Inhibition of IRAK-4 activity for rescuing endotoxin LPS-induced septic mortality in mice by lonicerae flos extract

Park, Sun Hong; Roh, Eunmiri; Kim, Hyun Soo; Baek, Seung Il; Choi, Nam Song; Kim, Na-Rae; Hwang, Bang Yeon; Han, Sang Bae; Kim, Youngsoo

doi:10.1016/j.bbrc.2013.11.045

Cited by 21 publications

(21 citation statements)

References 21 publications

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“…Nucleotide sequences of the PCR primers were previously described (21). In brief, total RNAs were reversely transcribed at 42˚C for 1 h and then subjected to 25-30 cycles of PCR consisting of 30 s denaturation at 94˚C, 60 s annealing at 50-60˚C, and 90 s extension at 72˚C.…”

Section: Rt-pcr Analysismentioning

confidence: 99%

“…1A) protects against CLP-induced septic mortality and multiorgan injury in mice (20). We recently reported that CGA is a major anti-inflammatory constituent of lonicerae flos extract, which improves Escherichia coli LPSinduced endotoxemia in mice (21). Thereby, the lonicerae flos extract is further developed as a drug candidate currently undergoing a phase I trial (Korea Food and Drug Administration, Identifier HSP Injection_101 Version 2.00) for sepsis treatment.…”

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confidence: 99%

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IRAK4 as a Molecular Target in the Amelioration of Innate Immunity–Related Endotoxic Shock and Acute Liver Injury by Chlorogenic Acid

Park

Baek

Yun

et al. 2015

The Journal of Immunology

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Mice lacking the IL-1R–associated kinase 4 (IRAK4) are completely resistant to LPS-induced endotoxic disorder or the TLR9 agonist CpG DNA plus d-galactosamine–induced acute liver injury (ALI), whereas wild-type strains succumb. However, translational drugs against sepsis or ALI remain elusive. Lonicerae flos extract is undergoing the clinical trial phase I in LPS-injected healthy human volunteers for sepsis treatment. In the current study, chlorogenic acid (CGA), a major anti-inflammatory constituent of lonicerae flos extract, rescued endotoxic mortality of LPS-intoxicated C57BL/6 mice, as well as ameliorated ALI of LPS/d-galactosamine–challenged C57BL/6 mice. As a mechanism, CGA inhibited various TLR agonist–, IL-1α–, or high-mobility group box-1–stimulated autophosphorylation (activation) of IRAK4 in peritoneal macrophages from C57BL/6 or C3H/HeJ mice via directly affecting the kinase activity of IRAK4, a proximal signal transducer in the MyD88-mediated innate immunity that enhances transcriptional activity of NF-κB or AP-1. CGA consequently attenuated protein or mRNA levels of NF-κB/AP-1 target genes encoding TNF-α, IL-1α, IL-6, and high-mobility group box-1 in vivo under endotoxemia or ALI. Finally, this study suggests IRAK4 as a molecular target of CGA in the treatment of innate immunity–related shock and organ dysfunction following insult of various TLR pathogens from bacteria and viruses.

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Section: Rt-pcr Analysismentioning

confidence: 99%

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confidence: 99%

IRAK4 as a Molecular Target in the Amelioration of Innate Immunity–Related Endotoxic Shock and Acute Liver Injury by Chlorogenic Acid

Park

Baek

Yun

et al. 2015

The Journal of Immunology

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“…A voucher specimen was deposited in the Herbarium of the College of Pharmacy, Hanyang University (HYUP‐LJF‐001). The crude extract of L. japonica was obtained by a previously described method . Briefly, flower buds of L. japonica were extracted with hot water (10 L × 2) for 3 h at 100°C.…”

Section: Methodsmentioning

confidence: 99%

Large‐scale purification of unstable, water‐soluble secologanic acid using centrifugal partition chromatography

Yeon

Jeon

et al. 2018

Phytochemical Analysis

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“…HS-23 decreased sepsis-induced mortality, enhanced bacterial clearance, and attenuated multiple organ failure in lipopolysaccharide (LPS)-induced and cecal ligation and puncture (CLP) septic mice (Park et al 2013b;Kim et al 2014). HS-23 inhibited the overproduction of HMGB1 and proinflammatory cytokines such as TNF-a, IL-1b and IL-6, and led to the improvement of outcomes in murine models of sepsis.…”

mentioning

confidence: 99%

“…Chlorogenic acid, an active component of L. japonica, ameliorated multiorgan dysfunction, enhanced bacterial clearance, and protected against sepsis-induced mortality through the suppression of HMGB1 release in CLP septic mice ). HS-23 and its major components including chlorogenic acid, neochlorogenic acid and cryptochlorogenic acid showed anti-inflammatory activity against LPS-induced septic mortality in mice partly through the inhibition of IL-1 receptor-associated kinase 4 (Park et al 2013b).…”

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confidence: 99%

Metabolism-mediated drug interaction potential of HS-23, a new herbal drug for the treatment of sepsis in human hepatocytes and liver microsomes

et al. 2014

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HS-23, an extract of the dried flower buds of Lonicera japonica, is a new botanical drug currently being evaluated in a phase I clinical study in Korea for the treatment of sepsis. The in vitro induction and inhibition potentials of HS-23 on the drug-metabolizing enzymes using human hepatocytes and liver microsomes were assessed to evaluate herb-drug interaction according to botanical drug guideline and drug interaction guidance of FDA. HS-23 slightly inhibited CYP2A6, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 enzyme activities in human liver microsomes with IC50 values of 80.6, 160.7, 169.5, 85.4, and 76.6 μg/mL, respectively. HS-23 showed negligible inhibition of CYP1A2, CYP2C8, CYP2D6, UGT1A1, UGT1A4, UGT1A9, and UGT2B7 activities in human liver microsomes. Based on these results, HS-23 may not inhibit the metabolism of CYP2A6, CYP2B6, CYP2C9, CYP2C19, and CYP3A4-catalyzed drugs in humans. HS-23 did not affect the mRNA expression of CYP1A2, CYP2B6, and CYP3A4 after 48 h treatment at three concentrations (0.5, 5, and 50 μg/mL) in three independent human hepatocytes, indicating that HS-23 has no effect on herb-drug interactions that up- or down-regulate CYP1A2, CYP2B6, and CYP3A4. These results indicate that the administration of HS-23 in human may not cause clinically relevant inhibition and induction of these cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes and HS-23 may be promising therapeutic agent for treatment of sepsis.

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Inhibition of IRAK-4 activity for rescuing endotoxin LPS-induced septic mortality in mice by lonicerae flos extract

Cited by 21 publications

References 21 publications

IRAK4 as a Molecular Target in the Amelioration of Innate Immunity–Related Endotoxic Shock and Acute Liver Injury by Chlorogenic Acid

IRAK4 as a Molecular Target in the Amelioration of Innate Immunity–Related Endotoxic Shock and Acute Liver Injury by Chlorogenic Acid

Large‐scale purification of unstable, water‐soluble secologanic acid using centrifugal partition chromatography

Metabolism-mediated drug interaction potential of HS-23, a new herbal drug for the treatment of sepsis in human hepatocytes and liver microsomes

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