课程文献中心 更多>>

关键词： Aspergillus fumigatus   IL-1β   Mycobacterium tuberculosis   NADPH oxidase complex   NOD2   TNF  

摘要： Aspergillus fumigatus may cause infections in individuals with underlying lung damage, such as those with pulmonary tuberculosis (TB). Simultaneous exposure to A. fumigatus and Mycobacterium tuberculosis may worsen lung tissue damage, but the combined immune response to these pathogens has not yet been fully characterized. Peripheral blood mononuclear cells (PBMCs) from healthy volunteers were stimulated with A. fumigatus conidia, M. tuberculosis H37Rv lysate, or both combined. TNF and IL-1β were measured from culture supernatants. The role of different pattern recognition receptors (PRRs) important for the recognition of both pathogens were explored by using PRR inhibitors and PBMCs from donors deficient in certain pathways. A. fumigatus and M. tuberculosis synergistically induced TNF and IL-1β release by PBMCs, and this response was independent of TLR2 and dectin-1. We found that the synergy is regulated through distinct intracellular pathways. The activation of the intracellular receptor NOD2 by M. tuberculosis and NADPH oxidase complex-dependent ROS production triggered by A. fumigatus mediate TNF but not IL-1β synergy. Together, these findings indicate that A. fumigatus and M. tuberculosis jointly exacerbate proinflammatory responses. This may help to explain the persistent inflammation and immunopathology observed in patients with concurrent TB and aspergillosis.

关键词： SIRT1   IL-6   Oxycodone tolerance   Deacetylation   MEK/ERK  

摘要： Oxycodone, an opioid analgesic, exhibits limited clinical utility due to the development of tolerance. This study aims to investigate the role of Sirtuin 1 (SIRT1), a histone deacetylase, in oxycodone-induced analgesic tolerance. Adult ICR mice were administered oxycodone subcutaneously once a day for seven consecutive days. The tail-flick test was used to establish a mouse model of oxycodone tolerance. RT-qPCR was employed to assess the mRNA levels of SIRT1-SIRT7. Western blotting was performed to measure the expression levels of SIRT1, interleukin (IL)-6, H3K9ac, H3K14ac, H3K18ac, total/phosphorylated extracellular signal-regulated kinase (ERK) (1/2), and mitogen-activated protein kinase/ERK kinase (MEK) (1/2). ChIP-qPCR were used to localize SIRT1/IL-6 expression, and to quantify histone acetylation at the IL-6 promoter. Mice developed analgesic tolerance by Day 7 of oxycodone administration. Oxycodone significantly reduced SIRT1 mRNA and protein levels in the lumbar spinal cord. Bioinformatics analysis identified IL-6 as the most prominently upregulated gene in the spinal cord. Correspondingly, IL-6 protein levels were elevated, along with increased levels of total H3K9ac (but not H3K14ac or H3K18ac) and enriched H3K9ac at the IL-6 promoter. While total ERK(1/2) and MEK(1/2) levels remained unchanged, their phosphorylated forms were significantly upregulated in tolerant mice. An SIRT1 agonist (SRT1720) inhibited the development of oxycodone tolerance, suppressed IL-6 overexpression, normalized H3K9ac and phospho-ERK/MEK levels, and reduced H3K9ac expression at the IL-6 promoter. Thus, SIRT1 promotes oxycodone tolerance by deacetylating histone H3K9 at the IL-6 promoter and activating the MEK/ERK pathway to upregulate IL-6 expression.

关键词： IL2RG   gene   hypomorphic mutation   interstitial lung disease   atypical severe combined immunodeficiency disease   Omenn syndrome   ILD   Interstitial lung disease   SCID   Severe combined immunodeficiency   Treg   Regulatory T  

摘要： In individuals with hypomorphic mutations of IL2RG , inflammatory or autoimmune disorders are rare. We present a child with prolonged and severe interstitial lung disease, Omenn-like syndrome, and a novel frameshift variant in IL2RG .

关键词： Angiotensin-(1–7)   Diabetes   Gut Permeability   Gut Microbiome   Inflammation   Myelopoiesis   ACE   Angiotensin-converting enzyme   Ang-(1-7)   Angiotensin-(1-7)   AT1R   Angiotensin II type 1 receptor   APC   Allophycocyanin   BM   Bone marrow   BM-sup   Bone marrow supernatant   BCA   Bicinchoninic acid   BSA   Boven serum albumin   CX3CR1   C-X3-C motif chemokine receptor 1   CXCL1   CXC motif chemokine ligand 1   CFU-GM   Colony-forming unit – granulocyte and macrophages   DAPI   4′,6-diamidino-2-phenylindole   Fas-L   Fas ligand   FITC   Fluorescein isothiocyanate   GSK-3   Glycogen synthase kinase-3   HSC   Hematopoietic stem cells   IFNγ   Interferon-gamma   IL   Interleukin   ISC   Intestinal stem cells   LBP   lipopolysaccharide-binding protein   Lgr   Leucine-rich repeat containing G protein-coupled receptor   LPS   Lipopolysaccharide   MasR   Mas receptor   MCP-1   Monocyte chemoattractant protein-1   M-CSF   Macrophage colony-stimulating factor   MD2   Myeloid differentiation protein 2   MIP1α   Macrophage inflammatory protein 1 alpha   MNC   Mononuclear cells   ND   Nondiabetic   Olfm   Olfactomedin   PBS   Phosphate buffered saline   PE   Phycoerythrin   PVDF   Polyvinylidene fluoride   RA   Relative abundance   RAS   Renin angiotensin system   SDS/PAGE   Sodium dodecyl-sulfate/polyacrylamide gel electrophoresis   STZ   Streptozotocin   TARC   Thymus and activation-regulated chemokine   TLR4   Toll-like receptor 4   TMAO   Trimethylamine N-oxide   TNFα   Tumor necrosis factor alpha   Wnt3   Wingless and Integration 1 proteins, member 3  

摘要： Diabetes promotes inflammation by compromising colon epithelial barrier integrity and upregulation of myelopoiesis in the bone marrow (BM). Angiotensin-(1–7) (Ang-(1–7)) is a cardiovascular protective peptide in diabetes. This study tested if Ang-(1–7) restores the colon epithelial barrier integrity and myelopoiesis in diabetes via restructuring dysbiotic gut microbiota and the BM-inflammatory landscape. Nondiabetic (ND) or streptozotocin-induced type 1 or db/db type 2 diabetic mice were treated with saline or Ang-(1–7). The intestinal permeability was evaluated by using FITC-dextran. Claudin1, occludin, Lgr5 + Olfm4 + intestinal stem cells (ISCs), Wnt3a and β-catenin were evaluated by immunohistochemistry or western blotting. Fecal microbiome was analyzed by 16S rRNA sequencing. Monocyte-macrophages were characterized by flow cytometry. Plasma trimethylamine N-oxide (TMAO) and lipopolysaccharide-binding protein (LBP) levels or BM-cytokines were quantified. Increased intestinal permeability in both models of diabetes was reversed by Ang-(1–7) ( P < 0.001, n = 5). In db/db colons, Wnt3a and the active β-catenin levels were lower compared to the ND, which were restored by Ang-(1–7). Monocytes and pro-inflammatory macrophages were higher diabetic mice that were decreased by Ang-(1–7), which was accompanied by decreased pro-inflammatory factors, IL6, M−CSF, leptin and others, in the db/db BM-supernatants. Ang-(1–7) increased Bacteroidetes over Firmicutes with abundance of Lactobacillaceae and Akkermansiaceae in the db/db gut microbiota, and decreased the plasma levels of TMAO and LBP in the plasma. The study provides compelling evidence for the pharmacological potential of Ang-(1–7) in ameliorating diabetic disruption of colon barrier integrity and inflammation by restoring the regenerative ISCs and by reversing myelopoiesis.

关键词： IL-11 signaling   Macrophage-TEC crosstalk   Neutralizing antibodies   Renal fibrosis   STAT3/ERK pathway  

摘要： Aims To investigate the pathogenic role of Interleukin-11 (IL-11) in chronic kidney disease (CKD) progression and evaluate the therapeutic potential of IL-11 neutralizing antibodies in attenuating renal inflammation and fibrosis. Materials and methods We conducted systematic molecular and cellular analyses to characterize IL-11-mediated signaling pathways in CKD models. The effects of IL-11 on macrophage polarization, cellular transitions, and stress responses were examined. Preclinical efficacy studies were performed using selective IL-11 neutralizing antibodies to assess their impact on renal pathology. Key findings IL-11 orchestrates renal injury through immune crosstalk between macrophages and tubular epithelial cells (TECs) via STAT3 signaling activation. IL-11 promotes M1 macrophage polarization, facilitates the macrophage-to-myofibroblast transition (MMT), and triggers epithelial-to-mesenchymal transition (EMT) in TECs. Additionally, IL-11 amplifies oxidative and endoplasmic reticulum stress responses. Treatment with IL-11 neutralizing antibodies effectively interrupted IL-11/IL-11Rα1 interaction and downstream STAT3/ERK1/2-mediated metadherin activation, resulting in reduced pro-fibrotic extracellular matrix deposition, enhanced TEC regenerative capacity, and improved renal parenchymal repair. Significance These findings establish the IL-11 signaling axis as a promising therapeutic target in CKD. The demonstrated efficacy of antibody-based interventions presents a novel precision medicine approach for CKD treatment, offering significant potential for clinical translation in nephrology.

关键词： ADC   Antibody-drug conjugate   AML   Acute myeloid leukemia   ALL   Acute lymphoblastic leukemia   Allo-HSCT   Allogeneic hematopoietic stem cell transplantation   BCL-2   B-cell lymphoma 2   BH   BCL-2 homology   BiTEs   Bispecific T-cell engagers   BiKEs   Bispecific killer-cell engagers   BPDCN   Blastic plasmacytoid dendritic cell neoplasm   CBL   Cbl proto-oncogene   CLL   Chronic lymphocytic leukemia   CR   Complete remission   CRh   Complete remission with partial hematologic recovery   CRi   Complete remission with incomplete hematologic recovery   CTLA-4   Cytotoxic T-lymphocyte-associated protein 4   DOT1L   Disruptor of telomeric silencing 1-like   EFS   Event-free survival   FGF2   Fibroblast growth factor 2   FL   FLT3 ligand   FLT3   FMS-related tyrosine kinase receptor 3   G-CSF   Granulocyte colony-stimulating factor   GO   Gemtuzumab ozogamicin   HDAC   Histone deacetylase   2-HG   2-Hydroxyglutarate   HLA   Human leukocyte antigen   HMA   Hypomethylating agent   HSC   Hematopoietic stem cell   HSP90   Heat shock protein 90   HSPC   Hematopoietic stem and progenitor cell   ICs   Immune checkpoints   IDH1/2   Isocitrate dehydrogenase 1/2   IDO1   Indoleamine 2,3-dioxygenase 1   IL-3Rα   Interleukin-3 receptor alpha chain   IRAK1/IRAK4   IL-1 receptor-associated kinases   ITD   Internal tandem duplication   α-KG   α-Ketoglutarate   LAG-3   Lymphocyte activation gene-3   LDAC   Low-dose cytarabine   LILRB4   Leukocyte immunoglobulin-like receptor B4   LSC   Leukemia stem cell   mAb   Monoclonal antibody   MDR   Multidrug resistance   MDS   Myelodysplastic syndromes   MDSC   Myeloid-derived suppressor cells   MHC   Major histocompatibility complex   NK   Natural killer   ORR   Overall response rate   OS   Overall survival   OxPHOS   Oxidative phosphorylation   PARP   Poly-ADP-ribose-polymerase   PBD   Pyrrolobenzodiazepine   PD-1   Programmed cell death protein 1   PD-L1   Programmed death-ligand 1   PFS   Progression-free survival   P-gp   P-glycoprotein   PI3K   Phosphatidylinositol 3-kinase   PROTAC   Proteolysis-targeting chimeras   PTCH1   Patched-1   RFS   Relapse-free survival   ROS   Reactive oxygen species   R/R AML   Refractory or relapsed AML   RTK   Receptor tyrosine kinase   RSK   Ribosomal S6 kinase   SIRPα   Signal regulatory protein  

摘要： Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by uncontrolled proliferation of immature myeloid blasts, leading to hematopoietic suppression and bone marrow failure. Advances in understanding the pathogenesis of AML have fueled the development of precision medicine approaches, with notable successes in targeting specific mutant proteins (e.g., FLT3, IDH1, IDH2), apoptotic regulators (e.g., BCL-2, MCL1), and cell-surface antigens (e.g., CD33, CD123, CD47). These targeted inhibitors exhibit moderate antileukemic activity as monotherapies and their clinical responses are often limited due to the emergence of drug resistance and disease relapse. Nevertheless, synergistic effects have been observed when these agents are combined with conventional chemotherapy or oncogenic pathway inhibitors. This review analyzes the current limitations of targeted therapies and explores multifaceted resistance drivers, encompassing on-target mutations, compensatory signaling pathway activation, drug-efflux mechanisms mediated by metabolic enzymes or transporters, intrinsic adaptive changes, and interactions with the tumor microenvironment. Corresponding therapeutic counterstrategies are also examined, such as mutation-specific molecular targeting, combinatorial suppression of alternative pathways, disruption of intrinsic adaptive responses, and immunotherapeutic approaches. These evolving interventions aim to overcome specific resistance mechanisms and reduce relapse rates. Future research integrating these strategies holds significant promise for addressing persistent challenges in AML management, ultimately advancing treatment paradigms and patient survival.

关键词： DNA damage   iNKT cells   AML   NF-kappa B   LncRNA   CD1d  

摘要： Acute myeloid leukemia (AML) is the most common and deadly type of leukemia with the high recurrence rates and poor prognosis. Despite extensive exploration of therapeutic strategies, there is currently no effective remedy for AML. Recently, there has been a growing focus on immunotherapeutic approaches for treating hematologic malignancies. CD1d-restricted invariant Natural Killer T (iNKT) cells have been recognized for their significant role in antitumor immunity. This study identified a potential therapeutic strategy based on the iNKT cells and demonstrated that treating AML cells with DNA damage agents can enhance iNKT cell-mediated cytotoxicity in vitro. Research has also demonstrated that DNA damage regulates CD1d gene transcription activity by specifically activating NF-kappa B/RELA. Additionally, lncRNA-HLA-DRB6 is involved in the targeted regulation of CD1d by RELA, thus promoting the stability of CD1d mRNA in the cytoplasm. The activation of the RELA/lncRNA-HLADRB6/CD1d pathway by DNA damage contributes to sensitizing AML cells to killing by iNKT cells. Furthermore, combination treatment with alpha-galactosylceramide (alpha-GalCer;which is an activator of iNKT cells) and DNA damage agents exhibited synergistic antitumor effects in vivo, which may be beneficial for alleviating the progression of AML. In conclusion, these findings provide information on the mechanism by which DNA damage in AML cells regulates iNKT cell activity, thus suggesting that the development of immune therapeutic strategies based on iNKT cells during chemotherapy may represent a potential avenue for AML treatment.

关键词： Orange-spotted grouper   MHC-I alpha   Polymorphism   Singapore grouper iridovirus (SGIV)   Red-spotted grouper nerve necrosis virus   RGNNV   Apoptosis  

摘要： The Major Histocompatibility Complex (MHC) is a group of tightly linked, highly polymorphic genes that play a critical role in vertebrate immune responses. MHC is closely associated with various diseases, including autoimmune disorders, antigen invasion, and inflammation. Notably, MHC class I (MHC-I) molecules exhibit extensive polymorphism and have the ability to specifically bind to a diverse array of viral antigens, which is crucial for antigen presentation and antiviral immunity. However, studies on the differential functions of different MHC-I genotypes in response to fish viral diseases are still scarce. In our previous research, we cloned three novel MHC-I alpha genotypes-EcMHC-IA*01, EcMHC-IA*02, and EcMHC-IA*03 based on transcriptomic data from SGIV-infected grouper spleen cells. It has been established that the EcMHC-IA*01 gene contributes to the resistance against SGIV infection. In this study, we investigated the differences in antiviral functions and apoptotic effects of EcMHC-IA*02 and EcMHC-IA*03. The full-length sequence homology of these two genotypes was 73.66 %, while the homology of the signal peptide was only 2.09 %. The polymorphism of domains may directly contribute to the functional differences among genotypes. Molecular characterization analysis revealed that EcMHC-IA*02 and EcMHC-IA*03 encoded 366-amino-acid and 357-amino-acid proteins, respectively, both containing typical domains of MHC class I molecules, including a signal peptide, MHC-I (alpha 1, alpha 2, alpha 3) domains, and a transmembrane region. Based on their conserved structural features, domain organization, and overall sequence similarity to known classical MHC-I molecules in other species, these two genotypes are presumed to be classical MHC class I genes. Subcellular localization analysis showed that EcMHC-IA*02 and EcMHC-IA*03 were distributed throughout the cytoplasm. Functional studies demonstrated that overexpression of EcMHC-IA*02 enhanced cytopathic effects (CPE), cell

关键词： Hydroxychloroquine   IgA nephropathy   network pharmacology   TNF   toll-like receptor signaling pathway  

摘要： Background IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis globally and has a high propensity to develop into end-stage renal disease (ESRD). Hydroxychloroquine has been proven to reduce proteinuria in IgAN patients, but the precise mechanism remains unclear. Therefore, network pharmacology was used to investigate the *** PubChem and SwissADME databases were utilized to acquire the structure of hydroxychloroquine. The SwissTargetPrediction, PharmMapper, DrugBank, TargetNet, and BATMAN-TCM databases were then utilized to obtain the targets. The target genes related to IgAN were then gathered from the databases, which included GeneCards, PHARMGKB, DrugBank, OMIM, and DisGeNET. Common targets were obtained by UniProt. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to define the main molecular mechanisms and pathways. Furthermore, a protein-protein interaction (PPI) network was constructed using the STRING tool, and the core targets were obtained by Cytoscape. Finally, molecular docking between the core targets and hydroxychloroquine was *** 167 common target genes were acquired by overlapping. The core targets were TNF, ALB, IL1B, JUN, FOS, SRC, and MMP9. The GO and KEGG results showed the targets to be related to the production of inflammatory cytokines and chemokines and were engaged in the toll-like receptor (TLR) signaling pathway. At the same time, the molecular docking results showed that the core targets all combined with hydroxychloroquine *** This study proved that hydroxychloroquine may treat IgAN through the TLR signaling pathway, and the restraint of TNF, TLR, IL1B, and JUN may be essential for the treatment.

关键词： Optical biosensor   Multi-resonance analysis   IL-6   IL-8   OSCC   Point-of-care diagnostics   Semi-distributed interferometer   Biomarker detection   Surface functionalization  

摘要： Biomarker-based diagnostics offer a promising approach for early cancer detection, while simultaneous analysis of multiple biomarkers can further improve disease diagnosis by enhancing sensitivity and specificity of the detection. This work presents a multi-resonance analysis strategy for the simultaneous detection of oral cancer biomarkers interleukin-6 and interleukin-8 in artificial saliva with a Fiber-Bragg grating-assisted semi-distributed interferometer-based probe. The analysis of the sensor response takes advantage of the entire spectral feature, which enhances the robustness and reliability of the detection results. Unlike single-feature approaches, multi-resonance analysis ensures greater resilience to spectral distortions, since the spectral features of the proposed sensor exhibit varying sensitivity to biomolecular interactions. The sensor demonstrated a limit of detection (LoD) of 480 aM for IL-6 and 23.4 fM for IL-8 in artificial saliva with high specificity to target proteins.