Qu Chang, Yuan Zhong-Wen, Yu Xiu-Ting, Huang Yan-Feng, Yang Guang-Hua, Chen Jian-Nan, Lai Xiao-Ping, Su Zi-Ren, Zeng Hui-Fang, Xie Ying, Zhang Xiao-Jun
School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China; Guangdong Provincial Key Laboratory of New Chinese Medicinal Development and Research, Guangzhou, Guangdong, PR China.
State Key Laboratory for Quality Research in Chinese Medicines, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau.
Pharmacol Res. 2017 Jul;121:70-82. doi: 10.1016/j.phrs.2017.04.017. Epub 2017 Apr 27.
Despite the increased morbidity of ulcerative colitis (UC) in recent years, available treatments remain unsatisfactory. Pogostemon cablin has been widely applied to treat a variety of gastrointestinal disorders in clinic for centuries, in which patchouli alcohol (PA, CHO) has been identified as the major active component. This study attempted to determine the bioactivity of PA on dextran sulfate sodium (DSS)-induced mice colitis and clarify the mechanism of action. Acute colitis was induced in mice by 3% DSS for 7 days. The mice were then given PA (10, 20 and 40mg/kg) or sulfasalazine (SASP, 200mg/kg) as positive control via oral administration for 7 days. At the end of study, animals were sacrificed and samples were collected for pathological and other analysis. In addition, a metabolite profiling and a targeted metabolite analysis, based on the Ultra-Performance Liquid Chromatography coupled with mass spectrometry (UPLC-MS) approach, were performed to characterize the metabolic changes in plasma. The results revealed that PA significantly reduced the disease activity index (DAI) and ameliorated the colonic injury of DSS mice. The levels of colonic MPO and cytokines involving TNF-α, IFN-γ, IL-1β, IL-6, IL-4 and IL-10 also declined. Furthermore, PA improved the intestinal epithelial barrier by enhancing the level of colonic expression of the tight junction (TJ) proteins, for instance ZO-1, ZO-2, claudin-1 and occludin, and by elevating the levels of mucin-1 and mucin-2 mRNA. The study also demonstrated that PA inhibited the DSS-induced cell death signaling by modulating the apoptosis related Bax and Bcl-2 proteins and down-regulating the necroptosis related RIP3 and MLKL proteins. By comparison, up-regulation of IDO-1 and TPH-1 protein expression in DSS group was suppressed by PA, which was in line with the declined levels of kynurenine (Kyn) and 5-hydroxytryptophan (5-HTP) in plasma. The therapeutic effect of PA was evidently reduced when Kyn was given to mice. In summary, the study successfully demonstrated that PA ameliorated DSS-induced mice acute colitis by suppressing inflammation, maintaining the integrity of intestinal epithelial barrier, inhibiting cell death signaling, and suppressing tryptophan catabolism. The results provided valuable information and guidance for using PA in treatment of UC.
尽管近年来溃疡性结肠炎（UC）的发病率有所上升，但现有的治疗方法仍不尽人意。几个世纪以来，广藿香已在临床上广泛应用于治疗多种胃肠道疾病，其中广藿香醇（PA，CHO）被确定为主要活性成分。本研究试图确定PA对葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎的生物活性，并阐明其作用机制。通过3% DSS诱导小鼠急性结肠炎7天。然后给小鼠口服PA（10、20和40mg/kg）或柳氮磺胺吡啶（SASP，200mg/kg）作为阳性对照，持续7天。在研究结束时，处死动物并收集样本进行病理和其他分析。此外，基于超高效液相色谱-质谱联用（UPLC-MS）方法进行了代谢物谱分析和靶向代谢物分析，以表征血浆中的代谢变化。结果显示，PA显著降低了疾病活动指数（DAI），改善了DSS小鼠的结肠损伤。结肠MPO水平以及涉及TNF-α、IFN-γ、IL-1β、IL-6、IL-4和IL-10的细胞因子水平也有所下降。此外，PA通过提高紧密连接（TJ）蛋白（如ZO-1、ZO-2、claudin-1和occludin）的结肠表达水平，以及提高粘蛋白-1和粘蛋白-2 mRNA水平，改善了肠道上皮屏障。该研究还表明，PA通过调节凋亡相关的Bax和Bcl-2蛋白以及下调坏死性凋亡相关的RIP3和MLKL蛋白，抑制了DSS诱导的细胞死亡信号。相比之下，PA抑制了DSS组中IDO-1和TPH-1蛋白表达的上调，这与血浆中犬尿氨酸（Kyn）和5-羟色氨酸（5-HTP）水平的下降一致。当给小鼠注射Kyn时，PA的治疗效果明显降低。总之，该研究成功证明，PA通过抑制炎症、维持肠道上皮屏障的完整性、抑制细胞死亡信号和抑制色氨酸分解代谢，改善了DSS诱导的小鼠急性结肠炎。这些结果为PA在UC治疗中的应用提供了有价值的信息和指导。
