Protective effects of 18β‐Glycyrrhetinic acid against myocardial infarction: Involvement of PI3K/Akt pathway activation and inhibiting Ca<sup>2+</sup> influx via L‐type Ca<sup>2+</sup> channels

Chu, Sijie; Wang, Weijie; Zhang, Ning; Liu, Tong; Li, Jing; Chu, Xi; Zuo, Sai-Jie; Ma, Zhihong; Ma, Donglai; Chu, Li

doi:10.1002/fsn3.2639

Cited by 18 publications

(10 citation statements)

References 46 publications

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“…These beneficial effects proved to be the consequence of GA’s ability to promote the expression of Bcl-2 and to inhibit the expression of Bax and caspase-8 through the PI3K/Akt pathway [ 180 ]. Similar inhibitory effects of the PI3K/Akt pathway were described by another study to be the cardioprotective mechanism of GA; Chu et al [ 181 ] reported that GA alleviates oxidative stress, inflammation, and apoptosis in a mice model of myocardial infarction via PI3K/Akt pathway inhibition while also decreasing Ca 2+ influx through L-type calcium channels, thus reducing cell contractility. The GA effect on Ca 2+ was also described in an ischemia-reperfusion rat model that demonstrated the significant decrease of intracellular Ca 2+ levels in cardiomyocytes through the inhibition of the late sodium current, thus improving diastolic function in patients with heart failure [ 182 ].…”

Section: Glycyrrhetinic Acidsupporting

confidence: 66%

Recent Advances Regarding the Molecular Mechanisms of Triterpenic Acids: A Review (Part II)

Mioc

Prodea

Racoviceanu

et al. 2022

IJMS

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Triterpenic acids are a widespread class of phytocompounds which have been found to possess valuable therapeutic properties such as anticancer, anti-inflammatory, hepatoprotective, cardioprotective, antidiabetic, neuroprotective, lipolytic, antiviral, and antiparasitic effects. They are a subclass of triterpenes bearing a characteristic lipophilic structure that imprints unfavorable in vivo properties which subsequently limit their applications. The early investigation of the mechanism of action (MOA) of a drug candidate can provide valuable information regarding the possible side effects and drug interactions that may occur after administration. The current paper aimed to summarize the most recent (last 5 years) studies regarding the MOA of betulinic acid, boswellic acid, glycyrrhetinic acid, madecassic acid, moronic acid, and pomolic acid in order to provide scientists with updated and accessible material on the topic that could contribute to the development of future studies; the paper stands as the sequel of our previously published paper regarding the MOA of triterpenic acids with therapeutic value. The recent literature published on the topic has highlighted the role of triterpenic acids in several signaling pathways including PI3/AKT/mTOR, TNF-alpha/NF-kappa B, JNK-p38, HIF-α/AMPK, and Grb2/Sos/Ras/MAPK, which trigger their various biological activities.

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Section: Glycyrrhetinic Acidsupporting

confidence: 66%

Recent Advances Regarding the Molecular Mechanisms of Triterpenic Acids: A Review (Part II)

Mioc

Prodea

Racoviceanu

et al. 2022

IJMS

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“…As compared with GA, the metabolite 18β‐GA inhibits LTCCs with a higher sensitivity (IC 50 ≈ 30 μM) (Chu et al, 2021). 18β‐GA also inhibits Na + currents in human atrial myocytes but has no effect on cardiac voltage‐gated K + channels, such as K v 1.5 and K v 11.1 (Du et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Licorice metabolite 18β‐glycyrrhetinic acid activates G protein‐gated inwardly rectifying K⁺ channels

Chen,

Yasuda,

Notomi

et al. 2023

British J Pharmacology

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Background and PurposeLicorice (liquorice) is a common food additive and is used in Chinese medicine. Excess licorice intake can induce atrial fibrillation. Patients with atrial fibrillation possess constitutively activated G protein‐gated inwardly rectifying K+ (GIRK) channels. Whether licorice affects GIRK channel activity is unknown. We aimed to clarify the effects of licorice ingredients on GIRK current and the mechanism of action.Experimental ApproachA major component of licorice, glycyrrhizic acid (GA), and its metabolite, 18β‐glycyrrhetinic acid (18β‐GA), were tested. We performed electrophysiological recordings in Xenopus oocytes to examine the effects of GA and 18β‐GA on various GIRK subunits (Kir3.1–Kir3.4), mutagenesis analyses to identify the crucial residues for drug action and motion analysis in cultured rat atrial myocytes to clarify effects of 18β‐GA on atrial functions.Key ResultsGA inhibited Kir3.1‐containing channels, while 18β‐GA activated all Kir3.x subunits. A pore helix residue Phe137 in Kir3.1 was critical for GA‐mediated inhibition, and the corresponding Ser148 in Kir3.2 was critical for 18β‐GA‐mediated activation. 18β‐GA activated GIRK channel in a Gβγ‐independent manner, whereas phosphatidylinositol 4,5‐bisphosphate (PIP2) was essential for activation. Glu236 located at the cytoplasmic pore of Kir3.2 appeared to be important to interactions with 18β‐GA. In rat atrial myocytes, 18β‐GA suppressed spontaneous beating via activation of GIRK channels.Conclusion and ImplicationsGA acts as a novel GIRK inhibitor, and 18β‐GA acts as a novel GIRK activator. 18β‐GA alters atrial function via activation of GIRK channels. This study elucidates the pharmacological activity of licorice ingredients and provides information for drug design.

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“…Glycyrrhetinic acid has an obvious protective effect on cardiovascular, and experiments show that it can regulate the permeability of rat heart mitochondria and mediate cardiac oxidative stress and apoptosis, and improve MIRI [ 74 , 75 ]. Moreover, glycyrrhetinic acid can affect myocardial muscle strength, inhibit oxidative stress, reduce the inflammatory response, and protect the heart through PI3K/Akt pathway [ 76 , 77 ].…”

Section: Discussionmentioning

confidence: 99%

To Explore the Key Active Compounds and Therapeutic Mechanism of Guizhi Gancao Decoction in Coronary Heart Disease by Network Pharmacology and Molecular Docking

Yuan

Yitao

2022

Evidence-Based Complementary and Alternative Medicine

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Objective. Coronary heart disease (CHD) is the leading cause of death from cardiovascular disease and has become an important public health problem worldwide. Guizhi Gancao Decoction (GGD) has been shown to be used in the treatment of CHD with good efficacy, but its specific therapeutic mechanism and active ingredients have not been fully clarified. This study aims to identify the active compounds and key targets of GGD in the treatment of CHD, explore the therapeutic mechanism of GGD, and provide candidate compounds for anti-CHD drug development. Methods. The main compounds of GGD were determined by UPLC-MS/MS analysis and screened by SwissADME. The corresponding targets of GGD compounds were obtained from SwissTargetPrediction, and the targets of CHD were obtained from the HERB and GeneCards databases. The STRING 11.5 database was used to analyze the PPI (Protein-Protein Interactions) network of potential therapeutic targets of GGD compounds. Cytoscape 3.7.2 was used to construct target-related networks and find core targets. The GEO database was used to validate the differential expression of core targets. The PANTHER Classification System was used to functionally classify potential therapeutic targets for GGD. The GO biological process analysis and KEGG pathway analysis of targets were completed by DAVID 6.8 database. AutoDockTools 1.5.6 and PyMol 2.5.2 were used to perform molecular docking of core targets with the active GGD compounds. Results. 7 active GGD compounds were obtained based on UPLC-MS/MS and pharmacological parameter evaluation, which corresponded to 131 CHD-related targets. Among them, EGFR, MAPK3, RELA, CCND1, ESR1, PTGS2, NR3C1, CYP3A4, MMP9, and PTPN11 were considered core targets. According to the targets related to CHD, glycyrrhetinic acid, liquiritigenin, and schisandrin are considered key active ingredients. GO biological process and KEGG analysis indicated that the potential targets of GGD in the treatment of CHD involve a variety of biological processes and therapeutic mechanisms. Molecular docking results showed that both the core targets and the corresponding compounds had the good binding ability. Conclusions. This study contributes to a more comprehensive understanding of the therapeutic mechanism and active ingredients of GGD for CHD and provides candidate compounds for drug development of CHD.

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Protective effects of 18β‐Glycyrrhetinic acid against myocardial infarction: Involvement of PI3K/Akt pathway activation and inhibiting Ca²⁺ influx via L‐type Ca²⁺ channels

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 18 publications

References 46 publications

Recent Advances Regarding the Molecular Mechanisms of Triterpenic Acids: A Review (Part II)

Recent Advances Regarding the Molecular Mechanisms of Triterpenic Acids: A Review (Part II)

Licorice metabolite 18β‐glycyrrhetinic acid activates G protein‐gated inwardly rectifying K⁺ channels

To Explore the Key Active Compounds and Therapeutic Mechanism of Guizhi Gancao Decoction in Coronary Heart Disease by Network Pharmacology and Molecular Docking

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Protective effects of 18β‐Glycyrrhetinic acid against myocardial infarction: Involvement of PI3K/Akt pathway activation and inhibiting Ca2+ influx via L‐type Ca2+ channels

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 18 publications

References 46 publications

Recent Advances Regarding the Molecular Mechanisms of Triterpenic Acids: A Review (Part II)

Recent Advances Regarding the Molecular Mechanisms of Triterpenic Acids: A Review (Part II)

Licorice metabolite 18β‐glycyrrhetinic acid activates G protein‐gated inwardly rectifying K+ channels

To Explore the Key Active Compounds and Therapeutic Mechanism of Guizhi Gancao Decoction in Coronary Heart Disease by Network Pharmacology and Molecular Docking

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Protective effects of 18β‐Glycyrrhetinic acid against myocardial infarction: Involvement of PI3K/Akt pathway activation and inhibiting Ca²⁺ influx via L‐type Ca²⁺ channels

Licorice metabolite 18β‐glycyrrhetinic acid activates G protein‐gated inwardly rectifying K⁺ channels