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关键词： Immune response   Cell biology  

摘要： Inflammatory cues affect hematopoietic stem cell (HSC) homeostasis and drive proliferation and myeloid skewing of HSCs. The HSC niche in the bone marrow (BM) is populated by a variety of stromal and immune cells that sense and respond to cellular stress. We investigated how BM-resident type 2 innate lymphoid cells (ILC2s) regulate HSC homeostasis and differentiation in steady state, during aging, and after genotoxic stress. We documented that PDGFR-alpha+sca-1+ mesenchymal stromal cells in the BM produced interleukin (IL)-33 with elevated levels after irradiation and during aging. IL-33/ST2 signaling in BM-resident ILC2s activated MAPK/NF-kappa B/JAK-STAT signaling and induced cytokine secretion. IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF), secreted by ILC2s, promoted HSCs to proliferate and differentiate into the myeloid lineage. Taken together, we identified that IL-33 produced by MSCs induced ILC2s to secrete myeloid differentiation factors leading to myeloid-skewed HSCs with reduced self-renewal during aging.

关键词： Immunology   Cell biology   Stem cell research  

摘要： Strong T cell receptor (TCR) and interleukin (IL)-27 signaling influence type 1 regulatory (Tr1) T cell development, but whether other signals determine their differentiation is unclear. Utilizing Tg4 TCR transgenic mice, we established a model for rapid Tr1 cell induction. A single high dose of [4Y]-MBP peptide drove the differentiation of Il10+ T cells with Tr1 cell mRNA and protein signatures. Kinetic transcriptional and phenotypic analyses revealed that the Tr1 cell module was transient and preceded by Ifng transcription in other CD4+ T cells. Changes in Tr1 cell frequency correlated with altered macrophage activation, while neutralization of interferon (IFN)y reduced Tr1 cell frequency and the TCR signal strength markers Nur77, inducible T cell costimulator (ICOS), and OX40. Antibody depletion experiments inferred that the relevant source of IFNy was not natural killer (NK) cell derived. Additionally, blocking IL-27 in combination with IFNy neutralization additively reduced Tr1 cell frequency in vivo. These findings reveal that IFNy has a non-redundant role in augmenting Tr1 cell differentiation in vivo.

关键词： Multiple sclerosis   IL2RA   rs2104286   Meta-analysis   Iranian population  

摘要： The interleukin-2 receptor alpha chain (IL2RA) gene has been implicated in multiple sclerosis (MS) susceptibility, particularly through the rs2104286 and rs12722489 SNPs. However, previous studies have yielded inconsistent results across different populations, likely due to small sample sizes and ethnic variations. This study aimed to investigate the association of IL2RA SNPs with MS risk in eastern Iranian population and through a comprehensive meta-analysis. Our case-control study included 400 Iranian individuals from North Khorasan and Sistan & Baluchistan provinces, comprising 200 MS patients across all subtypes and genders and 200 controls. The meta-analysis incorporated pooled odds ratios (ORs) with 95 % confidence intervals (CIs) to assess the strength of these associations. Our case-control findings demonstrated a significant association between rs2104286 and MS risk, which was further supported by the meta-analysis in Iranian populations. Specifically, the association was observed at both the genotype (P = 0.001) and allelic (P = 0.003) levels in North Khorasan and at the genotype level in Sistan & Baluchistan (P = 0.001). A global meta-analysis of rs2104286, encompassing 24,931 MS patients and 36,036 controls, revealed a significant association between the A allele and all genotype models with increased MS risk (P < 0.05). Similarly, a meta-analysis of rs12722489, including 19,797 MS patients and 32,085 controls, identified the CC + CT genotype as a risk factor for MS (P = 0.04). In conclusion, our findings suggest that the rs2104286 A allele and rs12722489 CC + CT genotype are associated with an increased risk of MS in both Caucasian and Asian populations, including Iranians.

关键词： 口腔鳞状细胞癌   肝细胞生长因子   间充质上皮转化因子   作用机制   磷脂酰肌醇3-激酶   蛋白激酶B   表皮生长因子   靶向治疗   单克隆抗体   酪氨酸激酶抑制剂  

摘要： 口腔鳞状细胞癌（oral squamous cell carcinoma，OSCC）是严重威胁人类健康的恶性疾病，其典型的生物学特征包括局部侵袭性强、淋巴结转移率高以及治疗后易复发等特点。来源于间充质的肝细胞生长因子（hepatocyte growth factor，HGF）、间充质上皮转化因子（cellular-mesenchymal to epithelial transition factor，c-Met）及HGF/c-Met信号通路参与调控OSCC的发生发展。一方面，HGF和c-Met蛋白在OSCC中过表达，且多项研究提示与肿瘤恶性特征和不良预后显著相关；HGF/c-Met信号通路的异常激活（由HGF依赖性自/旁分泌或MET基因突变、扩增、融合及蛋白过表达等非依赖性机制驱动）可通过激活下游信号通路，协同促进肿瘤细胞侵袭转移和血管生成；另一方面，HGF/c-Met还可通过促进乳酸分泌增加、诱导程序性细胞死亡配体（programmed death ligand 1，PD-L1）表达上调、激活和扩增髓源性抑制细胞以及促进调节性T细胞（regulatory T cells，Tregs）细胞增殖的方式介导免疫逃逸；此外，HGF/c-Met信号通路与磷脂酰肌醇3-激酶（phosphatidylinositide 3-kinases，PI3K）/蛋白激酶B（protein kinases B，AKT）、表皮生长因子（epidermal growth factor receptor，EGFR）、两面神激酶（Janus kinase，JAK）/转录激活蛋白（signal transducer and activator of transcription，STAT3）等关键通路和非编码RNA形成的串扰也可促进肿瘤进展。针对这一通路，目前已开发出三类靶向药物：HGF单抗、c-Met单抗和酪氨酸激酶抑制剂，其中部分药物已进入临床试验阶段。然而，治疗过程中出现的耐药现象，特别是EGFR等替代信号通路的双向代偿性激活，成为临床面临的重大挑战。本文通过深入分析HGF/c-Met通路在OSCC中的作用机制及其与其他通路的交互关系，梳理现有治疗药物的研究现状，旨在为开发更有效的联合治疗策略、实现个体化精准治疗提供重要理论基础，最终改善患者的临床预后和生活质量。

关键词： breast cancer brain metastasis   M2 microglia   IL6 and CCL2 cytokines   IL6-STAT3 signaling pathway   beta-elemene  

摘要： Introduction Brain metastasis (BM) is the most common and serious complication of breast cancer (BC). There is significant interest in investigating the crosstalk between BC cells and immune cells. beta-elemene is the main pharmacodynamic component of Curcumae Rhizoma, a traditional Chinese medicine that is commonly used for the clinical treatment and prevention of various tumors. However, the specific underlying mechanism of beta-elemene in BC-BM is still *** An intracardiac (ICT) injection model was used to establish specific BC-BM cells, then an intracarotid (ICD) injection model was used to verify the inhibitory effect of beta-elemene in BC-BM. Tumor-cell-conditioned media, a primary microglia co-culture model, and an in vitro recruitment experiment were used to explore crosstalk between BC cells and immune cells. TMT-based quantitative proteomic, ELISA, IF, and other molecular biotechnologies were used to investigate the *** The BC-BM cells established in our study not only increased BM rates but also exhibit mesenchymal phenotype and activated the JAK-STAT signaling pathway. Microglia, particularly M2 microglia, were enriched in BM lesions and secreted high levels of both IL6 and CCL2. Hypersecretory IL6 reversed the MET process of BC cells by regulating the JAK2/STAT3 signaling pathway to promote colonization in the brain. Increased levels of CCL2 significantly recruited monocytic myeloid-derived suppressor cells (M-MDSCs) to induce an immunosuppressive brain microenvironment. beta-elemene could significantly inhibit BC-BM in mice by regulating the IL6/STAT3 signaling pathway and suppressing the M-MDSC *** Our work first demonstrated that beta-elemene regulated the IL6/STAT3 axis and M-MDSC recruitment to reconstruct immunosuppressive brain microenvironment to suppress BC-BM.

关键词： gastric cancer   machine learning   IL1RAP   tumor microenvironment   M2-type macrophages  

摘要： Background Investigating the pivotal role of IL1RAP in the tumor microenvironment of gastric *** Download and collate transcriptomic and single-cell data from gastric cancer patients. Three machine learning algorithms identified distinct sets of prognostic genes in gastric cancer patients. The CIBERSORT and ssGSEA algorithms elucidated immune infiltration patterns, while TIDE and TCGA predicted immune-related outcomes. Furthermore, single-cell sequencing data confirmed the interaction of IL1RAP within the tumor microenvironment. Finally, differential expression levels of IL1RAP protein and mRNA were *** After machine learning screening and independent dataset validation, high IL1RAP expression was identified as a poor prognostic factor for gastric cancer patients. Immune infiltration analysis indicated that the low IL1RAP expression group was associated with higher infiltration of CD8+ T cells and M1-type macrophages, whereas the high IL1RAP expression group exhibited increased presence of M2-type macrophages. Immunotherapy prediction models suggested a more favorable response to PD-1 treatment in the low IL1RAP expression group. Prognostic models incorporating IL1RAP demonstrated superior predictive performance. Single-cell data analysis revealed that IL1RAP plays a critical role in regulating intercellular communication within the tumor microenvironment. Our findings were further validated by confirming elevated IL1RAP expression levels in gastric cancer *** IL1RAP plays a critical role in the tumor microenvironment of gastric cancer and serves as a robust predictor of immunotherapy efficacy in gastric cancer.

关键词： Alcoholic liver disease   Flos puerariae   Exosomes-like nanoparticles   Pharmacodynamics   Mechanism  

摘要： Background: Alcoholic liver disease (ALD) represents the most severe and irreversible form of liver damage caused by alcohol consumption and has become a major global health issue, leading to high morbidity and mortality associated with liver disease. Flos Puerariae (FP), a traditional Chinese medicine has demonstrated therapeutic efficacy for treating ALD in various studies. Results: In this research, exosome-like nanovesicles derived from FP (FP-ELNs) were isolated and purified using differential centrifugation and ultracentrifugation techniques. The particle size of FP-ELNs was measured at 83.2 +/- 15.8 nm, with a concentration of 2.08 x 1011 particles/mL. A total of 112 lipids, 13 proteins, and 64 miRNAs were identified in FP-ELNs. These nanovesicles exhibited remarkable stability, enduring multiple enzymatic digestions, extreme pH conditions, and simulated gastrointestinal fluids. Bio-distribution analysis revealed that FP-ELNs primarily accumulated in the intestines, liver, kidneys, lungs, thymus, and spleen of mice following oral administration. In vitro, FP-ELNs reduced the level of ALT, AST, TC, and TG;decreased the production of TNF-alpha, IL-1 beta, IL-6, MDA, and ROS;enhanced the activities of SOD and GSH-Px;and downregulated CYP2E1 protein expression. These findings were also corroborated by in vivo experiments in mice. Notably, oral administration of FP-ELNs in ALD mice significantly reduced serum concentrations and hepatic expression of IL-11, an upstream pro-inflammatory cytokine with critical negative effects on ALD, age-associated disease, and lifespan. Conclusions: In conclusion, this study provides compelling evidence that FP-ELNs can mitigate alcohol-induced oxidative stress and inflammation by downregulating the IL-11-related signaling pathways in a PI3K/AKT/

关键词： cannabidiol   phenotype reversion   protein regulation   proteomics   mass spectrometry   protein networks   cancer treatment  

摘要： Cannabidiol (CBD) has shown promise in treating cancers with an inflammatory microenvironment. Although it has been demonstrated that IL-1 beta induces epithelial-mesenchymal transition (EMT) of MCF-7 cells and CBD reverts this process, in restoring the epithelial non-invasive phenotype, there is limited understanding of how this cannabinoid regulates these processes. In this work, MCF-7 cells were induced to adopt an aggressive phenotype (6D cells), which was reversed by CBD. Then, protein expression was analyzed by mass spectrometry to compare 6D vs. MCF-7 cells and 6D+CBD vs. 6D cells proteomes. Novel proteins associated with EMT and CBD signaling were identified. Twenty-four of them were oppositely regulated by IL-1 beta and CBD, suggesting new points of crosstalk between the IL-1 beta and CBD signaling pathways. From the data, two protein networks were constructed: one related to EMT with 58 up-regulated proteins and another with 21 related to CBD signaling. The first one showed the proteins BRCA1, MSN, and CORO1A as the key axis that contributes to the establishment of a mesenchymal phenotype. In the CBD signaling, the key axis was formed by SUPT16H, SETD2, and H2BC12, which suggests epigenetic regulation by CBD in the restoration of an epithelial phenotype of breast cancer cells, providing new targets for anticancer therapy.

摘要： 帕金森病(Parkinson disease,PD)是中枢神经系统变性病,发病率高、致残率高、危险性高,给国家和家庭带来沉重的社会和经济负担.近期研究提示,PD患者脑内存在小胶质细胞激活及其表面表达主要组织相容性复合体(MHC),成为淋巴细胞攻击靶标.团队前期研究结果推测HLAII区基因参与了多巴胺(DA)神经元内a突触核蛋白降解及其免疫应答,在MHC的抗原呈递中发挥重要作用,但其分子机制尚不清楚,亟需攻克.本课题进一步探讨基于MHC抗原呈递介导的DA能神经元变性炎症免疫紊乱的分子机制研究及应用.