Role of ERK Pathway in the Pathogenesis of Atopic Dermatitis and Its Potential as a Therapeutic Target

Zeze, Nahoko; Kido‐Nakahara, Makiko; Tsuji, Gaku; Maehara, Eriko; Sato, Yuki; Sakai, Sawako; Fujishima, Kei; Hashimoto-Hachiya, Akiko; Furue, Masutaka; Nakahara, Takeshi

doi:10.3390/ijms23073467

Cited by 17 publications

(14 citation statements)

References 43 publications

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“…The mitogen-activated protein kinases (MAPKs) signaling pathway represent the major intracellular mechanisms involved in the regulation of the cellular responses to external stress signals and are crucial for the downstream production of pro-inflammatory mediators. MAPKs signaling plays a fundamental role in inflammation-based disorders and diseases at the skin level [ 40 , 41 , 42 , 43 ]. Among the MAPKs, the c-Jun N-terminal kinases (JNK) pathway has been reported to be involved in the barrier function of the epidermis [ 44 , 45 , 46 ].…”

Section: Resultsmentioning

confidence: 99%

A Novel Perilla frutescens (L.) Britton Cell-Derived Phytocomplex Regulates Keratinocytes Inflammatory Cascade and Barrier Function and Preserves Vaginal Mucosal Integrity In Vivo

Pressi¹,

Rigillo

Governa

et al. 2023

Pharmaceutics

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In the last years, the medicinal plant Perilla frutescens (L.) Britton has gained scientific interest because leaf extracts, due to the presence of rosmarinic acid and other polyphenols, have shown anti-allergic and skin protective potential in pre-clinical studies. Nevertheless, the lack of standardized extracts has limited clinical applications to date. In this work, for the first time, a standardized phytocomplex of P. frutescens, enriched in rosmarinic acid and total polyphenols, was produced through innovative in vitro cell culture biotechnology and tested. The activity of perilla was evaluated in an in vitro inflammatory model of human keratinocytes (HaCaT) by monitoring tight junctions, filaggrin, and loricrin protein levels, the release of pro-inflammatory cytokines and JNK MAPK signaling. In a practical health care application, the perilla biotechnological phytocomplex was tested in a multilayer model of vaginal mucosa, and then, in a preliminary clinical observation to explore its capacity to preserve vaginal mucosal integrity in women in peri-menopause. In keratinocytes cells, perilla phytocomplex demonstrated to exert a marked activity in epidermis barrier maintenance and anti-inflammatory effects, preserving tight junction expression and downregulating cytokines release through targeting JNK activation. Furthermore, perilla showed positive effects in retaining vaginal mucosal integrity in the reconstructed vaginal mucosa model and in vivo tests. Overall, our data suggest that the biotechnological P. frutescens phytocomplex could represent an innovative ingredient for dermatological applications.

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Section: Resultsmentioning

confidence: 99%

A Novel Perilla frutescens (L.) Britton Cell-Derived Phytocomplex Regulates Keratinocytes Inflammatory Cascade and Barrier Function and Preserves Vaginal Mucosal Integrity In Vivo

Pressi¹,

Rigillo

Governa

et al. 2023

Pharmaceutics

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“…The Erk pathway is involved in the pathogenesis of atopic dermatitis [60]. Berberine inhibits the proinflammatory cytokinin (e.g., IL-6) through the inhibition of Erk phosphorylation [38].…”

Section: Tsugunobu Andoh and Tadamichi Shimizumentioning

confidence: 99%

The Molecular Mechanisms underlying the Therapeutic Effect of Berberine in Inflammatory Skin Diseases

Andoh¹,

Shimizu²

2023

Asian J Complement Altern Med

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Clinical therapy of chronic inflammatory skin diseases such as atopic dermatitis is extremely difficult. Recently, the use of a number of traditional herbal medicines has been attempted to treat these skin diseases. Orengedokuto is a traditional herbal medicine consisting of four crude natural medicines, and in the field of dermatology, it is used to treat skin diseases accompanied by inflammation and pruritus. Our recent animal study showed that berberine, a major component of Orengedokuto, improves skin inflammation and itching in mice with atopy-like dermatitis. Furthermore, we identified EIF3F and MALT1 as factors involved in the suppression of cytokine production by berberine. In addition, berberine also activates AMP-activated protein kinase, which is involved in the expression of inflammatory and anti-inflammatory cytokines. In addition, berberine also attenuates epidermal hyperplasia though the inhibition of CDC6 expression. Taken together, these findings indicate that berberine improves inflammatory skin diseases by controlling gene expression related to both inflammation, anti-inflammation and keratinocyte hyperproliferation.

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“…From a genetic point of view, patients may present with a predetermined defect of the skin barrier (e.g., filaggrin-FLG deficiency due to mutation of the FLG gene), which clinically manifests as dry skin (xerosis) [ 2 ]. Although this genetic defect of the skin barrier occurs in a fair number of patients, mutations of the FLG gene are not a key condition for the onset of AD since mutations are detected in about 20% of patients with moderate-to-severe AD, and about 50% of individuals with mutations in the FLG gene do not develop AD [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Blockage of the IL-31 Pathway as a Potential Target Therapy for Atopic Dermatitis

Orfali

Aoki

2023

Pharmaceutics

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Atopic dermatitis (AD), a pruritic, inflammatory chronic disease with multifactorial pathogenesis, has been a therapeutic challenge. Novel target treatments aim to reduce not only the immunologic dysfunction and microbiome dysbiosis but also the recovery of the damaged skin barrier. The current review focuses on the interleukin 31 (IL-31) pathway and AD and offers an overview of the current clinical studies with monoclonal antibodies blocking this cascade. Pruritus, the key symptom of AD, has substantial participation of the IL-31 complex and activation of relevant signaling pathways. Epidermal keratinocytes, inflammatory cells, and cutaneous peripheral nerves express the interleukin-31 receptor α-chain (IL-31RA), upregulated by Staphylococcus aureus toxins or Th2 cytokines involved in AD. Nemolizumab is a humanized monoclonal antibody that antagonizes IL-31RA, inhibiting the IL-31 cascade and therefore contributing to reducing the pruritus and inflammation and recovering the damaged skin barrier in AD patients. Phases 2 and 3 clinical trials with nemolizumab in AD show a suitable safety profile, with a fast, efficient, and sustained reduction of pruritus and severity scores, especially when associated with topical treatment. Deciphering the full interplay of the IL-31 pathway and AD may expand the potential of nemolizumab as a targeted therapy for AD and other pruritic conditions.

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Role of ERK Pathway in the Pathogenesis of Atopic Dermatitis and Its Potential as a Therapeutic Target

Cited by 17 publications

References 43 publications

A Novel Perilla frutescens (L.) Britton Cell-Derived Phytocomplex Regulates Keratinocytes Inflammatory Cascade and Barrier Function and Preserves Vaginal Mucosal Integrity In Vivo

A Novel Perilla frutescens (L.) Britton Cell-Derived Phytocomplex Regulates Keratinocytes Inflammatory Cascade and Barrier Function and Preserves Vaginal Mucosal Integrity In Vivo

The Molecular Mechanisms underlying the Therapeutic Effect of Berberine in Inflammatory Skin Diseases

Blockage of the IL-31 Pathway as a Potential Target Therapy for Atopic Dermatitis

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