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关键词： Ilex rotunda   antioxidant   IL-2   MAPK   NF-kappa B   phenolics  

摘要： Ilex rotunda, an evergreen tree in the holly family, is a traditional medicine with a high phenolic content and various pharmacological effects. This study aimed to investigate phenolic constituents from enriched fractions guided by a total phenolic assay along with a feature-based molecular network. Nine compounds were isolated and identified using multiple chromatography and spectroscopic techniques. These isolates exhibited significantly high antioxidative effects in both free radical scavenging and ROS assays. They also remarkedly alternated interleukin (IL)-2 production in CD3/CD28-stimulated Jurkat T cells. The Western blotting assay suggested that these active compounds might decrease IL-2 production by blocking the activation of NF-kappa B and MAPK signaling pathways by downregulating the phosphorylation of p38 and p65 proteins as well as ERK and JNK kinases. Molecular docking data confirmed the above-mentioned biological properties of those active compounds by evaluating their binding affinities for target proteins. Our findings offer guidance for assessing the potential of phenolic chemicals from I. rotunda as pharmacological products to improve oxidative stress and enhance immune response in more in-depth studies.

摘要： Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate of only 10% in the United States. While immune checkpoint blockade (ICB) has shown efficacy in many solid tumors, PDAC remains largely unresponsive. Agonistic CD40 antibodies can activate PDAC-associated myeloid cells, enhancing innate and adaptive anti-tumor immunity. However, clinical trials with agonistic CD40 antibodies have demonstrated only modest efficacy and significant hepatotoxicity. We previously reported that IL-1 pathway blockade enhances CD40 agonist efficacy against melanoma by depleting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs; CD11b Ly6C Ly6G ). Since PMN-MDSCs also cause liver toxicity. This study investigates the impact of IL-1R1 blockade on the efficacy and toxicity of CD40 agonist therapy in PDAC. We found that treatment with an agonistic CD40 antibody induced immune activation and significantly prolonged survival in orthotopic PDAC-bearing mice. The transcriptomic profile revealed that IL-1R1 blockade as monotherapy downregulated innate and adaptive immune response and exacerbated tumor growth. However, the combination therapy of agonistic CD40 antibody and IL-1R1 blockade upregulated several immune-related pathways (GO enrichment analysis), including JAK-STAT signaling, antigen processing, and presentation, natural killer cell mediated cytotoxicity, boosted innate and adaptive immune responses, compared to CD40 agonist treatment alone. Paradoxically, despite these immunostimulatory effects, IL-1R1 blockade failed to improve the overall anti-tumor efficacy of CD40 agonist therapy and exacerbated liver toxicity. Liver toxicity was assessed by serum ALT and AST levels, and transcriptomic profiling of the liver revealed several pathways related to immune infiltration, liver metabolism, viral carcinogenesis and alcoholic liver disease were associated with hepatotoxicity. To further investigate the role of PMN-MDSCs in PDAC and understand the failure of

摘要： Tertiary lymphoid structures (TLSs) are de novo ectopic lymphoid aggregates that regulate immunity in chronically inflamed tissues, including tumours. Although TLSs form due to inflammation-triggered activation of the lymphotoxin (LT)-LT beta receptor (LT beta R) pathway1, the inflammatory signals and cells that induce TLSs remain incompletely identified. Here we show that interleukin-33 (IL-33), the alarmin released by inflamed tissues2, induces TLSs. In mice, Il33 deficiency severely attenuates inflammation- and LT beta R-activation-induced TLSs in models of colitis and pancreatic ductal adenocarcinoma (PDAC). In PDAC, the alarmin domain of IL-33 activates group 2 innate lymphoid cells (ILC2s) expressing LT that engage putative LT beta R+ myeloid organizer cells to initiate tertiary lymphoneogenesis. Notably, lymphoneogenic ILC2s migrate to PDACs from the gut, can be mobilized to PDACs in different tissues and are modulated by gut microbiota. Furthermore, we detect putative lymphoneogenic ILC2s and IL-33-expressing cells within TLSs in human PDAC that correlate with improved prognosis. To harness this lymphoneogenic pathway for immunotherapy, we engineer a recombinant human IL-33 protein that expands intratumoural lymphoneogenic ILC2s and TLSs and demonstrates enhanced anti-tumour activity in PDAC mice. In summary, we identify the molecules and cells of a druggable pathway that induces inflammation-triggered TLSs. More broadly, we reveal a lymphoneogenic function for alarmins and ILC2s.

关键词： 225Ac   T-cell adaptive immunity   bystander immunity   microenvironment   radioimmunotherapy   targeted radionuclide therapy  

摘要： Preclinical and clinical studies increasingly show that the immune response plays a major role in radiotherapy. Here, we investigated the role of major histocompatibility complex class I (MHC-I) molecules recognized by cytotoxic CD8 T cells in the response to radiopharmaceutical therapy (RPT). Two murine melanoma cell lines that express low and high MHC-I levels (B16F10 and B16K1, respectively) were grafted in syngeneic or athymic and nude mice, and the response to a single injection of [Ac]Ac-DOTA-TA99 monoclonal antibodies (9.25 or 18.5 kBq) was assessed and related to dosimetry. For clinical relevance, MHC-I expression was determined in samples from patients with well-differentiated, iodine-avid metastatic thyroid cancer and well-differentiated grade 2 mid-gut neuroendocrine tumors. RPT efficacy was enhanced by T-cell presence and MHC-I expression. In mice harboring B16F10 and B16K1 melanoma tumors, RPT showed a stronger antitumor effect in C57BL/6J (immunocompetent) animals than in athymic and nude (immunodeficient) animals, suggesting a crucial role of T-cell-mediated immune responses. Moreover, the response to irradiation was the same in B16K1 MHC-I tumors with a low absorbed dose of α-RPT and in B16F10 MHC-I tumors with a 4 times higher absorbed dose. These results indicate that CD8 T cells can counterbalance low tumor irradiation. Conversely, delivering high absorbed doses leads to side effects and seems to prevent immune system activation, thereby not taking advantage of these mechanisms. Our results also indicate that MHC-I can be used as a predictive biomarker of RPT response in lesions receiving low absorbed doses and that RPT treatment regimens should be reconsidered in the function of the MHC-I expression level. This study shows that MHC-I expression can predict RPT immunostimulatory effects. This is relevant in metastatic disease where lesions in the same patient can receive very low or very high absorbed doses.

关键词： hypertension   interleukin 17A   immunity   T helper 17 cells   inflammation  

摘要： Background The immune system is closely related to hypertension. Hypertension is an immune disorder to a certain extent, and inflammation is the basis of abnormally elevated blood pressure (BP). The accumulation of T cells and their cytokines can increase BP and end organ damage. T cells are activated by antigen-presenting cells of the innate immune system or by the influence of a high-sodium diet, the self-environment, or the gut microbiota. These cells produce inflammatory factors and cytokines, such as interleukin-17A (IL-17A) in T helper 17 cells, causing vascular inflammation, hypertension, and target organ damageMethods In this article, we provide an insightful review of the research progress regarding the role of IL-17A in the pathogenesis of hypertension and its effects on different organs while emphasizing the role of IL-17A and its mediated functions in the kidneys, brain, intestines, and vascular system in the development and progression of *** At the organ level, IL-17A is involved in the development and progression of hypertension in the kidneys, brain, intestines, and blood vessels, interacting with multiple signal *** These findings have significant implications for developing future immunomodulatory therapies, which may lead to the development of potential treatments for hypertension.

关键词： Chimeric antigen receptor  

关键词： epitope presentation   pretrained language model   deep learning  

摘要： Background Precise prediction of epitope presentation on human leukocyte antigen (HLA) molecules is crucial for advancing vaccine development and immunotherapy. Conventional HLA-peptide binding affinity prediction tools often focus on specific alleles and lack a universal approach for comprehensive HLA site analysis. This limitation hinders efficient filtering of invalid peptide *** We introduce TransHLA, a pioneering tool designed for epitope prediction across all HLA alleles, integrating Transformer and Residue CNN architectures. TransHLA utilizes the ESM2 large language model for sequence and structure embeddings, achieving high predictive accuracy. For HLA class I, it reaches an accuracy of 84.72% and an area under the curve (AUC) of 91.95% on IEDB test data. For HLA class II, it achieves 79.94% accuracy and an AUC of 88.14%. Our case studies using datasets like CEDAR and VDJdb demonstrate that TransHLA surpasses existing models in specificity and sensitivity for identifying immunogenic epitopes and *** TransHLA significantly enhances vaccine design and immunotherapy by efficiently identifying broadly reactive peptides. Our resources, including data and code, are publicly accessible at https://***/SkywalkerLuke/TransHLA

关键词： pelvic pain   endometriosis   infertility   sNCAM   sIL-2R alpha   VAS score  

摘要： Introduction Pelvic pain, often associated with endometriosis, significantly affects women's quality of life. This study explored the soluble neural cell adhesion molecules (sNCAM), soluble interleukin 2 receptor alpha (sIL-2R alpha), and IL-2 levels in the serum and peritoneal fluid of infertile women with pelvic *** We enrolled 86 infertile women aged 24 to 41 years undergoing diagnostic laparoscopy: 44 women with endometriosis and 42 women who acted as controls. Pain intensity was assessed using the visual analog scale. The soluble molecules were measured using enzyme-linked immunosorbent *** Serum and peritoneal sNCAM, sIL-2R alpha, and IL-2 levels were statistically significantly higher in women with pelvic pain. Both serum and peritoneal sNCAM levels correlated with visual analog scale scores, indicating a relationship between these markers and pain severity. Elevated peritoneal sIL-2R alpha levels were also associated with pelvic pain. Receiver operating characteristic curve analysis showed the potential of serum sNCAM in distinguishing between mild and moderate to severe *** Elevated levels of sNCAM, sIL-2R alpha, and IL-2 in serum and peritoneal fluid correlate with pelvic pain severity in infertile women, suggesting their involvement in disease pathogenesis and potential as objective biomarkers for pain assessment in endometriosis. Further research is needed to validate these findings for clinical use.

关键词： alendronate sodium bisphosphonate   bone mineral density   insulin-like growth factor   interleukin   osteoporosis  

摘要： Objective: To assess the effects of bisphosphonates (zoledronic acid injection) plus alendronate sodium on bone mineral density (BMD) and levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and insulin-like growth factor I (IGF-I) in patients with osteoporosis. Materials and methods: A total of 94 patients recruited from osteoporosis patients hospitalized in the period October 2021 to December 2022 were assigned to either a control group or an observation group using a random number table. The control group was treated with alendronate sodium alone, whereas the observation group received zoledronic acid injection in combination with alendronate sodium administered orally. Results: Pre-treatment values for BMD, serum levels of IL-6, TNF-alpha, and IGF-I did not differ between the two groups (p > 0.05). However, post-treatment BMD measured at the femoral neck, in lumbar vertebrae, and Ward's triangle were increased, as was serum IGF-I level (p < 0.05). In contrast, in comparison with the control group, reductions were observed in serum IL-6 and TNF-alpha (p < 0.05). The incidence of adverse reactions such as nausea and vomiting, diarrhea, musculoskeletal pain, and hypocalcemia was significantly lower in the observation group (p < 0.05). Conclusion: Zoledronic acid injection in combination with alendronate sodium increases the expression of IL-6, TNF-alpha, and IGF-I, suppresses bone resorption and promotes bone recovery in patients with osteoporosis.