Apocynin and enzymatically modified isoquercitrin suppress the expression of a NADPH oxidase subunit p22phox in steatosis-related preneoplastic liver foci of rats

Yoshida, Toshinori; Murayama, Hirotada; Kawashima, Masahi; Nagahara, Rei; Kangawa, Yumi; Mizukami, Sayaka; Kimura, Masayoshi; Abe, Hajime; Hayashi, Shim-mo; Shibutani, Makoto

doi:10.1016/j.etp.2016.10.003

Cited by 17 publications

(25 citation statements)

References 35 publications

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“…Fasting decreased glycogen deposition in the hepatocytes in each group, but steatosis was persistently observed with the HFD feeding ( Fig. 3A-D), when compared with the liver in our previous study using non-fasting rats (Yoshida et al, 2017). NAS and the scores of steatosis and ballooning change significantly increased in the HFD group with or without PC alone or in combination with AGIQ compared to the CTL group ( Fig.…”

Section: Treatment With Pc Alone or In Combination With Agiq Reduced mentioning

confidence: 63%

“…We recently developed a model for steatosis-related early hepatocarcinogenesis using a medium-term liver assay in high fat diet (HFD)-fed rats (Yoshida et al, 2017). In this study, we determined the effects of PC on obesity, insulin tolerance, and renal and liver lesions, and examined steatosis-related preneoplastic liver foci, with hepatic gene expression associated with lipid metabolism and oxidative stress, including NOX.…”

Section: Introductionmentioning

confidence: 99%

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Differential impacts of mineralocorticoid receptor antagonist potassium canrenoate on liver and renal changes in high fat diet-mediated early hepatocarcinogenesis model rats

et al. 2018

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Mineralocorticoid receptor (MR)/NADPH oxidase (NOX) signaling is involved in the development of obesity, insulin resistance, and renal diseases; however, the role of this signaling on steatotic preneoplastic liver lesions is not fully elucidated. We determined the effects of the MR antagonist potassium canrenoate (PC) on MR/NOX signaling in hepatic steatosis and preneoplastic glutathione S-transferase placental form (GST-P)-positive liver foci. Rats were subjected to a two-stage hepatocarcinogenesis model and fed with basal diet or high fat diet (HFD) that was co-administered with PC alone or in combination with the antioxidant alpha-glycosyl isoquercitrin (AGIQ). PC reduced obesity and renal changes (basophilic tubules that expressed MR and p22phox) but did not affect blood glucose tolerance and non-alcoholic fatty liver disease activity score (NAS) in HFD-fed rats. However, the drug increased the area of GST-P-positive liver foci that expressed MR and p22phox as well as increased expression of NOX genes (p22phox, Poldip2, and NOX4). PC in combination with AGIQ had the potential of inhibiting the effects of PC on the area of GST-P-positive liver foci and the effects were associated with increasing expression of an anti-oxidative enzyme (Catalase). The results suggested that MR/NOX signaling might be involved in development of preneoplastic liver foci and renal basophilic changes in HFD-fed rats; however, the impacts of PC were different in each organ.

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Section: Treatment With Pc Alone or In Combination With Agiq Reduced mentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Differential impacts of mineralocorticoid receptor antagonist potassium canrenoate on liver and renal changes in high fat diet-mediated early hepatocarcinogenesis model rats

et al. 2018

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“…The fourth group was administered HFD and SR as well as 5,000 ppm AGIQ (SR + AGIQ) in their drinking water. The dose of 5,000 ppm for AGIQ was administered as previously reported (Yoshida et al 2017). All the animals were subjected to two-thirds partial hepatectomy one week after SR treatment was initiated.…”

Section: Methodsmentioning

confidence: 99%

“…In Zucker obese rats, NOX4, p67phox, and p47phox, but not NOX2, are significantly overexpressed in steatotic livers compared with lean rats (Gupte et al 2009). We recently found that a NOX subunit p22phox is specifically expressed in the preneoplastic hepatic glutathione S-transferase placental form (GST-P)-positive foci in HFD-fed rats in a two-stage (initiation and promotion) hepatocarcinogenesis model (Yoshida et al 2017).…”

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confidence: 99%

Spironolactone in Combination with α-glycosyl Isoquercitrin Prevents Steatosis-related Early Hepatocarcinogenesis in Rats through the Observed NADPH Oxidase Modulation

et al. 2018

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Administration of the diuretic, spironolactone (SR), can inhibit chronic liver diseases. We determined the effects of SR alone or in combination with the antioxidant α-glycosyl isoquercitrin (AGIQ) on hyperlipidemia- and steatosis-related precancerous lesions in high-fat diet (HFD)-fed rats subjected to a two-stage hepatocarcinogenesis model. Rats were fed with control basal diet or HFD, which was administered with SR alone or in combination with an antioxidant AGIQ in drinking water. An HFD increased body weight, intra-abdominal fat (adipose) tissue weight, and plasma lipids, which were reduced by coadministration of SR and AGIQ. SR and AGIQ coadministration also reduced hepatic steatosis and preneoplastic glutathione S-transferase placental form-positive foci, in association with decrease in NADPH oxidase (NOX) subunit p22phox-positive cells and an increase in active-caspase-3-positive cells in the foci. Hepatic gene expression analysis revealed that the coadministration of SR and AGIQ altered mRNA levels of lipogenic enzymes ( Scd1 and Fasn), antioxidant-related enzymes ( Catalase), NOX component ( P67phox), and anti-inflammatory transcriptional factor ( Pparg). Our results indicated that SR in combination with AGIQ had the potential of suppressing hyperlipidemia- and steatosis-related early hepatocarcinogenesis through the reduced expression of NOX subunits.

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“…AGIQ has been found to possess a higher bioavailability than quercetin or isoquercitrin in humans 10 and has proven pharmacological benefits in vivo, including tumor suppressive and anti-oxidative effects. [11][12][13][14][15][16][17][18][19] AGIQ has been used as a natural food additive in Japan since 1987 and is in wide use as an anti-oxidant in a large number of products, ranging from beverages, frozen dairy products and puddings to chewing gums and canned soups. 20 Following the Japanese approval in 1996, the Expert Panel of the Flavor and Extract Manufacturers Association granted AGIQ a generally recognized as safe status in 2005, and the same status was granted by the US Food and Drug Administration (FDA) in 2007.…”

Section: Introductionmentioning

confidence: 99%

Ten-day and four-week toxicity and toxicokinetics studies of alpha-glycosyl isoquercitrin in juvenile Göttingen minipigs

Maronpot

Ramot

Koyanagi

et al. 2019

Toxicology Research and Application

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Background: Alpha-glycosyl isoquercitrin (AGIQ) is widely used as an anti-oxidative food additive in many products. Nevertheless, information on its safety and toxicity is still very limited. A 90-day toxicity study in rats and comprehensive genotoxic studies have proven AGIQ to be safe. Aim: The goal of this study was to assess the safety of use of AGIQ in infant formula. To test for potential adverse effects on growth or other safety issues specific for young animals, we performed a 10-day and a 4-week study in preweaning Gö ttingen minipigs. Method: Newborn minipigs were treated four times per day with oral AGIQ (0, 100, 300, or 1000 mg/kg/day) for 10 days or 4 weeks. Results: All animals remained in good health throughout both studies, and there were no treatment-related signs of toxicity or abnormal findings in blood parameters. In the 4-week study, yellow coloration of the bones was seen in all animals in the high-dose group with no related histological findings. Hepatocellular and sinusoidal/Kupffer cell iron deposition was seen in the liver of all animals in both studies, as expected after the routine administration of supplemental iron to newborn animals. There was sufficient evidence of systemic exposure based on plasma levels of AGIQ metabolites. Conclusion: Taken together, these findings show that oral administration of AGIQ in reconstituted milk supplement to preweaning Gö ttingen minipigs for 4 weeks at up to 1000 mg/ kg/day does not result in any adverse treatment-related effects and further support the safety of AGIQ as a food additive.

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Apocynin and enzymatically modified isoquercitrin suppress the expression of a NADPH oxidase subunit p22phox in steatosis-related preneoplastic liver foci of rats

Cited by 17 publications

References 35 publications

Differential impacts of mineralocorticoid receptor antagonist potassium canrenoate on liver and renal changes in high fat diet-mediated early hepatocarcinogenesis model rats

Differential impacts of mineralocorticoid receptor antagonist potassium canrenoate on liver and renal changes in high fat diet-mediated early hepatocarcinogenesis model rats

Spironolactone in Combination with α-glycosyl Isoquercitrin Prevents Steatosis-related Early Hepatocarcinogenesis in Rats through the Observed NADPH Oxidase Modulation

Ten-day and four-week toxicity and toxicokinetics studies of alpha-glycosyl isoquercitrin in juvenile Göttingen minipigs

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