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关键词： B lymphocytes   Xiaoqinglong Decoction   Yupingfeng Powder   antigen presentation   combined allergic rhinitis and asthma syndrome   immune response   major histocompatibility complex II  

摘要： ETHNOPHARMACOLOGICAL RELEVANCE:Xiaoqinglong Decoction combined with Yupingfeng Powder (XQLDwYPFP) is widely used to treat allergic rhinitis and bronchial asthma in Traditional Chinese Medicine, while its efficacy and mechanisms in combined allergic rhinitis and asthma syndrome (CARAS) remain underexplored. AIM OF THE STUDY:To elucidate the mechanisms and pharmacodynamic basis of XQLDwYPFP in CARAS treatment. MATERIALS AND METHODS:A CARAS mouse model was established using ovalbumin (OVA). Airway allergic symptoms were assessed by recording nasal rubbing and sneezing frequencies. Serum OVA-sIgE levels were measured via ELISA. Histopathological changes were evaluated using HE, PAS, and C2R staining. Flow cytometry quantified Th cell subsets. Proteomics identified differential protein expression with GO and KEGG databases used for pathway enrichment analysis. Immunofluorescence assessed B lymphocyte activation, while Western blot and immunohistochemistry evaluated JAK1/JAK2-STAT1 pathway activation. Molecular docking validated the binding affinity of XQLDwYPFP components to JAK2 and STAT1. RESULTS:XQLDwYPFP alleviated airway symptoms, reduced serum OVA-sIgE, and inhibited goblet cell hyperplasia and eosinophil infiltration in nasal and lung tissues. It decreased Th2 cell proportions and increased the Th1/Th2 ratio in lung and spleen tissues. Proteomics revealed that XQLDwYPFP suppresses CARAS by targeting the MHC II-mediated antigen presentation pathway. The formula reduced activated B lymphocytes and downregulated JAK2, p-JAK2, STAT1, and p-STAT1 expression in nasal and lung tissues. XQLDwYPFP representative components exhibited strong binding affinity to JAK2 and STAT1. CONCLUSIONS:XQLDwYPFP alleviates type 2 inflammation in CARAS by regulating the JAK2-STAT1-MHC II pathway and inhibiting B lymphocyte-mediated antigen presentation. These findings provide novel pharmacological evidence supporting its clinical use for CARAS.

关键词： Cord blood transplantation   Graft failure   HLA-haploidentical transplantation   Hemophagocytic lymphohistiocytosis   Post-transplant cyclophosphamide  

摘要： We describe a case of immunological rejection occurring twice after cord blood transplantation (CBT) for mixed phenotype blast phase chronic myeloid leukemia that was successfully salvaged by haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) with post-transplant cyclophosphamide (PT-Cy). Pre-engraftment immune reaction (PIR) and subsequent hemophagocytic lymphohistiocytosis (HLH), likely due to HLA mismatch in the graft-versus-host (GVH) direction, lead to poor graft function (PGF) and graft failure (GF). This case highlights the pathophysiology of PIR, HLH, PGF, and GF, collectively termed "post-transplant cytokine syndrome." PT-Cy haplo-PBSCT, with wide donor availability and reduced infection risk leading to HLH via rapid engraftment, may be a suitable salvage option for post-CBT cytokine syndrome-related GF.

关键词： Arthritis   Biomarkers   Chalcone   Cytokines   Inflammation   Oxidative stress  

摘要： Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and chronic pain due to the degradation of subchondral bone and the loss of cartilage function. The present study was designed to evaluate the activity of 1N,N-dimethyl chalcone (DGCHAL) against RA. A primary 28-day investigation was conducted on adjuvant-induced arthritic rats with DGCHAL (10 mg/kg, 20 mg/kg, and 30 mg/kg) and methotrexate (STDMTX). The therapeutic effect was estimated on the basis of measurements of paw diameter, fluctuations in body weight, oxidative stress biomarkers, and hematological parameters. In addition, the study sought to quantify the expression of key cytokines, including TNFα, IL-6, IL-10, IL-1β, and NFκβ, using qRT-PCR and ELISA techniques. Treatment with DGCHAL significantly restored the paw volume, body weight, arthritis-induced anemia, and leukocyte count. The tested compound remarkably downregulated the expression of COX-2, TNFα, IL-6, IL-1β, and NFκB and upregulated the expression of IL-10. The treatment groups increased the activities of SOD, CAT, and GSH, whereas they reduced the formation of MDA and NO as compared to the arthritic group. These findings provide an evident basis for the anti-arthritic potential of DGCHAL in a chronic arthritis rat model and should be further studied for dosage form design.

摘要： Resistance to DNA damage is one of the primary mechanisms by which tumor cells evade the effects of standard chemotherapeutic agents and radiotherapy. Dynamic and complex interactions between the tumor microenvironment (TME) and tumor cells critically influence the DNA damage response. Interleukin-33 (IL-33) is a multifunctional cytokine secreted at high levels in response to cellular damage and stress. Recently, increasing evidence has suggested that IL-33 plays a key role in promoting the therapeutic resistance of tumors. However, the actual source of IL-33 during cancer therapy and how IL-33 contributes to a resistant TME remain incompletely understood. In this study, we found that both cancer-associated fibroblasts (CAFs) and tumor cells treated with DNA damage-inducing agents expressed and secreted high levels of IL-33, subsequently leading to enhanced DNA damage repair efficacy. Mechanistically, nuclear IL-33 primarily functions as a transcriptional co-activator of homologous recombination repair (HRR) genes, whereas the active form of IL-33 can drive the non-homologous end joining (NHEJ) pathway via the canonical IL-33/ST2 axis. Overall, we demonstrated that IL-33 plays a key role in mediating a DNA damage-resistant TME, which could represent a potential therapeutic vulnerability in chemoresistant cancer cells.

关键词： Human leukocyte antigen (HLA)   brain imaging   genetic polymorphisms   magnetic resonance imaging (MRI)   multiple sclerosis (MS)  

摘要： This systematic review and meta-analysis synthesizes current evidence on associations between genetic polymorphisms of human leukocyte antigen (HLA) class I and II molecules, which play key roles in antigen presentation and immune response regulation, and brain imaging phenotypes across various neurological and psychiatric conditions. The strongest associations were observed in multiple sclerosis (MS), where HLA-DRB1*15:01 was linked to increased lesion volume and disease progression. Meta-analyses revealed significant pooled effect sizes for both T1 and T2 lesion volumes. Emerging evidence also suggests that variants in HLA class I and II genes contribute to brain structural changes associated with age-related cognitive decline, schizophrenia and Gulf War illness. Our findings revealed greater patterns of association between HLA class II polymorphisms with brain imaging implications as compared to class I in neurodegenerative conditions. Considering HLA class II roles in exogenous protein/peptide presentation, this highlights the potential importance of neuroimmune-environmental interactions as contributing factors to disease pathogenesis and progression. Population-based studies from the UK Biobank highlight the potential influence of HLA class I and II genetic polymorphisms on brain structure beyond disease-specific contexts, suggesting broader implications for neurodevelopment and neurodegeneration. Despite these emerging insights, the limited availability of studies using imaging modalities beyond structural MRI, along with inconsistent findings within specific diseases and across conditions, underscores the need for further investigation into the mechanistic contributions of specific genetic variants on impacting brain structural and functional outcomes. Future research should include larger, more diverse study cohorts and employ advanced genotyping technologies to provide a more comprehensive investigations of HLA's role on brain health across the lifespan.

关键词： Anti-TNF   IBD   MASLD   PFOA  

摘要： Perfluorooctanoic acid (PFOA) is a prevalent and chemically stable environmental contaminant. Our preliminary data suggest that chronic exposure to PFOA induces colonic damage in mice that resembles inflammatory bowel disease (IBD). Anti-TNF therapies are commonly used in the clinical management of IBD. Building upon our previous findings, we administered anti-TNF treatment to mice exposed to PFOA. Our results show that anti-TNF therapy significantly reduces the colonic inflammatory response, activation of the NLR family pyrin domain containing 3 (NLRP) inflammasome, and apoptosis induced by PFOA. Additionally, anti-TNF treatment restores intestinal barrier integrity, which is disrupted by PFOA exposure, and enhances the regenerative capacity of the colon by promoting intestinal stem cell function. Furthermore, anti-TNF therapy effectively mitigates hepatic inflammation, liver dysfunction, lipid metabolism disturbances, NLRP3 inflammasome activation, and apoptosis in the liver triggered by PFOA. In conclusion, our study provides compelling evidence that anti-TNF therapy can alleviate both colonic and hepatic injuries induced by PFOA exposure. This research expands our understanding of environmental toxin-induced diseases and offers potential therapeutic strategies for managing PFOA-related disorders in the future.

摘要： Acquired aplastic anemia (AA) is an immune-mediated bone marrow failure caused by autoreactive cytotoxic T lymphocytes targeting hematopoietic stem progenitor cells (HSPCs). Approximately 30% of AA patients exhibit leukocytes lacking HLA class I alleles (HLA[-]). In addition to this direct immune assault, the pathogenesis of AA is thought to involve indirect suppression mediated by the proinflammatory cytokine interferon-gamma (IFN-γ). Using HSPCs derived from induced pluripotent stem cells (iPSCs) with different HLA genotypes, HLA(-) HSPCs were found to be resistant to the suppressive effects of IFN-γ, whereas IFN-γ effectively suppressed the growth and development of HSPCs expressing HLA class I molecules. Further analysis showed that, in contrast to HLA(-) HSPCs, WT HSPCs showed enhanced CD119 expression in response to IFN-γ, activating downstream signaling pathways that promote apoptosis, suggesting that transcription factors involved in the apoptotic pathway following IFN-γ stimulation are differentially expressed between WT and HLA(-) HSPCs. Notably, IFN-γ stimulation reduced the expression of pSTAT3, a key regulator of apoptosis, in WT HSPCs, whereas its expression was elevated in HLA(-) HSPCs. In conclusion, this study showed that the selective hematopoietic inhibition of HSPCs by IFN-γ likely facilitates clonal hematopoiesis and contributes to the persistence of HLA(-) HSPCs in patients with AA.

关键词： Anti-inflammation   ER stress   Glutamatergic transmission   Kinsenoside   Pain  

摘要： Neuro-inflammation contributes to neuropathic pain by sensitizing ionic channels. Kinsenoside, a traditional Chinese medicine, has recognized anti-inflammatory properties. However, it remains unclear whether kinsenoside can be used for pain therapy. Network pharmacology analysis revealed that 57% of its targets are associated with pain, including inflammation and synaptic transmission. The analgesic effects of kinsenoside were confirmed in SNL and formalin rat models, with ED50 values of 47.99 μg and 36.80 μg, respectively. Transcriptome and WGCNA analyses indicated the involvement of cytokine release, anti-inflammatory activity, and synapse enrichment in the blue module. Furthermore, we confirmed that kinsenoside's efficacy was mainly mediated by IL-10 induction, phosphorylation of STAT3, and SOCS3 expression. Pretreatment with kinsenoside significantly inhibited the release of TNF-α, IL-1β, and IL-6. Kinsenoside also attenuated ER stress in both microglia and neural cells. Molecular docking analysis demonstrated significantly high binding energies of IL-10, STAT3, and SOCS3 with MHC. Additionally, whole-cell recordings revealed that bath application of kinsenoside reduced the frequency and amplitude of spinal glutamatergic transmission in a dose-dependent manner. In summary, pharmacological prediction and biological validation collectively indicate that kinsenoside significantly exerts significant analgesic effects by attenuating ER stress and inhibiting inflammatory responses via the IL-10/p-STAT3/SOCS3 axis, precisely regulating spinal glutamatergic transmission for pain relief.

关键词： Biomarkers   Diagnostic efficacy   Inflammation markers   Pulpal blood   Pulpitis   Th2 cytokines  

摘要： OBJECTIVE:To evaluate the diagnostic utility of T-helper type 2 (Th2) cytokines, specifically Interleukin-4 (IL-4), IL-5, IL-10, and IL-13, in distinguishing different stages of pulpitis and their combined performance in clinical diagnosis. METHODS:A total of 161 participants were enrolled and categorized into normal pulp (NP, n = 45), reversible pulpitis (RP, n = 75), and symptomatic irreversible pulpitis (IP, n = 41). Th2 cytokine levels in pulpal blood samples were measured using enzyme-linked immunosorbent assays (ELISA). RESULTS:Th2 cytokine levels (IL-4, IL-5, IL-10, and IL-13) were significantly elevated in pulpitis cases compared to normal pulp, with the highest concentrations observed in symptomatic IP. Diagnostic analysis showed that IL-4 and IL-13 had the highest diagnostic accuracy for distinguishing pulpitis (both RP and IP) from normal pulp, with AUCs of 0.91, and perfect specificity (100%). IL-5 demonstrated the best balance between sensitivity (68%) and specificity (97%) for differentiating IP from NP (AUC = 0.84). IL-13, though less effective overall, provided moderate accuracy (AUC = 0.63) for distinguishing RP from NP. Additionally, the combined diagnostic model of all four cytokines achieved high AUCs, particularly in distinguishing irreversible pulpitis from normal pulp (AUC = 0.94) and irreversible pulpitis from reversible pulpitis (AUC = 0.90). CONCLUSIONS:Th2 cytokines, especially IL-4, IL-5, and IL-13, are effective biomarkers for identifying different stages of pulpitis. Their elevated levels, particularly in irreversible pulpitis, provide strong diagnostic accuracy. Combined cytokine analysis enhances diagnostic precision, making Th2 cytokine profiling a valuable tool for assessing pulpitis severity.