Alisol B 23-acetate

The tubers of Alisma plantago-aquatica Linn.

Alisol B 23-acetate, a natural triterpenoid, produces protective effects against EE-induced cholestasis, due to FXR-mediated gene regulation. IC50 Value: Target: Anti-hepatotoxic natural product. In vitro: Alisol-B 23-acetate has an effect on FXR activation in a dose-dependent manner using luciferase reporter assay in HepG2 cells [3]. In vivo: In alisol B 23-acetate-treated mice, the changes in transporters and enzymes, as well as ameliorative liver histology were abrogated by FXR antagonist guggulsterone [1]. Alisol B 23-acetate treatment in a dose-dependent manner resulted in protection against hepatotoxicity induced by CCl4via FXR activation. Through FXR activation, alisol B 23-acetate promoted hepatocyte proliferation via an induction in hepatic levels of FoxM1b, Cyclin D1 and Cyclin B1. Alisol B 23-acetate also reduced hepatic bile acids through a decrease in hepatic uptake transporter Ntcp, bile acid synthetic enzymes Cyp7a1, Cyp8b1, and an increase in efflux transporter Bsep, Mrp2 expression. In addition, alisol B 23-acetate induced the expression of STAT3 phosphorylation, and STAT3 target genes Bcl-xl and SOCS3, resulting in decreased hepatocyte apoptosis [2].

References:
[1]. Meng Q, et al. Protective effects of alisol B 23-acetate from edible botanical Rhizoma alismatis against carbon tetrachloride-induced hepatotoxicity in mice. Food Funct. 2015 Apr 8;6(4):1241-50. [2]. Meng Q, et al. Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis. Toxicol Appl Pharmacol. 2015 Mar 15;283(3):178-86. [3]. Meng Q, et al. Alisol B 23-acetate promotes liver regeneration in mice after partial hepatectomy via activating farnesoid X receptor. Biochem Pharmacol. 2014 Nov 15;92(2):289-98. [4]. Meng Q, et al. Protective Effects of Alisol B 23-Acetate Via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Estrogen-Induced Cholestatic Liver Injury in Mice. Pharm Res. 2015 Jun 4.

Protective effects of alisol B 23-acetate from edible botanical Rhizoma alismatis against carbon tetrachloride-induced hepatotoxicity in mice.[Pubmed:25747392]

Food Funct. 2015 Apr;6(4):1241-50.

Carbon tetrachloride (CCl4)-induced hepatotoxicity is a common syndrome with simultaneous severe hepatocyte death and acute cholestasis. The purpose of the present study is to investigate the hepatoprotective effect of Alisol B 23-acetate (AB23A), a natural triterpenoid from edible botanical Rhizoma alismatis, on acute hepatotoxicity induced by CCl4 in mice, and further to elucidate the involvement of farnesoid X receptor (FXR), signal transducers and activators of transcription 3 (STAT3) in the hepatoprotective effect. H&E staining, BrdU immunohistochemistry and TUNEL assay were used to identify the amelioration of histopathological changes, hepatocyte proliferation and apoptosis. Real-time PCR and western blot assay were used to elucidate the mechanisms underlying AB23A hepatoprotection. The results indicated that AB23A treatment in a dose-dependent manner resulted in protection against hepatotoxicity induced by CCl4via FXR activation. Through FXR activation, AB23A promoted hepatocyte proliferation via an induction in hepatic levels of FoxM1b, Cyclin D1 and Cyclin B1. AB23A also reduced hepatic bile acids through a decrease in hepatic uptake transporter Ntcp, bile acid synthetic enzymes Cyp7a1, Cyp8b1, and an increase in efflux transporter Bsep, Mrp2 expression. In addition, AB23A induced the expression of STAT3 phosphorylation, and STAT3 target genes Bcl-xl and SOCS3, resulting in decreased hepatocyte apoptosis. In conclusion, AB23A produces a protective effect against CCl4-induced hepatotoxicity, due to FXR and STAT3-mediated gene regulation.

Reversal of P-glycoprotein-mediated multidrug resistance by Alisol B 23-acetate.[Pubmed:15294447]

Biochem Pharmacol. 2004 Sep 1;68(5):843-55.

Herbal drugs were screened for their activity in reversing multidrug resistance (MDR) in P-glycoprotein (P-gp) over-expressing cancer cells. Through bio-assay guided fractionation an active compound was isolated from Rhizoma Alismatis, the underground part of Alisma orientale and the chemical structure of the isolate compound was confirmed by HPLC, LC-MS and NMR as Alisol B 23-acetate (ABA). ABA restored the sensitivity of MDR cell lines HepG2-DR and K562-DR to anti-tumor agents that have different modes of action but are all P-gp substrates. It restored the activity of vinblastine, a P-gp substrate, in causing G2/M arrest in MDR cells. In a dose-dependent manner, ABA increased doxorubicin accumulation and slowed down the efflux of rhodamin-123 from MDR cells. ABA inhibited the photoaffinity labeling of P-gp by [125I]iodoarylazidoprazosin and stimulated the ATPase activity of P-gp in a concentration-dependent manner, suggesting that it could be a transporter substrate for P-gp. In addition, ABA was also a partial non-competitive inhibitor of P-gp when verapamil was used as a substrate. Our results suggest that ABA may be a potential MDR reversal agent and could serve as a lead compound in the development of novel drugs.

Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis.[Pubmed:25655198]

Toxicol Appl Pharmacol. 2015 Mar 15;283(3):178-86.

Intrahepatic cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. Appropriate regulation of bile acids in hepatocytes is critically important for protection against liver injury. In the present study, we characterized the protective effect of Alisol B 23-acetate (AB23A), a natural triterpenoid, on alpha-naphthylisothiocyanate (ANIT)-induced liver injury and intrahepatic cholestasis in mice and further elucidated the mechanisms in vivo and in vitro. AB23A treatment dose-dependently protected against liver injury induced by ANIT through reducing hepatic uptake and increasing efflux of bile acid via down-regulation of hepatic uptake transporters (Ntcp) and up-regulation of efflux transporter (Bsep, Mrp2 and Mdr2) expression. Furthermore, AB23A reduced bile acid synthesis through repressing Cyp7a1 and Cyp8b1, increased bile acid conjugation through inducing Bal, Baat and bile acid metabolism through an induction in gene expression of Sult2a1. We further demonstrate the involvement of farnesoid X receptor (FXR) in the hepatoprotective effect of AB23A. The changes in transporters and enzymes, as well as ameliorative liver histology in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo. In vitro evidences also directly demonstrated the effect of AB23A on FXR activation in a dose-dependent manner using luciferase reporter assay in HepG2 cells. In conclusion, AB23A produces protective effect against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes.

Alisol B 23-acetate promotes liver regeneration in mice after partial hepatectomy via activating farnesoid X receptor.[Pubmed:25278094]

Biochem Pharmacol. 2014 Nov 15;92(2):289-98.

Liver resection has become a common treatment for liver tumors and hepatocellular carcinoma over the past decades. However, after surgery, the remnant livers in some patients fail to regenerate. Therefore, there is an urgent medical need to develop drugs that can promote liver regeneration. The purpose of the current study is to investigate the promotive effect of Alisol B 23-acetate (AB23A) on liver regeneration in mice following partial hepatectomy (PH), and further elucidate the involvement of farnesoid X receptor (FXR) in the liver regeneration-promotive effect using in vivo and in vitro experiments. The results showed that AB23A dose-dependently promoted hepatocyte proliferation via upregulating hepatocyte proliferation-related protein forkhead box M1b (FoxM1b), Cyclin D1 and Cyclin B1 expression, and attenuated liver injury via an inhibition in Cyp7a1 and an induction in efflux transporters Bsep expression resulting in reduced hepatic bile acid levels. These changes in the genes, as well as accelerated liver regeneration in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo. In vitro evidences also directly showed the regulation of these genes by AB23A was abrogated when FXR was silenced. Luciferase reporter assay in HepG2 cells and molecular docking further demonstrated the effect of AB23A on FXR activation in vitro. In conclusions, AB23A produces promotive effect on liver regeneration, due to FXR-mediated regulation of genes involved in hepatocyte proliferation and hepato-protection. AB23A has the potential to be a novel therapeutic option for facilitating efficient liver regeneration in patients subjected to liver resection.

Effects of alisol B 23-acetate on ovarian cancer cells: G1 phase cell cycle arrest, apoptosis, migration and invasion inhibition.[Pubmed:27288915]

Phytomedicine. 2016 Jul 15;23(8):800-9.

BACKGROUND: Ovarian cancer is the first leading cause of death among gynecologic malignancies worldwide. Discovery of new chemotherapeutic drugs is still imperative for the improvement of the survival rate. PURPOSE: This study aims to investigate the anti-cancer potential of Alisol B 23-acetate (AB23), a protostane-type triterpene isolated from the Alismatis Rhizoma, in the parental and paclitaxel-resistant ovarian cancer cells. METHODS: MTT assay was performed to evaluate cell viability after treatment with AB23, along with flow cytometry for apoptosis and cell cycle analysis. Western blotting was conducted to determine the relative protein level. Wound healing and transwell assays were performed to investigate the effect of AB23 on cell migration and invasion. RESULTS: AB23 obviously inhibited proliferation of the three ovarian cancer cell lines, down-regulated the protein levels of CDK4, CDK6, and cyclin D1, and blocked the cell cycle progressions in G1 phase. Meanwhile, AB23 induced accumulation of the sub-G1 phase in the three cell lines in a concentration dependent manner. The protein levels of cleaved poly ADP-ribose polymerase (PARP) and the ratio of Bax/Bcl-2 were up-regulated after treatment with AB23. Further study showed that AB23 induced endoplasmic reticulum stress through IRE1 signaling pathway and silencing of IRE1alpha partially enhanced AB23-induced apoptosis. Wound healing and transwell assays showed that AB23 could also suppress the migration and invasion of HEY cells. Moreover, it down-regulated the protein levels of matrix metalloproteinases MMP-2 and MMP-9. CONCLUSION: AB23 possessed anti-proliferation, anti-migration and anti-invasion activities as a single agent on ovarian cancer cells.

Alisol B 23-acetate, a natural triterpenoid, produces protective effects against EE-induced cholestasis, due to FXR-mediated gene regulation.

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