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关键词： Docetaxel Prodrug   IL-12 mRNA   Lipid Nanoparticles   Lung-Targeted  

摘要： Despite the remarkable success of mRNA vaccines, extrahepatic tissue-specific delivery of therapeutic mRNAs remains challenging. Here, we report a lung-tropic lipid nanoparticles (LNPs) platform that is rationally engineered for simultaneously co-delivering interleukin-12 (IL-12) mRNA and docetaxel prodrug to address the lung metastatic issue. By optimizing a panel of synthetic cationic lipids, we identified N112 as the optimal cationic lipid, with N112-DOTAP LNP formulation demonstrating moderately enhanced transfection efficiency in lung tissue compared to the benchmark MC3-DOTAP LNP. Moreover, N112-DOTAP LNP has a uniform particle size and high encapsulation efficiency for both therapeutic payloads. In a B16F10 lung metastasis model, the combination therapy demonstrated superior antitumor efficacy, reducing tumor nodules compared to the saline treatment, while maintaining the safety profile with no significant body weight loss or organ toxicity. This study provides a robust therapeutic strategy for mRNA-based combination cancer therapy.

摘要： Immune aplastic anemia (iAA) frequently results in transfusion dependence on platelets and packed red blood cells, increasing the risk for complications. The most common immune-mediated cause for platelet-transfusion refractoriness is alloimmunization with HLA antibody (Ab) to nonself class I antigens. The clinical impact of the HLA alloimmunization has not been well studied in patients with iAA. We investigated the clinical relevance of HLA alloimmunization in our large cohort of patients with iAA from 5 prospective trials and correlated with disease outcomes. Of 444 patients with severe AA treated with immunosuppressive therapy (IST), 99 (22%) had HLA alloimmunization. The presence of HLA Ab was associated with shorter overall survival, reduced responses to IST and higher risk of clonal evolution. Our data suggest that HLA alloimmunization is a marker of disease outcome. Furthermore, using single-cell RNA sequencing, we show enhanced activation of both complement-mediated pathways and the adaptive immune system in alloimmunized patients, indicating an interconnection between immune compartments.

关键词： PM2.5   aryl hydrocarbon receptor   Interleukin 4 Induced 1   nasal mucosal barrier   epithelial–mesenchymal transition   chronic rhinosinusitis  

摘要： Environmental pollutants like PM2.5 contribute to chronic rhinosinusitis (CRS). The aryl hydrocarbon receptor (AhR), a contaminant sensor linked to tryptophan metabolites, is regulated by IL4I. However, how PM2.5 stimulation via IL4I1 influences AhR activation and CRS pathogenesis remains unclear. This study explored the IL4I1-AhR pathway in CRS using patient tissues, HNEpCs, and murine models. Methods included IHC, qRT-PCR, and WB under PM2.5 exposure, with further investigation into downstream effects on CYP1B1 and epithelial–mesenchymal transition (EMT). Significant upregulation of IL4I1, AhR, and CYP1B1 was observed in CRS tissues, with higher expression levels in CRS patients. Exposure to PM2.5 activated the IL4I1-AhR pathway, leading to decreased E-cadherin, increased N-cadherin and vimentin, and impaired nasal mucosal barrier function. In vitro experiments demonstrated that PM2.5-induced EMT in HNEpCs was mediated by IL4I1-dependent AhR activation. CH223191 reduced cell migration and EMT, while IL4I1 knockdown attenuated AhR activation and EMT marker expression. Murine models further confirmed that PM2.5 exacerbated nasal polyp formation and tissue remodeling via the IL4I1-AhR pathway. This study underscores the critical role of the IL4I1-AhR signaling pathway in PM2.5-induced nasal mucosal barrier dysfunction and EMT in CRS. IL4I1, as an upstream regulator of AhR, promotes EMT and nasal mucosal barrier disruption.

关键词： 复发性流产   25羟维生素D   免疫细胞亚群   妊娠结局   辅助性T细胞   白细胞介素   肿瘤坏死因子-α   调控机制  

摘要： 目的 探讨原因不明复发性流产（URSA）患者25羟维生素D[25（OH）D]、免疫细胞亚群以及辅助性T细胞（Th）1、Th2的表达及意义。方法 选取307例URSA患者作为URSA组,按照是否维持妊娠分为非维持妊娠组127例和维持妊娠组180例;另选取同期正常妊娠女性307例作为对照组。比较各组25（OH）D、免疫细胞亚群及Th1、Th2表达,并采用Pearson相关性分析探讨URSA患者25（OH）D、免疫细胞亚群与Th1、Th2表达的相关性。结果 与对照组相比,URSA组25（OH）D、IL-10水平更低,CD3+、CD3+CD4+、CD3+CD8+、CD4+/CD8+、CD16+CD56+、CD19+、IL-2、TNF-α水平更高,差异均有统计学意义（P<0.001）。与维持妊娠组相比,非维持妊娠组25（OH）D、IL-10水平更低,CD3+、CD3+CD4+、CD3+CD8+、CD4+/CD8+、CD16+CD56+、CD19+、IL-2、TNF-α水平更高,差异均有统计学意义（P<0.001）。Pearson分析显示,URSA患者25（OH）D与IL-2、TNF-α呈显著负相关（P<0.05）,与IL-10呈显著正相关（P<0.05）;URSA患者CD3+、CD3+CD4+、CD3+CD8+、CD4+/CD8+、CD16+CD56+、CD19+与IL-2、TNF-α呈显著正相关（P<0.05）,与IL-10呈显著负相关（P<0.05）。结论 URSA患者25（OH）D、免疫细胞亚群以及Th1、Th2细胞因子表达存在异常,且不同妊娠结局的URSA患者25（OH）D、免疫细胞亚群以及Th1、Th2细胞因子表达也存在差异,其机制可能与调节Th1/Th2细胞因子平衡的表达有关。

关键词： IL-17   Regnase-1   colorectal cancer  

摘要： Regnase-1 is a ribonuclease that regulates inflammation in immune cells by degrading cytokine mRNA. was identified as one of the frequently mutated genes in the inflamed colorectal epithelium of patients with ulcerative colitis; however, its significance in intestinal epithelial cells during the tumorigenic process remains unknown. Therefore, we developed an mouse model lacking in intestinal epithelia. deletion significantly enhanced colon tumor growth accompanied by elevated levels of extracellular signal-regulated kinase (ERK) phosphorylation in tumor tissues. Transcriptome analysis of the tumor tissues revealed that , a mediator of the interleukin (IL)-17 signaling pathway, was the primary degradative target of Regnase-1 in enterocytes and that deficiency enhanced IL-17 signaling. The treatment with antibiotics or IL-17-neutralizing antibody canceled the proliferative effect of colon tumors due to deletion, suggesting the protective role of Regnase-1 against colon tumor growth was dependent on IL-17 signaling triggered by gut microbes. Analysis of the knockout mouse model demonstrated that the tumor-suppressive effect of depended on expression. Remarkably, oral treatment of dimethyl fumarate, a potential inhibitor of Regnase-1 protein inactivation, suppressed tumor growth, downregulated , and suppressed ERK activation. Furthermore, TCGA data analysis revealed that low expression in colorectal cancer tissue was related to poor prognosis. Therefore, represses colon tumor growth by regulating IL-17 signaling via mRNA degradation. could be a potential therapeutic target in colon tumors.

关键词： B cells   IL16   plasma cells  

摘要： The regulation of terminal differentiation of B cells into plasma cells is influenced by transcription factors, epigenetics, and cytokines. Both human and murine B cells possess the capacity to produce interleukin 16 (IL16), a pleiotropic cytokine that serves as a chemoattractant. Despite its production, the precise role of IL16 in B cells has remained elusive. In this study, we showed that IL16 overexpression promoted primary B cell differentiation into B220CD138 plasma cells. This effect was independent of the secreted form of IL16. The overexpression of IL16 resulted in an increase in the expression of plasma transcription factors Blimp-1, IRF4, and Xbp-1, as well as the expression of immunoglobulin genes. Consistently, upon the inoculation of mice with influenza A virus, the absence of IL16 led to a decrease in the number of plasma cells and the production of virus-specific antibodies. Our data demonstrate that IL16 contributes to the terminal differentiation of B cells to plasma cells.

关键词： 金天格含药血清   类风湿关节炎   成纤维样滑膜细胞   迁移和侵袭   PI3K/Akt通路  

摘要： 探讨金天格含药血清对人类风湿关节炎成纤维样滑膜细胞（FLS）的作用及机制。制备SD大鼠空白血清，及金天格低、中、高剂量含药血清（JTG-CS）。超高效液相色谱-质谱联用技术检测血清内氨基酸成分和含量；肿瘤坏死因子α（TNF-α）刺激原代FLS细胞建立FLS炎症模型，CCK-8检测FLS细胞增殖，伤口愈合和Transwell试验分析FLS细胞的迁移和侵袭，Western blot分析相关蛋白的表达。JTG-CS能显著抑制FLS细胞的增殖和迁移，抑制FLS细胞的伤口愈合和侵袭能力，抑制黏附相关蛋白细胞间黏附分子-1（ICAM-1）、血管细胞黏附分子-1（VCAM-1）、基质金属蛋白酶（MMP）-2和MMP3的表达，降低炎性细胞因子TNF-α、白细胞介素（IL）-6和IL-1β的水平，抑制PI3K/Akt通路、NF-κB通路和JAK2/STAT3通路的激活。PI3K激动剂可逆转JTG-CS对FLS细胞炎性细胞因子和细胞侵袭的抑制作用。与空白大鼠血清相比，JTG-CS中46种氨基酸含量上升，20种氨基酸含量下降。JTG-CS通过抑制PI3K/Akt通路的激活，抑制TNF-α刺激的FLS细胞增殖、迁移、侵袭和炎症反应。

关键词： Clinical efficacy   Cold-dampness arthralgia type knee osteoarthritis   Fire-needle warming method   IL-1 beta   MMP-3  

摘要： ObjectiveThis study aims to explore the clinical efficacy of fire-needle warming therapy in managing knee osteoarthritis attributed to cold-dampness patterns. Specifically, it evaluates the therapy's influence on interleukin-1 beta (IL-1 beta) serum concentrations and matrix metalloproteinase-3 (MMP-3). MethodsA retrospective analysis was conducted on 80 patients treated for knee osteoarthritis from September 2023 to February 2024. Patients were divided into two groups: 40 received electroacupuncture, and 40 received fire acupuncture combined with warming techniques. The primary outcome measures included treatment efficacy, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, compare the changes in IL-1 beta and MMP-3 levels in serum and synovial fluid between two groups, and compare the total knee joint X-ray scores between the two groups: pain levels and knee joint function. Adverse reactions were also recorded. ResultsThe fire acupuncture group had a significantly higher treatment efficacy rate (92.5%) compared to the electroacupuncture group (75%, P < 0.05). Both groups showed significant reductions in WOMAC scores post-treatment, with a greater reduction in the fire acupuncture group (P < 0.05). Serum levels of IL-1 beta and MMP-3 decreased significantly in both groups, with a more pronounced decrease in the fire acupuncture group (P < 0.05). After 4 weeks of intervention and 8 weeks of follow-up, the levels of IL-1 beta and MMP-3 in the synovial fluid of the fire needle group and the electroacupuncture group were significantly reduced (P < 0.05), and the fire needle group was significantly lower than the electroacupuncture group (P < 0.05). Pain and knee function scores improved significantly in both groups, with the fire acupuncture group showing greater improvements (P < 0.05). After 4 weeks of intervention and 8 weeks of follow-up, the total joint X-ray scores of the fire needle group and the electroacupuncture group were significa

摘要： Long-acting controlled drug release formulations are highly desired for potentiating efficacy and reducing administration frequency. Here we present a kinetically controllable long-term interleukin-2 (IL-2) release platform by the fusion and boundary elimination of calcium carbonate and calcium phosphate amorphous phases. Unlike mixtures, a group of hybrid biominerals with the chemical formula Ca(CO3)(x)(PO4)(2(1-x)/3) (CaCPs, 0 < x < 1) was fabricated under high pressure (2 GPa), and the CaCPs showed crystallization-driven release behaviors to optimize the in vivo fate of IL-2. Ca(CO3)(1/2)(PO4)(1/3) dynamically remodeled immunosuppressive tumor microenvironments, preferentially activated cytotoxic and memory T cells by improving IL-2 redistribution and achieved weeks-long IL-2 retention in tumors with high tolerance and biosafety. In a melanoma model in female mice, Ca(CO3)(1/2)(PO4)(1/3) revealed superior antitumor effects to inhibit local tumor recurrence, hinder the growth of distant untreated tumors and maintain long-term T cell responses against the rechallenged metastatic tumors.

关键词： C5aR2   CAPS   complement   complosome   Crohn's disease   cryopyrin-associated periodic fever syndrome   IL-1β   prostacyclin   prostaglandin   rheumatoid arthritis   Th1 cell responses  

摘要： T helper 1 (Th1) cell initiation pathways are well characterized;however, those regulating their contraction are less understood. Here, we define a CD4⁺ T cell-autonomous pathway in which complement C5 orchestrated a shift from prostaglandin E2 (PGE2) dominance to enhanced prostacyclin (PGI2) production via activation of C5a receptor 2 (C5aR2). This pivot in lipid mediators induced autocrine signaling through the PGI2 receptor and expression of the interleukin-1 (IL-1) decoy IL-1 receptor type 2 (IL-1R2), which sequestered Th1 cell-driving intrinsic IL-1β, facilitating Th1 cell contraction. Disruption of this C5aR2-PGI2-R axis was a hallmark of pathologically persistent Th1 cell activity in inflammatory conditions, including cryopyrin-associated periodic syndromes (CAPS), Crohn's disease, and rheumatoid arthritis. Rebalancing this axis through selective PGE2 synthase inhibition rectified the hyperactive Th1 cell phenotype in vitro in T cells from individuals with CAPS. Therefore, complement is a key controller of prostanoid metabolism, and the latter is an intrinsic—and potentially druggable—checkpoint for the cessation of Th1 cell effector responses. © 2025