P = 3.22 x 10(-4)). Steiger's test confirmed directionality (P < 1.70 x 10(-15)), and Bayesian co-localization supported shared causal variants (PPH4 > 0.75 for IL23R/IL1RL2). PPI networks revealed interactions between ERAP1, IL23R, and known AS targets. Replication validated ERAP1 and IL23R associations but not IL1RL2. Conclusion: Genetically determined levels of ERAP1 and IL23R are robustly associated with AS risk, highlighting their potential as therapeutic targets. This study demonstrates the utility of MR in identifying drug targets for complex diseases, providing a foundation for further clinical investigation into their therapeutic potential.

关键词： Bacterial infection   Interleukin-18   Large yellow croaker (Larimichthys crocea)   Pro-inflammatory factor  

摘要： Interleukin-18 (IL-18), a pro-inflammatory cytokine of the IL-1 family, is crucial for protecting the host against pathogen infection in mammals. In this study, a IL-18 homolog gene was cloned from large yellow croaker (Larimichthys crocea) (LcIL-18), which has an open reading frame (ORF) of 609 bp that encodes a polypeptide of 202 amino acids. The LcIL-18 C-terminus contains a typical IL-1 family signature and a caspase cleavage site. Phylogenetic analysis showed that LcIL-18 was most closely related to IL-18 of Miichthys miiuy. It was found that LcIL-18 was constitutively expressed in all 12 tissues tested of large yellow croakers, with the highest expression in gills. The expression of LcIL-18 in head kidney, spleen, skin, gills, and liver showed a differential pattern following infection with Pseudomonas plecoglossicida and Vibrio alginolyticus. P. plecoglossicida strongly induced LcIL-18 expression in these tissues. Conversely, in the early stage of infection, V. alginolyticus significantly inhibited LcIL-18 expression in head kidney, spleen, skin, and gills, but not in the liver. In vitro, LPS, Poly(I:C), P. plecoglossicida, and V. alginolyticus significantly upregulated the expression of the LcIL-18 in large yellow croaker head kidney (LYCK) cells. Furthermore, recombinant LcIL-18 (rLcIL-18) significantly increased cell viability and upregulated the expression of pro-inflammatory cytokines (LcIL-1β, LcIL-6, and LcTNF-α1) in LYCK cells. Our findings therefore indicated that LcIL-18 was involved in pro-inflammatory response induced by pathogenic bacteria. © 2025 Elsevier Ltd

关键词： clinical trial   immune checkpoint inhibitors   melanoma   T cells   TNF  

摘要： Resistance to immune checkpoint inhibitors (ICI) in cancer patients is not fully understood, and predictive biomarkers are lacking. MELANF alpha (NCT03348891) is an open-label, prospective, multicenter cohort of 60 patients with advanced melanoma receiving ICI (bitherapy: ipilimumab + nivolumab;monotherapy: pembrolizumab or nivolumab). The primary objective was to evaluate whether changes in plasma TNF between baseline (W0) and week 12 (W12) identified patients with non-progressive disease at W12. Secondary and exploratory objectives were to assess the association between plasma TNF, tumor response, and changes in circulating T cells. Plasma TNF increased along therapy, but its W12/W0 fold change was not associated with non-progressive disease at W12. However, plasma TNF levels at W12 were significantly higher in non-responders than in responders across therapies (p = .0129). The remodeling of circulating T cell subpopulations was mostly triggered by bitherapy. Increased proportions of circulating central memory and effector memory CD8 T cells after bitherapy were positively and negatively associated with response to treatment, respectively. In this cohort, circulating T cells from responders and non-responders also displayed distinct molecular characteristics. Indeed, responders showed an increased proportion of CD8 T cells with low enrichment of TNF-related pathways and high cytotoxic potential, while non-responders displayed increased proportions of circulating CD8 EM T cells enriched for TNF-related pathways and directed toward cytokine expression. In conclusion, our study shows that elevated plasma TNF and enriched TNF pathways in T cells are associated with poorer clinical outcomes, reinforcing the notion that TNF may dampen ICI efficacy.

关键词： UIO-66   Enrichment   Selective adsorption   Photocatalysis   Fenton-like reaction   4-CP  

摘要： Persistent organic pollutants (POPs) represent a significant environmental and health risk due to their high toxicity, persistence, strong accumulation potential, and adverse effects on human health. 4-Chlorophenol (4CP), a type of POP, has low catalytic efficiency at low concentrations and is easily interfered with by other pollutants, making its degradation challenging. A new "recognition-enrichment-in-situ degradation" strategy is introduced to selectively remove chlorophenols from contaminated aqueous environments. In this study, ionic liquids were incorporated into the UIO-66 framework as active sites for selective adsorption. 4-CP contains phenolic hydroxyl groups and exhibits high polarity. The dispersive interactions between 4-CP and ionic liquids, along with hydrogen-bonding interactions between the Tf2N anion and the hydroxyl groups of 4-CP, enhance the selective enrichment of 4-CP within the nanocavities of the metal-organic frameworks (MOFs). Fe3+ was then introduced, enabling in-situ degradation of 4-CP through photo-induced generation of free radicals and cavities from H2O2 catalyzed by Fe-IL@UIO-66. The results indicated that the adsorption capacity of IL@UIO-66 for 4-CP reached 53 %, significantly higher than that for five other organic pollutants. The adsorption capacity of IL@UIO-66 for 4-CP reached 509.5 mg g- 1, 49.9 % greater than that of the original UIO-66. The degradation efficiency of 4-CP by Fe-IL@UIO-66 increased from 61 % to 81 %, and after four cycles, the material retained a catalytic activity with a degradation efficiency of 64.2 %. This study provides valuable insights into the recognition-enrichment-in-situ catalytic strategy for treating low-concentration, highly toxic wastewater.

关键词： 缺氧缺血性脑病   患儿   高压氧   肿瘤坏死因子⁃α   白介素⁃6   D⁃二聚体   预后   预测价值  

摘要： 目的探讨血清肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)及D-二聚体(D-D)水平对高压氧综合治疗缺氧缺血性脑病(HIE)患儿预后的预测价值。方法回顾性分析2020年1月至2023年12月东营市人民医院儿科收治、均予以高压氧综合治疗的92例HIE患儿的临床资料,按照治疗效果分为预后良好组(n=64)和预后不佳组(n=28)。收集2组患儿的临床资料,采用酶联免疫吸附法测定血清TNF-α、IL-6、D-D水平。采用非条件单因素和多因素Logistic回归分析患儿预后不佳的危险因素,采用受试者工作特征(ROC)曲线评估HIE患儿血清TNF-α、IL-6、D-D水平对HIE患儿预后的预测价值。结果预后不佳组患儿出生Apgar评分明显低于预后良好组,临床重度百分比及血清TNF-α、IL-6、D-D水平均明显高于预后良好组(均P<0.001)。多因素Logistic回归分析显示,Apgar评分(95%CI:0.036~0.292)、临床分度(95%CI:3.649~28.351)、TNF-α(95%CI:2.816~24.108)、IL-6(95%CI:2.143~14.381)、D-D(95%CI:1.045~1.110)均为患儿预后不佳的危险因素(P<0.05或P<0.01)。ROC曲线评估显示,TNF-α、IL-6、D-D三者联合预测患儿预后的ROC曲线下面积(AUC)值和敏感度均明显高于TNF-α、IL-6、D-D的单项预测(P<0.05)。结论高压氧综合治疗后,预后良好组HIE患儿血清TNF-α、IL-6、D-D水平均明显低于预后不良组,三者联合应用能较好地预测HIE患儿预后。

关键词： IL-34   VAP-1   Irisin   妊娠期糖尿病   血糖转归  

摘要： 目的:探讨血清白细胞介素-34(interleukin-34,IL-34)、血管黏附蛋白-1(vascular adhesion protein-1,VAP-1)、鸢尾素(Irisin)水平与妊娠期糖尿病(gestational diabetes mellitus, GDM)患者产后血糖转归的相关性。方法:回顾性选取2022年2月至2024年2月于汝州市妇幼保健院成功分娩的128例GDM患者为研究对象,依据产后6周血糖转归水平,将患者分为转归良好组85例、转归不良组43例。比较两组临床资料及不同时间点血清IL-34、VAP-1、Irisin及糖化血红蛋白(glycosylated hemoglobin, HbA1c)、空腹血糖(fasting blood glucose, FPG)水平并分析相关性,多因素分析两组患者产后血糖转归的影响因素。结果:转归不良组糖尿病确诊时间为孕晚期比例高于转归良好组,差异有统计学意义(P<0.05);产后1周血清IL-34、VAP-1水平、HbA1c、FPG水平>产后3周>产后6周,产后1周Irisin水平<产后3周<产后6周,差异有统计学意义(P<0.05);产后1周、产后3周、产后6周,转归不良组血清IL-34、VAP-1水平、HbA1c、FPG水平高于转归良好组,Irisin水平低于转归良好组,差异有统计学意义(P<0.05);血清IL-34、VAP-1与HbA1c、FPG水平呈正相关,Irisin水平与HbA1c、FPG水平呈负相关,差异有统计学意义(P<0.05);糖尿病确诊时间、产后1周、产后3周血清IL-34、VAP-1、Irisin水平、HbA1c、FPG水平均为GDM患者产后发生血糖转归不良的危险因素,差异有统计学意义(P<0.05)。结论:血清IL-34、VAP-1、Irisin水平与GDM患者产后血糖转归相关,可为临床预测GDM患者产后血糖转归提供参考。