Malicevic Ugljesa, Rai Vikrant, Skrbic Ranko, Agrawal Devendra K
Department of Translational Research, Western University of Health Sciences, Pomona, California 91766, USA.
Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina, Balkans.
J Biotechnol Biomed. 2024;7(4):433-444. doi: 10.26502/jbb.2642-91280167. Epub 2024 Oct 18.
Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a chronic and relapsing condition characterized by persistent inflammation of the gastrointestinal tract. The complex pathogenesis of IBD involves a combination of genetic, environmental, and immune factors, which complicates the achievement of long-term remission. Lower abdominal pain, stomach cramps, blood in stool, chronic diarrhea, fatigue, and unexpected weight loss are common presenting symptoms. Despite the range of therapies and medications, including anti-inflammatory and anti-diarrheal drugs, immunosuppressants, antibiotics, and analgesics aimed at managing symptoms and controlling inflammation, a definitive cure for IBD remains elusive. Current therapy targets inflammation, mainly cytokines, inflammatory receptors, and immune cells, however, there is a need for novel targets to improve clinical outcomes. To identify novel targets and interactions among various factors, we performed a network analysis using various cytokines, TLRs, and NLRP3 inflammasome as inputs. This analysis revealed orosomucoid-like protein 3/ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) as a central hub gene interacting with multiple factors. While the role of ORMDL3 in IBD pathogenesis is not well-established, our findings and existing literature suggest that ORMDL3 plays a role in inflammation, impaired mitochondrial function, and disrupted autophagy, all contributing to the disease progression. Given its central role in these pathogenic processes, targeting ORMDL3 presents a promising therapeutic target. Modulating ORMDL3 activity could alleviate inflammation, restore mitochondrial function, and enhance autophagy, potentially leading to more effective treatments and improved outcomes for IBD patients.
炎症性肠病（IBD）包括克罗恩病和溃疡性结肠炎，是一种慢性复发性疾病，其特征为胃肠道持续炎症。IBD的复杂发病机制涉及遗传、环境和免疫因素的综合作用，这使得实现长期缓解变得复杂。下腹部疼痛、胃痉挛、便血、慢性腹泻、疲劳和意外体重减轻是常见的症状。尽管有一系列的治疗方法和药物，包括抗炎和止泻药物、免疫抑制剂、抗生素和镇痛药，旨在控制症状和炎症，但IBD的根治方法仍然难以捉摸。目前的治疗主要针对炎症，主要是细胞因子、炎症受体和免疫细胞，然而，需要新的靶点来改善临床结果。为了确定新的靶点以及各种因素之间的相互作用，我们使用各种细胞因子、Toll样受体（TLRs）和NLRP3炎性小体作为输入进行了网络分析。该分析揭示类orosomucoid蛋白3/鞘脂生物合成调节因子3（ORMDL3）是与多种因素相互作用的中心枢纽基因。虽然ORMDL3在IBD发病机制中的作用尚未完全明确，但我们的研究结果和现有文献表明，ORMDL3在炎症、线粒体功能受损和自噬破坏中起作用，所有这些都促成了疾病的进展。鉴于其在这些致病过程中的核心作用，靶向ORMDL3是一个有前景的治疗靶点。调节ORMDL3的活性可以减轻炎症、恢复线粒体功能并增强自噬，这可能为IBD患者带来更有效的治疗和更好的治疗效果。
