• Preventive Nutrition and Food Science
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• v.19 no.4
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• pp.299-306
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• 2014

Hesperetin has been shown to possess a potential anti-angiogenic effect, including vascular formation by endothelial cells. However, the mechanisms underlying the potential anti-angiogenic activity of hesperetin are not fully understood. In the present study, we evaluated whether hesperetin has anti-angiogenic effects in human umbilical vascular endothelial cells (HUVECs). HUVECs were treated with 50 ng/mL vascular endothelial growth factor (VEGF) to induce proliferation as well as vascular formation, followed by treatment with several doses of hesperetin (25, 50, and $100{\mu}M$) for 24 h. Cell proliferation and vascular formation were analyzed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and tube formation assay, respectively. In addition, cell signaling related to cell proliferation and vascular formation was analyzed by western blot. Furthermore, a mouse aorta ring assay was performed to confirm the effect of hesperetin on vascular formation. Hesperetin treatment did not cause differences in HUVECs proliferation. However, hesperetin significantly inhibited VEGF-induced cell migration and tube formation of HUVECs (P<0.05). Moreover, hesperetin suppressed the expression of ERK, p38 MAPK, and PI3K/AKT in the VEGF-induced HUVECs. In an ex vivo model, hesperetin also suppressed microvessel sprouting of mouse aortic rings. Taken together, the findings suggest that hesperetin inhibited vascular formation by endothelial cells via the inhibition of the PI3K/AKT, ERK and p38 MAPK signaling.

• Journal of the Korean Applied Science and Technology
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• v.40 no.5
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• pp.988-1000
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• 2023

Hesperetin(HT) is a potent antioxidant flavonoid aglycone derived from hesperidin(HD). The antioxidant, anti-inflammatory, and antimicrobial activities of HT and its cyclodextrin(CD) inclusion complexes were compared in vitro. HT was prepared by enzymatic hydrolysis of HD, and HT/CD complexes were prepared using 𝛽-cyclodextrin(𝛽-CD) and hydroxypropyl-𝛽-cyclodextrin(HP-𝛽-CD) by solvent co-evaporation method. The solubility of the HT/HP-𝛽-CD inclusion complex increased 93.5-fold compared to HT, and the solubility of HT/𝛽-CD increased 22.5-fold. The HT/HP-𝛽-CD inclusion complex showed a similar effect as HT on radical scavenging activity in antioxidant assays, whereas the HT/𝛽-CD inclusion complex showed slightly lower activity than HT. Cytotoxicity was low in the following order; HT/HP-𝛽-CD, HT/𝛽-CD, and HT in murine macrophage RAW264.7 cells. Treatment with HT and HT/CD inclusion complexes reduced the levels of inflammatory mediators such as nitric oxide(NO), tumor necrosis factor-𝛼(TNF-𝛼) and interleukin-6(IL-6) in the cells. HT and HT/HP-𝛽-CD inclusion complex were more effective than HT/𝛽-CD inclusion complex at relatively low concentrations. Inhibitory effects were tested on skin-pathogenic bacteria, Staphylococcus aureus and Pseudomonas aeruginosa, and they showed an antimicrobial effect on S. aureus in the order of HT = HT/HP-𝛽-CD > HT/𝛽-CD, but they did not show any significant inhibitory effect on P. aeruginosa. In conclusion, HT, the aglycone form of HD, and its CD inclusion complexes showed various biological activities. HT/HP-𝛽-CD inclusion complex, which is the highly soluble form of HT, showed relatively higher activity compared to HT/𝛽-CD inclusion complex.

• Journal of Life Science
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• v.29 no.1
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• pp.129-134
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• 2019

In a previous study, we isolated 11 different kinds of compounds from ethyl acetate fractions of lees (jubak) which is a by-product of Korean traditional wine production. These compounds were identified as caffeic acid, coumaric acid, D-mannitol, ferulic acid, hesperetin, hesperidin, naringenin, naringin, sinapic acid, syringic acid, and vanilic acid. To evaluate their anti-inflammatory activities in an in vitro model, nitric oxide (NO) production was measured in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells after the treatment of these cells with each compound. Among the various chemicals, hesperetin and naringenin showed the highest inhibition of NO production in the LPS-activated RAW 264.7 cells. Hesperetin was chosen for further study because of its strong anti-inflammatory activity and because the mechanisms underlying its anti-inflammatory properties still remain unclear. Our results showed that hesperetin dramatically inhibited NO production in a dose-dependent manner as compared with in an LPS-only treated group, without affecting cell viability. In addition, hesperetin reduced the protein expression of the pro-inflammatory gene inducible nitric oxide synthase (iNOS) in a dose-dependent manner, whereas it did not affect cyclooxygenase-2 (COX-2) expression. Furthermore, hesperetin inhibited phosphorylation of p38 mitogen- activated protein kinase (MAPK) and extracellular signal regulated kinase (ERK) 1/2, whereas it did not affect phosphorylation of c-jun N- terminal kinase (JNK). The results indicated that hesperetin regulated the LPS-induced inflammatory response by suppressing p38 MAPK and ERK1/2 signaling. Overall, our results may help to understand the mechanisms underlying the anti-inflammatory activity mediated by hesperetin.

• Journal of Korean Medicine for Obesity Research
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• v.22 no.1
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• pp.1-10
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• 2022

Objectives: To investigate the protective effect of hesperidin and hesperetin against oxidative stress in 2,2'-azobis (2-aminopropane) dihydrochloride (AAPH)-induced liver toxicity in rats. Methods: Hesperidin or hesperetin (200 mg/kg/day, respectively) was orally administered for 7 days once daily in rats. Subsequently, AAPH (50 mg/kg/day) was administered intraperitoneally. Lipid peroxidation, nitric oxide production, catalase activity, and protein expressions of nuclear factor-kappa B (NF-κB) and inducible nitric oxide synthase (iNOS) in the liver tissues were measured. Results: Administration of hesperidin and hesperetin significantly decreased serum aspartate transaminase and alanine transaminase levels in AAPH-induced oxidative stress liver tissues compared with control group. Lipid peroxidation and nitric oxide (NO) production were also significantly reduced by hesperidin and hesperetin in AAPH-induced oxidative stress liver tissues. In particular, lipid peroxidation levels of hesperetin-administered group significantly decreased to 5.02 nmole/mg protein in oxidative stress rats. Hesperidin and hesperetin significantly increased antioxidant activity, such as that of catalase. Furthermore, administration of hesperidin and hesperetin substantially down-regulated the expression of NF-κB and iNOS in liver tissues. Administration of hesperidin reduced NO levels and iNOS expression more than in the hesperetin-administered group. Conclusions: Administration of hesperidin and hesperetin led to a reduction in AAPH-induced liver toxicity by regulating oxidative stress.

• Biomolecules & Therapeutics
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• v.21 no.2
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• pp.121-125
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• 2013

Hesperetin (3',5,7-trihydroxy 4'-methoxyflavanone) and its glycoside hesperidin (hesperetin 7-rhamnoglucoside) in oranges have been reported to possess pharmacological effects related to anti-obesity. However, hesperetin and hesperidin have not been studied on suppressive effects on appetite. This study examined that hesperetin and hesperidin can stimulate the release of cholecystokinin (CCK), one of appetite-regulating hormones, from the enteroendocrine STC-1 cells, and then examined the mechanisms involved in the CCK release. Hesperetin significantly and dose-dependently stimulated CCK secretion with an $EC_{50}$ of 0.050 mM and increased the intracellular $Ca^{2+}$ concentrations ($[Ca^{2+}]_i$) compared to the untreated control. The stimulatory effect by hesperetin was mediated via the entry of extracellular $Ca^{2+}$ and the activation of TRP channels including TRPA1. These results suggest that hesperetin can be a candidate biomolecule for the suppression of appetite and eventually for the therapeutics of obesity.

• Advances in Traditional Medicine
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• v.1 no.1
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• pp.28-36
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• 2000

Effects of hesperetin and naringenin on the concentration of triacylglycerol in the serum and liver were studied in male golden hamster fed with the semipurified diet containing at 1% level of them for 3 weeks. The concentration of triacylglycerol in serum of the naringenin group decreased by 31%, whereas that in liver increased by 37% compared to the control group. The concentration of triacylglycerol in the serum and liver of the hesperetin group was slightly lower than the control group. The activity of microsomal phosphatidate phosphohydrolase in the liver, which is a key enzyme for biosynthesis of triacylglycerol, was significantly inhibited in the hesperetin group, whereas it was not affected in the naringenin group. The effect of hesperetin on phosphatidate phosphohydrolase was also measured in vitro. Hesperetin decreased the activity of phosphatidate phosphohydrolase with a dose-dependent manner. Both naringenin and hesperetin did not statistically affect the daily food consumption, body weight, liver weight, and total cholesterol in the serum. The observation accounts for the hypotriglyceridemic effect of hesperetin in the hyperlipidemic hamster.

• Korean Journal of Agricultural Science
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• v.38 no.4
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• pp.717-722
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• 2011

In this study, we investigated the antioxidant activity of hesperidin and hesperetin, which are the active compounds from Citrus junos, in the cellular system. Under cellular model of oxidative damage using LLC-$PK_1$ renal epithelial cell, the oxidative damage induced by 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) led to the loss of cell viability, while treatment of hesperidin and hesperetin increased significantly the cell viability as dose-dependent manner. In addition, NO-induced cellular oxidative damage by sodium nitroprusside were significantly recovered by the treatment of hesperidin and hesperetin, showing the increase of cell viability. But hesperidin and hesperetin showed no significant protective effect on $O_2{^-}$-induced cellular oxidative damage. The present study indicates that hesperidin and hesperetin protect against free radical, especially AAPH-induced peroxyl radical. In particular, hesperetin has stronger protective effect against oxidative stress than hesperidin.

• Archives of Pharmacal Research
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• v.29 no.8
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• pp.699-706
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• 2006

The present study evaluated antioxidant and neuroprotective activities of hesperidin, a flavanone mainly isolated from citrus fruits, and its aglycone hesperetin using cell-free bioassay system and primary cultured rat cortical cells. Both hesperidin and hesperetin exhibited similar patterns of 1,1-diphenyl-2-picrylhydrazyl radical scavenging activities. While hesperidin was inactive, hesperetin was found to be a potent antioxidant, inhibiting lipid peroxidation initiated in rat brain homogenates by $Fe^{2+}$ and L-ascorbic acid. In consistence with these findings, hesperetin protected primary cultured cortical cells against the oxidative neuronal damage induced by $H_2O_2$ or xanthine and xanthine oxidase. In addition, it was shown to attenuate the excitotoxic neuronal damage induced by excess glutamate in the cortical cultures. When the excitotoxicity was induced by the glutamate receptor subtype-selective ligands, only the N-methyl-D-aspartic acid-induced toxicity was selectively and markedly inhibited by hesperetin. Furthermore, hesperetin protected cultured cells against the $A_{{\beta}(25-35)}-induced$ neuronal damage. Hesperidin, however, exerted minimal or no protective effects on the neuronal damage tested in this study. Taken together, these results demonstrate potent antioxidant and neuroprotective effects of hesperetin, implying its potential role in protecting neurons against various types of insults associated with many neurodegenerative diseases.

• Nutrition Research and Practice
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• v.15 no.5
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• pp.591-603
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• 2021

BACKGROUND/OBJECTIVES: Unregulated inflammatory responses caused by hyperglycemia may induce diabetes complications. Hesperetin, a bioflavonoid, is a glycoside in citrus fruits and is known to have antioxidant and anticarcinogenic properties. However, the effect of inflammation on the diabetic environment has not been reported to date. In this study, we investigated the effect of hesperetin on proinflammatory cytokine secretion and its underlying mechanistic regulation in THP-1 macrophages with co-treatment LPS and hyperglycemic conditions. MATERIALS/METHODS: THP-1 cells differentiated by PMA (1 µM) were cultured for 48 h in the presence or absence of hesperetin under normoglycemic (5.5 mM/L glucose) or hyperglycemic (25 mM/L glucose) conditions and then treated with LPS (100 ng/mL) for 6 h before harvesting. Inflammation-related proteins and mRNA levels were evaluated by enzyme-linked immunosorbent assay, western blot, and quantitative polymerase chain reaction analyses. RESULTS: Hesperetin (0-100 µM, 48 h) treatment did not affect cell viability. The tumor necrosis factor-α and interleukin-6 levels increased in cells co-treated with LPS under hyperglycemic conditions compared to normoglycemic conditions, and these increases were decreased by hesperetin treatment. The TLR2/4 and MyD88 activity levels increased in cells co-treated with LPS under hyperglycemic conditions compared to normoglycemic conditions; however, hesperetin treatment inhibited the TLR2/4 and MyD88 activity increases. In addition, nuclear factor-κB (NF-κB) and Acetyl-NF-κB levels increased in response to treatment with LPS under hyperglycemic conditions compared to normoglycemic conditions, but those levels were decreased when treated with hesperetin. SIRT3 and SIRT6 expressions were increased by hesperetin treatment. CONCLUSIONS: Our results suggest that hesperetin may be a potential agent for suppressing inflammation in diabetes.

• Korean journal of food and cookery science
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• v.19 no.3
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• pp.324-327
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• 2003

The quality characteristics of muffins prepared with hesperetin (0.2, 0.4 or 0.8%), a flavonoid, were evaluated. There were no significant differences in volumes and heights of the muffins due to the various additions of hesperetin, or in the L, a and b values of the crust and crumb of the various muffin groups. The sweetness of the muffins containing the highest level of hesperetin (0.8%) gave the highest scores in the sensory test. A stepwise regression analysis showed the sweetness and after taste were the significant factors affecting the overall preference for the muffins. Therefore, hesperetin may be useful as a muffin additive as its addition did not impair the sensory characteristics of the muffins.