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关键词： plasmacytoid dendritic cells   type I interferon   interferon-alpha   lactic acid bacteria   Lactobacillus paragasseri SBT2055   Toll-like receptor 9  

摘要： Previously, we reported that Lactobacillus paragasseri SBT2055 (LG2055) activates plasmacytoid dendritic cells (pDCs) and induces interferon alpha (IFN-alpha) in vitro. Our clinical trial suggested that LG2055 intake may enhance pDC activity, supporting immune maintenance and reducing subjective common cold symptoms. However, the precise mechanisms remain unclear. In this study, we investigated how LG2055 engages with pDCs to stimulate IFN-alpha production. We evaluated LG2055-induced pDC activation using flow cytometry, ELISA, and phagocytosis assays. Human peripheral blood mononuclear cells (PBMCs) were stimulated with LG2055 and its components to evaluate immune responses. An in vitro M cell model was used to examine LG2055 translocation. We found that DNA extracted from LG2055 activated pDCs and enhanced IFN-alpha production via Toll-like receptor 9 (TLR9). Phagocytosis assays demonstrated that LG2055 DNA was internalized by PBMC-derived pDCs, enabling TLR9-mediated signaling. Additionally, LG2055 translocated across M cells in vitro, suggesting potential transport into Peyer's patches, where it may interact with pDCs. These findings demonstrate that intestinal LG2055 can translocate across M cells, interact with pDCs, and exert immune-stimulatory effects to enhance host antiviral immunity. This study provides mechanistic insight into how dietary components support immune health and could inform the development of novel functional foods or therapeutic strategies.

关键词： Treatment   Immune response   Biotechnology  

摘要： Psoriasis is an inflammatory skin disease with aberrant epidermal differentiation and chronic inflammation. Plant-derived exosome-like nanovesicles (PDNVs) are exosome-mimetic structures isolated from plants with enhanced bioavailability and solubility. Herein, we investigated the therapeutic efficacy of PDNVs for psoriasis treatment. In our initial phenotype-driven screen, PDNVs from apple, garlic, and shallot displayed both pro-differentiation and anti-inflammatory activity in vitro. In imiquimod (IMQ)-induced psoriasis-like murine model, topical application of either shallot or garlic PDNV hydrogels led to complete recovery of normal skin phenotype. In porcine skin ex vivo assay, both shallot and garlic PDNVs displayed percutaneous penetration up to the suprabasal epidermis. Using next generation sequencing and quantitative mRNA profiling in keratinocytes and murine skin, we elucidated a suppressive effect of shallot and garlic PDNVs on IL-17 signaling via modulation of upstream nuclear factor erythroid-2-related factor 2 (NRF2) pathway. Since PDNVs are economical to produce, shallot and garlic PDNVs could be natural and cost-effective topical alternative for psoriasis.

关键词： Hymenolepis nana   Ulcerative colitis   Excretory/secretory products   Tuft/IL-13   Intestinal stem cell  

摘要： BackgroundHymenolepis nana (H. nana) is a zoonotic parasitic worm that parasitizes the small intestines of humans and rodents. Ulcerative colitis (UC) is a chronic and recurrent inflammatory bowel disease. Current symptom-based clinical treatments do not alter the natural course of UC, and mucosal healing has become a primary therapeutic goal for UC. However, the regulatory role of excretory/secretory products (ESPs) from H. nana adult worms in repairing the damaged intestinal mucosal barrier remains *** study investigated the protective effects of ESPs on intestinal mucosal integrity by using a dextran sulfate sodium (DSS)-induced colitis mouse model and a mouse small intestine organoid inflammation model. Histopathological alterations of mouse intestinal tissues were determined by pathological staining;the alterations in mucins, tight junction proteins, cytokines, and the number of various intestinal cells were detected by Western blotting (WB), immunohistochemistry (IHC), immunofluorescence (IF) and real-time quantitative polymerase chain reaction (RT-qPCR), *** significantly improved DSS-induced intestinal damage in mice. Meanwhile, ESPs increased mucins and tight junction proteins expression and promoted intestinal stem cell proliferation and differentiation, thereby maintaining intestinal mucosal barrier integrity and alleviating UC in mice. In the DSS-induced inflamed small intestinal organoid model, ESPs reduced organoid damage and promoted the proliferation and differentiation of intestinal stem cells. The protective mechanism of ESPs might be related to the activation of the tuft/IL-13 signaling pathway, regulating intestinal barrier function and promoting the regeneration of intestinal stem *** conclusion, H. nana-derived ESPs intervention facilitates healing of intestinal mucosa to alleviate UC in mice, enriching the feasibility and selectivity of "helminthic therapy."

关键词： AIH   Autoimmune hepatitis   BCMA   B cell maturation antigen   CAR   Chimeric antigen receptor   CAAR   Chimeric autoantibody receptor   CCA   Cholangiocellular carcinoma   CD   Cluster of Differentiation   CRS   Cytokine release syndrome   ECM   Extracellular matrix   GPC3   Glypican3   HLA   Human leukocyte antigen   HCC   Hepatocellular carcinoma   HIT   HLA-independent TCRs   HLH   hemophagocytic lymphohistiocytosis   HSC   Hepatic stellate cell   ICI   Immune checkpoint inhibitor   ICANS   Immune Effector Cell-Associated Neurotoxicity Syndrome   MHC   Major histocompatibility complex   TAA   Tumor-associated antigen   TCR   T cell receptor   TME   Tumor microenvironment   TRAF   Treg with amplified suppressor function   Treg   regulatory T cell   TRUCK   T cells Redirected for Universal Cytokine Killing  

摘要： Endogenous T cells recognize antigens through human leukocyte antigen (HLA)/peptide complexes. However, the polymorphism of HLA has posed significant challenges to the development of broadly applicable adoptive T-cell therapies. Engineered T cells can circumvent this barrier by targeting surface antigens independently from HLA through a synthetic chimeric antigen receptor (CAR) with an antibody-derived recognition domain fused to intracellular signaling motifs. CAR-T cell therapies have transformed the treatment of B-cell malignancies in hematology, and recent studies demonstrate therapeutic potential against solid tumors. This review presents an overview of CAR technology’s fundamental principles and achievements, focusing on CAR-T cell applications in hepatic viral infections, autoimmune liver disease, and hepatobiliary tumors. Emerging senolytic therapies that target senescent cells and hepatic fibrosis are highlighted alongside regulatory CAR-T cells that induce liver-specific immune tolerance in transplantation. Future and ongoing research is reviewed that seeks to enhance the specificity, efficacy, and safety of CAR-based therapies as "living drugs" that facilitate targeted, sustained, and personalized interventions for liver diseases.

摘要： Efferocytosis, wherein phagocytes engulf dead or dying cells, is a critical function of macrophages that supports cellular turnover, tissue repair, and resolution of inflammation. Despite its well-established anti-inflammatory mechanism in homeostasis, whether efferocytosis remains immunologically silent in the context of dysregulated immune responses such as sepsis or systemic inflammatory response syndrome (SIRS) has not been investigated. Here, we used mouse models of tumor necrosis factor (TNF)-induced SIRS and Escherichia coli-induced septic peritonitis to uncover a potential negative consequence of efferocytosis. We found that when activated with TNF, phagocytes efferocytosing neutrophils initiated a caspase-8-dependent, but NLRP3 inflammasome-independent, form of pyroptosis, which we termed "efferoptosis." The maturation of IL-1 beta, a hallmark of pyroptotic cell death, also occurred independently of canonical inflammasome activation, supporting direct cleavage by caspase-8. Inhibition of efferocytosis protected mice against TNF-induced SIRS, suggesting that efferoptosis contributes to the pathology of sepsis and other TNF-mediated inflammatory conditions.

关键词： Tumors  

摘要： Mutations in the tumor suppressor liver kinase B1 (LKB1) promote the development of gastrointestinal (GI) polyps of unknown etiology. Here, we identify IL-17 as a novel driver of LKB1-dependent polyp growth. GI tumors from mice bearing heterozygous mutations in Stk11 (which encodes LKB1) display signatures of pathogenic IL-17-producing CD4+ T helper 17 (TH17) cells. LKB1 constrains T cell inflammatory potential, as Stk11/LKB1 haploinsufficiency promotes T cell differentiation toward pathogenic IL-17-producing T cell lineages (CD4+ TH17 and CD8+ Tc17) in vitro and following intestinal infection. Mechanistically, aberrant CREB-regulated transcription coactivator 2 (CRTC2)-dependent signaling drives pathogenic TH17 cell programs downstream of LKB1 haploinsufficiency. Targeting this circuit via CRTC2 deletion or IL-17 blockade antagonizes GI polyp growth in mouse models of Peutz-Jeghers syndrome. These findings establish LKB1 as a gatekeeper of inflammatory type 3 (IL-17-dependent) T cell responses and identify a CRTC2-IL-17 signaling axis that can be targeted therapeutically to block the growth of LKB1 mutant GI tumors.

关键词： Ulcerative colitis   Atractylodes macrocephala polysaccharides 1   Gut microbiota   IL-17RA signaling pathway   Fecal microbiota transplantation   Functional food  

摘要： The development of ulcerative colitis (UC) is closely associated with dysregulation of the gut microbiota. Polysaccharides， recognized for their prebiotic and dietary supplement properties， are increasingly utilized for UC prevention and management. In this study， Atractylodes macrocephala polysaccharides 1 (AMP 1) were successfully isolated and purified from Atractylodes macrocephala Koidz. However， the therapeutic potential of AMP 1 in UC remains underexplored. This research investigates the effects of AMP 1 on UC in mice， with a focus on its modulation of the gut microbiota and IL-17RA signaling pathway. Our findings demonstrate that AMP 1 mitigates UC symptoms in a dose-dependent manner. Notably， AMP 1 was ineffective in UC mice treated with antibiotics (ABX). However， fecal microbiota transplantation (FMT) from AMP 1-treated mice to ABX-pretreated mice restored its therapeutic effects. Further analysis suggests that AMP 1’s protective effects may be mediated through the downregulation of the IL-17RA signaling pathway. Notably， IL-17RA gene inhibition enhanced AMP 1’s protective capacity. These results collectively indicate that AMP 1 exerts protective effects against UC by modulating the gut microbiota and IL-17RA signaling. In conclusion， AMP 1 shows promise as a potential functional food for UC management.

关键词： Cancer   Immunology   Microenvironment  

摘要： Radiotherapy (RT) can stimulate anti-cancer T cell responses, and cytokines, notably interleukin-2 (IL-2), are necessary for optimal T cell function and memory. However, timing and IL-2 receptor (IL-2R) bias of IL-2 signals are ill-defined. Using image-guided RT in a mouse colon cancer model, we observed single high-dose (20 Gy) RT transiently upregulated IL-2R alpha (CD25) on effector CD8+ T cells, facilitating the use of CD25-biased IL-2 immunotherapy. Timed administration of CD25-biased IL-2 treatment after RT favored intratumoral expansion of CD8+ T cells over regulatory T cells, which resulted in comparable anti-tumor effects as with RT plus IL-2R beta (CD122)-biased IL-2 immunotherapy. Moreover, intratumoral CD8+ T cells of animals receiving combined IL-2R-biased IL-2 and RT showed reduced markers of exhaustion. These combination treatments affected both primary irradiated and distant non-irradiated tumors and achieved durable responses. We demonstrate that timed IL-2R subunit-biased IL-2 immunotherapy synergizes with single high-dose RT to achieve potent anti-cancer immunity.

关键词： 赖氨酸特异性去甲基化酶1   前列腺癌   白细胞介素17通路   基质金属蛋白酶13  

摘要： 目的：本研究旨在阐明赖氨酸特异性脱甲基酶1(lysine specific demethylase 1,LSD1)在去势抵抗性前列腺癌（prostate cancer,PCa）中的作用及分子机制。方法：通过利用癌症基因组图谱（The Cancer Genome Atlas,TCGA）数据库进行生物信息学分析，探索LSD1在PCa中的差异表达和预后情况；为了构建雄激素非依赖性（androgen-independent,AI）细胞系，对PCa雄激素依赖细胞系LNCap进行雄激素剥夺处理，敲低LSD1观察细胞变化，并用LSD1抑制剂处理雄激素非依赖前列腺癌PC-3细胞系（Prostate Cancer-3 cell line,PC-3）；构建PCa原位瘤模型探究LSD1抑制对去势治疗敏感性的影响；最后通过转录组测序、实时荧光定量聚合酶链式反应（Realtime fluorescence quantitative PCR,qPCR）和蛋白质印迹技术（Western blot,WB）和染色质免疫沉淀（chromatin Immunoprecipitation,ChIP）实验探索机制。结果：LSD1在TCGA-PCa及去势抵抗性PCa中明显上调，高表达患者生存期短，且在LNCap-AI细胞中表达高于LNCap细胞，敲低LSD1可抑制细胞恶性行为、提高凋亡水平，LSD1抑制剂能抑制PC-3细胞恶性行为，抑制LSD1可提高PCa对去势治疗的敏感性，LSD1敲低降低基质金属蛋白酶13(Matrix Metalloproteinase13,MMP13)的表达、抑制白细胞介素17(interleukin 17,IL17)信号通路，并通过调节MMP13基因启动子区域组蛋白H3第9位赖氨酸（histone H3 lysine 9,H3K9）的甲基化水平调控其表达。结论：LSD1通过调节MMP13基因启动子区域H3K9的甲基化水平控制MMP13表达，进而影响IL-17信号通路，在前列腺癌去势抵抗性进程中发挥重要作用。