Publications

@article{Lee2023,

title = {Rg3-enriched Korean red ginseng alleviates chloroquine-induced itch and dry skin pruritus in an MrgprA3-dependent manner in mice},

author = {Wook-Joo Lee and Won-Sik Shim},

doi = {10.1016/j.imr.2022.100916},

issn = {2213-4220},

year  = {2023},

date = {2023-03-00},

urldate = {2023-03-00},

journal = {Integrative Medicine Research},

volume = {12},

number = {1},

publisher = {Elsevier BV},

abstract = {Background: Previous studies have found that Korean red ginseng extract (KRG) has antipruritic effects, which can be attributed to the presence of Rg3, one of the most potent ginsenosides. Therefore, Rg3-enriched KRG extract (Rg3EKRG) is anticipated to have enhanced antipruritic effects. The present study was conducted to examine the effects of Rg3EKRG in acute chloroquine (CQ)-induced and chronic dry skin pruritus.



Methods: Calcium imaging technique was used in HE293T cells expressing MrgprA3 and TRPA1 ("MrgprA3/TRPA1") and in primary cultures of mouse dorsal root ganglia (DRG) neurons. Mouse scratching behavior tests were performed on dry skin models. To verify the altered expression of itch-related genes, real-time RNA sequencing analysis and PCR were performed on DRG sections obtained from dry skin models.



Results: Rg3EKRG suppressed CQ-induced intracellular calcium changes to a greater degree than KRG. Rg3EKRG dose-dependently inhibited CQ-induced responses in MrgprA3/TRPA1 cells. Rg3EKRG likely targeted MrgprA3 rather than TRPA1 to exert its inhibitory effect. Further, Rg3EKRG strongly inhibited the scratching behavior in mice induced by acute CQ injection. Importantly, DRG neurons obtained from dry skin mice models showed increased mRNA levels of MrgprA3, and treatment with Rg3EKRG alleviated chronic dry skin conditions and suppressed spontaneous scratching behaviors.



Conclusion: The results of the present study imply that Rg3EKRG has a stronger antipruritic effect than KRG, inhibiting both acute CQ-induced and chronic dry skin pruritus in an MrgprA3-dependent manner. Therefore, Rg3EKRG is a potential antipruritic agent that can suppress acute and chronic itching at the peripheral sensory neuronal level.},

keywords = {Dry skin, Itch, Korean Red Ginseng, MrgprA3, RNA-seq, Scratching behavior, TRPA1},

pubstate = {published},

tppubtype = {article}

}

@article{Kim2022,

title = {Anoctamin 1/TMEM16A in pruritoceptors is essential for Mas-related G protein receptor–dependent itch},

author = {Hyesu Kim and Hyungsup Kim and Hawon Cho and Byeongjun Lee and Huan-Jun Lu and Kyungmin Kim and Sooyoung Chung and Won-Sik Shim and Young Kee Shin and Xinzhong Dong and John N. Wood and Uhtaek Oh},

doi = {10.1097/j.pain.0000000000002611},

issn = {1872-6623},

year  = {2022},

date = {2022-00-00},

urldate = {2022-00-00},

journal = {PAIN},

volume = {163},

number = {11},

pages = {2172--2184},

publisher = {Ovid Technologies (Wolters Kluwer Health)},

abstract = {<jats:title>Abstract</jats:title>

          <jats:p>Itch is an unpleasant sensation that evokes a desire to scratch. Pathologic conditions such as allergy or atopic dermatitis produce severe itching sensation. Mas-related G protein receptors (Mrgprs) are receptors for many endogenous pruritogens. However, signaling pathways downstream to these receptors in dorsal root ganglion (DRG) neurons are not yet understood. We found that anoctamin 1 (ANO1), a Ca<jats:sup>2+</jats:sup>-activated chloride channel, is a transduction channel mediating Mrgpr-dependent itch signals. Genetic ablation of <jats:italic toggle="yes">Ano1</jats:italic> in DRG neurons displayed a significant reduction in scratching behaviors in response to acute and chronic Mrgpr-dependent itch models and the epidermal hyperplasia induced by dry skin. In vivo Ca<jats:sup>2+</jats:sup> imaging and electrophysiological recording revealed that chloroquine and other agonists of Mrgprs excited DRG neurons via ANO1. More importantly, the overexpression of <jats:italic toggle="yes">Ano1</jats:italic> in DRG neurons of <jats:italic toggle="yes">Ano1</jats:italic>-deficient mice rescued the impaired itching observed in <jats:italic toggle="yes">Ano1</jats:italic>-deficient mice. These results demonstrate that ANO1 mediates the Mrgpr-dependent itch signaling in pruriceptors and provides clues to treating pathologic itch syndromes.</jats:p>},

keywords = {Anoctamin 1, Itch, MrgprA3, MrgprC11},

pubstate = {published},

tppubtype = {article}

}

@article{Choi2020,

title = {Crotamiton, an Anti-Scabies Agent, Suppresses Histamine- and Chloroquine-Induced Itch Pathways in Sensory Neurons and Alleviates Scratching in Mice},

author = {Da-Som Choi and Yeounjung Ji and Yongwoo Jang and Wook-Joo Lee and Won-Sik Shim},

doi = {10.4062/biomolther.2020.063},

issn = {2005-4483},

year  = {2020},

date = {2020-11-01},

urldate = {2020-11-01},

journal = {Biomolecules & Therapeutics},

volume = {28},

number = {6},

pages = {569--575},

publisher = {The Korean Society of Applied Pharmacology},

abstract = {Crotamiton is an anti-scabies drug, but it was recently found that crotamiton also suppresses non-scabietic itching in mice. However, the underlying mechanism is largely unclear. Therefore, aim of the study is to investigate mechanisms of the anti-pruritic effect of crotamiton for non-scabietic itching. Histamine and chloroquine are used as non-scabietic pruritogens. The effect of crotamiton was identified using fluorometric intracellular calcium assays in HEK293T cells and primary cultured dorsal root ganglion (DRG) neurons. Further in vivo effect was evaluated by scratching behavior tests. Crotamiton strongly inhibited histamine-induced calcium influx in HEK293T cells, expressing both histamine receptor 1 (H1R) and transient receptor potential vanilloid 1 (TRPV1), as a model of histamine-induced itching. Similarly, it also blocked chloroquine-induced calcium influx in HEK293T cells, expressing both Mas-related G-protein-coupled receptor A3 (MRGPRA3) and transient receptor potential A1 (TRPA1), as a model of histamine-independent itching. Furthermore, crotamiton also suppressed both histamine- and chloroquine-induced calcium influx in primary cultures of mouse DRG. Additionally, crotamiton strongly suppressed histamine- and chloroquine-induced scratching in mice. Overall, it was found that crotamiton has an anti-pruritic effect against non-scabietic itching by histamine and chloroquine. Therefore, crotamiton may be used as a general anti-pruritic agent, irrespective of the presence of scabies.},

keywords = {Calcium imaging, Chloroquine, H1R, Histamine, Itch, MrgprA3, TRPA1, TRPV1},

pubstate = {published},

tppubtype = {article}

}

@article{Lee2018,

title = {Korean Red Ginseng extract and ginsenoside Rg3 have anti-pruritic effects on chloroquine-induced itch by inhibition of MrgprA3/TRPA1-mediated pathway},

author = {Wook-Joo Lee and Young-Sik Kim and Won-Sik Shim},

doi = {10.1016/j.jgr.2017.05.004},

issn = {1226-8453},

year  = {2018},

date = {2018-10-00},

urldate = {2018-10-00},

journal = {Journal of Ginseng Research},

volume = {42},

number = {4},

pages = {470--475},

publisher = {Elsevier BV},

abstract = {Background: It was previously found that Korean Red Ginseng water extract (KRGE) inhibits the histamine-induced itch signaling pathway in peripheral sensory neurons. Thus, in the present study, we investigated whether KRGE inhibited another distinctive itch pathway induced by chloroquine (CQ); a representative histamine-independent pathway mediated by MrgprA3 and TRPA1. Methods: Intracellular calcium changes were measured by the calcium imaging technique in theHEK293T cells transfected with both MrgprA3 and TRPA1 (“MrgprA3/TRPA1”), and in primary culture ofmouse dorsal root ganglia (DRGs). Mouse scratching behavior tests were performed to verify proposed antipruritic effects of KRGE and ginsenoside Rg3.Results: CQ-induced Ca2þ influx was strongly inhibited by KRGE (10 mg/mL) in MrgprA3/TRPA1, and notablyginsenoside Rg3 dose-dependently suppressed CQ-induced Ca2þ influx in MrgprA3/TRPA1. Moreover, bothKRGE (10 mg/mL) and Rg3 (100 mM) suppressed CQ-induced Ca2þ influx in primary culture of mouse DRGs,indicating that the inhibitory effect of KRGE was functional in peripheral sensory neurons. In vivo tests revealed that not only KRGE (100 mg) suppressed CQ-induced scratching in mice [bouts of scratching:274.0  51.47 (control) vs. 104.7  17.39 (KRGE)], but also Rg3 (1.5 mg) oral administration significantly reduced CQ-induced scratching as well [bouts of scratching: 216.8  33.73 (control) vs.115.7  20.94 (Rg3)]. Conclusion: The present study verified that KRGE and Rg3 have a strong antipruritic effect against CQ-induced itch. Thus, KRGE is as a promising antipruritic agent that blocks both histamine-dependent and -independent itch at peripheral sensory neuronal levels.},

keywords = {Calcium imaging, Chloroquine, Korean Red Ginseng, MrgprA3, Scratching behavior, TRPA1},

pubstate = {published},

tppubtype = {article}

}