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关键词： Dendropanax morbiferus   reactive oxygen species   tumor necrosis factor-alpha   matrix metalloproteinase-1   MAPKs pathway   human dermal fibroblast  

摘要： In this study, we investigated the antiaging potential of dendropanoxide (DP), an active compound derived from Dendropanax morbiferus, in human dermal fibroblasts (NHDFs) induced by Tumor Necrosis Factor-alpha (TNF-alpha) and in human epidermal keratinocytes (NHEKs) induced by TNF-alpha and interferon gamma (IFN-gamma). We induced oxidative stress related to ultraviolet (UV) radiation with TNF-alpha and IFN-gamma and then treated the cells with various concentrations of DP to evaluate its effects on reactive oxygen species (ROS) production, matrix metalloproteinase-1 (MMP-1) expression, collagen synthesis, inflammatory cytokine expression, and skin barrier protection. The results showed that DP significantly reduced ROS production, indicating its potential to alleviate oxidative stress in the skin. Additionally, DP effectively inhibited MMP-1 production, suggesting that it could prevent collagen degradation in the dermis, significantly increase the secretion of pro-collagen I, promote collagen synthesis, and protect the dermal extracellular matrix (ECM). Moreover, DP significantly reduced the expression of inflammatory cytokines IL-1 beta and IL-6, thereby inhibiting excessive inflammatory responses in the skin. DP also enhanced the gene expression of key factors involved in skin barrier maintenance, including Kazal-type 5 (SPINK5), loricrin (LOR), aquaporin-3 (AQP3), filaggrin (FLG), and keratin 1 (KRT1), suggesting its potential to maintain and protect the skin barrier. Western blot analysis revealed that DP inhibited TNF-alpha-induced phosphorylation of JNK and p38, implying that DP exerts antiaging effects through the regulation of the JNK and p38 signaling pathways. Collectively, these findings suggest that DP has significant potential as an antiaging agent.

关键词： Dictamnus dasycarpus turcz.   Chemical composition   Rheumatoid arthritis   Alkaloid  

摘要： Ethnopharmacological relevance: Rheumatoid Arthritis (RA), a chronic inflammatory autoimmune condition, presents a substantial challenge to public health. Dictamnus dasycarpus Turcz. (D. dasycarpus) is a traditional Chinese medicinal plant recognized for its anti-inflammatory properties and is increasingly being utilized as a potential anti-RA agent, but the underlying mechanism is still unclear. Aim of the study: The objective of this research is to elucidate the potential active components and therapeutic properties of D. dasycarpus in experimental RA-induced DBA/1J mice, and to uncover the pharmacological basis of its action. Materials and methods: Surface plasmon resonance (SPR) was employed to ascertain the specificity of interactions between protein targets and D. dasycarpus active ingredients for treating RA. The extract of D. dasycarpus was obtained by HP-20 microresin column chromatography, and its chemical composition was assessed using UPLCOrbitrap-MS. This study utilized a collagen-induced arthritis (CIA) mouse model for in vivo experimentation. Body weight, foot thickness measurements, arthritis scores, immune organ index, and serum antibody levels of mice were used as indicators to evaluate the effects of D. dasycarpus components in treating RA. The serum levels of inflammatory factors in mice were measured using a cytokine antibody microarray assay. Additionally, this study quantified the protein expression levels associated with inflammatory responses through a combination of immunohistochemical staining and western blotting analyses. Results: This research investigated the interaction between D. dasycarpus active components and target proteins, including PTPN14, using a BIACORE system. The screened active components were identified as alkaloids through mass spectrometry. The UPLC-Orbitrap-MS analysis revealed that alkaloids were the predominant constituents in the 60% EtOH extract of D. dasycarpus. Alkaloid components significantly reduced the arthr

关键词： Fengshi gutong capsule   Rheumatoid arthritis   TNF-alpha   Bone destruction   Inflammation  

摘要： Ethnopharmacological relevance: Fengshi Gutong Capsule (FSGT) is a proprietary Chinese medicine with established clinical efficacy in Rheumatoid arthritis (RA);however, its underlying mechanisms remain unclear. Aim: This study aims to elucidate the mechanisms by which FSGT alleviates RA. Materials and methods: A collagen-induced arthritis (CIA) rat model was employed to assess the therapeutic effects of FSGT in RA. Network pharmacology and proteomics were integrated to identify potential mechanism and molecular targets, which were further validated via Western blot analysis. Molecular docking and microscale thermophoresis (MST) were utilized to assess the binding affinities of FSGT's active components to key proteins. Results: FSGT (280 and 840 mg/kg) alleviated CIA-induced RA in rats without significant side effects. Network pharmacology and label-free proteomic analysis displayed that FSGT exerted its therapeutic effects by modulating inflammation and bone destruction. FSGT significantly reduced serum levels of inflammatory cytokines and their protein expression in the ankle joints and synovial tissues. Additionally, FSGT attenuated bone destruction and significantly reversed the expression of bone destruction-related proteins. Molecular docking revealed that 18 active compounds in FSGT exhibited strong binding affinity for TNF-alpha, with hypaconitine, 18 alpha glycyrrhizic acid, and naringenin further validated by MST assays. Conclusion: FSGT improved CIA-induced RA in rats by targeting TNF-alpha to reduce inflammation and inhibit bone destruction, offering insights into its therapeutic mechanisms in RA.

关键词： Diazinon   Hippocampus   Novel object recognition memory   Anxiety-like behaviors   Amyloid precursor proteins   TNF-alpha   Amyloid beta  

摘要： Background: Organophosphate pesticides such as diazinon (DZN) are involved in developing psychological symptoms and memory deficits, but their effects on the amyloid precursor proteins (APP) gene expression remain unclear. Materials and Methods: Following low-level oral exposure to the DZN (2 mg/kg), we used novel object recognition, open field, and elevated plus-mazes (EPM) to assess memory and anxiety-like behaviors in rats. We also evaluated alteration in the levels of tumor necrosis factor (TNF-alpha), amyloid precursor protein (APP), APP-like protein-2 (APLP2), and amyloid-beta (A beta) via western blotting and ELISA. Real-time quantitative PCR was performed to evaluate the expression of the related genes in the hippocampus. Results: The findings demonstrated that whereas DZN exposure boosted anxiety-like behaviors at any exposure level, only prolonged exposure (12 weeks) resulted in memory impairment. The study also found that the hippocampal expression of APP and APLP2 decreased after 12 weeks of exposure but not after 5 days. Additionally, A beta increased after long-lasting exposure to DZN, indicating the APP contribution to AD pathologies. The TNF-alpha gene was up-regulated following 5 days of exposure, but 12 weeks had no effect. Conclusion: Our finding demonstrates that long-lasting exposure to low levels of DZN in adulthood stimulates APP degradation, possibly contributing to poor cognitive outcomes.

关键词： cytokine receptor   hepatic stellate cell   liver fibrosis   transcription factor   transcriptional regulation  

摘要： Background and Aims:Liver fibrosis, when dysregulated, contributes to irreversible loss of hepatic structure and function, heralding end-stage liver diseases, including cirrhosis and hepatocellular carcinoma (HCC). Hepatic stellate cells (HSCs) represent the common progenitor to myofibroblasts that produce extracellular matrix proteins to mediate liver fibrosis. In the present study, we investigated the role of Pre-B-cell leukemia transcription factor 1 (PBX1) in this process. Approach and Results:PBX1 was screened out of mining through liver fibrosis-related single-cell RNA-seq data sets as the most prominently upregulated transcription factor during HSC activation. Ingenuity pathway analysis, coupled with reporter assay and chromatin immunoprecipitation assay, demonstrated that Notch3 mediated the elevation of PBX1 expression at the transcriptional level in HSCs. PBX1 knockdown attenuated HSC-myofibroblast transition in vitro and liver fibrosis in mice. Integrated transcriptomic analysis suggested that PBX1 contributed to HSC activation by activating a host of pro-fibrogenic molecules, including IL-7 receptor (IL7R/CD127). Consistently, exposure to recombinant IL-7 promoted HSC activation, whereas IL7R knockdown hampered HSC activation. Mechanistically, IL7R interacted with TGF-beta receptors (I/II) to trigger a pro-fibrogenic signaling cascade. Importantly, blockade of the IL-7-IL7R signaling with neutralizing antibodies markedly ameliorated liver fibrosis in mice. Finally, a positive correlation between PBX1, IL7R, and HSC activation was identified in patients with cirrhosis. Conclusions:Our data uncover a previously unappreciated role for PBX1 in HSC activation and provide proof of concept for targeting IL-7 signaling in the intervention of liver fibrosis.

摘要： This study investigates the molecular mechanisms behind HLA-A*02 subtypes' differential responses to Tecelra, a TCR-engineered T-cell therapy targeting MAGE-A4. Using computational tools, the study identifies specific HLA-A*02 alleles, such as HLA-A*02:07, HLA-A*02:05, and others, with low affinity for the GV10 peptide or a risk of inducing alloreactivity. These findings provide insights into patient selection for Tecelra therapy, suggesting exclusion criteria for certain HLA-A*02 subtypes to optimize treatment efficacy and minimize adverse reactions.

关键词： 四物汤   辐射   免疫损伤   PI3k-Akt-mTOR   Sirt1   淋巴细胞  

摘要： 目的 探讨四物汤（Siwu decoction， SWD）对60Coγ射线辐射所致小鼠免疫损伤的防护作用及机制。方法 将C57BL/6J小鼠随机分为6组：对照组（Control）、模型组（Model）、四物汤低剂量组（SWD-L）、四物汤中剂量组（SWD-M）、四物汤高剂量组（SWD-H）、阳性药白藜芦醇组（resveratrol， Res），于辐照前11天及辐照后继续给药，单次全身照射4 Gy，照射后3天检测各指标。检测外周血象及脏器指数变化，酶联免疫吸附法（ELISA）检测血清中细胞因子γ干扰素（IFN-γ）、白细胞介素（IL）-1β、IL-2、IL-4、IL-6、IL-10、IL-17、转化生长因子-β（TGF-β）、肿瘤坏死因子（TNF）-α以及免疫球蛋白A（IgA）、IgG、IgM，补体蛋白3（C3）、C4的含量。流式细胞术检测小鼠脾脏B淋巴细胞、T淋巴细胞、NK细胞以及胸腺中T淋巴细胞；苏木精-伊红染色（HE）染色分析脾脏、胸腺病理损伤变化。免疫荧光染色检测辐射后脾脏组织Sirt1蛋白表达，Western blot实验检测脾脏中Sirt1，PI3K，Akt，p-Akt，mTOR蛋白含量变化。结果 SWD能明显提高LYMPH%，减轻脾脏和胸腺病理损伤，流式细胞术实验结果表明，SWD能明显提高脾脏中CD19+B淋巴细胞百分比，降低NK淋巴细胞百分比以及脾脏和胸腺中CD4+/CD8+比值。ELISA结果显示，SWD明显降低IL-1β、IL-2、IL-6、IL-17、IFN-γ、TGF-β、TNF-α的含量，以及增强抗炎因子IL-4、IL-10的含量。同时，SWD显著抑制辐射引起的IgA、IgG、IgM，C3、C4的升高。免疫荧光染色和Western blot实验结果表明，SWD能够降低PI3K，Akt，p-Akt，mTOR蛋白表达，增强Sirt1蛋白表达。结论 SWD对60Coγ射线辐射所致小鼠免疫损伤具有明显的预防作用，其机制可能与Sirt1-PI3k-Akt-mTOR有关。

关键词： duck   IFN-gamma   monoclonal antibody   intracellular cytokine staining  

摘要： Interferon-gamma (IFN-gamma), a member of the Type II IFN family, is a crucial cytokine in the immune system and serves as an important indicator of immune response. Intracellular cytokine staining (ICS) is a technique used to analyze the production of cytokines within individual cells, and it has a wide range of applications in the fields of immunological monitoring, vaccine trials, and the study of infectious diseases. This study aimed to prepare monoclonal antibodies against duck IFN-gamma protein and to establish an ICS protocol for detecting the duck IFN-gamma protein. The duIFN-gamma-His or duIFN-gamma-Fc gene was cloned into the pEE12.4 expression vector and expressed as a recombinant protein of size 20.2 KDa or 54.9 KDa in 293F cells. The purified recombinant proteins were inoculated into BALB/c mice to generate splenic lymphocytes capable of secreting anti-duIFN-gamma antibodies, and hybridoma cells were obtained after fusion with SP2/0 cells. A new hybridoma cell line named 24H4, which stably secreted IgG3 kappa subtype antibody against duck IFN-gamma, was established. This monoclonal antibody (mAb) was identified by Western blot to recognize duck IFN-gamma antibodies, and the indirect ELISA results showed that its ability to recognize IFN-gamma protein reached 0.001 mu g/mL. The established ICS method was used to stain PBMCs after Concanavalin A (ConA) stimulation, and duck IFN-gamma protein was successfully detected by flow cytometry, indicating that the ICS method was successful. In this study, we provide a crucial tool for subsequent research on duck cellular immune responses by using the monoclonal antibody 24H4.

摘要： The collapse of inflammatory signaling that recruits cytotoxic immune cells to the tumor microenvironment contributes to the immunologically cold tumor phenotype in neuroblastoma (NB) and is a barrier to NB immunotherapy. Multiple studies have reported that MYCN amplification, a trait of high-risk NB, correlates with a loss of inflammatory signaling;but MYCN also correlates with 1p36 deletions in NB where the SWI/SNF chromatin remodeling complex subunit ARID1A (1p36.11) is located. ARID1A is known to support inflammatory signaling in adult cancers but its role in NB inflammatory signaling is unexplored. We find MYCN overexpression causes a stronger inflammatory response to interferon-gamma (IFN gamma). ARID1A knockdown causes a weaker inflammatory response and reduces IFN gamma induced gene signatures for the transcription factor interferon response factor 1 (IRF1). We found ARID1A is a functional interactor of IRF1 by co-immunoprecipitation studies, and ARID1A silencing causes loss of activating chromatin marks at the IRF1 target gene CXCL10. We model that IRF1 uses ARID1A containing SWI/SNF to promote CXCL10 in response to IFN gamma. Our work clarifies that the loss of ARID1A, which tightly associates with MYCN amplification, causes reduced inflammatory signaling. This work finds that ARID1A is a critical regulator of inflammatory signaling in NB and provides rationale for testing immune therapies in MYCN amplified NB that are effective in adult ARID1A mutated cancers.

关键词： sepsis   septic shock   sepsis prognosis   cytokine   interleukin-6   IL-6   cytokine storm  

摘要： Sepsis, a life-threatening condition arising from a dysregulated immune response to infection, is a significant health burden globally. Interleukin-6 (IL-6), an inflammatory cytokine produced by immune cells as a response to infection and tissue damage, plays a key role in the pathogenesis of sepsis. This systematic review and meta-analysis aimed to investigate the association of the baseline plasma levels of IL-6, and the dynamic change in these levels over a timespan of 96 h, with short-term mortality. A systematic literature search was conducted across multiple databases. Studies were included if they assessed the independent prognostic value of IL-6 in adult sepsis patients, used well-defined sepsis criteria, and reported at least one IL-6 measurement. Pooled effect estimates for the association between IL-6 and 28-30-day mortality were determined using logistic regression and AUROC analysis. Thirty-one studies, encompassing 4566 patients, were included. While baseline IL-6 levels and 96 h IL-6 clearance were not significantly associated with mortality risk (pooled OR 1.001, 95% CI 0.999-1.003 and 1.019, 95% CI 0.925-1.112, respectively), AUROC analysis indicated moderate-to-good discriminatory power for both baseline (0.701, 95% CI 0.660-0.742) and 96 h IL-6 clearance (0.828, 95% CI 0.736-0.919) in predicting 28-day mortality. While not a strong independent predictor, IL-6 demonstrates some discriminatory ability, suggesting its potential value in conjunction with other biomarkers.