• Title, Summary, Keyword: hesperetin

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Hesperetin Inhibits Vascular Formation by Suppressing of the PI3K/AKT, ERK, and p38 MAPK Signaling Pathways

  • Kim, Gi Dae
    • 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.

Hesperetin Ameliorates Inflammatory Responses in Lipopolysaccharide-stimulated RAW 264.7 Cells via p38 MAPK and ERK1/2 (마우스 대식세포 RAW 264.7 세포주에서 hesperetin에 의한 p38 MAPK와 ERK1/2를 통한 염증반응 조절)

  • Lee, Seung-Hoon;Lee, Eun-Joo;Chung, Chungwook;Sohn, Ho-Yong;Kim, Jong-Sik
    • 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.

Effects of citrus aglycone flavonoids, hesperetin and naringenin, on triacylglycerol metabolism in hamsters fed with a cholesterol diet

  • Cha, Jae-Young;Lee, Jin-Woo;Lee, Young-Choon;Cho, Young-Su
    • Oriental Pharmacy and Experimental 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.

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Antioxidant and Neuroprotective Effects of Hesperidin and its Aglycone Hesperetin

  • Cho, Jung-Sook
    • 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.

Antioxidative effects of hesperidin and hesperetin under cellular system (Hesperidin과 hesperetin의 cellular system에서의 항산화 효과)

  • Cho, Eun-Ju;Li, Li;Yamabe, Noriko;Kim, Hyun-Young
    • 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.

Molecular Mechanism Underlying Hesperetin-induced Apoptosis by in silico Analysis and in Prostate Cancer PC-3 Cells

  • Sambantham, Shanmugam;Radha, Mahendran;Paramasivam, Arumugam;Anandan, Balakrishnan;Malathi, Ragunathan;Chandra, Samuel Rajkumar;Jayaraman, Gopalswamy
    • Asian Pacific Journal of Cancer Prevention
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    • v.14 no.7
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    • pp.4347-4352
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    • 2013
  • Aim: To investigate the molecular mechanisms underlying triggering of apoptosis by hesperetin using in silico and in vitro methods. Methods: The mechanism of binding of hesperetin with NF-${\kappa}B$ and other apoptotic proteins like BAX, BAD, $BCL_2$ and $BCL_{XL}$ was analysed in silico using Schrodinger suite 2009. In vitro studies were also carried out to evaluate the potency of hesperetin in inducing apoptosis using the human prostate cancer PC-3 cell line. Results: Hesperetin was found to exhibit high-affinity binding resulting from greater intermolecular forces between the ligand and its receptor NF-${\kappa}B$ (-7.48 Glide score). In vitro analysis using MTT assay confirmed that hesperetin reduced cell proliferation ($IC_{50}$ values of 90 and $40{\mu}M$ at 24 and 48h respectively) in PC-3 cells. Hesperetin also downregulated expression of the anti-apoptotic gene $BCL_{XL}$ at both mRNA and protein levels and increased the expression of pro-apoptotic genes like BAD at mRNA level and BAX at mRNA as well as protein levels. Conclusion: The results suggest that hesperetin can induce apoptosis by inhibiting NF-${\kappa}B$.

Hesperetin Stimulates Cholecystokinin Secretion in Enteroendocrine STC-1 Cells

  • Kim, Hye Young;Park, Min;Kim, Kyong;Lee, Yu Mi;Rhyu, Mee Ra
    • 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.

Quality Characteristics of Functional Muffins Containing Hesperetin (Hesperetin이 첨가된 기능성 머핀의 품질 특성)

  • 전소윤;김효정;김미라
    • 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.

Identfication of Phase I and Phase II Metabolites of Hesperetin in Rat Liver Microsomes by Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry

  • Kim, Un-Yong;Han, Sang-Beom;Kwon, Oh-Seung;Yoo, Hye-Hyun
    • Mass Spectrometry Letters
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    • v.2 no.1
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    • pp.20-23
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    • 2011
  • The purpose of this study is to investigate the in vitro metabolism of hesperetin, a bioflavonoid. Hesperetin was incubated with rat liver microsomes in the presence of NADPH and UDP-glucuronic acid for 30 min. The reaction mixture was analyzed by liquid chromatography-ion trap mass spectrometer and the chemical structures of hesperetin metabolites were characterzed based on their MS/MS spectra. As a result, a total of five metabolites were detected in rat liver microsomes. The metabolites were identified as a de-methylated metabolite (eriodictyol), two hesperetin glucuronides, and two eriodictyol glucuronides.

Antiherpetic Activities of Natural Hesperetin Alone and in Combinations with Acyclovir and Vidarabine (천연 Hesperetin의 항허피스바이러스작용과 Acyclovir 및 Vidarabine과의 병용효과)

  • Lee, Ji-Hyun;Eo, Seong-Kug;Kim, Young-So;Lee, Chong-Kil;Han, Seong-Sun
    • Korean Journal of Pharmacognosy
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    • v.30 no.1
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    • pp.40-47
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    • 1999
  • To search for less toxic antiherpetic agents, the inhibitory effects of natural hesperetin on the plaque formation of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in Vero cells were examined by the plaque reduction assay in vitro. Hesperetin inhibited plaque formations of HSV-1 and HSV-2 in a dose dependent manner. It also exhibited more potent antiherpetic activity on HSV-2 with selectivity index (SI) of 9.8 than on HSV-1 with SI of 8.4. The combined antiherpetic effects of hesperetin with nucleoside antiherpetic agents, acyclovir and vidarabine, were examined on the multiplication of these two strains of herpesviruses in Vero cells by the combination assay. The results of combination assay were evaluated by the combination index (CI) that was calculated by the multiple drug effect analysis. The combinations of hesperetin with acyclovir on HSV-1 and HSV-2 showed synergistic effects with CI values of $0.29{\sim}0.73$ for 50%, 70%, 90% effective levels and those with vidarabine showed partially synergistic or additive effects with CI values of $0.83{\sim}1.33$.

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