Tyrosine phenol-lyase inhibitor quercetin reduces fecal phenol levels in mice.

Tyrosine phenol-lyase (TPL), which is expressed in intestinal bacteria, catalyzes the formation of phenol from the substrate L-Tyr. Bacterial metabolite phenol and the sulfate conjugate (phenyl sulfate) are known as a type of uremic toxins, some of which exert cytotoxicity. Therefore, pathologically elevated phenol and phenyl sulfate levels are strongly implicated in the etiology and outcome of uremia. In this study, we explored the inhibitory effects of dietary polyphenols on TPL-catalyzed phenol production using a TPL activity assay. Quercetin, one of the most popular polyphenols, exhibited the strongest inhibitory activity (Ki = 19.9 µM). Quercetin competitively inhibited TPL, and its activity was stronger than that of a known TPL inhibitor (Tyr analog; 2-aza-Tyr, Ki = 42.0 µM). Additionally, quercetin significantly inhibited phenol production in TPL-expressing bacterial cultures (Morganella morganii and Citrobacter koseri) and Tyr-rich (5%) diet-fed C57BL/6J mouse feces. Our findings suggest that quercetin is the most promising polyphenol for reducing phenol levels. Because quercetin has a low gastrointestinal absorption rate, TPL inhibition in the intestinal tract by quercetin may be an effective strategy for treating uremia.

PA YEAST SC-1, Polyamine-Rich Saccharomyces cerevisiae, Induces Muscle Hypertrophy in C2C12 Myotubes.

Maintenance of appropriate muscle mass is necessary for good quality of life as skeletal muscles play critical roles in locomotion, metabolic homeostasis, and thermogenesis. Polyamines are essential metabolites that regulate several important cellular functions. In C57BL6 mice who underwent sciatic nerve transection of the hind limb, compensatory muscle hypertrophy is enhanced by the administration of polyamines. However, the action mechanisms of polyamines in muscle hypertrophy remain unclear. Here, we isolated PA YEAST SC-1, a polyamine-rich Saccharomyces cerevisiae, from Baker's yeast. We examined whether PA YEAST SC-1 induces muscle hypertrophy and elucidated the underlying action mechanisms of polyamines and the active ingredients in PA YEAST SC-1 using C2C12 myotubes. PA YEAST SC-1 at 1 mg/mL increased myosin heavy chain expression in C2C12 myotubes. Mechanistically, PA YEAST SC-1 induced the activation of Akt/mechanistic target of rapamycin kinase/p70S6K signaling. Furthermore, PA YEAST SC-1 decreased the expression levels of the ubiquitin ligases, atrogin-1 and muscle RING finger-1, via forkhead box O1 phosphorylation. These findings suggest PA YEAST SC-1 as an effective food ingredient for the treatment of muscle hypertrophy.

Single oral administration of quercetin glycosides prevented acute hyperglycemia by promoting GLUT4 translocation in skeletal muscles through the activation of AMPK in mice.

Quercetin is a natural flavonol and has various health beneficial functions. Our pervious study demonstrated that long-term feeding (13 weeks) of quercetin and its glycosides, isoquercitrin, rutin, and enzymatically modified isoquercitrin, which is a mixture of quercetin monoglycoside and its oligoglycosides, prevented hyperglycemia and adiposity in mice fed a high-fat diet but not standard diet. It is, however, unclear whether a single administration of these compounds prevent postprandial hyperglycemia or not. In the present study, we estimated their prevention effect on acute hyperglycemia by an oral glucose tolerance test in ICR mice and investigated its mechanism. It was found that quercetin glycosides, but not the aglycone, suppressed acute hyperglycemia and isoquercitrin showed the strongest effect among the glycosides. As the underlying mechanism, quercetin glycosides promoted translocation of glucose transporter 4 to the plasma membrane of skeletal muscle of mice through phosphorylation of adenosine monophosphate-activated protein kinase and its upstream Ca2+/calmodulin-dependent protein kinase kinase ß without activating the insulin- and JAK/STAT-signal pathways. In conclusion, single oral administration of quercetin glycosides prevented a blood sugar spike by promoting glucose transporter 4 translocation through activating the CAMKKß/AMPK signaling pathway.

Allyl Isothiocyanate Maintains DHA-Containing Glycerophospholipids and Ameliorates the Cognitive Function Decline in OVX Mice.

Low-temperature-induced fatty acid desaturation is highly conserved in animals, plants, and bacteria. Allyl isothiocyanate (AITC) is an agonist of the transient receptor potential ankyrin 1 (TRPA1), which is activated by various chemophysiological stimuli, including low temperature. However, whether AITC induces fatty acid desaturation remains unknown. We showed here that AITC increased levels of glycerophospholipids (GP) esterified with unsaturated fatty acids, especially docosahexaenoic acid (DHA) in TRPA1-expressing HEK cells. Additionally, GP-DHA including phosphatidylcholine (18:0/22:6) and phosphatidylethanolamine (18:0/22:6) was increased in the brain and liver of AITC-administered mice. Moreover, intragastrical injection of AITC in ovariectomized (OVX) female C57BL/6J mice dose-dependently shortened the Δlatency time determined by the Morris water maze test, indicating AITC ameliorated the cognitive function decline in these mice. Thus, the oral administration of AITC maintains GP-DHA in the liver and brain, proving to be a potential strategy for preventing cognitive decline.

Diosgenin prevents dexamethasone-induced myotube atrophy in C2C12 cells.

Several pathophysiological abnormalities, including a sedentary lifestyle, chronic diseases, and oxidative stress, can contribute to muscle atrophy triggered by an imbalance in muscle protein synthesis and degradation. Resolving muscle atrophy is a critical issue as it can reduce the quality of life. Here, one of the promising functional food factors, diosgenin (a steroidal sapogenin) showed strong preventive activities against dexamethasone (Dex)-induced muscle atrophy, as determined by the expression levels and morphology of the myosin heavy chain in C2C12 myotubes. Diosgenin inhibited protein expressions of Dex-induced skeletal muscle-specific ubiquitin ligase, including muscle RING finger 1 (MuRF1) and casitas B-lineage lymphoma protooncogene b (Cbl-b) but not atrogin-1. Diosgenin ameliorated Dex-induced declines of Akt phosphorylation at Ser473 and FoxO3a phosphorylation at Ser253, which probably at least partially contributed to the suppression of MuRF1, Cbl-b, and atrogin-1 gene expression. Additionally, diosgenin inhibited Dex-induced nuclear translocation of the glucocorticoid receptor (GR), diosgenin therefore may competitively inhibit the interaction between Dex and GR. These findings suggest that diosgenin is an effective functional food for preventing glucocorticoid-induced skeletal muscle atrophy.

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.

Non-target GC-MS analyses of fecal VOCs in NASH-hepatocellular carcinoma model STAM mice.

The increased incidence of obesity in the global population has increased the risk of several chronic inflammation-related diseases, including non-alcoholic steatohepatitis (NASH)-hepatocellular carcinoma (HCC). The progression from NASH to HCC involves a virus-independent liver carcinogenic mechanism; however, we currently lack effective treatment and prevention strategies. Several reports have suggested that fecal volatile organic compounds (VOCs) are strongly associated with NASH-HCC; therefore, we explored the biomarkers involved in its pathogenesis and progression. Fecal samples collected from control and NASH-HCC model STAM mice were subjected to headspace autosampler gas chromatography-electron ionization-mass spectrometry. Non-target profiling analysis identified diacetyl (2,3-butandione) as a fecal VOC that characterizes STAM mice. Although fecal diacetyl levels were correlated with the HCC in STAM mice, diacetyl is known as a cytotoxic/tissue-damaging compound rather than genotoxic or mutagenic; therefore, we examined the effect of bioactivity associated with NASH progression. We observed that diacetyl induced several pro-inflammatory molecules, including tumor necrosis factor-α, cyclooxygenase-2, monocyte chemoattractant protein-1, and transforming growth factor-ß, in mouse macrophage RAW264.7 and Kupffer KPU5 cells. Additionally, we observed that diacetyl induced α-smooth muscle actin, one of the hallmarks of fibrosis, in an ex vivo cultured hepatic section, but not in in vitro hepatic stellate TWNT-1 cells. These results suggest that diacetyl would be a potential biomarker of fecal VOC in STAM mice, and its ability to trigger the macrophage-derived inflammation and fibrosis may partly contribute to NASH-HCC carcinogenesis.

Mung bean peptides promote glucose uptake via Jak2 activation in L6 myotubes.

Mung beans are among the important edible legumes cultivated in Asia, Southern Europe, and Northern America. Mung beans contain 20-30% proteins with high digestibility and possess biological activities, but detailed health beneficial functions are not fully understood yet. In this study, we report the isolation and identification of active peptides from mung beans which promote glucose uptake and elucidate their mechanism in L6 myotubes. HTL, FLSSTEAQQSY, and TLVNPDGRDSY were isolated and identified as active peptides. These peptides promoted the translocation of glucose transporter 4 (GLUT4) to the plasma membrane. The tripeptide HTL promoted glucose uptake through the activation of adenosine monophosphate-activated protein kinase, while the oligopeptides FLSSTEAQQSY and TLVNPDGRDSY through the activation of the PI3K/Akt pathway. Furthermore, these peptides promoted the phosphorylation of Jak2 via interaction with the leptin receptor. Thus, mung bean is a promising functional food for the prevention of hyperglycemia and type 2 diabetes through promoting glucose uptake accompanied by JAK2 activation in the muscle cells.

Biosynthetic Gene Expression and Tissue Distribution of Diosgenin in Dioscorea japonica.

Diosgenin is an aglycone of dioscin, a major bioactive steroidal saponin found in plants, including Himalayan Paris (Paris polyphylla), fenugreek (Trigonella foenum-graecum), and yam (Dioscorea spp.). We have previously demonstrated that a species of natural yam, Dioscorea japonica, contains a promising bioactive compound diosgenin, which induces anti-carcinogenic and anti-hypertriacylglycerolemic activities. Here, we found for the first time that Japanese yam (D. japonica) bulbils are richer in diosgenin than the edible tubers (rhizomes) and leaves. LC-MS and imaging-MS analyses revealed that diosgenin accumulated in the peripheral region of D. japonica bulbils. Additionally, we performed RNA-seq analysis of D. japonica, and multiple sequence alignment identified D. japonica CYP90 (DjCYP90), the orthologous gene of CYP90G4 in P. polyphylla, CYP90B50 in T. foenum-graecum, CYP90G6 in Dioscorea zingiberensis, and CYP90G in Dioscorea villosa, which encodes a diosgenin biosynthetic rate-limiting enzyme. The expression levels of DjCYP90 were significantly upregulated in D. japonica bulbils than in its rhizomes and leaves. Since diosgenin is one of the most promising functional food factors executing several favorable bioactivities, D. japonica bulbils rich in diosgenin would be a beneficial natural resource.

Cytotoxic Homo- and Hetero-Dimers of o-toluidine, o-anisidine, and Aniline Formed by In Vitro Metabolism.

Several aromatic amine compounds are urinary bladder carcinogens. Activated metabolites and DNA adducts of polycyclic aromatic amines, such as 4-aminobiphenyl, have been identified, whereas those of monocyclic aromatic amines, such as o-toluidine (o-Tol), o-anisidine (o-Ans), and aniline (Ani), have not been completely determined. We have recently reported that o-Tol and o-Ans are metabolically converted in vitro and in vivo to cytotoxic and mutagenic p-semidine-type dimers, namely 2-methyl-N4-(2-methylphenyl) benzene-1,4-diamine (MMBD) and 2-methoxy-N4-(2-methoxyphenyl) benzene-1,4-diamine (MxMxBD), respectively, suggesting their roles in urinary bladder carcinogenesis. In this study, we found that when o-Tol and o-Ans were incubated with S9 mix, MMBD and MxMxBD as well as two isomeric heterodimers, MMxBD and MxMBD, were formed. Therefore, any two of o-Tol, o-Ans, and Ani (10 mM each) were incubated with the S9 mix for up to 24 h and then subjected to LC-MS to investigate their metabolic kinetics. Metabolic conversions to all nine kinds of p-semidine-type homo- and hetero-dimers were observed, peaking at 6 h of incubation with the S9 mix; MxMxBD reached the peak at 6.1 ± 1.4 µM. Homo- and hetero-dimers containing the o-Ans moiety in the diamine structure showed a faster dimerization ratio, whereas levels of these dimers, such as MxMxBD, markedly declined with further incubation. Dimers containing o-Tol and Ani were relatively stable, even after incubation for 24 h. The electron-donating group of the o-Ans moiety may be involved in rapid metabolic conversion. In the cytotoxic assay, dimers with an o-Ans moiety in the diamine structure and MMBD showed approximately two- to four-fold higher cytotoxicity than other dimers in human bladder cancer T24 cells. These chemical and biological properties of homo- and hetero-dimers of monocyclic aromatic amines may be important when considering the combined exposure risk for bladder carcinogenesis.

Anti-Cancer Effects of Dietary Polyphenols via ROS-Mediated Pathway with Their Modulation of MicroRNAs.

Consumption of coffee, tea, wine, curry, and soybeans has been linked to a lower risk of cancer in epidemiological studies. Several cell-based and animal studies have shown that dietary polyphenols like chlorogenic acid, curcumin, epigallocatechin-3-O-gallate, genistein, quercetin and resveratrol play a major role in these anticancer effects. Several mechanisms have been proposed to explain the anticancer effects of polyphenols. Depending on the cellular microenvironment, these polyphenols can exert double-faced actions as either an antioxidant or a prooxidant, and one of the representative anticancer mechanisms is a reactive oxygen species (ROS)-mediated mechanism. These polyphenols can also influence microRNA (miR) expression. In general, they can modulate the expression/activity of the constituent molecules in ROS-mediated anticancer pathways by increasing the expression of tumor-suppressive miRs and decreasing the expression of oncogenic miRs. Thus, miR modulation may enhance the anticancer effects of polyphenols through the ROS-mediated pathways in an additive or synergistic manner. More precise human clinical studies on the effects of dietary polyphenols on miR expression will provide convincing evidence of the preventive roles of dietary polyphenols in cancer and other diseases.

Phenylpropanoids and neolignans isolated from Myristica fragrans enhance glucose uptake in myotubes.

Nutmeg is the seed of Myristica fragrans or its powder and is used as a spice and a traditional medicine. The antidiabetic effect of nutmeg is not fully understood yet. In this study, we examine the isolation and identification of the active compounds of Myristica fragrans with regards to glucose uptake and elucidate their mechanism in L6 myotubes. Myrisiticin, licarin B, erythro-2-(4-allyl-2,6-dimethoxy-phenoxy)-1-(3,4-dimethoxyphenyl)-propan-1-ol (ADDP) and (7S,8R)-2-(4-allyl-2,6-dimethoxyphenoxy)-1-(3,4,5-trimethoxyphenyl)-propan-1-ol (ADTP) were isolated and identified as the active compounds. Myristicin or a mixture of ADDP and ADTP promoted the translocation of glucose transporter 4 (GLUT4) through phosphorylation of AMP-activated protein kinase in L6 myotubes 15 min after treatment, while licarin B promoted it 240 min after treatment. Oral administration of the fraction from Myristica fragrans containing these active compounds to ICR mice suppressed post-prandial hyperglycemia. Thus, Myristica fragrans is a promising functional food to prevent post-prandial hyperglycemia and type 2 diabetes mellitus by promoting glucose uptake in muscle.

Preventive effects of black soybean polyphenols on non-alcoholic fatty liver disease in three different mouse models.

Non-alcoholic fatty liver disease (NAFLD) and its advanced stage, non-alcoholic steatohepatitis (NASH), are a major health issue throughout the world. Certain food components such as polyphenols are expected to possess preventive effects on NAFLD and NASH. In this study, the preventive effects of black soybean polyphenols were examined by using three NAFLD/NASH animal models. In a choline-deficient and L-amino acid-defined high-fat diet-induced NASH model, the intake of black soybean polyphenols decreased oxidative stress, but failed in attenuating liver injury and decreasing the expression of alpha-smooth muscle actin (α-SMA). In a Western diet with sucrose and fructose containing sweetened water-induced NAFLD model, black soybean polyphenols suppressed hepatic lipid accumulation, oxidative stress, aminotransferase activities in the plasma, inflammatory cytokine expression, and α-SMA expression accompanied by modulation of lipid metabolism. In a combination of Western diet and carbon tetrachloride model, black soybean polyphenols also suppressed hepatic lipid accumulation, oxidative stress, aminotransferase activities in the plasma, and α-SMA expression. In conclusion, black soybean is an attractive food for the prevention of NAFLD and NASH due to its strong antioxidant activity.

Nitrogen Balance and Bioavailability of Amino Acids in Spirulina Diet-Fed Wistar Rats.

Spirulina widely known to consumers as a health food is mainly a dried product. Since data for raw spirulina as a protein source are insufficient, the nutritional values of dry and raw spirulina diets in Wistar rats were determined. Digestibility coefficients were significantly lower in the dry (84.1 ± 0.5%) and raw (85.7 ± 0.4%) spirulina diets than that in the casein diet (96.6 ± 0.2%), although biological values of dry (86.3 ± 1.3%) and raw (77.9 ± 2.6%) spirulina diets were significantly higher than that of the casein diet (71.9 ± 2.5%). The protein digestibility-corrected amino acid score of raw spirulina (86.6 ± 0.5%) was significantly higher than that of dry spirulina (85.1 ± 0.5%). Additionally, amino acid profiling of portal/venous blood in spirulina diet-fed rats revealed that Ala, Gly, Val, and Leu/Ile were markedly decreased after systemic circulation. These results suggest that dry and raw spirulina diets may be effective not only as a protein source but also as a supplement to support protein/amino acid bioavailability.

Enzymatically synthesized glycogen protects inflammation induced by urban particulate matter in normal human epidermal keratinocytes.

Urban particulate matters (PM) exposure is significantly correlated with extrinsic skin aging signs and skin cancer incidence. PM contains polycyclic aromatic hydrocarbons, and they act as the agonists of aryl hydrocarbon receptor (AhR). Activation of AhR promotes generation of intracellular reactive oxygen species (ROS) and inflammation. Enzymatically synthesized glycogen (ESG), which is synthesized from starch, possesses various functions, such as anti-tumor, anti-obesity and antioxidant. However, the effects of ESG on PM-induced skin inflammation remain unclear. In this study, we investigated whether ESG has a protective effect on PM-induced oxidative stress and inflammation in human epidermal keratinocytes. ESG inhibited PM-induced expression of inflammatory cytokines IL6, TNFA and PTGS2. ESG also inhibited PM-induced phosphorylation of MAPKs and ROS accumulation. However, ESG had no effect on PM-induced expression of CYP1A1, one of the target proteins of AhR. On the other hand, ESG increased nuclear translocation of Nrf2 and expression of antioxidant proteins, HO-1 and NQO1. These results suggest that ESG suppressed PM-induced inflammation by decreasing ROS accumulation through the Nrf2 pathway.

Enzymatically synthesized glycogen prevents ultraviolet B-induced cell damage in normal human epidermal keratinocytes.

Enzymatically synthesized glycogen is a product from starch. Enzymatically synthesized glycogen has been reported to possess various health beneficial effects such as anti-oxidative and anti-inflammatory effects. In this study, we investigated the effect of enzymatically synthesized glycogen on ultraviolet B-induced oxidative stress and apoptosis in normal human epidermal keratinocytes. Treatment with enzymatically synthesized glycogen suppressed ultraviolet B-induced reactive oxygen species, caspase-3 activity, and DNA fragmentation in normal human epidermal keratinocytes. Furthermore, enzymatically synthesized glycogen increased in the expression level of heme oxygenase-1, NAD(P)H: quinone oxidoreductase 1, and NF-E2-related factor 2, a transcriptional factor for heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1. Although enzymatically synthesized glycogen did not increase in its mRNA expression level of NF-E2-related factor 2, enzymatically synthesized glycogen retained its protein degradation. Knockdown of heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1 canceled enzymatically synthesized glycogen-suppressed reactive oxygen species accumulation in normal human epidermal keratinocytes. It is, therefore, concluded that enzymatically synthesized glycogen inhibited ultraviolet B-induced oxidative stress through increasing the expression level of heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1 through the NF-E2-related factor 2 pathway in normal human epidermal keratinocytes.

Enzymatically synthesized glycogen inhibited degranulation and inflammatory responses through stimulation of intestine.

The patients of type I allergic diseases were increased in the developed countries. Recently, many studies have focused on food factors with anti-allergic activities. Enzymatically synthesized glycogen, a polysaccharide with a multi-branched α-1,4 and α-1,6 linkages, is a commercially available product from natural plant starch, and has immunostimulation activity. However, effect of enzymatically synthesized glycogen on the anti-allergic activity was unclear yet. In this study, we investigated that enzymatically synthesized glycogen inhibited allergic and inflammatory responses using a co-culture system consisting of Caco-2 and RBL-2H3 cells. Enzymatically synthesized glycogen inhibited antigen-induced ß-hexosaminidase release and production of TNF-α and IL-6 in RBL-2H3 cells in the co-culture system. Furthermore, enzymatically synthesized glycogen inhibited antigen-induced phosphorylation of tyrosine kinases, phospholipase C γ1/2, mitogen-activated protein kinases and Akt. Anti-allergic and anti-inflammatory activities of enzymatically synthesized glycogen were indirect action through stimulating Caco-2 cells, but not by the direct interaction with RBL-2H3 cells, because enzymatically synthesized glycogen did not permeate Caco-2 cells. These findings suggest that enzymatically synthesized glycogen is an effective food ingredient for prevention of type I allergy through stimulating the intestinal cells.

4-Hydroxyderricin and xanthoangelol isolated from Angelica keiskei prevent dexamethasone-induced muscle loss.

Since a decrease in muscle mass leads to an increased risk of mortality, the prevention of muscle wasting contributes to maintaining the quality of life. Recently, we reported that glabridin, a prenylated flavonoid in licorice, prevents dexamethasone-induced muscle loss. In this study, we focused on the other prenylated chalcones 4-hydroxyderricin and xanthoangelol in Ashitaba (Angelica keiskei) and investigated their prevention effect on dexamethasone-induced muscle loss. It was found that 4-hydroxyderricin and xanthoangelol significantly prevented dexamethasone-induced protein degradation in C2C12 myotubes by suppressing the expression of ubiquitin ligases, Cbl-b and MuRF-1. These prenylated chalcones acted as the antagonists of the glucocorticoid receptor and inhibited the binding of dexamethasone to this receptor and its subsequent nuclear translocation. In addition, the chalcones suppressed the phosphorylation of p38 and FoxO3a as the upstream factors for ubiquitin ligases. Dexamethasone-induced protein degradation and upregulation of Cbl-b were attenuated by the knockdown of the glucocorticoid receptor but not by the knockdown of p38. In male C57BL/6J mice, the Ashitaba extract, containing 4-hydroxyderricin and xanthoangelol, suppressed dexamethasone-induced muscle mass wasting accompanied by a decrease in the expression of ubiquitin ligases by inhibiting the nuclear translocation of the glucocorticoid receptor and phosphorylation of FoxO3a. In conclusion, 4-hydroxyderricin and xanthoangelol are effective compounds to inhibit steroid-induced muscle loss.

6-(Methylsulfinyl)hexyl isothiocyanate protects acetaldehyde-caused cytotoxicity through the induction of aldehyde dehydrogenase in hepatocytes.

In the body, alcohol dehydrogenase rapidly converts ethanol to its toxic metabolite, acetaldehyde, which is further metabolized to non-toxic acetic acid by aldehyde dehydrogenase (ALDH). 6-(methylsulfinyl)hexyl isothiocyanate (6-MSITC), a major bioactive compound in Wasabi (Wasabia japonica) has various physiological effects such as anti-oxidative, anti-inflammatory and anti-cancer effects. However, the effect of 6-MSITC on alcohol metabolism has not been studied. In this study, we investigated the effects of 6-MSITC on hepatic ALDH activity and protein expression both in vitro and in vivo. 6-MSITC inhibited ethanol- and acetaldehyde-induced cytotoxicity. Treatment with 6-MSITC to HepG2 cells enhanced ALDH activity through the induction of mitochondrial ALDH2 expression, but not cytosolic ALDH1A1. Knockdown of Nrf2 canceled the 6-MSITC-induced ALDH2 expression, indicating that Nrf2 regulated ALDH2 expression. Moreover, 6-MSITC increased the nuclear translocation of Nrf2 and the expression levels of HO-1 and SOD2, Nrf2-regulated phase II drug-metabolizing enzymes. Oral administration of 6-MSITC increased the mitochondrial ALDH2 activity and its expression in the liver of C57BL/6J mice. These results suggested that 6-MSITC is possible to protect acetaldehyde toxicity in hepatocytes by induction of mitochondrial ALDH2 expression through Nrf2/ARE pathway.

Enzymatically modified isoquercitrin promotes energy metabolism through activating AMPKα in male C57BL/6 mice.

Quercetin possesses various health beneficial functions, but its poor bioavailability limits these functions. Enzymatically modified isoquercitrin (EMIQ) is a quercetin glycoside with a greater bioavailability than quercetin. In this study, we investigated whether EMIQ regulates energy metabolism in mice and its underlying molecular mechanism. Male C57BL/6 mice were fed a normal diet with different doses of EMIQ or quercetin (0.02%, 0.1% and 0.5%) for two weeks. Supplementation with 0.1% EMIQ significantly decreased white adipose tissue (WAT) weight. Supplementation with 0.02% and 0.1% EMIQ promoted phosphorylation of adenosine monophosphate activated protein kinase (AMPK) in the WAT, liver, and muscle. In the WAT, 0.1% EMIQ downregulated peroxisome proliferator-activated receptor (PPAR)γ, CCAAT-enhancer-binding protein (C/EBP)α, C/EBPß, and sterol regulatory element-binding protein 1 expression, as well as upregulated mitochondrial uncoupling protein (UCP) 2 and carnitine palmitoyltransferase-1 expression. Supplementation with 0.1% EMIQ also promoted the expression of thermogenesis-associated factors including PPARγ coactivator α (PGC-1α), UCP1, PR-domain containing protein 16, and sirtuin 1 in the WAT. In the liver, EMIQ promoted the phosphorylation of acetyl-CoA carboxylase, and increased the expression of PPARα, constitutive androstane-receptor, and farnesoid X receptor. Furthermore, supplementation with 0.02% or 0.1% EMIQ suppressed the plasma glucose level accompanied by the translocation of glucose transporter 4 to the plasma membrane of the muscle. Our results suggest that EMIQ is a potential food additive for the regulation of energy metabolism through AMPK phosphorylation.