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关键词： Hypoxia-inducible factor-1 alpha   Periodontitis   Saliva   SuPAR   Tumor necrosis factor alpha  

摘要： Background The aim of the study is to evaluate saliva levels of Soluble urokinase plasminogen activator receptor (suPAR), Hypoxia-inducible factor-1 alpha (HIF-1 alpha) and tumor necrosis factor-alpha (TNF-alpha) in stage III grade A, grade B, grade C periodontitis and periodontal health and to understand the roles of these molecules in periodontal inflammation process and also to compare the three biomarkers' discriminative efficacy in periodontal disease. Methods A total of 80 individuals, 20 with stage III grade A periodontitis (group A), 20 with stage III grade B periodontitis (group B), 20 with stage III grade C periodontitis (group C) and 20 with healthy periodontium (group H) were recruited for this study. Full-mouth clinical periodontal measurements were recorded in periodontal charts. Whole saliva samples were collected to determine the levels of suPAR, HIF-1 alpha and TNF-alpha in study groups using enzyme-linked immunosorbent assay (ELISA) method. Results The saliva concentration of suPAR, HIF-1 alpha, and TNF alpha was significantly higher in group A, group B, and group C compared with group H (p < .05). Additionally, salivary suPAR concentration was significantly higher in group C than in groups A and B (p < .05). Positive statistically significant correlations were observed between three biomarkers and all clinical parameters (p < .05). Conclusions Increased levels of saliva suPAR, HIF-1 alpha, and TNF alpha suggest that these molecules may play a role in periodontitis. In addition, the higher salivary suPAR levels in grade C periodontitis compared to other grades suggest that suPAR may be one of the potential molecules that can be used to predict disease progression and periodontal disease classification.

关键词： 纳米乳佐剂   单磷酰脂质A   QS-21   复合佐剂   免疫原性  

摘要： 目的 制备基于纳米乳（nano-emulsion,NE）佐剂的不同复合佐剂，探讨其用于流感疫苗的免疫效果。方法 将NE佐剂分别与单磷酰脂质A(monophosphoryl lipid A,MPLA)、QS-21联用制备复合佐剂后，与流感疫苗配伍，于第0和28天经肌内注射免疫雌性BALB/c小鼠，初免后第28及42天，采用血凝抑制（hemagglutination inhibition,HI）、ELISA试验及流式细胞术评价免疫效果；加强免疫后第14天，用10 LD50H1N1流感病毒毒株A/Victoria/2570/2019(IVR-215)(H1N1)鼻内感染雌性BALB/c小鼠，评价攻毒保护效果。结果 复合佐剂组小鼠均能产生高水平的特异性IgG抗体以及功能性HI抗体；两种复合佐剂的加入均能提高小鼠脾脏CD3+CD4+、CD3+CD8+T细胞水平。复合佐剂组小鼠攻毒后存活率达100%，体质量下降率低于10%。结论 免疫辅以复合佐剂的流感疫苗，较单独佐剂疫苗具有更高的免疫原性，本研究为流感疫苗佐剂的开发以及佐剂复合化研发奠定了基础。

关键词： Formononetin   ischemic stroke   molecular mechanisms   neuronal injury   protective effects  

摘要： BACKGROUNDS:Inflammation plays a pivotal role in the advancement of ischemic stroke, and Formononetin has been recognized for its potential benefits due to its anti-inflammatory effects. Although Formononetin shows promise for reducing cerebral ischemic injury, its precise effectiveness and the underlying molecular mechanisms still need to be thoroughly explored. The research aimed to investigate Formononetin's impact and mechanisms on ischemic brain damage. METHODS:In this study, both the ischemia/reperfusion (I/R) mouse model and the oxygen-glucose deprivation/reperfusion (OGD/R) cell model were used. The I/R mouse model was prepared using the middle cerebral artery occlusion (MCAO) method, while the OGD/R SH-SY5Y cell model was established using the oxygen-glucose OGD/R method. Hematoxylin and Eosin (H&E) staining, Tunnel fluorescence staining, and Nissl staining were employed to observe the effects of Formononetin on neuronal damage, apoptosis, and survival in I/R mouse brain tissue. Additionally, the effects of Formononetin on the levels of pro-inflammatory factors in I/R mice and OGD/R cells were detected using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) and Enzyme-Linked Immunosorbent Assay (ELISA) methods. The c-Fos/Interleukin-10 (IL-10)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway in I/R mice and OGD/R cells was examined using RT-qPCR and Western Blot (WB). Furthermore, rescue validation was performed using targeted interventions of IL-10 and c-Fos, confirming that the c-Fos/IL-10/STAT3 signaling pathway is a key target of Formononetin. RESULTS:Our findings reveal that Formononetin notably decreased infarct size and neuronal damage ( < 0.001). Additionally, Formononetin decreased inflammation and lowered levels of pro-inflammatory cytokines ( < 0.05). In cell models, Formononetin effectively suppressed neuronal injury induced by OGD/R and the related inflammatory markers ( < 0.001). Mechanistic studies showed

关键词： MIR3142HG   IL-6   STAT3   Trx-1   CRC  

摘要： BackgroundColorectal cancer (CRC) is a prevalent and highly malignant neoplasm on a global scale, ranking as the second most widespread cause of cancer-associated death. Long noncoding RNAs (lncRNAs) control tumorigenic processes in CRC by modulating inflammatory signals. However, the precise mechanisms remain *** regulated by thioredoxin-1 (Trx-1) and interleukin (IL)-6 were identified by RNA sequencing (RNA-seq). The effect of MIR3142HG on CRC growth, migration, and invasion was assessed through methods of cell counting kit-8 (CCK-8), colony formation assay, Transwell assay, and animal experimentation, respectively. The regulation of signal transducer and activator of transcription 3 (STAT3) on the MIR3142HG promoter was verified using chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. The interaction of MIR3142HG with Trx-1 and STAT3 proteins was validated with RNA-binding protein immunoprecipitation (RIP) and RNA-pulldown experiments. Bioinformatics analysis and tissue microarray were utilized for evaluating the clinical value of MIR3142HG in *** identified a lncRNA, MIR3142HG, regulated by Trx-1 knockdown and IL-6 treatment. Overexpression of MIR3142HG enhanced CRC cell proliferation, migration, and invasion, while its knockdown impaired these processes. STAT3 bound to the MIR3142HG promoter and activated its transcription. Upregulated MIR3142HG acted as a scaffold for the Trx-1/STAT3 complex to inhibit the degradation of Trx-1 and phosphorylated STAT3 (p-STAT3). In situ hybridization (ISH) results of CRC tissues indicated that MIR3142HG expression was significantly elevated during the early stages of CRC. Moreover, consistent with the Cancer Genome Atlas (TCGA) dataset, high MIR3142HG expression predicted better *** study identified a novel lncRNA MIR3142HG, which interacts with STAT3 and Trx-1 to promote CRC progression, providing a possible diagnostic target for CRC.

摘要： Background: 3-acetyl-11-keto-beta-boswellic acid (AKBA) is a monomer extracted from the traditional Chinese herbs of Boswellia that has antitumor effects. However, the therapeutic effects and mechanisms of AKBA in prostate cancer (PCa) are unclear. Objective: To predict the target of AKBA treatment of PCa using network pharmacology methods and validate the predicted targets through CCK-8, flow cytometry, cell scratch test, Transwell chamber assay, and proteomics. Methods: The protein-protein interaction (PPI) network was established. Further analysis was performed by gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes for biological functionality and pathway enrichment. CCK-8 assay, flow cytometry, wound healing assay, and Transwell chamber assay were used to detect cell proliferation, apoptosis, invasion, and metastasis, respectively. Transcriptomics was used to detect the effects of AKBA on protein levels in PCa cells. Results: 120 potential targets for the AKBA treatment of PCa were obtained. GO enrichment analysis revealed that the biological processes of AKBA treatment of PCa include the steroid metabolic process, drug response, and fatty acid metabolic process. The results of KEGG enrichment revealed that the IL-17 signaling pathway is the key pathway for the AKBA treatment of PCa. In addition, experimental results demonstrate that AKBA inhibits the proliferation of PCa cells, induces cell apoptosis, and suppresses cell invasion and metastasis. Proteomics identified 119 differentially expressed proteins, which were primarily enriched in pathways closely related to the phogosome, pathways in cancer, IL-17 signaling pathway, spliceosome, PPAR signaling pathway, and HIF-1 signaling pathway. Conclusion: Through the methodologies of network pharmacology and transcriptomics, AKBA may exert its therapeutic effects on PCa by modulating the expression of the IL-17 signaling pathway.

关键词： 宫颈癌   桂枝茯苓汤加味   放化疗   疗效   T淋巴细胞亚群  

摘要： 目的 分析桂枝茯苓汤加味对宫颈癌术后放化疗增效作用及对T淋巴细胞亚群水平的影响。方法 回顾性分析2017年1月至2020年5月医院收治的106例宫颈癌患者的资料，所有患者均行宫颈癌根治术，根据术后治疗方式分为研究组（54例，术后放化疗联合桂枝茯苓汤加味治疗）、对照组（52例，术后放化疗治疗），两组术后随访3年。对比两组中医证候评分、肿瘤标志物、T淋巴细胞亚群、免疫球蛋白免疫球蛋白（Immunoglobulin，Ig）、补体及不良反应情况及抗肿瘤效果。结果 两组治疗后主症、次症中医证候评分均低于治疗前（P＜0.05），研究组治疗后更低（P＜0.05）。两组治疗后（Carcinoembryonic Antigen，CEA）、糖类抗原125（Carbohydrate Antigen 125，CA125）、鳞状细胞癌抗原（Squamous Cell Carcinoma Antigen，SCCA）均低于治疗前（P＜0.05），研究组治疗后更低（P<0.05）。研究组治疗前后的Th1/Th2、Th17/Treg、CD4＋/CD8＋对比差异均无统计学意义（P＞0.05）；对照组治疗后的Th1/Th2、Th17/Treg均高于治疗前，CD4＋/CD8＋均低于治疗前（P＜0.05）；研究组治疗后Th1/Th2、Th17/Treg低于对照组，CD4＋/CD8＋高于对照组（P＜0.05）。研究组治疗前后的IgG、IgM、C3、C4对比差异均无统计学意义（P＞0.05），对照组治疗后的IgG、IgM、C3、C4均低于治疗前（P＜0.05），研究组治疗后的IgG、IgM、C3、C4均高于对照组（P＜0.05）。研究组的皮肤反应、放射性膀胱炎发生率低于对照组（P＜0.05）。研究组的3年无病生存曲线优于对照组（P＜0.05）。结论 桂枝茯苓汤加味治疗用于宫颈癌术后放化疗患者可增强抗肿瘤效果，降低肿瘤标志物，维持机免疫功能稳定，减轻毒副反应。

关键词： ILC2   Type 1 diabetes (T1D)   cell therapy   immune tolerance   islet transplantation  

摘要： Group 2 innate lymphoid cells (ILC2s) that produce IL-10 (IL-10ILC2s) have demonstrated regulatory and tissue-protective properties in murine studies, but preclinical studies are lacking that explore the potential of human IL-10ILC2s as a tolerance-promoting cell therapy for transplantation or autoimmunity. Here, we investigated whether human IL-10ILC2s could enhance islet function and prevent allograft rejection in humanized mouse models of islet transplantation. In vitro, human IL-10ILC2s did not display cytotoxicity towards allogeneic deceased-donor islets or stem cell-derived islet-like cells, and co-transplantation with IL-10ILC2s significantly improved glucose control post-transplantation. Allogeneic IL10ILC2s directly inhibited T cell-mediated cytotoxicity against islet-like cells in vitro, and in an antigen-specific transplant rejection model, prevented T cell-mediated rejection of deceased donor islet grafts. Effects were greater with allogeneic IL-10ILC2s, as autologous cells did not inhibit T cell IFN-γ production or cytotoxic activity in vitro, and were not sufficient to prevent islet rejection in ***, these studies provide proof-of-principle that human IL-10ILC2s have therapeutic potential for islet transplantation and type 1 diabetes, and support their use as an allogeneic regulatory cell therapy.

关键词： 慢性肾衰竭   血液透析   医院感染   微小核糖核酸-155   微小核糖核酸-141   白细胞介素-22   白细胞介素-17   临床转归  

摘要： 目的 分析慢性肾衰竭(CRF)血液透析(HD)患者并发医院感染外周血微小核糖核酸(miR)-155、miR-141、白细胞介素(IL)-22和IL-17表达及病原菌分布与临床转归。方法 纳入2022年6月—2023年6月武汉市第一医院收治CRF HD患者561例,根据是否并发医院感染分为感染组182例、未感染组379例;感染组患者随访6个月根据临床转归情况分为存活组138例、死亡组44例。分析CRF HD患者医院感染的病原菌分布,比较感染组、未感染组临床资料,各组血清miR-155、miR-141、IL-22和IL-17水平,绘制受试者工作特征(ROC)曲线分析血清指标对CRF HD医院感染患者临床归转的预测价值。结果 感染组透析时间≥1年、置管部位股静脉、导管类型为长期置管比例高于未感染组(P<0.05)。感染组检出病原菌202株,主要为革兰阴性菌125株,占比61.88%。感染组和未感染组血清miR-155、miR-141、IL-22和IL-17水平比较,差异有统计学意义(P<0.05),差值最大指标为miR-141(t=37.145,P<0.0,01);感染组不同预后患者,存活组与死亡组血清miR-155、miR-141、IL-22和IL-17水平比较,差异有统计学意义(P<0.05),差值最大指标为IL-17(t=35.848,P<0.001)。绘制ROC曲线分析四指标对医院感染CRF HD患者预后的预测价值,联合检测曲线下面积(AUC)最高为0.922(P<0.05)。结论 CRF HD患者医院感染病原菌分布以革兰阴性菌为主,随着感染的发生及预后恶化患者血清miR-155、miR-141、IL-22和IL-17水平升高,联合检测的预测价值较高。

摘要： MDM2 inhibitors are promising therapeutics for acute myeloid leukemia (AML) with wild-type TP53. Through an integrated analysis of functional genomic data from primary patient samples, we found that an MDM2 inhibitor, idasanutlin, like venetoclax, is ineffective against monocytic leukemia (French-American-British [FAB] subtype M4/M5). To dissect the underlying resistance mechanisms, we explored both intrinsic and extrinsic factors. We found that monocytic leukemia cells express elevated levels of CEBPB, which promote monocytic differentiation, suppress CASP3 and CASP6, and upregulate MCL1, BCL2A1, and the interleukin (IL-1)/tumor necrosis factor alpha (TNF-alpha)/NF-kappa B pathway members, thereby conferring drug resistance to a broad range of MDM2 inhibitors, BH3 mimetics, and venetoclax combinations. In addition, aberrant monocytes in M4/M5 leukemia produce elevated levels of IL-1 and TNF-alpha, which promote monocytic differentiation and upregulate inflammatory cytokines and receptors, thereby extrinsically protecting leukemia blasts from venetoclax and MDM2 inhibition. Interestingly, IL-1 beta and TNF-alpha only increase CEBPB levels and protect M4/M5 cells from these drugs but not M0/M1 leukemia cells. Treatment with venetoclax and idasanutlin induces compensatory upregulation of CEBPB and the IL-1/TNF-alpha/NF-kappa B pathway independent of the FAB subtype, indicating drug-induced compensatory protection mechanisms. The combination of venetoclax or idasanutlin with inhibitors that block the IL-1/TNF-alpha pathway demonstrates synergistic cytotoxicity in M4/M5 AML. As such, we uncovered a targetable positive feedback loop that involves CEBPB, IL-1/TNF-alpha, and monocyte differentiation in M4/M5 leukemia and promotes both intrinsic and extrinsic drug resistance and drug-induced protection against venetoclax and MDM2 inhibitors.

关键词： IL-1 alpha   iNOS   macrophages   obesity   Th17 cells   tuberculosis  

摘要： IL-1 alpha, IL-1 beta, IFN-gamma, IL-17 and the expression of inducible nitric oxide synthase (iNOS) enzyme by macrophages, which generate nitric oxide, are protective against tuberculosis, a disease caused by Mycobacterium tuberculosis. The severity of tuberculosis can be dependent on bacterial load and/or lung immunopathology. Tuberculosis is aggravated by existing comorbidities such as obesity. Obesity induces metabolic dysfunction, meta inflammation and dysbiosis, which increase the prevalence of respiratory diseases and worsen immunopathology. The deficiency of IL-1 alpha (IL-1 alpha-/-) induces deleterious lung monocytic inflammation and functional activation of the adaptive immune response mediated by T cells during M. tuberculosis infection in non-obese mice. Although iNOS and IFN-gamma have been described as protective in experimental tuberculosis, using a model of obesity induced by high-fat diet, we show here an increase in iNOS-expressing interstitial macrophages positively correlated with M. tuberculosis numbers in the lungs of IL-1 alpha-/- animals, followed by increased frequency of IFN-gamma and decreased frequency of IL-17-producing T cells, showing that IFN-gamma and iNOS contribute to immunopathology and pulmonary damage. The protective effect of IL-1 alpha, characterised by reduction of lung immunopathology, is dependent on IL-17-producing CD4+ cells that negatively regulate iNOS expression on macrophages. Our data provide important implications for tuberculosis with existing obesity that aggravates lung immunopathology associated with an exacerbation of IFN-gamma-producing and iNOS-expressing cells.