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关键词： 免疫抑制剂   结核   T淋巴细胞   综述文献(主题)  

摘要： 结核病仍然是全球范围内最具威胁的传染性疾病之一。在结核分枝杆菌潜伏感染中，病原体可以长时间处于休眠状态，等待宿主免疫功能下降时再激活。结核病的免疫应答依赖于适应性免疫，特别是T淋巴细胞。其中CD4+T淋巴细胞通过释放γ-干扰素来激活巨噬细胞，而CD8+T淋巴细胞则直接杀伤受感染的宿主细胞。长期慢性的感染往往导致T淋巴细胞功能的衰竭，免疫系统无法有效清除病原体。程序性死亡受体1（programmed death 1， PD-1）和程序性死亡配体1（programmed cell death-Ligand 1， PD-L1）抑制剂作为免疫检查点抑制剂，已经展现出恢复免疫应答、杀伤肿瘤细胞的强大潜力，并在癌症治疗中得到了广泛应用。然而，在结核病中的作用机制、治疗前景仍需进一步研究。为了更好地推动PD-1和PD-L1抑制剂在传染病领域的应用，作者综述了结核病中T淋巴细胞适应性免疫的特征，PD-1/PD-L1信号通路的功能及在结核病中的作用，并对阻断PD-1/PD-L1通路在结核病治疗中的最新研究进展进行了总结和讨论。旨在为免疫检查点抑制剂在感染性疾病中的应用提供参考。

关键词： IL-37d   Tumor microenvironment   Pre-metastatic niche   Neutrophil infiltration   Neutrophil spontaneous migration  

摘要： BackgroundChronic inflammation plays a pivotal role in cancer progression, with tumor-associated neutrophils (TANs) actively shaping the pre-metastatic niche. Interleukin-37 (IL-37), a known immunosuppressive cytokine, is implicated in this regulation, although its precise function remains ***, this study seeks to further elucidate the inhibitory effect of IL-37d on neutrophil recruitment within the pre-metastatic lung microenvironment and its underlying mechanisms, thereby providing a theoretical foundation for clinical interventions in the early stages of cancer *** study investigates the impact of IL-37d on tumor growth, metastasis, and survival in a murine model, with a focus on the molecular mechanisms involved. Specifically, we explored IL-37d's ability to inhibit toll-like receptor 3 (TLR3) activation in lung epithelial cells, reduce calcium-binding proteins S100A8/A9 (S100a8/9) expression, and suppress matrix metalloproteinase 9 (MMP9) activity. We also examined IL-37d's effect on neutrophil migration from the bone marrow to the lungs during early ***-37d treatment significantly reduced lung metastasis and extended survival in mice. Mechanistically, IL-37d inhibited TLR3 activation, downregulated S100a8/9 expression, and reduced MMP9 activity, thereby impairing the migration of bone marrow-derived neutrophils to the lungs. This led to decreased neutrophil infiltration and a disruption of the pre-metastatic niche *** study represents the first investigation into the role of IL-37d in inhibiting tumor metastasis during the early stages by suppressing S100A8/9 and MMP9 expression in lung tissue, thereby reducing neutrophil recruitment and spontaneous migration from the bone marrow.

关键词： caspase-8   cathepsins   chronic diseases   cognition   inflammation   microglia signalling  

摘要： Background. Organ transplantation reverses cognitive impairment in chronic kidney disease (CKD), indicating that cognitive impairment driven by CKD is therapeutically amendable. We recently demonstrated that impaired cognition in CKD is linked to interleukin1S (IL-1 S) release from microglia and IL-1 receptor type 1 signalling in neuronal cells, thereby identifying a signalling pathway that can be exploited therapeutically. However, the mechanism of IL-1 S maturation in microglia in CKD remains unknown. We hypothesized that microglia cells require caspase-1 for CKD-driven cognitive impairment. Methods. We used a combination of single-cell analyses, in situ analyses, genetically modified mouse models (including newly generated Cre-LoxP mouse models) and in vitro models. The current study builds on a recently identified intercellular cross-talk between microglia and neurons that impairs cognition in CKD. Results. Here we show that despite NLRP3 inflammasome activation in the brain and protection of mice with constitutive NLRP3 deficiency from CKD-induced cognitive impairment, caspase-1 is not required for IL-1 S maturation in microglia and targeted caspase-1 deficiency in microglia does not improve cognition in CKD mice. These data indicate that IL-1 S maturation in microglia is independent of the NLRP3-caspase-1 interaction in CKD. Indeed, microglia activation in CKD induces noncanonical, cathepsin C-caspase-8- mediated IL-1 S maturation. Depletion of cathepsin C or caspase-8 blocks IL-1 S maturation in microglia. Preliminary analyses suggest that noncanonical microglia IL-1 S maturation occurs also in diabetes mellitus. Conclusion. These results identify a noncanonical IL-1 S-maturation pathway as a potential therapeutic target to combat microgliainduced neuronal dysfunction in CKD and possibly other peripheral diseases.

关键词： gastric cancer   IL-17   tumor microenvironment   Helicobacter pylori   immunotherapy  

摘要： Cytokines, which are important to the tumor microenvironment (TME), play critical roles in tumor development, metastasis, and immune responses. Interleukin-17(IL-17) has emerged as a key biomarker in many malignancies;however, its precise involvement in gastric cancer is less fully understood. Elevated levels of IL-17 have been observed in stomach diseases such as Helicobacter pylori infection and autoimmune gastritis, indicating that a sustained Th17 response may precede the development of gastric cancer. While IL-17 is related to inflammatory processes that may lead to cancer, its specific influence on gastric cancer development and therapy needs to be completely understood. Specifically, the release of IL-17A by diverse immune cells has been associated with both tumor development and inhibition in gastric cancer. It may impact tumor development through mechanisms such as boosting cell proliferation, inducing angiogenesis, and enabling immune cell recruitment or, conversely, suppressing tumor growth via the activation of anti-tumor immune responses. The dual role of IL-17 in cancer, along with its various effects depending on the TME and immune cell composition, highlights the complexity of its activity. Current research reveals that although IL-17 might serve as a target for immunotherapy, its therapeutic potential is hindered by its various activities. Some studies have shown that anti-IL-17 drugs may be helpful, especially when paired with immune checkpoint inhibitors, whereas others point to concerns about the validity of IL-17 in gastric cancer therapy. The lack of clinical trials and the heterogeneity of human tumors underscore the necessity for individualized treatment approaches. Further studies are needed to identify the specific mechanisms of IL-17 in gastric cancer and to design targeted therapeutics appropriately.

摘要： Chimeric antigen receptors (CAR) that mimic T cell receptors (TCR) on eliciting peptide-major histocompatibility complex (pMHC) specific T cell responses hold great promise in the development of immunotherapies against solid tumors, infections, and autoimmune diseases. However, broad applications of TCR-mimic (TCRm) CARs are hindered to date largely due to lack of a facile approach for the effective isolation of TCRm CARs. Here, we establish a highly efficient process for discovery of TCRm CARs from human naïve antibody repertories by combining recombinase-mediated large-diversity monoclonal library construction with T cell activation-based positive and negative screenings. Panels of highly functional TCRm CARs with peptide-specific recognition, minimal cross-reactivity, and low tonic signaling were rapidly identified towards MHC-restricted intracellular tumor-associated antigens MAGE-A3, NY-ESO-1, and MART-1. Transduced TCRm CAR-T cells exhibited pMHC-specific functional avidity, potent cytokine release, and efficacious and persistent cytotoxicity. The developed approach could be used to generate safe and potent immunotherapies targeting MHC-restricted antigens.

关键词： COVID-19   interleukin-6   molecular docking   molecular dynamics simulation   network pharmacology   Qing Yan He Ji  

摘要： Since the coronavirus disease 2019 (COVID-19) outbreak, although have controlled, severe acute respiratory syndrome coronavirus 2 is constantly mutating and affects people's health. FDA has approved Paxlovid and Molnupiravir for COVID-19 treatment, however, they have not been approved for children under 12 years old. Therefore, it is urgent to explore new drugs for treating COVID-19 in children. As a traditional Chinese medicine, Qing Yan He Ji (QYHJ) has been widely used as an antiviral in our hospital. Therefore, we presumed that it may be ideal for treating COVID-19 and explored its therapeutic effect in patients with COVID-19. The targets and underlying mechanisms of QYHJ against COVID-19 in children were investigated using bioinformatics. QYHJ target sets, and related target genes of COVID-19 were retrieved from public databases. Subsequently, gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to investigate the potential mechanism of QYHJ against COVID-19. Finally, molecular docking was carried out to analyze the affinity between the effective molecule and the target protein. A total of 15 bioactive ingredients of QYHJ and 111 predicted potential targets of QYHJ against COVID-19 were screened. A protein-protein interaction network and subnetworks identified 21 core target genes. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that QYHJ functions against COVID-19 primarily through antiviral and anti-inflammatory effects. Molecular docking of interleukin-6 (IL-6) revealed that 5 active compounds had relatively stable binding activities with IL-6. Molecular dynamics simulation was performed for molecular docking results, showing IL-6-(4aS,6aR,6aS,6bR,8aR,10R,12aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydropicene-4a-carboxylic acid (4aS) complex, IL-6-stigmasterol complex, IL-6-poriferasterol complex, IL-6-sitosterol complex, and

关键词： Armadillidium vulgare Latreille   CXCL10   IFN-γ   IL-12   Neuron-astrocyte crosstalk   Neuropathic pain  

摘要： ETHNOPHARMACOLOGICAL RELEVANCE:Armadillidium vulgare Latreille (AV), the dried body of pillbug, was originally described in Shennong's Classic of Materia Medica. As a common analgesic in animal-based traditional Chinese medicine, it is mainly used to relieve pain, promoting diuresis, relieving fatigue and so on. Our work demonstrated that AV could alleviate various types of acute and chronic pain including neuropathic pain (NP). And transcriptome sequencing analysis revealed that AV could suppress CXCL10 to alleviate NP, however, the upstream mechanisms governing CXCL10 synthesis remain vague. AIM OF THE STUDY:The research's goal was to identify the mechanism via which AV regulates CXCL10 to ameliorate NP. MATERIALS AND METHODS:Chronic constriction injury (CCI) to the sciatic nerve was used to induce the NP model 14 days following surgery. To identify cell signaling pathways, various approaches were used, including transcriptome sequencing, western blotting, immunofluorescence, as well as ELISA. The in vitro assay involved the cultivation of neuron PC12 cells and astrocyte C6 cells. RESULTS:Both in vivo and in vitro results demonstrated that IL-12/IL-18 enhanced IFN-γ production in spinal neurons, which acted on IFN-γ receptors on neurons and astrocytes to upregulate CXCL10 expression in these cells, illustrating the pivotal role of IL-12 in the crosstalk between neurons and astrocytes. The role of IL-12 in pain regulation was elucidated for the first time within the nervous system. Additionally, its synergistic interaction with IL-18 on the downstream IFN-γ-CXCL10 pathway dramatically altered the activation of neurons and astrocytes. And AV could suppress CXCL10 to alleviate NP by mediating the IL-12-IFN-γ-IFNGR signaling pathway. CONCLUSIONS:We explored a new target for NP by regulating neuron-astrocyte crosstalk and provided a theoretical basis for AV in clinical use.

关键词： Bushen Zhuyun decoction (BSZY)   Decidualization   Endometrial Receptivity   IL-6/STAT3   Infertility   Treg/Th17  

摘要： BACKGROUND:Reproductive endocrine disorder can impair endometrial receptivity, preventing embryo implantation and increasing miscarriage risk. Impaired endometrial receptivity contributes significantly to female infertility. Inflammatory signaling pathways including the IL-6/STAT3 pathway help embryos implant. Therefore, it is crucial to explore the relationship between the IL-6/STAT3 signaling pathway and endometrial receptivity. OBJECTIVE:To investigate the mechanism by which Bushen Zhuyun decoction (BSZY) enhances endometrial receptivity in rats through the IL-6/STAT3 signaling pathway. METHODS:Mifepristone-induced poor endometrial receptivity models of female SD rats were established, followed by histopathological observation. ELISA was used to measure serum sex hormones and VEGF. Western blotting or IHC was used to measure steroid receptors, IGFBP1, and IL-6/STAT3 pathway activation in the uterus during each estrus cycle and early gestation of normal rats. The Treg/Th17 balance was assessed using flow cytometry. RESULTS:Significant differences were found in the protein expressions of steroid receptors, IL6, STAT3, and p-STAT3 during each estrus cycle and early gestation of normal rats. The protein expressions of STAT3 and PR were strongly correlated with each other. BSZY notably improved uterine morphology increased the expression of implantation markers and raised the serum concentrations of sex hormones and VEGF. BSZY enhanced the expressions of IL-6 and its receptors and restored the expressions of STAT3 and p-STAT3 in the uterus of pregnant rats. In addition, BSZY effectively restored the Treg/Th17 balance in the peripheral blood of pregnant rats. CONCLUSION:BSZY enhances endometrial receptivity and promotes decidualization in SD rats via the IL-6/STAT3 signaling pathway.

摘要： Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), remains a significant threat to global public health. Immunopathological damage plays a role in driving pneumonia, acute respiratory distress syndrome (ARDS), and multiorgan failure in severe COVID-19. Therefore, dissecting the pulmonary immune response to SARS-CoV-2 infection is critical to understand disease pathogenesis and identify immune pathways targetable by therapeutic intervention. Considering that the type 2 cytokine IL-13 enhances COVID-19 disease severity, therapeutic targeting of upstream signals that drive type 2 immunity may confer further protection. In this study, we investigate the role of the IL-33/ST2 signaling axis, a potent inducer of type 2 immunity in the lung, in a mouse model of COVID-19. Upon infection with mouse-adapted SARS-CoV-2 MA10, ST2 mice had significantly improved weight loss and survival (69.2% vs 13.3% survival; P = 0.0005), as compared to wild-type mice. In a complementary pharmacologic approach, IL-33/ST2 signaling was inhibited using HpBARI_Hom2, a helminth derived protein that binds to mouse ST2 and blocks IL-33 signaling. In SARS-CoV-2 MA10 infection, HpBARI_Hom2-treated mice had significantly improved weight loss and survival (60% vs 10% survival; P = 0.0035), as compared to inert control-treated mice. These data demonstrate that loss of IL-33/ST2 signaling confers protection during acute SARS-CoV-2 MA10 infection, implicating the IL-33/ST2 signaling axis as an enhancer of COVID-19 disease severity. The protection conferred by pharmacologic blockade of IL-33/ST2 signaling was independent of viral control, as HpBARI_Hom2-treated mice had no reduction in viral titers. This finding suggests an immunopathogenic role for IL-33/ST2 signaling. One potential mechanism through which IL-33/ST2 signaling may drive severe disease is through enhancement of type 2 immune pathways including IL-5 production, as pulmon

关键词： Trichinellosis   Probiotic   Linex   IFN-gamma   IL-4   IL-13  

摘要： Trichinellosis is a zoonotic, foodborne parasitic infection causing muscle damage. This study investigated the potential therapeutic effects of the commercially available probiotic treatment Linex, both alone and in combination with Albendazole (ALB), on the intestinal and muscular stages of Trichinella spiralis infection in mice, assessing outcomes through parasitological, immunological, and histopathological measures. This study is the first to demonstrate the synergistic effect of combining the commercially available probiotic Linex with Albendazole for trichinellosis treatment. By enhancing both parasitological and immunological outcomes, this combined therapy not only significantly reduces parasite burden but also modulates the immune response, shifting it toward a protective Th1 profile. In parasitological terms, the highest adult and larval count reduction was observed in combined Linex and Albendazole treatment (100%, 97.7%) respectively. Lesser percentage of reduction were recorded in Linex alone therapy (43.2%, 88.4%) respectively. Histopathologically there was amelioration of the inflammatory cellular infiltration in all treated groups with best results in combined Linex and Albendazole treatment. Immunologically, serum IFN-gamma levels increased significantly in all treated groups with highest levels in combined Linex and Albendazole treatment, while IL-4 and IL-13 level decreased significantly in all treated groups with best results observed in Linex alone treatment. To conclude;combined Linex and Albendazole treatment of mice infected with T. spirals could ameliorate the infection and improve the immune response.