课程文献中心 更多>>

关键词： Atherosclerosis   Tanyu tongzhi formula   Macrophage   Il-10   Efferocytosis   ACVD   atherosclerotic cardiovascular disease   BMDMs   bone marrow derived macrophages   DEGs   differentially expressed genes   DUSP1   dual Specificity Protein Phosphatase 1   FBS   fetal bovine serum   GO   Gene Ontology   IL-10   interleukin-10   ORO   oil red O   PMs   peritoneal macrophages   TLR   toll-like receptor   TTF   Tanyu Tongzhi Formula   TCM   traditional Chinese medicine   VLC   very long-chain  

摘要： Background Traditional Chinese Medicine (TCM), a significant subdiscipline within the realm of complementary medicine, has witnessed a surge in popularity across both Asian and Western nations over the past few decades. It holds potential as an adjunctive therapy for the management of atherosclerotic cardiovascular disease (ACVD). Tanyu Tongzhi Formula (TTF) —a TCM formula with decades of clinical application—has been demonstrated through completed randomized, controlled multicenter clinical studies to extend the maximum exercise duration in patients with chronic coronary syndrome and ameliorate TCM syndromes. TTF emerges as a promising therapeutic candidate for coronary artery disease characterized by phlegm stasis interaction. Additionally, TTF has demonstrated efficacy in protecting against atherosclerosis in murine models. However, the mechanisms by which TTF modulates macrophage function in atherosclerosis remain to be elucidated. Purpose To investigate IL-10-dependent efferocytosis regulation as a pivotal mechanism underlying TTF's modulation of macrophage function in atherosclerosis. Study design and methods Low-density lipoprotein receptor or Apolipoprotein E null mice were subjected to a western diet for 8 weeks to induce atherosclerosis, after which they received TTF treatment for an additional 12 weeks. RNA sequencing was employed to identify interleukin-10 (IL-10) as a key downstream molecule. To verify the role of IL-10 in mediating the effects of TTF in reducing atherosclerosis, macrophage-specific IL-10 knockout mice were used. Results TTF administration significantly alleviated atherosclerosis in mice, evidenced by a reduction in atherosclerotic lesions and plaque necrosis, alongside an augmentation in collagen content. RNA sequencing revealed a substantial upregulation of IL-10 following TTF treatment, which corroborated in various macrophage populations and within mouse atherosclerotic plaques. IL-10 plays a crucial role in mediating the effects of

关键词： IFNγ   Macrophage activation syndrome   Pediatric Still’s disease   Systemic juvenile idiopathic arthritis   biomarkers  

摘要： Objectives To evaluate diagnostic and prognostic significance of traditional laboratory parameters of hyperinflammation and of the IFNγ-related biomarkers interleukin-18 (IL-18), CXCL9 and neopterin in macrophage activation syndrome (MAS) secondary to Still’s disease (SD). Methods Forty-one patients with MAS and 24 patients with active pediatric SD from six Italian centers were enrolled. Samples were obtained at baseline (at initiation or within 48 hours of initiation of specific treatments) for MAS or active SD and at T1 (5-15 days from baseline) only from MAS. CXCL9, IL-18 and neopterin were measured by ELISA. The MAS clinical severity score (MCSS) was developed to define MAS severity (mild: score 0-4; severe: score 5-8). Results In addition to the parameters included in the 2016 MAS criteria, lymphopenia and increased LDH reliably discriminated MAS from active SD. Levels of CXCL9, IL-18 and neopterin effectively discriminated MAS from active SD. Higher levels of the three IFNγ-related biomarkers at baseline were associated with a severe course MAS (MCSS>4). Combining levels at baseline of CXCL9 with those of ferritin, platelet count, fibrinogen and LDH, led to a prognostic score with sensitivity of 100 % and specificity of 74 % for severe MAS. Contingency analysis showed that CXCL9 >830 pg/ml and IL-18 >83,000 pg/ml at T1 had a significant risk of failing to achieve MAS remission in ≤2 months (odds ratio 9.3 and 5.4, respectively). Conclusions These findings highlight the potential role of CXCL9 measurement in supporting the diagnosis and guiding the therapeutic management of patients with MAS in clinical practice.

关键词： ACC   acetyl-CoA carboxylase   α-KG   α-ketoglutarate   AMPK   AMP-activated protein kinase   AP-1   Activator Protein 1   Arg1   arginase 1   CCL   C-C motif chemokine ligand   CCR2   C-C chemokine receptor type 2   CD   cluster of differentiation   CXCL   C-X-C motif chemokine ligand   CXCR4   C-X-C motif chemokine receptor 4   Cx43   connexin 43   DNMT3B   DNA methyltransferase 3β   EZH2   enhancer of zeste homolog 2   FAK   focal adhesion kinase   FAO   fatty acid oxidation   FcεRI   Fc epsilon receptor I   FIZZ1   found in inflammatory zone 1   FOXP3   forkhead box P3   FOXO   forkhead box O   GLUD1   glutamate dehydrogenase 1   GLUT1   glucose transporter 1   GM-CSF   granulocyte-macrophage colony-stimulating factor   H3K27ac   histone H3 lysine 27 acetylation   H3K27me3   histone H3 lysine 27 trimethylation   H3K4me3   histone H3 lysine 4 trimethylation   HF   heart failure   HFpEF   HF with preserved ejection fraction   HIF-1α   hypoxia-inducible factor 1α   HK1   hexokinase 1   HLA-DR   human leukocyte antigen-DR   HMGB1   high mobility group box 1   HO-1   heme oxygenase-1   IFN-γ   interferon-γ   IL   interleukin   INOS   inducible nitric oxide synthase   IRF1   interferon regulatory factor 1   ISO   isoproterenol   KLF4   Kruppel-like factor 4   LAD   Left Anterior Descending Coronary Artery   LDHA   lactate dehydrogenase A   L-NAME   L-NG-nitro arginine methyl ester   LPS   lipopolysaccharide   MCAD   medium-chain acyl-CoA dehydrogenase   MerTK   myeloid-epithelial-reproductive tyrosine kinase   MHC-II   major histocompatibility complex class II   MI   myocardial infarction   NE   neutrophil elastase   NETs   neutrophil extracellular traps   NF-κB   nuclear factor kappa B   NLRP3   NOD-like receptor protein 3   NO   nitric oxide   Nrf2   nuclear factor E2-related factor 2   OGT   O-GlcNAc transferase   OXPHOS   oxidative phosphorylation   PDHA1   pyruvate dehydrogenase E1α   PDH   pyruvate dehydrogenase complex   PDK   pyruvate dehydrogenase kinase   PFKP   phosphofructokinase-platelet isoform   PGC   peroxisome proliferator-activated receptor gamma coactivator   PI3K   phosphoinositide 3-kinase   PKM2   pyruvate kinase M2   PPAR   peroxisome proliferator-activated receptor   RKIP   RAF kinase inhibitor protein   SDH   succinate dehydrogenase   SIRTs  

摘要： Heart failure (HF) is an end-stage cardiovascular syndrome caused by structural or functional cardiac abnormalities. Its high morbidity and mortality underscore the urgent need for novel therapeutic strategies. In recent years, the dynamic regulatory mechanisms underlying macrophage polarization in the onset and progression of HF have attracted widespread attention. The Sirtuin family, as NAD + -dependent deacetylases, has emerged as a key regulatory factor in reshaping the macrophage polarization phenotype by integrating metabolic reprogramming, epigenetic regulation, and immune cell interactions. This paper systematically elaborates the molecular mechanisms by which Sirtuins (SIRT1-SIRT7) regulate metabolic reprogramming (e.g., glucose metabolism, lipid metabolism, and glutamine metabolism), coordinate epigenetic modifications (e.g., DNA methylation, histone modifications, and non-coding RNA regulation), and mediate interactions between immune cells to dynamically balance macrophage polarization. Furthermore, this review summarizes recent advances in the active components of phytomedicines, such as resveratrol, pterostilbene, astragaloside IV, quercetin, dihydromyricetin, berberine, honokiol, ginsenoside Rc, ginsenoside Rg1, and ginsenoside Rg3, in targeting the Sirtuin–macrophage polarization axis for the prevention and treatment of HF. This review aims to provide a theoretical framework and translational guidance for developing HF-targeted therapeutic strategies based on Sirtuin-mediated macrophage polarization, as well as for the research and development of related natural products.

关键词： AGE/sRAGE   GCF   Periodontitis   SRAGE   Saliva   Type-2 diabetes  

摘要： Objective Diabetes, if uncontrolled, increases the risk of periodontal disease and associated tooth loss. While AGE and sRAGE levels have been explored in diabetes, their role in localized inflammation in periodontium is poorly understood. The aim of this study was to investigate AGE/sRAGE ratio and IL-17 in saliva&gingival crevicular fluid in the presence of periodontitis in diabetic patients which may underlie disease development or progression. Design This cross-sectional study included 64 patients, divided into 4 groups as healthy (H), periodontitis without diabetes(P), periodontitis patients with controlled diabetes(DP), periodontitis patients with poorly controlled diabetes(PDP). Periodontal clinical parameters were recorded. AGE, sRAGE, IL-17 levels in GCF and saliva samples were measured with ELISA and AGE/sRAGE ratio was determined. Results GCF AGE/sRAGE ratio and IL-17 levels of periodontitis groups were significantly higher than H group, while sRAGE levels were significantly lower (p < 0.05). In addition, AGE/sRAGE ratio of PDP group were significantly higher than DP group in GCF and saliva (p < 0.05). ROC curve analysis showed significantly discriminative performance of the parameters in both GCF and saliva. HbA1c levels were positively correlated with AGE/sRAGE ratio in GCF and saliva(p < 0.05). Conclusions This study demonstrated that GCF and salivary biomarkers, particularly IL-17 and AGE/sRAGE ratio, may have diagnostic potential in distinguishing periodontal disease severity in relation to glycemic status. ROC analysis supported the discriminative ability of these markers, especially in GCF, with satisfactory sensitivity and specificity. The AGE/sRAGE ratio in both GCF and saliva showed promise as a non-invasive biomarker, especially in patients with poorly controlled diabetes.

摘要： The clinical-grade iPSC line UNIONi001-A is derived from HLA-homozygous (HLAh) umbilical cord blood mononuclear cells (CBMCs) of a healthy Han Chinese male neonate. Cells were reprogrammed using episomal plasmids with OCT3/4, SOX2, KLF4, c-MYC and BCL-XL. The iPSCs exhibited typical pluripotent stem cell morphology, expressed pluripotency markers, maintained a normal karyotype, and could differentiate into three germ layers, making them suitable for cell therapy research and clinical use.

关键词： 白细胞介素-1β   中枢神经特异蛋白   神经元特异性烯醇化酶   脑瘫   诊断  

摘要： 目的探讨血清神经元特异性烯醇化酶(NSE)、白细胞介素-1β(IL-1β)、中枢神经特异蛋白(S100-β)对脑瘫患儿的诊断价值。方法选取70例脑瘫患儿作为研究组,另选取20例参与体检的健康儿童作为对照组。检测并比较两组血清NSE、IL-1β、S100-β水平;比较两组体质量指数;分析血清IL-1β、S100-β、NSE对脑瘫的诊断效能。结果研究组体质量指数为(13.874±3.250)kg/m2,低于对照组的(17.294±3.547)kg/m2,差异有统计学意义(P<0.05)。研究组和对照组血清NSE、IL-1β、S100-β水平比较,差异均无统计学意义(P>0.05)。血清IL-1β的受试者工作特征曲线(ROC曲线)的曲线下面积(AUC)为0.583[95%CI=(0.432,0.734)],最佳截断值为1.985 pg/ml,敏感度为65.70%,特异度为55.00%;血清S100-β的AUC为0.573[95%CI=(0.430,0.715)],最佳截断值为0.475μg/L,敏感度为77.10%,特异度为30.00%;血清NSE的AUC为0.600[95%CI=(0.461,0.740)],最佳截断值为2.275 ng/ml,敏感度为77.10%,特异度为40.00%。结论血清NSE对脑瘫的诊断价值较低,血清IL-1β、S100-β对脑瘫不具有诊断价值。

关键词： Signaling bias   Biased ligands   GPCRs   Biophysics   Molecular dynamics   5-HT   1A   R/5-HT   1B   R/5-HT   2A   R/5-HT   2B   R   serotonin receptors type 1A, 1B, 2A, 2B   A   2A   R   adenosine receptor type 2A   ACKR3   atypical chemokine receptor type 3   aMD   accelerated molecular dynamics   AngII   angiotensin II   AT   1   R   angiotensin II receptor type 1   AWH   accelerated weighted histogram   BAM   biased allosteric modulator   cAMP   3′,5′-cyclic adenosine monophosphate   CB   1/2   R   cannabinoid receptor type 1/2   CG-MD   coarse-grained molecular dynamics   CMAP   contact map   CNS   central nervous system   cryo-EM   cryogenic electron microscopy   CVs   collective variable(s)   CXCR4   CXC chemokine receptor type 4   DAG   diacylglycerol   DEER   double electron-electron resonance   EBP   extended binding pocket (for 5-HT   2A   R   ECL1/2/3   first/s/third extracellular loop   EGFR   epidermal growth factor receptor   EPR   electron paramagnetic resonance   ERK   extracellular signal-regulated kinase   FDA   Food and Drug Administration   (sm)FRET   single-molecule Förster resonance energy transfer   GaMD   Gaussian accelerated molecular dynamics   GEF   guanine exchange factor   GIRK   G protein-gated inwardly rectifying potassium channels   GPCR   G protein-coupled receptor   GRK   G protein-coupled receptor kinase   H8   helix 8   HDX-MS   hydrogen‑deuterium exchange mass spectrometry   HMQC   heteronuclear multiple quantum coherence   HRFMS   hydroxyl radical mediated protein foot-printing with mass spectrometry   HSQC   heteronuclear single quantum coherence   ICL1/2/3   first/s/third intracellular loop   IL   interleukin   IP3   inositol 1,4,5-trisphosphate   M2R   muscarine receptor type 2   MAPK   mitogen-activated protein kinase   MD   molecular dynamics   MetaD   metadynamics   mtfF   3′-trifluoromethyl-phenylalanine   MTSLs   methanethiosulfonate spin labels   NAM   negative allosteric modulator   NMR   nuclear magnetic resonance   PAM   positive allosteric modulator   pAS   pseudo-active state   PCVs   path collective variables   PCV-MetaD   metadynamics performed with path collective variables   PDB   Protein Data Bank   PROXYL   2,2,5,5-tetramethyl-1-pyrrolidinyloxy   PTM   post-translational modification   REMD   replica-exch  

摘要： G protein-coupled receptors (GPCRs) are a ubiquitous family of transmembrane proteins essential for signal transduction and serve as key targets for numerous drug classes. A single GPCR often mediates multiple, largely independent pathways, which can sometimes be selectively modulated by biased ligands that preferentially activate specific signaling routes. These molecules stabilize distinct receptor conformations, with even subtle structural variations capable of driving different cellular responses. Capturing the conformations responsible for biased signaling, however, often proves challenging with traditional experimental techniques. Recent advances in experimental methods, coupled with computational modeling, have shed new light on the structural mechanisms underlying biased signaling. This review highlights therapeutically relevant examples, focusing on mechanisms such as (i) partial occupation of the orthosteric pocket, resulting in submaximal activation, and (ii) binding to alternative sites via bitopic or allosteric compounds. Emphasis is placed on studies that integrate biophysical and computational approaches, demonstrating their synergistic potential to unravel the complexities of GPCR signaling. This combined strategy paves the way for the rational design of innovative drugs with greater precision and therapeutic efficacy.

关键词： 肺结核   能谱CT成像   腺苷脱氨酶   白细胞介素-34   细胞因子信号转导抑制因子1   诊断  

摘要： 目的:探讨能谱CT成像联合血清腺苷脱氨酶(ADA)、白细胞介素-34(IL-34)及细胞因子信号转导抑制因子1(SOCS1)水平在肺结核诊断中的应用价值。方法:将本院2021年1月至2023年1月收治的76例肺结核患者作为研究组,另选取同期体检健康志愿者124例为对照组。研究组根据抗结核治疗预后情况,分为预后良好组52例、预后不良组24例。分析能谱CT成像和ADA、IL-34、SOCS1对肺结核的诊断价值,并分析其对抗结核治疗预后的评估作用。结果:能谱CT成像联合ADA、IL-34、SOCS1诊断肺结核的灵敏度、特异度、阳性预测值、阴性预测值均显著高于单一诊断(P<0.05)。研究组ADA、IL-34水平明显高于对照组,SOCS1水平明显低于对照组,均存在显著差异(P<0.05);Pearson相关系数显示,能谱CT成像与ADA呈显著性正相关(r=0.538,P=0.000),能谱CT成像与IL-34呈显著性正相关(r=0.581,P=0.000),能谱CT成像与SOCS1呈显著性负相关(r=-0.563,P=0.000)。Logistic回归模型显示,CT评分、ADA、IL-34、SOCS1均是肺结核患者抗结核治疗预后不良的重要影响因素(P<0.05)。ROC曲线分析显示,联合预测患者预后不良的AUC=0.897,95%CI为0.829~0.964,灵敏度为0.875,特异度为0.808;与Az=0.5相比,存在显著差异(P<0.05)。结论:能谱CT成像联合血清ADA、IL-34及SOCS1水平在肺结核诊断中具有较高的诊断价值,且可对抗结核治疗预后情况进行评估,具有重要的临床应用价值。

关键词： HLA class I   Immunotherapy   PHLA binding   Pan-allele   T cell epitope  

摘要： Predicting peptide–HLA binding is crucial for advancing immunotherapy; however, current models face several challenges, including peptide length variability, HLA sequence similarity, and a lack of experimentally validated negative data. To address these issues, we present PHLA-SiNet, an efficient pipeline that combines innovative representations with a lightweight architecture. PHLA-SiNet introduces three key components: (1) ESM-Pep, a peptide representation derived from a pre-trained language model (ESM), enabling flexible and training-free embedding of variable-length peptides; (2) IC-HLA, an HLA representation that captures allele-specific discriminative features using information content from binding and non-binding peptides; and (3) SiNet, a Siamese neural network that aligns peptide and HLA embeddings, bringing true binders closer in feature space. Prioritizing sensitivity—essential for reliably identifying candidate binders in early-stage immunotherapy—PHLA-SiNet is rigorously validated across benchmarks, including comparisons of IC-HLA with standard HLA encodings, analysis of SiNet's internal representations, evaluations against 11 leading predictors, and performance assessments across diverse cancer types, rare and unseen HLA types. Through computational validation using molecular docking and analysis of clinical data related to the peptide-based vaccine KIF20A-66, PHLA-SiNet demonstrates strong predictive potential in real-world contexts and highlights HLA-B08:01 as a candidate restriction element for future biological investigation. Overall, PHLA-SiNet offers a generalizable, interpretable, and resource-efficient solution for PHLA binding prediction, with strong promise to accelerate personalized immunotherapy development.

关键词： Cardiology   Alloantibodies   Heart transplantation   Flow cytometry   Immunosuppression  

摘要： Purpose Heart transplantation (HTx) is an established method of treating patients with end-stage heart failure. Properly selected immunosuppression effectively reduces the risk of acute transplant rejection; however, it may also lead to various side effects including cardiac allograft vasculopathy (CAV), which is one of the most common causes of death in patients during the first year after HTx. There is an urgent need to develop new strategies for monitoring a patient's immune system to modify the immunosuppressive therapy, if needed. The purpose of this study is to compare the immune status of patients with diagnosed CAV ​+ ​to that of patients without CAV-. Material and methods We collected blood samples from patients long-term after transplantation: 19 clinically stable patients CAV+ and 19 CAV-. Immunological parameters were assessed by analyzing lymphocyte subpopulations with flow cytometry and detecting the presence of alloantibodies with the use of Luminex technology. Results Statistical analysis demonstrated significant differences between CAV+ and CAV- patients only within the group of patients with detected alloantibodies (AlloAb+). The most notable observation is that a significantly higher proportion of CAV ​+ ​AlloAb ​+ ​patients demonstrated the CD4 + T lymphocyte population expressing IL2 compared to CAV-AlloAb ​+ ​patients. Similarly, in these groups, we observed a prevalence of CD8 + lymphocytes expressing IFNγ+ and IL2+TNFα+IFNγ+. Conclusion Our study provides new evidence that the presence of alloantibodies in the bloodstream of patients after HTx impacts T cells activation and subsequent cytokine production. These data may facilitate establishing parameters that could help identify patients with a higher risk of CAV progression.