List of Publications (2011-Current)
2025
Jeon, Hyejin; Seo, Yohan; Lee, Wook-Joo; Heo, Yunkyung; Shim, Won-Sik; Namkung, Wan
Blockade of PAR2 Signaling by Punicalagin as a Therapeutic Strategy for Atopic Dermatitis Journal Article
In: IJMS, vol. 26, no. 18, 2025, ISSN: 1422-0067.
Abstract | Links | BibTeX | Tags: Atopic dermatitis, PAR2, TSLP
@article{Jeon2025,
title = {Blockade of PAR2 Signaling by Punicalagin as a Therapeutic Strategy for Atopic Dermatitis},
author = {Hyejin Jeon and Yohan Seo and Wook-Joo Lee and Yunkyung Heo and Won-Sik Shim and Wan Namkung},
doi = {10.3390/ijms26188920},
issn = {1422-0067},
year = {2025},
date = {2025-09-00},
urldate = {2025-09-00},
journal = {IJMS},
volume = {26},
number = {18},
publisher = {MDPI AG},
abstract = {<jats:p>Atopic dermatitis is a chronic inflammatory skin disorder characterized by persistent inflammation and severe pruritus. Current anti-inflammatory agents carry risks of long-term adverse effects, while antihistamines provide limited relief of pruritus. Protease-activated receptor 2 (PAR2) has emerged as a critical mediator of both inflammation and pruritus, representing a promising therapeutic target. In this study, we investigated the therapeutic potential of punicalagin (PCG), a potent PAR2 antagonist, in atopic dermatitis. PCG fully and potently inhibited trypsin-induced PAR2 activation in HaCaT cells with an IC50 of 1.30 µM, exhibiting over 40-fold greater selectivity over PAR1. PCG significantly inhibited PAR2-induced phosphorylation of ERK1/2 and NF-κB in both HaCaT and human dermal fibroblast cells and reduced IL-8 secretion in HaCaT cells. In addition, PCG did not significantly affect other pruritus-related GPCRs including H1R, H4R, TGR5, 5HT2A, 5HT2B, and MRGPRX2 at 30 µM. Notably, PCG strongly blocked PAR2-AP-induced scratching in mice. In addition, PCG improved skin lesions, reduced dermatitis severity scores, and alleviated scratching behavior in a DNFB-induced atopic dermatitis model. These effects were associated with reduced epidermal thickness, decreased serum TSLP levels, and inhibition of PAR2-dependent calcium signaling in dorsal root ganglion neurons. These findings demonstrate that PCG is a selective PAR2 antagonist that effectively alleviates both inflammatory and pruritic symptoms of atopic dermatitis, suggesting its potential as a novel therapeutic agent.</jats:p>},
keywords = {Atopic dermatitis, PAR2, TSLP},
pubstate = {published},
tppubtype = {article}
}
<jats:p>Atopic dermatitis is a chronic inflammatory skin disorder characterized by persistent inflammation and severe pruritus. Current anti-inflammatory agents carry risks of long-term adverse effects, while antihistamines provide limited relief of pruritus. Protease-activated receptor 2 (PAR2) has emerged as a critical mediator of both inflammation and pruritus, representing a promising therapeutic target. In this study, we investigated the therapeutic potential of punicalagin (PCG), a potent PAR2 antagonist, in atopic dermatitis. PCG fully and potently inhibited trypsin-induced PAR2 activation in HaCaT cells with an IC50 of 1.30 µM, exhibiting over 40-fold greater selectivity over PAR1. PCG significantly inhibited PAR2-induced phosphorylation of ERK1/2 and NF-κB in both HaCaT and human dermal fibroblast cells and reduced IL-8 secretion in HaCaT cells. In addition, PCG did not significantly affect other pruritus-related GPCRs including H1R, H4R, TGR5, 5HT2A, 5HT2B, and MRGPRX2 at 30 µM. Notably, PCG strongly blocked PAR2-AP-induced scratching in mice. In addition, PCG improved skin lesions, reduced dermatitis severity scores, and alleviated scratching behavior in a DNFB-induced atopic dermatitis model. These effects were associated with reduced epidermal thickness, decreased serum TSLP levels, and inhibition of PAR2-dependent calcium signaling in dorsal root ganglion neurons. These findings demonstrate that PCG is a selective PAR2 antagonist that effectively alleviates both inflammatory and pruritic symptoms of atopic dermatitis, suggesting its potential as a novel therapeutic agent.</jats:p>
2024
Cha, Jieun; Ryu, Juhee; Rawal, Diwas; Lee, Wook-Joo; Shim, Won-Sik
Antipruritic effect of ursolic acid through MRGPRX2/MrgprB2-dependent inhibition of mast cell degranulation and reduced TSLP production Journal Article
In: European Journal of Pharmacology, vol. 981, 2024, ISSN: 0014-2999.
Links | BibTeX | Tags: Mast cell, MrgprB2, MRGPRX2, TSLP, Ursolic acid
@article{Cha2024,
title = {Antipruritic effect of ursolic acid through MRGPRX2/MrgprB2-dependent inhibition of mast cell degranulation and reduced TSLP production},
author = {Jieun Cha and Juhee Ryu and Diwas Rawal and Wook-Joo Lee and Won-Sik Shim},
doi = {10.1016/j.ejphar.2024.176896},
issn = {0014-2999},
year = {2024},
date = {2024-10-00},
urldate = {2024-10-00},
journal = {European Journal of Pharmacology},
volume = {981},
publisher = {Elsevier BV},
keywords = {Mast cell, MrgprB2, MRGPRX2, TSLP, Ursolic acid},
pubstate = {published},
tppubtype = {article}
}
Kim, Ji Young Um Han Bi Kim Won‐Sik Shim Wook Joo Lee So Yeon Lee Jin Seo Park Jin Cheol Kim In Suk Kwak Bo Young Chung Chun Wook Park Hye One
In: Clin Experimental Allergy, vol. 54, no. 2, pp. 152–155, 2024, ISSN: 1365-2222.
Links | BibTeX | Tags: Itch, Keratinocytes, TRPV3, TSLP
@article{Um2023,
title = {The transient receptor potential vanilloid‐3 (TRPV3) channel in epidermal keratinocytes induce thymic interstitial lymphopoietin: Implications for TRPV3‐mediated itch pathways},
author = {Ji Young Um
Han Bi Kim
Won‐Sik Shim
Wook Joo Lee
So Yeon Lee
Jin Seo Park
Jin Cheol Kim
In Suk Kwak
Bo Young Chung
Chun Wook Park
Hye One Kim},
doi = {10.1111/cea.14426},
issn = {1365-2222},
year = {2024},
date = {2024-02-00},
urldate = {2024-02-00},
journal = {Clin Experimental Allergy},
volume = {54},
number = {2},
pages = {152--155},
publisher = {Wiley},
keywords = {Itch, Keratinocytes, TRPV3, TSLP},
pubstate = {published},
tppubtype = {article}
}
2021
Lee, Wook-Joo; Shim, Won-Sik
Cutaneous Neuroimmune Interactions of TSLP and TRPV4 Play Pivotal Roles in Dry Skin-Induced Pruritus Journal Article
In: Front. Immunol., vol. 12, 2021, ISSN: 1664-3224.
Abstract | Links | BibTeX | Tags: Calcium imaging, Dorsal root ganglia, Dry skin, Itch, TSLP
@article{Lee2021,
title = {Cutaneous Neuroimmune Interactions of TSLP and TRPV4 Play Pivotal Roles in Dry Skin-Induced Pruritus},
author = {Wook-Joo Lee and Won-Sik Shim},
doi = {10.3389/fimmu.2021.772941},
issn = {1664-3224},
year = {2021},
date = {2021-12-02},
urldate = {2021-12-02},
journal = {Front. Immunol.},
volume = {12},
publisher = {Frontiers Media SA},
abstract = {<jats:p>Dry skin is a symptom of skin barrier dysfunction that evokes pruritus; however, the cutaneous neuroimmune interactions underlying dry skin-induced pruritus remain unclear. Therefore, we aimed to elucidate the mechanisms underlying dry skin-induced pruritus. To this end, an acetone/ethanol/water (AEW)-induced mouse model of dry skin was used in this study. We observed that the production of thymic stromal lymphopoietin (TSLP) significantly increased in the keratinocytes of AEW mice. Importantly, treatment with an antagonist of transient receptor potential cation channel subfamily V member 4 (TRPV4), HC067047, ameliorated dry skin conditions in AEW mice. The symptoms of dry skin were significantly reduced in <jats:italic>Trpv4</jats:italic> knockout (KO) mice following treatment with AEW. The increase in the intracellular calcium levels by TSLP in the dorsal root ganglia (DRG) of <jats:italic>Trpv4</jats:italic> KO mice was also significantly attenuated. The spontaneous scratching bouts were significantly decreased in both the HC067047-treated and <jats:italic>Trpv4</jats:italic> KO AEW mice. Importantly, the TSLP-dependent release of tryptase from the mast cells was significantly reduced in both the HC067047-treated mice and <jats:italic>Trpv4</jats:italic> KO AEW mice. Notably, inhibition of the TSLP-induced signaling pathway in DRG selectively reduced the spontaneous scratching bouts in AEW mice. Overall, the results demonstrated that the cutaneous neuroimmune interactions of TSLP and TRPV4 play pivotal roles in dry skin-induced pruritus.</jats:p>},
keywords = {Calcium imaging, Dorsal root ganglia, Dry skin, Itch, TSLP},
pubstate = {published},
tppubtype = {article}
}
<jats:p>Dry skin is a symptom of skin barrier dysfunction that evokes pruritus; however, the cutaneous neuroimmune interactions underlying dry skin-induced pruritus remain unclear. Therefore, we aimed to elucidate the mechanisms underlying dry skin-induced pruritus. To this end, an acetone/ethanol/water (AEW)-induced mouse model of dry skin was used in this study. We observed that the production of thymic stromal lymphopoietin (TSLP) significantly increased in the keratinocytes of AEW mice. Importantly, treatment with an antagonist of transient receptor potential cation channel subfamily V member 4 (TRPV4), HC067047, ameliorated dry skin conditions in AEW mice. The symptoms of dry skin were significantly reduced in <jats:italic>Trpv4</jats:italic> knockout (KO) mice following treatment with AEW. The increase in the intracellular calcium levels by TSLP in the dorsal root ganglia (DRG) of <jats:italic>Trpv4</jats:italic> KO mice was also significantly attenuated. The spontaneous scratching bouts were significantly decreased in both the HC067047-treated and <jats:italic>Trpv4</jats:italic> KO AEW mice. Importantly, the TSLP-dependent release of tryptase from the mast cells was significantly reduced in both the HC067047-treated mice and <jats:italic>Trpv4</jats:italic> KO AEW mice. Notably, inhibition of the TSLP-induced signaling pathway in DRG selectively reduced the spontaneous scratching bouts in AEW mice. Overall, the results demonstrated that the cutaneous neuroimmune interactions of TSLP and TRPV4 play pivotal roles in dry skin-induced pruritus.</jats:p>
Kim, J; Kim, H; Shim, W; Kwak, I; Chung, B; Kang, S; Park, C; Kim, H
Activation of Transient Receptor Potential Vanilloid-3 Channels in Keratinocytes Induces Pruritus in Humans Journal Article
In: Acta Derm Venereol, vol. 101, no. 8, 2021, ISSN: 1651-2057.
Abstract | Links | BibTeX | Tags: Itch, TRPV3, TSLP
@article{Kim2021,
title = {Activation of Transient Receptor Potential Vanilloid-3 Channels in Keratinocytes Induces Pruritus in Humans},
author = {J Kim and H Kim and W Shim and I Kwak and B Chung and S Kang and C Park and H Kim},
doi = {10.2340/00015555-3855},
issn = {1651-2057},
year = {2021},
date = {2021-08-00},
urldate = {2021-08-00},
journal = {Acta Derm Venereol},
volume = {101},
number = {8},
publisher = {Medical Journals Sweden AB},
abstract = {Carvacrol, a natural transient receptor potential vanilloid-3 activator, has been reported to cause pruritus in mice. This study aimed to evaluate the effects of carvacrol and various antipruritic agents in humans. A stimulation test with carvacrol, β-alanine, and histamine was performed. After application of the pruritic solutions, the skin was stimulated with pinpricks. In inhibition test A, Forsythia suspensa extract, containing forsythoside B (a transient receptor potential vanilloid-3 inhibitor), was applied by pricking prior to stimulation with pruritogens. In inhibition test B, olopatadine solution, tacrolimus ointment, and Scutellaria baicalensis root extract were applied, and carvacrol was applied to the same region. Carvacrol induces moderate pruritus in humans. The pruritus was relieved by Forsythia suspensa extract and olopatadine solution after 20 min of application and by tacrolimus ointment and Scutellaria baicalenis extract after 24 h of application. These results suggest that carvacrol is a pruritogen in humans, and that carvacrol-induced pruritus is inhibited by various antipruritic agents.},
keywords = {Itch, TRPV3, TSLP},
pubstate = {published},
tppubtype = {article}
}
Carvacrol, a natural transient receptor potential vanilloid-3 activator, has been reported to cause pruritus in mice. This study aimed to evaluate the effects of carvacrol and various antipruritic agents in humans. A stimulation test with carvacrol, β-alanine, and histamine was performed. After application of the pruritic solutions, the skin was stimulated with pinpricks. In inhibition test A, Forsythia suspensa extract, containing forsythoside B (a transient receptor potential vanilloid-3 inhibitor), was applied by pricking prior to stimulation with pruritogens. In inhibition test B, olopatadine solution, tacrolimus ointment, and Scutellaria baicalensis root extract were applied, and carvacrol was applied to the same region. Carvacrol induces moderate pruritus in humans. The pruritus was relieved by Forsythia suspensa extract and olopatadine solution after 20 min of application and by tacrolimus ointment and Scutellaria baicalenis extract after 24 h of application. These results suggest that carvacrol is a pruritogen in humans, and that carvacrol-induced pruritus is inhibited by various antipruritic agents.
2019
Kim, Bo Hyun; Lee, Wook-Joo; Sanjel, Babina; Cho, Kyohee; Son, Youn Kyoung; Park, Hye Yoon; Kim, Sun Yeou; Shim, Won-Sik
Extracts of the leaves of Pyrus ussuriensis Maxim. Alleviate itch sensation via TSLP-dependent manner in mouse models of atopic dermatitis Journal Article
In: Physiology & Behavior, vol. 210, 2019, ISSN: 0031-9384.
Abstract | Links | BibTeX | Tags: Animal model, Atopic dermatitis, Calcium imaging, Itch, Scratching behavior, TSLP
@article{Kim2019,
title = {Extracts of the leaves of Pyrus ussuriensis Maxim. Alleviate itch sensation via TSLP-dependent manner in mouse models of atopic dermatitis},
author = {Bo Hyun Kim and Wook-Joo Lee and Babina Sanjel and Kyohee Cho and Youn Kyoung Son and Hye Yoon Park and Sun Yeou Kim and Won-Sik Shim},
doi = {10.1016/j.physbeh.2019.112624},
issn = {0031-9384},
year = {2019},
date = {2019-10-00},
urldate = {2019-10-00},
journal = {Physiology & Behavior},
volume = {210},
publisher = {Elsevier BV},
abstract = {Pyrus ussuriensis Maxim. commonly known as “Sandolbae” in Korean is a pear tree widely distributed across East Asia. Recent studies indicate that P. ussuriensis Maxim. leaves (PUL) have antipruritic effects. This study aimed to determine the effects of PUL extract and its fractions in decreasing the itch sensation and skin lesions in two distinct animal models of atopic dermatitis (AD) induced by dinitrofluorobenzene (DNFB) or house dust mite(HDM). Our results showed that the total ethanol extract of PUL decreased the scratching behavior in mice withDNFB- and HDM-induced AD. Moreover, the ethyl acetate fraction of PUL significantly improved the overallcondition of the mice with AD induced by HDM. Further, we used HEK293T cells that express receptors and ion channels for thymic stromal lymphopoietin (TSLP), a potent pruritogen for AD, to determine the mechanismsunderlying the antipruritic effects of PUL extract/fractions. Specific subfractions of the PUL strongly inhibited the increase in calcium levels induced by TSLP. In addition, the specific subfraction of PUL inhibited the TSLP-induced increase in calcium levels in cultured mouse dorsal root ganglia neurons. Thus, our results showed thatthe PUL extract could be effective for alleviating pruritus, and the antipruritic effects were exerted probably viathe inhibition of the TSLP pathway in peripheral sensory neurons governing the itch sensation in AD.},
keywords = {Animal model, Atopic dermatitis, Calcium imaging, Itch, Scratching behavior, TSLP},
pubstate = {published},
tppubtype = {article}
}
Pyrus ussuriensis Maxim. commonly known as “Sandolbae” in Korean is a pear tree widely distributed across East Asia. Recent studies indicate that P. ussuriensis Maxim. leaves (PUL) have antipruritic effects. This study aimed to determine the effects of PUL extract and its fractions in decreasing the itch sensation and skin lesions in two distinct animal models of atopic dermatitis (AD) induced by dinitrofluorobenzene (DNFB) or house dust mite(HDM). Our results showed that the total ethanol extract of PUL decreased the scratching behavior in mice withDNFB- and HDM-induced AD. Moreover, the ethyl acetate fraction of PUL significantly improved the overallcondition of the mice with AD induced by HDM. Further, we used HEK293T cells that express receptors and ion channels for thymic stromal lymphopoietin (TSLP), a potent pruritogen for AD, to determine the mechanismsunderlying the antipruritic effects of PUL extract/fractions. Specific subfractions of the PUL strongly inhibited the increase in calcium levels induced by TSLP. In addition, the specific subfraction of PUL inhibited the TSLP-induced increase in calcium levels in cultured mouse dorsal root ganglia neurons. Thus, our results showed thatthe PUL extract could be effective for alleviating pruritus, and the antipruritic effects were exerted probably viathe inhibition of the TSLP pathway in peripheral sensory neurons governing the itch sensation in AD.