List of Publications (2011-Current)
2026
Seo, Kyoung Hee; Jang, Bo Ko; Yeon, Seul Ki; Kim, Hyeon Ji; Lee, Ye Rim; Seo, Ran; Lee, Wok-Joo; Kim, Yoowon; Lee, Elijah Hwejin; Lee, Dong-Gi; Lee, Han-Seung; Park, Jong-Hyun; Shim, Won-Sik; Lee, Jong-Seung; Choi, Ji Won; Park, Ki Duk
In: J. Med. Chem., vol. 69, no. 2, pp. 1154–1177, 2026, ISSN: 1520-4804.
Abstract | Links | BibTeX | Tags: Atopic dermatitis, TSLP
@article{Seo2025,
title = {Synthetic Strategy and Evaluation of the Benzyloxy Benzylamide Derivatives as Thymic Stromal Lymphopoietin Modulators for the Treatment of Atopic Dermatitis},
author = {Kyoung Hee Seo and Bo Ko Jang and Seul Ki Yeon and Hyeon Ji Kim and Ye Rim Lee and Ran Seo and Wok-Joo Lee and Yoowon Kim and Elijah Hwejin Lee and Dong-Gi Lee and Han-Seung Lee and Jong-Hyun Park and Won-Sik Shim and Jong-Seung Lee and Ji Won Choi and Ki Duk Park},
doi = {10.1021/acs.jmedchem.5c02461},
issn = {1520-4804},
year = {2026},
date = {2026-01-22},
urldate = {2026-01-22},
journal = {J. Med. Chem.},
volume = {69},
number = {2},
pages = {1154--1177},
publisher = {American Chemical Society (ACS)},
abstract = {Atopic dermatitis (AD) is a chronic inflammatory skin disease driven by immune dysregulation, in which thymic stromal lymphopoietin (TSLP) plays a critical role by triggering type 2 inflammation and exacerbating disease progression. In this study, a screening of our in-house library for inhibition of CCL17 mRNA expression led to identification of hit compound 6a. Based on this scaffold, benzyloxy benzylamide derivatives were systematically designed and synthesized, followed by the evaluation of their anti-inflammatory potential. Among them, compound 14o exhibited the most potent inhibition of CCL17 and IL-1B mRNA expression in HaCaT keratinocytes, along with favorable drug-like properties. 14o interfered with TSLP receptor dimerization and suppressed the TSLP-induced signal transducer and activator of transcription 5 phosphorylation. Furthermore, 14o significantly attenuated TSLP-induced calcium influx and effectively alleviated pruritus and AD-like symptoms in a house dust mite (HDM)-induced AD mouse model. Collectively, these findings highlight 14o as a promising topical therapeutic candidate targeting TSLP signaling for the treatment of AD.},
keywords = {Atopic dermatitis, TSLP},
pubstate = {published},
tppubtype = {article}
}
Atopic dermatitis (AD) is a chronic inflammatory skin disease driven by immune dysregulation, in which thymic stromal lymphopoietin (TSLP) plays a critical role by triggering type 2 inflammation and exacerbating disease progression. In this study, a screening of our in-house library for inhibition of CCL17 mRNA expression led to identification of hit compound 6a. Based on this scaffold, benzyloxy benzylamide derivatives were systematically designed and synthesized, followed by the evaluation of their anti-inflammatory potential. Among them, compound 14o exhibited the most potent inhibition of CCL17 and IL-1B mRNA expression in HaCaT keratinocytes, along with favorable drug-like properties. 14o interfered with TSLP receptor dimerization and suppressed the TSLP-induced signal transducer and activator of transcription 5 phosphorylation. Furthermore, 14o significantly attenuated TSLP-induced calcium influx and effectively alleviated pruritus and AD-like symptoms in a house dust mite (HDM)-induced AD mouse model. Collectively, these findings highlight 14o as a promising topical therapeutic candidate targeting TSLP signaling for the treatment of AD.
Kim, Yejoon; Choi, Junhyeok; Kim, Minjun; Rawal, Diwas; Lee, Wook-Joo; Shim, Won-Sik
Vitexin alleviates atopic dermatitis–associated itch via TRPV4 inhibition in sensory neurons and MRGPRX2/MrgprB2 blockade in mast cells Journal Article
In: International Immunopharmacology, vol. 168, 2026, ISSN: 1567-5769.
Abstract | Links | BibTeX | Tags: Atopic dermatitis, Itch, Mast cell, MrgprB2, MRGPRX2, Sensory neurons, TRPV4
@article{Kim2026,
title = {Vitexin alleviates atopic dermatitis–associated itch via TRPV4 inhibition in sensory neurons and MRGPRX2/MrgprB2 blockade in mast cells},
author = {Yejoon Kim and Junhyeok Choi and Minjun Kim and Diwas Rawal and Wook-Joo Lee and Won-Sik Shim},
doi = {10.1016/j.intimp.2025.115757},
issn = {1567-5769},
year = {2026},
date = {2026-01-00},
urldate = {2026-01-00},
journal = {International Immunopharmacology},
volume = {168},
publisher = {Elsevier BV},
abstract = {Chronic itch is a debilitating symptom in atopic dermatitis (AD), often resistant to current antipruritic therapies. Here, we demonstrate that vitexin (VTX) exerts antipruritic effects through modulation of neuronal and mast cell pathways. Calcium imaging in TRPV4-transfected HEK293T cells and primary mouse dorsal root ganglion neurons demonstrated that VTX substantially inhibited TRPV4-dependent calcium influx, reducing both peak responses and the proportion of agonist-responsive neurons. Parallel assays in HEK293T cells expressing human MRGPRX2 and murine MrgprB2 revealed dose-dependent suppression of compound 48/80-induced calcium signaling. Mast-cell degranulation assays indicated that VTX markedly decreased β-hexosaminidase release from primary mouse peritoneal mast cells and HMC1.2 cells upon compound 48/80 stimulation. In silico molecular docking analysis showed that VTX occupied overlapping binding regions with known agonists in TRPV4 and MRGPRX2/MrgprB2, suggesting direct receptor interactions. In an MC903-induced murine model of AD, VTX reduced scratching behavior, mast cell activation, and transcriptional upregulation of Trpv4 and MrgprB2. Notably, antipruritic effects were enhanced in Trpv4-deficient mice, indicating the contribution of MRGPRX2/MrgprB2 suppression. These findings identify VTX as a promising antipruritic candidate for AD-associated pruritus, and mechanistic insights provide a rationale for further exploration of VTX in advanced AD models and eventual translation to clinical therapies.},
keywords = {Atopic dermatitis, Itch, Mast cell, MrgprB2, MRGPRX2, Sensory neurons, TRPV4},
pubstate = {published},
tppubtype = {article}
}
Chronic itch is a debilitating symptom in atopic dermatitis (AD), often resistant to current antipruritic therapies. Here, we demonstrate that vitexin (VTX) exerts antipruritic effects through modulation of neuronal and mast cell pathways. Calcium imaging in TRPV4-transfected HEK293T cells and primary mouse dorsal root ganglion neurons demonstrated that VTX substantially inhibited TRPV4-dependent calcium influx, reducing both peak responses and the proportion of agonist-responsive neurons. Parallel assays in HEK293T cells expressing human MRGPRX2 and murine MrgprB2 revealed dose-dependent suppression of compound 48/80-induced calcium signaling. Mast-cell degranulation assays indicated that VTX markedly decreased β-hexosaminidase release from primary mouse peritoneal mast cells and HMC1.2 cells upon compound 48/80 stimulation. In silico molecular docking analysis showed that VTX occupied overlapping binding regions with known agonists in TRPV4 and MRGPRX2/MrgprB2, suggesting direct receptor interactions. In an MC903-induced murine model of AD, VTX reduced scratching behavior, mast cell activation, and transcriptional upregulation of Trpv4 and MrgprB2. Notably, antipruritic effects were enhanced in Trpv4-deficient mice, indicating the contribution of MRGPRX2/MrgprB2 suppression. These findings identify VTX as a promising antipruritic candidate for AD-associated pruritus, and mechanistic insights provide a rationale for further exploration of VTX in advanced AD models and eventual translation to clinical therapies.
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>
2022
Sanjel, Babina; Shim, Won-Sik
The contribution of mouse models to understanding atopic dermatitis Journal Article
In: Biochemical Pharmacology, vol. 203, 2022, ISSN: 0006-2952.
Abstract | Links | BibTeX | Tags: Animal model, Atopic dermatitis, Itch
@article{Sanjel2022,
title = {The contribution of mouse models to understanding atopic dermatitis},
author = {Babina Sanjel and Won-Sik Shim},
doi = {10.1016/j.bcp.2022.115177},
issn = {0006-2952},
year = {2022},
date = {2022-09-00},
urldate = {2022-09-00},
journal = {Biochemical Pharmacology},
volume = {203},
publisher = {Elsevier BV},
abstract = {Atopic dermatitis (AD) is a dermatological disease accompanied by dry and cracked skin with severe pruritus. Although various therapeutic strategies have been introduced to alleviate AD, it remains challenging to cure the disorder. To achieve such a goal, understanding the pathophysiological mechanisms of AD is a prerequisite, requiring mouse models that properly reflect the AD phenotypes. Currently, numerous AD mouse models have been established, but each model has its own advantages and weaknesses. In this review, we categorized and summarized mouse models of AD and described their characteristics from a researcher’s perspective.},
keywords = {Animal model, Atopic dermatitis, Itch},
pubstate = {published},
tppubtype = {article}
}
Atopic dermatitis (AD) is a dermatological disease accompanied by dry and cracked skin with severe pruritus. Although various therapeutic strategies have been introduced to alleviate AD, it remains challenging to cure the disorder. To achieve such a goal, understanding the pathophysiological mechanisms of AD is a prerequisite, requiring mouse models that properly reflect the AD phenotypes. Currently, numerous AD mouse models have been established, but each model has its own advantages and weaknesses. In this review, we categorized and summarized mouse models of AD and described their characteristics from a researcher’s perspective.
Sanjel, Babina; Kim, Bo‐Hyun; Song, Myung‐Hyun; Carstens, Earl; Shim, Won‐Sik
Glucosylsphingosine evokes pruritus via activation of 5‐HT2A receptor and TRPV4 in sensory neurons Journal Article
In: British J Pharmacology, vol. 179, no. 10, pp. 2193–2207, 2022, ISSN: 1476-5381.
Abstract | Links | BibTeX | Tags: 5-HT2R, Atopic dermatitis, Calcium imaging, Dorsal root ganglia, Glucosylsphingosine, TRPV4
@article{Sanjel2022b,
title = {Glucosylsphingosine evokes pruritus via activation of 5‐HT_{2A} receptor and TRPV4 in sensory neurons},
author = {Babina Sanjel and Bo‐Hyun Kim and Myung‐Hyun Song and Earl Carstens and Won‐Sik Shim},
doi = {10.1111/bph.15733},
issn = {1476-5381},
year = {2022},
date = {2022-05-00},
urldate = {2022-05-00},
journal = {British J Pharmacology},
volume = {179},
number = {10},
pages = {2193--2207},
publisher = {Wiley},
abstract = {Background and purpose
Glucosylsphingosine (GS), an endogenous sphingolipid, is highly accumulated in the epidermis of patients with atopic dermatitis (AD) due to abnormal ceramide metabolism. More importantly, GS can evoke scratching behaviours. However, the precise molecular mechanism by which GS induces pruritus has been elusive. Thus, the present study aimed to elucidate the molecular signalling pathway of GS, especially at the peripheral sensory neuronal levels.
Experimental approach
Calcium imaging was used to investigate the responses of HEK293T cells or mouse dorsal root ganglion (DRG) neurons to application of GS. Scratching behaviour tests were also performed with wild-type and Trpv4 knockout mice.
Key results
GS activated DRG neurons in a manner involving both the 5-HT2A receptor and TRPV4. Furthermore, GS-induced responses were significantly suppressed by various inhibitors, including ketanserin (5-HT2A receptor antagonist), YM254890 (Gαq/11 inhibitor), gallein (Gβγ complex inhibitor), U73122 (phospholipase C inhibitor), bisindolylmaleimide I (PKC inhibitor) and HC067047 (TRPV4 antagonist). Moreover, DRG neurons from Trpv4 knockout mice exhibited significantly reduced responses to GS. Additionally, GS-evoked scratching behaviours were greatly decreased by pretreatment with inhibitors of either 5-HT2A receptor or TRPV4. As expected, GS-evoked scratching behaviour was also significantly decreased in Trpv4 knockout mice.
Conclusion and implications
Overall, the present study provides evidence for a novel molecular signalling pathway for GS-evoked pruritus, which utilizes both 5-HT2A receptor and TRPV4 in mouse sensory neurons. Considering the high accumulation of GS in the epidermis of patients with AD, GS could be another pruritogen in patients with AD.},
keywords = {5-HT2R, Atopic dermatitis, Calcium imaging, Dorsal root ganglia, Glucosylsphingosine, TRPV4},
pubstate = {published},
tppubtype = {article}
}
Background and purpose
Glucosylsphingosine (GS), an endogenous sphingolipid, is highly accumulated in the epidermis of patients with atopic dermatitis (AD) due to abnormal ceramide metabolism. More importantly, GS can evoke scratching behaviours. However, the precise molecular mechanism by which GS induces pruritus has been elusive. Thus, the present study aimed to elucidate the molecular signalling pathway of GS, especially at the peripheral sensory neuronal levels.
Experimental approach
Calcium imaging was used to investigate the responses of HEK293T cells or mouse dorsal root ganglion (DRG) neurons to application of GS. Scratching behaviour tests were also performed with wild-type and Trpv4 knockout mice.
Key results
GS activated DRG neurons in a manner involving both the 5-HT2A receptor and TRPV4. Furthermore, GS-induced responses were significantly suppressed by various inhibitors, including ketanserin (5-HT2A receptor antagonist), YM254890 (Gαq/11 inhibitor), gallein (Gβγ complex inhibitor), U73122 (phospholipase C inhibitor), bisindolylmaleimide I (PKC inhibitor) and HC067047 (TRPV4 antagonist). Moreover, DRG neurons from Trpv4 knockout mice exhibited significantly reduced responses to GS. Additionally, GS-evoked scratching behaviours were greatly decreased by pretreatment with inhibitors of either 5-HT2A receptor or TRPV4. As expected, GS-evoked scratching behaviour was also significantly decreased in Trpv4 knockout mice.
Conclusion and implications
Overall, the present study provides evidence for a novel molecular signalling pathway for GS-evoked pruritus, which utilizes both 5-HT2A receptor and TRPV4 in mouse sensory neurons. Considering the high accumulation of GS in the epidermis of patients with AD, GS could be another pruritogen in patients with AD.
Glucosylsphingosine (GS), an endogenous sphingolipid, is highly accumulated in the epidermis of patients with atopic dermatitis (AD) due to abnormal ceramide metabolism. More importantly, GS can evoke scratching behaviours. However, the precise molecular mechanism by which GS induces pruritus has been elusive. Thus, the present study aimed to elucidate the molecular signalling pathway of GS, especially at the peripheral sensory neuronal levels.
Experimental approach
Calcium imaging was used to investigate the responses of HEK293T cells or mouse dorsal root ganglion (DRG) neurons to application of GS. Scratching behaviour tests were also performed with wild-type and Trpv4 knockout mice.
Key results
GS activated DRG neurons in a manner involving both the 5-HT2A receptor and TRPV4. Furthermore, GS-induced responses were significantly suppressed by various inhibitors, including ketanserin (5-HT2A receptor antagonist), YM254890 (Gαq/11 inhibitor), gallein (Gβγ complex inhibitor), U73122 (phospholipase C inhibitor), bisindolylmaleimide I (PKC inhibitor) and HC067047 (TRPV4 antagonist). Moreover, DRG neurons from Trpv4 knockout mice exhibited significantly reduced responses to GS. Additionally, GS-evoked scratching behaviours were greatly decreased by pretreatment with inhibitors of either 5-HT2A receptor or TRPV4. As expected, GS-evoked scratching behaviour was also significantly decreased in Trpv4 knockout mice.
Conclusion and implications
Overall, the present study provides evidence for a novel molecular signalling pathway for GS-evoked pruritus, which utilizes both 5-HT2A receptor and TRPV4 in mouse sensory neurons. Considering the high accumulation of GS in the epidermis of patients with AD, GS could be another pruritogen in patients with AD.
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.