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Review
. 2022 Aug 11;10(8):1945.
doi: 10.3390/biomedicines10081945.

Pharmacological Properties and Molecular Targets of Alisol Triterpenoids from Alismatis Rhizoma

Affiliations
Review

Pharmacological Properties and Molecular Targets of Alisol Triterpenoids from Alismatis Rhizoma

Christian Bailly. Biomedicines. .

Abstract

More than 100 protostane triterpenoids have been isolated from the dried rhizomes of Alisma species, designated Alismatis rhizoma (AR), commonly used in Asian traditional medicine to treat inflammatory and vascular diseases. The main products are the alisols, with the lead compounds alisol-A/-B and their acetate derivatives being the most abundant products in the plant and the best-known bioactive products. The pharmacological effects of Ali-A, Ali-A 24-acetate, Ali-B, Ali-B 23-acetate, and derivatives have been analyzed to provide an overview of the medicinal properties, signaling pathways, and molecular targets at the origin of those activities. Diverse protein targets have been proposed for these natural products, including the farnesoid X receptor, soluble epoxide hydrolase, and other enzymes (AMPK, HCE-2) and functional proteins (YAP, LXR) at the origin of the anti-atherosclerosis, anti-inflammatory, antioxidant, anti-fibrotic, and anti-proliferative activities. Activities were classified in two groups. The lipid-lowering and anti-atherosclerosis effects benefit from robust in vitro and in vivo data (group 1). The anticancer effects of alisols have been largely reported, but, essentially, studies using tumor cell lines and solid in vivo data are lacking (group 2). The survey shed light on the pharmacological properties of alisol triterpenoids frequently found in traditional phytomedicines.

Keywords: Alismatis rhizoma; alisol; cancer; inflammation; molecular targets; pharmacology; protostane triterpenoids.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Medicinal uses of Alismatis rhizoma. The dried rhizomes of the plant Alisma plantago-aquatica are used to prepare the traditional medicinal products in Asian countries and the medicine is used to treat different pathologies, as indicated.
Figure 2
Figure 2
Structures of the protostane terpenoid skeleton and the main alisol compounds, Ali-A/-B and their acetate derivatives. The numbering of specific positions (discussed in the text) is indicated.
Figure 3
Figure 3
Structures of 8 selected alisol derivatives. The series includes 22 compounds (Ali-A to Ali-V) and 100 derivatives.
Figure 4
Figure 4
Anti-atherosclerosis activity of Ali-B 23-acetate. The compound binds to the FRX protein and displays an agonist activity which leads to the regulation of the expression of genes implicated in the control of inflammation, glucose, and lipid levels. Via this mechanism, Ali-B 23-acetate reduces atherosclerotic plaque.
Figure 5
Figure 5
Binding of 11-deoxy-25-anhydro alisol-E to soluble epoxide hydrolase (sEH), the enzyme which converts epoxide molecules into diol molecules, as represented. The modulation of the epoxide/diol ratio is a mechanism by which the compound exerts activities against multiple pathologies, as indicated.
Figure 6
Figure 6
Inhibition of RANKL-induced osteoclast differentiation and function by Ali-C 23-acetate (AC23A). The compound would act selectively on osteoblast precursors, rather than mature osteoblasts, by inhibiting RANKL-induced osteoclastogenesis. The compound blocks phosphorylation of JNK and reduces expression of osteoclastogenic mediators, such as TRAP, c-Fos, MMP9, NFATc1, and cathepsin K [104]. AC23A can be found in phytomedicines made from Alisma rhizoma, such as Liuwei Dihuang and Yukmi-jihang-tang-Jahage, both used to treat osteoporosis.
Figure 7
Figure 7
Proposed protein targets for Ali-B 23-acetate. Molecular modeling studies have evaluated binding of the compound to soluble epoxide hydrolase (sEH) [81,82], 5’-adenosine monophosphate-activated protein kinase (AMPK) [70], liver X receptor β (LXRβ) [67], farnesoid X receptor (FXR) [51], human liver carboxylesterase 1 (HCE-2) [126], Yes-associated protein (YAP) [115], sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SR Ca2+-ATPase) [125]. The protein models shown correspond to the PDB structures 4HAI for sEH, 7MYJ for AMPK, 6K9H for LXRβ, 6HL1 for FXR, YA4 for HCE-1, 3KYS for YAP, 1VFP for SR Ca2+-ATPase.
Figure 8
Figure 8
Pharmacological effects reported with alisol derivatives. The effects can be separated into two categories: the effects benefiting from robust in vitro and in vivo data obtained with animal models representative of the pathology (indicated in bold) and the effects evidenced essentially using in vitro data, with purified molecular systems and/or laboratory cell lines.

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