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关键词： IL-8   metastatic dormancy   nuclear translocation   stemness   TRAF4  

摘要： Tumor necrosis factor receptor-associated factor 4 (TRAF4), an E3 ubiquitin ligase, is frequently overexpressed in tumors. Although its cytoplasmic role in tumor progression is well-documented, the precise mechanisms underlying its nuclear localization and functional contributions in tumor cells remain elusive. This study demonstrated a positive correlation between the expression of nuclear TRAF4 and both tumor grades and stemness signatures in human cancer tissues. Notably, reduced nuclear TRAF4 led to decreased stemness properties and metastatic dormancy of tumor cells. Conversely, restoring nuclear TRAF4 in TRAF4-knockout (TRAF4-KO) cells augmented these cellular capabilities. Within the nucleus, the TRAF domain of TRAF4 interacted with c-Jun, thereby stimulating its transcriptional activity. This interaction subsequently led to an enhancement of the promoter activity of interleukin-8 (IL-8), which is identified as a mediator of nuclear TRAF4-induced tumor dormancy. Additionally, activation of AKT signaling by nerve growth factor facilitated TRAF4 phosphorylation at Ser242, enhancing its interaction with 14-3-3 theta and promoting its nuclear translocation. Importantly, pharmacological modulation of TRAF4 nuclear translocation is found to suppress tumor tumorigenicity and metastasis in tumor models. This study highlights the critical role of nuclear TRAF4 in regulating tumor stemness and dormancy, positioning it as a potential therapeutic target for metastatic and refractory cancers.

关键词： 冬虫夏草(CS)   慢性肾脏病(CKD)   成纤维细胞   IL-6反式信号通路   肾纤维化  

摘要： 目的 探究冬虫夏草通过抑制IL-6反式信号通路介导的成纤维细胞活化，进而治疗肾纤维化的分子机制。方法 建立小鼠单侧缺血再灌注（unilateral ischemia/reperfusion,UIR）肾纤维化模型，同时给药虫草菌粉、可溶性糖蛋白130Fc(soluble glycoprotein 130 Fc,sgp130Fc)或Hyper-IL-6。Masson染色评估肾小管间质纤维化程度；PAS染色评估肾损伤情况；Western blot检测纤维化标志物[α-平滑肌肌动蛋白（alpha-smooth muscle actin,α-SMA），纤连蛋白（fibronectin,FN）]和IL-6反式信号通路相关蛋白[磷酸化信号转导及转录激活因子3(phosphorylatedsignaltransducerandactivatoroftranscription3,p-STAT3)，可溶性白介素6受体（soluble interleukin-6 receptor,sIL-6R）]的表达水平；免疫组化、免疫荧光和qPCR等手段检测纤维化蛋白表达量以及定位情况。体外细胞实验进一步探究虫草提取物虫草素对成纤维细胞中IL-6反式信号的影响。结果 体内实验结果显示，在慢性期给药虫草菌粉可显著减轻患肾的炎症和纤维化，降低血清肌酐水平和胶原沉积。Western blot结果显示，治疗组α-SMA、FN的表达水平降低，IL-6信号通路蛋白p-STAT3、sIL-6R蛋白表达水平降低，单核细胞趋化蛋白-1(monocyte chemoattractant protein-1,MCP-1)、CXC趋化因子配体12(C-X-C motif chemokine ligand12,CXCL12)等的mRNA表达水平均下降。此外，Hyper-IL-6可部分抵消虫草菌粉的治疗效果。体外实验结果显示，虫草素可抑制NRK-52E分泌IL-6，而IL-6-sIL-6R复合物处理可诱导成纤维细胞NRK-49F活化，表现为α-SMA、FN和p-STAT3表达量显著升高。虫草素和sgp130Fc处理显著抑制IL-6反式信号通路引起的成纤维细胞的活化。结论 冬虫夏草可显著抑制肾小管上皮细胞分泌IL-6和成纤维细胞中IL-6反式信号通路的激活，从而改善肾间质纤维化。

关键词： articular cartilage breakdown   chondrogenic 3D model   immune cells   matrix degeneration   mesenchymal stromal cell   microfluidic system   pro-inflammatory cytokine   TNF-alpha  

摘要： Osteoarthritis (OA) is a leading cause of disability, often resulting from overuse or injury, but inactivity can also contribute to cartilage degeneration. Conventional in vivo models struggle to isolate and study the specific effects of mechanical stress on cartilage health. To address this limitation, a microphysiological system (MPS) is established to examine how varying levels of shear stress impact cartilage homeostasis. The system allows for the cultivation of 3D chondrogenic microconstructs (CMCs) derived from human mesenchymal stromal cells, simulating both physiological and pathophysiological shear stress. Inflammation is induced via TNF-alpha or activated peripheral blood mononuclear cells to model cartilage damage, enabling the evaluation of therapeutic interventions. The study demonstrates the development of an arthritis-like phenotype and successful restoration of cartilage conditions through a JAK inhibitor under physiological shear stress. Physiological shear stress is identified as a critical factor in maintaining cartilage integrity. This MPS offers a standardized method to study shear stress, replicate cytokine-induced cartilage damage, and simulate key features of arthritis, providing a valuable alternative to animal models.

关键词： 18β-glycyrrhetinic acid   Apoptosis   Bisphenol A   Hepatotoxicity   Inflammation   Nephrotoxicity  

摘要： Bisphenol A (BPA) has been commonly used in various consumer products, including water bottles, food containers, and canned food linings. However, there are concerns about its potential toxicity to human health, particularly its impact on the liver and kidneys. The objective of this research was to investigate the potential ameliorative effects of 18β-glycyrrhetinic acid (GA) against BPA-induced hepatotoxicity and nephrotoxicity in rats. The animals were supplemented with BPA (250 mg/kg b.w.) alone or with GA (50 and 100 mg/kg b.w.) for 14 days. GA treatment alleviated the BPA-induced hepato-renal tissue injuries through reducing the serum ALT, AST and ALP levels, and urea and creatinine levels. GA co-treatment also increased activities of SOD, CAT and GPx enzymes and levels of GSH, and suppressed MDA levels in BPA induced tissues. BPA also induced inflammation by increasing the levels of TNF-α, NF-κB, JAK1, STAT1, P38 MAPK and JNK in liver and kidney tissues and GA treatment ameliorated these effects. BPA triggered apoptosis by increasing caspase-3, Bax, and cytochrome c at protein levels and also by decreasing the antiapoptotic Bcl-2 level. However, treatment with GA (50 and 100 mg/kg) decreased apoptosis. Overall, our results have revealed the potential ameliorative mechanisms of GA, as a possible agent for BPA-induced hepatotoxicity and nephrotoxicity.

关键词： Hemorrhagic shock   Mesenchymal stromal cells   Multiple organ failure   Priming IL-1β   Vascular permeability  

摘要： BACKGROUND:Hemorrhagic shock (HS) corresponds to absolute hypovolemia creating an imbalance between oxygen supply and consumption. This causes an impaired hemostasis, a systemic inflammatory response, and microvascular permeability which can lead to multiple organ failure (MOF). There is no specific treatment for the endothelial dysfunction that plays a major role in the evolution towards MOF. Mesenchymal stromal cells (MSC) have been used in clinical trials for their immunomodulation and tissue repair capabilities for many years. Moreover, we previously showed that IL-1β-primed-MSC (MSCp) attenuated HS-induced organ injuries. The objective of the study was to determine whether MSCp could prevent the onset of MOF after HS by preventing endothelial dysfunction. METHODS:We established a rat model of HS, inducing 90 min of HS at a fixed mean arterial pressure of 35 mmHg, followed by resuscitation and transfusion. MSCp treatment was administered intravenously at the onset of resuscitation. After 6 h, we assessed plasma levels of endothelial markers, vascular permeability using Evans Blue (EB) dye, and renal and hepatic water content by measuring the wet-to-dry weight difference. Additionally, we investigated the ability of MSCp to inhibit leukocyte adhesion to activated endothelium in vitro. RESULTS:Our results indicate that early administration of MSCp significantly reduced the percentage of water content and EB dye in the liver but not in the kidney. These results were associated with a trend toward decreased plasma levels of Syndecan-1, ICAM-1, vWF, and VCAM-1. In vitro, MSCp reduced leukocyte-endothelial cell adhesion. Together, our results suggest that MSCp help to prevent endothelial dysfunction and vascular leakage, which, in turn, could protect the liver from injury.

关键词： 针刺   免疫细胞   COPD   研究进展   综述  

摘要： 慢性阻塞性肺疾病（Chronic obstructive pulmonary disease,COPD）是临床常见病，以气流受限导致呼吸困难为特征，细胞免疫在COPD的发生发展中扮演着重要角色。针刺能有效改善COPD患者临床症状及生活质量，其治疗作用可能通过免疫细胞介导。介导途径可能集中在调控免疫细胞增殖、分化，激活抗原提呈效能、免疫炎性反应及相关途径通路，促进抗炎因子表达，进而减轻肺组织免疫炎症浸润及全身免疫炎症反应发挥治疗作用。本文梳理总结针刺调控细胞免疫治疗COPD作用途径与机制，为针刺治疗COPD的免疫机制深入研究提供一定思路与参考。

关键词： CP: Immunology   IL-10   ILC2s   Tregs   cell therapy   graft-versus-host disease   graft-versus-leukemic effect   hematopoietic stem cell transplant   immune tolerance   innate lymphoid cells   transplantation  

摘要： Interleukin-10 (IL-10)-producing group 2 innate lymphoid cells (ILC2) regulate inflammatory immune responses, yet their therapeutic potential remains largely unexplored. Here, we demonstrate that cell therapy with human ILC2 inhibits pathogenic T cell responses in humanized mouse models of graft-versus-host disease (GVHD), resulting in reduced GVHD severity and improved overall survival without limiting the graft-versus-leukemia effect. ILC2 conferred superior protection from GVHD than IL-10 ILC2s, and blocking IL-10 and IL-4 abrogated ILC2 protective effects, indicating that these cytokines are important for the protective effects of ILC2. Notably, ILC2 provided comparable protection from GVHD to regulatory T cells without impairing T cell engraftment, instead decreasing intestinal T cell infiltration and suppressing CD4 Th1 and CD8 Tc1 cells. CITE-seq of expanded ILC2s revealed CD49d and CD86 are markers that allow for enrichment of ILC2 from conventional ILC2s and tracking of ILC2 in patient studies. Altogether, these findings demonstrate the potential of ILC2 in cell therapies for GVHD and other immune-mediated diseases.

关键词： Association study   HLA   Psoriatic arthritis  

摘要： INTRODUCTION/OBJECTIVES:Psoriatic arthritis (PsA) is a chronic inflammatory rheumatism belonging to the spondyloarthritis family. It is a multifactorial disease whose genetic determinism is still poorly understood. It is favored by environmental factors in genetically predisposed individuals. This study aims to investigate the association of HLA-A, HLA-B, and HLA-C alleles with PsA and its various manifestations in patients from Southern Tunisia. PATIENTS AND METHODS:A case-control association study was conducted involving 48 PsA patients and 123 controls. HLA-A and HLA-B typing was performed using microlymphocytotoxicity complement-dependent assays, and HLA-C typing was done using polymerase chain reaction-sequence specific primer. RESULTS:Positive associations were confirmed for HLA-B27 and -C*06 alleles with PsA in our Southern Tunisian population with a more pronounced association in cases of -C*06 homozygosity. The HLA-B*27-C*02 and HLA-B*50-C*06 haplotypes were significantly more frequent in PsA patients, whereas the HLA-B*35-C*04 haplotype was negatively associated with PsA. Specific HLA alleles were linked to disease manifestations: -C04 with female sex, -B27 with familial spondyloarthritis, and -B17 with sporadic PsA. Cervical spine involvement was associated with -C02, and hip involvement with -B35 and -C02. Uveitis was linked to -C02 and -B27. A negative association was observed between a BASFI score > 4 and the presence of -B45 and -C07. CONCLUSION:The HLA class I system contributes to PsA susceptibility in the Southern Tunisian population. Key Points • This is the first study exploring the association between HLA class I alleles and psoriatic arthritis in Southern Tunisia. • HLA-B27 and -C06 alleles are strongly associated with PsA, with a more pronounced effect in -C06 homozygosity. • Specific HLA alleles are linked to clinical manifestations: -B27 is associated with familial PsA, -B17 with sporadic PsA, and -B35 with hip involvement. • These findings

关键词： Alzheimer’s disease   Datura stramonium L. leaves   Microglia   Neuroinflammation   Withanolide  

摘要： Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of beta-amyloid (Aβ) peptides. Microglia-mediated neuroinflammation is one of the primary contributors to the pathogenesis of AD. Withanolides, the main constituents in the leaves of Datura stramonium L., exhibit anti-neuroinflammatory activity. It is unknown if total withanolide from Datura stramonium L. leaves (TWD) reduces nerve inflammation and potentially mitigates the pathogenic elements of AD. This study examined the potential effects of TWD on neuroinflammation in triple transgenic AD (3 × Tg-AD) mice and LPS-induced BV-2, as well as associated signaling pathways. HPLC-Q-TOF-MS/MS was used in this study to examine the main chemical components of the TWD extract. 3 × Tg-AD as in vivo AD models and LPS induce BV-2 cells in vitro AD models. The molecular process was investigated by ELISA, WB, IHC, and IF. In 3 × Tg-AD mice, TWD dramatically ameliorates cognitive impairment. Treatment with TWD can counteract the increased activation of microglia and Aβ deposits observed in 3 × Tg-AD mice. Further research indicates that TWD can enhance TOM 1 and mitigate inflammatory responses by reducing the levels of IL-1β, TNF-α, IL-6, IL1R1, and IL-18. Additionally, TWD may inhibit neuroinflammation through the pathways of IL1R1/MyD88/NF-κB and NLRP3/IL-1β/IL1R1. In summary, this study reveals for the first time that TWD effectively improves cognitive deficits in 3 × Tg-AD mice by modulating the IL1R1/MyD88/NF-κB and NLRP3/IL-1β/IL1R1 pathways. It also alleviates excessive activation of microglia and suppresses Aβ accumulation. Therefore, TWD has the potential as a therapeutic agent for AD.

关键词： CP: Immunology   IFN-γ   intestinal epithelial cell   intestinal organoids   NKT cell  

摘要： Intestinal homeostasis is maintained through the combined functions of epithelial and immune cells that collaborate to preserve the integrity of the intestinal barrier. However, the mechanisms by which immune cell populations regulate intestinal epithelial cell (IEC) homeostasis remain unclear. Here, we use a multi-omics approach to study the immune-epithelial crosstalk and identify CD1d-restricted natural killer T (NKT) cells as key regulators of IEC biology. We find that NKT cells are abundant in the proximal small intestine and show hallmarks of activation at steady state. Subsequently, NKT cells regulate the survival and the transcriptional and cellular composition landscapes of IECs in intestinal organoids, through interferon-γ (IFN-γ) and interleukin-4 secretion. In vivo, lack of NKT cells results in an increase in IEC turnover, while NKT cell activation leads to IFN-γ-dependent epithelial apoptosis. Our findings propose NKT cells as potent producers of cytokines that contribute to the regulation of IEC homeostasis. © 2024 The Author(s)