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

Park, Sun Hong; Baek, Seung-Il; Yun, Jieun; Lee, Seungmin; Yoon, Da Young; Jung, Jae‐Kyung; Jung, Sang‐Hun; Hwang, Bang Yeon; Hong, Jin Tae; Han, Sang‐Bae; Kim, Youngsoo

doi:10.4049/jimmunol.1402101

Cited by 43 publications

(21 citation statements)

References 36 publications

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“…In an experimental model of osteoarthritis in rats and human chondrocytes, chlorogenic acid inhibited the COX-2/PGE 2 expression via the p65 NF-kB and I-kBɑ pathways (Lee et al, 2018;Liu et al, 2017). In neutrophils, in a similar model of inflammation as the described in this study, chlorogenic acid decreased the LPS-induced shock by interruption of MyD88-dependent early cascade triggered via TLRs (Park et al, 2015).…”

Section: Discussionsupporting

confidence: 62%

Clinopodium vulgare L. (wild basil) extract and its active constituents modulate cyclooxygenase-2 expression in neutrophils

Amirova

Dimitrova

Marchev

et al. 2019

Food and Chemical Toxicology

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Clinopodium vulgare L. (wild basil) has a wide range of ethnopharmacological applications and accumulates a broad spectrum of phenolic compounds, recognized for their anti-inflammatory and anticancer properties. The triggered cyclooxygenase-2 (COX-2) expression is creating an immunosuppressive microenvironment in the inflamed tissue and considered to be the main cause of failure of even new anticancer-/immune-therapies. Nowadays, selective and novel plant-derived COX-2 inhibitors with safe profile are subject of profound research interest. This study aimed to analyze the metabolic profile of C. vulgare and search for phenolic molecules with potential biological properties. By application of 1 H and 2D-NMR (Nuclear Magnetic Resonance) profiling, caffeic, chlorogenic acids and catechin were identified along with a bunch of primary and secondary metabolites. Further, the biological effect of C. vulgare extract (CVE) and its constituents on zymosan-induced COX-2 expression and apoptosis of murine neutrophils have been studied. The CVE, caffeic and chlorogenic acids inhibited zymosan-induced COX-2 expression in bone marrow neutrophils, in vitro and in vivo activated. The obtained data indicate that CVE may have a good potential to manipulate neutrophil functions, however, its action may depend on the cellular state, the inflammatory milieu and the relative content of caffeic and chlorogenic acid in the extract.

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Section: Discussionsupporting

confidence: 62%

Clinopodium vulgare L. (wild basil) extract and its active constituents modulate cyclooxygenase-2 expression in neutrophils

Amirova

Dimitrova

Marchev

et al. 2019

Food and Chemical Toxicology

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“…Chlorogenic acid (CGA) ( Figure 2 ) is a major component of lonicerae flos extract. Intravenous administration of CGA protected C57BL/6 mice from septic shock after intraperitoneal LPS challenge [ 97 ]. At the dosage 3 mg/kg (CGA), the survival rate was increased up to 70%.…”

Section: Tlr4 Antagonists From Natural Sourcesmentioning

confidence: 99%

TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis

et al. 2017

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Toll-Like Receptor 4 (TLR4) signal pathway plays an important role in initiating the innate immune response and its activation by bacterial endotoxin is responsible for chronic and acute inflammatory disorders that are becoming more and more frequent in developed countries. Modulation of the TLR4 pathway is a potential strategy to specifically target these pathologies. Among the diseases caused by TLR4 abnormal activation by bacterial endotoxin, sepsis is the most dangerous one because it is a life-threatening acute system inflammatory condition that still lacks specific pharmacological treatment. Here, we review molecules at a preclinical or clinical phase of development, that are active in inhibiting the TLR4-MyD88 and TLR4-TRIF pathways in animal models. These are low-molecular weight compounds of natural and synthetic origin that can be considered leads for drug development. The results of in vivo studies in the sepsis model and the mechanisms of action of drug leads are presented and critically discussed, evidencing the differences in treatment results from rodents to humans.

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“… 28 , 29 LPS/GalN-challenged mice with ALF stimulate the phosphorylation of NF-κB p65, c-Jun or IRF3 in the liver. 30 CpG ODN/GalN-injected mice with ALF also markedly increased phosphor (p)-NF-κB p65 or p-c-Fos levels in the liver, while CpG ODN-, GalN- or PMOC alone-injected mice did not show any activation of the transcription factors ( Supplementary Figure S2a ). C57BL/6J mice were intoxicated with LPS/GalN or CpG ODN/GalN (i.p.)…”

Section: Resultsmentioning

confidence: 97%

Piperidylmethyloxychalcone improves immune-mediated acute liver failure via inhibiting TAK1 activity

et al. 2017

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Mice deficient in the toll-like receptor (TLR) or the myeloid differentiation factor 88 (MyD88) are resistant to acute liver failure (ALF) with sudden death of hepatocytes. Chalcone derivatives from medicinal plants protect from hepatic damages including ALF, but their mechanisms remain to be clarified. Here, we focused on molecular basis of piperidylmethyloxychalcone (PMOC) in the treatment of TLR/MyD88-associated ALF. C57BL/6J mice were sensitized with D-galactosamine (GalN) and challenged with Escherichia coli lipopolysaccharide (LPS, TLR4 agonist) or oligodeoxynucleotide containing unmethylated CpG motif (CpG ODN, TLR9 agonist) for induction of ALF. Post treatment with PMOC sequentially ameliorated hepatic inflammation, apoptosis of hepatocytes, severe liver injury and shock-mediated death in ALF-induced mice. As a mechanism, PMOC inhibited the catalytic activity of TGF-β-activated kinase 1 (TAK1) in a competitive manner with respect to ATP, displaced fluorescent ATP probe from the complex with TAK1, and docked at the ATP-binding active site on the crystal structure of TAK1. Moreover, PMOC inhibited TAK1 auto-phosphorylation, which is an axis in the activating pathways of nuclear factor-κB (NF-κB) or activating protein 1 (AP1), in the liver with ALF in vivo or in primary liver cells stimulated with TLR agonists in vitro. PMOC consequently suppressed TAK1-inducible NF-κB or AP1 activity in the inflammatory injury, an early pathogenesis leading to ALF. The results suggested that PMOC could contribute to the treatment of TLR/MyD88-associated ALF with the ATP-binding site of TAK1 as a potential therapeutic target.

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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

Cited by 43 publications

References 36 publications

Clinopodium vulgare L. (wild basil) extract and its active constituents modulate cyclooxygenase-2 expression in neutrophils

Clinopodium vulgare L. (wild basil) extract and its active constituents modulate cyclooxygenase-2 expression in neutrophils

TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis

Piperidylmethyloxychalcone improves immune-mediated acute liver failure via inhibiting TAK1 activity

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