The multi-functional roles of forkhead box protein O in skin aging and diseases

Moon, Kyoung Mi; Lee, Min‐Kyeong; Hwang, Taehyeok; Choi, Chun Whan; Kim, Min Soo; Kim, Hyeung‐Rak; Lee, Bonggi

doi:10.1016/j.redox.2021.102101

Cited by 10 publications

(7 citation statements)

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“…Like IL-17, IL-22 also enhances inflammation by inducing various cytokines, chemokines, and AMPs 29 . Other regulators such as Rho-Associated Protein Kinase 2, which is involved in the differentiation and proliferation of keratinocytes 40 , and Forkhead Box Protein O1, which is involved in the motility of keratinocytes 41 , also show decreased activity z score by NB-UVB treatment in the CE skin.…”

Section: Discussionmentioning

confidence: 99%

Elucidating the NB-UVB mechanism by comparing transcriptome alteration on the edge and center of psoriatic plaques

Boonpethkaew

Meephansan

Charoensuksira

et al. 2023

Sci Rep

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Narrow band-ultraviolet B (NB-UVB) is an effective treatment for psoriasis. We aim to generate a potential mechanism of NB-UVB through comparing the transcriptomic profile before and after NB-UVB treatment between the peripheral edge of lesional skin (PE skin) and the center of lesional skin (CE skin) on the basis of molecular mechanisms of these two areas display different downstream functions. More than one-fourth of the NB-UVB-altered genes were found to be plaque-specific. Some of them were psoriasis signature genes that were downregulated by NB-UVB in, both, PE and CE skin (core alteration), such as IL36G, DEFB4A/B, S100A15, KRT16, and KRT6A. After NB-UVB treatment, the activity score of upstream cytokines, such as interferons, interleukin (IL)-6, IL-17, and IL-22 in pathogenesis decreased. In addition, NB-UVB could restore normal keratinization by upregulating LORICRIN and KRT2, particularly in the CE skin. Finally, we illustrated that NB-UVB is capable of suppressing molecules from the initiation to maintenance phase of plaque formation, thereby normalizing psoriatic plaques. This finding supports the usefulness of NB-UVB treatment in clinical practice and may help in the development of new treatment approaches in which NB-UVB treatment is included for patients with psoriasis or other inflammatory skin diseases.

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Section: Discussionmentioning

confidence: 99%

Elucidating the NB-UVB mechanism by comparing transcriptome alteration on the edge and center of psoriatic plaques

Boonpethkaew

Meephansan

Charoensuksira

et al. 2023

Sci Rep

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“…FOXO3a, a transcriptional factor, maintains cellular homeostasis and extends lifespan via regulation of the expression of multiple downstream target genes that are involved in energy metabolism, redox status, mitochondrial functions, autophagy, stress resistance, cell proliferation, DNA repair, and telomere maintenance [ 52 , 53 , 77 , 78 ]. Previous studies have indicated that FOXO3a participates in the maintenance of skin homeostasis and skin health [ 79 , 80 ]. Therefore, activation of FOXO3a is a promising therapeutic strategy for reducing skin aging [ 50 , 81 ].…”

Section: Discussionmentioning

confidence: 99%

Hesperetin activates CISD2 to attenuate senescence in human keratinocytes from an older person and rejuvenates naturally aged skin in mice

Shen,

Chang,

Yeh

et al. 2024

J Biomed Sci

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Background CDGSH iron-sulfur domain-containing protein 2 (CISD2), a pro-longevity gene, mediates healthspan in mammals. CISD2 is down-regulated during aging. Furthermore, a persistently high level of CISD2 promotes longevity and ameliorates an age-related skin phenotype in transgenic mice. Here we translate the genetic evidence into a pharmaceutical application using a potent CISD2 activator, hesperetin, which enhances CISD2 expression in HEK001 human keratinocytes from an older person. We also treated naturally aged mice in order to study the activator’s anti-aging efficacy. Methods We studied the biological effects of hesperetin on aging skin using, firstly, a cell-based platform, namely a HEK001 human keratinocyte cell line established from an older person. Secondly, we used a mouse model, namely old mice at 21-month old. In the latter case, we investigate the anti-aging efficacy of hesperetin on ultraviolet B (UVB)-induced photoaging and naturally aged skin. Furthermore, to identify the underlying mechanisms and potential biological pathways involved in this process we carried out transcriptomic analysis. Finally, CISD2 knockdown HEK001 keratinocytes and Cisd2 knockout mice were used to study the Cisd2-dependent effects of hesperetin on skin aging. Results Four findings are pinpointed. Firstly, in human skin, CISD2 is mainly expressed in proliferating keratinocytes from the epidermal basal layer and, furthermore, CISD2 is down-regulated in the sun-exposed epidermis. Secondly, in HEK001 human keratinocytes from an older person, hesperetin enhances mitochondrial function and protects against reactive oxygen species-induced oxidative stress via increased CISD2 expression; this enhancement is CISD2-dependent. Additionally, hesperetin alleviates UVB-induced damage and suppresses matrix metalloproteinase-1 expression, the latter being a major indicator of UVB-induced damage in keratinocytes. Thirdly, transcriptomic analysis revealed that hesperetin modulates a panel of differentially expressed genes that are associated with mitochondrial function, redox homeostasis, keratinocyte function, and inflammation in order to attenuate senescence. Intriguingly, hesperetin activates two known longevity-associated regulators, namely FOXO3a and FOXM1, in order to suppress the senescence-associated secretory phenotype. Finally, in mouse skin, hesperetin enhances CISD2 expression to ameliorate UVB-induced photoaging and this occurs via a mechanism involving CISD2. Most strikingly, late-life treatment with hesperetin started at 21-month old and lasting for 5 months, is able to retard skin aging and rejuvenate naturally aged skin in mice. Conclusions Our results reveal that a pharmacological elevation of CISD2 expression at a late-life stage using hesperetin treatment is a feasible approach to effectively mitigating both intrinsic and extrinsic skin aging and that hesperetin could act as a functional food or as a skincare product for fighting skin aging.

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“…Among them, PI3K-AKT, FoxO, TNF, and MAPK signaling pathways were enriched in more than 10 targets, suggesting that YQD has a certain intervention effect on these signaling pathways. It was reported that these pathways were involved in the regulation of melanin production [50][51][52][53][54][55] . The main vitiligo related pathways involved in YQD and the relationship between active components and pathway targets were shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

Discover the Active Constituents and Mechanism of Yiqi Qubai Decoction (YQD) in Treating Vitiligo based on Serum Pharmacochemistry Combining Network Pharmacology, Molecular Docking and Zebrafish Experiment

Cui

Shi

et al. 2022

Preprint

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Yiqi Qubai Decoction (YQD) is composed of four herbs, namely, Astragalus propinquus Schischkin, Akebiae Fructu, Leonuri Fructus, and Caragana Sinica Roots. For decades, the decoction has been utilized in the form of granules for the treatment of vitiligo in China, with a remarkable curative result and widespread recognition among patients. However, the chemical contents and active substances of YQD absorption into the plasma, as well as its mechanism of vitiligo treatment, remain unknown. This problem was solved based on serum pharmacochemistry combining network pharmacology, molecular docking, and zebrafish experiments. First, the chemical components of YQD in vitro and the absorption components in rat plasma were identified using UPLC-Q-TOF/MS. Second, network pharmacology was integrated with molecular docking analysis to reveal the active ingredients and a putative mechanism for YQD vitiligo treatment. Finally, an in vivo zebrafish experiment validated the impact of enhancing melanin synthesis. A total of 44 chemical constituents and 36 absorption compounds, consisting of 4 prototype components and 32 metabolites were identified. Network pharmacology studies demonstrated that apigenin, astraisoflavan, akebia saponin D, genkwanin glucuronidation metabolites, and apigenin-glucuronidation metabolites might be the key active components of YQD for the treatment of vitiligo, while AKT1, mTOR, and MAPK1 may serve as the key targets. The main functional pathways involving these key targets include PI3K-AKT-mTOR, PI3K-AKT-FoxO, and MAPK signaling pathways. Molecular docking analysis found that the active components have a high affinity for AKT1, MAPK1, and mTOR. YQD could accelerate the new generation of melanin in zebrafish, which is of great significance for treating vitiligo. Our research not only looked at the absorptive and possibly useful ingredients and mechanisms of YQD for treating vitiligo, but it also confirmed the anti-vitiligo impact and served as a reference for further research, development, and application of YQD.

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The multi-functional roles of forkhead box protein O in skin aging and diseases

Cited by 10 publications

References 100 publications

Elucidating the NB-UVB mechanism by comparing transcriptome alteration on the edge and center of psoriatic plaques

Elucidating the NB-UVB mechanism by comparing transcriptome alteration on the edge and center of psoriatic plaques

Hesperetin activates CISD2 to attenuate senescence in human keratinocytes from an older person and rejuvenates naturally aged skin in mice

Discover the Active Constituents and Mechanism of Yiqi Qubai Decoction (YQD) in Treating Vitiligo based on Serum Pharmacochemistry Combining Network Pharmacology, Molecular Docking and Zebrafish Experiment

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