Therapeutic Effects of Anti-Inflammatory N-Acylhydrazones in the Resolution of Experimental Colitis.
- 作者列表："Cordeiro NM","Freitas RHCN","Fraga CAM","Fernandes PD
:Inflammatory bowel diseases (IBDs) are caused by inflammation of the gastrointestinal tract, which may or may not have a specific cause or pathogen. They affect millions of people around the world and there are still few effective treatments. The aim of this work is to investigate anti-inflammatory effect of IKK-β inhibitor, LASSBio-1524, and its three analogues, LASSBio-1760, LASSBio-1763 and LASSBio-1764 in experimental animal models of intestinal inflammatory diseases, in mediators production and expression of inflammatory enzymes. Colitis was performed using two different models, which mimic Crohn's disease (induced by dinitrobenzene acid, DNBS) and ulcerative colitis (induced by sodium dextran sulphate, DSS) in mice. In both models was performed a therapeutic protocol with 1, 3 or 30 μmol/kg daily dose. LASSBio-1524 and its three analogues reduced the secretion of TNF-α, IL-1β, IL-6, IL-12, IFN-γ and increased secretion of IL-10, protecting gastrointestinal homeostasis. All compounds reduced macro and microscopic colonic damage caused by experimental colitis and p38 MAPK expression in the colon, as well as leukocytosis and anemia resulting from the disease. Our data may suggest LASSBio-1524 and its analogues (LASSBio-1760, LASSBio-1763 and LASSBio-1764) as promising candidates for new prototypes designed to inflammatory bowel diseases treatment.
: 炎症性肠病 (ibd) 是由胃肠道炎症引起的，可能有也可能没有特定的病因或病原体。它们影响着全世界数百万人，有效的治疗方法仍然很少。旨在研究 IKK-β 抑制剂 LASSBio-1524 及其 3 种类似物 LASSBio-1760 、 LASSBio-1763 和 LASSBio-1764 在肠道炎症性疾病实验动物模型中的抗炎作用。在介质中产生和表达炎症酶。采用两种不同的模型进行结肠炎，模拟小鼠克罗恩病 (由二硝基苯酸诱导) 和溃疡性结肠炎 (由葡聚糖硫酸钠诱导)。在两种模型中进行了 1 、 3 或 30 μ mol/kg 日剂量的治疗方案。LASSBio-1524 及其 3 种类似物减少 TNF-α 、 il-1 β 、 IL-6 、 IL-12 、 IFN-γ 的分泌，增加 IL-10 的分泌，保护胃肠稳态。所有化合物都减少了实验性结肠炎引起的结肠宏观和微观损伤，减少了结肠中 p38 MAPK 的表达，以及该疾病导致的白细胞增多和贫血。我们的数据可能表明，LASSBio-1524 及其类似物 (LASSBio-1760 、 LASSBio-1763 和 LASSBio-1764) 有望成为炎症性肠病治疗新原型的候选药物。
METHODS::Chronic diseases, including inflammatory bowel disease (IBD) urgently need new biomarkers as a significant proportion of patients, do not respond to current medications. Inflammation is a common factor in these diseases and microbial sensing in the intestinal tract is critical to initiate the inflammation. We have identified ELMO1 (Engulfment and Cell Motility Protein-1) as a microbial sensor in epithelial and phagocytic cells that turns on inflammatory signals. Using a stem-cell-based "gut-in-a-dish" coculture model, we studied the interactions between microbes, epithelium and monocytes in the context of IBD. To mimic the in-vivo cell physiology, enteroid-derived monolayers (EDMs) were generated from the organoids isolated from WT and ELMO1-/- mice and colonic biopsies of IBD patients. The EDMs were infected with the IBD-associated microbes to monitor the inflammatory responses. ELMO1-depleted EDMs displayed a significant reduction in bacterial internalization, a decrease in pro-inflammatory cytokine productions and monocyte recruitment. The expression of ELMO1 is elevated in the colonic epithelium and in the inflammatory infiltrates within the lamina propria of IBD patients where the higher expression is positively correlated with the elevated expression of pro-inflammatory cytokines, MCP-1 and TNF-α. MCP-1 is released from the epithelium and recruits monocytes to the site of inflammation. Once recruited, monocytes require ELMO1 to engulf the bacteria and propagate a robust TNF-α storm. These findings highlight that the dysregulated epithelial ELMO1→MCP-1 axis can serve as an early biomarker in the diagnostics of IBD and other inflammatory disorders.
METHODS:BACKGROUND:Peripheral blood eosinophilia (PBE) is a biomarker of an aggressive multiyear natural history in adults with inflammatory bowel diseases (IBDs). Additionally, PBE at diagnosis is associated with higher disease activity in pediatric-onset IBD. We sought to determine if PBE can function as a biomarker of long-term disease severity in pediatric-onset IBD patients who are followed into adulthood. METHODS:We analyzed a consented, prospective, natural history IBD registry at an adult tertiary center from 2009 to 2018. Prevalence of PBE was evaluated in both pediatric- and adult-onset IBD patients. Demographics, clinical characteristics, and health care utilization data were compared in patients with and without PBE. RESULTS:Among 2800 adult IBD patients, 23.4% had pediatric-onset disease. PBE was found in 34% of the pediatric-onset patients compared with 26.8% of the adult-onset IBD patients (P < 0.001). In the pediatric-onset IBD cohort, PBE was associated with higher rates of allergies (P < 0.0001), but not of asthma, allergic rhinitis, or primary sclerosing cholangitis. In the adult IBD patients with pediatric-onset disease, PBE was associated with higher rates of C-reactive protein elevation (P < 0.0001), erythrocyte sedimentation rate elevation (P < 0.0001), higher health care utilization, and higher average health care charges per year (P < 0.00001). CONCLUSIONS:Peripheral blood eosinophilia was more prevalent in adult IBD patients with pediatric-onset compared with adult-onset disease. Among all IBD patients with long-term follow-up, PBE defined a subgroup with more severe illness. These data suggest that PBE may be a biomarker for a high-risk subgroup with high cost trajectory and long-term severity in pediatric-onset IBD that persists into adulthood.
METHODS::Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex pathogenesis, affecting people of all ages. They are characterized by alternating phases of clinical relapse and remission, depending on the fine balance between immune cells and the gut microbiota. The cross talk between cells of the immune system and the gut microbiota can result in either tolerance or inflammation, according to multifactorial triggers, ranging from environmental factors to genetic susceptibility. Glucocorticoid (GC) administration remains the first-line treatment for IBDs, although long-term use is limited by development of serious adverse effects. Recently, new alternative pharmacological therapies have been developed, although these are not always effective in IBD patients. There is a constant demand for effective new drug targets to guarantee total remission and improve the quality of life for IBD patients. The glucocorticoid-induced leucine zipper (GILZ) has been implicated as a promising candidate for this purpose, in view of its powerful anti-inflammatory effects that mimic those of GCs while avoiding their unwanted adverse reactions. Here we present and discuss the latest findings about the involvement of GILZ in IBDs.