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关键词： 挂线引流术   抗TNF-α单抗   免疫抑制剂   克罗恩病   肛瘘  

摘要： 对接受挂线引流术治疗的克罗恩病合并肛瘘患者术后分别应用抗TNF-α单抗、免疫抑制剂治疗,观察并分析两种不同治疗方案的疗效,促进临床治疗方案的改进与优化,加快患者康复进度。方法 选取2023年1月-2024年12月本院收治的56例克罗恩病合并肛瘘患者,通过随机数据表法予以分组。所有患者均接受挂线引流术和术后抗感染治疗。研究组在术后加入抗TNF-α单抗医治(英夫利西单抗静脉滴注),对照组则加入联合免疫抑制剂治疗(硫唑嘌呤片口服)。评估两组治疗效果。结果 研究组疗效优于对照组(P<0.05);研究组CD4+、CD4+/CD8+较对照组明显降低,CD8+较对照组明显升高(P<0.05);研究组IL-10较对照组明显升高,IL-12、TNF-α较对照组明显降低(P<0.05);研究组不良反应发生率远低于对照组(P<0.05)。结论 对于患有克罗恩病并伴有肛瘘的病人,在进行挂线引流手术后,采用英夫利西单抗进行联合治疗,其效果优于使用硫唑嘌呤片的联合疗法。这种治疗方式能够显著提升患者的免疫系统功能,缓解炎症状况,并减少不良反应的可能性。

关键词： 丹皮酚   酒精性肝病   肠道菌群   吲哚乙酸   AhR/IL-22/STAT3   肠道屏障  

摘要： 目的 探究丹皮酚是否通过调节肠道菌群色氨酸代谢，激活环芳香烃受体（aryl hydrocarbon receptor，AhR）/白细胞介素22（Interleukin-22，IL-22）/转录激活因子3（signal transducer and activator of transcription 3，STAT3）通路，发挥对酒精性肝病（alcoholic liver disease，ALD）的改善作用。方法 将C57BL/6 J小鼠分为对照组、模型组、丹皮酚高剂量（480 mg/kg）组、丹皮酚低剂量（120 mg/kg）组、丹皮酚（480 mg/kg）+抗生素组、抗生素组，每组10只。采用Lieber-DeCarli乙醇液体饲料喂养建立ALD小鼠模型，用药组在模型复制后第2天灌胃给药，持续10 d。测定小鼠肝功能[丙氨酸氨基转移酶（alanine aminotransferase，ALT）、天门冬氨酸氨基转移酶（aspartate aminotransferase，AST）]、血脂[甘油三酯（triglyceride，TG、总胆固醇（telecine，TC）、高密度脂肪酸（high density lipoprotein cholesterol，HDL-C）、低密度脂肪酸（low density lipoprotein，LDL）]及氧化应激指标[还原型谷胱甘肽（glutathione，GSH）、过氧化氢酶（catalase，CAT）、超氧化物歧化酶（superoxide dismutase，SOD）、丙二醛（malondialdehyde，MDA）]；采用苏木素-伊红染色法、油红O染色法观察各组小鼠肝脏、回肠组织病理形态变化；采用16S rDNA基因测序技术分析对照组、模型组和丹皮酚高剂量组小鼠肠道菌群差异；采用ELISA法检测小鼠血清、回肠组织中吲哚乙酸（3-indoleacetic acid、IAA）水平；采用Western blot、免疫组化法以及免疫荧光法检测小鼠回肠组织中AhR/IL-22/STAT3通路相关蛋白及回肠组织闭锁小带蛋白1（zonula occludens-1，ZO-1）、紧密连接蛋白-1（Claudin-1）表达水平。结果 与模型组比较，丹皮酚高剂量组小鼠体质量显著升高（P＜0.05），血脂（TG、TC、HDL-C）、肝功能（ALT、AST）及氧化应激（GSH、CAT、SOD）水平显著降低（P＜0.05），MDA水平显著升高（P＜0.05）；肠道菌群发生改变，厚壁菌门（Firmicutes）、放线菌门（Actinobacteriota）丰度升高，拟杆菌门(Bacteroidetes)和变形菌门（Proteobacteria）丰度降低；乳酸杆菌属（Lactobacillus）、梭菌属（Clostridium）等有益菌属丰度升高，克雷伯氏菌属（Klebsiella）、阿德勒克罗伊茨菌属（Adlercreutzia）等有害菌属丰度降低；小鼠血清及回肠组织中IAA水平显著升高（P＜0.05）；肝脏的脂肪堆积和回肠黏膜的损伤得到显著改善；小鼠回肠组织中AhR/IL-22/STAT3信号通路蛋白、胰岛再生源蛋白Ⅲγ和ZO-1、Claudin-1等蛋白表达水平显著升高（P＜0.05）；同时，抗生素的实验结果显示其减弱了丹皮酚的治疗效果。结论 丹皮酚对小鼠的酒精性肝病具有显著改善作用，其可能是通过调节ALD小鼠肠道菌群结构，增强肠道菌群相关色氨酸代谢，激活AhR/IL-22/STAT3通路，改善肠道屏障功能实现的。

关键词： 心力衰竭   血清脑钠肽   心肌酶谱  

摘要： 目的 分析血清脑钠肽（serum brain natriuretic peptide，BNP）、血清可溶性ST2（serum soluble ST2，sST2）、白介素-33（interleukin-33，IL-33）及心肌酶谱检测在心力衰竭（heart failure，HF）的应用价值。方法 纳入2021年1月—2024年12月淄博市博山区中医院收治的45例HF患者，设为观察组，另选择同期该院45例健康体检者设为对照组，比对两组血清BNP、sST2、IL-33及心肌酶谱检测结果。结果 观察组BNP、sST2、IL-33及心肌酶谱水平显著高于对照组（P<0.05）；BNP、sST2、IL-33、同工酶（creatine kinase isoenzymes，CK）、α-羟基丁酸脱氢酶（α-hydroxybutyrate dehydrogenase，α-HBDH）、肌酸激酶同工酶（creatine kinase isoenzyme，CK-MB）、乳酸脱氢酶（lactate dehydrogenase，LDH）、谷草转氨酶（aspartate transaminase，AST）指标均随心功能等级升高而升高，且差异具有统计学意义（P<0.05）。结论 血清BNP、sST2、IL-33及心肌酶谱检测可反映HF患者心功能受损状况。

关键词： Xiaoqinglong decoction   Yupingfeng powder   Combined allergic rhinitis and asthma   syndrome   Major histocompatibility complex II   Antigen presentation   Immune response   B lymphocytes  

摘要： Ethnopharmacological relevance: Xiaoqinglong Decoction combined with Yupingfeng Powder (XQLDwYPFP) is widely used to treat allergic rhinitis and bronchial asthma in Traditional Chinese Medicine, while its efficacy and mechanisms in combined allergic rhinitis and asthma syndrome (CARAS) remain underexplored. Aim of the study: To elucidate the mechanisms and pharmacodynamic basis of XQLDwYPFP in CARAS treatment. Materials and methods: A CARAS mouse model was established using ovalbumin (OVA). Airway allergic symptoms were assessed by recording nasal rubbing and sneezing frequencies. Serum OVA-sIgE levels were measured via ELISA. Histopathological changes were evaluated using HE, PAS, and C2R staining. Flow cytometry quantified Th cell subsets. Proteomics identified differential protein expression with GO and KEGG databases used for pathway enrichment analysis. Immunofluorescence assessed B lymphocyte activation, while Western blot and immunohistochemistry evaluated JAK1/JAK2-STAT1 pathway activation. Molecular docking validated the binding affinity of XQLDwYPFP components to JAK2 and STAT1. Results: XQLDwYPFP alleviated airway symptoms, reduced serum OVA-sIgE, and inhibited goblet cell hyperplasia and eosinophil infiltration in nasal and lung tissues. It decreased Th2 cell proportions and increased the Th1/Th2 ratio in lung and spleen tissues. Proteomics revealed that XQLDwYPFP suppresses CARAS by targeting the MHC II-mediated antigen presentation pathway. The formula reduced activated B lymphocytes and down-regulated JAK2, p-JAK2, STAT1, and p-STAT1 expression in nasal and lung tissues. XQLDwYPFP representative components exhibited strong binding affinity to JAK2 and STAT1. Conclusions: XQLDwYPFP alleviates type 2 inflammation in CARAS by regulating the JAK2-STAT1-MHC II pathway and inhibiting B lymphocyte-mediated antigen presentation. These findings provide novel pharmacological evidence supporting its clinical use for CARAS.

摘要： INTRODUCTION:Toll-like receptor (TLR) engagement on macrophages can improve responsiveness to infection. TNF is upregulated following TLR2 or TLR4 stimulation. We sought to determine whether and how the two bioactive forms of TNF, soluble (sTNF) and transmembrane (tmTNF), may be contributing to macrophage priming, which improved responsiveness to subsequent Staphylococcus aureus infection. METHODS:RNA sequencing and cytokine quantification assays identified differentially upregulated cytokines in response to TLR2 stimulation. Immortalized and primary bone marrow derived macrophages (BMDMs) coupled with receptor blocking and cytokine supplementation were used to investigate whether/how prior TLR-primed macrophages improved S. aureus clearance. RESULTS:TLR2 or TLR4 stimulated TNF-/- BMDMs failed to efficiently clear a subsequent S. aureus infection compared to TLR stimulated WT BMDMs. Depletion of sTNF from TLR-stimulated WT BMDMs retained their improved S. aureus clearance. Exogenous sTNF supplementation to TNF-/- BMDMs did not rescue improved S. aureus clearance. Cell density assays showed cell-to-cell contact was important for TLR-induced improvement of S. aureus clearance. Conversely, blocking TNFR2 reduced BMDM clearance of S. aureus, despite TLR2 stimulation. CONCLUSIONS:Our results demonstrated that TNF produced in response to TLR stimulated BMDMs was required for improved clearance of a subsequent S. aureus infection. We found that sTNF did not contribute to this priming, which suggested that tmTNF may be critical for BMDM priming which leads to improved S. aureus clearance.

关键词： Intervertebral disc degeneration   Macrophage   Microangiogenesis   Nucleus pulposus  

摘要： BackgroundMacrophage infiltration accompanied by pathological microangiogenesis in the nucleus pulposus (NP) plays a critical role in the progression of intervertebral disc degeneration (IDD). However, the involvement of M2 macrophages in mediating NP pathological angiogenesis and their underlying mechanisms remain ***, the expression of M2 macrophage (CD206) and microangiogenic (CD34) markers in human degenerated NP was observed by immunohistochemical staining, subsequently, a co-culture system of M2 macrophages and NP cells was established. IL-10 expression was silenced using siRNA to assess the pro-angiogenic effects of M2 macrophages in IDD via IL-10 and its downstream janus kinase (JAK) 2/ signal transducer and activator of transcription (STAT) 3 pathway. AG490, a specific JAK2/STAT3 inhibitor, was applied to determine whether IL-10 exerts its effects through this pathway and to evaluate its impact on angiogenesis and extracellular matrix (ECM) metabolism in NP ***206 and CD34 were co-expressed in degenerated NP tissue. Degenerated NP cells secreted CCL17, CCL18, and CD206, exhibiting M2-like characteristics. Co-culture of M2 macrophages with degenerated NP cells led to IL-10 secretion to promote CD34 expression, and downregulated anabolic genes (type II collagen (COL2), aggrecan), and upregulated catabolic genes (matrix metalloproteinase (MMP)-3, MMP-7). JAK2 and STAT3 expression was significantly increased following co-culture. Activation of the JAK2/STAT3 pathway enhanced vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), and CD34 expression and induced further downregulation of COL2 and aggrecan and upregulation of MMP-3 and ***2 macrophage infiltration and pathological neovascularization are prominent in degenerated NP tissue. IL-10 secreted by M2 macrophages activates the JAK2/STAT3 pathway to promote pathological microangiogenesis by up-regulate the expression o

关键词： extracellular vesicles   mesenchymal stem/stromal cells   immunoregulation   extracellular vesicle cargo   programmed cell death ligand 1   large extracellular vesicles   small extracellular vesicles  

摘要： Mesenchymal stem/stromal cells (MSCs) possess immunoregulatory capacity, which is enhanced in an inflammatory environment. Participation of extracellular vesicles (EVs) in this function is proposed, as they can transport various immunoregulatory molecules. However, the impact of the inflammatory microenvironment on the load of the different types of EVs released by these cells is not fully known. Therefore, this work analyzes in detail the temporal effect of IFN-gamma, alone or in combination with TNF-alpha (TNF-alpha + IFN-gamma), on the cargo of immunoregulatory molecules (programmed cell death ligand 1 [PD-L1], CD73, and intercellular adhesion molecule 1 [ICAM-1]) in large extracellular vesicles (L-EVs) released by human bone marrow mesenchymal stem cells (BM-MSCs). The presence of these molecules on the surface of L-EVs was determined by flow cytometry. Our results demonstrate that exposing BM-MSCs to TNF-alpha + IFN-gamma for 24 h increases the percentage of PD-L1+ and CD73+ L-EVs. However, if this stimulus persists, the release of L-EVs with an immunoregulatory phenotype (PD-L1+, CD73+, and PD-L1+CD73+) decreases. The impact of pro-inflammatory cytokines on the transport of ICAM-1 by L-EVs is late, since up to 72 h of treatment with IFN-gamma or TNF-alpha + IFN-gamma, the percentage of ICAM-1+ L-EVs increases. In contrast, stimulation with IFN-gamma for 72 h favors the release of CD73high and ICAM-1high L-EVs, but this effect also decreases in the presence of TNF-alpha. Our study generates novel knowledge about the impact of the inflammatory microenvironment on the cargo composition of L-EVs released by BM-MSCs and demonstrates, for the first time, that the prolonged presence of TNF-alpha reduces the cargo of immunoregulatory molecules in these structures.

关键词： cell death   IFN-gamma   mesenchymal stem/stromal cells   necroptosis   TNF-alpha  

摘要： IFN-gamma and TNF-alpha are two vital inflammatory factors elevated aberrantly in many diseases. Such an inflammatory microenvironment is detrimental to residual cells such as mesenchymal stem cells (MSCs), yet the precise mechanisms are not fully understood. IFN-gamma and TNF-alpha have distinct effects on the immunoregulatory properties of MSCs, and they have been proposed as optimal priming factors to enhance the immunosuppressive capacity of engineered MSCs. Thus, the overall effects of IFN-gamma and/or TNF-alpha exposure on MSCs needs to be elucidated. Here, it is found that IFN-gamma and TNF-alpha synergistically induce cell death of MSCs via necroptosis. When MSCs are exposed to both IFN-gamma and TNF-alpha, their morphological features and biological functions are impaired. Mechanistically revealed by RNA-Sequencing, the injured MSCs undergo a unique cell death process, namely necroptosis. Compared with controls, IFN-gamma synergized with TNF-alpha to increase the expression of RIPK1, RIPK3, MLKL, and all other genes associated with necroptosis. Rescue experiments further demonstrate that this process can be reversed by RIPK3 and MLKL inhibitors but not by the RIPK1 inhibitor, suggesting a RIPK1-independent pathway. Collectively, this study discloses an inflammatory injury mechanism of MSCs, which may shed new light on revealing the MSCs deficits in many inflammatory diseases with expectations to inspire potential targeted therapies. In addition, inflammatory impairment should be taken into consideration when delivering cell therapy based on MSCs primed with IFN-gamma and TNF-alpha.

关键词： Astilbin   Flavonoid   Endometritis   PPAR-gamma   NF-kappa B   STAT3  

摘要： Ethnopharmacological relevance: Astilbin (ATB), a natural flavonoid compound with anti-inflammatory bioactivities, can be isolated from Smilax china L., which has been used in traditional Chinese medicine to treat pelvic inflammatory disease (PID) (including endometritis). Our previous studies reported that flavonoids from Smilax china rhizome (FSCR) have therapeutic effects in rats with PID. However, the effects of ATB, the main active component of FSCR, against endometritis remain unknown. Aim of the study: We aim to investigate the role of ATB on endometritis induced by lipopolysaccharide (LPS) in rats and elucidate the mechanisms underlying anti-inflammatory action of ATB on LPS-stimulated endometrial epithelial cells (EECs). Methods: The effects and action mechanisms of ATB on LPS-induced endometritis in rats and LPS-induced EECs were systematically assessed using H&E staining, immunohistochemistry, ELISA, RT-PCR, western blotting, immunofluorescence, molecular docking and siRNA knockdown technology. Results: ATB significantly alleviated typical uterine pathological damages in endometritis, decreased inflammatory cytokine levels in both serum and uterus, and also inhibited the excessive release of inflammatory cytokines in EECs induced by LPS. Mechanistically, ATB markedly upregulated PPAR-gamma levels and suppressed the overexpression of TLR4 and IL-6R proteins and their downstream signals, MyD88, and phosphorylation of NF-kappa B P65, JAK2, and STAT3, in vivo. Further, the effects of ATB on PPAR-gamma protein expression, and NF-kappa B and STAT3 signalling activation in LPS-induced EECs were consistent with the results of in vivo experiments. Furthermore, both PPAR-gamma-specific siRNA transfection and a selective PPAR-gamma antagonist abolished ATB-induced inhibition of NF-kappa B and STAT3 signalling activation and production of inflammatory cytokines. Molecular docking and in vitro experiments further proved that ATB can target PPAR-gamma binding. Conclusi

关键词： Interferon gamma (IFN-gamma)   tumor necrosis factor alpha (TNF-alpha)   granzyme B   vitiligo   Meta-analysis  

摘要： Background: Vitiligo is a chronic autoimmune skin depigmenting condition. IFN-gamma, TNF-alpha and granzyme B play key roles in vitiligo pathogenesis, some findings suggest their roles may be contradictory. Objective: We aimed to assess IFN-gamma, TNF-alpha and granzyme B levels in blood and skin of vitiligo patients using a meta-analysis approach. Additionally, we evaluated their association with disease activity. Methods: A Meta-analysis was conducted using Review Manager 5.4 software. A total of 55 studies including 3,023 vitiligo patients and 2,534 controls were included in the study. Results: Pooled results from our meta-analysis indicated significantly elevated IFN-gamma protein and transcript levels in blood and skin of vitiligo patients (p < 0.05). TNF-alpha protein levels were also significantly increased in blood and skin of vitiligo patients (p < 0.05). IFN-gamma and TNF-alpha levels were significantly higher in the lesional skin as compared to non-lesional skin (p < 0.05). Furthermore, elevated levels of IFN-gamma and TNF-alpha were observed in patients with active vitiligo (p < 0.05). Additionally, our study suggested a significant increase in granzyme B levels in vitiligo patients (p < 0.05). Conclusion: Overall, the meta-analysis suggests that IFN-gamma, TNF-alpha and granzyme B play a crucial role in vitiligo pathogenesis and progression and may serve as potential therapeutic targets for managing the disease. The PROSPERO registration no. for meta-analysis is CRD42024620274