课程文献中心 更多>>

关键词： Jianpi Lishi Jiedu granules   IL-6/JAK/STAT3 signal pathway   Colorectal adenoma   Postoperative recurrence   Proteomics  

摘要： Globally, colorectal cancer (CRC) is the primary cause of cancer-related fatalities. Our previous study demonstrated the efficacy of Jianpi Lishi Jiedu Granules (JLJG) in preventing postoperative recurrence of colorectal adenoma (CRA). Building on this foundation, the current study aims to elucidate whether the mechanism by which JLJG prevents postoperative recurrence of CRA involves the classical JAK/STAT inflammatory signaling pathway and to assess its specific impact on this pathway. Utilizing proteomics, we discerned 143 differentially expressed proteins (DEPs) regulated by JLJG, whose functional roles are intimately linked to the JAK/STAT signaling pathway. Among these, we identified key proteins such as IL-6, JAK1, JAK2, STAT3, CCND1, MYC, BclXL, and SOCS3 that are regulated by JLJG and play pivotal roles in the JAK/STAT signaling cascade. Our findings indicate that the sustained activation of the IL-6/JAK/STAT3 signaling pathway is significantly associated with CRA recurrence. JLJG was found to effectively modulate the expression levels of these proteins, as well as the expression of downstream genes including BCL2, MCL1, P21, and JAK1, STAT3, thereby inhibiting the IL-6/JAK/ STAT3 signaling pathway. Consequently, this study demonstrates that JLJG prevents the postoperative recurrence of CRA by inhibiting the IL-6/JAK/STAT3 signaling pathway and its negative feedback loops.

关键词： Autoimmune diseases   Rheumatoid arthritis   Systemic lupus erythematosus   Systemic sclerosis   Idiopathic inflammatory myopathies   Primary Sjögren's syndrome   Metabolic reprogramming   2-DG   2-deoxyglucose   AKT   Protein Kinase B, PKB   AMPK   AMP kinase   BAFF   B cell-activating factor   CPT1   Carnitine palmitoyltransferase1   CPT1A   carnitine palmitoyl transferase 1   COX   coxidase   DAMPs   damage-associated molecular patterns   DCs   Dendritic cells   DIOC6   3′3-dihexyloxacarbocyanineiodide   DM   Dermatomyositis   DNT   double-negative T   ER   endoplasmic reticulum   FA   Fatty Acid   FKBP12   FK506-binding protein 12   G6PD   glucose-6-phosphate dehydrogenase   GAPDH   glyceraldehyde 3-phosphate dehydrogenase   GC   germinal center   Gln   glutamine   GLS   glutaminase   GLUT   glucose transporters   GPD1   3-phosphoglycerate dehydrogenase   GSH   glutathione   GZMK   Granzyme K   HIF-1   Hypoxia-Inducible Factor-1   HK   hexokinase   HKII   hexokinase II   HLA   Major Histocompatibility Complex   IIMs   Idiopathic Inflammatory Myopathies   IFN   Type I interferon   IFN-γ   Interferon-γ   IBM   Inclusion Body Myositis   IL-10   interleukin-10   IL-6   interleukin-6   IMNM   Immune-Mediated Necrotizing Myopathy   LDHA   lactate dehydrogenase   LKB1   liver kinase B1   MHC-1   Major-Histocompatibility Complex   mTORC1   mammalian Target Of Rapamycin   MRSS   Modified Rodnan Skin Score   NAC   N-acetylcysteine   NADH   Nicotinamide Adenine Dinucleotide   NXP2   Nuclear Matrix Protein 2   NLRP3   NOD-like receptor thermal protein domain associated protein 3   NO   Nitric Oxide   OXPHOS   oxidative phosphorylation   PKM2   Pyruvate kinase M2   PM   Polymyositis   PPP   pentose phosphate pathway   pSS   Primary Sjögren's Syndrome   ROS   Reactive Oxygen Species   SGECs   salivary gland epithelial cells   SLE   Systemic Lupus Erythematosus   SNPs   single nucleotide polymorphisms   SS   Sjögren's Syndrome   TCA   Tricarboxylic acid   TGF-β   transforming growth factor-beta   Tfh   Follicular helper T cells   TIF1   Transcriptional Intermediary Factor 1   TLRs   Toll-like receptors   Trm   tissue-resident memory T cells   TNF-α   tumor necrosis factor-alpha  

摘要： AbstractAutoimmune diseases occur when the immune system abnormally attacks the body's normal tissues, causing inflammation and damage. Each disease has unique immune and metabolic dysfunctions during pathogenesis. In rheumatoid arthritis (RA), immune cells have different metabolic patterns and mitochondrial/lysosomal dysfunctions at different disease stages. In systemic lupus erythematosus (SLE), type I interferon (IFN) causes immune cell metabolic dysregulation, linking activation to metabolic shifts that may worsen the disease. In systemic sclerosis (SSc), mitochondrial changes affect fibroblast metabolism and the immune response. Idiopathic inflammatory myopathies (IIMs) patients have mitochondrial and metabolic issues. In primary Sjögren's syndrome (pSS), immune cell metabolism is imbalanced and mitochondrial damage can lead to cell/tissue damage. Metabolic reprogramming links cellular energy needs and immune dysfunctions, causing inflammation, damage, and symptoms in these diseases. It also affects immune cell functions like differentiation, proliferation, and secretion. This review discusses the potential of targeting metabolic pathways to restore immune balance, offering directions for future autoimmune disease research and treatment.

关键词： acetylation   EPAC   histone   IL-10   lactic acid   regulatory B cells  

摘要： Tumor cells are known to enhance glycolysis, even under normoxic conditions, via the Warburg effect, producing excess lactic acid in the tumor microenvironment. Lactic acid enhances the IL-23/IL-17 pathway and induces chronic inflammation. The acidic microenvironment formed by lactic acid suppresses immune cell proliferation and activation. In the present study, we clarified that lactic acid had two novel activities for immune cells. First, lactic acid specifically enhanced acetylation at lysine 27 of histone H3 (H3K27ac) in splenic B cells and monocytes/macrophages, and this epigenetically up-regulates the expression of genes. Acetylation and methylation of other residues of histone H3 were rarely induced. Second, lactic acid induced a particularly-marked enhancement of Il10 gene expression in B cells, leading to an increase in IL-10-producing regulatory B (Breg) cells. Furthermore, two pathways should be involved in both the enhancement of H3K27ac and the induction of Breg cells by lactic acid: a direct pathway that enhances the CD40 signal in B cells, and an indirect pathway that affects B cells by activating the exchange protein directly activated by cAMP (EPAC) 1/2 in non-B cells. In tumor-bearing mice, the levels of H3K27ac of tumor-infiltrating B cells were significantly higher than splenic B cells and were suppressed by intraperitoneal injection of the EPAC1/2 inhibitor. In conclusion, tumor-derived lactic acid increases H3K27ac and IL-10-producing Breg cells, causing the suppression of anti-tumor immunity.

关键词： Network Pharmacology   Ayurveda   Traditional Chinese Medicines   Interstitial Lung Diseases   Interstitial Pneumonia   Idiopathic Pulmonary Fibrosis   Pneumoconiosis   Sarcoidosis   AEC   Alveolar Epithelial Cells   AI   Artificial Intelligence   AIP   Acute Interstitial Pneumonia   AKT   Protein Kinase B   AMPK   AMP-Activated Protein Kinase   AMs   Alveolar Macrophages   ATS   American Thoracic Society   BAL   Bronchoalveolar Lavage   BATMAN-TCM   Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine   BLM   Bleomycin   BSYD   Bu-Shen-Yi-Qi Decoction   CASP4   Caspase 4   CCL18   Chemokine C–C Motif Ligand 18   cGAS-STING   Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes   COP   Cryptogenic Organizing Pneumonia   COPD   Chronic Obstructive Pulmonary Disease   CoToD   Comparative Toxicogenomics Database   COVID-19   Coronavirus Disease 2019   COX-2   Cyclooxygenase-2   CREB   cAMP Response Element-Binding Protein   DIP   Desquamative Interstitial Pneumonia   DisGeNET   Disease Gene Network   DTI   Drug-Target Interaction   ECM   Extracellular Matrix   EGF   Epidermal Growth Factor   EGFR   Epidermal Growth Factor Receptor   EMT   Epithelial-Mesenchymal Transition   ErILDs   Exposure-related Interstitial Lung Diseases   ERK   Extracellular Signal-Regulated Kinase   ETCM   Encyclopedia of Traditional Chinese Medicine   FDA   Food and Drug Administration   FGFR   Fibroblast Growth Factor Receptors   FOX   Forkhead Box   FOXO-3a   Forkhead Box O3a   GERD   Gastro-Oesophageal Reflux Disease   GPX4   Glutathione Peroxidase 4   HERB   Database for Traditional Chinese Medicine Herbs   HGF   Hepatocyte Growth Factor   HIF   Hypoxia-Inducible Factor   HIF-1α   Hypoxia-Inducible Factor 1-Alpha   HPLC   High-Performance Liquid Chromatography   IgA   Immunoglobulin A   IGF-1   Insulin Growth Factor 1   IgG   Immunoglobulin G   IIM-ILD   Idiopathic Inflammatory Myopathies-Interstitial Lung Disease   IIP   Idiopathic Interstitial Pneumonia   IL-6   Interleukin 6   IL-8   Interleukin 8   ILD   Interstitial Lung Disease   ILDs   Interstitial Lung Diseases   IPF   Idiopathic Pulmonary Fibrosis   JAK   Janus Kinase   JAK/STAT   Janus Kinase/Signal Transducer and Activator of Transcription   KDR   Kinase Insert Domain  

摘要： This review explores the progressive domain of network pharmacology and its potential to revolutionize therapeutic approaches for Interstitial Lung Diseases (ILDs), a collective term encompassing Interstitial Pneumonia, Pneumoconiosis, Connective Tissue Disease-related ILDs, and Sarcoidosis. The exploration focuses on the profound legacy of traditional medicines, particularly Ayurveda and Traditional Chinese Medicines (TCM), and their largely unexplored capacity in ILD treatment. These ancient healing systems, characterized by their holistic methodologies and multifaceted treatment modalities, offer a promising foundation for discovering innovative therapeutic strategies. Moreover, the review underscores the amalgamation of artificial intelligence (AI) and machine learning (ML) methodologies with bioinformatics, creating a computational synergy capable of deciphering the intricate biological networks associated with ILDs. Network pharmacology has tailored the hypothesis from the conventional “one target, one drug” towards a “network target, multi-component therapeutics” approach. The fusion of traditional literature and computational technology can unveil novel drugs, targets, and pathways, augmenting effective therapies and diminishing adverse effects related to current medications. In conclusion, this review provides a comprehensive exposition of how Network Pharmacology tools can leverage the insights of Ayurveda and TCM to craft efficacious therapeutic solutions for ILDs. It sets the stage for future investigations in this captivating interdisciplinary domain, validating the use of traditional medicines worldwide.

关键词： NLRP3 inflammasome   NEK7   NLRP3-NEK7   Inhibitors  

摘要： Aberrant activation of NLRP3 inflammasome is involved in various inflammatory diseases, making it a promising target for therapeutic intervention. NEK7, a member of the NIMA-related kinase (NEK) family, functions as a key NLRP3-binding protein and plays a crucial role in the regulation of NLRP3 inflammasome assembly and activation. Thus, disrupting NLRP3-NEK7 interactions by targeting NEK7 could be a promising strategy to inhibit the activation of NLRP3 inflammasome. In this work, a series of novel urea derivatives were designed and synthesized based on the reported NEK7 inhibitors. Among these, compound 23 exhibited potent activity against IL-1/3 release with low cytotoxicity. Moreover, compound 23 enhanced the thermal stability of NEK7 and disrupted the NLRP3-NEK7 interaction, thereby regulating NLRP3 inflammasome assembly.

关键词： 家禽养殖   禽白血病病毒   单克隆抗体   杆状病毒表达系统  

摘要： 为提高禽类养殖场对禽白血病病毒(Avian Leukosis Virus,ALV)的检测效率,采用原核表达系统制备J亚群禽白血病病毒(Avian Leukosis Virus Subgroup J,ALV-J)的P27蛋白,并基于该蛋白制备了高特异性的单克隆抗体。首先,通过BABL/c小鼠抗原免疫反应,获得杂交瘤细胞株诱生的小鼠腹水。随后,利用辛酸-硫酸铵沉淀法和Protein G琼脂凝胶亲和层析柱法对腹水中的单克隆抗体进行纯化。通过酶联免疫吸附试验(Enzyme linked immunosorbent assay,ELISA)对纯化抗体进行效价和特异性鉴定。最后,利用杆状病毒表达系统表达的P27蛋白检测制备的抗体的特异性。研究结果显示,本实验成功获得了4株杂交瘤细胞(3C9、1H15、1H6和7G2)。其中,作为酶标抗体的7G2表现出最佳性能,而3C9则为最佳抗原。间接免疫荧光法(Indirect Immunofluorescence Assay,IFA)的结果显示,单克隆抗体能够与表达禽白血病P27的杆状病毒发生特异性反应。这表明禽白血病病毒P27蛋白单克隆抗体制备成功。

关键词： 骨包虫病   包虫抗原B   RANKL/NF-κB/TAK1   TAZ   破骨细胞分化  

摘要： 目的探讨包虫抗原B(hydatid antigen-B,Hyd-B)促进破骨细胞发生的分子机制。方法细胞实验分组-1:BMSCs细胞分为Control组、MCSF+RANKL组和MCSF+RANKL+Hyd-B组;使用巨噬细胞集落刺激因子(macrophage colony-stimulating factor,MCSF)联合可溶性核因子κB受体激活配体(receptor activator of nuclear factor-κb ligand,RANKL),外加/不加Hyd-B联合诱导骨髓间充质干细胞(bone marrow mesenchymal stem cells,BMSCs)向破骨细胞分化。细胞实验分组-2:BMSCs细胞分为Ctrl组和Hyd-B处理组(Treat组)。免疫共沉淀(co-IP)法测定Hyd-B对TAZ(transcriptional coactivator with PDZ-binding motif)和TAK1(transforming growth factorβ-activated kinase 1)的直接相互作用的影响,使用抗TAK1抗体进行IP、IB检测TAZ的表达。细胞实验分组-3:BMSCs细胞分为Control组、MCSF+RANKL组、MCSF+RANKL+Hyd-B组、MCSF+RANKL+Hyd-B+TAZ-OE组和MCSF+RANKL+Hyd-B+OE-vector组。BMSCs转染腺病毒-TAZ OE或腺病毒-OE vector介导过表达TAZ。qPCR法检测破骨细胞分化标志物TRAP和Cathepsin K mRNA相对表达水平。蛋白质印迹检测细胞核p-P65、细胞质P65、细胞核NFATc1、p-AKT、AKT、p-ERK 1/2、ERK 1/2、p-TAZ、TAZ和TAK1的表达水平。结果与Control组比较,MCSF+RANKL组和MCSF+RANKL+Hyd-B组细胞TRAP和Cathepsin K mRNA水平升高(P<0.05);p-P65、p-AKT、p-ERK 1/2水平升高(P<0.05);细胞核内p-P65和NFATc1的水平升高(P<0.05)。与MCSF+RANKL组相比较,MCSF+RANKL+Hyd-B组细胞上述指标表达水平进一步升高(P<0.05)。与MCSF+RANKL+Hyd-B组相比较,MCSF+RANKL+Hyd-B+TAZ OE组细胞上述指标表达水平降低(P<0.05)。Co-IP结果,与Ctrl组相比较,Treat组中TAZ与TAK1的相互作用增加(P<0.05)。与Ctrl组相比较,Treat组中细胞质p-TAZ磷酸化水平增加(P<0.05),TAZ表达水平降低(P<0.05)。结论Hyd-B通过抑制TAZ上调RANKL/NF-κB/TAK1介导的破骨细胞发生。

关键词： Sevoflurane   IL-17A   Neuroinflammation   Neurodevelopment   Cognitive impairment   Neuron   ERK  

摘要： Increasing numbers of animal studies have shown that repeat sevoflurane exposure during developmental stage may lead to long-term cognitive impairment. Nevertheless, the exact pathogenesis remains unclear. Interleukin 17A (IL-17A) has been associated with cognitive decline in various neurological disorders. Here we found that the expression of IL-17A was up-regulated in hippocampus of sevoflurane exposed neonatal mice. Genetic deletion of IL-17A or inhibition of IL-17A improved behavioral function and down-regulated neuroinflammation related genes, interleukin 1n (IL-1n), interleukin 6 (IL-6), Nicotinamide adenine dinucleotide phosphate(NADPH) oxidase 2 (NOX2) and NADPH oxidase 4 (NOX4) in hippocampus of sevoflurane exposed neonatal mice. Moreover, negative regulation of IL-17A/Interleukin 17A receptor(IL-17RA) promoted the extracellular signal- regulated protein kinase (ERK) signaling pathway and nucleation of cyclic adenosine monophosphate (cAMP) response element-binding (CREB) in neurons of cognitive impaired mice. Knockdown of IL-17A in vivo identified neurons-localized IL-17A as a major factor in neuroinflammation and neurodevelopment. Collectively, our results suggested that IL-17A was required for the pathogenesis of neuroinflammatory response and identify IL-17A as a potential therapeutic target for cognitive impairment exposed by general anesthetics during infancy.

关键词： α-Hemolysin protein   Aptamer   Real-time PCR   Apta-qPCR  

摘要： AbstractAlpha-toxin of Staphylococcus aureus belongs to the pore-forming toxin (PFT) family, which can lyse red and white blood cells. In addition to the existence of the hla gene in the majority of S. aureus strains (about 95 %), higher expression exhibits enhanced pathogenicity to the bacteria. Various methods, such as antibodies and aptamers, could serve to detect this toxin. In the current study, for the first time, an improved sandwich aptamer-antibody-based method was developed using specific murine polyclonal antibodies and a specific aptamer to detect a wide range of α-toxin levels. Denatured recombinant α-toxin was administered to mice to trigger the production of specific antibodies, which were subsequently purified from immune sera. These antibodies served as capturers in the designed apta-qPCR assay, with an aptamer employed as a detector. The results showed that spiked α-toxin in the undiluted serum samples could detect α-toxin between 300 and 0.5 ng/mL with no cross-reactivity. The coefficient of variation (CV) percent of intra- and inter-assays were 0.84 and 1.06, respectively. Since in the apta-qPCR assay, a combination of specific polyclonal antibodies as capture and specific aptamer along with real-time PCR (qPCR) sensitivity is used, this robust method could be used in diagnostic laboratories to detect various levels of the toxin in human serum samples.