Venkataraman Balaji, Almarzooqi Saeeda, Raj Vishnu, Dudeja Pradeep K, Bhongade Bhoomendra A, Patil Rajesh B, Ojha Shreesh K, Attoub Samir, Adrian Thomas E, Subramanya Sandeep B
Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, PO Box-17666, Al Ain, UAE.
Zayed Bin Sultan Center for Health Sciences, College of Medicine and Health Sciences, United Arab Emirates University, PO Box-17666, Al Ain, UAE.
PPAR Res. 2022 Apr 13;2022:5498115. doi: 10.1155/2022/5498115. eCollection 2022.
The incidence and prevalence of inflammatory bowel disease (IBD, Crohn's disease, and ulcerative colitis) are increasing worldwide. The etiology of IBD is multifactorial, including genetic predisposition, dysregulated immune response, microbial dysbiosis, and environmental factors. However, many of the existing therapies are associated with marked side effects. Therefore, the development of new drugs for IBD treatment is an important area of investigation. Here, we investigated the anti-inflammatory effects of -bisabolol, a naturally occurring monocyclic sesquiterpene alcohol present in many aromatic plants, in colonic inflammation. To address this, we used molecular docking and dynamic studies to understand how -bisabolol interacts with PPAR-, which is highly expressed in the colonic epithelium: in vivo (mice) and in vitro (RAW264.7 macrophages and HT-29 colonic adenocarcinoma cells) models. The molecular docking and dynamic analysis revealed that -bisabolol interacts with PPAR-, a nuclear receptor protein that is highly expressed in the colon epithelium. Treatment with -bisabolol in DSS-administered mice significantly reduced Disease Activity Index (DAI), myeloperoxidase (MPO) activity, and colonic length and protected the microarchitecture of the colon. -Bisabolol treatment also reduced the expression of proinflammatory cytokines (IL-6, IL1, TNF-, and IL-17A) at the protein and mRNA levels. The expression of COX-2 and iNOS inflammatory mediators were reduced along with tissue nitrite levels. Furthermore, -bisabolol decreased the phosphorylation of activated mitogen-activated protein kinase (MAPK) signaling and nuclear factor kappa B (NFB) proteins and enhanced colon epithelial PPAR- transcription factor expression. However, the PPAR- and / expression was not altered, indicating -bisabolol is a specific stimulator of PPAR-. -Bisabolol also increased the PPAR- transcription factor expression but not PPAR- and / in pretreated in LPS-stimulated RAW264.7 macrophages. -Bisabolol significantly decreased the expression of proinflammatory chemokines (CXCL-1 and IL-8) mRNA in HT-29 cells treated with TNF- and HT-29 PPAR- promoter activity. These results demonstrate that -bisabolol mitigates colonic inflammation by inhibiting MAPK signaling and stimulating PPAR- expression.
炎症性肠病（IBD，包括克罗恩病和溃疡性结肠炎）的发病率和患病率在全球范围内都在上升。IBD的病因是多因素的，包括遗传易感性、免疫反应失调、微生物生态失调和环境因素。然而，许多现有疗法都伴有明显的副作用。因此，开发用于治疗IBD的新药是一个重要的研究领域。在此，我们研究了红没药醇（一种存在于许多芳香植物中的天然单环倍半萜醇）对结肠炎症的抗炎作用。为了解决这个问题，我们使用分子对接和动力学研究来了解红没药醇如何与在结肠上皮中高表达的过氧化物酶体增殖物激活受体γ（PPAR-γ）相互作用：体内（小鼠）和体外（RAW264.7巨噬细胞和HT-29结肠腺癌细胞）模型。分子对接和动力学分析表明，红没药醇与PPAR-γ相互作用，PPAR-γ是一种在结肠上皮中高表达的核受体蛋白。在给予葡聚糖硫酸钠（DSS）的小鼠中用红没药醇治疗可显著降低疾病活动指数（DAI）、髓过氧化物酶（MPO）活性和结肠长度，并保护结肠的微观结构。红没药醇治疗还在蛋白质和mRNA水平上降低了促炎细胞因子（IL-6、IL-1、肿瘤坏死因子-α和IL-17A）的表达。环氧合酶-2（COX-2）和诱导型一氧化氮合酶（iNOS）炎症介质的表达以及组织亚硝酸盐水平均降低。此外，红没药醇降低了活化的丝裂原活化蛋白激酶（MAPK）信号和核因子κB（NF-κB）蛋白的磷酸化，并增强了结肠上皮PPAR-γ转录因子的表达。然而，PPAR-γ和/的表达未改变，表明红没药醇是PPAR-γ的特异性刺激剂。红没药醇还增加了经脂多糖（LPS）刺激的RAW264.7巨噬细胞预处理后的PPAR-γ转录因子表达，但未增加PPAR-γ和/的表达。红没药醇显著降低了用肿瘤坏死因子-α处理的HT-29细胞中促炎趋化因子（CXCL-1和IL-8）mRNA的表达以及HT-29细胞中PPAR-γ启动子活性。这些结果表明，红没药醇通过抑制MAPK信号和刺激PPAR-γ表达来减轻结肠炎症。
