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关键词： Neuroimmunology   Pediatric Demyelinating Disease   Early Stage Investigator  

关键词： gut microbiota   cytokine   claudin-3   lipopolysaccaride-binding protein   intercellular adhesion molecule 1   AST   Aspartate aminotransferase   ALT   Alanine transaminase   APRi   AST-to-platelet ratio index   BA   Biliary atresia   GGT   Gamma-glutamyl transferase   ICAM-1   Intercellular adhesion molecule 1   IFABP   Intestinal fatty acid binding protein   IL   Interleukin   IFNγ   Interferon gamma   LT   Liver transplantation   LPS   Lipopolysaccharide   LSM   Liver Stiffness Measurement   LBP   Lipopolysaccharide binding protein   TNFα   Tumor necrosis factor alpha   TB   Total bilirubin   VCAM-1   Vascular cell adhesion molecule 1  

摘要： Objective: To explore the relationship among bacterial translocation, intestinal barrier integrity, and systemic inflammation in early biliary atresia (BA). Study design: Newly diagnosed infants with BA were assessed longitudinally before as well as 6, 12, and 24 weeks after undergoing Kasai portoenterostomy. Plasma immune marker measurement included interleukin (IL)-2, interferon-gamma (IFN gamma), IL-4, IL-10, tumor necrosis factor alpha, IL-6, IL-8, IL-1 beta, IL-17, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Bacterial translocation (lipopolysaccharide binding protein [LBP];D-lactate), intestinal barrier (claudin-3;intestinal fatty acid binding protein [IFABP], fecal calprotectin) biomarkers, and fecal microbiota genus abundance were analyzed. Results: Fifty-five infants were included, of whom 60% cleared their jaundice. Early post-Kasai, upregulation of plasma adhesion molecules and pro-inflammatory cytokines were associated with poorer jaundice clearance and liver fibrosis and correlated with jaundice severity. Elevated claudin-3 early post-Kasai was associated with poor jaundice clearance [OR 1.02 (1.00, 1.04);P = .02] and jaundice severity [P < .01]. On multivariable analysis, early ICAM-1 elevation (OR 1.008 [1.002, 1.014];P = .01) and claudin-3 (OR 1.038 [1.009, 1.068];P = .02), represented independent prognostic markers for persistent jaundice. Increased longitudinal trends of LBP (OR 0.79 [0.71, 0.89];P < .01) and IFABP (OR <0.01 [2.4E-43, 0.24];P = .04) were associated with poor jaundice clearance. LBP positively correlated with pro-inflammatory-cytokines (IL-6, P < .01: TNF alpha, P < .01) and ICAM-1 (P < .01) early post-Kasai. Fecal calprotectin positively correlated with jaundice severity (P < .01) by 24 weeks post-Kasai. No correlation between fecal microbiota abundance and bacterial translocation/intestinal integrity markers was demonstrated. Conclusions: Bacterial translocation may be linked to post-K

关键词： Chronic obstructive pulmonary disease   Interleukin-36   Airway inflammation   Emphysema   Skeletal muscle dysfunction  

摘要： Chronic inflammation is a crucial driver in the development of chronic obstructive pulmonary disease (COPD) and its comorbidities, such as skeletal muscle dysfunction. Heightened IL-36 expression in the lung and systemic circulation has been observed in patients with COPD, but the potential role of IL-36 in COPD still needs further exploration. Herein, we established a COPD model through long-term cigarette smoke (CS) exposure in mice with or without IL-36R deletion. Elevated IL-36 cytokines were observed in the lung and peripheral blood of CS-exposed wild-type mice. IL-36R gene deficiency attenuated CS-induced lung parenchymal destruction and airway inflammation, as evidenced by decreased secretion of inflammatory mediators, such as IL-6, IL-1 beta, TNF-alpha and MMP9, and a diminished Th1/Tc1-and Tfh-biased immune response. In addition, skeletal muscle dysfunction was alleviated in CS-exposed mice by IL-36R deletion. Further investigations indicated that CS treatment induced the expression of IL-36 cytokines and IL-36R in C2C12 myotubes and skeletal muscles, and that IL-36 cytokines could upregulate FBXO32 and TRIM63 expression by activating NF-kappa B p65 pathway, thereby leading to skeletal muscle atrophy in an endocrine and autocrine/paracrine manner. Our findings provide evidence for a critical role of the IL-36/IL-36R signaling in the pathogenesis of CS-induced COPD and comorbid skeletal muscle dysfunction.

关键词： Collagen-induced arthritis   Fibroblast-like synoviocytes   Fraxetin   MAPKs   MEK inhibitor   Rheumatoid arthritis  

摘要： Rheumatoid arthritis (RA) is a chronic autoimmune disease that profoundly affects patients' lives. Developing new treatments by screening small molecule compounds targeting RA-related signaling pathways is a key area of research. This study employs bioinformatics analysis, Western blotting, and cellular thermal shift assay (CETSA) to demonstrate, for the first time, that fraxetin may function as a novel natural MEK inhibitor, modulating RA pathogenesis via the MEK/ERK signaling pathway. We further evaluated fraxetin's therapeutic effects on collagen-induced arthritis (CIA) in rats in vivo and its inhibitory effects on TNFα-induced arthritic fibroblast-like synoviocytes (FLSs) in vitro. The results showed that fraxetin significantly alleviated ankle joint inflammation and bone destruction in CIA rats and markedly suppressed TNFα-induced proliferation, migration, and cytokine secretion (IL-1β, IL-6, and TNFα) in arthritic FLSs. These findings highlight fraxetin's potential as a promising therapeutic agent for RA.

关键词： Psoriasis   Autoimmune disorder   PDB ID   Keratinocytes   Target proteins   Skin inflammation   Abbreviation   Full Form   ACKR2   Atypical Chemokine Receptor 2   AQP3   Aquaporin-3   CARD14   Caspase Recruitment Domain Family Member 14   CALML3   Calmodulin-Like Protein 3   CXCL10   C-X-C Motif Chemokine Ligand 10   CYR61   Cysteine-rich angiogenic inducer 61   DC-LAMP   Dendritic Cell-Lysosome Associated Membrane Protein   DC-SIGN   Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin   FABP4   Fatty Acid Binding Protein 4   GPCR   G-Protein Coupled Receptor   GPR43   G-Protein Coupled Receptor 43   HLA   Human Leukocyte Antigen   IDO   Indoleamine 2,3-Dioxygenase   IL   Interleukin   JAK   Janus Kinase   KC   Keratinocyte   KPNA2   Karyopherin Subunit Alpha 2   KYNU   Kynureninase   LCE   Late Cornified Envelope   LL37   Cathelicidin Antimicrobial Peptide   NF-κB   Nuclear Factor kappa-light-chain-enhancer of activated B cells   NFKBIZ   Nuclear Factor Kappa B Inhibitor Zeta   PDB   Protein Data Bank   PK2   Prokineticin 2   POMP   Proteasome Maturation Protein   RORγt   Retinoic acid-Related Orphan Receptor Gamma t   Skp2   S-phase Kinase-Associated Protein 2   SOX9   SRY-Box Transcription Factor 9   SRC-1   Steroid Receptor Coactivator-1   STAT   Signal Transducer and Activator of Transcription   sAPPα   Soluble Amyloid Precursor Protein Alpha   TNF   Tumor Necrosis Factor   TNIP1   TNFAIP3-Interacting Protein 1   TWEAK   TNF-like Weak Inducer of Apoptosis   UVB   Ultraviolet B radiation   YKL-40   Chitinase-3-Like Protein 1  

摘要： Over 125 million individuals worldwide suffer from psoriasis, a chronic inflammatory skin condition that is immune-mediated. It is often linked to systemic comorbidities such psoriatic arthritis, cardiovascular disease, and mental health conditions. It is characterised by erythematous plaques, itching, and scaling. Psoriasis is caused by a complex interaction of environmental factors, genetic predisposition, and dysregulated immune responses, which leads to chronic inflammation and keratinocyte hyperproliferation. This review examines the treatment potential of important protein targets linked to psoriasis. Transcriptional regulators that affect inflammatory cascades and immune cell behavior include ACKR2, NFKBIZ, and TNIP1. Proteins like PK2 and KPNA2 affect the growth and differentiation of keratinocytes, and kynurenine pathway enzymes like KYNU and IDO lead to immunological imbalance. Inflammatory mediators like CXCL10 and CYR61, as well as antimicrobial peptides like LL37 and S100A15, are significantly increased in psoriatic lesions and maintain the chronic inflammatory state. Using information from the Protein Data Bank (PDB), the review also looks at the structural biology of these proteins, providing insights into molecular interactions and drug-binding sites. The study highlights the importance of these proteins in promoting individualised psoriasis treatment by combining molecular targeting techniques with new biologic treatments. This review surveys molecular proteins implicated in psoriasis, focusing on their potential as biomarkers or therapeutic targets. While many, such as CXCL10 or S100A15, are broadly involved in inflammatory cascades, others like LL37, TNIP1, and RORγt exhibit roles more uniquely tied to psoriatic pathology and may underpin future personalized treatment approaches.

关键词： Colorectal cancer   Lipid droplets   Metformin   Monocyte subsets   NF-κB p65/RelA   NLRP3 inflammasome   Tumor microenvironment   Tumor-conditioned medium  

摘要： Background Colorectal cancer (CRC) generates a complex tumor microenvironment (TME) known to profoundly alter the function and phenotype of immune cells, including monocytes. Key aspects of this environment can be mimicked by tumor-conditioned medium (TCM). Metformin has emerged as a promising candidate to counteract TCM-induced immune and inflammatory dysregulation. Therefore, this study aimed to evaluate the effects of metformin on NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome expression, monocyte subset distribution, and lipid droplet (LD) accumulation upon exposure to colorectal TCM. Methods Assays were performed on primary human monocytes exposed to colorectal TCM in the presence or absence of metformin. Results TCM significantly increased nitric oxide (NO, p  < 0.001) and hydrogen peroxide (H 2 O 2 , p  < 0.001) production, intracellular free calcium ions ( if Ca 2+ ) ( p  < 0.001) levels, expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB p65/RelA, p  < 0.001), NLRP3 ( p  < 0.01), and interleukin-1 beta (IL-1β, p  < 0.0001), as well as intracellular triacylglycerols ( i TAGs, p  < 0.05), total cellular cholesterol content ( tcc CHOL, p  < 0.001), and lipid droplet accumulation ( p  < 0.05). It also impaired phagocytic activity ( p  < 0.05) and altered monocyte phenotype, along with a shift toward a CD14 low , CD16 high phenotype ( p  < 0.0001 for both markers). Notably, metformin treatment exerted broad and significant reversing effects, specifically on respiratory burst (NO, p  < 0.05; H 2 O 2 , p  < 0.01), if Ca 2+ levels ( p  < 0.01), NF-κB p65/RelA and NLRP3 expression, and IL-1β production ( p  < 0.0001 for all), and the lipid droplet accumulation ( p  < 0.0001), i TAGs ( p  < 0.001), and tcc CHOL ( p  < 0.01). Metformin also significantly restored CD14 expression ( p  < 0.05) and increased CD14 + monocyte frequency ( p  < 0.01), while reducing CD16 expression ( p  < 0.05) and CD16 + monocyte fre

关键词： Regulatory B cells   STING   IRF3   IL-35   Hemozoin   TLR9  

摘要： Augmented regulatory B cell (Breg) responses are commonly observed in malaria;however, the specific parasite components and Breg subtypes involved remain unclear. In this study, we investigated C57BL/6 mice infected with Plasmodium berghei ANKA, which induces cerebral malaria pathology, in comparison to P. yoelii YM, which does not. We found that distinct Breg types differentiated in response to these infections, driven by hemozoinmediated Toll-like receptor 9 activation. Interleukin-35-positive (IL-35+) Breg expansion occurred in P. yoelii YM-infected mice but not in those infected with P. berghei ANKA. We demonstrated that stimulator of interferon genes (STING)-mediated interferon regulatory factor 3 (IRF3) phosphorylation suppressed IL-35+ Breg differentiation, potentially contributing to experimental cerebral malaria (ECM). In contrast, P. yoelii YM infection activated IRF3 in a STING-independent manner, promoting IL-35+ Breg expansion. These findings highlight IL-35+ Bregs as key modulators in malarial immunopathology.

关键词： CAR-T cell therapy   CAR   chimeric antigen receptor T cell therapy   chimeric antigen receptor therapy   ICANS   immune effector cell-associated neurotoxicity syndrome   ANG1   angiopoietin 1   ANG2   angiopoietin 2   ASTCT   American Society for Transplantation and Cellular Therapy   Axi-cel   axicabtagene ciloleucel   B-ALL   B-cell acute lymphoblastic leukaemia   BBB   blood-brain barrier   BCMA   B-cell maturation antigen   BiTE   bispecific T cell engagers   Brexu-cel   brexucabtagene autoleucel   CAPD   Cornell Assessment of Pediatric Delirium   CAR   chimeric antigen receptor   CAR-NK   chimeric antigen receptor natural killer cell   CAR-T   chimeric antigen receptor T cell   CARTOX   CAR T-Cell Therapy–Associated Toxicity   Cas9   CRISPR-associated protein 9   CD   cluster of differentiation   Cilta-cel   ciltacabtagene autoleucel   CLL   chronic lymphocytic leukaemia   CNS   central nervous system   CRISP   Clustered Regularly Interspaced Short Palindromic Repeats   CRP   C-reactive protein   CRS   cytokine release syndrome   CSF   cerebrospinal fluid   CT   computed tomography   CTCAE   Common Terminology Criteria for Adverse Events   DAMPs   damage-associated molecular patterns   DLBCL   diffuse large B-cell lymphoma   EASIX   Endothelial Activation and Stress Index   EBMT   The European Society for Blood and Marrow Transplantation   EEG   electroencephalography   FDA   Food and Drug Administration   FDG-PET   Fluorodeoxyglucose Positron Emission Tomography   FIRDA   frontal intermittent rhythmic delta activity   GFAP   Glial Fibrillary Acidic Protein   GM-CSF   granulocyte–macrophage colony-stimulating factor   GPRC5DG   protein-coupled receptor, class C, group 5, member D   ICANS   immune-effector cell associated neurotoxicity syndrome   iCasp9   inducible caspase-9   ICE   immune effector cell-associated encephalopathy   Ide-cel   decabtagene vicleucel   IEC-HS   Immune Effector Cell-Associated Hemophagocytic Syndrome   IFNγ   interferon gamma   IL   interleukin   IVIg   intravenous immunoglobulin G   JAK   Janus kinase   LBCL   large B-cell lymphoma   Liso-cel   lisocabtagene maraleucel   MRI   magnetic resonance imaging   MNTs   movement and neurocognitive toxicities   NfL   neurofilament light chain   N  

摘要： Chimeric antigen receptor T cell (CAR-T) therapy involves reengineering patient-derived or donor-derived T cells to express a synthetic CAR that can recognise specific cell-surface antigens, independently of major histocompatibility complex molecules. As of March 2025, six autologous CAR-T cell products have received regulatory approval from the United States Food and Drug Administration (FDA) for B-cell derived haematological malignancies and multiple myeloma, delivering effective and durable treatment responses. All currently approved CAR-T cell therapy products target either CD19 or B-cell maturation antigen (BCMA). However, there is an expansive list of new CAR-T constructs and/or indications currently being explored in the pre-clinical stages and clinical trials. Although the therapeutic potential of CAR-T cell therapy is substantial, the more widespread application of CAR-T cell therapy faces challenges, including overcoming unique and clinically significant CAR-T therapy-associated toxicities, namely cytokine release syndrome (CRS) and immune-effector cell associated neurotoxicity syndrome (ICANS). CAR-T cell-associated neurotoxicity can present with a diverse range of neurological and cognitive symptoms and signs, including tremor, dysgraphia, cognitive dysfunction, aphasia, seizures, and rarely cerebral oedema and death. As new CAR-T constructs and indications enter the therapeutic landscape, new class-specific toxicities have also emerged, including delayed-onset neurotoxicity with features of parkinsonism, as seen with BCMA-directed therapies in the pivotal clinical trials for multiple myeloma. Whilst much progress has been made in understanding CRS, comprehensive information about the clinical, biological and radiological correlates of CAR-T cell-associated neurotoxicity, and its mechanistic underpinnings remain largely unknown. Furthermore, prophylactic or pre-emptive intervention strategies have been hindered by the lack of predictive or diagnostic bio

关键词： Histone lactylation   Ischemic stroke   Plxnb2   Microglia   Neuroinflammation   CNS   Central nervous system   MCAO   Middle cerebral artery occlusion   pan kla   Pan lactylation   H3K18la   Histone H3 lysine 18 lactylation   NOR   Novel object recognition   MWM   Morris water maze   Ldha   Lactate dehydrogenase A   Plxnb2   Plexin-B2   Tnfa   Tumor necrosis factor-alpha   Tgfb   Transforming growth factor-β   Ifng   Interferon-γ   Arg1   Arginase 1   Il   Interleukin  

摘要： Microglia are major resident immune cells in the central nervous system and are actively involved in the pathogenesis of ischemic stroke. Histone lactylation confers macrophage homeostatic gene expressions and regulates physiological and immune-related pathological conditions. However, the spatiotemporal expression and functional role of histone lactylation in microglial reprogramming and neurological injuries after ischemic stroke remain elusive. In this study, we observed increased levels of histone lactylation in peri-infarct areas after the middle cerebral artery occlusion-induced focal cerebral ischemia in mice. The enhanced histone lactylation favored an anti-inflammatory micro-environment and provided neuroprotective effects after ischemia, which might be mediated by histone H3 lysine 18 lactylation (H3K18la)-regulated plxnb2 expression in microglia. Microglia-specific inhibition of plxnb2 abrogated the neuroprotective effects of lactate after ischemic stroke. These findings suggest that interventions aimed at the lactate/lactylation(H3K18la)/plxnb2 axis may represent a promising therapeutic strategy for ischemic stroke treatment.