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Puppels GJ, Hourihane JO, Nico C, Chaoimh CN, Wong C, Common JE, Caspers PJ, Irvine AD. Highly accurate, noninvasive early identification of infants with a filaggrin loss-of-function mutation by in vivo Raman spectroscopy, followed from birth to 12 months. Ann Allergy Asthma Immunol 2025; 134:457-464. [PMID: 39826898 DOI: 10.1016/j.anai.2025.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/08/2025] [Accepted: 01/08/2025] [Indexed: 01/22/2025]
Abstract
BACKGROUND Loss-of-function FLG mutation (FLGmut) carriers are at an increased risk of developing atopic dermatitis (AD), characterized by earlier onset and more severe disease. AD is driven by a complex interplay between skin barrier function, TH2 and TH2-dominant immune dysregulation, and dysbiosis. Results from the Short-Term Topical Application for Prevention of Atopic Dermatitis study suggest 2 early initiating AD pathogenetic pathways: an FLGmut-related skin barrier deficiency pathway and an immune function-related inflammatory pathway. The Short-Term Topical Application for Prevention of Atopic Dermatitis study suggested that early preventative intervention with specialized emollients for barrier function augmentation may benefit newborns with FLGmut. This requires early identification of FLGmut carriers, for which noninvasive Raman spectroscopic determination of natural moisturizing factor (NMF) levels in the stratum corneum of the thenar eminence provides a surrogate marker. OBJECTIVE To identify strategies for early identification of infants with FLGmut. METHODS FLG sequencing was performed on 253 infants, and NMF concentrations were measured in the stratum corneum of the palmar eminence (pSC-NMF) using noninvasive Raman spectroscopy at 6 time points after birth. Furthermore, the pSC-NMF concentrations were obtained from both parents of 150 infants. RESULTS Babies are born with little to no NMF. In the first days after birth, NMF levels rapidly increase and 65% of newborns with FLG wild type already reach pSC-NMF concentrations, which excludes them as FLGmut carriers with high specificity. At 2 weeks of age, FLGmut carriers could be distinguished from newborns with FLG wild type with high sensitivity (97%) and specificity (97%). In addition, parent pSC-NMF concentrations offer the possibility to exclude their newborn as FLGmut carriers with high specificity. CONCLUSION Noninvasive Raman spectroscopy enables the accurate early identification of infants with FLGmut.
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Affiliation(s)
- Gerwin J Puppels
- RiverD International B.V. Marconistraat 16, Rotterdam, The Netherlands
| | - Jonathan O'B Hourihane
- Paediatrics and Child Health, Royal College of Surgeons in Ireland, Dublin, Ireland; The Irish Centre for Maternal and Child Health Research (INFANT) Research Centre, University College Cork, Ireland
| | - Claudio Nico
- RiverD International B.V. Marconistraat 16, Rotterdam, The Netherlands
| | - Carol Ni Chaoimh
- The Irish Centre for Maternal and Child Health Research (INFANT) Research Centre, University College Cork, Ireland
| | - Colin Wong
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research (A*STAR), Immunos, Singapore
| | - John E Common
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research (A*STAR), Immunos, Singapore; Translational and Clinical Research Institute and National Institute for Health and Care Research Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Peter J Caspers
- RiverD International B.V. Marconistraat 16, Rotterdam, The Netherlands
| | - Alan D Irvine
- Clinical Medicine, Trinity College Dublin, Dublin, Ireland.
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Yuan Y, Zhong B, Qin X, Xu H, Li Z, Li L, Wang X, Zhang W, Lou Z, Fan Y, Wang L. An epidermal serine sensing system for skin healthcare. Nat Commun 2025; 16:2681. [PMID: 40102486 PMCID: PMC11920223 DOI: 10.1038/s41467-025-58147-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 03/10/2025] [Indexed: 03/20/2025] Open
Abstract
Portable biosensors mainly focus on detecting biomarkers in biofluids but neglect the abundant skin biomarkers on the stratum corneum, which are associated with the functionality and integrity of the skin barrier. Here, we propose a sensing patch designed for direct sampling and in situ quantification of epidermal serine, an important biomarker for skin healthcare. The patch consists of a porous hydrogel for serine diffusion and ion conduction, and a molecular imprinted polymer-based electrochemical serine sensor. By integrating with a customized handheld serine tester, the serine sensing system enables in situ measurement of epidermal serine levels. We demonstrate the application of this serine sensing system in assessing the moisturizing effect of a skincare product and tracking the recovery progress of skin barrier function in a patient with atopic dermatitis. Our work opens up a potential application scenario for portable biosensors in personalized skin healthcare.
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Affiliation(s)
- Ying Yuan
- State Key Laboratory of Semiconductor Physics and Chip Technologies, Institute of Semiconductors, Chinese Academy of Sciences, Beijing, China
- Center of Materials Science and Optoelectronic Engineering, University of Chinese Academy of Sciences, Beijing, China
- Key Laboratory of Lignocellulosic Chemistry, College of Material Science and Technology, Beijing Forestry University, Beijing, China
| | - Bowen Zhong
- State Key Laboratory of Semiconductor Physics and Chip Technologies, Institute of Semiconductors, Chinese Academy of Sciences, Beijing, China
- Center of Materials Science and Optoelectronic Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Xiaokun Qin
- State Key Laboratory of Semiconductor Physics and Chip Technologies, Institute of Semiconductors, Chinese Academy of Sciences, Beijing, China
- Center of Materials Science and Optoelectronic Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Hao Xu
- State Key Laboratory of Semiconductor Physics and Chip Technologies, Institute of Semiconductors, Chinese Academy of Sciences, Beijing, China.
- Center of Materials Science and Optoelectronic Engineering, University of Chinese Academy of Sciences, Beijing, China.
| | - Zhexin Li
- State Key Laboratory of Semiconductor Physics and Chip Technologies, Institute of Semiconductors, Chinese Academy of Sciences, Beijing, China
- Center of Materials Science and Optoelectronic Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Linlin Li
- State Key Laboratory of Semiconductor Physics and Chip Technologies, Institute of Semiconductors, Chinese Academy of Sciences, Beijing, China
- Center of Materials Science and Optoelectronic Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Xiaofeng Wang
- State Key Laboratory of Semiconductor Physics and Chip Technologies, Institute of Semiconductors, Chinese Academy of Sciences, Beijing, China
- Center of Materials Science and Optoelectronic Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Wenxuan Zhang
- State Key Laboratory of Semiconductor Physics and Chip Technologies, Institute of Semiconductors, Chinese Academy of Sciences, Beijing, China
- Center of Materials Science and Optoelectronic Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Zheng Lou
- State Key Laboratory of Semiconductor Physics and Chip Technologies, Institute of Semiconductors, Chinese Academy of Sciences, Beijing, China.
- Center of Materials Science and Optoelectronic Engineering, University of Chinese Academy of Sciences, Beijing, China.
| | - Yongming Fan
- Key Laboratory of Lignocellulosic Chemistry, College of Material Science and Technology, Beijing Forestry University, Beijing, China.
| | - Lili Wang
- State Key Laboratory of Semiconductor Physics and Chip Technologies, Institute of Semiconductors, Chinese Academy of Sciences, Beijing, China.
- Center of Materials Science and Optoelectronic Engineering, University of Chinese Academy of Sciences, Beijing, China.
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Wen P, Zhuo X, Wang L. Skin barrier dysfunction in cutaneous T-cell lymphoma: From pathogenic mechanism of barrier damage to treatment. Crit Rev Oncol Hematol 2025; 205:104559. [PMID: 39549893 DOI: 10.1016/j.critrevonc.2024.104559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 10/30/2024] [Accepted: 11/08/2024] [Indexed: 11/18/2024] Open
Abstract
Cutaneous T-cell lymphoma (CTCL) is a group of non-Hodgkin lymphomas characterized by multiple erythematous patches, plaques, or even nodules on the skin. As the disease progresses, patients develop widespread pruritic skin lesions, leading to skin barrier dysfunction, which significantly impacts their quality of life, appearance, and social adaptation. The pathogenesis of CTCL is not fully understood. Recent studies have recognized the important role of skin barrier dysfunction in the development and progression of CTCL, yet a comprehensive review on this topic is lacking. This review summarizes recent findings on skin barrier dysfunction in CTCL, focusing on physical barrier dysfunction, chronic inflammation, and immune dysregulation. We also discuss current and potential therapies aimed at restoring barrier function in CTCL. By emphasizing the integration of barrier-centric approaches into CTCL management, this review provides valuable insights for improving treatment outcomes.
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Affiliation(s)
- Pengfei Wen
- Department of Dermatology, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu, Sichuan 610041, China.
| | - Xiaoxue Zhuo
- Department of Dermatology, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu, Sichuan 610041, China.
| | - Lin Wang
- Department of Dermatology, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu, Sichuan 610041, China.
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4
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Shi A, Yun F, Shi L, Liu X, Jia Y. Research progress on the mechanism of common inflammatory pathways in the pathogenesis and development of lymphoma. Ann Med 2024; 56:2329130. [PMID: 38489405 PMCID: PMC10946270 DOI: 10.1080/07853890.2024.2329130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 02/25/2024] [Indexed: 03/17/2024] Open
Abstract
In recent years, the incidence and mortality rates of lymphoma have gradually increased worldwide. Tumorigenesis and drug resistance are closely related to intracellular inflammatory pathways in lymphoma. Therefore, understanding the biological role of inflammatory pathways and their abnormal activation in relation to the development of lymphoma and their selective modulation may open new avenues for targeted therapy of lymphoma. The biological functions of inflammatory pathways are extensive, and they are central hubs for regulating inflammatory responses, immune responses, and the tumour immune microenvironment. However, limited studies have investigated the role of inflammatory pathways in lymphoma development. This review summarizes the relationship between abnormal activation of common inflammatory pathways and lymphoma development to identify precise and efficient targeted therapeutic options for patients with advanced, drug-resistant lymphoma.
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Affiliation(s)
- Aorong Shi
- Department of Pathology, Basic Medical Sciences College, Inner Mongolia Medical University, Hohhot, China
| | - Fen Yun
- Department of Pathology, Basic Medical Sciences College, Inner Mongolia Medical University, Hohhot, China
- Department of Pathology, The First Affiliated Hospital of Inner Mongolia Medical University, Huhhot, China
| | - Lin Shi
- Department of Pathology, Basic Medical Sciences College, Inner Mongolia Medical University, Hohhot, China
- Department of Pathology, The First Affiliated Hospital of Inner Mongolia Medical University, Huhhot, China
| | - Xia Liu
- Department of Pathology, Basic Medical Sciences College, Inner Mongolia Medical University, Hohhot, China
- Department of Pathology, The First Affiliated Hospital of Inner Mongolia Medical University, Huhhot, China
| | - Yongfeng Jia
- Department of Pathology, Basic Medical Sciences College, Inner Mongolia Medical University, Hohhot, China
- Department of Pathology, The First Affiliated Hospital of Inner Mongolia Medical University, Huhhot, China
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Thonthula S, Sousa SD, Dubuis A, Boudah S, Mehta R, Singh A, Eilstein J, Tabet JC, John S, Roy D, Pannakal ST. Improved Skin Barrier Function Along with Hydration Benefits of Viola yedoensis Extract, Aesculin, and Schaftoside and LC-HRMS/MS Dereplication of Its Bio-Active Components. Int J Mol Sci 2024; 25:12770. [PMID: 39684479 DOI: 10.3390/ijms252312770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 11/19/2024] [Accepted: 11/23/2024] [Indexed: 12/18/2024] Open
Abstract
The skin hydration level is a key factor that influences the physical and mechanical properties of the skin. The stratum corneum (SC), the outermost layer of the epidermis, is responsible for the skin's barrier function. In this study, we investigated the role of a unique composition of Viola yedoensis extract for its ability to activate CD44, a cell-surface receptor of hyaluronic acid, and aquaporin-3, a water-transporting protein, in human keratinocytes (HaCaT). An ELISA assay evaluating the protein expression levels of CD44, aquaporin-3 (AQP3), filaggrin, and keratin-10 revealed that V. yedoensis extract upregulated the levels of CD44 and AQP3 by 15% and 78%, respectively. Additionally, V. yedoensis extract demonstrated a comparative effect on water vapor flux in TEWL and lipid perturbation in DSC versus the reference, glycerin. In light of this new biological efficacy, a detailed phytochemical characterization was undertaken using an integrated LC-HRMS/MS-based metabolomics approach, which provided further insights on the chemistry of V. yedoensis. This led to the identification of 29 secondary metabolites, 14 of which are reported here for the first time, including esculetin, aesculin, apigenin and kaempferol C-glycosides, megastigmane glycosides, roseoside, platanionoside B, and an eriojaposide B isomer, along with the rare, calenduloside F and esculetin diglucoside, which are reported for the first time from the genus, Viola. Notably, two active components identified in the V. yedoensis extract, namely, aesculin and schaftoside, showed an upregulation of the protein expression of CD44 in HaCaT cells by 123% and 193% within 24 h of treatment, respectively, while aesculin increased AQP3 levels by 46%. Aesculin and schaftoside also significantly upregulated the expression of K-10 levels by 299% and 116%, which was considerably higher than sodium hyaluronate, the positive control. The rationale used to characterize the new structures is outlined along with the related biosynthetic pathways envisioned to generate roseoside and Eriojaposide B. These findings provide new molecular insights to deepen the understanding of how V. yedoensis extract, along with the biomarkers aesculin and schaftoside, restores the skin barrier and skin hydration benefits.
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Affiliation(s)
| | - Sandra De Sousa
- L'Oréal Research and Innovation, 93600 Aulnay-Sous-Bois, France
| | - Alexis Dubuis
- L'Oréal Research and Innovation, 93600 Aulnay-Sous-Bois, France
| | - Samia Boudah
- L'Oréal Research and Innovation, 93600 Aulnay-Sous-Bois, France
| | - Richa Mehta
- L'Oréal Research and Innovation, Bangalore 560067, India
| | - Akanksha Singh
- L'Oréal Research and Innovation, Bangalore 560067, India
| | - Joan Eilstein
- L'Oréal Research and Innovation, 93600 Aulnay-Sous-Bois, France
| | - Jean-Claude Tabet
- Faculty of Sciences and Engineering, Institut Parisien de Chimie Moléculaire, Sorbonne University, 75005 Paris, France
- Medicines and Health Technologies Department (DMTS), CEA, INRAE, MetaboHUB, Paris-Saclay University, 91190 Gif sur Yvette, France
| | - Sherluck John
- L'Oréal Research and Innovation, Bangalore 560067, India
| | - Dhimoy Roy
- L'Oréal Research and Innovation, Mumbai Maharashtra 410210, India
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6
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Zhou Z, Yang J, Liu Q, Gao J, Ji W. Patho-immunological mechanisms of atopic dermatitis: The role of the three major human microbiomes. Scand J Immunol 2024; 100:e13403. [PMID: 39267301 DOI: 10.1111/sji.13403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 08/01/2024] [Accepted: 08/05/2024] [Indexed: 09/17/2024]
Abstract
Atopic dermatitis (AD) is a genetically predisposed allergic inflammatory dermatosis with chronic, pruritic, and recurrent features. Patients with AD have dry and itchy skin, often accompanied by chronic eczematous lesions, allergic rhinitis, or asthma, which has a considerable impact on their daily lives. With advances in genome sequencing technology, it has been demonstrated that microorganisms are involved in this disease, and the microorganisms associated with AD are attracting considerable research attention. An increasing number of studies conducted in recent years have demonstrated that an imbalanced microbiome in AD patients has substantial impact on disease prognosis, and the causes are closely tied to various immune mechanisms. However, the involvement of microorganisms in the pathogenesis of AD remains poorly understood. In this paper, we review the advances in research on the immunological mechanisms of the skin microbiome, intestinal microbiome, and lung microbiome that are related to AD prognosis and immunotherapy protocols. It is hoped that this approach will lay the foundation for exploring the pathogenesis of and emerging treatments for AD.
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Affiliation(s)
- Zhaosen Zhou
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Jing Yang
- Department of Nursing in Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Qin Liu
- Department of Nursing in Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Jing Gao
- Department of Nursing in Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Wenting Ji
- Department of Nursing in Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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7
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Brown M, Williams A, Chilcott RP, Brady B, Lenn J, Evans C, Allen L, McAuley WJ, Beebeejaun M, Haslinger J, Beuttel C, Vieira R, Guidali F, Miranda M. Topically Applied Therapies for the Treatment of Skin Disease: Past, Present, and Future. Pharmacol Rev 2024; 76:689-790. [PMID: 38914467 DOI: 10.1124/pharmrev.123.000549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 05/31/2024] [Accepted: 06/03/2024] [Indexed: 06/26/2024] Open
Abstract
The purpose of this review is to summarize essential biological, pharmaceutical, and clinical aspects in the field of topically applied medicines that may help scientists when trying to develop new topical medicines. After a brief history of topical drug delivery, a review of the structure and function of the skin and routes of drug absorption and their limitations is provided. The most prevalent diseases and current topical treatment approaches are then detailed, the organization of which reflects the key disease categories of autoimmune and inflammatory diseases, microbial infections, skin cancers, and genetic skin diseases. The complexity of topical product development through to large-scale manufacturing along with recommended risk mitigation approaches are then highlighted. As such topical treatments are applied externally, patient preferences along with the challenges they invoke are then described, and finally the future of this field of drug delivery is discussed, with an emphasis on areas that are more likely to yield significant improvements over the topical medicines in current use or would expand the range of medicines and diseases treatable by this route of administration. SIGNIFICANCE STATEMENT: This review of the key aspects of the skin and its associated diseases and current treatments along with the intricacies of topical formulation development should be helpful in making judicious decisions about the development of new or improved topical medicines. These aspects include the choices of the active ingredients, formulations, the target patient population's preferences, limitations, and the future with regard to new skin diseases and topical medicine approaches.
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Affiliation(s)
- Marc Brown
- MLBT Investments and Consultancy, Aylesbury, United Kingdom (M.Br.); MedPharm Ltd, Guildford, United Kingdom (M.Br., B.B., C.E., J.H., F.G.); Reading School of Pharmacy, Reading, United Kingdom (A.W.); School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom (R.P.C., W.J.M.); MedPharm Ltd, Durham. North Carolina (J.L., L.A., C.B.); Medicine Development and Supply, GlaxoSmithKline R&D, Stevenage, United Kingdom (M.Be.); Department of Dermatology, CUF Tejo Hospital, Lisbon, Portugal (R.V.); Centro de Investigação Interdisciplinar Egas Moniz, Egas Moniz School of Health and Science, Monte de Caparica, Portugal (M.M.); and Department of Chemistry, Coimbra Chemistry Center, University of Coimbra, Coimbra, Portugal (M.M.)
| | - Adrian Williams
- MLBT Investments and Consultancy, Aylesbury, United Kingdom (M.Br.); MedPharm Ltd, Guildford, United Kingdom (M.Br., B.B., C.E., J.H., F.G.); Reading School of Pharmacy, Reading, United Kingdom (A.W.); School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom (R.P.C., W.J.M.); MedPharm Ltd, Durham. North Carolina (J.L., L.A., C.B.); Medicine Development and Supply, GlaxoSmithKline R&D, Stevenage, United Kingdom (M.Be.); Department of Dermatology, CUF Tejo Hospital, Lisbon, Portugal (R.V.); Centro de Investigação Interdisciplinar Egas Moniz, Egas Moniz School of Health and Science, Monte de Caparica, Portugal (M.M.); and Department of Chemistry, Coimbra Chemistry Center, University of Coimbra, Coimbra, Portugal (M.M.)
| | - Robert P Chilcott
- MLBT Investments and Consultancy, Aylesbury, United Kingdom (M.Br.); MedPharm Ltd, Guildford, United Kingdom (M.Br., B.B., C.E., J.H., F.G.); Reading School of Pharmacy, Reading, United Kingdom (A.W.); School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom (R.P.C., W.J.M.); MedPharm Ltd, Durham. North Carolina (J.L., L.A., C.B.); Medicine Development and Supply, GlaxoSmithKline R&D, Stevenage, United Kingdom (M.Be.); Department of Dermatology, CUF Tejo Hospital, Lisbon, Portugal (R.V.); Centro de Investigação Interdisciplinar Egas Moniz, Egas Moniz School of Health and Science, Monte de Caparica, Portugal (M.M.); and Department of Chemistry, Coimbra Chemistry Center, University of Coimbra, Coimbra, Portugal (M.M.)
| | - Brendan Brady
- MLBT Investments and Consultancy, Aylesbury, United Kingdom (M.Br.); MedPharm Ltd, Guildford, United Kingdom (M.Br., B.B., C.E., J.H., F.G.); Reading School of Pharmacy, Reading, United Kingdom (A.W.); School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom (R.P.C., W.J.M.); MedPharm Ltd, Durham. North Carolina (J.L., L.A., C.B.); Medicine Development and Supply, GlaxoSmithKline R&D, Stevenage, United Kingdom (M.Be.); Department of Dermatology, CUF Tejo Hospital, Lisbon, Portugal (R.V.); Centro de Investigação Interdisciplinar Egas Moniz, Egas Moniz School of Health and Science, Monte de Caparica, Portugal (M.M.); and Department of Chemistry, Coimbra Chemistry Center, University of Coimbra, Coimbra, Portugal (M.M.)
| | - Jon Lenn
- MLBT Investments and Consultancy, Aylesbury, United Kingdom (M.Br.); MedPharm Ltd, Guildford, United Kingdom (M.Br., B.B., C.E., J.H., F.G.); Reading School of Pharmacy, Reading, United Kingdom (A.W.); School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom (R.P.C., W.J.M.); MedPharm Ltd, Durham. North Carolina (J.L., L.A., C.B.); Medicine Development and Supply, GlaxoSmithKline R&D, Stevenage, United Kingdom (M.Be.); Department of Dermatology, CUF Tejo Hospital, Lisbon, Portugal (R.V.); Centro de Investigação Interdisciplinar Egas Moniz, Egas Moniz School of Health and Science, Monte de Caparica, Portugal (M.M.); and Department of Chemistry, Coimbra Chemistry Center, University of Coimbra, Coimbra, Portugal (M.M.)
| | - Charles Evans
- MLBT Investments and Consultancy, Aylesbury, United Kingdom (M.Br.); MedPharm Ltd, Guildford, United Kingdom (M.Br., B.B., C.E., J.H., F.G.); Reading School of Pharmacy, Reading, United Kingdom (A.W.); School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom (R.P.C., W.J.M.); MedPharm Ltd, Durham. North Carolina (J.L., L.A., C.B.); Medicine Development and Supply, GlaxoSmithKline R&D, Stevenage, United Kingdom (M.Be.); Department of Dermatology, CUF Tejo Hospital, Lisbon, Portugal (R.V.); Centro de Investigação Interdisciplinar Egas Moniz, Egas Moniz School of Health and Science, Monte de Caparica, Portugal (M.M.); and Department of Chemistry, Coimbra Chemistry Center, University of Coimbra, Coimbra, Portugal (M.M.)
| | - Lynn Allen
- MLBT Investments and Consultancy, Aylesbury, United Kingdom (M.Br.); MedPharm Ltd, Guildford, United Kingdom (M.Br., B.B., C.E., J.H., F.G.); Reading School of Pharmacy, Reading, United Kingdom (A.W.); School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom (R.P.C., W.J.M.); MedPharm Ltd, Durham. North Carolina (J.L., L.A., C.B.); Medicine Development and Supply, GlaxoSmithKline R&D, Stevenage, United Kingdom (M.Be.); Department of Dermatology, CUF Tejo Hospital, Lisbon, Portugal (R.V.); Centro de Investigação Interdisciplinar Egas Moniz, Egas Moniz School of Health and Science, Monte de Caparica, Portugal (M.M.); and Department of Chemistry, Coimbra Chemistry Center, University of Coimbra, Coimbra, Portugal (M.M.)
| | - William J McAuley
- MLBT Investments and Consultancy, Aylesbury, United Kingdom (M.Br.); MedPharm Ltd, Guildford, United Kingdom (M.Br., B.B., C.E., J.H., F.G.); Reading School of Pharmacy, Reading, United Kingdom (A.W.); School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom (R.P.C., W.J.M.); MedPharm Ltd, Durham. North Carolina (J.L., L.A., C.B.); Medicine Development and Supply, GlaxoSmithKline R&D, Stevenage, United Kingdom (M.Be.); Department of Dermatology, CUF Tejo Hospital, Lisbon, Portugal (R.V.); Centro de Investigação Interdisciplinar Egas Moniz, Egas Moniz School of Health and Science, Monte de Caparica, Portugal (M.M.); and Department of Chemistry, Coimbra Chemistry Center, University of Coimbra, Coimbra, Portugal (M.M.)
| | - Mubinah Beebeejaun
- MLBT Investments and Consultancy, Aylesbury, United Kingdom (M.Br.); MedPharm Ltd, Guildford, United Kingdom (M.Br., B.B., C.E., J.H., F.G.); Reading School of Pharmacy, Reading, United Kingdom (A.W.); School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom (R.P.C., W.J.M.); MedPharm Ltd, Durham. North Carolina (J.L., L.A., C.B.); Medicine Development and Supply, GlaxoSmithKline R&D, Stevenage, United Kingdom (M.Be.); Department of Dermatology, CUF Tejo Hospital, Lisbon, Portugal (R.V.); Centro de Investigação Interdisciplinar Egas Moniz, Egas Moniz School of Health and Science, Monte de Caparica, Portugal (M.M.); and Department of Chemistry, Coimbra Chemistry Center, University of Coimbra, Coimbra, Portugal (M.M.)
| | - Jasmin Haslinger
- MLBT Investments and Consultancy, Aylesbury, United Kingdom (M.Br.); MedPharm Ltd, Guildford, United Kingdom (M.Br., B.B., C.E., J.H., F.G.); Reading School of Pharmacy, Reading, United Kingdom (A.W.); School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom (R.P.C., W.J.M.); MedPharm Ltd, Durham. North Carolina (J.L., L.A., C.B.); Medicine Development and Supply, GlaxoSmithKline R&D, Stevenage, United Kingdom (M.Be.); Department of Dermatology, CUF Tejo Hospital, Lisbon, Portugal (R.V.); Centro de Investigação Interdisciplinar Egas Moniz, Egas Moniz School of Health and Science, Monte de Caparica, Portugal (M.M.); and Department of Chemistry, Coimbra Chemistry Center, University of Coimbra, Coimbra, Portugal (M.M.)
| | - Claire Beuttel
- MLBT Investments and Consultancy, Aylesbury, United Kingdom (M.Br.); MedPharm Ltd, Guildford, United Kingdom (M.Br., B.B., C.E., J.H., F.G.); Reading School of Pharmacy, Reading, United Kingdom (A.W.); School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom (R.P.C., W.J.M.); MedPharm Ltd, Durham. North Carolina (J.L., L.A., C.B.); Medicine Development and Supply, GlaxoSmithKline R&D, Stevenage, United Kingdom (M.Be.); Department of Dermatology, CUF Tejo Hospital, Lisbon, Portugal (R.V.); Centro de Investigação Interdisciplinar Egas Moniz, Egas Moniz School of Health and Science, Monte de Caparica, Portugal (M.M.); and Department of Chemistry, Coimbra Chemistry Center, University of Coimbra, Coimbra, Portugal (M.M.)
| | - Raquel Vieira
- MLBT Investments and Consultancy, Aylesbury, United Kingdom (M.Br.); MedPharm Ltd, Guildford, United Kingdom (M.Br., B.B., C.E., J.H., F.G.); Reading School of Pharmacy, Reading, United Kingdom (A.W.); School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom (R.P.C., W.J.M.); MedPharm Ltd, Durham. North Carolina (J.L., L.A., C.B.); Medicine Development and Supply, GlaxoSmithKline R&D, Stevenage, United Kingdom (M.Be.); Department of Dermatology, CUF Tejo Hospital, Lisbon, Portugal (R.V.); Centro de Investigação Interdisciplinar Egas Moniz, Egas Moniz School of Health and Science, Monte de Caparica, Portugal (M.M.); and Department of Chemistry, Coimbra Chemistry Center, University of Coimbra, Coimbra, Portugal (M.M.)
| | - Florencia Guidali
- MLBT Investments and Consultancy, Aylesbury, United Kingdom (M.Br.); MedPharm Ltd, Guildford, United Kingdom (M.Br., B.B., C.E., J.H., F.G.); Reading School of Pharmacy, Reading, United Kingdom (A.W.); School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom (R.P.C., W.J.M.); MedPharm Ltd, Durham. North Carolina (J.L., L.A., C.B.); Medicine Development and Supply, GlaxoSmithKline R&D, Stevenage, United Kingdom (M.Be.); Department of Dermatology, CUF Tejo Hospital, Lisbon, Portugal (R.V.); Centro de Investigação Interdisciplinar Egas Moniz, Egas Moniz School of Health and Science, Monte de Caparica, Portugal (M.M.); and Department of Chemistry, Coimbra Chemistry Center, University of Coimbra, Coimbra, Portugal (M.M.)
| | - Margarida Miranda
- MLBT Investments and Consultancy, Aylesbury, United Kingdom (M.Br.); MedPharm Ltd, Guildford, United Kingdom (M.Br., B.B., C.E., J.H., F.G.); Reading School of Pharmacy, Reading, United Kingdom (A.W.); School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom (R.P.C., W.J.M.); MedPharm Ltd, Durham. North Carolina (J.L., L.A., C.B.); Medicine Development and Supply, GlaxoSmithKline R&D, Stevenage, United Kingdom (M.Be.); Department of Dermatology, CUF Tejo Hospital, Lisbon, Portugal (R.V.); Centro de Investigação Interdisciplinar Egas Moniz, Egas Moniz School of Health and Science, Monte de Caparica, Portugal (M.M.); and Department of Chemistry, Coimbra Chemistry Center, University of Coimbra, Coimbra, Portugal (M.M.)
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8
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Silverberg JI, Boguniewicz M, Quintana FJ, Clark RA, Gross L, Hirano I, Tallman AM, Brown PM, Fredericks D, Rubenstein DS, McHale KA. Tapinarof validates the aryl hydrocarbon receptor as a therapeutic target: A clinical review. J Allergy Clin Immunol 2024; 154:1-10. [PMID: 38154665 DOI: 10.1016/j.jaci.2023.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 11/09/2023] [Accepted: 12/08/2023] [Indexed: 12/30/2023]
Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that has wide-ranging roles, including regulation of inflammation and homeostasis. AhR is not a cell surface receptor; rather, it exists in a cytoplasmic complex that responds to a wide variety of structurally dissimilar endogenous, microbial, and environmental ligands. The ubiquitous expression of AhR, its ability to be activated by a wide range of ligands, and its capacity to act as a master regulator for gene expression and homeostasis make it a promising new therapeutic target. Clinical trials of tapinarof cream have now validated AhR agonism as a therapeutic approach that can deliver significant efficacy for treating inflammatory skin diseases, including psoriasis and atopic dermatitis. Tapinarof 1% cream is a first-in-class, nonsteroidal, topical, AhR agonist with a pharmacokinetic profile that results in localized exposure at sites of disease, avoiding systemic safety concerns, drug interactions, or off-target effects. Psoriasis and atopic dermatitis both involve epidermal inflammation, cellular immune responses, dysregulation of skin barrier protein expression, and oxidative stress. On the basis of the clinical effectiveness of tapinarof cream for treating inflammatory skin diseases, we review how targeting AhR may offer a significant opportunity in other conditions that share key aspects of pathogenesis, including asthma, inflammatory bowel disease, eosinophilic esophagitis, ophthalmic, and nervous system diseases.
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Affiliation(s)
| | - Mark Boguniewicz
- Division of Allergy-Immunology, Department of Pediatrics, National Jewish Health and University of Colorado School of Medicine, Denver, Colo
| | - Francisco J Quintana
- Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass
| | | | - Lara Gross
- Dallas Allergy and Asthma Center, and the Allergy and Immunology Division, Baylor University Medical Center, Dallas, Tex
| | - Ikuo Hirano
- Northwestern University Feinberg School of Medicine, Chicago, Ill
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9
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Schmuth M, Eckmann S, Moosbrugger-Martinz V, Ortner-Tobider D, Blunder S, Trafoier T, Gruber R, Elias PM. Skin Barrier in Atopic Dermatitis. J Invest Dermatol 2024; 144:989-1000.e1. [PMID: 38643989 DOI: 10.1016/j.jid.2024.03.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 02/27/2024] [Accepted: 03/07/2024] [Indexed: 04/23/2024]
Abstract
A compromised permeability barrier is a hallmark of atopic dermatitis (AD). Localized to the outermost skin layer, the stratum corneum (SC) is critically dependent on terminal differentiation of epidermal keratinocytes, which transform into protein-rich corneocytes surrounded by extracellular lamellae of unique epidermal lipids, conferring permeability barrier function. These structures are disrupted in AD. A leaky barrier is prone to environmental insult, which in AD elicits type 2-dominant inflammation, in turn resulting in a vicious cycle further impairing the SC structure. Therapies directed at enforcing SC structure and anti-inflammatory strategies administered by topical and systemic route as well as UV therapy have differential effects on the permeability barrier. The expanding armamentarium of therapeutic modalities for AD treatment warrants optimization of their effects on permeability barrier function.
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Affiliation(s)
- Matthias Schmuth
- Dermatology, Venerology and Allergy, Medical University Innsbruck, Innsbruck, Austria; Institute for Pediatric Dermatology and Rare Diseases, Karl Landsteiner Society, Innsbruck, Austria.
| | - Sonja Eckmann
- Dermatology, Venerology and Allergy, Medical University Innsbruck, Innsbruck, Austria
| | | | | | - Stefan Blunder
- Dermatology, Venerology and Allergy, Medical University Innsbruck, Innsbruck, Austria
| | - Thomas Trafoier
- Dermatology, Venerology and Allergy, Medical University Innsbruck, Innsbruck, Austria
| | - Robert Gruber
- Dermatology, Venerology and Allergy, Medical University Innsbruck, Innsbruck, Austria; Institute for Pediatric Dermatology and Rare Diseases, Karl Landsteiner Society, Innsbruck, Austria
| | - Peter M Elias
- Dermatology, Veteran Affairs Health Care System, San Francisco, California, USA; University of California San Francisco, San Francisco, California, USA
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10
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Fluhr JW, Moore DJ, Lane ME, Lachmann N, Rawlings AV. Epidermal barrier function in dry, flaky and sensitive skin: A narrative review. J Eur Acad Dermatol Venereol 2024; 38:812-820. [PMID: 38140732 DOI: 10.1111/jdv.19745] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 11/17/2023] [Indexed: 12/24/2023]
Abstract
The stratum corneum (SC)-the outermost layer of the epidermis-is the principal permeability and protective barrier of the skin. Different components of the SC, including corneocytes, natural moisturizing factor, a variety of enzymes and their inhibitors, antimicrobial peptides and lipids, work interactively to maintain barrier function. The main barrier properties of the SC are the limitation of water loss and the prevention of infection and contact with potentially harmful exogenous factors. Although the SC functions consistently as a protective barrier throughout the body, variations in functions and morphology occur across body sites with age and skin type. Healthy SC function also depends on the interplay between the chemosensory barrier, the skin's microbiome and the innate immune system. Dysregulation of SC barrier function can lead to the development of skin disorders, such as dry, flaky or sensitive skin, but the complete underlying pathophysiology of these are not fully understood. This review provides insight into the current literature and emerging themes related to epidermal barrier changes that occur in the context of dry, flaky and sensitive skin. Additional studies are needed to further elucidate the underlying aetiology of dry, flaky and sensitive skin and to provide tailored treatment.
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Affiliation(s)
- Joachim W Fluhr
- Institute of Allergology IFA Charité Universitätsmedizin, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
| | | | - Majella E Lane
- Department of Pharmaceutics, UCL School of Pharmacy, London, UK
| | | | - Anthony V Rawlings
- Department of Pharmaceutics, UCL School of Pharmacy, London, UK
- AVR Consulting Ltd., Northwich, UK
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11
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Kruse LL, Mancini AJ. Atopic Dermatitis in Children. Pediatr Ann 2024; 53:e121-e128. [PMID: 38574071 DOI: 10.3928/19382359-20240205-02] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/06/2024]
Abstract
Atopic dermatitis (AD) is extremely common in the pediatric population, and most children with AD will first present to their primary care provider (PCP). The PCP can recognize AD by its clinical features, including itch, a chronic relapsing course, and the characteristic eruption. The cornerstone of AD therapy is dry skin care, typically a short daily bath/shower followed by an emollient applied to all skin. Most children with AD will also require topical medications, such as topical corticosteroids and/or topical nonsteroidal therapies. For children with more severe disease, systemic agents, including several novel therapies, may be required. In managing AD, the clinician must monitor for side effects of medications as well as complications of the AD itself, the most common of which is secondary infection. An understanding of the pathogenesis, treatments, and complications of AD is essential for the PCP, as untreated (or undertreated) AD has a significant impact on the quality of life of affected children and their caregivers. [Pediatr Ann. 2024;53(4):e121-e128.].
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12
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Lu HF, Zhou YC, Yang LT, Zhou Q, Wang XJ, Qiu SQ, Cheng BH, Zeng XH. Involvement and repair of epithelial barrier dysfunction in allergic diseases. Front Immunol 2024; 15:1348272. [PMID: 38361946 PMCID: PMC10867171 DOI: 10.3389/fimmu.2024.1348272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 01/15/2024] [Indexed: 02/17/2024] Open
Abstract
The epithelial barrier serves as a critical defense mechanism separating the human body from the external environment, fulfilling both physical and immune functions. This barrier plays a pivotal role in shielding the body from environmental risk factors such as allergens, pathogens, and pollutants. However, since the 19th century, the escalating threats posed by environmental pollution, global warming, heightened usage of industrial chemical products, and alterations in biodiversity have contributed to a noteworthy surge in allergic disease incidences. Notably, allergic diseases frequently exhibit dysfunction in the epithelial barrier. The proposed epithelial barrier hypothesis introduces a novel avenue for the prevention and treatment of allergic diseases. Despite increased attention to the role of barrier dysfunction in allergic disease development, numerous questions persist regarding the mechanisms underlying the disruption of normal barrier function. Consequently, this review aims to provide a comprehensive overview of the epithelial barrier's role in allergic diseases, encompassing influencing factors, assessment techniques, and repair methodologies. By doing so, it seeks to present innovative strategies for the prevention and treatment of allergic diseases.
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Affiliation(s)
- Hui-Fei Lu
- Department of Graduate and Scientific Research, Zhuhai Campus of Zunyi Medical University, Zhuhai, China
- Department of Otolaryngology, Longgang Otolaryngology Hospital & Shenzhen Key Laboratory of Otolaryngology, Institute of Otolaryngology Shenzhen, Shenzhen, China
| | - Yi-Chi Zhou
- Department of Gastroenterology, Beijing University of Chinese Medicine Shenzhen Hospital (Longgang), Shenzhen, China
| | - Li-Tao Yang
- Clinical Laboratory Department of The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People’s Hospital of Shenzhen, Shenzhen, China
| | - Qian Zhou
- Department of Graduate and Scientific Research, Zhuhai Campus of Zunyi Medical University, Zhuhai, China
| | - Xi-Jia Wang
- Department of Graduate and Scientific Research, Zhuhai Campus of Zunyi Medical University, Zhuhai, China
- Department of Otolaryngology, Longgang Otolaryngology Hospital & Shenzhen Key Laboratory of Otolaryngology, Institute of Otolaryngology Shenzhen, Shenzhen, China
| | - Shu-Qi Qiu
- Department of Otolaryngology, Longgang Otolaryngology Hospital & Shenzhen Key Laboratory of Otolaryngology, Institute of Otolaryngology Shenzhen, Shenzhen, China
| | - Bao-Hui Cheng
- Department of Otolaryngology, Longgang Otolaryngology Hospital & Shenzhen Key Laboratory of Otolaryngology, Institute of Otolaryngology Shenzhen, Shenzhen, China
| | - Xian-Hai Zeng
- Department of Graduate and Scientific Research, Zhuhai Campus of Zunyi Medical University, Zhuhai, China
- Department of Otolaryngology, Longgang Otolaryngology Hospital & Shenzhen Key Laboratory of Otolaryngology, Institute of Otolaryngology Shenzhen, Shenzhen, China
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13
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Mok B, Jang YS, Moon JH, Moon S, Jang YK, Kim SY, Jang SJ, Moh SH, Kim DH, Shin JU. The Potential of Campanula takesimana Callus Extract to Enhance Skin Barrier Function. Int J Mol Sci 2023; 24:17333. [PMID: 38139162 PMCID: PMC10743976 DOI: 10.3390/ijms242417333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 11/23/2023] [Accepted: 12/04/2023] [Indexed: 12/24/2023] Open
Abstract
Atopic dermatitis (AD) is a prevalent inflammatory skin disease characterized by epidermal barrier dysfunction and Th2-skewed inflammation. Campanula takesimana (C. takesimana), a Korean endemic plant grown on Ulleng Island, has long been associated with a traditional alternative medicine for asthma, tonsillitis, and sore throat. In this study, we reported the effect of C. takesimana callus extract on upregulating epidermal barrier-related proteins dysregulated by Th2 cytokines. C. takesimana callus extract induced the expression of skin barrier proteins, such as filaggrin, claudin-1, and zonula occludens-1, in both human primary keratinocytes and Th2-induced AD-like skin-equivalent models. Additionally, RNA sequencing analysis demonstrated that C. takesimana callus extract partially restored Th2 cytokine-induced dysregulation of the epidermal development and lipid metabolic pathways. Considering the advantages of callus as a sustainable eco-friendly source of bioactive substances, and its effect on skin barrier proteins and lipid metabolic pathways, C. takesimana callus extracts can possibly be utilized to improve the integrity of the skin barrier.
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Affiliation(s)
- Boram Mok
- Department of Biomedical Science, CHA University School of Medicine, CHA University, Seongnam 13488, Republic of Korea
| | - Young Su Jang
- Department of Biomedical Science, CHA University School of Medicine, CHA University, Seongnam 13488, Republic of Korea
| | - Ji Hwan Moon
- Samsung Genome Institute, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Sujin Moon
- Department of Dermatology, Bundang CHA Medical Center, School of Medicine, CHA University, Seongnam 13496, Republic of Korea
| | - Yun Kyung Jang
- Department of Dermatology, Bundang CHA Medical Center, School of Medicine, CHA University, Seongnam 13496, Republic of Korea
| | - Soo Yun Kim
- Plant Cell Research Institute of BIO-FD&C Co., Ltd., Incheon 21990, Republic of Korea
| | - Sung Joo Jang
- Plant Cell Research Institute of BIO-FD&C Co., Ltd., Incheon 21990, Republic of Korea
| | - Sang Hyun Moh
- Plant Cell Research Institute of BIO-FD&C Co., Ltd., Incheon 21990, Republic of Korea
| | - Dong Hyun Kim
- Department of Dermatology, Bundang CHA Medical Center, School of Medicine, CHA University, Seongnam 13496, Republic of Korea
| | - Jung U Shin
- Department of Dermatology, Bundang CHA Medical Center, School of Medicine, CHA University, Seongnam 13496, Republic of Korea
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14
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Zolotas M, Schleusener J, Lademann J, Meinke MC, Kokolakis G, Darvin ME. Atopic Dermatitis: Molecular Alterations between Lesional and Non-Lesional Skin Determined Noninvasively by In Vivo Confocal Raman Microspectroscopy. Int J Mol Sci 2023; 24:14636. [PMID: 37834083 PMCID: PMC10572245 DOI: 10.3390/ijms241914636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 09/14/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
Atopic dermatitis (AD)/atopic eczema is a chronic relapsing inflammatory skin disease affecting nearly 14% of the adult population. An important pathogenetic pillar in AD is the disrupted skin barrier function (SBF). The atopic stratum corneum (SC) has been examined using several methods, including Raman microspectroscopy, yet so far, there is no depth-dependent analysis over the entire SC thickness. Therefore, we recruited 21 AD patients (9 female, 12 male) and compared the lesional (LAS) with non-lesional atopic skin (nLAS) in vivo with confocal Raman microspectroscopy. Our results demonstrated decreased total intercellular lipid and carotenoid concentrations, as well as a shift towards decreased orthorhombic lateral lipid organisation in LAS. Further, we observed a lower concentration of natural moisturising factor (NMF) and a trend towards increased strongly bound and decreased weakly bound water in LAS. Finally, LAS showed an altered secondary and tertiary keratin structure, demonstrating a more folded keratin state than nLAS. The obtained results are discussed in comparison with healthy skin and yield detailed insights into the atopic SC structure. LAS clearly shows molecular alterations at certain SC depths compared with nLAS which imply a reduced SBF. A thorough understanding of these alterations provides useful information on the aetiology of AD and for the development/control of targeted topical therapies.
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Affiliation(s)
- Michael Zolotas
- Center of Experimental and Applied Cutaneous Physiology, Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Johannes Schleusener
- Center of Experimental and Applied Cutaneous Physiology, Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Jürgen Lademann
- Center of Experimental and Applied Cutaneous Physiology, Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Martina C Meinke
- Center of Experimental and Applied Cutaneous Physiology, Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Georgios Kokolakis
- Psoriasis Research and Treatment Centre, Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Maxim E Darvin
- Center of Experimental and Applied Cutaneous Physiology, Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
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15
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Bratu D, Boda D, Caruntu C. Genomic, Epigenomic, Transcriptomic, Proteomic and Metabolomic Approaches in Atopic Dermatitis. Curr Issues Mol Biol 2023; 45:5215-5231. [PMID: 37367080 PMCID: PMC10297041 DOI: 10.3390/cimb45060331] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/03/2023] [Accepted: 06/07/2023] [Indexed: 06/28/2023] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease with a high prevalence in the developed countries. It is associated with atopic and non-atopic diseases, and its close correlation with atopic comorbidities has been genetically demonstrated. One of the main roles of genetic studies is to comprehend the defects of the cutaneous barrier due to filaggrin deficit and epidermal spongiosis. Recently, epigenetic studies started to analyze the influence of the environmental factors on gene expression. The epigenome is considered to be a superior second code that controls the genome, which includes alterations of the chromatin. The epigenetic changes do not alter the genetic code, however, changes in the chromatin structure could activate or inhibit the transcription process of certain genes and consequently, the translation process of the new mRNA into a polypeptide chain. In-depth analysis of the transcriptomic, metabolomic and proteomic studies allow to unravel detailed mechanisms that cause AD. The extracellular space and lipid metabolism are associated with AD that is independent of the filaggrin expression. On the other hand, around 45 proteins are considered as the principal components in the atopic skin. Moreover, genetic studies based on the disrupted cutaneous barrier can lead to the development of new treatments targeting the cutaneous barrier or cutaneous inflammation. Unfortunately, at present, there are no target therapies that focus on the epigenetic process of AD. However, in the future, miR-143 could be an important objective for new therapies, as it targets the miR-335:SOX axis, thereby restoring the miR-335 expression, and repairing the cutaneous barrier defects.
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Affiliation(s)
- Dalia Bratu
- Department of Dermatology, ‘Colentina’ Clinical Hospital, 020125 Bucharest, Romania;
- Department of Dermatology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Daniel Boda
- Department of Dermatology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania;
- Department of Dermatology, ‘Ponderas’ Academic Hospital, 014142 Bucharest, Romania
- Department of Dermatology, “Prof. N.C. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania
| | - Constantin Caruntu
- Department of Dermatology, “Prof. N.C. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania
- Department of Physiology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
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16
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Grigolon G, Nowak K, Poigny S, Hubert J, Kotland A, Waldschütz L, Wandrey F. From Coffee Waste to Active Ingredient for Cosmetic Applications. Int J Mol Sci 2023; 24:ijms24108516. [PMID: 37239862 DOI: 10.3390/ijms24108516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/04/2023] [Accepted: 05/05/2023] [Indexed: 05/28/2023] Open
Abstract
Coffee silverskin (CS) is the thin epidermis covering and protecting the coffee bean and it represents the main by-product of the coffee roasting process. CS has recently gained attention due to its high content in bioactive molecules and the growing interest in valuable reutilization of waste products. Drawing inspiration from its biological function, here its potential in cosmetic applications was investigated. CS was recovered from one of the largest coffee roasters located in Switzerland and processed through supercritical CO2 extraction, thereby generating coffee silverskin extract. Chemical profiling of this extract revealed the presence of potent molecules, among which cafestol and kahweol fatty acid esters, as well as acylglycerols, β-sitosterol and caffeine. The CS extract was then dissolved in organic shea butter, yielding the cosmetic active ingredient SLVR'Coffee™. In vitro gene expression studies performed on keratinocytes showed an upregulation of genes involved in oxidative stress responses and skin-barrier functionality upon treatment with the coffee silverskin extract. In vivo, our active protected the skin against Sodium Lauryl Sulfate (SLS)-induced irritation and accelerated its recovery. Furthermore, this active extract improved measured as well as perceived skin hydration in female volunteers, making it an innovative, bioinspired ingredient that comforts the skin and benefits the environment.
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Affiliation(s)
| | - Kathrin Nowak
- Mibelle Group Biochemistry, Mibelle AG, 5033 Buchs, Switzerland
| | - Stéphane Poigny
- Mibelle Group Biochemistry, Mibelle AG, 5033 Buchs, Switzerland
| | | | | | - Laura Waldschütz
- NATECO2-Hopfenveredlung St. Johann GmbH, 85283 Wolnzach, Germany
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17
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van den Bogaard EH, Elias PM, Goleva E, Berdyshev E, Smits JPH, Danby SG, Cork MJ, Leung DYM. Targeting Skin Barrier Function in Atopic Dermatitis. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:1335-1346. [PMID: 36805053 PMCID: PMC11346348 DOI: 10.1016/j.jaip.2023.02.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/22/2023]
Abstract
Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in the general population. Skin barrier dysfunction is the central abnormality leading to AD. The cause of skin barrier dysfunction is complex and rooted in genetic mutations, interactions between the immune pathway activation and epithelial cells, altered host defense mechanisms, as well as environmental influences that cause epithelial cell activation and release of alarmins (such as thymic stromal lymphopoietin) that can activate the type 2 immune pathway, including generation of interleukins 4 and 13, which induces defects in the skin barrier and increased allergic inflammation. These inflammatory pathways are further influenced by environmental factors including the microbiome (especially Staphylococcus aureus), air pollution, stress, and other factors. As such, AD is a syndrome involving multiple phenotypes, all of which have in common skin barrier dysfunction as a key contributing factor. Understanding mechanisms leading to skin barrier dysfunction in AD is pointing to the development of new topical and systemic treatments in AD that helps keep skin borders secure and effectively treat the disease.
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Affiliation(s)
- Ellen H van den Bogaard
- Department of Dermatology, Radboud Institute for Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Peter M Elias
- Department of Dermatology, University of California San Francisco and VA Medical Center, San Francisco, Calif
| | - Elena Goleva
- Department of Pediatrics, Division of Pediatric Allergy and Immunology, National Jewish Health, Denver, Colo
| | - Evgeny Berdyshev
- Department of Pulmonology, Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, Colo
| | - Jos P H Smits
- Department of Dermatology, Radboud Institute for Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Simon G Danby
- Department of Infection, Immunity and Cardiovascular Disease, The Medical School at The University of Sheffield, Beech Hill Road, Sheffield, UK
| | - Michael J Cork
- Department of Infection, Immunity and Cardiovascular Disease, The Medical School at The University of Sheffield, Beech Hill Road, Sheffield, UK
| | - Donald Y M Leung
- Department of Pediatrics, Division of Pediatric Allergy and Immunology, National Jewish Health, Denver, Colo.
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18
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Hori H, Kotani A, Abe J, Matsuguchi S, Hirai Y. Extracellular epimorphin impairs expression and processing of profilaggrin in HaCaT keratinocytes. Cytotechnology 2023; 75:123-133. [PMID: 36969570 PMCID: PMC10030722 DOI: 10.1007/s10616-022-00566-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 12/10/2022] [Indexed: 12/23/2022] Open
Abstract
The expression and processing of filaggrin, a filament-associated protein in the skin epidermis, is closely associated with keratinocyte cornification. The large precursor profilaggrin (Pro-FLG) is initially detected at the granular layer in keratohyalin granules, subsequently processed into 10 to 12 filaggrin monomers (mFLGs) for keratin assembly, and ultimately degraded into smaller peptides that behave as natural moisturizing factor (NMF) at the outermost epidermis. We previously reported that epimorphin (EPM) extruded upon external stimuli severely perturbs epidermal terminal differentiation. Using HaCaT keratinocytes with inducible expression and recombinant EPM and FLG, we investigated the effect of extracellular EPM on the expression profile of filaggrin. As expression and processing of Pro-FLG in primary keratinocytes are accompanied with apoptotic cell death, we employed HaCaT keratinocytes that grow and express filaggrin mRNA in standard culture medium. In response to ectopic stimulation with extracellular EPM, Pro-FLG expression decreased with elimination of keratohyalin granules in the cells, with filaggrin mRNA remained constant and profilaggrin processing was not accelerated. Additionally, using a recombinant form of mFLG engineered for intracellular localization, we found that extracellular EPM hindered proteolytic cleavage of mFLG for production of NMF. Taken together, extracellularly extruded EPM, an epidermal cornification blocker, not only decreases Pro-FLG expression but also reduces the production of NMF in HaCaT keratinocytes. Supplementary Information The online version contains supplementary material available at 10.1007/s10616-022-00566-8.
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Affiliation(s)
- Haruna Hori
- Department of Biomedical Sciences, Graduate School of Science and Technology, Kwansei Gakuin University, 1, GakuenUegahara, Sanda, 669-1330 Japan
- Present Address: Oppen Cosmetics Co, LTD. 2-17-1 Kisibeminami, Suita, 565-8501 Japan
| | - Ayaka Kotani
- Department of Biomedical Sciences, Graduate School of Science and Technology, Kwansei Gakuin University, 1, GakuenUegahara, Sanda, 669-1330 Japan
| | - Junya Abe
- Department of Biomedical Sciences, Graduate School of Science and Technology, Kwansei Gakuin University, 1, GakuenUegahara, Sanda, 669-1330 Japan
| | - Shuji Matsuguchi
- Department of Biomedical Sciences, Graduate School of Science and Technology, Kwansei Gakuin University, 1, GakuenUegahara, Sanda, 669-1330 Japan
| | - Yohei Hirai
- Department of Biomedical Sciences, Graduate School of Science and Technology, Kwansei Gakuin University, 1, GakuenUegahara, Sanda, 669-1330 Japan
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19
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Perälä M, Kaustio M, Salava A, Jakkula E, Pelkonen AS, Saarela J, Remitz A, Mäkelä MJ. RELEVANCE OF CODING VARIATION IN FILAGGRIN AND DOCK8 IN FINNISH PEDIATRIC PATIENTS WITH EARLY-ONSET MODERATE-TO-SEVERE ATOPIC DERMATITIS. JID INNOVATIONS 2023. [PMID: 37533579 PMCID: PMC10392095 DOI: 10.1016/j.xjidi.2023.100203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2023] Open
Abstract
Early-onset, persistent atopic dermatitis (AD) is proposed as a distinct subgroup that may have specific genotypic features. FLG gene loss-of-function variants are the best known genetic factors contributing to epidermal barrier impairment and eczema severity. In a cohort of 140 Finnish children with early-onset moderate-to-severe AD, we investigated the effect of coding variation in FLG and 13 other genes with epidermal barrier or immune function through the use of targeted amplicon sequencing and genotyping. A FLG loss-of-function variant (Arg501Ter, Ser761fs, Arg2447Ter, or Ser3247Ter) was identified in 20 of 140 patients showing higher transepidermal water loss values than patients without these variants. Total FLG loss-of-function variant frequency (7.14%) was significantly higher than in the general Finnish population (2.34%). When tested separately, only Arg2447Ter showed a significant association with AD (P = 0.003104). In addition, a modest association with moderate-to-severe pediatric AD was seen for rs12730241 and rs6587667 (FLG2:Gly137Glu). Loss-of-function variants, previously reported pathogenic variants, or statistically significant enrichment of nonsynonymous coding region variants were not found in the 13 candidate genes studied by amplicon sequencing. However, higher IgE and eosinophil counts were found in carriers of potentially pathogenic DOCK8 missense variants, suggesting that the role of DOCK8 variation in AD should be further investigated in larger cohorts.
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20
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Investigations into the filaggrin null phenotype: showcasing the methodology for CRISPR/Cas9 editing of human keratinocytes. J Invest Dermatol 2023:S0022-202X(23)00165-3. [PMID: 36893939 DOI: 10.1016/j.jid.2023.02.021] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 01/20/2023] [Accepted: 02/11/2023] [Indexed: 03/09/2023]
Abstract
Ever since the association between filaggrin (FLG) loss-of-function mutations and ichthyosis vulgaris and atopic dermatitis disease onset was identified, filaggrins function has been under investigation. Intra-individual genomic predisposition, immunological confounders, and environmental interactions complicate the comparison between FLG genotypes and related causal effects. Using CRISPR/Cas9, we generated human FLG knockout (ΔFLG) N/TERT-2G keratinocytes. Filaggrin deficiency was demonstrated by immunohistochemistry of human epidermal equivalent (HEE) cultures. Next to (partial) loss of structural proteins (IVL, HRNR, KRT2, and TGM1), the stratum corneum was more dense and lacked the typical basket weave appearance. In addition, electrical impedance spectroscopy and transepidermal water loss analyses highlighted a compromised epidermal barrier in ΔFLG-HEEs. Correction of FLG reinstated the presence of keratohyalin granules in the stratum granulosum, filaggrin protein expression, and expression of aforementioned proteins. The beneficial effects on stratum corneum formation were reflected by normalization of EIS and TEWL. This study demonstrates the causal phenotypical and functional consequences of filaggrin deficiency, indicating filaggrin is not only central in epidermal barrier function but also vital for epidermal differentiation by orchestrating the expression of other important epidermal proteins. These observations pave the way to fundamental investigations into the exact role of filaggrin in skin biology and disease.
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21
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Rinnov MR, Halling AS, Gerner T, Ravn NH, Knudgaard MH, Trautner S, Goorden SMI, Ghauharali-van der Vlugt KJM, Stet FS, Skov L, Thomsen SF, Egeberg A, Rosted ALL, Petersen T, Jakasa I, Riethmüller C, Kezic S, Thyssen JP. Skin biomarkers predict development of atopic dermatitis in infancy. Allergy 2023; 78:791-802. [PMID: 36112082 DOI: 10.1111/all.15518] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 07/14/2022] [Accepted: 08/08/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND There is currently no insight into biomarkers that can predict the onset of pediatric atopic dermatitis (AD). METHODS Nested in a prospective birth cohort study that examined the occurrence of physician-diagnosed AD in 300 children, 44 random children with onset of AD in the first year of life were matched on sex and season of birth with 44 children who did not develop AD. Natural moisturizing factor (NMF), corneocyte surface protrusions, cytokines, free sphingoid bases (SBs) of different chain lengths and their ceramides were analyzed from tape strips collected at 2 months of age before onset of AD using liquid chromatography, atomic force microscopy, multiplex immunoassay, and liquid chromatography mass spectrometry, respectively. RESULTS Significant alterations were observed for four lipid markers, with phytosphingosine ([P]) levels being significantly lower in children who developed AD compared with children who did not (median 240 pmol/mg vs. 540 pmol/mg, p < 0.001). The two groups of children differed in the relative amounts of SB of different chain lengths (C17, C18 and C20). Thymus- and activation-regulated chemokine (TARC/CCL17) was slightly higher in children who developed AD, whereas NMF and corneocyte surface texture were similar. AD severity assessed by the eczema area and severity index (EASI) at disease onset was 4.2 (2.0;7.2). [P] had the highest prediction accuracy among the biomarkers (75.6%), whereas the combination of 5 lipid ratios gave an accuracy of 89.4%. CONCLUSION This study showed that levels and SB chain length were altered in infants who later developed AD, and that TARC/CCL17 levels were higher.
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Affiliation(s)
- Maria Rasmussen Rinnov
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Anne-Sofie Halling
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.,Department of Dermatology and Venereology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Trine Gerner
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Nina Haarup Ravn
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Mette Hjorslev Knudgaard
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Simon Trautner
- Department of Neonatology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Susan M I Goorden
- Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Karen J M Ghauharali-van der Vlugt
- Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Femke S Stet
- Department of Dermatology and Venereology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Lone Skov
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Simon Francis Thomsen
- Department of Dermatology and Venereology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Alexander Egeberg
- Department of Dermatology and Venereology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Aske L L Rosted
- Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark
| | - Troels Petersen
- Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark
| | - Ivone Jakasa
- Laboratory for Analytical Chemistry, Department of Chemistry and Biochemistry, Faculty of Food Technology and Biotechnology, University of Zagreb, Zagreb, Croatia
| | | | - Sanja Kezic
- Amsterdam Public Health research institute, Department of Public and Occupational Health Amsterdam UMC, Department of Public and Occupational Health, University of Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands
| | - Jacob P Thyssen
- Department of Dermatology and Venereology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
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22
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Epicutaneous Sensitization and Food Allergy: Preventive Strategies Targeting Skin Barrier Repair-Facts and Challenges. Nutrients 2023; 15:nu15051070. [PMID: 36904070 PMCID: PMC10005101 DOI: 10.3390/nu15051070] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/16/2023] [Accepted: 02/18/2023] [Indexed: 02/25/2023] Open
Abstract
Food allergy represents a growing public health and socio-economic problem with an increasing prevalence over the last two decades. Despite its substantial impact on the quality of life, current treatment options for food allergy are limited to strict allergen avoidance and emergency management, creating an urgent need for effective preventive strategies. Advances in the understanding of the food allergy pathogenesis allow to develop more precise approaches targeting specific pathophysiological pathways. Recently, the skin has become an important target for food allergy prevention strategies, as it has been hypothesized that allergen exposure through the impaired skin barrier might induce an immune response resulting in subsequent development of food allergy. This review aims to discuss current evidence supporting this complex interplay between the skin barrier dysfunction and food allergy by highlighting the crucial role of epicutaneous sensitization in the causality pathway leading to food allergen sensitization and progression to clinical food allergy. We also summarize recently studied prophylactic and therapeutic interventions targeting the skin barrier repair as an emerging food allergy prevention strategy and discuss current evidence controversies and future challenges. Further studies are needed before these promising strategies can be routinely implemented as prevention advice for the general population.
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23
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Thibault Greugny E, Bensaci J, Fages F, Stamatas GN. Computational modelling predicts impaired barrier function and higher sensitivity to skin inflammation following pH elevation. Exp Dermatol 2023; 32:177-185. [PMID: 36321871 DOI: 10.1111/exd.14698] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 07/04/2022] [Accepted: 10/27/2022] [Indexed: 11/07/2022]
Abstract
Skin surface pH has been identified as a key regulator of the epidermal homeostasis through its action on serine protease activity. These enzymes, like kallikreins (KLK), are responsible for the degradation of corneodesmosomes, the protein structures linking together corneocytes, and are regulated by Lympho-Epithelial Kazal-Type-related Inhibitor (LEKTI). KLK activity increases at pH levels higher than physiological. An increase in skin surface pH has been observed in patients suffering from skin diseases characterized by impaired barrier function, like atopic dermatitis. In this work, we introduce an agent-based model of the epidermis to study the impact of a change in skin surface pH on the structural and physiological properties of the epidermis, through the LEKTI-KLK mechanism. We demonstrate that a less acidic pH, compared to the slightly acidic pH observed in healthy skin, is sufficient to significantly affect the water loss at the surface and the amount of irritant permeating through the epidermis. This weakening of the skin barrier function eventually results in a more intense skin inflammation following exposure to an external irritant. This work provides additional evidence that skin surface pH and serine proteases can be therapeutic targets to improve skin barrier integrity.
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Affiliation(s)
- Eléa Thibault Greugny
- Essential Health Translational Science, Johnson & Johnson Santé Beauté France, Issy-les-Moulineaux, France.,Inria Saclay Île-de-France, Lifeware Team, Palaiseau, France
| | - Jalil Bensaci
- Essential Health Translational Science, Johnson & Johnson Santé Beauté France, Issy-les-Moulineaux, France
| | - François Fages
- Inria Saclay Île-de-France, Lifeware Team, Palaiseau, France
| | - Georgios N Stamatas
- Essential Health Translational Science, Johnson & Johnson Santé Beauté France, Issy-les-Moulineaux, France
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24
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Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signaling in cutaneous T-cell lymphoma. Blood 2023; 141:180-193. [PMID: 36122387 DOI: 10.1182/blood.2022016690] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 09/01/2022] [Accepted: 09/07/2022] [Indexed: 01/17/2023] Open
Abstract
Cutaneous T-cell lymphoma (CTCL) is a devastating lymphoid malignancy characterized by the accumulation of malignant T cells in the dermis and epidermis. Skin lesions cause serious symptoms that hamper quality of life and are entry sites for bacterial infection, a major cause of morbidity and mortality in advanced diseases. The mechanism driving the pathological processes that compromise the skin barrier remains unknown. Here, we report increased transepidermal water loss and compromised expression of the skin barrier proteins filaggrin and filaggrin-2 in areas adjacent to TOX-positive T cells in CTCL skin lesions. Malignant T cells secrete mediators (including cytokines such as interleukin 13 [IL-13], IL-22, and oncostatin M) that activate STAT3 signaling and downregulate filaggrin and filaggrin-2 expression in human keratinocytes and reconstructed human epithelium. Consequently, the repression of filaggrins can be counteracted by a cocktail of antibodies targeting these cytokines/receptors, small interfering RNA-mediated knockdown of JAK1/STAT3, and JAK1 inhibitors. Notably, we show that treatment with a clinically approved JAK inhibitor, tofacitinib, increases filaggrin expression in lesional skin from patients with mycosis fungoides. Taken together, these findings indicate that malignant T cells secrete cytokines that induce skin barrier defects via a JAK1/STAT3-dependent mechanism. As clinical grade JAK inhibitors largely abrogate the negative effect of malignant T cells on skin barrier proteins, our findings suggest that such inhibitors provide novel treatment options for patients with CTCL with advanced disease and a compromised skin barrier.
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25
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Murashkin NN, Epishev RV, Ivanov RA, Materikin AI, Opryatin LA, Savelova AA, Nezhvedilova RY, Ambarchian ET, Fedorov DV, Rusakova LL. Innovations in Therapeutic Improvement of the Cutaneous Microbiome in Children with Atopic Dermatitis. CURRENT PEDIATRICS 2022. [DOI: 10.15690/vsp.v21i5.2449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Biofilm is the dominant form of skin microbiota organization that provides adhesion and preservation of microorganisms in the skin micro-environment. It is necessary to ensure epidermal barrier function and local immunomodulation. Staphylococcus aureus becomes the major colonizer of skin lesions in case of atopic dermatitis exacerbation, and it also can form the biofilms. S. aureus growth and biofilm formation due to other microbial commensals on the skin of patients with atopic dermatitis leads to chronic output of pro-inflammatory cytokines and later to abnormalities in healthy skin microbiome. The role of microbial biofilm in human’s health makes the skin microbiota an attractive target for therapeutic intervention in various skin diseases.
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Affiliation(s)
- N. N. Murashkin
- National Medical Research Center of Children’s Health; Sechenov First Moscow State Medical University; Central State Medical Academy of Department of Presidential Affairs
| | - R. V. Epishev
- National Medical Research Center of Children’s Health
| | - R. A. Ivanov
- National Medical Research Center of Children’s Health
| | | | | | | | | | - E. T. Ambarchian
- Pediatrics and Child Health Research Institute in Petrovsky National Research Centre of Surgery
| | - D. V. Fedorov
- National Medical Research Center of Children’s Health
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26
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Berdyshev E, Goleva E, Bissonnette R, Bronova I, Bronoff AS, Richers BN, Garcia S, Ramirez-Gama M, Taylor P, Praestgaard A, Agueusop I, Jurvilliers P, Boguniewicz M, Levit NA, Rossi AB, Zhang A, Leung DYM. Dupilumab significantly improves skin barrier function in patients with moderate-to-severe atopic dermatitis. Allergy 2022; 77:3388-3397. [PMID: 35815904 DOI: 10.1111/all.15432] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 06/01/2022] [Accepted: 06/03/2022] [Indexed: 01/28/2023]
Abstract
BACKGROUND Atopic dermatitis (AD) is characterized by abnormal skin lipids that are largely driven by hyperactivated type 2 immune responses. The antibody to the α-subunit of interleukin (IL)-4 receptor, dupilumab, was recently approved to treat AD and demonstrated strong efficacy. However, the role of dupilumab therapy in the regulation of skin barrier structure and function has not been fully explored. METHODS We have evaluated the content of lipids and transepidermal water loss (TEWL) in lesional and non-lesional skin of adults and adolescents with moderate-to-severe AD over the course of 16-week treatment with dupilumab and compared those values with that of matched healthy volunteers. RESULTS Dupilumab treatment provided a significant decrease in TEWL in AD lesions, lowering it almost to the levels seen in the skin of healthy subjects. Blocking IL-4/IL-13 signaling with dupilumab normalized lipid composition (decreased levels of ceramides with non-hydroxy fatty acids and C18-sphingosine and increased the level of esterified omega-hydroxy fatty acid-containing ceramides) and increased ceramide chain length in lesional as well as non-lesional stratum corneum of AD patients. Partial changes for these parameters were already observed after 2 weeks, with a full response achieved after 8 weeks of dupilumab treatment. CONCLUSIONS Inhibition of IL-4/IL-13 signaling by dupilumab allows restoration of skin lipid composition and barrier function in patients with moderate-to-severe AD.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Noah A Levit
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA
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27
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Lee MK, Ryu H, Lee JY, Jeong HH, Baek J, Van JY, Kim MJ, Jung WK, Lee B. Potential Beneficial Effects of Sargassum spp. in Skin Aging. Mar Drugs 2022; 20:540. [PMID: 36005543 PMCID: PMC9410049 DOI: 10.3390/md20080540] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/10/2022] [Accepted: 08/18/2022] [Indexed: 11/21/2022] Open
Abstract
Seaweeds are receiving much attention as a rich source of bioactive compounds with cosmeceutical potential. Recent studies have revealed that Sargassum spp., a genus of brown algae in the family Sargassaceae, has multiple functions in preventing and improving skin aging. Sargassum spp. contains many bioactive compounds, such as fucoidan, fucoxanthin, terpenoids, flavonoids, and meroterpenoids. These Sargassum spp. extracts and derivative compounds have excellent potential for skincare, as they exhibit skin health-promoting properties, including antioxidants, anti-inflammation, whitening, skin barrier repair, and moisturizing. Therefore, searching for bioactive compounds in marine resources such as Sargassum spp. could be an attractive approach to preventing and improving skin aging. The current review focused on the various biological abilities of Sargassum extracts or derived compounds for anti-skin aging.
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Affiliation(s)
- Min-Kyeong Lee
- Department of Food Science and Nutrition, Pukyong National University, Daeyeon-dong, Nam-gu, Busan 48513, Korea
| | - Heeyeon Ryu
- Department of Food Science and Nutrition, Pukyong National University, Daeyeon-dong, Nam-gu, Busan 48513, Korea
| | - Ji Yun Lee
- Department of Food Science and Nutrition, Pukyong National University, Daeyeon-dong, Nam-gu, Busan 48513, Korea
| | - Hyeon Hak Jeong
- Department of Food Science and Nutrition, Pukyong National University, Daeyeon-dong, Nam-gu, Busan 48513, Korea
| | - Jiwon Baek
- Department of Food Science and Nutrition, Pukyong National University, Daeyeon-dong, Nam-gu, Busan 48513, Korea
| | - Ji Yun Van
- Department of Food Science and Nutrition, Pukyong National University, Daeyeon-dong, Nam-gu, Busan 48513, Korea
| | - Myeong-Jin Kim
- Department of Food Science and Nutrition, Pukyong National University, Daeyeon-dong, Nam-gu, Busan 48513, Korea
| | - Won-Kyo Jung
- Division of Biomedical Engineering and Research Center for Marine Integrated Bionics Technology, Pukyong National University, Daeyeon-dong, Nam-gu, Busan 48513, Korea
| | - Bonggi Lee
- Department of Food Science and Nutrition, Pukyong National University, Daeyeon-dong, Nam-gu, Busan 48513, Korea
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28
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Paredes-Barquero M, Niso-Santano M, Fuentes JM, Martínez-Chacón G. In vitro and in vivo models to study the biological and pharmacological properties of queen bee acid (QBA, 10-hydroxy-2-decenoic acid): A systematic review. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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29
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Ujiie H, Rosmarin D, Schön MP, Ständer S, Boch K, Metz M, Maurer M, Thaci D, Schmidt E, Cole C, Amber KT, Didona D, Hertl M, Recke A, Graßhoff H, Hackel A, Schumann A, Riemekasten G, Bieber K, Sprow G, Dan J, Zillikens D, Sezin T, Christiano AM, Wolk K, Sabat R, Kridin K, Werth VP, Ludwig RJ. Unmet Medical Needs in Chronic, Non-communicable Inflammatory Skin Diseases. Front Med (Lausanne) 2022; 9:875492. [PMID: 35755063 PMCID: PMC9218547 DOI: 10.3389/fmed.2022.875492] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 05/09/2022] [Indexed: 12/15/2022] Open
Abstract
An estimated 20-25% of the population is affected by chronic, non-communicable inflammatory skin diseases. Chronic skin inflammation has many causes. Among the most frequent chronic inflammatory skin diseases are atopic dermatitis, psoriasis, urticaria, lichen planus, and hidradenitis suppurativa, driven by a complex interplay of genetics and environmental factors. Autoimmunity is another important cause of chronic skin inflammation. The autoimmune response may be mainly T cell driven, such as in alopecia areata or vitiligo, or B cell driven in chronic spontaneous urticaria, pemphigus and pemphigoid diseases. Rare causes of chronic skin inflammation are autoinflammatory diseases, or rheumatic diseases, such as cutaneous lupus erythematosus or dermatomyositis. Whilst we have seen a significant improvement in diagnosis and treatment, several challenges remain. Especially for rarer causes of chronic skin inflammation, early diagnosis is often missed because of low awareness and lack of diagnostics. Systemic immunosuppression is the treatment of choice for almost all of these diseases. Adverse events due to immunosuppression, insufficient therapeutic responses and relapses remain a challenge. For atopic dermatitis and psoriasis, a broad spectrum of innovative treatments has been developed. However, treatment responses cannot be predicted so far. Hence, development of (bio)markers allowing selection of specific medications for individual patients is needed. Given the encouraging developments during the past years, we envision that many of these challenges in the diagnosis and treatment of chronic inflammatory skin diseases will be thoroughly addressed in the future.
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Affiliation(s)
- Hideyuki Ujiie
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - David Rosmarin
- Department of Dermatology, Tufts Medical Center, Boston, MA, United States
| | - Michael P. Schön
- Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany
- Lower Saxony Institute of Occupational Dermatology, University Medical Center Göttingen, Göttingen, Germany
| | - Sonja Ständer
- Center for Chronic Pruritus, Department of Dermatology, University Hospital Muenster, Muenster, Germany
| | - Katharina Boch
- Department of Dermatology, University of Lübeck, Lübeck, Germany
| | - Martin Metz
- Institute for Allergology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Allergology and Immunology, Berlin, Germany
| | - Marcus Maurer
- Institute for Allergology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Allergology and Immunology, Berlin, Germany
| | - Diamant Thaci
- Institute and Comprehensive Center for Inflammation Medicine, University of Lübeck, Lübeck, Germany
| | - Enno Schmidt
- Department of Dermatology, University of Lübeck, Lübeck, Germany
- Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany
| | - Connor Cole
- Division of Dermatology, Rush University Medical Center, Chicago, IL, United States
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL, United States
| | - Kyle T. Amber
- Division of Dermatology, Rush University Medical Center, Chicago, IL, United States
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL, United States
| | - Dario Didona
- Department of Dermatology and Allergology, Philipps-Universität, Marburg, Germany
| | - Michael Hertl
- Department of Dermatology and Allergology, Philipps-Universität, Marburg, Germany
| | - Andreas Recke
- Department of Dermatology, University of Lübeck, Lübeck, Germany
| | - Hanna Graßhoff
- Department of Rheumatology and Clinical Immunology, University of Lübeck, Lübeck, Germany
| | - Alexander Hackel
- Department of Rheumatology and Clinical Immunology, University of Lübeck, Lübeck, Germany
| | - Anja Schumann
- Department of Rheumatology and Clinical Immunology, University of Lübeck, Lübeck, Germany
| | - Gabriela Riemekasten
- Department of Rheumatology and Clinical Immunology, University of Lübeck, Lübeck, Germany
| | - Katja Bieber
- Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany
| | - Gant Sprow
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, United States
| | - Joshua Dan
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, United States
| | - Detlef Zillikens
- Department of Dermatology, University of Lübeck, Lübeck, Germany
| | - Tanya Sezin
- Department of Dermatology, Columbia University Medical Center, New York, NY, United States
| | - Angela M. Christiano
- Department of Dermatology, Columbia University Medical Center, New York, NY, United States
| | - Kerstin Wolk
- Psoriasis Research and Treatment Centre, Charité—Universitätsmedizin Berlin, Berlin, Germany
- Interdisciplinary Group Molecular Immunopathology, Dermatology/Medical Immunology, Charité—Universitätsmedizin Berlin, Berlin, Germany
| | - Robert Sabat
- Psoriasis Research and Treatment Centre, Charité—Universitätsmedizin Berlin, Berlin, Germany
- Interdisciplinary Group Molecular Immunopathology, Dermatology/Medical Immunology, Charité—Universitätsmedizin Berlin, Berlin, Germany
| | - Khalaf Kridin
- Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Victoria P. Werth
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, United States
| | - Ralf J. Ludwig
- Department of Dermatology, University of Lübeck, Lübeck, Germany
- Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany
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Moosbrugger-Martinz V, Leprince C, Méchin MC, Simon M, Blunder S, Gruber R, Dubrac S. Revisiting the Roles of Filaggrin in Atopic Dermatitis. Int J Mol Sci 2022; 23:5318. [PMID: 35628125 PMCID: PMC9140947 DOI: 10.3390/ijms23105318] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/03/2022] [Accepted: 05/06/2022] [Indexed: 12/31/2022] Open
Abstract
The discovery in 2006 that loss-of-function mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris and can predispose to atopic dermatitis (AD) galvanized the dermatology research community and shed new light on a skin protein that was first identified in 1981. However, although outstanding work has uncovered several key functions of filaggrin in epidermal homeostasis, a comprehensive understanding of how filaggrin deficiency contributes to AD is still incomplete, including details of the upstream factors that lead to the reduced amounts of filaggrin, regardless of genotype. In this review, we re-evaluate data focusing on the roles of filaggrin in the epidermis, as well as in AD. Filaggrin is important for alignment of keratin intermediate filaments, control of keratinocyte shape, and maintenance of epidermal texture via production of water-retaining molecules. Moreover, filaggrin deficiency leads to cellular abnormalities in keratinocytes and induces subtle epidermal barrier impairment that is sufficient enough to facilitate the ingress of certain exogenous molecules into the epidermis. However, although FLG null mutations regulate skin moisture in non-lesional AD skin, filaggrin deficiency per se does not lead to the neutralization of skin surface pH or to excessive transepidermal water loss in atopic skin. Separating facts from chaff regarding the functions of filaggrin in the epidermis is necessary for the design efficacious therapies to treat dry and atopic skin.
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Affiliation(s)
- Verena Moosbrugger-Martinz
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria; (V.M.-M.); (S.B.); (R.G.)
| | - Corinne Leprince
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), Toulouse University, CNRS UMR5051, Inserm UMR1291, UPS, 31059 Toulouse, France; (C.L.); (M.-C.M.); (M.S.)
| | - Marie-Claire Méchin
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), Toulouse University, CNRS UMR5051, Inserm UMR1291, UPS, 31059 Toulouse, France; (C.L.); (M.-C.M.); (M.S.)
| | - Michel Simon
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), Toulouse University, CNRS UMR5051, Inserm UMR1291, UPS, 31059 Toulouse, France; (C.L.); (M.-C.M.); (M.S.)
| | - Stefan Blunder
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria; (V.M.-M.); (S.B.); (R.G.)
| | - Robert Gruber
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria; (V.M.-M.); (S.B.); (R.G.)
| | - Sandrine Dubrac
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria; (V.M.-M.); (S.B.); (R.G.)
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Singh S, Behl T, Sharma N, Zahoor I, Chigurupati S, Yadav S, Rachamalla M, Sehgal A, Naved T, Pritima, Arora S, Bhatia S, Al-Harrasi A, Mohan S, Aleya L, Bungau S. Targeting therapeutic approaches and highlighting the potential role of nanotechnology in atopic dermatitis. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:32605-32630. [PMID: 35195869 DOI: 10.1007/s11356-021-18429-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 12/27/2021] [Indexed: 06/14/2023]
Abstract
Atopic dermatitis is a chronic as well as widespread skin disease which has significant influence on the life attributes of affected people and their families. Systemic immunosuppressive drugs can be utilised for effective care of disease, although they are often prescribed for rigorous disruption or disease that is complicated to manage. Therefore, topical applications of corticosteroids are considered the primary pharmacologic therapies for atopic dermatitis, and research recommends that these medications might be helpful in preventing disease flare-ups. However, topical medicine administration to deeper layers of skin is challenging because of the skin anatomic barrier that restricts deeper drug permeation, and also due to barrier function abnormalities in atopic dermatitis skin, which might result in systemic drug absorption, provoking systemic consequences. Hence, effective management of atopic dermatitis needs new, effective, safe and targeted treatments. Therefore, nanotechnology-based topical therapeutics have attracted much interest nowadays because of their tendency to increase drug diffusion and bioavailability along with enormous drug targeting potential to affected cells, and, thereby, reducing the adverse effects of medications. In this review, we mention different symptoms of atopic dermatitis, and provide an overview of the different triggering factors causing atopic dermatitis, with emphasis on its epidemiology, pathophysiology, clinical features and diagnostic, and preventive measures. This review discusses existing therapeutics for treating atopic dermatitis, and the newer approaches as well as the current classical pharmacotherapy of atopic dermatitis against new nanoparticle skin delivery systems. This review has also briefly summarised the recent patents and clinical status of therapeutic modalities for atopic dermatitis.
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Affiliation(s)
- Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Ishrat Zahoor
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Sridevi Chigurupati
- Department of Medicine Chemistry and Pharmacognosy, Qassim University, Buraidah, Kingdom of Saudi Arabia
| | - Shivam Yadav
- Yashraj Institute of Pharmacy, Noida, Uttar Pradesh, India
| | - Mahesh Rachamalla
- Department of Biology, University of Saskatchewan, 112 Science Place, Saskatoon, Canada
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Tanveer Naved
- Amity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh, India
| | - Pritima
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Sandeep Arora
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Saurabh Bhatia
- Natural & Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
- School of Health Science, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
| | - Syam Mohan
- Substance Abuse and Toxicology Research Center, Jazan University, Jazan, Saudi Arabia
| | - Lotfi Aleya
- School of Health Science, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
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Beck LA, Cork MJ, Amagai M, De Benedetto A, Kabashima K, Hamilton JD, Rossi AB. Type 2 Inflammation Contributes to Skin Barrier Dysfunction in Atopic Dermatitis. JID INNOVATIONS 2022; 2:100131. [PMID: 36059592 PMCID: PMC9428921 DOI: 10.1016/j.xjidi.2022.100131] [Citation(s) in RCA: 115] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 01/04/2022] [Accepted: 01/06/2022] [Indexed: 01/02/2023] Open
Abstract
Skin barrier dysfunction, a defining feature of atopic dermatitis (AD), arises from multiple interacting systems. In AD, skin inflammation is caused by host-environment interactions involving keratinocytes as well as tissue-resident immune cells such as type 2 innate lymphoid cells, basophils, mast cells, and T helper type 2 cells, which produce type 2 cytokines, including IL-4, IL-5, IL-13, and IL-31. Type 2 inflammation broadly impacts the expression of genes relevant for barrier function, such as intracellular structural proteins, extracellular lipids, and junctional proteins, and enhances Staphylococcus aureus skin colonization. Systemic anti‒type 2 inflammation therapies may improve dysfunctional skin barrier in AD.
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Key Words
- AD, atopic dermatitis
- AMP, antimicrobial peptide
- CLDN, claudin
- FFA, free fatty acid
- ILC2, type 2 innate lymphoid cell
- Jaki, Jak inhibitor
- K, keratin
- KC, keratinocyte
- MMP, matrix metalloproteinase
- NMF, natural moisturizing factor
- PAR, protease-activated receptor
- PDE-4, phosphodiesterase-4
- SC, stratum corneum
- SG, stratum granulosum
- TCI, topical calcineurin inhibitor
- TCS, topical corticosteroid
- TEWL, transepidermal water loss
- TJ, tight junction
- TLR, toll-like receptor
- TNF-α, tumor necrosis factor alpha
- TYK, tyrosine kinase
- Th, T helper
- ZO, zona occludens
- hBD, human β-defensin
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Affiliation(s)
- Lisa A. Beck
- Department of Dermatology, University of Rochester Medical Center, Rochester, New York, USA,Correspondence: Lisa A. Beck, Department of Dermatology, University of Rochester Medical Center, 601 Elmwood Ave, Box 697, Rochester, New York 14642, USA.
| | - Michael J. Cork
- Sheffield Dermatology Research, Department of Infection, Immunity and Cardiovascular Disease (IICD), The University of Sheffield, The Medical School, Sheffield, United Kingdom
| | - Masayuki Amagai
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan,Laboratory for Skin Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Anna De Benedetto
- Department of Dermatology, University of Rochester Medical Center, Rochester, New York, USA
| | - Kenji Kabashima
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Podobas EI, Gutowska-Owsiak D, Moretti S, Poznański J, Kulińczak M, Grynberg M, Gruca A, Bonna A, Płonka D, Frączyk T, Ogg G, Bal W. Ni 2+-Assisted Hydrolysis May Affect the Human Proteome; Filaggrin Degradation Ex Vivo as an Example of Possible Consequences. Front Mol Biosci 2022; 9:828674. [PMID: 35359602 PMCID: PMC8960189 DOI: 10.3389/fmolb.2022.828674] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 01/31/2022] [Indexed: 01/28/2023] Open
Abstract
Deficiency in a principal epidermal barrier protein, filaggrin (FLG), is associated with multiple allergic manifestations, including atopic dermatitis and contact allergy to nickel. Toxicity caused by dermal and respiratory exposures of the general population to nickel-containing objects and particles is a deleterious side effect of modern technologies. Its molecular mechanism may include the peptide bond hydrolysis in X1-S/T-c/p-H-c-X2 motifs by released Ni2+ ions. The goal of the study was to analyse the distribution of such cleavable motifs in the human proteome and examine FLG vulnerability of nickel hydrolysis. We performed a general bioinformatic study followed by biochemical and biological analysis of a single case, the FLG protein. FLG model peptides, the recombinant monomer domain human keratinocytes in vitro and human epidermis ex vivo were used. We also investigated if the products of filaggrin Ni2+-hydrolysis affect the activation profile of Langerhans cells. We found X1-S/T-c/p-H-c-X2 motifs in 40% of human proteins, with the highest abundance in those involved in the epidermal barrier function, including FLG. We confirmed the hydrolytic vulnerability and pH-dependent Ni2+-assisted cleavage of FLG-derived peptides and FLG monomer, using in vitro cell culture and ex-vivo epidermal sheets; the hydrolysis contributed to the pronounced reduction in FLG in all of the models studied. We also postulated that Ni-hydrolysis might dysregulate important immune responses. Ni2+-assisted cleavage of barrier proteins, including FLG, may contribute to clinical disease associated with nickel exposure.
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Affiliation(s)
- Ewa Izabela Podobas
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
- Medical Research Council Human Immunology Unit, National Institute for Health Research Oxford Biomedical Research Centre, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Institute of Genetics and Biotechnology, University of Warsaw, Warsaw, Poland
| | - Danuta Gutowska-Owsiak
- Medical Research Council Human Immunology Unit, National Institute for Health Research Oxford Biomedical Research Centre, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- University of Gdansk, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Gdansk, Poland
| | - Sébastien Moretti
- SIB Swiss Institute of Bioinformatics, Vital-IT Team, Lausanne, Switzerland
| | - Jarosław Poznański
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Mariusz Kulińczak
- The Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Marcin Grynberg
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Aleksandra Gruca
- Institute of Informatics, Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, Gliwice, Poland
| | - Arkadiusz Bonna
- Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
| | - Dawid Płonka
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Tomasz Frączyk
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Graham Ogg
- Medical Research Council Human Immunology Unit, National Institute for Health Research Oxford Biomedical Research Centre, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Wojciech Bal
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
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Hoober JK, Eggink LL. The Discovery and Function of Filaggrin. Int J Mol Sci 2022; 23:ijms23031455. [PMID: 35163390 PMCID: PMC8835998 DOI: 10.3390/ijms23031455] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/17/2022] [Accepted: 01/26/2022] [Indexed: 12/11/2022] Open
Abstract
Keratohyalin granules were discovered in the mid-19th century in cells that terminally differentiate to form the outer, cornified layer of the epidermis. The first indications of the composition of these structures emerged in the 1960s from a histochemical stain for histidine, followed by radioautographic evidence of a high incidence of histidine incorporation into newly synthesized proteins in cells containing the granules. Research during the next three decades revealed the structure and function of a major protein in these granules, which was initially called the ‘histidine-rich protein’. Steinert and Dale named the protein ‘filaggrin’ in 1981 because of its ability to aggregate keratin intermediate filaments. The human gene for the precursor, ‘profilaggrin,’ was reported in 1991 to encode 10, 11 or 12 nearly identical repeats. Remarkably, the mouse and rat genes encode up to 20 repeats. The lifetime of filaggrin is the time required for keratinocytes in the granular layer to move into the inner cornified layer. During this transition, filaggrin facilitates the collapse of corneocytes into ‘building blocks’ that become an impermeable surface barrier. The subsequent degradation of filaggrin is as remarkable as its synthesis, and the end-products aid in maintaining moisture in the cornified layer. It was apparent that ichthyosis vulgaris and atopic dermatitis were associated with the absence of this protein. McLean’s team in 2006 identified the cause of these diseases by discovering loss-of-function mutations in the profilaggrin gene, which led to dysfunction of the surface barrier. This story illustrates the complexity in maintaining a healthy, functional epidermis.
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Gallinger J, Kuhn A, Wessel S, Behm P, Heinecke S, Filbry A, Hillemann L, Rippke F. Depth-dependent hydration dynamics in human skin: Vehicle-controlled efficacy assessment of a functional 10% urea plus NMF moisturizer by near-infrared confocal spectroscopic imaging (KOSIM IR) and capacitance method complemented by volunteer perception. Skin Res Technol 2022; 28:342-349. [PMID: 35034387 PMCID: PMC9907705 DOI: 10.1111/srt.13137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 12/18/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Stratum corneum (SC) hydration is vital for the optimal maintenance and appearance of healthy skin. In this context, we evaluated the efficacy of an NMF-enriched moisturizer containing 10% urea on different aspects of SC hydration of dry skin. MATERIAL AND METHODS In two clinical studies, the hydration efficacy of the moisturizer in comparison to its vehicle was investigated. In the first study, 42 subjects applied the moisturizer and the vehicle to one lower leg each. Thirty minutes and 24 h after this single treatment, SC hydration was measured by corneometry. Volunteers also rated skin moisturization and evaluated product properties. In the second study, 27 subjects each treated one forearm twice daily for 2 weeks with the moisturizer and the vehicle. Then, depth-resolved water-absorption spectra were measured by near-infrared confocal spectroscopic imaging (KOSIM IR). RESULTS The moisturizer exerted a superior hydrating effect compared to the vehicle. KOSIM IR measurements show that, compared to the vehicle, the moisturizer significantly improved the water gradient in the SC from the surface to a depth of 15 μm. Moreover, the moisturizer received high acceptance ratings from the volunteers and was preferred to the vehicle. CONCLUSION The humectants applied in the investigated moisturizer improved SC water content in total and as a function of depth. The combination of depth-resolved data (KOSIM IR) with classical corneometry provides an integrated concept in the measurement of skin hydration, rendering both methods complementary. These findings were in line with the volunteers` self-assessments of the moisturizer properties that are relevant to treatment adherence.
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Affiliation(s)
| | - Andreas Kuhn
- Research and Development, Beiersdorf AG, Hamburg, Germany
| | - Sonja Wessel
- Research and Development, Beiersdorf AG, Hamburg, Germany
| | - Peter Behm
- Research and Development, Beiersdorf AG, Hamburg, Germany
| | - Silke Heinecke
- Research and Development, Beiersdorf AG, Hamburg, Germany
| | | | | | - Frank Rippke
- Research and Development, Beiersdorf AG, Hamburg, Germany
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Ghezzi M, Pozzi E, Abbattista L, Lonoce L, Zuccotti GV, D’Auria E. Barrier Impairment and Type 2 Inflammation in Allergic Diseases: The Pediatric Perspective. CHILDREN (BASEL, SWITZERLAND) 2021; 8:1165. [PMID: 34943362 PMCID: PMC8700706 DOI: 10.3390/children8121165] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/30/2021] [Accepted: 11/30/2021] [Indexed: 01/02/2023]
Abstract
Allergic diseases represent a global burden. Although the patho-physiological mechanisms are still poorly understood, epithelial barrier dysfunction and Th2 inflammatory response play a pivotal role. Barrier dysfunction, characterized by a loss of differentiation, reduced junctional integrity, and altered innate defence, underpins the pathogenesis of allergic diseases. Epithelial barrier impairment may be a potential therapeutic target for new treatment strategies Up now, monoclonal antibodies and new molecules targeting specific pathways of the immune response have been developed, and others are under investigation, both for adult and paediatric populations, which are affected by atopic dermatitis (AD), asthma, allergic rhinitis (AR), chronic rhinosinusitis with nasal polyps (CRSwNP), or eosinophilic esophagitis (EoE). In children affected by severe asthma biologics targeting IgE, IL-5 and against IL-4 and IL-13 receptors are already available, and they have also been applied in CRSwNP. In severe AD Dupilumab, a biologic which inhibits both IL-4 and IL-13, the most important cytokines involved in inflammation response, has been approved for treatment of patients over 12 years. While a biological approach has already shown great efficacy on the treatment of severe atopic conditions, early intervention to restore epithelial barrier integrity, and function may prevent the inflammatory response and the development of the atopic march.
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Affiliation(s)
- Michele Ghezzi
- Allergology and Pneumology Unit, V. Buzzi Children’s Hospital, 20154 Milan, Italy;
| | - Elena Pozzi
- Department of Pediatrics, V. Buzzi Children’s Hospital, 20154 Milan, Italy; (E.P.); (L.A.); (L.L.); (G.V.Z.)
| | - Luisa Abbattista
- Department of Pediatrics, V. Buzzi Children’s Hospital, 20154 Milan, Italy; (E.P.); (L.A.); (L.L.); (G.V.Z.)
| | - Luisa Lonoce
- Department of Pediatrics, V. Buzzi Children’s Hospital, 20154 Milan, Italy; (E.P.); (L.A.); (L.L.); (G.V.Z.)
| | - Gian Vincenzo Zuccotti
- Department of Pediatrics, V. Buzzi Children’s Hospital, 20154 Milan, Italy; (E.P.); (L.A.); (L.L.); (G.V.Z.)
- Department of Biomedical and Clinical Science “L. Sacco”, University of Milan, 20157 Milan, Italy
| | - Enza D’Auria
- Allergology and Pneumology Unit, V. Buzzi Children’s Hospital, 20154 Milan, Italy;
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Narla S, Silverberg JI. Dermatology for the internist: optimal diagnosis and management of atopic dermatitis. Ann Med 2021; 53:2165-2177. [PMID: 34787024 PMCID: PMC8604464 DOI: 10.1080/07853890.2021.2004322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/02/2021] [Indexed: 11/29/2022] Open
Abstract
Internists are front-line health care providers that commonly provide the first encounter to patients for dermatological conditions, especially atopic dermatitis (AD). Internists need to be comfortable with managing mild-moderate AD in their practices. Criteria and guidelines established in dermatology literature are available to help the general practitioner diagnose and treat AD. AD is a systemic disease associated with multiple cutaneous and extra-cutaneous comorbidities that warrant screening by internists, especially mental health conditions. Environmental factors may play a role in the development or worsening of AD; however, there is currently no strong evidence to guide specific population- or clinic-based interventions for their avoidance. While food allergies are common in AD patients, the role of food allergens as an exacerbating factor for AD is controversial. Before starting any dietary modifications, careful evaluation should be performed by an allergist. If the patient is not well-controlled despite adequate topical therapies or is experiencing severe/worsening disease, early referral to dermatology is warranted to rule out confounding diagnoses and/or escalation to systemic therapies. Finally, it is important to recognise the racial disparities present in AD and address these when formulating treatment plans.Key messages:Confounding dermatoses, either instead of or in addition to AD, should be considered in treatment-refractory AD, and the appropriate workup may be initiated while awaiting dermatology referral.AD patients have multiple cutaneous and extra-cutaneous comorbidities that warrant screening by internists, especially mental health conditions.
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Affiliation(s)
- Shanthi Narla
- Department of Dermatology, St. Luke’s University Health Network, Easton, PA, USA
| | - Jonathan I. Silverberg
- Department of Dermatology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
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38
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Hoyer A, Rehbinder EM, Färdig M, Asad S, Lødrup Carlsen KC, Endre KMA, Granum B, Haugen G, Hedlin G, Monceyron Jonassen C, Katayama S, Konradsen JR, Landrø L, LeBlanc M, Mägi Olsson CA, Rudi K, Skjerven HO, Staff AC, Vettukattil R, Bradley M, Nordlund B, Söderhäll C. Filaggrin mutations in relation to skin barrier and atopic dermatitis in early infancy. Br J Dermatol 2021; 186:544-552. [PMID: 34698386 DOI: 10.1111/bjd.20831] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND Loss-of-function mutations in the skin barrier gene filaggrin (FLG) increase the risk of atopic dermatitis (AD), but their role in skin barrier function, dry skin and eczema in infancy is unclear. OBJECTIVES To determine the role of FLG mutations for impaired skin barrier function, dry skin, eczema and AD at three months of age and through infancy. METHODS FLG mutations were analyzed in 1836 infants in the Scandinavian population-based PreventADALL study. Transepidermal water loss (TEWL), dry skin, eczema and AD were assessed at three, six and 12 months of age. RESULTS Filaggrin mutations were observed in 166 (9%) infants. At three months, carrying FLG mutations was not associated with impaired skin barrier function (TEWL > 11.3 g/m2 /h) or dry skin, but with eczema (OR(95%CI): 2.76 (1.81, 4.23), p < 0.001). At six months, mutation carriers had significantly higher TEWL than non-mutation carriers (mean (95%CI) 9.68 (8.69, 10.68) vs. 8.24 (7.97, 8.15), p < 0.01) and at three and six months an increased risk of dry skin on truncus (OR: 1.87 (1.25, 2.80), p = 0.002; 2.44 (1.51, 3.95), p < 0.001) or extensor limb surfaces (1.52 (1.04, 2.22), p = 0.028; 1.74 (1.17, 2.57), p = 0.005). FLG mutations were associated with eczema and AD in infancy. CONCLUSION Filaggrin mutations were not associated with impaired skin barrier function or dry skin in general at three months of age, but increased the risk for eczema, as well as for dry skin on truncus and extensors at three and six months.
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Affiliation(s)
- A Hoyer
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - E M Rehbinder
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Dermatology and Venerology, Oslo University Hospital, Oslo, Norway
| | - M Färdig
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
| | - S Asad
- Dermatology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - K C Lødrup Carlsen
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
| | - K M A Endre
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Dermatology and Venerology, Oslo University Hospital, Oslo, Norway
| | - B Granum
- Department of Environmental Health, Norwegian Institute of Public Health, Oslo, Norway
| | - G Haugen
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway
| | - G Hedlin
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
| | - C Monceyron Jonassen
- Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, Ås, Norway.,Genetic Unit, Centre for Laboratory Medicine, Østfold Hospital Trust, Kalnes, Norway
| | - S Katayama
- Folkhälsan Research Center, Helsinki, Finland.,Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden.,Stem Cells and Metabolism Research Program, University of Helsinki, Helsinki, Finland
| | - J R Konradsen
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
| | - L Landrø
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Dermatology and Venerology, Oslo University Hospital, Oslo, Norway
| | - M LeBlanc
- Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway
| | - C A Mägi Olsson
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
| | - K Rudi
- Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, Ås, Norway
| | - H O Skjerven
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
| | - A C Staff
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway
| | - R Vettukattil
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
| | - M Bradley
- Dermatology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - B Nordlund
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
| | - C Söderhäll
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
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39
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Altgilbers S, Rippke F, Filbry A, Conzelmann S, Vietzke JP, Burkhardt T, Segger D, Roggenkamp D, Grönniger E. A Biomimetic Combination of Actives Enhances Skin Hydration and Barrier Function via Modulation of Gene Expression: Results of Two Double-Blind, Vehicle-Controlled Clinical Studies. Skin Pharmacol Physiol 2021; 35:102-111. [PMID: 34619676 DOI: 10.1159/000520009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 10/01/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Xerosis cutis is characterized by a decreased stratum corneum (SC) hydration and an impaired skin barrier function. Urea, the most prevalent natural moisturizing factor (NMF), is currently considered the gold standard. Its efficacy can further be increased by combining urea with other NMF and skin barrier lipids (SBLs). OBJECTIVE We set out to evaluate physiological effects of a novel functional moisturizer containing 10% urea, additional NMF components, and a combination of SBLs on skin hydration and skin barrier integrity on a cellular and phenotypic level in female volunteers suffering from xerosis. METHODS Two double-blind, vehicle-controlled clinical studies were conducted. In the first study, 44 female subjects having very dry body skin applied the moisturizer or its vehicle twice daily to their volar forearms. Twenty-four hours after a single product application as well as 24 h after 2 weeks of treatment, SC hydration was measured by corneometry. Skin barrier function was assessed by transepidermal water loss 24 h and 48 h after 2 weeks of regular use. Twenty-four hours after 2 weeks of application, skin tape stripping was performed, and urea content was determined in the 3rd strip by means of high-performance liquid chromatography/tandem mass spectrometry. In the second study, 22 women with self-reported very dry skin applied the moisturizer or vehicle twice daily to their volar forearms for 2 weeks. Then, suction blister samples were obtained for gene expression analysis using RT-PCR. RESULTS Application of the actives led to significantly improved skin hydration and barrier function at all points in time. Compared to the vehicle, application of the moisturizer for 2 weeks resulted in a significant increase in SC urea content. Relative gene expression data revealed significant upregulation of genes associated with skin barrier function, hydration, differentiation, and lipid metabolism compared to the vehicle-treated area. CONCLUSIONS Overall, our data demonstrate that the functional moisturizer provides an adequate bioavailability of urea and a beneficial biophysical impact on xerotic skin. Topical treatment with a combination of urea and additional NMF as well as SBL can modify mRNA expression of important epidermal genes stimulating cellular processes and functions. The well-tolerated novel functional moisturizer stimulates molecular mechanisms involved in skin hydration and barrier function and is a profoundly effective treatment option for xerosis cutis.
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Affiliation(s)
| | - Frank Rippke
- Research and Development, Beiersdorf AG, Hamburg, Germany
| | | | | | | | | | - Dörte Segger
- SGS Institut Fresenius GmbH (former SIT Skin Investigation and Technology), Hamburg, Germany
| | | | - Elke Grönniger
- Research and Development, Beiersdorf AG, Hamburg, Germany
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40
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Holvoet S, Nutten S, Dupuis L, Donnicola D, Bourdeau T, Hughes-Formella B, Simon D, Simon HU, Carvalho RS, Spergel JM, Koletzko S, Blanchard C. Partially Hydrolysed Whey-Based Infant Formula Improves Skin Barrier Function. Nutrients 2021; 13:nu13093113. [PMID: 34578990 PMCID: PMC8472312 DOI: 10.3390/nu13093113] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/24/2021] [Accepted: 09/01/2021] [Indexed: 12/25/2022] Open
Abstract
Specific partially hydrolysed whey-based infant formulas (pHF-W) have been shown to decrease the risk of atopic dermatitis (AD) in infants. Historically, AD has been associated primarily with milk allergy; however, defective skin barrier function can be a primary cause of AD. We aimed to ascertain whether oral supplementation with pHF-W can improve skin barrier function. The effect of pHF-W was assessed on transepidermal water loss (TEWL) and antibody productions in mice epicutaneously exposed to Aspergillus fumigatus. Human primary keratinocytes were stimulated in vitro, and the expression of genes related to skin barrier function was measured. Supplementation with pHF-W in neonatal mice led to a significant decrease in TEWL and total IgE, but not in allergen-specific antibody levels. The whey hydrolysate was sufficient to decrease both TEWL and total IgE. Aquaporin-3 gene expression, linked with skin hydration, was modulated in the skin of mice and human primary keratinocytes following protein hydrolysate exposure. Skin barrier improvement may be an additional mechanism by which pHF-W may potentially reduce the risk of AD development in infants. Further human studies are warranted to confirm the clinical efficacy of these observations.
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Affiliation(s)
- Sébastien Holvoet
- Department of Gastrointestinal Health, Nestlé Institute of Health Sciences, Nestlé Research, Société des Produits Nestlé S.A., Vers-chez-les-Blanc, 1000 Lausanne, Switzerland; (S.H.); (S.N.); (D.D.); (T.B.)
| | - Sophie Nutten
- Department of Gastrointestinal Health, Nestlé Institute of Health Sciences, Nestlé Research, Société des Produits Nestlé S.A., Vers-chez-les-Blanc, 1000 Lausanne, Switzerland; (S.H.); (S.N.); (D.D.); (T.B.)
| | - Lénaïck Dupuis
- Biostatistics and Data Management, Clinical Research Unit, Nestlé Research, Société des Produits Nestlé S.A., Vers-chez-les-Blanc, 1000 Lausanne, Switzerland;
| | - Dominique Donnicola
- Department of Gastrointestinal Health, Nestlé Institute of Health Sciences, Nestlé Research, Société des Produits Nestlé S.A., Vers-chez-les-Blanc, 1000 Lausanne, Switzerland; (S.H.); (S.N.); (D.D.); (T.B.)
| | - Tristan Bourdeau
- Department of Gastrointestinal Health, Nestlé Institute of Health Sciences, Nestlé Research, Société des Produits Nestlé S.A., Vers-chez-les-Blanc, 1000 Lausanne, Switzerland; (S.H.); (S.N.); (D.D.); (T.B.)
| | | | - Dagmar Simon
- Department of Dermatology, Inselspital, Bern University Hospital, 3010 Bern, Switzerland;
| | - Hans-Uwe Simon
- Institute of Pharmacology, University of Bern, 3012 Bern, Switzerland;
- Department of Clinical Immunology and Allergology, Sechenov University, 119991 Moscow, Russia
- Laboratory of Molecular Immunology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
- Institute of Biochemistry, Medical School Brandenburg, 16816 Neuruppin, Germany
| | | | - Jonathan M. Spergel
- Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA 19104, USA;
| | - Sibylle Koletzko
- Department of Pediatrics, Dr. von Hauner Children’s Hospital and University Hospital, LMU Munich, 80337 Munich, Germany;
- Department of Pediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum, University of Warmia and Mazury, 10-719 Olsztyn, Poland
| | - Carine Blanchard
- Department of Gastrointestinal Health, Nestlé Institute of Health Sciences, Nestlé Research, Société des Produits Nestlé S.A., Vers-chez-les-Blanc, 1000 Lausanne, Switzerland; (S.H.); (S.N.); (D.D.); (T.B.)
- Correspondence: ; Tel.: +41-21-785-87-56
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41
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van Mierlo MMF, Caspers PJ, Jansen MS, Puppels GJ, Nouwen AEM, Bronner MB, Pardo LM, van Geel M, Pasmans SGMA. Natural moisturizing factor as a biomarker for filaggrin mutation status in a multi-ethnic paediatric atopic dermatitis cohort. Clin Exp Allergy 2021; 51:1510-1513. [PMID: 34411363 PMCID: PMC9291917 DOI: 10.1111/cea.14001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 08/15/2021] [Indexed: 01/16/2023]
Affiliation(s)
- Minke M F van Mierlo
- Department of Dermatology-Center of Pediatric Dermatology, Erasmus MC University Medical Center Rotterdam- Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Peter J Caspers
- Department of Dermatology, Center for Optical Diagnostics and Therapy, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.,RiverD International B.V, Rotterdam, The Netherlands
| | - Marieke S Jansen
- Department of Dermatology-Center of Pediatric Dermatology, Erasmus MC University Medical Center Rotterdam- Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Gerwin J Puppels
- Department of Dermatology, Center for Optical Diagnostics and Therapy, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.,RiverD International B.V, Rotterdam, The Netherlands
| | - Anouk E M Nouwen
- Department of Dermatology-Center of Pediatric Dermatology, Erasmus MC University Medical Center Rotterdam- Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Madelon B Bronner
- Department of Dermatology-Center of Pediatric Dermatology, Erasmus MC University Medical Center Rotterdam- Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Luba M Pardo
- Department of Dermatology-Center of Pediatric Dermatology, Erasmus MC University Medical Center Rotterdam- Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Michel van Geel
- Department of Dermatology, Maastricht University Medical Centre, Maastricht, The Netherlands.,Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Suzanne G M A Pasmans
- Department of Dermatology-Center of Pediatric Dermatology, Erasmus MC University Medical Center Rotterdam- Sophia Children's Hospital, Rotterdam, The Netherlands
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42
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Ota M, Sasaki T, Ebihara T, Yokosawa E, Murakami Y, Matsunaka H, Chinuki Y, Amagai M, Morita E. Filaggrin-gene mutation has minimal effect on the disease severity in the lesions of atopic dermatitis. J Dermatol 2021; 48:1688-1699. [PMID: 34322929 DOI: 10.1111/1346-8138.16087] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/22/2021] [Accepted: 07/14/2021] [Indexed: 11/29/2022]
Abstract
Loss-of-function mutations of filaggrin (FLG) gene (FLG) are the strongest known genetic risk factor for atopic dermatitis (AD). It is still debatable how FLG gene mutations and the resulting abnormal amount of FLG protein contribute to skin barrier function and symptoms of AD. In this study, we examined the effects of loss-of-function mutations of FLG gene on the severity of skin lesions and skin barrier function in 55 patients with AD by evaluating eight patients with AD with FLG gene mutations and 47 patients with AD without mutations. The results showed that the FLG gene mutation did not affect the duration of AD, severity of AD, degree of local inflammatory symptoms, skin water content and trans-epidermal water loss of the lesions. Next, in these eight mutation carriers and the 47 non-carriers, stratum corneum was collected from the three site of skin lesions using tape-stripping method, and the amounts of FLG protein and total amino acid contained in the stratum corneum was measured to investigate the effect of the FLG gene mutation on the amount of FLG gene product in the local lesion. FLG abnormalities had little effect on FLG protein and total amino acid content in the stratum corneum in the lesional skin. The amount of the FLG products, especially amino acids derived from FLG, in the stratum corneum of AD lesional skin is influenced by development of dermatitis. The results obtained from this study supports that the activation of Th2-dominant inflammatory cells, together with FLG abnormality, plays a role in suppressing the production of FLG in skin lesions.
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Affiliation(s)
- Masataka Ota
- Department of Dermatology, Shimane University Faculty of Medicine, Izumo, Japan
| | - Takashi Sasaki
- Center for Supercentenarian Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - Tamotsu Ebihara
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
| | - Emiko Yokosawa
- NOV Academic Research, Tokiwa Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Yumi Murakami
- NOV Academic Research, Tokiwa Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Hiroshi Matsunaka
- NOV Academic Research, Tokiwa Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Yuko Chinuki
- Department of Dermatology, Shimane University Faculty of Medicine, Izumo, Japan
| | - Masayuki Amagai
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
| | - Eishin Morita
- Department of Dermatology, Shimane University Faculty of Medicine, Izumo, Japan
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43
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Lai QWS, Guo MSS, Wu KQ, Liao Z, Guan D, Dong TT, Tong P, Tsim KWK. Edible Bird's Nest, an Asian Health Food Supplement, Possesses Moisturizing Effect by Regulating Expression of Filaggrin in Skin Keratinocyte. Front Pharmacol 2021; 12:685982. [PMID: 34354585 PMCID: PMC8329658 DOI: 10.3389/fphar.2021.685982] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 06/03/2021] [Indexed: 11/13/2022] Open
Abstract
Edible bird's nest (EBN) has been consumed as a Chinese delicacy for hundreds of years; the functions of which have been proposed to prevent lung disease, strengthen immune response, and restore skin youthfulness. To support the skin function of EBN, the water extract and the enzymatic digest of EBN with enriched digested peptides were tested in cultured keratinocyte, HaCaT cell line. The effects of EBN extract and digest in inducing proteins crucial for skin moisturizing were determined in both in vitro and ex vivo models. In cultured keratinocytes, the expressions of S100-fused type proteins contributing to skin barrier function in the stratum corneum, e.g. filaggrin and filaggrin-2, were determined in both mRNA and protein levels, which were markedly induced in the treatment of EBN extract or digest. The EBN-induced gene transcriptions of filaggrin and filaggrin-2 were mediated by activation of p38 MAPK pathway and various transcription factors, e.g. GATA3, PPARα, PPARβ, and PPARγ: these transcriptional factors were markedly activated by the digested products of EBN, as compared to the extract, in cultured keratinocytes. By using atomic force microscopy (AFM), the EBN-treated keratinocyte was shown to have more liquid-like morphology, as compared to a control cell. The EBN digest showed better induction on these moisturizing effects as compared to the extract. These lines of evidence therefore suggested the water moisturizing effect of EBN in skin function.
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Affiliation(s)
- Queenie Wing Sze Lai
- Shenzhen Research Institute, The Hong Kong University of Science and Technology, Shenzhen, China.,Division of Life Science and Center for Chinese Medicine R and D, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Maggie Sui Sui Guo
- Shenzhen Research Institute, The Hong Kong University of Science and Technology, Shenzhen, China.,Division of Life Science and Center for Chinese Medicine R and D, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Kevin Qiyun Wu
- Shenzhen Research Institute, The Hong Kong University of Science and Technology, Shenzhen, China.,Division of Life Science and Center for Chinese Medicine R and D, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Zhitao Liao
- Department of Physics, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Dongshi Guan
- State Key Laboratory of Nonlinear Mechanics, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
| | - Tina Tingxia Dong
- Shenzhen Research Institute, The Hong Kong University of Science and Technology, Shenzhen, China.,Division of Life Science and Center for Chinese Medicine R and D, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Penger Tong
- Department of Physics, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Karl Wah Keung Tsim
- Shenzhen Research Institute, The Hong Kong University of Science and Technology, Shenzhen, China.,Division of Life Science and Center for Chinese Medicine R and D, The Hong Kong University of Science and Technology, Hong Kong, China
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44
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Yang M, Zhang Z, He Y, Li C, Wang J, Ma X. Study on the structure characterization and moisturizing effect of Tremella polysaccharide fermented from GCMCC5.39. FOOD SCIENCE AND HUMAN WELLNESS 2021. [DOI: 10.1016/j.fshw.2021.04.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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45
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Dębińska A. New Treatments for Atopic Dermatitis Targeting Skin Barrier Repair via the Regulation of FLG Expression. J Clin Med 2021; 10:jcm10112506. [PMID: 34198894 PMCID: PMC8200961 DOI: 10.3390/jcm10112506] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/31/2021] [Accepted: 06/01/2021] [Indexed: 12/16/2022] Open
Abstract
Atopic dermatitis (AD) is one of the most common chronic, inflammatory skin disorders with a complex etiology and a broad spectrum of clinical phenotypes. Despite its high prevalence and effect on the quality of life, safe and effective systemic therapies approved for long-term management of AD are limited. A better understanding of the pathogenesis of atopic dermatitis in recent years has contributed to the development of new therapeutic approaches that target specific pathophysiological pathways. Skin barrier dysfunction and immunological abnormalities are critical in the pathogenesis of AD. Recently, the importance of the downregulation of epidermal differentiation complex (EDC) molecules caused by external and internal stimuli has been extensively emphasized. The purpose of this review is to discuss the innovations in the therapy of atopic dermatitis, including biologics, small molecule therapies, and other drugs by highlighting regulatory mechanisms of skin barrier-related molecules, such as filaggrin (FLG) as a crucial pathway implicated in AD pathogenesis.
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Affiliation(s)
- Anna Dębińska
- 1st Department and Clinic of Paediatrics, Allergology and Cardiology, Wroclaw Medical University, Chałubińskiego 2a, 50-368 Wrocław, Poland
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46
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SoRelle JA, Chen Z, Wang J, Yue T, Choi JH, Wang K, Zhong X, Hildebrand S, Russell J, Scott L, Xu D, Zhan X, Bu CH, Wang T, Choi M, Tang M, Ludwig S, Zhan X, Li X, Moresco EMY, Beutler B. Dominant atopy risk mutations identified by mouse forward genetic analysis. Allergy 2021; 76:1095-1108. [PMID: 32810290 DOI: 10.1111/all.14564] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 06/01/2020] [Accepted: 06/07/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Atopy, the overall tendency to become sensitized to an allergen, is heritable but seldom ascribed to mutations within specific genes. Atopic individuals develop abnormally elevated IgE responses to immunization with potential allergens. To gain insight into the genetic causes of atopy, we carried out a forward genetic screen for atopy in mice. METHODS We screened mice carrying homozygous and heterozygous N-ethyl-N-nitrosourea (ENU)-induced germline mutations for aberrant antigen-specific IgE and IgG1 production in response to immunization with the model allergen papain. Candidate genes were validated by independent gene mutation. RESULTS Of 31 candidate genes selected for investigation, the effects of mutations in 23 genes on papain-specific IgE or IgG1 were verified. Among the 20 verified genes influencing the IgE response, eight were necessary for the response, while 12 repressed IgE. Nine genes were not previously implicated in the IgE response. Fifteen genes encoded proteins contributing to IgE class switch recombination or B-cell receptor signaling. The precise roles of the five remaining genes (Flcn, Map1lc3b, Me2, Prkd2, and Scarb2) remain to be determined. Loss-of-function mutations in nine of the 12 genes limiting the IgE response were dominant or semi-dominant for the IgE phenotype but did not cause immunodeficiency in the heterozygous state. Using damaging allele frequencies for the corresponding human genes and in silico simulations (Monte Carlo) of undiscovered atopy mutations, we estimated the percentage of humans with heterozygous atopy risk mutations. CONCLUSIONS Up to 37% of individuals may be heterozygous carriers for at least one dominant atopy risk mutation.
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Affiliation(s)
- Jeffrey A. SoRelle
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
- Department of Pathology University of Texas Southwestern Medical Center Dallas TX USA
| | - Zhe Chen
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
| | - Jianhui Wang
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
| | - Tao Yue
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
| | - Jin Huk Choi
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
- Department of Immunology University of Texas Southwestern Medical Center Dallas TX USA
| | - Kuan‐wen Wang
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
| | - Xue Zhong
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
| | - Sara Hildebrand
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
| | - Jamie Russell
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
| | - Lindsay Scott
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
| | - Darui Xu
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
| | - Xiaowei Zhan
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
| | - Chun Hui Bu
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
| | - Tao Wang
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
- Department of Population and Data Sciences Quantitative Biomedical Research Center University of Texas Southwestern Medical Center Dallas TX USA
| | - Mihwa Choi
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
| | - Miao Tang
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
| | - Sara Ludwig
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
| | - Xiaoming Zhan
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
| | - Xiaohong Li
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
| | - Eva Marie Y. Moresco
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
| | - Bruce Beutler
- Center for the Genetics of Host Defense University of Texas Southwestern Medical Center Dallas TX USA
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47
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Edslev SM, Olesen CM, Nørreslet LB, Ingham AC, Iversen S, Lilje B, Clausen ML, Jensen JS, Stegger M, Agner T, Andersen PS. Staphylococcal Communities on Skin Are Associated with Atopic Dermatitis and Disease Severity. Microorganisms 2021; 9:microorganisms9020432. [PMID: 33669791 PMCID: PMC7921937 DOI: 10.3390/microorganisms9020432] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/15/2021] [Accepted: 02/16/2021] [Indexed: 12/16/2022] Open
Abstract
The skin microbiota of atopic dermatitis (AD) patients is characterized by increased Staphylococcus aureus colonization, which exacerbates disease symptoms and has been linked to reduced bacterial diversity. Skin bacterial communities in AD patients have mostly been described at family and genus levels, while species-level characterization has been limited. In this study, we investigated the role of the bacteria belonging to the Staphylococcus genus using targeted sequencing of the tuf gene with genus-specific primers. We compared staphylococcal communities on lesional and non-lesional skin of AD patients, as well as AD patients with healthy controls, and determined the absolute abundance of bacteria present at each site. We observed that the staphylococcal community, bacterial alpha diversity, and bacterial densities were similar on lesional and non-lesional skin, whereas AD severity was associated with significant changes in staphylococcal composition. Increased S. aureus, Staphylococcus capitis, and Staphylococcus lugdunensis abundances were correlated with increased severity. Conversely, Staphylococcus hominis abundance was negatively correlated with severity. Furthermore, S. hominis relative abundance was reduced on AD skin compared to healthy skin. In conclusion, various staphylococcal species appear to be important for skin health.
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Affiliation(s)
- Sofie Marie Edslev
- Bacteria, Parasites, and Fungi, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, Denmark; (A.C.I.); (S.I.); (B.L.); (J.S.J.); (M.S.); (P.S.A.)
- Correspondence:
| | - Caroline Meyer Olesen
- Department of Dermatology, Bispebjerg Hospital, Bispebjerg bakke 23, 2400 Copenhagen, Denmark; (C.M.O.); (L.B.N.); (M.-L.C.); (T.A.)
| | - Line Brok Nørreslet
- Department of Dermatology, Bispebjerg Hospital, Bispebjerg bakke 23, 2400 Copenhagen, Denmark; (C.M.O.); (L.B.N.); (M.-L.C.); (T.A.)
| | - Anna Cäcilia Ingham
- Bacteria, Parasites, and Fungi, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, Denmark; (A.C.I.); (S.I.); (B.L.); (J.S.J.); (M.S.); (P.S.A.)
| | - Søren Iversen
- Bacteria, Parasites, and Fungi, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, Denmark; (A.C.I.); (S.I.); (B.L.); (J.S.J.); (M.S.); (P.S.A.)
| | - Berit Lilje
- Bacteria, Parasites, and Fungi, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, Denmark; (A.C.I.); (S.I.); (B.L.); (J.S.J.); (M.S.); (P.S.A.)
| | - Maja-Lisa Clausen
- Department of Dermatology, Bispebjerg Hospital, Bispebjerg bakke 23, 2400 Copenhagen, Denmark; (C.M.O.); (L.B.N.); (M.-L.C.); (T.A.)
| | - Jørgen Skov Jensen
- Bacteria, Parasites, and Fungi, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, Denmark; (A.C.I.); (S.I.); (B.L.); (J.S.J.); (M.S.); (P.S.A.)
| | - Marc Stegger
- Bacteria, Parasites, and Fungi, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, Denmark; (A.C.I.); (S.I.); (B.L.); (J.S.J.); (M.S.); (P.S.A.)
| | - Tove Agner
- Department of Dermatology, Bispebjerg Hospital, Bispebjerg bakke 23, 2400 Copenhagen, Denmark; (C.M.O.); (L.B.N.); (M.-L.C.); (T.A.)
| | - Paal Skytt Andersen
- Bacteria, Parasites, and Fungi, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, Denmark; (A.C.I.); (S.I.); (B.L.); (J.S.J.); (M.S.); (P.S.A.)
- Department of Veterinary and Animal Sciences, University of Copenhagen, Grønnegårdsvej 15, 1870 Frederiksberg, Denmark
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48
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Genetics and Individual Predispositions in Contact Dermatitis. Contact Dermatitis 2021. [DOI: 10.1007/978-3-030-36335-2_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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49
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Ulrich NH, Thyssen JP, Mizutani H, Nixon RL. Hand Eczema: Causative Factors, Diagnosis, Personal and Societal Consequences. Contact Dermatitis 2021. [DOI: 10.1007/978-3-030-36335-2_61] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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50
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Cork MJ, Danby SG, Ogg GS. Atopic dermatitis epidemiology and unmet need in the United Kingdom. J DERMATOL TREAT 2020; 31:801-809. [PMID: 31631717 PMCID: PMC7573657 DOI: 10.1080/09546634.2019.1655137] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 07/31/2019] [Indexed: 01/17/2023]
Abstract
Atopic dermatitis (AD), also known as atopic eczema, is a chronic inflammatory skin condition associated with a significant health-related and socioeconomic burden, and is characterized by intense itch, disruption of the skin barrier, and upregulation of type 2-mediated immune responses. The United Kingdom (UK) has a high prevalence of AD, affecting 11-20% of children and 5-10% of adults. Approximately 2% of all cases of childhood AD in the UK are severe. Despite this, most AD treatments are performed at home, with little contact with healthcare providers or services. Here, we discuss the course of AD, treatment practices, and unmet need in the UK. Although the underlying etiology of the disease is still emerging, AD is currently attributed to skin barrier dysfunction and altered inflammatory responses. Management of AD focuses on avoiding triggers, improving skin hydration, managing exacerbating factors, and reducing inflammation through topical and systemic immunosuppressants. However, there is a significant unmet need to improve the overall management of AD and help patients gain control of their disease through safe and effective treatments. Approaches that target individual inflammatory pathways (e.g. dupilumab, anti-interleukin (IL)-4 receptor α) are emerging and likely to provide further therapeutic opportunities for patient benefit.
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Affiliation(s)
- Michael J. Cork
- Sheffield Dermatology Research, Department of Infection, Immunity & Cardiovascular Disease, Faculty of Medicine, Dentistry & Health, The University of Sheffield, Sheffield, UK
- Sheffield Children’s Hospital and Sheffield Teaching Hospitals Clinical Research Facilities, Sheffield, UK
| | - Simon G. Danby
- Sheffield Dermatology Research, Department of Infection, Immunity & Cardiovascular Disease, Faculty of Medicine, Dentistry & Health, The University of Sheffield, Sheffield, UK
- Sheffield Children’s Hospital and Sheffield Teaching Hospitals Clinical Research Facilities, Sheffield, UK
| | - Graham S. Ogg
- MRC Human Immunology Unit, NIHR Biomedical Research Centre, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
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