Two Prenylated Chalcones, 4-Hydroxyderricin, and Xanthoangelol Prevent Postprandial Hyperglycemia by Promoting GLUT4 Translocation via the LKB1/AMPK Signaling Pathway in Skeletal Muscle Cells.

SCOPE: Stimulation of glucose uptake in the skeletal muscle is crucial for the prevention of postprandial hyperglycemia. Insulin and certain polyphenols enhance glucose uptake through the translocation of glucose transporter 4 (GLUT4) in the skeletal muscle. The previous study reports that prenylated chalcones, 4-hydroxyderricin (4-HD), and xanthoangelol (XAG) promote glucose uptake and GLUT4 translocation in L6 myotubes, but their underlying molecular mechanism remains unclear. This study investigates the mechanism in L6 myotubes and confirms antihyperglycemia by 4-HD and XAG. METHODS AND RESULTS: In L6 myotubes, 4-HD and XAG promote glucose uptake and GLUT4 translocation through the activation of adenosine monophosphate-activated protein kinase (AMPK) and liver kinase B1 (LKB1) signaling pathway without activating phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) and Janus kinases (JAKs)/signal transducers and activators of transcriptions (STATs) pathways. Moreover, Compound C, an AMPK-specific inhibitor, as well as siRNA targeting AMPK and LKB1 completely canceled 4-HD and XAG-increased glucose uptake. Consistently, oral administration of 4-HD and XAG to male ICR mice suppresses acute hyperglycemia in an oral glucose tolerance test. CONCLUSION: In conclusion, LKB1/AMPK pathway and subsequent GLUT4 translocation in skeletal muscle cells are involved in Ashitaba chalcone-suppressed acute hyperglycemia.

Theophylline Prevents Dexamethasone-Induced Atrophy in C2C12 Myotubes.

Skeletal muscle mass is maintained by a balance between the synthesis and degradation of muscle proteins, the collapse of which causes muscle wasting. The prevention of muscle wasting improves the quality of life and extends a healthy life. The methyl xanthine theophylline showed strong preventive activity against dexamethasone-induced muscle atrophy, as determined using the expression level of myosin heavy chain in C2C12 myotubes. Mechanistically, theophylline inhibited the expression of ubiquitin ligases MuRF1 and Cbl-b, but not that of atrogin-1. Furthermore, theophylline inhibits glucocorticoid receptor translocation to the nucleus. A pull-down assay using a theophylline probe revealed that theophylline and dexamethasone competitively interacted with the glucocorticoid receptor, suggesting an antagonistic activity of theophylline on glucocorticoid receptors. Additionally, theophylline inhibited the dexamethasone-induced phosphorylation of p38 and FoxO3a in C2C12 myotubes. These findings suggest that theophylline is an effective food ingredient in the prevention of glucocorticoid-induced skeletal muscle atrophy.

Lowering effect of combined sweet potato and onion intake on plasma quercetin concentration and underlying mechanism involving intestinal ß-glucosidase activity.

A combined intake of cooked sweet potato and fried onion in humans was found to suppress the increase of plasma quercetin metabolite concentration. Experiments using rat ß-glucosidase indicated that excess carbohydrate digestion products, especially glucose-containing saccharides, interfere with the deglycosylation of quercetin glucosides during intestinal epithelial uptake. Combined meals of sweet potato and onion may lower the bioavailability of onion quercetin glucosides.

Role of Intestinal Microbiota in the Bioavailability and Physiological Functions of Dietary Polyphenols.

Polyphenols are categorized as plant secondary metabolites, and they have attracted much attention in relation to human health and the prevention of chronic diseases. In recent years, a considerable number of studies have been published concerning their physiological function in the digestive tract, such as their prebiotic properties and their modification of intestinal microbiota. It has also been suggested that several hydrolyzed and/or fission products, derived from the catabolism of polyphenols by intestinal bacteria, exert their physiological functions in target sites after transportation into the body. Thus, this review article focuses on the role of intestinal microbiota in the bioavailability and physiological function of dietary polyphenols. Monomeric polyphenols, such as flavonoids and oligomeric polyphenols, such as proanthocyanidins, are usually catabolized to chain fission products by intestinal bacteria in the colon. Gallic acid and ellagic acid derived from the hydrolysis of gallotannin, and ellagitannin are also subjected to intestinal catabolism. These catabolites may play a large role in the physiological functions of dietary polyphenols. They may also affect the microbiome, resulting in health promotion by the activation of short chain fatty acids (SCFA) excretion and intestinal immune function. The intestinal microbiota is a key factor in mediating the physiological functions of dietary polyphenols.

Functional properties of anti-inflammatory substances from quercetin-treated Bifidobacterium adolescentis.

The genus Bifidobacterium is well known to have beneficial health effects. We discovered that quercetin and related polyphenols enhanced the secretion of anti-inflammatory substances by Bifidobacterium adolescentis. This study investigated characteristics of the anti-inflammatory substances secreted by B. adolescentis. The culture supernatant of B. adolescentis with quercetin reduced the levels of inflammatory mediators in activated macrophages. Spontaneous quercetin degradant failed to increase anti-inflammatory activity, while the enhancement of anti-inflammatory activity by quercetin was sustained after washout of quercetin. Physicochemical treatment of the culture supernatant indicated that its bioactive substances may be heat-stable, non-phenolic, and acidic biomolecules with molecular weights less than 3 kDa. Acetate and lactate have little or no effect on nitric oxide production. Taken together, the anti-inflammatory substances secreted by B. adolescentis may be small molecules but not short chain fatty acids. In agreement with these findings, stearic acid was tentatively identified as a bioactive candidate compound.

Triterpenoids Isolated from Ziziphus jujuba Enhance Glucose Uptake Activity in Skeletal Muscle Cells.

Jujube (Ziziphus jujuba Mill.), a traditional folk medicine and functional food in China and South Korea, is known for its beneficial properties, which include anti-cancer, anti-oxidative, and anti-obesity effects. To assess the anti-hyperglycemic effect of jujube in this study, we investigated the glucose uptake-promoting activity of jujube in rat L6 myotubes. After determining that the jujube extract induces muscle glucose uptake, we identified the following active compounds by bioassay-guided fractionation: betulonic acid, betulinic acid, and oleanonic acid. Ursonic acid, known to be present in jujube, was semi-synthesized from ursolic acid and also observed to enhance glucose uptake. These four triterpenic acids induced glucose uptake in a glucose transporter 4-dependent manner. Comparison experiments of jujube fruits from three countries, namely, China, South Korea, and Japan, revealed that Japanese jujube has a higher content of active triterpenoids and is the most potent enhancer of glucose uptake.

Measurement of Glucose Uptake in Cultured Cells.

Facilitative glucose uptake transport systems are ubiquitous in animal cells and are responsible for transporting glucose across cell surface membranes. Evaluation of glucose uptake is crucial in the study of numerous diseases and metabolic disorders such as myocardial ischemia, diabetes mellitus, and cancer. Detailed in this unit are laboratory methods for assessing glucose uptake into mammalian cells. The unit is divided into five sections: (1) a brief overview of glucose uptake assays in cultured cells; (2) a method for measuring glucose uptake using radiolabeled 3-O-methylglucose; (3) a method for measuring glucose uptake using radiolabeled 2-deoxyglucose (2DG); (4) a microplate method for measuring 2DG-uptake using an enzymatic, fluorometric assay; and (5) a microplate-based method using a fluorescent analog of 2DG.

Quercetin and related polyphenols: new insights and implications for their bioactivity and bioavailability.

The physiological functions and bioavailability of flavonoids have been widely investigated since their bioactivities were identified about 80 years ago. Quercetin is a typical flavonoid ubiquitously contained in vegetables and fruits with several biological effects demonstrated in vitro and in vivo including antioxidative, anti-inflammatory, anticancer, and antidiabetic activities. After the ingestion of vegetables and fruits, quercetin glycosides are metabolized, absorbed, and circulated as types of conjugates in the blood. Thereafter, quercetin-3-O-ß-D-glucuronide (Q3GA), a major metabolite of quercetin, is distributed throughout the body where it may exert beneficial functions in target tissues. Hydrophilic Q3GA has been found to be deconjugated into hydrophobic quercetin aglycone at injured sites which, in turn, may improve the pathological conditions. This review presents updated information on the biological aspects and mechanisms of action of quercetin and its related polyphenols. In particular, new insights into their beneficial health effects on the brain, blood vessels, muscle, and intestine will be discussed.

Effects of phytochemicals on in vitro anti-inflammatory activity of Bifidobacterium adolescentis.

Probiotics have been shown to improve the condition of not only the human gastrointestinal tract but also the entire body. We found that quercetin enhances the anti-inflammatory activity of Bifidobacterium adolescentis, which is abundant in human intestines. Here, we assessed whether certain phytochemicals could enhance the anti-inflammatory activity of B. adolescentis. Bifidobacteria were anaerobically cultured with phytochemicals for 3 h, and the anti-inflammatory activity of the supernatants was estimated by testing their ability to inhibit nitric oxide (NO) production by lipopolysaccharide-stimulated RAW264 macrophages. Of the 55 phytochemicals tested, phloretin, (+)-taxifolin, and (-)-epigallocatechin gallate as well as quercetin-3-O-glucoside and quercetin-4'-O-glucoside were similar to quercetin in promoting NO suppression by B. adolescentis. In addition, the phytochemicals excluding quercetin increased the concentrations of lactic and acetic acids in the co-culture supernatants. These results suggest that some phytochemicals may activate the anti-inflammatory function of B. adolescentis.

Quercetin-3-O-glucuronide inhibits noradrenaline-promoted invasion of MDA-MB-231 human breast cancer cells by blocking ß2-adrenergic signaling.

Endogenous catecholamines such as adrenaline (A) and noradrenaline (NA) are released from the adrenal gland and sympathetic nervous system during exposure to stress. The adrenergic system plays a central role in stress signaling, and excessive stress was found to be associated with increased production of reactive oxygen species (ROS). Overproduction of ROS induces oxidative damage in tissues and causes the development of diseases such as cancer. In this study, we investigated the effects of quercetin-3-O-glucuronide (Q3G), a circulating metabolite of quercetin, which is a type of natural flavonoid, on the catecholamine-induced ß2-adrenergic receptor (ß2-AR)-mediated response in MDA-MB-231 human breast cancer cells expressing ß2-AR. Treatment with A or NA at concentrations above 1µM generated significant levels of ROS, and NA treatment induced the gene expression of heme oxygenase-1 (HMOX1), and matrix metalloproteinase-2 (MMP-2) and -9 (MMP9). Inhibitors of p38 MAP kinase (SB203580), cAMP-dependent protein kinase (PKA) (H-89), activator protein-1 (AP-1) transcription factor (SR11302), and NF-κB and AP-1 (Tanshinone IIA) decreased MMP2 and MMP9 gene expression. NA also enhanced cAMP induction, RAS activation and phosphorylation of ERK1/2. These results suggested that the cAMP-PKA, MAPK, and ROS-NF-κB pathways are involved in ß2-AR signaling. Treatment with 0.1µM Q3G suppressed ROS generation, cAMP and RAS activation, phosphorylation of ERK1/2 and the expression of HMOX1, MMP2, and MMP9 genes. Furthermore, Q3G (0.1µM) suppressed invasion of MDA-MB-231 breast cancer cells and MMP-9 induction, and inhibited the binding of [(3)H]-NA to ß2-AR. These results suggest that Q3G may function to suppress invasion of breast cancer cells by controlling ß2-adrenergic signaling, and may be a dietary chemopreventive factor for stress-related breast cancer.

Inhibitory effects of 4-hydroxyderricin and xanthoangelol on lipopolysaccharide-induced inflammatory responses in RAW264 macrophages.

The Japanese herb, Ashitaba (Angelica keiskei Koidzumi), contains two prenylated chalcones, 4-hydroxyderricin and xanthoangelol, which are considered to be the major active compounds of Ashitaba. However, their effects on inflammatory responses are poorly understood. In the present study, we investigated the effects and underlying molecular mechanisms of 4-hydroxyderricin and xanthoangelol on lipopolysaccharide (LPS)-induced inflammatory responses in RAW264 mouse macrophages. LPS-mediated production of nitric oxide (NO) was markedly reduced by 4-hydroxyderricin (10 µM) and xanthoangelol (5 µM) compared with their parent compound, chalcone (25 µM). They also inhibited LPS-induced secretion of tumor necrosis factor-alpha (TNF-α) and expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). Although chalcone decreased the DNA-binding activity of both activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB), 4-hydroxyderricin and xanthoangelol suppressed only AP-1 and had no effect on NF-κB. On the other hand, all of the tested chalcones reduced the phosphorylation (at serine 536) level of the p65 subunit of NF-κB. 4-Hydroxyderricin and xanthoangelol may be promising for the prevention of inflammatory diseases.

Mitochondrial dysfunction leads to deconjugation of quercetin glucuronides in inflammatory macrophages.

Dietary flavonoids, such as quercetin, have long been recognized to protect blood vessels from atherogenic inflammation by yet unknown mechanisms. We have previously discovered the specific localization of quercetin-3-O-glucuronide (Q3GA), a phase II metabolite of quercetin, in macrophage cells in the human atherosclerotic lesions, but the biological significance is poorly understood. We have now demonstrated the molecular basis of the interaction between quercetin glucuronides and macrophages, leading to deconjugation of the glucuronides into the active aglycone. In vitro experiments showed that Q3GA was bound to the cell surface proteins of macrophages through anion binding and was readily deconjugated into the aglycone. It is of interest that the macrophage-mediated deconjugation of Q3GA was significantly enhanced upon inflammatory activation by lipopolysaccharide (LPS). Zymography and immunoblotting analysis revealed that ß-glucuronidase is the major enzyme responsible for the deglucuronidation, whereas the secretion rate was not affected after LPS treatment. We found that extracellular acidification, which is required for the activity of ß-glucuronidase, was significantly induced upon LPS treatment and was due to the increased lactate secretion associated with mitochondrial dysfunction. In addition, the ß-glucuronidase secretion, which is triggered by intracellular calcium ions, was also induced by mitochondria dysfunction characterized using antimycin-A (a mitochondrial inhibitor) and siRNA-knockdown of Atg7 (an essential gene for autophagy). The deconjugated aglycone, quercetin, acts as an anti-inflammatory agent in the stimulated macrophages by inhibiting the c-Jun N-terminal kinase activation, whereas Q3GA acts only in the presence of extracellular ß-glucuronidase activity. Finally, we demonstrated the deconjugation of quercetin glucuronides including the sulfoglucuronides in vivo in the spleen of mice challenged with LPS. These results showed that mitochondrial dysfunction plays a crucial role in the deconjugation of quercetin glucuronides in macrophages. Collectively, this study contributes to clarifying the mechanism responsible for the anti-inflammatory activity of dietary flavonoids within the inflammation sites.

Flavonols enhanced production of anti-inflammatory substance(s) by Bifidobacterium adolescentis: prebiotic actions of galangin, quercetin, and fisetin.

The gut microbiota is capable of the bioconversion of flavonoids whereas influences of probiotic anaerobes on the bioactivities of flavonoids and vice versa are still unclear. Here, we investigated functional interactions with respect to the anti-inflammatory activity between flavonols and probiotic bacteria. Ten enteric (6 probiotic and 4 indigenous) bacteria were incubated with flavonols (galangin, kaempferol, quercetin, myricetin, and fisetin) under anaerobic conditions, and the supernatants were assessed for their effects on nitric oxide (NO) production in lipopolysaccaride-stimulated RAW264 cells. Although the conditioned medium from the flavonol mono-culture and almost all of the tested co-cultures failed to inhibit NO production, the medium from the Bifidobacterium adolescentis/flavonols (galangin, quercetin, and fisetin) co-culture highly suppressed NO production. This activity increased during the 1-6 H incubation in a time-dependent manner and was not observed in the co-culture using heat-inactivated B. adolescentis. Interestingly, when the B. adolescentis cell number was increased, the supernatant from the mono-culture of the bacteria showed NO suppression, suggesting that B. adolescentis may produce NO suppressant(s), and flavonols may have a promoting effect. These findings indicate that flavonols have a prebiotic-like effect on the anti-inflammatory activity of B. adolescentis.

Effect of quercetin and its glucuronide metabolite upon 6-hydroxydopamine-induced oxidative damage in Neuro-2a cells.

Quercetin is ubiquitously distributed in plant foods. This antioxidative polyphenol is mostly converted to conjugated metabolites in the body. Parkinson disease (PD) has been suggested to be related to oxidative stress derived from abnormal dopaminergic activity. We evaluated if dietary quercetin contributes to the antioxidant network in the central nervous system from the viewpoint of PD prevention. A neurotoxin, 6-hydroxydopamine (6-OHDA), was used as a model of PD. 6-OHDA-induced H2O2 production and cell death in mouse neuroblastoma, Neuro-2a. Quercetin aglycone suppressed 6-OHDA-induced H2O2 production and cell death, although aglycone itself reduced cell viability at higher concentration. Quercetin 3-O-ß-D-glucuronide (Q3GA), which is an antioxidative metabolite of dietary quercetin, was little incorporated into the cell resulting in neither suppression of 6-OHDA-induced cell death nor reduction of cell viability. Q3GA was found to be deconjugated to quercetin by microglial MG-6 cells. These results indicate that quercetin metabolites should be converted to their aglycone to exert preventive effect on damage to neuronal cells.

Ameliorative effects of polyunsaturated fatty acids against palmitic acid-induced insulin resistance in L6 skeletal muscle cells.

BACKGROUND: Fatty acid-induced insulin resistance and impaired glucose uptake activity in muscle cells are fundamental events in the development of type 2 diabetes and hyperglycemia. There is an increasing demand for compounds including drugs and functional foods that can prevent myocellular insulin resistance. METHODS: In this study, we established a high-throughput assay to screen for compounds that can improve myocellular insulin resistance, which was based on a previously reported non-radioisotope 2-deoxyglucose (2DG) uptake assay. Insulin-resistant muscle cells were prepared by treating rat L6 skeletal muscle cells with 750 µM palmitic acid for 14 h. Using the established assay, the impacts of several fatty acids on myocellular insulin resistance were determined. RESULTS: In normal L6 cells, treatment with saturated palmitic or stearic acid alone decreased 2DG uptake, whereas unsaturated fatty acids did not. Moreover, co-treatment with oleic acid canceled the palmitic acid-induced decrease in 2DG uptake activity. Using the developed assay with palmitic acid-induced insulin-resistant L6 cells, we determined the effects of other unsaturated fatty acids. We found that arachidonic, eicosapentaenoic and docosahexaenoic acids improved palmitic acid-decreased 2DG uptake at lower concentrations than the other unsaturated fatty acids, including oleic acid, as 10 µM arachidonic acid showed similar effects to 750 µM oleic acid. CONCLUSIONS: We have found that polyunsaturated fatty acids, in particular arachidonic and eicosapentaenoic acids prevent palmitic acid-induced myocellular insulin resistance.

Absorption and metabolism of 4-hydroxyderricin and xanthoangelol after oral administration of Angelica keiskei (Ashitaba) extract in mice.

To investigate the absorption and metabolism of 4-hydroxyderricin and xanthoangelol, we established an analytical method based on liquid chromatography-tandem mass spectrometry and measured these compounds in the plasma, urine, feces, liver, kidney, spleen, muscle and white adipose tissues of mice orally administered with Ashitaba extract (50-500mg/kg body weight). 4-Hydroxyderricin and xanthoangelol were quickly absorbed into the plasma, with time-to-maximum plasma concentrations of 2 and 0.5h for 4-hydroxyderricin and xanthoangelol, respectively. Although these compounds have similar structures, the total plasma concentration of 4-hydroxyderricin and its metabolites was approximately 4-fold greater than that of xanthoangelol and its metabolites at 24h. 4-Hydroxyderricin and xanthoangelol were mostly excreted in their aglycone forms and related metabolites (glucuronate and/or sulfate forms) in urine between 2 and 4h after oral administration of Ashitaba extract. On the other hand, these compounds were only excreted in their aglycone forms in feces. When tissue distribution of 4-hydroxyderricin and xanthoangelol was estimated 2h after administration of Ashitaba extract, both compounds were detected in all of the tissues assessed, mainly in their aglycone forms, except in the mesenteric adipose tissue. These results suggest that 4-hydroxyderricin and xanthoangelol are rapidly absorbed and distributed to various tissues.

Measurement of glucose uptake in cultured cells.

Facilitative glucose uptake transport systems are ubiquitous in animal cells and responsible for transporting glucose across the cell surface membrane. Evaluation of glucose uptake is crucial in the study of numerous diseases and metabolic disorders, such as myocardial ischemia, diabetes mellitus, and cancer. Methods for assessing glucose uptake into mammalian cells are detailed in this unit. The work is divided into four sections: (1) a brief overview of glucose uptake assays in cultured cells; (2) a method for measuring glucose uptake using radiolabeled 3-O-methylglucose; (3) a method for measuring glucose uptake using radiolabeled 2-deoxyglucose (2DG); and (4) an improved method for measuring 2DG-uptake using an enzymatic, fluorometric assay, eliminating the need for radiolabeled glucose analogs.

1,2-Di-O-α-linolenoyl-3-O-ß-galactosyl-sn-glycerol as a superoxide generation inhibitor from Perilla frutescens var. crispa.

Using a superoxide (O(2)(-)) generation assay system with differentiated HL-60 cells, 1,2-di-O-α-linolenoyl-3-O-ß-galactosyl-sn-glycerol (DLGG) was identified as an O(2)(-) generation inhibitor from Perilla frutescens var. crispa (a local variety, kida-chirimen shiso). DLGG suppressed the O(2)(-) level in a dose-dependent manner with an IC(50) value of 21 µM, comparable to those of rosmarinic acid (RoA, IC(50) = 29 µM) and caffeic acid (CA, IC(50) = 30 µM). While RoA and CA also dose-dependently inhibited O(2)(-) generation in a xanthine-xanthine oxidase system, DLGG had no effect in the same system. Thus DLGG appeared to decrease the O(2)(-) level in the HL-60 assay system by mechanisms different from those of RoA and CA, which appeared to act as O(2)(-) scavengers.

Dietary flavonoids as cancer-preventive and therapeutic biofactors.

Flavonoids are present in many plants, and hence, in foods and ingredients derived from them. These polyphenolic compounds have attracted renewed attention as potential anticarcinogens, and the molecular mechanisms of their anticarcinogenic effects and their bioavailability have been extensively explored. In this review, we focus on the major dietary flavonoids; flavones, flavonols, and flavan-3-ols (catechins), and evaluate their roles in cancer prevention. After absorption with or without metabolic conjugation, flavonoids are transported to target organs where they exert their anticarcinogenic activity. The molecular mechanisms of the anticarcinogenic effects of flavonoids include their antagonistic effect on the aryl hydrocarbon receptor (AhR), and regulation of phase I and II drug metabolizing enzymes and phase III transporters. Experimental evidence suggests that flavonoids modulate signal transduction pathways at each stage of carcinogenesis. The interactions between flavonoids and biomolecules in vivo must be investigated in detail to identify specific targets. In addition, the potential side effects should be considered when flavonoid supplements are used for cancer prevention. Therefore, the use of flavonoids as chemopreventive agents should be further investigated to establish safe levels of flavonoid intake.

Effect of quercetin and glucuronide metabolites on the monoamine oxidase-A reaction in mouse brain mitochondria.

OBJECTIVE: Quercetin is a flavonoid found in plant foods and herbal medicines. It possesses antidepressant-like effects in forced swimming test-loaded rodents. We wanted to clarify the mechanism of action of dietary quercetin for exerting antidepressant-like effects. The effect of quercetin and its antioxidative metabolite quercetin 3-glucuronide (Q3GA) on the activity of mouse brain mitochondrial monoamine oxidase-A (MAO-A) was evaluated by measuring the deamination product of serotonin, 5-hydroxyindole acetaldehyde (5-HIAL). METHODS: An ultraviolet high-performance liquid chromatographic analysis was applied to measure the 5-HIAL generated by the reaction of MAO-A with serotonin. The inhibitory effect of quercetin and Q3GA on mitochondrial MAO-A activity was estimated by the content of 5-HIAL and hydrogen peroxide accompanied by the MAO-A reaction. RESULTS: Quercetin (but not Q3GA) decreased the production of 5-HIAL by MAO-A activity. Q3GA inhibited the generation of hydrogen peroxide from the MAO-A reaction with serotonin. A periodic forced swimming test in mice increased brain mitochondrial MAO-A activity. Brain mitochondrial MAO-A activity was decreased in mice administered quercetin for 7 d, but its effect was much weaker than that of the selective MAO-A inhibitor clorgyline. CONCLUSION: Quercetin is effective in the modulation of serotonergic activity by attenuating mitochondrial MAO-A activity in the brain. Its antioxidative metabolite Q3GA attenuates oxidative stress by interrupting the generation of hydrogen peroxide accompanying the MAO-A reaction.