Impact on Inflammation and Recovery of Skin Barrier by Nordihydroguaiaretic Acid as a Protease-Activated Receptor 2 Antagonist

Kim, Hyo Young; Goo, Jung Hyun; Joo, Yeon Ah; Lee, Ha Yoen; Lee, Se Mi; Oh, Chang Taek; Ahn, Soo Mi; Kim, Nam Hoon; Hwang, Jae Sung

doi:10.4062/biomolther.2012.20.5.463

Cited by 13 publications

(10 citation statements)

References 23 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PAR2 activation regulates terminal differentiation of keratinocytes and persistent PAR2 activation might cause abnormal differentiation (Derian et al ., 1997; Kim et al ., 2012). We investigated whether lobaric acid antagonizes these changes in protein expression induced by PAR2 activation of HaCaT keratinocytes and NHEKs.…”

Section: Resultsmentioning

confidence: 99%

Skin Barrier Recovery by Protease-Activated Receptor-2 Antagonist Lobaric Acid

Joo

Chung

Yoon

et al. 2016

Biomol Ther (Seoul)

View full text Add to dashboard Cite

Atopic dermatitis (AD) results from gene and environment interactions that lead to a range of immunological abnormalities and breakdown of the skin barrier. Protease-activated receptor 2 (PAR2) belongs to a family of G-protein coupled receptors and is expressed in suprabasal layers of the epidermis. PAR2 is activated by both trypsin and a specific agonist peptide, SLIGKV-NH2 and is involved in both epidermal permeability barrier homeostasis and epithelial inflammation. In this study, we investigated the effect of lobaric acid on inflammation, keratinocyte differentiation, and recovery of the skin barrier in hairless mice. Lobaric acid blocked trypsin-induced and SLIGKV-NH2-induced PAR2 activation resulting in decreased mobilization of intracellular Ca2+ in HaCaT keratinocytes. Lobaric acid reduced expression of interleukin-8 induced by SLIGKV-NH2 and thymus and activation regulated chemokine (TARC) induced by tumor necrosis factor-a (TNF-α) and IFN-γ in HaCaT keratinocytes. Lobaric acid also blocked SLIGKV-NH2-induced activation of ERK, which is a downstream signal of PAR2 in normal human keratinocytes (NHEKs). Treatment with SLIGKV-NH2 downregulated expression of involucrin, a differentiation marker protein in HaCaT keratinocytes, and upregulated expression of involucrin, transglutamase1 and filaggrin in NHEKs. However, lobaric acid antagonized the effect of SLIGKV-NH2 in HaCaT keratinocytes and NHEKs. Topical application of lobaric acid accelerated barrier recovery kinetics in a SKH-1 hairless mouse model. These results suggested that lobaric acid is a PAR2 antagonist and could be a possible therapeutic agent for atopic dermatitis.

show abstract

Section: Resultsmentioning

confidence: 99%

Skin Barrier Recovery by Protease-Activated Receptor-2 Antagonist Lobaric Acid

Joo

Chung

Yoon

et al. 2016

Biomol Ther (Seoul)

View full text Add to dashboard Cite

show abstract

“…Targeting PAR‐2 ameliorated pathologic changes in inflammatory colon and joint diseases . Moreover, PAR‐2 inhibition attenuated the severity of experimental biliary pancreatitis and blocked PAR2‐mediated inflammatory signaling pathways in atopic dermatitis . Additionally, PAR‐2 inhibition by FSLLRY‐NH2 reduced the number of fully muscularized vessels and reversed established pulmonary hypertension in a hypoxia mouse model .…”

Section: Targeting Pars In Fibrotic Diseasesmentioning

confidence: 98%

Targeting coagulation factor receptors – protease‐activated receptors in idiopathic pulmonary fibrosis

Lin

Borensztajn

Spek

2017

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with a 5-year mortality rate of > 50% and unknown etiology. Treatment options remain limited and, currently, only two drugs are available, i.e. nintedanib and pirfenidone. However, both of these antifibrotic agents only slow down the progression of the disease, and do not remarkably prolong the survival of IPF patients. Hence, the discovery of new therapeutic targets for IPF is crucial. Studies exploring the mechanisms that are involved in IPF have identified several possible targets for therapeutic interventions. Among these, blood coagulation factor receptors, i.e. protease-activated receptors (PARs), are key candidates, as these receptors mediate the cellular effects of coagulation factors and play central roles in influencing inflammatory and fibrotic responses. In this review, we will focus on the controversial role of the coagulation cascade in the pathogenesis of IPF. In the light of novel data, we will attempt to reconciliate the apparently conflicting data and discuss the possibility of pharmacologic targeting of PARs for the treatment of fibroproliferative diseases.

show abstract

“…12,13 Nordihydroguaiaretic acid (NDGA, 23, Figure 6) was recently reported as a PAR2 selective antagonist, inhibiting PAR2-induced calcium release, production of IL-8, and intercellular cell adhesion molecule 1 in HaCat keratinocytes. 197 It showed some anti-inflammatory activity, attenuating oxazoloneinduced chronic dermatitis symptoms in hairless mice model. 197 Unfortunately, the effective concentrations of this compound in cell-based assays and animal models were not reported.…”

Section: ■ Par2 Antagonistsmentioning

confidence: 99%

“…197 It showed some anti-inflammatory activity, attenuating oxazoloneinduced chronic dermatitis symptoms in hairless mice model. 197 Unfortunately, the effective concentrations of this compound in cell-based assays and animal models were not reported. NPS-1557 (structure not disclosed) was also reported to have anti-inflammatory activity in oxazolone-induced chronic dermatitis mice model but inhibited calcium mobilization in HCT-15 .…”

Section: ■ Par2 Antagonistsmentioning

confidence: 99%

“…3.3D), and it was found to be 5-fold less potent than the reported PAR2 agonist (2f-LIGRLO-NH 2 ). In addition, compounds containing electron-withdrawing groups on the benzyl ring, such as chloro, nitro, trifluoromethyl and trifluoromethoxy (197)(198)(199)(200), were not antagonists as all displayed agonist responses up to 40% at 10 µM. It was important that all potential antagonists were assessed for agonist activity to eliminate the possibility of the observed antagonist activity (i.e.…”

Section: Truncation Of Gb110 and Incorporation Of Various Benzylaminesmentioning

confidence: 99%

See 1 more Smart Citation

Novel agonists & antagonists for protease-activated receptor 2 and C3a receptor

Yau¹

View full text Add to dashboard Cite

About 30-40% of all drugs currently in the market place target G-protein coupled receptors, however of the 900 plus GPCRs predicted to exist only about 30 are targeted by approved drugs. Two novel human GPCRs were investigated in this thesis, namely protease-activated receptor 2 (PAR2) and C3a receptor (C3aR). These membranebound receptors are implicated in a variety of diseases in which inflammation is a common component, making them attractive targets for drugs that can treat such disorders. This thesis describes the rational design, synthesis and in vitro assay of ligands targeting these two GPCRs and they will become useful probes for investigating the pathology of inflammatory disorders and may lead to possible future treatments.Chapter 1 of this thesis summarises peptidic and non-peptidic ligands for proteaseactivated receptor and C3a receptor reported in the literature to date, together with their known physiological effects.Chapter 2 examines structure-activity relationships for analogues of the only known potent PAR2 antagonist (GB88) discovered at IMB. The chemical features of GB88 were investigated separately by dividing the molecule into fragments, which were independently varied to study the effect of structure on agonist/antagonist function of the ligands. A potent and selective PAR2 agonist (132) was developed with EC 50 of 0.4 µM in calcium release assays on HT29 cells. Agonist 132 has comparable agonist potency and better ligand efficiency to 2f-LIGRLO-NH 2 , which was previously the most potent PAR2 agonist prior to these studies. In addition, a new PAR2 antagonist was developed (167), which was 2-fold more potent than GB88 in the calcium mobilisation assay.Chapter 3 describes the non-peptidic PAR2 agonist (GB110) and SAR studies for the truncation of this compound that led to the development of new PAR2 antagonists (192, 209, 211, 212). These ligands inhibited the activation of PAR2 induced by 1 µM 2f-LIGRLO-NH 2 with IC 50 0.4-0.6 µM in the calcium release assay.Chapter 4 evaluates the anti-inflammatory properties of newly developed PAR2antagonists (133, 159, 167, 192 -from Chapters 2 & 3) in both in vivo and in vitro experiments. The most potent PAR2 antagonists (167 and 192) were stable in rat plasma and rat liver homogenates and were able to inhibit PAR2 activation induced by peptide agonist 2f-LIGRLO-NH 2 as well as the endogenous activator, trypsin. These iv antagonists have been demonstrated to be anti-inflammatory agents, inhibiting proinflammatory cytokine release (IL6 and TNF-α) and were effective in relieving joint inflammation in rat models of arthritis.Chapter 5 explores various aromatic heterocycles that confer a turn conformation to ligands and this mimics the turn conformation observed for the C-terminus of C3a in its crystal structure. The study investigates how the hydrogen bonding capabilities of heteroatoms in each heterocycle affect the binding and functions of the ligands.Increasing the hydrogen bond acceptor properties of the heterocycle improves binding affinity...

show abstract

Impact on Inflammation and Recovery of Skin Barrier by Nordihydroguaiaretic Acid as a Protease-Activated Receptor 2 Antagonist

Cited by 13 publications

References 23 publications

Skin Barrier Recovery by Protease-Activated Receptor-2 Antagonist Lobaric Acid

Skin Barrier Recovery by Protease-Activated Receptor-2 Antagonist Lobaric Acid

Targeting coagulation factor receptors – protease‐activated receptors in idiopathic pulmonary fibrosis

Novel agonists & antagonists for protease-activated receptor 2 and C3a receptor

Contact Info

Product

Resources

About