Eriodictyol

BMB Rep. 2013 Dec;46(12):594-9.

Binding model for eriodictyol to Jun-N terminal kinase and its anti-inflammatory signaling pathway.[Pubmed: 24195792]

The anti-inflammatory activity of Eriodictyol and its mode of action were investigated.
METHODS AND RESULTS:
Eriodictyol suppressed tumor necrosis factor (mTNF)-α, inducible nitric oxide synthase (miNOS), interleukin (mIL)-6, macrophage inflammatory protein (mMIP)-1, and mMIP-2 cytokine release in LPS-stimulated macrophages. We found that the anti-inflammatory cascade of Eriodictyol is mediated through the Toll-like Receptor (TLR)4/CD14, p38 mitogen-activated protein kinases (MAPK), extracellular-signal-regulated kinase (ERK), Jun-N terminal kinase (JNK), and cyclooxygenase (COX)-2 pathway. Fluorescence quenching and saturation-transfer difference (STD) NMR experiments showed that Eriodictyol exhibits good binding affinity to JNK, 8.79 × 10(5) M(-1). Based on a docking study, we propose a model of Eriodictyol and JNK binding, in which Eriodictyol forms 3 hydrogen bonds with the side chains of Lys55, Met111, and Asp169 in JNK, and in which the hydroxyl groups of the B ring play key roles in binding interactions with JNK.
CONCLUSIONS:
Therefore, Eriodictyol may be a potent anti-inflammatory inhibitor of JNK.

Biol Pharm Bull. 2007 Jan;30(1):32-7.

The anti-apoptotic and anti-oxidant effect of eriodictyol on UV-induced apoptosis in keratinocytes.[Pubmed: 17202655]

Recently, considerable scientific and therapeutic interest has focused on the structure and functions of the flavonoids. In a previous study, we suggested that hydroxyl (OH) substitutions on specific carbons in the skeleton of the flavonoids might significantly affect their apoptosis-modulating properties.
METHODS AND RESULTS:
Here, to investigate the effect of various OH substitutions on their diphenylpropane (C6C3C6) skeleton carbons, we selected 10 different flavonoids and assessed their role on UV-induced apoptosis of human keratinocytes, the principal cell type of epidermis. The results showed that 5,7,3',4'-tetrahydroxylflavanone (Eriodictyol) and 3,4'-dihydroxy flavone (3,4'-DHF) had a positive effect on cell proliferation of human HaCaT keratinocytes. Treatment with Eriodictyol in particular resulted in significant suppression of cell death induced by ultraviolet (UV) light, a major skin-damaging agent. We found that Eriodictyol treatment apparently reduced the percentage of apoptotic cells and the cleavage of poly(ADP-ribose) polymerase, concomitant with the repression of caspase-3 activation and reactive oxygen species (ROS) generation. The anti-apoptotic and anti-oxidant effects of Eriodictyol were also confirmed in UV-induced cell death of normal human epidermal keratinocyte (NHEK) cells.
CONCLUSIONS:
Taken together, these findings suggest that Eriodictyol can be used to protect keratinocytes from UV-induced damage, implying the presence of a complex structure-activity relationship (SAR) in the differential apoptosis-modulating activities of various flavonoids.

Exp Ther Med . 2015 Dec;10(6):2259-2266.

Eriodictyol, a plant flavonoid, attenuates LPS-induced acute lung injury through its antioxidative and anti-inflammatory activity[Pubmed: 26668626]

Abstract Acute lung injury (ALI) is characterized by excessive inflammatory responses and oxidative injury in the lung tissue. It has been suggested that anti-inflammatory or antioxidative agents could have therapeutic effects in ALI, and Eriodictyol has been reported to exhibit antioxidative and anti-inflammatory activity in vitro. The aim of the present study was to investigate the effect of Eriodictyol on lipopolysaccharide (LPS)-induced ALI in a mouse model. The mice were divided into four groups: Phosphate-buffered saline-treated healthy control, LPS-induced ALI, vehicle-treated ALI (LPS + vehicle) and Eriodictyol-treated ALI (LPS + Eriodictyol). Eriodictyol (30 mg/kg) was administered orally once, 2 days before the induction of ALI. The data showed that Eriodictyol pretreatment attenuated LPS-induced ALI through its antioxidative and anti-inflammatory activity. Furthermore, the Eriodictyol pretreatment activated the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway in the ALI mouse model, which attenuated the oxidative injury and inhibited the inflammatory cytokine expression in macrophages. In combination, the results of the present study demonstrated that Eriodictyol could alleviate the LPS-induced lung injury in mice by regulating the Nrf2 pathway and inhibiting the expression of inflammatory cytokines in macrophages, suggesting that Eriodictyol could be used as a potential drug for the treatment of LPS-induced lung injury. Keywords: acute lung injury; Eriodictyol; lipopolysaccharide-induced acute lung injury; nuclear factor erythroid-2-related factor 2 pathway.

Biol Pharm Bull. 2013;36(8):1375-9.

Effect of eriodictyol on the development of atopic dermatitis-like lesions in ICR mice.[Pubmed: 23902981]

Atopic dermatitis (AD) is a chronic, allergic, and inflammatory skin disease associated with eczema and dermatitis symptoms. Our previous studies have reported that Eriodictyol extract inhibits immunoglobulin E (IgE)/Ag-induced type I hypersensitivity by suppressing the activation of proinflammatory cytokines, such as interleukin-4 (IL-4), and the expression of ceramide kinase.
METHODS AND RESULTS:
In this study, we investigated the inhibitory effect of Eriodictyol on 2,4-dinitrochlorobenzene (DNCB)-induced AD-like skin lesions in ICR mice. Treatment with 2 mg/mL Eriodictyol for DNCB-induced AD-like skin lesions in ICR mice improved scratching behavior and skin severity score. Histological analysis demonstrated that thickening of the skin lesions were significantly reduced in the Eriodictyol-treated group. Also, Eriodictyol suppressed the DNCB-mediated elevation of IgE serum levels.
CONCLUSIONS:
These results suggest that Eriodictyol may be a potential therapeutic resource for AD and an adjunctive agent to control itchiness in AD.

Biochem Pharmacol. 2012 Jul 1;84(1):88-92.

Eriodictyol prevents early retinal and plasma abnormalities in streptozotocin-induced diabetic rats.[Pubmed: 22484312 ]

Diabetic retinopathy is a complex disease that has potential involvement of inflammatory and oxidative stress-related pathways in its pathogenesis. We hypothesized that Eriodictyol, one of the most abundant dietary flavonoids, could be effective against diabetic retinopathy, which involves significant oxidative stress and inflammation.
METHODS AND RESULTS:
The aim of the present study was to investigate the effects of Eriodictyol in early retinal and plasma changes of streptozotocin-induced diabetic rats. The effect of Eriodictyol treatment (0.1, 1, 10 mg/kg daily for 10 days) was evaluated by TNF-α, ICAM-1, VEGF, and eNOS protein levels measurement in the retina, plasma lipid peroxidation, and blood-retinal barrier (BRB) integrity. Increased amounts of cytokines, adhesion molecule, and nitric oxide synthase were observed in retina from diabetic rats. Eriodictyol treatment significantly lowered retinal TNF-α, ICAM-1, VEGF, and eNOS in a dose-dependent manner. Further, treatment with Eriodictyol significantly suppressed diabetes-related lipid peroxidation, as well as the BRB breakdown.
CONCLUSIONS:
These data demonstrated that Eriodictyol attenuates the degree of retinal inflammation and plasma lipid peroxidation preserving the BRB in early diabetic rats.

Biochem Pharmacol. 2011 Feb 15;81(4):544-51.

Eriodictyol: a flavonoid antagonist of the TRPV1 receptor with antioxidant activity.[Pubmed: 21087598 ]

The transient potential vanilloid 1 receptor (TRPV1) is a calcium-permeable channel responsible for the transduction and modulation of acute and chronic pain signaling. As such, this receptor is a potential target for the treatment of a number of pain disorders. However, AMG517, a TRPV1 antagonist, presents several clinical limitations that include the induction of severe hyperthermia.
METHODS AND RESULTS:
The aim of this study was to investigate the possible interaction of the flavonoid Eriodictyol with the TRPV1 receptor and to determine its putative antinociceptive and hyperthermic effects. Eriodictyol was able to displace [(3)H]-resiniferatoxin binding (IC(50)=47; 21-119nM) and to inhibit calcium influx mediated by capsaicin (IC(50)=44; 16-125nM), suggesting that Eriodictyol acts as a TRPV1 antagonist. Moreover, Eriodictyol induced antinociception in the intraplantar capsaicin test, with maximal inhibition of 49±10 and 64±4% for oral (ID(50)=2.3; 1.1-5.7mg/kg) and intrathecal (ID(50)=2.2; 1.7-2.9nmol/site) administration, respectively. Eriodictyol did not induce any change in body temperature or locomotor activity. Orally administered Eriodictyol (4.5mg/kg) prevented the nociception induced by intrathecal injections of capsaicin, as well as the non-protein thiol loss and 3-nitrotyrosine (3-NT) formation induced by capsaicin in spinal cord. Eriodictyol also reduced the thermal hyperalgesia and mechanical allodynia elicited by complete Freund's adjuvant (CFA) paw injection.
CONCLUSIONS:
In conclusion, Eriodictyol acts as an antagonist of the TRPV1 receptor and as an antioxidant; it induces antinociception without some of the side effects and limitations such as hyperthermia that are expected for TRPV1 antagonists.

J Biol Chem. 2011 Jan 21;286(3):2057-66.

Eriodictyol inhibits RSK2-ATF1 signaling and suppresses EGF-induced neoplastic cell transformation.[Pubmed: 21098035]

RSK2 is a widely expressed serine/threonine kinase, and its activation enhances cell proliferation.
METHODS AND RESULTS:
Here, we report that ATF1 is a novel substrate of RSK2 and that RSK2-ATF1 signaling plays an important role in EGF-induced neoplastic cell transformation. RSK2 phosphorylated ATF1 at Ser-63 and enhanced ATF1 transcriptional activity. Docking experiments using the crystal structure of the RSK2 N-terminal kinase domain combined with in vitro pulldown assays demonstrated that Eriodictyol, a flavanone found in fruits, bound with the N-terminal kinase domain of RSK2 to inhibit RSK2 N-terminal kinase activity. In cells, Eriodictyol inhibited phosphorylation of ATF1 but had no effect on the phosphorylation of RSK, MEK1/2, ERK1/2, p38 or JNKs, indicating that Eriodictyol specifically suppresses RSK2 signaling. Furthermore, Eriodictyol inhibited RSK2-mediated ATF1 transactivation and tumor promoter-induced transformation of JB6 Cl41 cells. Eriodictyol or knockdown of RSK2 or ATF1 also suppressed Ras-mediated focus formation.
CONCLUSIONS:
Overall, these results indicate that RSK2-ATF1 signaling plays an important role in neoplastic cell transformation and that Eriodictyol is a novel natural compound for suppressing RSK2 kinase activity.

J Agric Food Chem. 2012 Aug 8;60(31):7652-8.

Effect of eriodictyol on glucose uptake and insulin resistance in vitro.[Pubmed: 22809065]

Eriodictyol [2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-2,3-dihydrochromen-4-one] is a flavonoid with anti-inflammatory and antioxidant activities.
METHODS AND RESULTS:
Because inflammation and oxidative stress play critical roles in the pathogenesis of diabetes mellitus, the present study was designed to explore whether Eriodictyol has therapeutic potential for the treatment of type 2 diabetes. The results show that Eriodictyol increased insulin-stimulated glucose uptake in both human hepatocellular liver carcinoma cells (HepG2) and differentiated 3T3-L1 adipocytes under high-glucose conditions. Eriodictyol also up-regulated the mRNA expression of peroxisome proliferator-activated receptor γ2 (PPARγ2) and adipocyte-specific fatty acid-binding protein (aP2) as well as the protein levels of PPARγ2 in differentiated 3T3-L1 adipocytes. Furthermore, it reactivated Akt in HepG2 cells with high-glucose-induced insulin resistance. This response was strongly inhibited by pretreatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, indicating that Eriodictyol increased Akt phosphorylation by activating the PI3K/Akt pathway.
CONCLUSIONS:
These results imply that Eriodictyol can increase glucose uptake and improve insulin resistance, suggesting that it may possess antidiabetic properties.

Planta Med. 1999 Apr;65(3):234-8.

Vasodilatory effect in rat aorta of eriodictyol obtained from Satureja obovata.[Pubmed: 10232068]

METHODS AND RESULTS:
The vasodilator effect of Eriodictyol (5,7,3',4'-tetrahydroxyflavanone), isolated previously from the medicinal plant Satureja obovata Lag., was studied in rat thoracic aorta rings. Eriodictyol relaxed in a concentration-dependent manner the noradrenaline (10(-6) M) and KCl (80 mM) induced contractions. The relaxant effect was more potent in noradrenaline precontracted preparations (IC50 = 6.11 +/- 0.2 x 10(-5) M) than in those precontracted with KCl (IC50 = 2.96 +/- 0.1 x 10(-4) M). Eriodictyol produced weakly concentration-dependent inhibition of the phasic component induced by KCl and noradrenaline while the inhibition of the tonic phase of these contractions was more pronounced. These effects were endothelium independent. In addition, Eriodictyol (10(-5) and 5 x 10(-5) M) inhibited CaCl2 cumulative concentration response curves. Eriodictyol weakly inhibited the release of calcium from the sarcoplasmic reticulum and its contribution to the relaxant effect seems to be slight. We have also observed the relaxant effect of Eriodictyol on phorbol-12-myristate-13-acetate (PMA) (10(-7) M) induced contractions both in normal calcium (IC50 = 4.69 +/- 0.3 x 10(-5) M) and calcium-free medium (IC50 = 3.74 +/- 0.4 x 10(-5) M). Finally we studied the effects on protein kinase C (PKC) activity.
CONCLUSIONS:
This flavonoid did not show any activity. These results suggest that the vasodilator effect of Eriodictyol in rat thoracic aorta could be partially related to the inhibition of calcium influx or other enzymatic protein subsequent to activation of PKC related to the activation of contractile proteins like myosin light chain kinase (MLCK).