课程文献中心 更多>>

关键词： Chordoma   Tumor-associated macrophage   IL-6   STAT3   TNF alpha  

摘要： Aims: Chordoma is a rare and aggressive bone tumor with high-recurrence and lack of effective treatment methods. Tumor associated macrophages (TAMs) are abundant in tumor microenvironment (TME) and polarize toward M2 in chordoma. It has been observed that the high proportion of M2 cells is associated with chordoma rapid progression. However, the mechanism of TAMs polarization and promotion to tumor progression in chordoma is still unclear. The is an urgent need for further research. Materials and methods: Flow cytometry and immunohistochemical staining was used to detect the degree of macrophages infiltration in chordoma. A co-culture model of chordoma cells and macrophages was established in vitro to investigate the effects of their interaction on cell function, cytokine secretion, and RNA transcriptome expression. Key findings: In this study, we found M2 macrophage was predominantly abundant immune cell population in chordoma, and its proportion was associated with the degree of bone destruction. We demonstrated that interleukin 6 (IL-6) derived from chordoma cells could induce TAMs polarization by activating STAT3 phosphorylation, and TAMs could enhance chordoma cells migration and invasion through TNF alpha/NF-kappa B kappa B pathway. The interaction of chordoma cells and TAMs could promote the bone destruction-related factor Cathepsin B (CTSB) and inhibitory immune checkpoints expression. We also confirmed blocking IL-6/STAT3 pathway could significantly attenuate the M2 polarization of TAMs and decrease the secretion of TNF alpha. Significance: This study illustrates the dynamics between chordoma cells and TAMs in promoting chordoma invasion and suggests that IL-6/STAT3 pathway is a potential therapeutic target to reduce TAM-induced chordoma invasion.

关键词： Interleukin-38   NLRP3   Inflammasome   Fibroblasts   Myocardial ischemia-reperfusion injury  

摘要： Objective: Although IL-38 is recognized for its regulatory role in a spectrum of chronic inflammatory diseases, investigations into its cardiac physiological and pathophysiological functions are nascent. Our aim was to delineate the biological impact of IL-38 in the context of myocardial ischemia-reperfusion injury (MIRI) and to uncover the mechanisms through which it exerts its effects. Methods and Results: In this study, we used an MIRI mouse model, LPS/ATP stimulation, and a hypoxia/reoxygenation cell model to determine the regulatory influence of IL-38 on MIRI. We observed that the administration of recombinant IL-38 to mice led to a reduction in infarct size, an enhancement in cardiac function, and a suppression of NLRP3 inflammasome activation. In contrast, genetic deletion of IL-38 was associated with an increase in infarct size, worsening of cardiac function, and upregulation of NLRP3 inflammasome activity. The detrimental effects associated with the absence of IL-38 were mitigated by the administration of a specific NLRP3 inhibitor, suggesting that the inhibition of NLRP3 is a critical component of the protective effect mediated by IL- 38 in MIRI. In vitro assays revealed that IL-38 inhibited NLRP3 inflammasome activation in cardiac fibroblasts through the engagement of IL-1R8 and the modulation of SYK phosphorylation. Silencing of IL-1R8 negated the suppressive effect of IL-38 on the NLRP3 inflammasome. Conclusion: IL-38 acts as a potent negative regulator of inflammasome activation after MIRI. It achieves this regulatory effect within cardiac fibroblasts by inhibiting SYK phosphorylation, a process mediated by IL-1R8.

关键词： Gentamicin   Acute kidney injury   Betanin   TapSAKI   NEAT1   miRNA-22-3p   Bioinformatics  

摘要： Introduction: Gentamicin (GNT) is a broad-spectrum antibiotic that is widely prescribed in critically ill patients. However, GNT exerts deleterious effects on renal proximal tubules which could predispose to acute kidney injury (AKI). Aim: The study aimed to investigate the interplay of TapSAKI, NEAT-1, and miR-22-3p in GNT-induced AKI via modulating the TLR4/MyD88/NF-KB/IL-1 beta trajectory. The study was extended to show the role of betanin (BET) in alleviating GNT-induced AKI. Methods: BET (25 mg/kg/day) was administered via oral route for 28 consecutive days in addition to GNT (100 mg/kg/day) i.p. during the last 8 days. TapSAKI, NEAT-1, and miR-22-3p gene expressions were measured using RT-PCR. The levels of SCr, urea were measured using colorimetric assay, whereas KIM-1, TLR4, and IL-1 beta were measured using ELISA technique. Additionally, histopathological examinations were done. Results: The present study revealed that the expression of TapSAKI and NEAT-1 were significantly upregulated in GNT-induced AKI group, whereas miR-22-3p was significantly downregulated. There were significant associations between the expression of these non-coding RNAs and TLR4/NF-KB/MyD88/IL-1 beta axis as well as malondialdehyde and glutathione levels. Favorably, BET pretreated group normalized the levels of SCr, urea, and KIM1 and showed a significant downregulation of TapSAKI and NEAT-1 and upregulation of miR-22-3p compared with GNT-induced AKI group. Furthermore, BET showed a marked inhibition of TLR4/MyD88/NF-KB/IL-1 beta cascade compared with non-treated AKI rats. Moreover, BET normalized oxidative stress markers. Conclusion: BET reduced GNT's toxic effects on kidneys through modulating TLR4/MyD88/NF-KB/IL-1 beta signaling pathway under the influence of lncRNAs TapSAKI, NEAT-1, and miRNA-22-3p, which consequently suppress oxidative stress and inflammation.

关键词： Low-intensity pulsed ultrasound   IL-11   Wnt/beta-Catenin   Bone marrow mesenchymal stromal cell   Osteoporosis  

摘要： Background: Osteoporosis (OP) is a common metabolic bone disease. Low-intensity pulsed ultrasound (LIPUS) can effectively promote bone formation and fracture healing. The Wnt/(3-catenin (3- catenin signaling pathway is crucial for regulating bone homeostasis and bone diseases, and its downregulation is one of the main mechanisms of osteoporosis pathogenesis. Interleukin-11 (IL-11), which is regulated by mechanical stress, is a key factor in bone remodeling. Here, we investigated the optimal intervention parameters for LIPUS, the relationships among LIPUS, IL-11, and the Wnt/(3-catenin (3- catenin signaling pathway, and the effects of LIPUS on bone loss and potential molecular mechanisms in ovariectomized (OVX) mice. Methods: Bone marrow mesenchymal stromal cells (BMSCs) were subjected to LIPUS intervention for 0, 10, or 20 min to determine the optimal intervention time. The mediating role of IL-11 in LIPUS intervention was explored through IL-11 knockdown and overexpression. Finally, animal experiments were conducted to investigate the in vivo therapeutic effects of LIPUS. Results: The optimal intervention time for LIPUS was 20 min. LIPUS promoted IL-11 expression and upregulated the Wnt/(3-catenin (3- catenin signaling pathway, thereby promoting osteogenic differentiation and inhibiting adipogenic differentiation of BMSCs. IL-11 mediates the regulation of the Wnt/(3-catenin (3- catenin signaling pathway by LIPUS. Additionally, LIPUS effectively improved the bone microstructure in ovariectomized mice, inhibited bone loss, promoted IL-11 expression in bone tissue, and activated the Wnt/(3-catenin (3- catenin signaling pathway in the femur. Conclusion: Low-intensity pulsed ultrasound can regulate BMSCs differentiation and inhibit bone loss by promoting IL-11 expression and activating the Wnt/(3-catenin (3- catenin signaling pathway.

关键词： IL-6 receptor   Janus kinase (JAK)   Preferential inhibition   Rheumatoid arthritis   Signal transducer and activator of transcription (STAT)  

摘要： Interleukin-6 (IL-6) is a relevant cytokine in rheumatoid arthritis (RA) pathogenesis, potentially activating Janus kinases (JAK)-1, -2, and tyrosine kinase 2 (TYK2), and thus, three signal transducer and activator of transcription (STAT)-1, -3 or - 5 pathways. This pilot study aims to explore differences in phosphorylated (p)STAT3 levels among patients with RA, those not classified as RA (nRA), and healthy donors (HD), providing some clues on the relative contribution of each JAK protein to the downstream of the IL-6-induced STAT3 pathway. Clinical data and blood samples from 80 subjects (41 RA, 14 nRA, and 25 HD) were collected. The activity of the JAK-STAT3 pathway was assessed by Western Blot and Real Time-PCR analysis for the quantification of STAT3 in peripheral blood mononuclear cells (PBMC). Furthermore, the impact of JAK-1, -2, and TYK2 inhibitors on pSTAT3 was assessed in vitro by FACS, with and without IL-6 stimulation in RA patients naïve to treatment with DMARD and steroids. The pSTAT3 (%) was significantly higher in PBMC from RA compared to nRA patients and HD. Furthermore, pSTAT3 (%) was significantly associated with inflammation and disease activity (ESR, CRP, and DAS28). The JAK-1 inhibitor was more effective in reducing pSTAT3 expression in CD14 cells of RA patients, while the JAK-2 selective compound was more effective in CD4 cells of RA patients. On the contrary, the TYK2 selective agent showed no significant effects. This study highlights the importance of the JAK/STAT3 pathway in RA. Some differences among various JAK proteins have been pointed out, with JAK1 and JAK2 standing as the most relevant mediators of the STAT3 pathway in this in-vitro model after IL-6R activation.

关键词： Yak   IFN beta 3   Klebsiella pneumoniae   Macrophages  

摘要： Interferon-beta (IFN beta) is an important member of the type I interferon family and plays key roles in antiviral response and treatment of autoimmune disease. However, the immunomodulation and antimicrobial potential of yak IFN beta 3 protein are still unclear. In the current study, the 558 bp long cDNA sequence of the yak IFN beta 3 gene was amplified and successfully expressed in a prokaryotic system. The mRNA expression level of IFN beta 3 in yak spleen was higher than in heart, liver, lung and kidney. The minimum inhibitory concentration of recombinant IFN beta 3 protein against Klebsiella pneumoniae was determined to be 64 mu g/mL. The activity, phagocytosis, and nucleic acid intensity of yak macrophages were significantly increased by IFN beta 3 protein (P < 0.05). In addition, the vitality of macrophages infected with Klebsiella pneumoniae was significantly increased by IFN beta 3 protein (P < 0.05). The IFN beta 3 protein significantly reduced the release of nitric oxide (NO) from macrophages infected with Klebsiella pneumoniae (P < 0.05). The mRNA levels of Capg, Man2b1, Mrc-1, gamma-actin and Marco in macrophages were upregulated by IFN beta 3 protein (P < 0.05). The contents of aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) in the serum of mice after Klebsiella pneumoniae infection were reduced by IFN beta 3 protein (P < 0.05). The lung and kidney injuries in mice induced by Klebsiella pneumoniae infection were alleviated by IFN beta 3 protein. In summary, the yak IFN beta 3 protein enhanced macrophage activity and reduced the damage caused by Klebsiella pneumoniae infection in mice.

关键词： 定痫丸   癫痫   海马   神经元凋亡   TNF-α/TNFR1/TRADD信号通路  

摘要： 目的:基于TNF-α/TNFR1/TRADD途径探讨定痫丸对癫痫小鼠海马神经元凋亡的影响。方法:将60只昆明小鼠随机分为正常对照组、模型组、卡马西平(30 mg/kg)阳性对照组及定痫丸低(4.08 g/kg)、中(8.16 g/kg)、高(16.32 g/kg)剂量组,每组10只。采用匹罗卡品诱导建立癫痫小鼠模型,连续灌胃给药2 w,1次/d,脑电图观察小鼠造模是否成功。HE染色观察小鼠海马组织病理学变化,TUNEL染色观察海马神经元凋亡,免疫组织化学法(IHC)、Real-time PCR、Western Blot检测海马组织TNF-α、TNFR1、TRADD m RNA及蛋白表达。结果:与正常对照组比较,模型组小鼠脑电图连续性痫性放电波升高,海马神经元形态结构受损,海马神经元凋亡程度加重,海马组织中TNF-α、TNFR1、TRADD m RNA及蛋白表达显著升高(P<0.05)。与模型组比较,各给药组小鼠脑电图痫性放电减少,海马神经元形态结构明显复原,海马神经元凋亡不同程度改善,海马组织中TNF-α、TNFR1、TRADD m RNA及蛋白表达显著降低(P<0.05)。结论:定痫丸通过抑制TNF-α/TNFR1/TRADD信号通路缓解海马神经元凋亡进而发挥抗癫痫作用。

关键词： T细胞免疫组库   T细胞受体   神经退行性疾病   免疫治疗  

摘要： T细胞介导的获得性免疫是人类免疫系统的重要组成部分，T细胞免疫组库是个体所独特T细胞受体（TCR）的集合。神经退行性疾病中TCR多样性的失衡和对抗原特异性T细胞的鉴定是近年来的一项重要发现，进一步探索神经退行性疾病中特异性的免疫紊乱是监测患者临床进展、寻找特异性防治靶点的关键，为神经退行性疾病的免疫治疗提供依据。

关键词： Breast cancer   Tumor-associated macrophages   Metastasis   Interleukin-6   Epithelial-mesenchymal transition   TGM2  

摘要： Breast cancer is one of the most common tumors in the world and metastasis is the major cause of tumor-related death. Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and often associated with cancer metastasis. Nevertheless, the mechanism by which TAMs regulate breast cancer metastasis remain unclear. In this study, we found that transglutaminase 2 (TGM2) could serve as a crucial target in the modulation of TAMs-induced epithelial-mesenchymal transition (EMT) and invasion of breast cancer cells. Further analysis revealed that IL-6 secreted from TAMs, which was capable of inducing TGM2 expression through the activation of the JAK/STAT3 signaling pathway. Subsequent luciferase reporter assays demonstrated that STAT3 binds to the TGM2 promoter region, thereby transcriptionally enhancing TGM2 expression. In conclusion, our current research has identified the IL-6/STAT3/TGM2 axis as a pivotal regulator in breast tumorigenesis caused by TAMs, presenting a novel target for the treatment of breast cancer.

关键词： BDNF   IL-1 beta   IL-6   GHQ-28   DASS-21   Sulfur mustard  

摘要： Sulfur mustard (SM), a chemical warfare weapon has been used in conflicts. The delayed impact of sulfur mustard on mental and physical health of veterans remains a topic of significant concern. This cross-sectional study investigated the serum levels of brain-derived neurotrophic factor (BDNF), interleukin (IL)-1 beta, and IL-6 in 227 SM-chemical veterans receiving long-term financial support and 77 healthy individuals. Their mental health status and life satisfaction were assessed through three self-report questionnaires (General Health Questionnaire - 28, GHQ-28;Depression, Anxiety & Stress Scale, DASS-21;36-Item Short Form Survey, SF-36). Our findings revealed higher levels of anxiety/insomnia, and psychiatric symptoms in the veterans compared to the control group (P < 0.05), accompanied by depression, stress, and anxiety as measured by the GHQ-28 and DASS-21 assessments. Severe depression and social dysfunction were not prevalent in the veterans compared to the control group (P > 0.05) according to the GHQ-28 findings. The SF-36 assessment indicated overall better health conditions for SM participants, with higher scores across various domains (general health, social function, and mental health) and two mental and physical dimensions in the veterans compared to the control group (P < 0.05). IL-1 beta and IL-6 levels were lower in the SM-exposed group than in the control group, while the BDNF level was higher in the SM-exposed group (P < 0.05). Alterations in BDNF, IL-1 beta, and IL-6 levels along with results of the mentioned questionnaires may be evidence of partial improvement in the mental and physical health of the SM-exposed individuals receiving the financial support.