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关键词： CircPHLPP2   Colorectal cancer   NK cell   Immune evasion  

摘要： BackgroundMost Colorectal Cancer (CRC) patients exhibit limited responsiveness to anti-programmed cell death protein 1 (PD-1) therapy, with the underlying mechanisms remaining elusive. Circular RNAs (circRNAs) play a significant role in tumorigenesis and development, with potential applications in tumor screening and predicting treatment efficacy. However, there are few studies exploring the role of circRNAs in CRC immune *** microarrays were used to identify circPHLPP2. RT-qPCR was used to examine the associations between the expression level of circPHLPP2 and the clinical characteristics of CRC patients. MTS assay, clone formation experiment, subcutaneous tumor implantation and multicolor flow cytometry were used to confirm the biological function of circPHLPP2. RAN-seq, RT-qPCR, and WB experiments were performed to investigate the downstream signaling pathways involved in circPHLPP2. RNA pull-down, RNA immunoprecipitation (RIP) and immunofluorescence staining were performed to identify the proteins associated with ***2 is up-regulated in CRC patients who exhibit resistance to anti-PD-1 based therapy. circPHLPP2 significantly promotes the proliferation and tumor growth of CRC cells. Knockdown of circPhlpp2 enhances the efficacy of anti-PD-1 in vivo. Mechanistically, the specific interaction between circPHLPP2 and ILF3 facilitates the nuclear accumulation of ILF3, which subsequently enhances the transcription of IL36 gamma. This process reduces NK cell infiltration and impairs NK cells' granzyme B and IFN-gamma production, thereby promoting tumor ***, our findings reveal a novel mechanism by which circRNA regulates CRC immune evasion. circPHLPP2 may serve as a prognostic biomarker and potential therapeutic target for CRC patients.

关键词： Osteoarthritis   Hck   Chondrocytes   Apoptosis extracellular matrix   JAK-STAT3  

摘要： We investigated role of haematopoietic cell kinase (Hck) in osteoarthritis (OA) and to explore the underlying mechanisms driving its effects. An OA animal model was established and after OA induction, rats received intra-articular injections of lentivirus twice a week for four weeks. Rats were divided into four groups: control (healthy rats without OA), OA model (rats with induced OA), OA + Len-si-NC (OA rats treated with a non-targeting control lentivirus), and OA + Len-si-Hck (OA rats treated with lentivirus targeting Hck). Blood samples were collected, and serum cytokine levels were measured using ELISA. Afterward, the rats were sacrificed for histological analysis and TUNEL assay. In vitro, IL-1 beta-treated human chondrocytes were transfected with Hck, and the effects on cell viability, apoptosis, ECM degradation, and JAK-STAT3 signaling were assessed. Colivelin, a JAK-STAT3 agonist, was used to confirm the pathway's involvement. Results indicated increased Hck expression in the cartilage tissues of OA rats and in IL-1 beta-stimulated chondrocytes. Silencing Hck in vivo reduced IL-6 and TNF-alpha levels, apoptosis, and preserved cartilage structure. In vitro, Hck knockdown in IL-1 beta-treated chondrocytes resulted in enhanced cell viability, reduced apoptosis, and decreased ECM degradation. Notably, the expression of MMP3 and MMP13 was significantly lowered, while collagen II and aggrecan levels were restored. Additionally, Hck knockdown inhibited JAK-STAT3 activation, which was evident from reduced levels of phosphorylated JAK1 and STAT3. The addition of colivelin reversed these effects, confirming that Hck mediates its effects through the JAK-STAT3 pathway. Overall, our findings indicate that Hck is critical in OA progression by promoting inflammation, apoptosis, and ECM degradation through the JAK-STAT3 signaling pathway activation.

关键词： B2 haplotype chickens   CD8(+)T cell   epitope   ALV-J   MHC  

摘要： MHC B2 haplotype chickens have been reported to induce strong immune response against various avian pathogens. However, little is known about the CD8(+)T-cell epitope with MHC B2-restricted on subgroup J avian leukosis virus (ALV-J). In this study, we explored the ALV-J-induced cellular immune response in B2 haplotype chickens in vivo. We found that ALV-J infection significantly increased the proportion of CD8(+)T cells in chickens and up-regulated the expression of cytotoxic genes like Granzyme A and antiviral genes like IFIT5 at 14 days post-infection (dpi). We selected 32 candidate peptides based on the peptide-binding motif and further identified three MHC B2-restricted CD8(+)T epitopes on ALV-J, including Pol(652-660), Gag(374-382,) and Gag(403-411) which induced significant levels of chicken IFN-gamma production in splenocytes from ALV-J infected chickens using the ELISpot assay. In addition, we also verified that the three identified epitopes stimulated memory splenocytes elevating TNF-alpha and IL-2 protein expression. Importantly, we found that the three positive peptides were highly conserved among ALV-A, ALV-B, ALV-E, ALV-J, and ALV-K. Taken together, we identified three MHC B2-restricted CD8(+)T cell epitopes on ALV-J, providing a foundation for developing effective T cell epitope vaccines targeting conserved internal viral proteins.

关键词： Arthritis, juvenile   Cardiovascular diseases   Heart failure   Spondylitis, ankylosing   Tumor necrosis factor inhibitors  

摘要： The safety of tumor necrosis factor (TNF) inhibitors has been demonstrated for over two decades. However, their effects on cardiovascular function in patients with rheumatic diseases remain controversial, and conclusions are additionally hampered by the cardiovascular complications inherent in such diseases. We present two 15-year-old patients diagnosed with ankylosing spondylitis and juvenile idiopathic arthritis classified as polyarthritis with positive rheumatoid factor, respectively. Soon after treatment onset with adalimumab and etanercept, respectively, they developed myocardial inflammation leading to heart failure. Their condition improved upon treatment discontinuation and onset of secukinumab and tocilizumab, respectively. A thorough literature search revealed that these are the only cases of heart failure reported to date after anti-TNF treatment in adolescents with rheumatic diseases. Although cardiovascular adverse effects seem to be very rare in this population, even atypical symptoms of cardiac failure should not be ignored, and cardiac function should be closely monitored when administering anti-TNF-α.

关键词： And colorectal cancer   Breast   Interleukin-35   Lung   Regulatory T cells   Therapeutic role   Treg cells plasticity  

摘要： T lymphocytes are among the immunological cells that make up the tumor microenvironment (TME), and they are essential in the growth of tumors and anti-tumor reactions. Regulatory T cells (Treg cells) are a subset of CD4+ T cells in the immune system that suppress the immune system. They are distinguished by their expression of the master transcription factor forkhead box protein P3 (FOXP3). Furthermore, Treg cells are essential for maintaining immunological homeostasis, inhibiting inflammation, and maintaining self-tolerance. In a variety of malignancies within the TME, Treg cells demonstrate notable flexibility and functional diversity. Highly plastic Treg cells can change into Th-like Treg cells in specific circumstances, which allow them to secrete particular pro-inflammatory cytokines. Interleukin 35 (IL-35) is a part of the immunosuppressive cytokines that belong to the IL-12 family. Treg cells release IL-35, which was elevated in the peripheral blood and TME of numerous cancer patients, implying that IL-35 in the TME may be an intriguing target for cancer therapy. In cancer, IL-35 is a two-edged sword; it promotes tumorigenicity in cancer cells while shielding them from apoptosis. Nonetheless, other investigations have mentioned its conflicting effects on cancer prevention. Herein, we provide an updated understanding of the critical mechanisms behind the anticancer immunity mediated by Treg cells plasticity, the role of IL-35, and tactics to strengthen the immune response against malignancies, outlining major clinical trials that used Treg cells/IL-35 therapies in the three main cancer types (lung, breast, and colorectal cancers).

关键词： Ixeridium gramineum (Fisch.) Tzvel.   JAK/STAT pathway   TNF pathway   Taraxasterol   fulminant hepatitis   inflammatory response  

摘要： ETHNOPHARMACOLOGICAL RELEVANCE:Taraxasterol (TAR), a compound highly abundant and easily obtainable from Tibetan medicine Ixeridium gramineum (Fisch.) Tzvel., exhibits a variety of biological effects, including hepatoprotective, anti-inflammatory, and antioxidant activities. AIM OF THE STUDY:To investigated the protective role and underlying mechanisms of TAR in fulminant hepatitis (FH) through the regulation of oxidative stress, inflammatory responses, and apoptosis by modulating the JAK/STAT and TNF signalling pathways. MATERIAL AND METHODS:The study used Kunming mice to establish a D-GalN/LPS-induced FH model, which was divided into the following groups: Control group, D-GalN/LPS group, D-GalN/LPS + Silymarin group, D-GalN/LPS + TAR 2.5 group, D-GalN/LPS + TAR 5 group, D-GalN/LPS + TAR 10 group, and TAR 10 group. H&E staining and biochemical analyses were employed to evaluate liver pathological changes. Oxidative stress factors and inflammatory response were assessed via ELISA. RNA sequencing analysis was used to detect changes in inflammatory factor genes and apoptosis genes with TAR intervention in liver tissues. The distribution of the proteins p-STAT3 and p-JNK in liver tissues was ascertained using immunohistochemical staining. In vitro experiments were conducted on RAW264.7 cells exposed to LPS and TAR. Apoptosis was evaluated via flow cytometry and Hoechst 33258 staining. Immunofluorescence staining was employed to determine the protein expression levels of p-STAT3 and p-JNK in RAW264.7 cells. Gene and protein expression in the JAK/STAT and TNF signalling pathways, as well as apoptosis, were analyzed using qRT-PCR and Western blotting. RESULTS:TAR effectively reduced hepatocyte necrosis, diminished inflammatory factor release, inhibited oxidative stress, significantly decreased the apoptosis of RAW264.7 cells, inhibited the protein expressions of p-JAK2, p-STAT3, p-MEK4, p-JNK, Caspase-3, Caspase-8, and Bax, and increased the protein expressions of SOCS3 a

关键词： 非酒精性脂肪性肝炎   祛脂愈肝汤   白介素17(IL-17)   脂质代谢  

摘要： 目的 观察祛脂愈肝汤对NASH细胞模型脂质代谢及IL-17表达的影响。方法 采用1mmol/L游离脂肪酸混合液(FFA)诱导建立NASH模型;空白组、模型组、沉默组(加入空白兔血清100μl)、祛脂愈肝汤低、中、高剂量组(分别加入5%、10%、15%含药血清100μl)、多烯磷脂酰胆碱组(加入10%含药血清100μl);油红染色观察NASH细胞脂滴染色情况;RT-qPCR和Western blot检测IL-17mRNA及蛋白质的表达量。结果 空白组,细胞结构清晰,细胞核呈蓝色,细胞内未见明显橘红色脂滴;模型组,细胞内出现很多大小不等的橘红色脂滴;沉默和药物干预组,细胞中脂滴含量较模型组显著减少。与模型组比较,沉默组、祛脂愈肝汤低、中、高剂量组、多烯磷脂酰胆碱组IL-17蛋白及mRNA的表达均显著降低(P<0.01),祛脂愈肝汤高剂量组降低更为显著。结论 祛脂愈肝汤可能通过抑制炎性因子IL-17的表达,减轻炎症反应,改善脂质代谢,从而发挥对NASH细胞的保护作用。

关键词： 猴痘   氨基酸突变   免疫逃逸   预测   致病性   结构损伤  

摘要： 目的 对猴痘病毒的高风险氨基酸突变进行预测，为疫苗和治疗药物的开发提供重要靶点。方法 以猴痘病毒的重要抗原蛋白A27L、A29L、B5R、H3L、L1R、M1R和C9L为研究对象，通过适应度、差异性和可及性3个指标对抗原蛋白的所有可能氨基酸突变的免疫逃逸能力进行预测和评分。选择每个抗原蛋白评分排名前10.00%的氨基酸突变位点进行了致病性和结构损伤的分析。结果 筛选出4 906个具有高免疫逃逸能力的氨基酸突变位点，其中大多数是潜在高风险氨基酸突变。高免疫逃逸能力位点集中分布在抗原表位上。筛选出的位点中，34.00%具有高致病性，这些位点的蛋白质结构损伤主要集中在破坏蛋白结构和蛋白相互作用上。最终筛选出745个具有高免疫逃逸能力、致病性和结构损伤的高危氨基酸突变位点。结论 预测出745个猴痘病毒抗原蛋白的高免疫逃逸能力、致病性和蛋白质结构损伤的氨基酸突变，为猴痘病毒疫苗和药物的开发提供了关键靶点，也对防控工作的开展具有指导意义。

关键词： Autoimmunity   Epigenetics   Immunology   Lupus   T cells  

摘要： In systemic lupus erythematosus (lupus), environmental effects acting within a permissive genetic background lead to autoimmune dysregulation. Dysfunction of CD4+ T cells contributes to pathology by providing help to autoreactive B and T cells, and CD4+ T cell dysfunction coincides with altered DNA methylation and histone modifications of select gene loci. However, chromatin accessibility states of distinct T cell subsets and mechanisms driving heterogeneous chromatin states across patients remain poorly understood. We defined the transcriptome and epigenome of multiple CD4+ T cell populations from lupus patients and healthy individuals. Most lupus patients, regardless of disease activity, had enhanced chromatin accessibility bearing hallmarks of inflammatory cytokine signals. Single cell approaches revealed that chromatin changes extended to naive CD4+ T cells; uniformly affecting naive subpopulations. Transcriptional data and cellular and protein analyses suggested that the TNF family members, TNFɑ, LIGHT, and TWEAK, were linked to observed molecular changes and the altered lupus chromatin state. However, we identified a patient subgroup prescribed angiotensin receptor blockers (ARBs) which lacked TNF-linked lupus chromatin accessibility features. These data raise questions about the role of lupus-associated chromatin changes in naive CD4+ T cell activation and differentiation and implicate ARBs in the regulation of disease-driven epigenetic states.

关键词： cGAS-STING   immune activation   MHC-I   PD-L1 blockade   small-cell lung cancer  

摘要： Lurbinectedin is an approved second-line treatment for small-cell lung cancer (SCLC). SCLC clinical trials combining lurbinectedin with PD-L1 blockade are currently ongoing. However, the immunomodulatory effects of lurbinectedin remain largely unknown. In this study, we demonstrate that lurbinectedin treatment activates the STING pathway, which increases interferon (IFN) signaling, pro-inflammatory chemokines, and major histocompatibility complex class I (MHC-I) in SCLC models. Lurbinectedin treatment augments the anti-tumor immune response of PD-L1 blockade with significant tumor regression in first-line and maintenance settings in SCLC mouse models. In vivo, lurbinectedin treatment increases CD8⁺ T cells and M1 macrophages and decreases immunosuppressive M2 macrophages. STING and CD8 depletion reverses the anti-tumor response. Interestingly, our study shows that lurbinectedin treatment upregulates MHC-I/II genes and CD8 in SCLC clinical samples. We provide mechanistic insights into the effect of lurbinectedin on STING-mediated multimodal immune activation and demonstrate that lurbinectedin treatment represents a promising therapeutic strategy to potentiate the efficacy of immunotherapy in SCLC. © 2024 The Author(s)