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关键词： IL-17   Pharmacokinetic   Thiazole   X-Ray  

摘要： The pro-inflammatory cytokine interleukin-17A (IL-17) plays an important role in the body's defense against bacterial and fungal infections. However, overexpression of IL-17 has been associated with several diseases, including rheumatoid arthritis, asthma, psoriasis, and even cancer. The role of IL-17 in psoriasis has been confirmed by clinical use of IL-17 antibodies, e.g. secukinumab (Cosentyx®). Ongoing research is focused on discovering low molecular weight IL-17 inhibitors. In this publication, we present thiazole-based IL-17 inhibitors discovered through a scaffold-morphing strategy. This strategy involved ring-opening of a known scaffold and utilization of a chalcogen interaction between thiazole-sulfur and central amide-oxygen to maintain the coplanar conformation found in the parent compound. The new scaffold enabled the generation of highly potent compounds with good overall profile. The optimized compounds 11 and 15 demonstrated good exposure in rats after oral dosing. Importantly, compound 11 exhibited no adverse effects in a rat tolerability study after a four-day administration of up to 300 mg/kg/day.

关键词： BRD4   Cardiac   Macrophage  

摘要： Bromodomain and extra-terminal domain (BET) proteins, including BRD4, bind acetylated chromatin and co-activate gene transcription. A BET inhibitor, JQ1, prevents and reverses pathological cardiac remodeling in preclinical models of heart failure. However, the underlying cellular mechanisms by which JQ1 improves cardiac structure and function remain poorly defined. Here, we demonstrate that BRD4 knockdown reduced expression of genes encoding CC chemokines in cardiac fibroblasts, suggesting a role for this epigenetic reader in controlling fibroblast-immune cell crosstalk. Consistent with this, JQ1 dramatically suppressed recruitment of monocytes to the heart in response to stress. Normal mouse hearts were found to have approximately equivalent numbers of major histocompatibility complex (MHC-II) and MHC-II resident macrophages, while MHC-II macrophages predominated following JQ1 treatment. Single-cell RNA-seq data confirmed that JQ1 treatment or BRD4 knockout in CX3CR1 cells reduced MHC-II gene expression in cardiac macrophages, and studies with cultured macrophages further illustrated a cell autonomous role for BET proteins in controlling the MHC-II axis. Bulk RNA-seq analysis demonstrated that JQ1 blocked proinflammatory macrophage gene expression through a mechanism that likely involves repression of NF-κB signaling. JQ1 treatment reduced cardiac infarct size in mice subjected to ischemia/reperfusion. Our findings illustrate that BET inhibition affords a powerful pharmacological approach to manipulate monocyte-derived and resident macrophages in the heart. Such an approach has the potential to enhance the reparative phenotype of macrophages to promote wound healing and limit infarct expansion following myocardial ischemia.

关键词： Asthma   Inflammation   Interleukin-6 (IL-6)   Metabolic dysfunction   Obesity  

摘要： INTRODUCTION:Asthma is a complex condition characterized by airway inflammation. Interleukin-6 (IL-6) plays a significant role in asthma pathogenesis through its effects on T cells and its association with pro-inflammatory responses. Both lung and circulating IL-6 levels are elevated in asthma. IL-6 is positively associated with disease severity, frequent exacerbations, and impaired lung function, all of which can be observed clinically. We developed an IL-6 cut-off model to examine the association between high IL-6, race, high body mass index (BMI), metabolic disease, and asthma severity as assessed by reduced lung function. METHODS:This study utilized the Coronary Artery Risk Development in Young Adults (CARDIA) database, comprised of 5115 adults, to investigate the relationship between IL-6 levels, asthma, race, and metabolic dysfunction. A "healthy" subset of 427 patients was used to compute the IL-6 cut-off. IL-6 levels within detection limits (0.15-12 pg/mL) were analyzed. The IL-6 cut-off was determined using the 95th percentile of log-transformed IL-6 values for lean (BMI < 25) and healthy individuals. Specific cut-offs were established for racial groups. Statistical analyses involved comparing patient characteristics between high and low IL-6 groups, regression analyses, and assessment of factors influencing lung function changes. RESULTS:Using an IL-6 cut-off of 4.979 pg/mL, the cohort was divided into high and low IL-6 groups. High IL-6 correlated with Black race, higher BMI, hypertension, and markers of metabolic dysfunction, e.g., elevated HbA1c, C-reactive protein (CRP), and reduced lung function. Multivariable analysis linked high IL-6 with male gender, high BMI, Black race, HbA1c, CRP, and inversely with lung function and total cholesterol. Obesity showed a consistent positive association with elevated IL-6, regardless of the presence or absence of asthma. Patients with asthma and high IL-6 were more likely to be Black and showed increased CRP. Lung

关键词： Children   Complex febrile seizures   Interleukin   Neutrophils/lymphocyte ratio   Viral epidemic  

摘要： This report aimed to analyze the potential effects of cytokines and neutrophils-to-lymphocytes ratio (NLR) on the occurrence of febrile seizures (FS) in children during the epidemic of novel coronavirus and influenza virus. Between July 2022 and April 2023, clinical data of 422 children with FS hospitalized in the Pediatrics, Shaoxing People's Hospital and the First Affiliated Hospital of Shaoxing University, during the epidemic and non-epidemic periods of novel coronavirus and influenza virus were analyzed. By comparing the various clinical characteristics of children with FS at different periods, comparison of variations in peripheral blood cell count, neutrophils, lymphocytes, hypersensitive C-creation protein, NLR, and inflammatory cytokines. Among 422 cases, 130 cases were classified as complex FS (CFS), while 292 cases of simple FS (SFS) were identified. During the time of the viral epidemic, 315 FS cases were observed, among which the incidence of CFS was 33.65%. In the non-viral epidemic period, there were 105 cases of FS. The incidence of CFS accounted for 22.86%. In addition, the levels of IL-4, IL-10, and tumor necrosis factor α (TNF-α) in children in the viral epidemic period were significantly higher than those in the non-epidemic period (P < 0.05). ROC curve analysis revealed that during the epidemic period, NLR (AUC = 0.724), IL-4 (AUC = 0.826), and IL-10 (AUC = 0.688) exhibited high predictive value for CFS children, and the indexes were statistically significant (P < 0.05). This study suggests that IL-4, IL-10, and NLR may play an important role in the pathogenesis of children with FS, especially those with CFS.

关键词： 附子   多糖   结构表征   免疫活性   葡聚糖   RAW 264.7细胞  

摘要： 目的 探讨附子多糖(Aconiti Lateralis Radix Praeparata polysaccharide, ACP)的结构特征及其对RAW264.7细胞的免疫活性影响。方法 采用水提醇沉的方法获得附子粗多糖，通过阴离子交换色谱柱和分子筛凝胶色谱柱对附子粗多糖进行分离、纯化，获得ACP。采用高效凝胶渗透色谱法测定ACP的分子量分布；采用离子色谱法测定ACP的单糖组成；采用甲基化实验及核磁图谱解析ACP的糖苷键类型及多糖一级结构。最后，通过体外细胞实验，测定ACP对于RAW 264.7细胞的作用。结果与结论 从附子中分离得到一种分子量为11.37 kDa的均一多糖，该多糖主要由葡萄糖组成，且以→4)-Glcp-(1→糖苷键为主链的结构，端基Glcp-(1→为支链经→4,6)-Glcp-(1→的O-6链接到主链。体外细胞实验结果表明，ACP能够促进诱导型一氧化氮合酶(iNOS)、白介素-1β(IL-1β)、IL-6及肿瘤坏死因子(TNF-α)分泌，具有一定的免疫活性。

关键词： autophagy   immune escape   ITGB4/BNIP3   MHC-I   pancreatic cancer  

摘要： This study attempted to identify the relevant pathways involved in autophagy activation of pancreatic cancer and explore the mechanisms underlying immune evasion. Western blot (WB) was used to detect the expression of ITGB4, BNIP3, autophagy-related proteins and MHC-I. Co-immunoprecipitation (Co-IP) was used to verify the binding mode of ITGB4 and BNIP3. Flow cytometry was used to detect the expression of MHC-I on the cell membrane. Transmission electron microscope (TEM) was used to observe cell autophagy. Confocal microscopy was used to observe the co-localisation relationship between MHC-I and autophagosomes in cells. ELISA was used to detect the level of lactate dehydrogenase and granzyme B in a tumour cell-CD8+ T-cell co-culture system. Mouse syngeneic transplant tumour model and orthotopic tumour model were constructed and treated with PD-1 monoclonal antibody to observe tumour growth. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression of ITGB4 and BNIP3 in tumour tissues. WB was used to determine the expression of autophagy-related proteins. Flow cytometry was used to detect the expression of MHC-I on cell membranes and the proportion of CD3+ and CD8+ cells. The results of Co-IP experiments showed that ITGB4 could bind to BNIP3. It was observed under confocal microscopy that activating ITGB4/BNIP3 could promote the phagocytosis of MHC-I by autophagosomes. Finally, the subcutaneous tumour transplantation and orthotopic tumour experiments in mice demonstrated the downregulation of ITGB4 significantly improved the therapeutic effect of PD-1 antibodies on pancreatic cancer. In pancreatic cancer cells, autophagy is positively correlated with the ITGB4-BNIP3 complex protein expression level. Autophagy diminishes the protein expression of MHC-I, thereby promoting immune escape in pancreatic cancer cells.

关键词： BCL6   GPR61   IL‐1β   osteoarthritis  

摘要： Osteoarthritis (OA) is the most common joint disease and its pathogenic mechanism remains to be ensured. This study focused on the regulatory relation between B-cell lymphoma 6 (BCL6) and G-protein-coupled receptor 61 (GPR61) underlying IL-1β in OA. Real-time quantitative polymerase chain reaction and western blot were performed for mRNA and protein detection. Oxidative injury was assessed by reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) via kits. Fe level was measured via an iron assay kit. Relation analysis between BCL6 and GPR61 was implemented employing ChIP assay and dual-luciferase reporter assay. GPR61 was downregulated in OA samples and IL-1β-induced C28/I2 cells. IL-1β-induced cell inflammation, extracellular matrix (ECM) degradation, oxidative stress, and ferroptosis were all returned by overexpression of GPR61. BCL6 downregulation was detected in OA patients and IL-1β-exposed C28/I2 cells. BCL6 could promote the transcription of GPR61. BCL6 suppressed IL-1β-induced OA progression by upregulating GPR61. The BCL6/GPR61 axis activated the PKA/CREB pathway in IL-1β-treated C28/I2 cells. The above results suggested that BCL6 mitigated OA progression induced by IL-1β by enhancing transcription of GPR61. BCL6/GPR61/PKA/CREB axis may be considered as a novel regulatory mechanism in OA, and BCL6 has the potential to act as a novel target for OA.

摘要： The hypoxic microenvironment is an essential feature of solid tumors. Autophagy has been controversial in its role in immune regulation. This project aims to elucidate the impact of autophagy in pancreatic cancer (PC) under specific conditions (hypoxia) on CD8+ T cells and the regulatory mechanisms behind *** levels of HIF1 alpha and autophagy were analyzed by western blot (WB) and immunofluorescence (IF). The effects of HIF1 alpha on cell autophagy were assessed in normoxic or hypoxic treatments using KC7F2 (HIF-1 channel inhibitor) or chloroquine (autophagy inhibitor). CD8+ T cells were co-cultured with PC cells to assess the cytotoxicity using lactate dehydrogenase (LDH) and Hoechst/PI staining. The content of cytokines and the activation level of CD8+ T cells were measured by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. MHC-I expression in PC cells (membranes) was analyzed using quantitative reverse transcription polymerase chain reaction (qRT-PCR), WB, IF, and flow cytometry. Humanized immune-reconstituted mice were applied to investigate the impact of HIF1 alpha-induced autophagy on in vivo *** cells were in hypoxia, the levels of HIF1 alpha and autophagy were higher compared to normoxic conditions. Treatment with KC7F2 resulted in similar levels of HIF1 alpha and autophagy as those in normoxic state. Chloroquine treatment reversed the autophagy level to the normoxic state. The autophagy level of PC cells transfected with oe-HIF1 alpha was increased, with reduced MHC-I expression on cells (membranes), which impaired the cytotoxicity of CD8+ T cells, and thus decreasing the probability of recognition and attack by CD8+ T cells when co-cultured with them. In mice, overexpression of HIF1 alpha hindered the immune suppressive function of CD8+ T cells and facilitated the immune escape of PC by reducing antigen presentation of *** hypoxia, HIF1 alpha-induced autophagy reduces the cytotoxicity of CD8+ T cells by repressing MHC-I

关键词： Adrenomedullin   C-Reactive Protein   Diagnosis Biomarkers   Interleukin 6   Late Neonatal Sepsis   Prognosis Biomarkers  

摘要： Background:Diagnosing and predicting neonatal sepsis is challenging because of its nonspecific symptoms, lack of diagnostic criteria consensus, and absence of early, sensitive, and specific diagnostic laboratory tests. Purpose:To evaluate the diagnostic and prognostic potential of adrenomedullin (ADM), interleukin-6 (IL-6), and C-reactive protein (CRP) in late-onset neonatal sepsis (LOS). Methods:We studied 53 neonates with culture-proven LOS by sampling at admission and on antibiotic treatment days 3 and 7. These data were compared with those of 22 healthy full-term controls sampled on day 3 before hospital discharge. Survivors and non-survivors in the sepsis group were analyzed separately. Results:Coagulase-negative Staphylococcus was the most commonly detected pathogen. ADM (cutoff, 0.5 ng/mL) and CRP (cutoff, <5 mg/L) values aligned with manufacturer recommendations, while IL-6 levels (cutoff, 10 pg/mL) were higher than expected, likely due to labor stress. The median biomarker levels significantly distinguished neonates with sepsis from controls (p < 0.0001) at all time points with ADM and IL-6 levels elevated at admission, indicating their potential as early diagnostic markers. CRP level was diagnostically useful starting on day 3. Prognostically, IL-6 (p < 0.001) and ADM (p < 0.05) differentiated survivors from non-survivors; however, only IL-6 consistently predicted mortality at all time points (area under the curve [AUC] > 0.90). ADM and CRP levels showed poor prognostic value (AUC < 0.70). ADM and IL-6 demonstrated strong diagnostic utility in early LOS, whereas CRP became relevant later. IL-6 was the only reliable biomarker for predicting mortality, supporting its integration into clinical protocols. Combining IL-6 with CRP may enhance early detection and management, potentially improving neonatal outcomes. Conclusion:IL-6 is a robust biomarker for the early diagnosis and prognosis of LOS. Incorporating IL-6 into clinical practice with CRP could improve e