课程文献中心 更多>>

关键词： Bacteriophage display technology   Bacteriophage vaccine   Bacteriophages   Gene electrotransfer   Immunotherapy   Interleukin   Malignant melanoma  

摘要： Our study introduces a novel bacteriophage-based vaccine strategy and evaluates its antitumor efficacy, both as a standalone therapy and in combination with gene electrotransfer (GET) of interleukin-12 (IL-12) plasmids. Using phage display technology, we produced engineered M13 bacteriophages expressing tumour peptides MAGE-A1, gp100, or MART-1/MELAN-A on the surface of the capsid. The therapeutic potential of bacteriophage vaccination alone or in combination with GET IL-12 was tested in vivo in a mouse malignant melanoma model. Response to treatment was further characterized by histological and immunohistochemical analyses of tumour tissue. No negative side effects were observed during treatment in mice. Engineered bacteriophage therapy significantly delayed tumour growth. GET IL-12 contributed to the therapeutic effect of engineered bacteriophages and increased tumour growth delay. Both therapies had a synergistic effect and led to complete responses in 30% of cases. Histological and immunohistochemical analyses have shown that both bacteriophage monotherapy and, especially in combination with GET IL-12, activate the immune system and increase the proportion of necrosis and the infiltration of macrophages, CD4 + and CD8 + T lymphocytes in tumours. For the first time, a cocktail of three engineered M13 bacteriophages displaying different melanoma-associated antigens with intratumoral IL-12 gene electrotransfer were applied, demonstrating a synergistic therapeutic effect in a highly aggressive melanoma model. Nanotechnological approaches, such as the use of genetically engineered bacteriophages, offer promising new avenues for the development of anti-tumour vaccines. © The Author(s) 2025.

关键词： CDC42   Cutaneous melanoma   IL-6   Tetrandrine  

摘要： Background: Cutaneous melanoma (CM) is a skin melanocytes-derived malignant tumor accounting for most of the death in skin cancers. The clinical drug for CM is limited or with poor efficacy. Tetrandrine is a natural alkaloid with diverse pharmacological effects including anti-cancer. This study investigated the anti-cancer potential and mechanisms of tetrandrine in CM, which might provide more therapeutic options for CM. Methods: The effects of tetrandrine on CM cell proliferation were evaluated via CCK8 and colony formation assay. The cell cycle analysis was conducted by flow cytometry. qRT-PCR and western blotting were performed to determine relevant RNA and protein levels. Co-Immunoprecipitation assay was used to detect the protein-protein interaction. Small interfering RNA transfection or lentiviral transduction were used to knockdown or overexpress target proteins, respectively. Results: Tetrandrine triggered a significant G0/G1 cell cycle arrest in A375 and SK-MEL-2 cells. Tetrandrine decreased the expression of the cell cycle activator cyclin D1 and increased cell cycle inhibitor p21. In-depth study revealed that the anti-CM activities of tetrandrine mainly dependent on Interleukin-6 (IL-6) and cell division cycle 42 (CDC42) regulation. A direct interaction between IL-6 and CDC42 was identified. Tetrandrine suppressed IL-6 expression and subsequently inhibited CDC42, which in turns lead to G0/G1 cell cycle arrest in CM cells. Conclusion: Tetrandrine suppressed CM cell growth by triggering G0/G1 cell cycle arrest via IL-6/CDC42 inhibition. Tetrandrine should be a promising compound for CM treatment. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2025.

关键词： 造血干细胞   造血干细胞移植   造血干细胞动员   细胞因子   血小板生成素   CXCR4拮抗剂   整合素拮抗剂   化疗   动员效能  

摘要： 背景:造血干细胞移植是一种广泛应用于血液系统恶性和非恶性疾病的重要治疗手段,动员和收集足够的造血干细胞是保证患者移植后快速、持续造血功能重建的前提,但最常用的粒细胞集落刺激因子联合或不联合化疗的经典方案仍有10%-40%的动员失败率。目的:综述近年来造血干细胞动员现状,分析不同方案的优缺点,展望未来动员新方案。方法:以“造血干细胞,造血干细胞移植,造血干细胞动员,细胞因子,血小板生成素,CXCR4拮抗剂,整合素拮抗剂,化疗,动员效能”为中文关键词,以“hematopoietic stem cell,hematopoietic stem cell transplantation,hematopoietic stem cell mobilization,cytokines,thrombopoietin,CXCR4 antagonists,integrin antagonist,chemotherapy,mobilization efficiency”为英文关键词,在CNKI、PubMed、万方数据库进行检索,文献语种限制为中文、英文,检索年限为1990-2024年,共检索到300多篇文献,最终纳入68篇文献进行分析。结果与结论:越来越多的研究发现粒细胞集落刺激因子联合普乐沙福、白细胞介素、血小板生成素及整合素拮抗剂等能够更加有效地动员造血干细胞,联合使用可以减少粒细胞集落刺激因子的使用剂量,减少相关不良反应。一些新药如可溶性重组flt3-配体(简称CDX-301)、双重α9β1/α4β1整合素抑制剂BOP等可与粒细胞集落刺激因子联合,促进造血干细胞动员。此外还发现一些潜在的动员靶点如前列腺素E2受体及1-磷酸鞘氨醇等,尚在研究阶段。除固有的患者特征、治疗特征外,开发纳入生物标志物的预测模型,有助于有效预测造血干细胞动员失败,提升干细胞动员技术。

关键词： Autoubiquitination   Dimerization   IBD   MARCH2   MARCH8  

摘要： Background: Regulation of the nuclear factor-kappa B (NF-kB) signaling pathway is a major host homeostatic mechanism for controlling hyper-inflammation or chronic inflammation. Despite extensive research, the regulatory factors of NF-kB signaling required to preserve homeostasis and control inflammatory disorders are not fully understood. Moreover, the role of MARCH2 in chronic inflammation models and the regulation of MARCH2 activation remain to be elucidated. Methods: We monitored disease severity and mortality in MARCH2^−/− or MARCH2^+/+ mice induced experimental colitis. Susceptibility to DSS-induced experimental colitis was determined by various methods, including Swiss roll assay and fluorescein isothiocyanate (FITC)-dextran treatment, respectively. RNA-sequencing was conducted to recognize the inflammatory response-related genes in the distal colon of colitis-induced mice. Enzyme-linked immunosorbent assay (ELISA) was used to measure the cytokines and chemokines with in vitro and in vivo samples. Affinity purification and LC-MS/MS analysis were used to identify the MARCH2 interacting proteins and posttranslational modifications. The underlying mechanism was elucidated using immunoblotting, co-immunoprecipitation, ubiquitination assay, and confocal microscopy. Result: Here, we report that MARCH2^−/− mice were more susceptible to experimental inflammatory bowel disease (IBD) due to the massive production of cytokines. Stimulation by inflammatory cytokines such as TNF induces dimerization of MARCH2 at a later stage and dimerized MARCH2 undergoes K63-linked autoubiquitination at lysine 127 and 238, which promotes NEMO recognition, ubiquitination and proteasomal degradation. We also show an interaction between MARCH2 and MARCH8 in resting cells that inhibits MARCH2 activation. Taken together, these findings provide new insights into the molecular mechanism of MARCH2 and suggest a crucial role of MARCH2 in the modulation of inflammatio

摘要： PTPδ, encoded by PTPRD, is implicated in various neurological, psychiatric, and neurodevelopmental disorders, but the underlying mechanisms remain unclear. PTPδ trans-synaptically interacts with multiple postsynaptic adhesion molecules, which involves its extracellular alternatively spliced mini-exons, meA and meB. While PTPδ-meA functions have been studied in vivo, PTPδ-meB has not been studied. Here, we report that, unlike homozygous PTPδ-meA-mutant mice, homozygous PTPδ-meB-mutant (Ptprd-meB^–/–) mice show markedly reduced early postnatal survival. Heterozygous Ptprd-meB^+/– male mice show behavioral abnormalities and decreased excitatory synaptic density and transmission in dentate gyrus granule cells (DG-GCs). Proteomic analyses identify decreased postsynaptic density levels of IL1RAP, a known trans-synaptic partner of meB-containing PTPδ. Accordingly, IL1RAP-mutant mice show decreased excitatory synaptic transmission in DG-GCs. Ptprd-meB^+/– DG interneurons with minimal IL1RAP expression show increased excitatory synaptic density and transmission. Therefore, PTPδ-meB is important for survival, synaptic, and behavioral phenotypes and regulates excitatory synapses in cell-type-specific and IL1RAP-dependent manners. © The Author(s) 2025.

关键词： Antibody-repertoires   B-cells   GWAS   HLA-II   MHC-II   PhIP-Seq  

摘要： Background: Human leukocyte antigen class II (HLA-II) genes are highly polymorphic affecting the specificity of human antibody responses, as presentation of processed antigen peptides by HLA-II on B cells is essential for T helper cell dependent affinity maturation and class switching. The combination of high-throughput immunoassays and genome-wide association studies has recently revealed strong associations between HLA-II variants and antibody responses against specific antigens. However, factors underlying these associations remain incompletely understood. Methods: Here, we have leveraged paired data sets of SNP arrays and functional antibody epitope repertoires against 344,000 peptide antigens in 1940 individuals to mine for key determinants linking genetics and antibody specificity. Results: We show that secreted proteins and antigens presented in small modules (i.e., viruses) are significantly more frequently associated with HLA-II alleles, than membrane bound or intracellular proteins. This data suggests a model in which antibody responses against separate antigen units composed of single or few proteins dominate HLA-II associations. In contrast, the presence of manifold intracellular or membrane proteins (peptides of which could be bound by different HLA-II alleles) on bacterial cells dilutes potential associations to antibody specificities. Conclusions: Hence, genetic associations to antibody specificities are shaped by antigen intrinsic properties. Given the prominent role of HLA-II alleles in infection, autoimmune diseases, allergies, and cancer, our work provides a theoretical framework to study antigen/HLA-II risk factors in these disease settings and will fuel the design of improved immunogenetics screens. © The Author(s) 2025.

摘要： Recent studies have uncovered evidences for pro-tumorigenic activities attributed to IL-11, prompting a renewed focus on therapeutic strategies targeting IL-11 signaling for anti-tumor treatment. Here, we introduce 9MW3811, a monoclonal antibody designed to neutralize IL-11 effectively. By disrupting the IL-11/IL-11Rα/gp130 complex, 9MW3811 inhibits JAK/STAT3 signaling, significantly reducing tumor growth in diverse mouse models. More importantly, 9MW3811 synergizes with anti-PD-1 therapy, even in PD-1 non-responsive models like CT26. Single-cell RNA-seq analysis reveals that 9MW3811 remodels the tumor microenvironment by enhancing CD8+ T cell infiltration and reversing T cell exhaustion via upregulated XCL1 and downregulated CCL7, boosting anti-tumor cytotoxicity. Furthermore, 9MW3811 counteracts PD-1-induced T cell exhaustion, with anti-PD-1 antibodies effectively mitigating PD-1 upregulation post-9MW3811 treatment. These compelling findings support ongoing clinical trials of 9MW3811, aiming to translate these preclinical insights into therapeutic benefits for cancer patients. © The Author(s) 2025.

关键词： Adhesion GPCR   Cytoskeletal remodelling   GPR56   IL-6   Melanoma   Signalling  

摘要： Background: GPR56/ADGRG1 is an adhesion G protein-coupled receptor involved in cell-matrix interactions and metastasis of human melanoma cells. Previously, we demonstrated that GPR56 activation in melanoma cells triggers Gα_12/13-RhoA signaling, leading to increased IL-6 production and enhanced cell migration. Yet little is known of the downstream signaling effectors and their specific roles in regulating melanoma cellular phenotypes. Results: In this study, we show that GPR56 activation induces Rho-ROCK-MLC and JAK-STAT3 signaling, which temporally and differentially drive amoeboid-like morphology and IL-6 upregulation. Interestingly, GPR56-induced JAK-STAT3 activation is partially regulated by Rho-ROCK-MLC signaling but not vice versa. Moreover, receptor auto-proteolysis modulates the magnitude of GPR56-mediated signaling, and its unique intracellular regions contribute to the selective regulation of unique signaling pathways and associated cellular phenotypes. Conclusion: Our findings reveal complex GPR56-mediated biased signaling through the Rho-ROCK-MLC and JAK-STAT3 pathways, highlighting these networks as potential therapeutic targets for modulating distinct tumorigenic phenotypes in human melanoma cells. © The Author(s) 2025.

关键词： Cardiac hypertrophy   IL-21   STAT3  

摘要： Increased cytokine secretion from immune cells is often associated with cardiac remodeling and heart failure due to pressure overload. Several reports suggest that the IL-21/IL-21 receptor (IL-21R) signaling pathway may play a critical role in heart failure progression, but the exact mechanism remains unclear. In this study, isoproterenol (ISO) was used to induce heart failure in mice and found that ISO injection caused significant upregulation of IL-21 and the IL-21R in the heart of mice. Subsequently, IL-21 receptor-deficient (IL-21R^−/−) mice were used to evaluate the cardioprotective effects of IL-21/IL-21R. Importantly, we found a significant reduction in myocardial hypertrophy, inflammation, and apoptosis in ISO-treated IL-21R^−/− mice compared to WT mice. Furthermore, the frequency of CD4⁺IFN-γ⁺ cells was significantly reduced in ISO-treated IL-21R^−/− mice. Co-culture studies showed that the adhesion rate of CD4⁺ T cells isolated from IL-21R^−/− to cardiac fibroblasts was significantly reduced compared to co-cultures isolated from WT mice. Accordingly, significant downregulation of α-SMA was detected in cardiac fibroblasts when cocultured with CD4⁺ T cells isolated from IL-21R^−/− mice. Furthermore, IL-21 could directly induce cardiomyocyte hypertrophy and apoptosis and exacerbate ISO-induced myocardial damage through activation of STAT3 signaling pathway. Our study demonstrates the mechanism of IL-21 and its receptor in the progression of myocardial hypertrophy and fibrosis and highlights that the absence of IL-21R may provide protection against myocardial damage, thus providing a new potential therapeutic target for the treatment of heart failure. © The Author(s) 2025.

关键词： Chiral metal-organic polyhedron   Gas chromatography   Stationary phase   Separation  

摘要： Chiral metal-organic polyhedra (CMOPs) have come to be recognized as ideal materials for chromatographic enantioseparation owing to their unique molecular recognition ability. Herein, the utilization of a novel chiral stationary phase (CSP) based on CMOP-IL ([Cu12(LIL)12(H2O)12], IL = L-isoleucine) for gas chromatographic separation was explored. A variety of mixtures (n-alkanes, n-alcohols and alkylbenzenes) and multiple isomers were effectively separated on the CMOP-IL capillary column. The separation performance of the CMOP-IL column for most mixtures and isomers is superior to that of the previously reported MOP-V ([Cu12(LV)12(H2O)12], V = L-valine) column. Notably, the CMOP-IL capillary column exhibited excellent enantioselectivity towards various racemates that include alcohols, ethers, aldehydes, epoxides, and amino acid derivatives. In comparison with the commercial beta-DEX 120 column, MOP-V column, and Co-L-GG column, the complementary chiral resolving capabilities of the MOP capillary column were demonstrated in separating racemates. Additionally, the relative standard deviation (RSD) values of retention time and peak area of allyl glycidyl ether and o,m,pnitrotoluene stayed within a range below 1 %, indicating good repeatability and stability of the MOP column in gas chromatographic separation. The study indicates that CMOP based on L-isoleucine, as a novel CSP, holds promising applications in gas chromatography.