Caffeic acid phenethyl ester is a potent inhibitor of HIF prolyl hydroxylase: structural analysis and pharmacological implication

Choi, Daekyu; Han, Jeongoh; Lee, You-Na; Choi, Jungyun; Han, Sang-oh; Hong, Sungchae; Jeon, Hyunchu; Kim, Young Mi; Jung, Yunjin

doi:10.1016/j.jnutbio.2009.06.002

Cited by 30 publications

(27 citation statements)

References 45 publications

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“…It can minimize radiation-induced hearing damage in rats [20]. Moreover, CAPE has been found to be a protective agent against chemotherapy-induced and radiotherapy-induced toxicity [21]. Further study suggested that CAPE can induce the expression of HIF-1α protein and concomitantly trans- …”

Section: Discussionmentioning

confidence: 99%

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CAPE promotes the expansion of human umbilical cord blood-derived hematopoietic stem and progenitor cells in vitro

Liu¹,

Zhang²,

Zhang³

et al. 2014

Sci. China Life Sci.

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Due to the low number of collectable stem cells from single umbilical cord blood (UCB) unit, their initial uses were limited to pediatric therapies. Clinical applications of UCB hematopoietic stem and progenitor cells (HSPCs) would become feasible if there were a culture method that can effectively expand HSPCs while maintaining their self-renewal capacity. In recent years, numerous attempts have been made to expand human UCB HSPCs in vitro. In this study, we report that caffeic acid phenethyl ester (CAPE), a small molecule from honeybee extract, can promote in vitro expansion of HSPCs. Treatment with CAPE increased the percentage of HSPCs in cultured mononuclear cells. Importantly, culture of CD34 + HSPCs with CAPE resulted in a significant increase in total colony-forming units and high proliferative potential colony-forming units. Burst-forming unit-erythroid was the mostly affected colony type, which increased more than 3.7-fold in 1 μg mL 1 CAPE treatment group when compared to the controls. CAPE appears to induce HSPC expansion by upregulating the expression of SCF and HIF1-α. Our data suggest that CAPE may become a potent medium supplement for in vitro HSPC expansion.hematopoietic stem and progenitor cells, caffeic acid phenethyl ester, expansion Citation:Liu YM, Zhang BW, Zhang J, Wang SH, Yao HL, He LJ, Chen L, Yue W, Li YH, Pei XT. CAPE promotes the expansion of human umbilical cord blood-derived hematopoietic stem and progenitor cells in vitro.

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Section: Discussionmentioning

confidence: 99%

“…activate the HIF-1 target genes, such as vascular endothelial growth factor and heme oxygenase-1 (HO-1), which play a protective role in I/R injury [21]. By using gene chip analysis, Wang reported that the expression levels of SCF and HO-1 genes were significantly upregulated in HUVECs.…”

Section: Figurementioning

confidence: 99%

CAPE promotes the expansion of human umbilical cord blood-derived hematopoietic stem and progenitor cells in vitro

Liu¹,

Zhang²,

Zhang³

et al. 2014

Sci. China Life Sci.

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“…CAPE was purchased from Sigma-Aldrich. The structural derivatives of CAPE, biotin tagged CA, -DHC, and -DMC were synthesized as described previously27. Monosodium urate (MSU) and ATP were purchased from Invivogen (Carlsbad, CA).…”

Section: Methodsmentioning

confidence: 99%

Targeting ASC in NLRP3 inflammasome by caffeic acid phenethyl ester: a novel strategy to treat acute gout

Lee

Yang

Kim

et al. 2016

Sci Rep

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Gouty arthritis is caused by the deposition of uric acid crystals, which induce the activation of NOD-like receptor family, pyrin domain containing 3(NLRP3) inflammasome. The NLRP3 inflammasome, composed of NLRP3, the adaptor protein ASC, and caspase-1, is closely linked to the pathogenesis of various metabolic diseases including gouty arthritis. We investigated whether an orally administrable inhibitor of NLRP3 inflammasome was effective for alleviating the pathological symptoms of gouty arthritis and what was the underlying mechanism. In primary mouse macrophages, caffeic acid phenethyl ester(CAPE) blocked caspase-1 activation and IL-1β production induced by MSU crystals, showing that CAPE suppresses NLRP3 inflammasome activation. In mouse gouty arthritis models, oral administration of CAPE suppressed MSU crystals-induced caspase-1 activation and IL-1β production in the air pouch exudates and the foot tissues, correlating with attenuation of inflammatory symptoms. CAPE directly associated with ASC as shown by SPR analysis and co-precipitation, resulting in blockade of NLRP3-ASC interaction induced by MSU crystals. Our findings provide a novel regulatory mechanism by which small molecules harness the activation of NLRP3 inflammasome by presenting ASC as a new target. Furthermore, the results suggest the preventive or therapeutic strategy for NLRP3-related inflammatory diseases such as gouty arthritis using orally available small molecules.

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“…To test this possibility, NO donors were subjected to an in vitro VHL capture assay under hyperoxia (100% oxygen) and normoxia (21% oxygen), and VHL binding was compared. Ciclopirox and caffeic acid phenethylester (CAPE), a natural product with HPH inhibitory activity [16], were used as controls. Hyperoxia did not substantially increase VHL binding in the control HPH reactions without NO donors (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Cells were cultured with 13 C-labeled proline in the absence or presence of SNAP (0.3–1.0 mM) and radiolabeled collagen released into the medium was analyzed for hydroxyproline content after acid hydrolysis and TLC separation. The effects were also measured with known common inhibitors of HPHs, CAPE and ciclopirox [16,17]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Hyperoxia attenuates the inhibitory effect of nitric oxide donors on HIF prolyl-4-hydroxylase-2: Implication on discriminative effect of nitric oxide on HIF prolyl-4-hydroxylase-2 and collagen prolyl-4-hydroxylase

Yum

Choi

Hong

et al. 2011

Biochemical Pharmacology

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Prolyl 4-hydroxylases (P4Hs), such as collagen prolyl-4-hydroxylases (CPHs) and hypoxia inducible factor prolyl-4-hydroxylases (HPHs), have recently been recognized as promising drug targets for the treatment of fibrotic and ischemic diseases. CPHs and HPHs catalyze identical metabolic reactions, yet lead to quite different physiological consequences, collagen synthesis and the regulation of oxygen homeostasis. Selective modulation of the two enzymes should provide a therapeutic benefit upon pharmacotherapy. In an in vitro VHL capture assay, hydroxylation of the 19mer HIF peptide (corresponding to HIF-1α residues 556–574) by HPH-2 was effectively prevented by nitric oxide (NO) donors, (±)-S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione. The NO donors also caused inhibition of HPHs and accumulation of nonhydroxylated HIF-1α protein in A549 human lung adenocarcinoma cells. Hyperoxia (100% O2) attenuated both NO donor-induced accumulation of HIF-1α and inhibition of HPH-mediated hydroxylation. In the presence of a proteasome inhibitor, MG132, the hyperoxia-mediated degradation of HIF-1α was deterred and hydroxylated HIF-1α was detected. SNAP, while being an effective inhibitor of proline 4-hydroxylation of HIF-1α by HPH-2, did not diminish proline hydroxylation of collagen by CPHs. Our data suggest that NO inhibits HPH-2 via competing with dioxygen and that the discriminative effect of NO on CPHs and HPH-2 is attributable to the difference in the affinity of the two enzymes toward dioxygen.

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Caffeic acid phenethyl ester is a potent inhibitor of HIF prolyl hydroxylase: structural analysis and pharmacological implication

Cited by 30 publications

References 45 publications

CAPE promotes the expansion of human umbilical cord blood-derived hematopoietic stem and progenitor cells in vitro

CAPE promotes the expansion of human umbilical cord blood-derived hematopoietic stem and progenitor cells in vitro

Targeting ASC in NLRP3 inflammasome by caffeic acid phenethyl ester: a novel strategy to treat acute gout

Hyperoxia attenuates the inhibitory effect of nitric oxide donors on HIF prolyl-4-hydroxylase-2: Implication on discriminative effect of nitric oxide on HIF prolyl-4-hydroxylase-2 and collagen prolyl-4-hydroxylase

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