课程文献中心 更多>>

关键词： 丹参多糖   Mn   PLGA   佐剂   细胞免疫   体液免疫  

摘要： 本研究利用PLGA包封了免疫刺激效果强和生物安全性良好的丹参多糖和Mn2+，评价了该体系作为灭活PCV2佐剂的免疫增强效果。首先我们利用复乳溶剂挥发法制备了共载丹参多糖和Mn2+的PLGA纳米佐剂递送系统（SM-PLGA），将SM-PLGA与PCV2抗原混合，对小鼠左右大腿皮下分别注射100 μL进行初免，同时设立空白对照组、PCV2组、Alhydrogel （Algel）-PCV2组、丹参多糖-PLGA组、SM组、丹参多糖组和PLGA组，免疫后的第14天对小鼠进行加强免疫。初免后的第5天通过流式细胞术评估腘淋巴结和腹股沟淋巴结中DCs的活化情况。在初免后的第21、28、35、42天收集小鼠血清，对PCV2特异性抗体IgG、IgG1、IgG2a进行动态监测，评价佐剂对PCV2特异性体液免疫反应的增强效果。在初免后的第21、28天采集小鼠脾脏淋巴细胞，分别对CD4+T细胞、CD8+T细胞、细胞毒性T细胞、记忆性T细胞和生发中心B细胞活化情况进行测定，并对第28天细胞上清中INF-β、INF-γ、IL-6进行测定。最后，在初免后的第35天采集小鼠淋巴结，测定生发中心B细胞的活化情况。通过上述不同时段的测定结果，评价SM-PLGA对机体免疫反应的增强效果。由结果可知SM-PLGA在初免后的第5天可以极显著促进淋巴结DCs的活化，在初免后第21～42天可以持续刺激PCV2特异性抗体IgG及其亚型的分泌。在初免后第21天SM-PLGA可显著促进脾脏CD4+T细胞、CD8+T细胞和CD8+T细胞CTL应答，并在初免后第28和35天仍对记忆性T细胞和生发中心B细胞有较强的刺激作用，同时极显著促进相关细胞因子IFN-β、IFN-γ、IL-6的分泌。结果表明SM-PLGA作为灭活PCV2的佐剂，可以诱导强效的Th1/Th2免疫应答，为PCV2的预防提供参考。

关键词： Disease Modification   Early Intervention   IL-17 Inhibitor   Ixekizumab   Psoriasis   Secukinumab  

摘要： BACKGROUND:Although IL-17 inhibitors like Secukinumab and Ixekizumab have shown significant efficacy in psoriasis, the impact of early intervention with biologics to modify the disease course and achieve long-term remission remains unclear. OBJECTIVES:To examine the potential of early intervention with IL-17 inhibitors for disease modification in psoriasis. METHODS:We conducted a multicenter retrospective cohort study on moderate-to-severe plaque psoriasis patients who received at least 4 weeks of treatment with Secukinumab or Ixekizumab between April 2019 and April 2023, taking the relapse rate one year after cessation of treatment as the primary endpoint. RESULTS:Among 400 patients who discontinued treatment after achieving PASI90, the median relapse time was 3.29 months(approximately 14 weeks). Of 141 patients who discontinued treatment after achieving PASI90 for over a year, 24 (88.89%) in the ultra-short disease duration(USDD, psoriasis duration ≤ 1 year) group and 33 (82.5%) in the short disease duration(SDD, psoriasis duration ≤ 2 year) group achieved one year of drug-free remission. LIMITATIONS:The potential impact of early intervention on comorbidity development was not addressed in this study. CONCLUSION:Early intervention with IL-17 inhibitors leads to faster responses and may promote disease modification in psoriasis.

关键词： Epitope prediction   Epitope presentation   Helper T cells   SARS-CoV-2   Spike protein  

摘要： Early in the COVID-19 pandemic, multiple studies used prediction methods to identify candidate peptides to be included in prospective vaccines. While subsequent studies identified epitopes from convalescent and vaccinated subjects, few studies have compared the predicted to identified epitopes. Here we used three methods to predict SARS-CoV-2 spike protein helper T cell epitopes and compared the results to experimentally determined peptide binding as well as published epitopes. The correspondence between the predicted and experimental binding results and published epitopes depended more on the HLA being investigated than the prediction method used. Lastly, these observations were used to predict peptides which bind to the most HLAs. These peptides were previously identified and predicted to maintain HLA binding in the current variants of interest. This study highlights which prediction methods and conditions lead to the most reliable prediction results which would be of great interest for improving the design of future vaccines.

关键词： Astragalus injection   Melanoma   Anti-PD-1   MHC-II   STAT1   CIITA  

摘要： Ethnopharmacological relevance: Astragalus injection, a solution derived from Astragalus mongholicus Bunge, has been used in cancer patients for its immune-boosting properties. The effects of Astragalus injection combined with immune checkpoint inhibitors (ICIs) in cancer remain unsuspected. Aim of the study: This study aims to investigate the efficacy of combining Astragalus injection with anti-PD-1 and to elucidate the potential mechanisms. Materials and methods: A melanoma-bearing mouse model was established to observe the effects of Astragalus injection combined with anti-PD-1 treatment. The immune cell infiltration in tumor tissues was evaluated by flow cytometry. Subsequently, network pharmacology and RNA sequencing were conducted to anticipate latent mechanisms of Astragalus in melanoma. Finally, these predictions were validated by flow cytometry, qPCR, Western blotting, and ELISA. Results: Astragalus injection significantly antagonized the efficacy of anti-PD-1 in melanoma, resulting in a notable reduction of immune cell infiltration. The network pharmacology and RNA sequencing analysis revealed critical signaling routes, encompassing T-cell receptor activation, immune antigen presentation, and the JAK/ STAT pathway. Subsequent data suggested that Astragalus injection could down-regulate the expressions of MHCII in dendritic cells and B16-OVA cells and restrict the activation of dendritic cells. Moreover, the expressions of CIITA and phosphorylated STAT1 were prominently inhibited by Astragalus injection, whereas the overexpression of STAT1 partially reversed the Astragalus injection-induced decrease of MHC-II. Conclusions: Astragalus antagonized the therapeutic effect of anti-PD-1 in melanoma. These effects were partially through inhibiting JAK/STAT signaling and down-regulating MHC-II expression.

关键词： RAB3IL1   SLC7A11   ferroptosis   male infertility   spermatogenesis microenvironment  

摘要： Ferroptosis, an iron-dependent form of regulated cell death characterized by phospholipid peroxidation, plays a pivotal role in various diseases. However, its involvement in male infertility, particularly in idiopathic non-obstructive azoospermia (iNOA), remains largely unexplored. iNOA accounts for 10-15% of male infertility cases, presenting a significant clinical challenge due to its unknown origins. This study investigated the potential link between ferroptosis and iNOA, revealing excessive activation of both ferroptosis and autophagy in the testes of iNOA patients, along with severe disruption of the blood-testis barrier (BTB). The BTB, formed by tight junctions between Sertoli cells, is essential for maintaining the spermatogenesis microenvironment. Using the ferroptosis inducer erastin, an antagonist of the cystine antiporter SLC7A11, we established a ferroptosis model in mouse Sertoli cells, demonstrating that ferroptosis activation led to cytoskeletal disarray and BTB disruption, accompanied by excessive autophagy activation. Notably, inhibition of autophagy using 3-methyladenine significantly rescued erastin-induced ferroptosis and restored BTB integrity, highlighting a crucial cross-talk between ferroptosis and autophagy in maintaining the spermatogenic microenvironment. Furthermore, through combined transcriptome analysis of iNOA testes and Sertoli cells, we identified RAB3IL1 as a novel regulator of ferroptosis. Mechanistically, Rab3il1 knockdown induced ferroptosis via translocation of SLC7A11, resulting in cytoskeletal defects and BTB damage. Our findings underscore the critical role of the ferroptosis-autophagy axis, regulated by RAB3IL1, in preserving the spermatogenic microenvironment, offering a potential therapeutic target for restoring spermatogenesis in iNOA patients.

关键词： DILI   DRESS   Lamotrigine   Phenytoin   Trimethoprim-Sulfamethoxazole  

摘要： INTRODUCTION:Drug reaction with eosinophilia and systemic symptoms (DRESS) can sometimes occur in patients with drug-induced liver injury (DILI). However, detailed studies of DRESS in patients with DILI from the US are lacking. We investigated the characteristics and HLA risks for DILI who also developed DRESS. METHODS:Patients with definite, highly likely, or probable DILI enrolled into US DILI Network studies between September 2004 and August 2023 were included. DRESS was defined based on modified RegiSCAR criteria. HLA alleles were compared between DILI-DRESS cases and two control groups (DILI with non-DRESS rash [n=244] and DILI without rash [n=1637). RESULTS:Of 2,121 participants with DILI during the study period, 128 participants had DRESS (6%). The most frequently implicated drugs causing DRESS were trimethoprim/sulfamethoxazole, lamotrigine, phenytoin, allopurinol, and vancomycin. Compared to 1993 DILI patients without DRESS, patients with DILI + DRESS were younger (mean age 42.3 yrs vs 50.6 years), more likely to be Black (26% vs 12%), had shorter latency (median 31 days vs 47 days), higher frequency of rash (100% vs 13%), eosinophilia (55% vs 13%), and fever (76% vs 16%) (P<0.001 for all). Compared to DILI without DRESS, DILI + DRESS had more severe liver injury (severe/fatal: 45% vs 21.5%, p<0.001) and higher overall (15.6% vs 6.3%, P<0.001) and liver-related (9% vs 2.3%, p < 0.001) mortality. HLA A*32:01, HLA B*53:01 and HLA B*58:01 were significantly enriched in DILI-DRESS cases, compared to control groups. CONCLUSIONS:Patients with DILI and DRESS are younger, more likely to be Black, had shorter time to DILI onset with more severe liver injury and higher overall and liver-related mortality. HLA A*32:01, HLA B*53:01 and HLA B*58:01 are risk factors for DILI-DRESS.

关键词： 补阳还五汤   坏死性凋亡   心肌梗死   心室重构  

摘要： 目的：探索补阳还五汤对TNF/RIPK1通路的影响，阐明补阳还五汤抑制心肌梗死后心室病理性重构的作用机制。方法：将70只Wistar大鼠随机分为对照组，模型组，补阳还五汤低、中、高剂量组，西药组以及TNF-α 抑制剂组，每组10只。补阳还五汤低、中、高剂量组分别给予补阳还五汤3.22 g·kg-1·d-1、 6.44 g·kg-1·d-1、12.87 g·kg-1·d-1，西药组给予培哚普利叔丁胺片0.36 mg·kg-1·d-1，TNF-α 抑制剂组给予TNF-α 抑制剂依那西普5 mg·kg-1·w-1皮下注射，对照组与模型组均给予生理盐水灌胃，连续给药4周。采用多普勒超声检测各组大鼠心脏的左室射血分数（ejection fraction of left ventricular， LVEF）、左室短轴缩短率（left ventricular fractional shortening， FS）、左室舒张末期内径（left ventricular end diastolic diameter， LVEDD）和左室收缩末期内径（left ventricular end systolic diameter， LVESD）。病理切片进行HE染色和Masson染色观察心肌组织的病理形态及纤维化程度；Tunel染色观察心肌细胞凋亡情况。RT-qPCR检测心肌组织中TNF-α、RIPK1、RIPK3、MLKL的mRNA表达水平。Western blot检测心肌组织中TNF-α、RIPK1、P-RIPK1、RIPK3、MLKL的蛋白表达水平。结果：与对照组相比，模型组大鼠的正常心脏结构被破坏、室壁变薄、心肌细胞排列紊乱、局部出现纤维化重构，LVEF、FS明显降低，LVEDD、LVESD明显升高，TNF-α、RIPK1、RIPK3、MLKL的mRNA表达和TNF-α、P-RIPK1、RIPK3、MLKL的蛋白表达明显升高（P<0.05）；与模型组比较，补阳还五汤低、中、高剂量组、西药组以及TNF-α 抑制剂组大鼠的心脏结构破坏程度和心肌纤维化程度均有所改善，LVEF、FS明显增高，LVEDD、LVESD明显降低，TNF-α、RIPK1、RIPK3、MLKL的mRNA表达水平和TNF-α、P-RIPK1、RIPK3、MLKL的蛋白表达水平降低（P<0.05），且补阳还五汤高剂量组疗效最好。结论：补阳还五汤可能通过抑制TNF/RIPK1通路减少心肌细胞坏死性凋亡从而改善心肌梗死后心室病理性重构。

关键词： SARS-CoV-2   AMP-activated protein kinase   autophagy   lipid metabolism   antiviral agents  

摘要： AMP-activated protein kinase (AMPK) plays a central role in regulating cell energy balance. When activated, AMPK suppresses energy-consuming pathways, such as lipid and protein synthesis, while increasing nutrient availability through the activation of autophagy. These pathways downstream of AMPK activation contribute to SARS-CoV-2 infection, which hijacks autophagy and accumulates lipid droplets in viral factories to support viral replication. Here, we assessed the antiviral activity of the direct pan-AMPK allosteric activator MK-8722 in vitro. MK-8722 efficiently inhibited infection of Alpha and Omicron SARS-CoV-2 variants in Vero76 and human bronchial epithelial Calu-3 cells at micromolar concentration. This inhibition relied on restoring the autophagic flux, which redirected newly synthesized viral proteins for degradation, and reduced lipid metabolism, which affected viral factories. Furthermore, MK-8722 treatment increased the type I interferon (IFN-I) response. Post-infection treatment with MK-8722 was enough to inhibit efficient viral replication and restore the IFN-I response. Finally, MK-8722 treatment did not alter the SARS-CoV-2-specific CD8+ T cell response mounted upon Spike vaccination. Overall, by activating AMPK, MK-8722 acts as an effective antiviral against SARS-CoV-2 infection, even when applied post-exposure, paving the way for preclinical tests aimed at inhibiting viral replication and improving patients' *** disease 2019, caused by SARS-CoV-2 infection, has led to severe acute respiratory syndrome with very high mortality. Despite available vaccines and public health measures, new SARS-CoV-2 variants emerge with increased transmissibility requiring the development of novel therapeutic strategies. Recently, the AMP-activated protein kinase (AMPK), a cellular energy sensor, has emerged as a potential broad-spectrum antiviral target, as AMPK can modulate the intracellular environment in turn impeding viral replication.

关键词： antisense oligonucleotide   cell transplant   inflammation   SC islets   TNF-α  

摘要： One of the many challenges for islet transplantation as a treatment for type 1 diabetes is inflammation that contributes to islet de-differentiation and death. Innate immune cells such as monocytes and macrophages secrete tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), inducible nitric oxide synthase (iNOS), and IL-6, which directly contribute to islet dysfunction. Attenuation of the early inflammatory response post-transplantation may protect cell survival and subsequent function. Herein, we investigate the development of anti-TNF-α antisense-oligonucleotide-conjugated polylactide-co-glycolide nanoparticles (PLG-aTNF-α NPs) as an anti-inflammatory therapy after stem-cell-derived islet transplantation. PLG-aTNF-α NPs are shelf stable and successfully reduce TNF-α secretion and expression in inflammatory macrophages. Synergy between the aTNF-α antisense oligonucleotide and the polylactide-co-glycolide NPs results in further knockdown of IL-1β, IL-6, iNOS, and IL-12 in vitro indicating PLG-aTNF-α NPs may protect against the inflammatory cascade in vivo. In a diabetic mouse model, stem-cell-derived islets transplanted to the peritoneal fat were protected after treatment with PLG-aTNF-α NPs compared with PLG NPs alone. Tnfα and Il1β expression was reduced in mice treated with PLG-aTNF-α NPs, indicating inflammation was reduced after transplant. PLG-aTNF-α NPs reduce TNF-α and protect islets, supporting their potential use as a therapeutic in islet transplantation. © 2025 The Author(s)