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关键词： 骨细胞   骨衰老   免疫微环境   免疫细胞   细胞因子   免疫衰老   免疫治疗   工程化组织构建  

摘要： 背景:骨骼微环境中富含各种免疫细胞和细胞因子,它们与骨细胞紧密联系形成了相互影响的网络,因此,骨骼的衰老不单单是由骨细胞衰老导致,免疫系统衰老同样会加速骨衰老过程。目的:综述骨髓间充质干细胞、成骨细胞和破骨细胞以及骨微环境中免疫细胞的年龄相关变化,强调免疫微环境在骨衰老中的关键作用以及免疫治疗在骨衰老治疗中的潜力。方法:检索PubMed数据库、中国知网中关于骨骼细胞衰老与免疫细胞衰老相互作用的文献,英文检索词为“Osteocytes,Bone aging,Immune microenvironment,Immune cells,Cytokines,Immunosenescence,Immunotherapy”,中文检索词为“骨细胞,骨衰老,免疫微环境,免疫细胞,细胞因子,免疫衰老,免疫治疗”。根据纳入与排除标准,最终纳入128篇文献进行综述。结果与结论:骨衰老是老年人普遍存在的一种病理状态,以多种生物学过程相互作用为特征,其中免疫因素起着关键作用。免疫微环境中的细胞、分子和信号通路共同构成了一个复杂的网络,这个网络的失衡会加速骨衰老进程。抗细胞衰老与免疫治疗相结合可能为骨衰老疾病的治疗带来新的方法,包括清除衰老的细胞、衰老相关分泌表型靶向药物、炎症细胞因子靶向治疗、免疫细胞调节疗法、干细胞治疗及分子治疗等。为了更有效且合理地清除衰老细胞,需要更深入地了解衰老细胞的机制,这将有助于更准确地识别衰老细胞。免疫治疗在骨衰老治疗中展现出强大的潜力和前途,但存在一些潜在的风险。相信随着科技的进步,人们可以更准确地了解人体的遗传信息和免疫状态,制定更个性化的免疫治疗方案。

关键词： GTS   CUMS   抑郁症   细胞因子  

摘要： 目的:本研究通过建立慢性不可预见性温和应激(chronic unpredicted mild stress, CUMS)大鼠抑郁模型,观察人参总皂苷(ginseng total saponins, GTS)对前额叶皮质(prefrontal cortex, PFC)细胞因子表达水平的调控作用,探讨其发挥抗抑郁作用的机制。方法:48只雄性无特定病原体(specific pathogen free, SPF)动物级(sprague-dawley, SD)大鼠适应性喂养1 w后,按照数字随机法分为6组(n=8):正常对照组,模型组,GTS低、中、高剂量组(13 mg/kg, 26 mg/kg, 52 mg/kg)和阳性药物对照组(盐酸帕罗西汀,2.06 mg/kg),每组分两笼饲养。除正常对照组外,给予夹尾、禁食、禁水、鼠笼倾斜等应激刺激,同时,给药组灌胃,正常对照组与模型组同体积生理盐水灌胃,每日1次,连续28 d。Lab Ex多因子方法检测细胞因子的表达情况。结果:与正常对照组相比,模型组大鼠白介素-1ɑ(interleukin-1ɑ,IL-1ɑ)、白介素-2(interleukin-6,IL-2)等炎性细胞因子以及巨噬细胞趋化因子-1(monocyte chemoattractant protein-1,MCP-1)、重组趋化因子(chemokine c-motif ligand 5,CCL5)等趋化因子的表达水平升高(P<0.05),同时,白介素-4(interleukin-4,IL-4)、白介素-10(interleukin-10,IL-10)等抗炎细胞因子和巨噬细胞集落刺激因子(macrophage colony-stimulating factor, M-CSF),血管内皮生长因子(vascular endothelial growth factor, VEGF)等生长因子的表达水平降低(P<0.05);与模型组相比较,GTS治疗组及阳性药物对照组大鼠以上指标的表达水平出现逆转(P<0.05)。结论:GTS通过降低CUMS抑郁模型大鼠中枢神经系统PFC区趋化因子、炎症因子的表达水平发挥抗抑郁作用。

关键词： Ferroptosis   IL-37   Lipid deposition   Macrophage polarization   Non-alcoholic fatty liver disease  

摘要： Non-alcoholic fatty liver disease (NAFLD), which acts as a predominant contributor to chronic liver disease, remains a pervasive global epidemic. Interleukin-37（IL-37） is documented to have protective effects against various liver diseases. This work focuses on investigating the role and relevant action mechanism of IL-37 in NAFLD. Immunofluorescence assay and Western blot（WB）were used to estimate M1 macrophage markers. For immunofluorescence analysis, images from five randomly selected fields per sample were captured using a confocal microscope (Leica). Fluorescence intensity was quantified by ImageJ software (version 1.53) with background subtraction, and data were normalized to DAPI-positive *** lipid Reactive Oxygen Species（ROS）and cell lipid droplet deposition were assessed via BODIPY 581/591 C11 staining and Oil Red O staining. Fe^{2 +}, triglycerides and cholesterol levels were assessed utilizing appropriate assay kits. WB was adopted for the estimation of proteins associated with ferroptosis and apoptosis. Protein band intensities were quantified using Image Lab software (Bio-Rad) and normalized to β-actin expression. Three technical replicates were analyzed for each biological replicate (n = 3). Our data revealed that IL-37 alleviated PA-stimulated（Palmitic acid-stimulaed）M1 macrophage polarization. It was also identified that IL-37 suppressed lipid accumulation and apoptosis in RAW264.7 cells through inhibiting the polarization of M1 macrophages. Collectively, IL-37 could improve PA-stimulated lipid accumulation and apoptosis in liver cells through suppressing M1 macrophage polarization, which might be mediated by ferroptosis. © 2025

关键词： 天然产物   细胞焦亡   炎性小体   炎症   脊髓损伤   继发性损伤   神经功能   经典途径  

摘要： 背景:神经炎症是脊髓损伤后病情加重的主要原因。近年来,细胞焦亡因显著的促炎特征而受到广泛关注。部分天然产物通过调控脊髓损伤后的细胞焦亡水平,能显著抑制炎症反应,改善受损的神经功能,为脊髓损伤提供了新的治疗思路。目的:总结天然产物调控细胞焦亡治疗脊髓损伤的作用机制,以期为今后脊髓损伤的治疗研究提供借鉴和参考。方法:以“spinal cord injury,pyroptosis,inflammasome,natural products,natural compounds,Traditional Chinese Medicine”“脊髓损伤,细胞焦亡,炎性小体,天然产物,天然化合物,中药”为检索词,在PubMed、Web of Science、万方、中国知网检索自建库以来至2024年9月的有关文献,按照纳入和排除标准,最终得到75篇相关文献。结果与结论:①细胞焦亡是脊髓损伤的重要促炎途径,控制细胞焦亡是改善受损神经功能的有效方式;②部分天然产物可以通过NLRP3/Caspase-1经典焦亡途径、核因子κB相关通路、Nrf2/HO-1等其他上游通路和自噬来调控细胞焦亡,从而影响脊髓损伤后的组织炎症水平,加快神经功能恢复;③这些天然产物的抗细胞焦亡作用多依赖于NLRP3经典焦亡途径,尚缺少关于其他焦亡途径的研究;④该领域仍存在很多问题,如这些天然产物目前没有相应的临床研究证据支持;⑤天然产物在调控细胞焦亡中具有巨大的潜能,有望成为治疗脊髓损伤的有力武器。

关键词： Lung cancer   neutrophils   IL-8   PD-L1   immune escape   tumor microenvironment  

摘要： Background Lung cancer remains a major global health threat due to its complex microenvironment, particularly the role of neutrophils, which are crucial for tumor development and immune evasion mechanisms. This study aimed to delve into the impact of lung cancer cell-conditioned media on neutrophil functions and their potential implications for lung cancer *** Employing in vitro experimental models, this study has analyzed the effects of lung cancer cell-conditioned media on neutrophil IL-8 and IFN-gamma secretion, apoptosis, PD-L1 expression, and T-cell proliferation by using techniques, such as ELISA, flow cytometry, immunofluorescence, and CFSE proliferation assay. The roles of IL-8/PD-L1 in regulating neutrophil functions were further explored using inhibitors for IL-8 and *** Lung cancer cell lines were found to secrete higher levels of IL-8 compared to normal lung epithelial cells. The conditioned media from lung cancer cells significantly reduced apoptosis in neutrophils, increased PD-L1 expression, and suppressed T-cell proliferation and IFN-gamma secretion. These effects were partially reversed in the presence of IL-8 inhibitors in Tumor Tissue Culture Supernatants (TTCS), while being further enhanced by IL-8. Both apoptosis and PD-L1 expression in neutrophils demonstrated dose-dependency to TTCS. Additionally, CFSE proliferation assay results further confirmed the inhibitory effect of lung cancer cell-conditioned media on T-cell *** This study has revealed lung cancer cell-conditioned media to modulate neutrophil functions through regulating factors, such as IL-8, thereby affecting immune regulation and tumor progression in the lung cancer microenvironment.

关键词： Anti-inflammatory alkaloids   SARS-CoV-2   respiratory infections   mechanistic action   drug   Human immunodeficiency virus (HIV)  

摘要： Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the deadliest viruses among respiratory viruses which resulted in COVID-19 pandemic. The virus gets transmitted by the nasal route and moves down to the trachea, bronchi, and then to the lungs. Once replicated inside the alveolar cells, the SARS-CoV-2 makes the membrane of the alveolar sac porous, which causes the leaking of plasma from surrounding blood vessels into the alveolar sac leading to its buildup. This process results in the production of pro-inflammatory cytokines like interleukin-1 beta (IL-1 beta) and Tumor necrosis factor-alpha (TNF-alpha) by the helper T-cells at the site of the infection, causing difficulty in breathing. Plant-based alkaloids can be promising to treat viral infections. Plants have contributed to drug development against viruses like Herpes simplex virus (HSV), Human immunodeficiency virus (HIV), Hepatitis B virus (HBV), and viruses that cause respiratory diseases in humans. Plant alkaloids, either in the form of extract, infusion, or powder, have shown potential in treating viral diseases mainly by targeting the replication of viruses. Alkaloids like Tetrandrine, Oxymatrine, and Berberine have been shown to have a positive role in mediating pro-inflammatory cytokines like IL-1. These alkaloids thus inactivate the nuclear factor kappa-B (NF-kB) pathway, inhibiting the expression of its targeted genes, IL-1 beta and TNF-alpha. This inactivation of NF-kB results in reduced levels of IL-1 and TNF-alpha, and consequently reduced inflammation, decreasing the stress on the immune cells and increasing the ability of the patient to fight the infection. Despite vaccine development for SARS-CoV-2, the virus is continuously evolving into new varieties, posing a threat to humans and it is necessary to develop effective drug discovery programs. Natural products can pave the way in this regard. This review can contribute towards safer drug development against SARS-CoV-2, combati

关键词： Endometrial cancer   Interleukin-6   KIAA1429   Ferroptosis  

摘要： Endometrial cancer (EC) exhibits significant resistance to ferroptosis. Interleukin (IL)-6 is a pleiotropic cytokine that is a regulator of the expression of various oncogenes and tumour suppressor genes. Notably, N6methyladenosine (m6A) modification has been demonstrated to play a significant role in tumour occurrence and development. However, IL-6 regulatory role in ferroptosis during carcinogenesis and whether it affects m6A modification in EC remain unclear. The present study aimed to investigate the effect of IL-6 on m6A modification in EC. The degree of ferroptosis of EC in vitro and in vivo was evaluated using a cell proliferation assay, western blotting, total reactive oxygen species (ROS) detection, a lipid peroxidation assay, and a subcutaneous xenograft tumour model. The regulation of downstream molecules by KIAA1429 was confirmed using dot blot, RNA and methylated RNA immunoprecipitation (RIP), a RNA stability assay, and fluorescence in situ hybridisation (FISH). IL-6 upregulated overall m6A levels in EC cells, with the KIAA1429 expression upregulation being the most significant. Functionally, IL-6 inhibited EC cell ferroptosis and promoted proliferation. The downregulation of KIAA1429 triggered ferroptosis, subsequently suppressing the proliferation of EC cells in vitro and tumour growth in vivo. Mechanistically, IL-6 activated KIAA1429 expression through the JAK1/STAT3 pathway. KIAA1429 regulated DDIT3 expression and promoted its degradation through m6A modification. IL-6 is crucial in EC cell ferroptosis resistance. Overall, the IL-6/KIAA1429/DDIT3 axis is a novel pathway that promotes EC progression and provides novel directions for targeted EC therapy.

关键词： Tripterygium hypoglaucum   Celastraceae   Flavanol-hydroxytyrosol hybrids and   diterpenoids   Anti-neuroinflammatory activity   NF   kappa B and IL-1 beta  

摘要： The study aimed to identify the anti-neuroinflammatory compounds present in the rhizomes of Tripterygium hypoglaucum (Levl.) Hutch while simultaneously elucidating their mechanisms of action against neuroinflammation in vitro. Seven previously undescribed compounds, including a pair of flavanol-hydroxytyrosol hybrids (1-2) and three diterpenoids (5-7), were isolated from T. hypoglaucum rhizomes through sequential chromatographic methods under the guidance of LC-MS analyses. Their structures were determined by HRESIMS, NMR spectroscopic analysis combined with quantum-chemical ECD calculations. The anti-neuroinflammation activities of the isolates on LPS-induced BV-2 cells were evaluated that compounds 1-7 notably suppressed NO production to demonstrate anti-neuroinflammatory effects. Compounds 1-4 attenuated the expression of phosphorylated NF-kappa B, thereby mitigating NF-kappa B activation, whereas compounds 5-7 inhibited IL-1 beta expression to exhibit anti-neuroinflammatory activity. Compound 5 further inhibited the generation of inflammatory factors IL-6, IL-10, and COX-2. The results of molecular docking complemented the in vitro findings related to antineuroinflammation, demonstrating that all compounds exhibited strong binding affinity to the associated targets, characterized by high energy values, as well as favorable composite Log P values, NHBD, and NHBR. Collectively, these structurally diverse compounds expand the repertoire of candidate molecules for the development of drugs aimed at treating neurodegenerative diseases.

关键词： Neuro-Beh & ccedil   et disease   IL-35   Cerebrospinal fluid   IL-1 alpha   IL-18   IL-33   36   Tregs  

摘要： Background: IL-35 is a recently discovered immunoregulatory cytokine that inhibits inflammatory cytokines by suppressing their lineage-specific transcription factors. The objective of this study was to investigate the expression of IL-35 in the cerebrospinal fluid (CSF) of patients with Neuro-Beh & ccedil;et Disease (NBD). An immunocomparative analysis was performed between parenchymal NBD (pNBD) and non-parenchymal NBD (npNBD). Methods: We are investigating CSF IL-35 levels in 45 patients with (NBD), comprising 25 patients with pNBD and 20 with npNBD, compared to 27 patients with multiple sclerosis (MS) and 20 patients with non-inflammatory neurological diseases (NIND). We assessed the inflammatory cytokines (IL-1 alpha, IL-18, IL-33, IL-36), Foxp3 and CD4+ CD25+ Foxp3+ regulatory Treg T cells (Tregs). The following methodologies were employed: flow cytometry, ELISA, and real-time polymerase chain reaction (RT-PCR). For RT-PCR analysis, we calculated relative gene expression in target genes using the comparative CT method with the equation 2-Delta Delta Ct. We employed a receiver operating characteristic (ROC) curve to investigate the predictive value of IL-35 levels. Results: Protein and relative mRNA expression of IL-35 were significantly decreased in NBD and MS patients compared to the NIND group. Significantly lower CSF IL-35 mRNA (p = 0.0001) and protein (p = 0.0004) were observed in patients with pNBD compared to npNBD. The study revealed that NBD patients exhibited low Treg counts, and a significant positive correlation was identified between Treg numbers and CSF IL-35 (r = 0.554, p = 0.0001). Negative associations were observed between Tregs and CRP (r =- 0.518;p = 0.0001) and ESR (r = -0.571;p = 0.0001) in NBD. Levels of the pro-inflammatory mediators were found to be elevated in contrast to a low Foxp3 level in NBD, which was more reduced in pNBD compared to npNBD. In vitro cultured memory T cells from pNBD patients stimulated with LPS showed high levels

关键词： IL-4 inducing peptides   ESM-2 model   Protein language model   SMOTE   ENN  

摘要： Despite progress in developing antiviral drugs and vaccines, infections continue to be a significant challenge. Interleukin-4 (IL-4) is crucial for regulating immune responses and mediating allergic reactions. This research aims to improve the predictive accuracy of IL-4-inducing peptides by tackling data imbalance and enhancing feature extraction. Specifically, we introduce a new approach that utilizes SMOTE and ENN for balancing the dataset and applies a 30-layer ESM-2 model for extracting deep features. The extracted features are subsequently processed through a Gated Recurrent Unit (GRU) model, which is optimized through hyperparameter tuning. Our method achieves notable improvements, with an AUC of 0.98 and an accuracy of 93.1 %, highlighting its potential to support future immunotherapy and vaccine development efforts. The PLM-IL4 web server is freely accessible at http://***/PLM-IL4, and the datasets used in this research are also available for download from the website.