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Dai X, Mizukami Y, Watanabe K, Tsuda T, Shidahara M, Yoshida S, Yatsuzuka K, Shiraishi K, Mori H, Murakami M, Kawakami R, Imamura T, Fujisawa Y, Muto J. Trehalose Prevents IL-4/IL-13-Induced Skin Barrier Impairment by Suppressing IL-33 Expression and Increasing NRF2 Activation in Human Keratinocytes In Vitro. J Invest Dermatol 2025; 145:1422-1432.e10. [PMID: 39384017 DOI: 10.1016/j.jid.2024.08.038] [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: 10/07/2023] [Revised: 08/16/2024] [Accepted: 08/25/2024] [Indexed: 10/11/2024]
Abstract
Skin barrier dysfunction initiates or deteriorates various cutaneous problems, such as atopic dermatitis. At high concentrations, the nonreducing disaccharide trehalose (α-d-glucopyranosyl α-d-glucopyranoside) induces a transient senescence-like state in fibroblasts and promotes wound repair. In this study, we investigated the effect of trehalose on normal human keratinocytes and demonstrated its specific role in the skin barrier. RNA-sequencing analysis revealed that trehalose regulates the expression of many skin barrier-associated genes. T helper 2 cytokines IL-4/IL-13 were observed to downregulate several differentiation markers (FLG, loricrin, keratin 1, and keratin 10) and epidermal antimicrobial proteins in monolayer-cultured keratinocytes and living skin equivalents and impaired skin barrier function in living skin equivalents, all of which were significantly upregulated or restored by trehalose. Trehalose inhibited IL-33 expression and reduced nuclear IL-33 levels by activating MAPK/extracellular signal-regulated kinase kinase 5-extracellular signal-regulated kinase 5 and suppressing extracellular signal-regulated kinase kinase 1/2-extracellular signal-regulated kinase pathway. It also increased NRF2 activation to trigger antioxidant enzyme production through JNK, thus neutralizing IL-4/IL-13-mediated oxidative stress. Trehalose prevented IL-4/IL-13-mediated signal transducer and activator of transcription 3/signal transducer and activator of transcription 6 activation and restored IL-4/IL-13-suppressed skin barrier molecules through IL-33 downregulation and NRF2 activation. This study demonstrated that trehalose may play a role in skin barrier repair in atopic dermatitis.
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Affiliation(s)
- Xiuju Dai
- Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan; Department of Dermatology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
| | - Yoichi Mizukami
- Institute of Gene Research, Yamaguchi University Science Research Center, Yamaguchi, Japan
| | - Kenji Watanabe
- Institute of Gene Research, Yamaguchi University Science Research Center, Yamaguchi, Japan
| | - Teruko Tsuda
- Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Mutsumi Shidahara
- Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Satoshi Yoshida
- Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Kazuki Yatsuzuka
- Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Ken Shiraishi
- Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Hideki Mori
- Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Masamoto Murakami
- Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Ryosuke Kawakami
- Department of Molecular Medicine for Pathogenesis, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Takeshi Imamura
- Department of Molecular Medicine for Pathogenesis, Ehime University Graduate School of Medicine, Ehime, Japan; Translational Research Center, Ehime University Hospital, Ehime, Japan
| | - Yasuhiro Fujisawa
- Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Jun Muto
- Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan.
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Snowball JM, Jarrold BB, DeAngelis Y, Li C, Rovito HA, Hare MC, Laughlin T, Evdokiou AL, Oblong JE. Integration of transcriptomics and spatial biology analyses reveals Galactomyces ferment filtrate promotes epidermal interconnectivity via induction of keratinocyte differentiation, proliferation and cellular bioenergetics. Int J Cosmet Sci 2024; 46:927-940. [PMID: 38924095 DOI: 10.1111/ics.12991] [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: 04/05/2024] [Revised: 05/10/2024] [Accepted: 05/14/2024] [Indexed: 06/28/2024]
Abstract
OBJECTIVE Human skin is the first line of defence from environmental factors such as solar radiation and is susceptible to premature ageing, including a disruption in epidermal differentiation and homeostasis. We evaluated the impact of a Galactomyces Ferment Filtrate (GFF) on epidermal differentiation and response to oxidative stress. METHODS We used transcriptomics, both spatial and traditional, to assess the impact of GFF on epidermal biology and homeostasis in keratinocytes (primary or immortalized) and in ex vivo skin explant tissue. The effect of GFF on cell adhesion rates, cellular ATP levels and proliferation rates were quantitated. Oxidative phosphorylation and glycolytic rates were measured under normal and stress-induced conditions. RESULTS Transcriptomics from keratinocytes and ex vivo skin explants from multiple donors show GFF induces keratinocyte differentiation, skin barrier development and cell adhesion while simultaneously repressing cellular stress and inflammatory related processes. Spatial transcriptomics profiling of ex vivo skin indicated basal keratinocytes at the epidermal-dermal junction and cornifying keratinocytes in the top layer of the epidermis as the primary cell types influenced by GFF treatment. Additionally, GFF significantly increases crosstalk between suprabasal and basal keratinocytes. To support these findings, we show that GFF can significantly increase cell adhesion and proliferation in keratinocytes. GFF also protected overall cellular bioenergetics under metabolic or oxidative stress conditions. CONCLUSION Our findings provide novel insights into cellular differences and epidermal spatial localization in response to GFF, supporting previous findings that this filtrate has a significant impact on epidermal biology and homeostasis, particularly on spatially defined crosstalk. We propose that GFF can help maintain epidermal health by enhancing keratinocyte crosstalk and differentiation/proliferation balance as well as promoting an enhanced response to stress.
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Affiliation(s)
| | | | | | - Chuiying Li
- The Procter & Gamble Company, Cincinnati, Ohio, USA
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Sousa LPB, Pinto LFB, Cruz VAR, Oliveira GA, Rojas de Oliveira H, Chud TS, Pedrosa VB, Miglior F, Schenkel FS, Brito LF. Genome-wide association and functional genomic analyses for various hoof health traits in North American Holstein cattle. J Dairy Sci 2024; 107:2207-2230. [PMID: 37939841 DOI: 10.3168/jds.2023-23806] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Accepted: 10/19/2023] [Indexed: 11/10/2023]
Abstract
Hoof diseases are a major welfare and economic issue in the global dairy cattle production industry, which can be minimized through improved management and breeding practices. Optimal genetic improvement of hoof health could benefit from a deep understanding of the genetic background and biological underpinning of indicators of hoof health. Therefore, the primary objectives of this study were to perform genome-wide association studies, using imputed high-density genetic markers data from North American Holstein cattle, for 8 hoof-related traits: digital dermatitis, sole ulcer, sole hemorrhage, white line lesion, heel horn erosion, interdigital dermatitis, interdigital hyperplasia, and toe ulcer, and a hoof health index. De-regressed estimated breeding values from 25,580 Holstein animals were used as pseudo-phenotypes for the association analyses. The genomic quality control, genotype phasing, and genotype imputation were performed using the PLINK (version 1.9), Eagle (version 2.4.1), and Minimac4 software, respectively. The functional genomic analyses were performed using the GALLO R package and the DAVID platform. We identified 22, 34, 14, 22, 28, 33, 24, 43, and 15 significant markers for digital dermatitis, heel horn erosion, interdigital dermatitis, interdigital hyperplasia, sole hemorrhage, sole ulcer, toe ulcer, white line lesion disease, and the hoof health index, respectively. The significant markers were located across all autosomes, except BTA10, BTA12, BTA20, BTA26, BTA27, and BTA28. Moreover, the genomic regions identified overlap with various previously reported quantitative trait loci for exterior, health, meat and carcass, milk, production, and reproduction traits. The enrichment analyses identified 44 significant gene ontology terms. These enriched genomic regions harbor various candidate genes previously associated with bone development, metabolism, and infectious and immunological diseases. These findings indicate that hoof health traits are highly polygenic and influenced by a wide range of biological processes.
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Affiliation(s)
- Luis Paulo B Sousa
- Department of Animal Sciences, Federal University of Bahia, Salvador, BA, 40170-110, Brazil
| | - Luis Fernando B Pinto
- Department of Animal Sciences, Federal University of Bahia, Salvador, BA, 40170-110, Brazil
| | - Valdecy A R Cruz
- Department of Animal Sciences, Federal University of Bahia, Salvador, BA, 40170-110, Brazil
| | - Gerson A Oliveira
- Centre for Genetic Improvement of Livestock, Department of Animal Biosciences, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Hinayah Rojas de Oliveira
- Centre for Genetic Improvement of Livestock, Department of Animal Biosciences, University of Guelph, Guelph, ON, N1G 2W1, Canada; Department of Animal Sciences, Purdue University, West Lafayette, IN 47907
| | - Tatiane S Chud
- Centre for Genetic Improvement of Livestock, Department of Animal Biosciences, University of Guelph, Guelph, ON, N1G 2W1, Canada; PEAK, Madison, WI 53718
| | - Victor B Pedrosa
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907
| | - Filippo Miglior
- Centre for Genetic Improvement of Livestock, Department of Animal Biosciences, University of Guelph, Guelph, ON, N1G 2W1, Canada; Lactanet Canada, Guelph, ON, N1K 1E5, Canada
| | - Flávio S Schenkel
- Centre for Genetic Improvement of Livestock, Department of Animal Biosciences, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Luiz F Brito
- Centre for Genetic Improvement of Livestock, Department of Animal Biosciences, University of Guelph, Guelph, ON, N1G 2W1, Canada; Department of Animal Sciences, Purdue University, West Lafayette, IN 47907.
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Significant Reversal of Facial Wrinkle, Pigmented Spot and Roughness by Daily Application of Galactomyces Ferment Filtrate-Containing Skin Products for 12 Months-An 11-Year Longitudinal Skin Aging Rejuvenation Study. J Clin Med 2023; 12:jcm12031168. [PMID: 36769815 PMCID: PMC9917576 DOI: 10.3390/jcm12031168] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/18/2023] [Accepted: 01/24/2023] [Indexed: 02/05/2023] Open
Abstract
Facial skin aging is an important psychophysical and social concern, especially in women. We compared facial parameters reflecting aging of the skin in 1999 and 2010 in 86 female volunteers. Then, all subjects applied three Galactomyces ferment filtrate-containing skin care products (G3 products; SK-II Facial Treatment Essence, SK-II Cellumination Essence, and SK-II Skin Signature Cream) twice daily for 12 months (M), with the skin parameters being measured at 2 M, 8 M, and 12 M during this period. Facial skin aging parameters such as wrinkles, hyperpigmented spots, and roughness significantly deteriorated during the 11-year interval. This 11-year aging process was associated with reduced hydration and increased transepidermal water loss (TEWL). Notably, treatment with G3 products significantly and cumulatively increased skin hydration with a correlated reduction of TEWL during the 12 M treatment period. Such treatment also significantly and cumulatively reversed the 11-year facial skin aging in the three parameters of wrinkles, spots, and roughness. These results suggest that facial skin retains the potential to recover from the aging process when it is applied with appropriate cosmetic agents.
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Yan X, Tsuji G, Hashimoto-Hachiya A, Furue M. Galactomyces Ferment Filtrate Potentiates an Anti-Inflammaging System in Keratinocytes. J Clin Med 2022; 11:6338. [PMID: 36362566 PMCID: PMC9657190 DOI: 10.3390/jcm11216338] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/21/2022] [Accepted: 10/25/2022] [Indexed: 12/24/2023] Open
Abstract
Skincare products play a crucial role in preventing the dry skin induced by various causes. Certain ingredients can help to improve the efficacy of skincare products. Galactomyces ferment filtrate (GFF) is such a functional ingredient. Its use originated from the empirical observation that the hands of sake brewers who deal with yeast fermentation retain a beautiful and youthful appearance. Consequently, skincare products based on GFF are widely used throughout the world. Recent studies have demonstrated that GFF activates an aryl hydrocarbon receptor (AHR) and upregulates the expression of filaggrin, a pivotal endogenous source of natural moisturizing factors, in epidermal keratinocytes. It also activates nuclear factor erythroid-2-related factor 2 (NRF2), the antioxidative master transcription factor, and exhibits potent antioxidative activity against oxidative stress induced by ultraviolet irradiation and proinflammatory cytokines, which also accelerate inflammaging. GFF-mediated NRF2 activation downregulates the expression of CDKN2A, which is known to be overexpressed in senescent keratinocytes. Moreover, GFF enhances epidermal terminal differentiation by upregulating the expression of caspase-14, claudin-1, and claudin-4. It also promotes the synthesis of the antiinflammatory cytokine IL-37 and downregulates the expression of proallergic cytokine IL-33 in keratinocytes. In addition, GFF downregulates the expression of the CXCL14 and IL6R genes, which are involved in inflammaging. These beneficial properties might underpin the potent barrier-protecting and anti-inflammaging effects of GFF-containing skin formulae.
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Affiliation(s)
- Xianghong Yan
- SK-II Science Communications, Kobe Innovation Center, Procter and Gamble Innovation, Kobe 651-0088, Japan
| | - Gaku Tsuji
- Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka 812-8582, Japan
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Akiko Hashimoto-Hachiya
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Masutaka Furue
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
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Nakajima A, Sakae N, Yan X, Hakozaki T, Zhao W, Laughlin T, Furue M. Transcriptomic Analysis of Human Keratinocytes Treated with Galactomyces Ferment Filtrate, a Beneficial Cosmetic Ingredient. J Clin Med 2022; 11:jcm11164645. [PMID: 36012891 PMCID: PMC9409768 DOI: 10.3390/jcm11164645] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/01/2022] [Accepted: 08/08/2022] [Indexed: 11/16/2022] Open
Abstract
Galactomyces ferment filtrate (GFF, Pitera™) is a cosmetic ingredient known to have multiple skin care benefits, such as reducing redness and pore size via the topical application of its moisturizer form. Although GFF is known to act partly as an antioxidative agonist for the aryl hydrocarbon receptor (AHR), its significance in keratinocyte biology is not fully understood. In this study, we conducted a transcriptomic analysis of GFF-treated human keratinocytes. Three different lots of GFF consistently modulated 99 (22 upregulated and 77 downregulated) genes, including upregulating cytochrome P450 1A1 (CYP1A1), a specific downstream gene for AHR activation. GFF also enhanced the expression of epidermal differentiation/barrier-related genes, such as small proline-rich proteins 1A and 1B (SPRR1A and SPRR1B), as well as wound healing-related genes such as serpin B2 (SERPINB2). Genes encoding components of tight junctions claudin-1 (CLDN1) and claudin-4 (CLDN4) were also target genes upregulated in the GFF-treated keratinocytes. In contrast, the three lots of GFF consistently downregulated the expression of inflammation-related genes such as chemokine (C-X-C motif) ligand 14 (CXCL14) and interleukin-6 receptor (IL6R). These results highlight the beneficial properties of GFF in maintaining keratinocyte homeostasis.
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Affiliation(s)
- Akiko Nakajima
- Kobe Innovation Center, Procter and Gamble Innovation GK, Kobe 651-0088, Japan
- Correspondence:
| | - Nahoko Sakae
- Kobe Innovation Center, Procter and Gamble Innovation GK, Kobe 651-0088, Japan
| | - Xianghong Yan
- Kobe Innovation Center, Procter and Gamble Innovation GK, Kobe 651-0088, Japan
| | - Tomohiro Hakozaki
- The Procter & Gamble Company, Mason Business Center, Mason, OH 45040, USA
| | - Wenzhu Zhao
- The Procter & Gamble Company, Mason Business Center, Mason, OH 45040, USA
| | - Timothy Laughlin
- The Procter & Gamble Company, Mason Business Center, Mason, OH 45040, USA
| | - Masutaka Furue
- Department of Dermatology, Kyushu University, Fukuoka 812-8582, Japan
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Tsuji G, Hashimoto-Hachiya A, Matsuda-Taniguchi T, Takai-Yumine A, Takemura M, Yan X, Furue M, Nakahara T. Natural Compounds Tapinarof and Galactomyces Ferment Filtrate Downregulate IL-33 Expression via the AHR/IL-37 Axis in Human Keratinocytes. Front Immunol 2022; 13:745997. [PMID: 35663970 PMCID: PMC9161696 DOI: 10.3389/fimmu.2022.745997] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 04/22/2022] [Indexed: 12/12/2022] Open
Abstract
Interleukin (IL)-37 suppresses systemic and local inflammation. It is expressed in the epidermis, the external layer of the skin, and is decreased in inflammatory skin diseases including atopic dermatitis (AD) and psoriasis. Therefore, an agent applied topically on the skin that can increase IL-37 could be promising for treating AD and psoriasis; however, the mechanism regulating IL-37 remains largely unknown. Given that IL-37 expression is induced in differentiated keratinocytes, a major component of the epidermis, and that activation of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, promotes keratinocyte differentiation, we hypothesized that AHR might be involved in the IL-37 expression in human keratinocytes. We analyzed normal epidermal human keratinocytes (NHEKs) treated with tapinarof and Galactomyces ferment filtrate (GFF), which are potent AHR modulators. We found that tapinarof and GFF upregulated IL-37 in NHEKs, which was canceled by the knockdown of AHR using siRNA transfection, indicating that AHR mediates IL-37 expression in NHEKs. Furthermore, we found that the knockdown of IL-37 resulted in the upregulation of IL-33, an alarmin cytokine with crucial roles in the pathogenesis of AD and psoriasis. These findings suggest that IL-37 negatively regulates IL-33 expression in NHEKs. Finally, we examined whether tapinarof and GFF treatment modulates IL-33 expression in NHEKs. Such treatment inhibited IL-33 expression, which was partially reversed by the knockdown of either AHR or IL-37. Taken together, our findings provide the first evidence that tapinarof and GFF could have potential to prevent IL-33-overexpressing disorders such as AD and psoriasis via the AHR/IL-37 axis.
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Affiliation(s)
- Gaku Tsuji
- Research and Clinical Center for Yusho and Dioxin, Kyushu University, Fukuoka, Japan.,Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akiko Hashimoto-Hachiya
- Research and Clinical Center for Yusho and Dioxin, Kyushu University, Fukuoka, Japan.,Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoyo Matsuda-Taniguchi
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ayako Takai-Yumine
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaki Takemura
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Xianghong Yan
- Science Communications, Procter & Gamble (P&G) Innovation Godo Kaisha, Kobe, Japan
| | - Masutaka Furue
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeshi Nakahara
- Research and Clinical Center for Yusho and Dioxin, Kyushu University, Fukuoka, Japan.,Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Miyamoto K, Munakata Y, Yan X, Tsuji G, Furue M. Enhanced Fluctuations in Facial Pore Size, Redness, and TEWL Caused by Mask Usage Are Normalized by the Application of a Moisturizer. J Clin Med 2022; 11:jcm11082121. [PMID: 35456214 PMCID: PMC9030563 DOI: 10.3390/jcm11082121] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/08/2022] [Accepted: 04/10/2022] [Indexed: 12/16/2022] Open
Abstract
Mask wearing is described as one of the main public health measures against COVID-19. Mask wearing induces various types of subjective and objective facial skin damage, such as hair pore dilatation and redness. Facial pore size and redness show morning-to-evening intra-day fluctuations. It remains unknown whether mask usage affects fluctuations in pore size and redness. We measured facial skin hydration, transepidermal water loss (TEWL), pore size, and redness four times a day for 6 weeks in 20 healthy young women. After a 2-week no-mask-usage period (baseline period), all subjects wore unwoven masks for 2 weeks; then, for the following 2 weeks, they applied masks after the topical application of a moisturizer containing a Galactomyces ferment filtrate (GFF) skin care formula (Pitera™). We demonstrated that mask wearing significantly increased the intra-day fluctuations of pore size, redness, and TEWL. In addition, significant correlations were evident among these three parameters. Notably, these mask-induced skin changes were significantly improved, achieving a return to baseline levels, by the application of a GFF-containing moisturizer. In conclusion, mask wearing aggravates intra-day fluctuations in pore size and redness. Appropriate moisturization can minimize this mask-related skin damage, most likely by normalizing the elevated TEWL.
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Affiliation(s)
- Kukizo Miyamoto
- Research and Development, Kobe Innovation Center, Procter and Gamble Innovation GK, Kobe 651-0088, Japan; (Y.M.); (X.Y.)
- Correspondence:
| | - Yoko Munakata
- Research and Development, Kobe Innovation Center, Procter and Gamble Innovation GK, Kobe 651-0088, Japan; (Y.M.); (X.Y.)
| | - Xianghong Yan
- Research and Development, Kobe Innovation Center, Procter and Gamble Innovation GK, Kobe 651-0088, Japan; (Y.M.); (X.Y.)
| | - Gaku Tsuji
- Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka 812-8582, Japan;
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
| | - Masutaka Furue
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
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Murugan NJ, Voutsadakis IA. Proteasome regulators in pancreatic cancer. World J Gastrointest Oncol 2022; 14:38-54. [PMID: 35116102 PMCID: PMC8790418 DOI: 10.4251/wjgo.v14.i1.38] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/14/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic adenocarcinoma is one of the most lethal cancers with rising incidence. Despite progress in its treatment, with the introduction of more effective chemotherapy regimens in the last decade, prognosis of metastatic disease remains inferior to other cancers with long term survival being the exception. Molecular characterization of pancreatic cancer has elucidated the landscape of the disease and has revealed common lesions that contribute to pancreatic carcinogenesis. Regulation of proteostasis is critical in cancers due to increased protein turnover required to support the intense metabolism of cancer cells. The proteasome is an integral part of this regulation and is regulated, in its turn, by key transcription factors, which induce transcription of proteasome structural units. These include FOXO family transcription factors, NFE2L2, hHSF1 and hHSF2, and NF-Y. Networks that encompass proteasome regulators and transduction pathways dysregulated in pancreatic cancer such as the KRAS/ BRAF/MAPK and the Transforming growth factor beta/SMAD pathway contribute to pancreatic cancer progression. This review discusses the proteasome and its transcription factors within the pancreatic cancer cellular micro-environment. We also consider the role of stemness in carcinogenesis and the use of proteasome inhibitors as therapeutic agents.
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Affiliation(s)
- Nirosha J Murugan
- Department of Biology, Algoma University, Sault Sainte Marie P6A3T6, ON, Canada
| | - Ioannis A Voutsadakis
- Department of Medical Oncology, Sault Area Hospital, Sault Sainte Marie P6A3T6, ON, Canada
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Cannabidiol modulation of oxidative stress and signalling. Neuronal Signal 2021; 5:NS20200080. [PMID: 34497718 PMCID: PMC8385185 DOI: 10.1042/ns20200080] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/27/2021] [Accepted: 07/30/2021] [Indexed: 12/18/2022] Open
Abstract
Cannabidiol (CBD), one of the primary non-euphoric components in the Cannabis sativa L. plant, has undergone clinical development over the last number of years as a therapeutic for patients with Lennox-Gastaut syndrome and Dravet syndromes. This phytocannabinoid demonstrates functional and pharmacological diversity, and research data indicate that CBD is a comparable antioxidant to common antioxidants. This review gathers the latest knowledge regarding the impact of CBD on oxidative signalling, with focus on the proclivity of CBD to regulate antioxidants and control the production of reactive oxygen species. CBD is considered an attractive therapeutic agent for neuroimmune disorders, and a body of literature indicates that CBD can regulate redox function at multiple levels, with a range of downstream effects on cells and tissues. However, pro-oxidant capacity of CBD has also been reported, and hence caution must be applied when considering CBD from a therapeutic standpoint. Such pro- and antioxidant functions of CBD may be cell- and model-dependent and may also be influenced by CBD dose, the duration of CBD treatment and the underlying pathology.
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Miyamoto K, Dissanayake B, Omotezako T, Takemura M, Tsuji G, Furue M. Daily Fluctuation of Facial Pore Area, Roughness and Redness among Young Japanese Women; Beneficial Effects of Galactomyces Ferment Filtrate Containing Antioxidative Skin Care Formula. J Clin Med 2021; 10:jcm10112502. [PMID: 34198790 PMCID: PMC8200969 DOI: 10.3390/jcm10112502] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/02/2021] [Accepted: 06/03/2021] [Indexed: 12/20/2022] Open
Abstract
Young women often complain about the daily fluctuation of their facial skin conditions. However, no objective study has been carried out on such changes. This study is aimed at quantitatively elucidating daily skin fluctuation and evaluating the efficacy of cosmetic skin care treatment. We developed the first portable and self-guided facial skin imaging device (eMR Pro) to reproducibly capture facial images at home. Two 8 week clinical studies were then conducted to analyze daily skin fluctuation of facial pore areas, roughness and redness in young Japanese women (n = 47 in study 1 and n = 57 in study 2) by collecting facial images three times a day, during the morning after wake-up, during the morning after face wash, and during the evening after face wash. After a 4 week baseline measurement period (week -4 to week -1), all subjects applied Galactomyces ferment filtrate (GFF, Pitera®) skin care formula twice a day for 4 weeks (week 1 to week 4). These three skin conditions did exhibit different fluctuation patterns. The pore area and roughness showed the “morning after wake-up”-largest fluctuation pattern, whereas redness showed the “evening after face wash”-largest fluctuation pattern. GFF treatment significantly reduced the net values and delta fluctuation of pore area, roughness, and redness, which were consistently observed in two studies. In conclusion, the daily fluctuation of facial skin conditions is potentially a new target field for investigating healthy skin maintenance.
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Affiliation(s)
- Kukizo Miyamoto
- Research and Development, Kobe Innovation Center, Procter and Gamble Innovation GK, Kobe 651-0088, Japan;
- Correspondence:
| | - Bandara Dissanayake
- Research and Development, Beauty Care, P&G International Operations (SA) Singapore Branch, Singapore 138547, Singapore;
| | - Tatsuya Omotezako
- Research and Development, Kobe Innovation Center, Procter and Gamble Innovation GK, Kobe 651-0088, Japan;
| | - Masaki Takemura
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; (M.T.); (G.T.); (M.F.)
| | - Gaku Tsuji
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; (M.T.); (G.T.); (M.F.)
- Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka 812-8582, Japan
| | - Masutaka Furue
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; (M.T.); (G.T.); (M.F.)
- Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka 812-8582, Japan
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Furue M. Regulation of Skin Barrier Function via Competition between AHR Axis versus IL-13/IL-4‒JAK‒STAT6/STAT3 Axis: Pathogenic and Therapeutic Implications in Atopic Dermatitis. J Clin Med 2020; 9:E3741. [PMID: 33233866 PMCID: PMC7700181 DOI: 10.3390/jcm9113741] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 11/16/2020] [Accepted: 11/19/2020] [Indexed: 02/07/2023] Open
Abstract
Atopic dermatitis (AD) is characterized by skin inflammation, barrier dysfunction, and chronic pruritus. As the anti-interleukin-4 (IL-4) receptor α antibody dupilumab improves all three cardinal features of AD, the type 2 cytokines IL-4 and especially IL-13 have been indicated to have pathogenic significance in AD. Accumulating evidence has shown that the skin barrier function is regulated via competition between the aryl hydrocarbon receptor (AHR) axis (up-regulation of barrier) and the IL-13/IL-4‒JAK‒STAT6/STAT3 axis (down-regulation of barrier). This latter axis also induces oxidative stress, which exacerbates inflammation. Conventional and recently developed agents for treating AD such as steroid, calcineurin inhibitors, cyclosporine, dupilumab, and JAK inhibitors inhibit the IL-13/IL-4‒JAK‒STAT6/STAT3 axis, while older remedies such as coal tar and glyteer are antioxidative AHR agonists. In this article, I summarize the pathogenic and therapeutic implications of the IL-13/IL-4‒JAK‒STAT6/STAT3 axis and the AHR axis in AD.
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Affiliation(s)
- Masutaka Furue
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; ; Tel.: +81-92-642-5581; Fax: +81-92-642-5600
- Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka 812-8582, Japan
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Furue M. Regulation of Filaggrin, Loricrin, and Involucrin by IL-4, IL-13, IL-17A, IL-22, AHR, and NRF2: Pathogenic Implications in Atopic Dermatitis. Int J Mol Sci 2020; 21:E5382. [PMID: 32751111 PMCID: PMC7432778 DOI: 10.3390/ijms21155382] [Citation(s) in RCA: 226] [Impact Index Per Article: 45.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 07/28/2020] [Accepted: 07/28/2020] [Indexed: 12/16/2022] Open
Abstract
Atopic dermatitis (AD) is an eczematous, pruritic skin disorder with extensive barrier dysfunction and elevated interleukin (IL)-4 and IL-13 signatures. The barrier dysfunction correlates with the downregulation of barrier-related molecules such as filaggrin (FLG), loricrin (LOR), and involucrin (IVL). IL-4 and IL-13 potently inhibit the expression of these molecules by activating signal transducer and activator of transcription (STAT)6 and STAT3. In addition to IL-4 and IL-13, IL-22 and IL-17A are probably involved in the barrier dysfunction by inhibiting the expression of these barrier-related molecules. In contrast, natural or medicinal ligands for aryl hydrocarbon receptor (AHR) are potent upregulators of FLG, LOR, and IVL expression. As IL-4, IL-13, IL-22, and IL-17A are all capable of inducing oxidative stress, antioxidative AHR agonists such as coal tar, glyteer, and tapinarof exert particular therapeutic efficacy for AD. These antioxidative AHR ligands are known to activate an antioxidative transcription factor, nuclear factor E2-related factor 2 (NRF2). This article focuses on the mechanisms by which FLG, LOR, and IVL expression is regulated by IL-4, IL-13, IL-22, and IL-17A. The author also summarizes how AHR and NRF2 dual activators exert their beneficial effects in the treatment of AD.
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Affiliation(s)
- Masutaka Furue
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan; ; Tel.: +81-92-642-5581; Fax: +81-92-642-5600
- Research and Clinical Center for Yusho and Dioxin, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan
- Division of Skin Surface Sensing, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan
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Sumida K, Han Z, Dashputre AA, Potukuchi PK, Kovesdy CP. Association between Nrf2 and CDKN2A expression in patients with end-stage renal disease: a pilot study. Aging (Albany NY) 2020; 12:16357-16367. [PMID: 32661200 PMCID: PMC7485736 DOI: 10.18632/aging.103685] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 06/29/2020] [Indexed: 04/12/2023]
Abstract
Patients with end-stage renal disease (ESRD) display phenotypic features of premature biological aging, characterized by disproportionately high morbidity and mortality at a younger age. Nuclear factor erythroid 2-related factor 2 (Nrf2) activity, a master regulator of antioxidative responses, declines with age and is implicated in the pathogenesis of age-related disorders; however, little is known about the association between Nrf2 and premature biological aging in ESRD patients. In a cross-sectional pilot cohort of 34 ESRD patients receiving maintenance hemodialysis, we measured the expression of Nrf2 and cyclin-dependent kinase inhibitor 2A (CDKN2A, or p16INK4a, a biomarker of biological aging) genes in whole blood and examined the association of Nrf2 with CDKN2A expression, using Spearman's rank correlation and multivariable linear regression models with adjustment for potential confounders. There was a significant negative correlation between Nrf2 and CDKN2A expression (rho=-0.51, P=0.002); while no significant correlation was found between Nrf2 expression and chronological age (rho=-0.02, P=0.91). After multivariable adjustment, Nrf2 expression remained significantly and negatively associated with CDKN2A expression (β coefficient=-1.51, P=0.01), independent of chronological age, gender, race, and diabetes status. These findings suggest a potential contribution of Nrf2 dysfunction to the development of premature biological aging and its related morbidities in ESRD patients.
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Affiliation(s)
- Keiichi Sumida
- Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Zhongji Han
- Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Ankur A. Dashputre
- Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
- Institute for Health Outcomes and Policy, College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Praveen K. Potukuchi
- Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Csaba P. Kovesdy
- Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
- Nephrology Section, Memphis VA Medical Center, Memphis, TN 38104, USA
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