AMPK-mediated GSK3β inhibition by isoliquiritigenin contributes to protecting mitochondria against iron-catalyzed oxidative stress

Choi, Soon Ho; Kim, Young Woo; Kim, Sang Geon

doi:10.1016/j.bcp.2009.12.011

Cited by 106 publications

(77 citation statements)

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“…For instance, ISLQ has been shown to have spasmolytic effects in the intestine (33,34), which may help reduce diarrheal symptoms in cholera since recent evidence has shown that cholera toxins can stimulate enteric neural reflexes, leading to enhanced gastrointestinal motility (35). Furthermore, ISLQ has been reported to stimulate AMP-activated kinases (AMPK), a negative regulator of CFTR and the mammalian target of rapamycin (mTOR) (36). Indeed, inhibition of CFTR and mTOR by the AMPK activator metformin has been shown to inhibit Cl − secretion and cell proliferation, respectively, in renal epithelial cells and slow cyst growth in a mouse model of autosomal dominant PKD (37).…”

Section: CLmentioning

confidence: 99%

Novel Action of the Chalcone Isoliquiritigenin as a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Inhibitor: Potential Therapy for Cholera and Polycystic Kidney Disease

et al. 2012

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Abstract. Overstimulation of cAMP-activated Cl− secretion can cause secretory diarrhea. Isoliquiritigenin (ISLQ) is a plant-derived chalcone that has a wide range of biological activities. The present study thus aimed to investigate the effect of ISLQ on cAMP-activated Cl − secretion in human intestinal epithelium, especially the underlying mechanism and therapeutic application. Short-circuit current analysis of human intestinal epithelial (T84) cell monolayers revealed that ISLQ dose-dependently inhibited cAMP-activated Cl − secretion with an IC 50 of approximately 20 μM. ISLQ had no effect on either basal short-circuit current or Ca 2+ -activated Cl − secretion. Apical Cl − current analysis of T84 cell monolayers indicated that ISLQ blocked mainly the cystic fibrosis transmembrane conductance regulator (CFTR) Cl − channels, but not other unidentified cAMPdependent Cl − channels. ISLQ did not affect intracellular cAMP levels or cell viability. ISLQ completely abolished the cholera toxin-induced transepithelial Cl − secretion in T84 cells and reduced the cholera toxin-induced intestinal fluid secretion in mouse closed loop models by 90%. Similarly, ISLQ completely inhibited the cAMP-activated apical Cl − current across monolayers of Madin-Darby Canine Kidney (MDCK) cells and retarded cyst growth in MDCK cyst models by 90%. This study reveals a novel action of ISLQ as a potent CFTR inhibitor with therapeutic potential for treatment of cholera and polycystic kidney disease.

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Section: CLmentioning

confidence: 99%

Novel Action of the Chalcone Isoliquiritigenin as a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Inhibitor: Potential Therapy for Cholera and Polycystic Kidney Disease

et al. 2012

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“…AA also induced dysfunction of mitochondrial membrane potential (MMP). 16,20) MMP analysis was performed using flow cytometry after staining of cells with Rh123 (a membrane-permeable cationic fluorescent). 16,33) Our results showed that MCE was significantly recovered in AA+iron-induced mitochondrial dysfunction (Figs.…”

Section: Mces Inhibit Aa+fe-induced Apoptosis In Hepg2mentioning

confidence: 99%

“…18,19) Moreover, inhibition of AMPK induces lipid accumulation and decreases oxidized free fatty acids in the mitochondria, ultimately leading to increased production of ROS in hepatocytes. 20) Herbal medicines have recently used in treatment of a variety of diseases, including neuronal disorders, cardiovascular disease, cancer, diabetes, obesity-related disorders, liver disease and lifespan extension. [21][22][23] Herbal medicines can also be used as alternative therapeutic strategies for treatment of disease because they are a rich source of bioactivity with few side effects.…”

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confidence: 99%

“…In this study, we examined the antioxidant effects of Moutan Cortex Extract (MCE) on AA and iron-induced hepatotoxicity and demonstrated their hepato-protective activities and amounts of proteins were separated using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to a polyvinylidenefluoride (PVDF) membrane (Amersham, IL, U.S.A.). After blocking with TBS-T buffer [20 dard Solution The amount preparations of materials (Paeonol, Benzoyl Paeoniflorin, Albiflorin, Paeoniflorin, Benzoic acid, and then Chlorogenic acid) were measured accurately and they were melted by methanol, and then they were made from a standard undiluted solution which 1 µg/mL. After that, the standard solution were diluted with the methanol to be contained 1, 5, 10 ng/mL and they were a standard solution.…”

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confidence: 99%

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Moutan Cortex Protects Hepatocytes against Oxidative Injury through AMP-Activated Protein Kinase Pathway

Jang

Kim

Song

et al. 2017

Biological & Pharmaceutical Bulletin

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Moutan Cortex, the root bark of Paeonia suffruticosa ANDREWS in Ranunculaceae, has widely demonstrated analgesic, anti-spasmodic, and anti-inflammatory effects in various cancer and immune cell lines. Oxidative stress is associated with development of several diseases, including liver disease. We prepared the water extract of Moutan Cortex (MCE) to investigate the cytoprotective activities and its mechanism. MCE protected hepatocytes from arachidonic acid (AA) iron induced oxidative stress, as indicated by reactive oxygen species (ROS) production and cell viability analysis. MCE also suppressed mitochondrial dysfunction in AA iron-treated human hepatocyte-derived hepatocellular carcinoma cell line, HepG2 cells. In addition, MCE treatment induces AMP-activated protein kinase (AMPK) and liver kinase B1 phosphorylation, which play a role in inhibition of oxidative stress induced cell death. Moreover, one of the MCE compounds, chlorogenic acid, exerted protective effects against oxidative stress and apoptosis. Taken together, MCE protected hepatocytes against AA iron-induced oxidative stress through AMPK activation, and may be a candidate for the treatment of liver disease.

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“…Thus, GSK3β is critically required for the regulation of MMP transition, and it is believed that the inhibitory phosphorylation of GSK3β is related to cell survival. [18][19][20] Glycyrrhizae radix (G. radix, Licorice) is one of the oldest, most frequently employed botanicals in herbal medicine in Asia, and currently occupies an important place among food products. In traditional medicine, it is used for its lifeenhancing properties, detoxifying effects, and to treat injuries and swellings.…”

mentioning

confidence: 99%

Tacrine, an Oral Acetylcholinesterase Inhibitor, Induced Hepatic Oxidative Damage, Which Was Blocked by Liquiritigenin through GSK3-beta Inhibition

Park

Han

et al. 2015

Biological & Pharmaceutical Bulletin

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Although the cholinesterase inhibitor tacrine has been successfully used for the treatment of Alzheimer's disease, it is known to have hepatotoxic effects. Liquiritigenin (LQ), an active flavonoid in Glycyrrhizae radix, exerts protective effects against liver damage. This study investigated the toxic effect of tacrine on hepatocytes and the beneficial effect of LQ on tacrine intoxication in vivo and in vitro, and the underlying mechanism involved. In hepatocyte cell lines, tacrine induced cell death and oxidative stress, as indicated by decreases in cell viability and glutathione (GSH) contents, which were blocked by pretreatment with LQ. Fluorescent activated cell sorter (FACS) analysis revealed that LQ inhibited cellular H 2 O 2 production and mitochondrial dysfunction induced by tacrine in HepG2 cells. Furthermore, LQ promoted inhibitory phosphorylation of glycogen synthase kinase-3β (GSK3β) and prevented decreases in GSK3β phosphorylation induced by tacrine. In rats treatment with tacrine at 30 mg/kg increased hepatic damage as assessed by blood biochemistry and histopathology. Administration of LQ (10 or 30 mg/kg/d, per os (p.o.)) or the hepatoprotective drug sylimarin (100 mg/kg/d) for 3 d inhibited elevations in alanine aminotransferase, aspartate aminotransferase, and histological changes induced by tacrine. These results show that LQ efficaciously protects the rat liver against tacrine-induced liver damage, and suggest that LQ is a therapeutic candidate for ameliorating the hepatotoxic effects of tacrine.Key words tacrine; liquiritigenin; glycogen synthase kinase-3β; liver; oxidative stress; mitochondria Tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride) is recommended as the first-line treatment for Alzheimer's disease by the US Food and Drug Administration. It is an active cholinesterase inhibitor that blocks the degradation of cholinergic nerves in the cerebral cortex and hippocampus to increase cholinergic transmission. 1) However, although tacrine has positive therapeutic effects, it has been demonstrated to increased serum alanine aminotransferase (ALT) levels in about 30% of patients, and this seriously limits its clinical use.2) A number of authors have reported that tacrine-induced hepatotoxicity is related to cytochrome P450 1A2 in human liver microsomes and is associated with mitochondrial dysfunction.3-5) Studies also have showed that the hepatotoxic effect of tacrine is associated with oxidative stress, as demonstrated by increased reactive oxygen species (ROS) production and decreased intracellular glutathione (GSH).6-8) However, mechanism responsible for tacrine-induced hepatotoxicity has not yet been elucidated. Nevertheless many studies have shown that anthraquinones, chromone glycosides, phenolic amide, and an herbal medicine protect hepatocytes from the toxic effects of tacrine. [9][10][11][12] Oxidative stress is state in which the balance between ROS production and antioxidants is shifted in favor of ROS, and is associated with severity of liver damage.13) ROS normally work ...

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AMPK-mediated GSK3β inhibition by isoliquiritigenin contributes to protecting mitochondria against iron-catalyzed oxidative stress

Cited by 106 publications

References 50 publications

Novel Action of the Chalcone Isoliquiritigenin as a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Inhibitor: Potential Therapy for Cholera and Polycystic Kidney Disease

Novel Action of the Chalcone Isoliquiritigenin as a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Inhibitor: Potential Therapy for Cholera and Polycystic Kidney Disease

Moutan Cortex Protects Hepatocytes against Oxidative Injury through AMP-Activated Protein Kinase Pathway

Tacrine, an Oral Acetylcholinesterase Inhibitor, Induced Hepatic Oxidative Damage, Which Was Blocked by Liquiritigenin through GSK3-beta Inhibition

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