title: Untargeted Metabolomics Reveals Dose-Response Characteristics for Effect of Rhubarb in a Rat Model of Cholestasis.
abstract: Cholestasis is a serious manifestation of liver diseases with limited therapies. Rhubarb, a widely used herbal medicine, has been frequently used at a relatively large dose for treating cholestasis. However, whether large doses are optimal and the therapeutic mechanism remain unclear. To explore these questions, the anti-cholestatic effect of five doses of rhubarb (0.21, 0.66, 2.10, 6.60, and 21.0 g/kg) in an alpha-naphthylisothiocyanate (ANIT)-induced rat model of cholestasis was examined by histopathology and serum biochemistry. A dose-dependent anti-cholestatic effect of rhubarb (0.21-6.6 g/kg) was observed, and an overdose of 21.0 g/kg showed a poor effect. LC-MS-based untargeted metabolomics together with pathway analysis were further applied to characterize the metabolic alterations induced by the different rhubarb doses. Altogether, 13 biomarkers were identified. The dose-response curve based on nine important biomarkers indicated that doses in the 0.42-6.61 g/kg range (EC20-EC80 range, corresponding to 4.00-62.95 g in the clinic) were effective for cholestasis treatment. The pathway analysis showed that bile acid metabolism and excretion, inflammation and amino acid metabolism were altered by rhubarb in a dose-dependent manner and might be involved in the dose-response relationship and therapeutic mechanism of rhubarb for cholestasis treatment.
authors.affiliation: College of Pharmacy, Chengdu University of Traditional Chinese MedicineChengdu, China; China Military Institute of Chinese Medicine, 302 Military HospitalBeijing, China.
authors.forename: Cong-En
authors.initials: CE
authors.lastname: Zhang
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military Hospital Beijing, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Niu
authors.affiliation: College of Pharmacy, Chengdu University of Traditional Chinese MedicineChengdu, China; China Military Institute of Chinese Medicine, 302 Military HospitalBeijing, China.
authors.forename: Rui-Yu
authors.initials: RY
authors.lastname: Li
authors.affiliation: College of Pharmacy, Chengdu University of Traditional Chinese MedicineChengdu, China; China Military Institute of Chinese Medicine, 302 Military HospitalBeijing, China.
authors.forename: Wu-Wen
authors.initials: WW
authors.lastname: Feng
authors.affiliation: College of Pharmacy, Chengdu University of Traditional Chinese MedicineChengdu, China; China Military Institute of Chinese Medicine, 302 Military HospitalBeijing, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Ma
authors.affiliation: College of Pharmacy, Chengdu University of Traditional Chinese MedicineChengdu, China; China Military Institute of Chinese Medicine, 302 Military HospitalBeijing, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Dong
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military HospitalBeijing, China; Department of Pharmacy, Beijing Friendship Hospital, Capital Medical UniversityBeijing, China.
authors.forename: Zhi-Jie
authors.initials: ZJ
authors.lastname: Ma
authors.affiliation: College of Pharmacy, Chengdu University of Traditional Chinese MedicineChengdu, China; China Military Institute of Chinese Medicine, 302 Military HospitalBeijing, China.
authors.forename: Guang-Quan
authors.initials: GQ
authors.lastname: Li
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military Hospital Beijing, China.
authors.forename: Ya-Kun
authors.initials: YK
authors.lastname: Meng
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military Hospital Beijing, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Wang
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military Hospital Beijing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yin
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military Hospital Beijing, China.
authors.forename: Lan-Zhi
authors.initials: LZ
authors.lastname: He
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military Hospital Beijing, China.
authors.forename: Yu-Meng
authors.initials: YM
authors.lastname: Li
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military Hospital Beijing, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Tan
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military Hospital Beijing, China.
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Zhao
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military Hospital Beijing, China.
authors.forename: Jia-Bo
authors.initials: JB
authors.lastname: Wang
authors.affiliation: College of Pharmacy, Chengdu University of Traditional Chinese Medicine Chengdu, China.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Dong
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military Hospital Beijing, China.
authors.forename: Xiao-He
authors.initials: XH
authors.lastname: Xiao
keywords: cholestasis; dose response; metabolomics; pathway analysis; rhubarb