A New Oleanolic Acid Derivative against CCl4-Induced Hepatic Fibrosis in Rats

Xiang, Hongjun; Han, Yaotian; Zhang, Yuzhong; Yan, Wenqiang; Xu, Bing; Chu, Fuxiang; Xie, Tianxin; Jia, Menglu; Yan, Mengmeng; Zhao, Rui; Wang, Penglong; Lei, Haimin

doi:10.3390/ijms18030553

Cited by 29 publications

(21 citation statements)

References 35 publications

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“…Daily intraperitoneal administration of Oxy‐Di‐OA (14‐28 mg/kg, ip for 11 weeks) prevented the development of chronic CCl 4 (9 weeks)‐induced liver fibrosis, as evidenced by histology and immunohistochemistry analysis. Oxy‐Di‐OA also decreased the expression of TGF‐β1 . Taken together, OA is beneficial against CCl 4 ‐induced chronic fibrosis and cirrhosis.…”

Section: Low Doses Of Oa Protect Against Hepatotoxicity Induced By a mentioning

confidence: 75%

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Oleanolic acid reprograms the liver to protect against hepatotoxicants, but is hepatotoxic at high doses

Liu

Lü

et al. 2018

Liver International

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Oleanolic acid (OA) is a triterpenoid that exists widely in fruits, vegetables and medicinal herbs. OA is included in some dietary supplements and is used as a complementary and alternative medicine (CAM) in China, India, Asia, the USA and European countries. OA is effective in protecting against various hepatotoxicants, and one of the protective mechanisms is reprogramming the liver to activate the nuclear factor erythroid 2-related factor 2 (Nrf2). OA derivatives, such as CDDO-Im and CDDO-Me, are even more potent Nrf2 activators. OA has recently been shown to also activate the Takeda G-protein-coupled receptor (TGR5). However, whereas a low dose of OA is hepatoprotective, higher doses and long-term use of OA can produce liver injury, characterized by cholestasis. This paradoxical hepatotoxic effect occurs not only for OA, but also for other OA-type triterpenoids. Dose and length of time of OA exposure differentiate the ability of OA to produce hepatoprotection vs hepatotoxicity. Hepatotoxicity produced by herbs is increasingly recognized and is of global concern. Given the appealing nature of OA in dietary supplements and its use as an alternative medicine around the world, as well as the development of OA derivatives (CDDO-Im and CDDO-Me) as therapeutics, it is important to understand not only that they program the liver to protect against hepatotoxic chemicals, but also how they produce hepatotoxicity.

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Section: Low Doses Of Oa Protect Against Hepatotoxicity Induced By a mentioning

confidence: 75%

“…Oxy-Di-OA also decreased the expression of TGF-β1. 55 Taken together, OA is beneficial against CCl 4 -induced chronic fibrosis and cirrhosis.…”

Section: Oa Protects Against Chronic Liver Injury Fibrosis and Cirmentioning

confidence: 98%

Oleanolic acid reprograms the liver to protect against hepatotoxicants, but is hepatotoxic at high doses

Liu

Lü

et al. 2018

Liver International

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“…[ 12 ]. Due to its favorable properties, OA is considered as a base molecule for further synthetic modifications to develop lead compounds for hepatoprotective agents in our reported studies and others [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ], and some of these derivatives have been therapeutic candidates in clinical trials [ 20 ]. However, there are some shortcomings in poor water-solubility, low bioavailability, and weak bioactivity, which seriously restrict their further clinical application.…”

Section: Introductionmentioning

confidence: 99%

Oleanolic Acid-amino Acids Derivatives: Design, Synthesis, and Hepatoprotective Evaluation In Vitro and In Vivo

et al. 2018

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Activated hepatic stellate cells (HSCs) are the main extracellular matrix (ECM)-producing cells in the injured liver and the key mediators of liver fibrosis; they also promote the progression of hepatocellular carcinoma (HCC). In the acidic extracellular microenvironment of HCC, HSCs are activated to promote the migration of HCC cells. It is worth attempting to alter the weak acidic microenvironment to promote activated HSC apoptosis to treat liver fibrosis and liver cancer. In the present study, a series of novel OA-amino acids analogues were designed and synthesized to introduce different amino acids in the 3-hydroxyl of OA using the ester condensation reaction to enhance hydrophilicity, alkalinity, and biological activity. We found that OA-lysine derivative (3g) could improve the hydrophilic of OA and induce HSCs apoptosis via inducing MMP depolarization and increasing intracellular Ca2+ levels. Additionally, 3g displayed a better hepatoprotective effect than OA (20 mg/kg, intragastric administration) against the acute liver injury induced by carbon tetrachloride (CCl4) in mice. The results suggested that basic amino acids (lysine) could effectively enhance OA’s hydrophilicity, alkalinity, and hepatoprotective activity in vitro and in vivo, which might be likely associated with increasing bioavailability and altering an extracellular weak acidic microenvironment with further verification. Therefore, the OA-lysine derivative (3g) has the potential to be developed as an agent with hepatoprotective activity.

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“…Hallmarks of clinical liver injury will be presented in the Special Issue “Molecular Research on Drug Induced Liver Injury” published in the International Journal of Molecular Sciences to address the progress and current standing in the vast field of liver injury. A total of 10 reviews and original articles [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ] have been published in this Special Issue, as detailed in Table 1 .…”

mentioning

confidence: 99%

“…In another experimental study carried out in rats, Xiang et al [ 10 ] reported on the effects of a novel oleanolic acid derivative Oxy-Di-AO on CCl 4 -induced hepatic fibrosis. As a derivative of the hepatoprotective oleanolic acid originally from Ligustrum lucidum , the synthetic Oxy-Di-AO has a protective effect and prevented the development of CCl 4 -induced liver fibrosis when given intraperitoneally daily for 9 weeks.…”

mentioning

confidence: 99%