Ascorbic acid derivative DDH-1 ameliorates psoriasis-like skin lesions in mice by suppressing inflammatory cytokine expression

Kitahata, Kosuke; Matsuo, Keitaro; Hara, Yuta; Naganuma, Takanori; Oiso, Naoki; Kawada, Akira; Nakayama, Takashi

doi:10.1016/j.jphs.2018.11.002

Cited by 14 publications

(21 citation statements)

References 14 publications

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“…Upon restoration of TET expression in low calcium cultures via ascorbic acid treatment, human KSCs exhibited higher levels of 5-hmC and switched to a more normal differentiation status, as assessed cytologically and via nestin expression. Ascorbic acid derivatives have been shown to ameliorate psoriasis (Kitahata et al, 2018), and our results raise the possibility that increase of TET-mediated DNA hydroxymethylation by ascorbic acid is an underlying mechanism in psoriasis treatment by ascorbic acid derivatives. Thus, loss of 5-hmC in psoriasis appears to function, at least in part, in modulating gene expression important for maintenance of stem cell behavior during psoriasis pathogenesis.…”

Section: Discussionsupporting

confidence: 61%

Loss of the Epigenetic Mark 5-hmC in Psoriasis: Implications for Epidermal Stem Cell Dysregulation

Feng

Yuan

et al. 2020

Journal of Investigative Dermatology

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Epigenetic regulation has a profound influence on stem cell fate during normal development in maintenance of physiologic tissue homeostasis. Here we report diminished ten-eleven translocation (TET) methylcytosine dioxygenase expression and loss of the DNA hydroxymethylation mark 5-hydroxymethylcytosine (5-hmC) in keratinocyte stem cells and transit amplifying cells in human psoriasis and in imiquimod-induced murine psoriasis. Loss of 5-hmC was associated with dysregulated keratinocyte stem cell kinetics, resulting in accumulation of nestin and FABP5-expressing transit amplifying cells to produce classic psoriatic epidermal architecture. Moreover, 5-hmC loss was accompanied by diminished TET1 and TET2 mRNA expression. Genome-wide mapping of epidermal 5-hmC in murine psoriasis revealed loci-specific loss of 5-hmC in genes regulating stem cell homeostasis, including MBD1, RTN1, STRN4, PRKD2, AKT1, and MAPKAP2, as well as those associated with RAR and Wnt/b-catenin signaling pathways. In vitro restoration of TET expression by ascorbic acid was accomplished in cultured human keratinocyte stem cells to show similar Ca þþ-induced differentiation, resulting in increased 5-hmC levels and reduced nestin expression. To our knowledge, an epigenetic deficiency in psoriasis with relevance to stem cell dysregulation has not been previously reported. This observation raises the possibility that epigenetic modifiers that impact on the TETe5-hmC pathway may be a relevant approach of heretofore unappreciated therapeutic utility.

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Section: Discussionsupporting

confidence: 61%

Loss of the Epigenetic Mark 5-hmC in Psoriasis: Implications for Epidermal Stem Cell Dysregulation

Feng

Yuan

et al. 2020

Journal of Investigative Dermatology

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“…Importantly, the investigators demonstrate that enhancing TET functions through the delivery of ascorbic acid in vitro could reverse some of the psoriatic changes, suggesting that targeting this pathway may have therapeutic efficacy in psoriasis ( Figure 1b). These observations support a recent study indicating that ascorbic acid derivatives may have therapeutic efficacy in the models of psoriasis (Kitahata et al, 2018).…”

supporting

confidence: 91%

“…Whether these effects can be recapitulated in vivo to improve psoriasis phenotypes, and how targeting this pathway would affect the immune component of psoriasis are important outstanding questions for future research. These are particularly relevant questions given previous data suggesting that ascorbic acid derivatives may be effective in a mouse model of psoriasis through their ability to repress inflammatory gene expression (Kitahata et al, 2018). It is unclear from this study whether or not inflammatory gene expression was tested in their models.…”

mentioning

confidence: 89%

Loss of Methylation Modification Marks the Presence of Psoriasis

Capell

Seykora

2020

Journal of Investigative Dermatology

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The reversibility of epigenetic alterations makes them the attractive targets for therapeutic discovery; however, their potential remains untapped owing to a lack of mechanistic understanding, particularly for inflammatory skin disorders. Here, Li and colleagues begin to fill these gaps by identifying the loss of the DNA hydroxymethylation mark 5-hmC in psoriasis and presenting compelling evidence for its potential contribution to disease manifestations.

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“…Skin adipocytes and sebocytes are the next large PPARγ depositions [ 9 , 10 ], and the protein is vital for their differentiation [ 11 , 12 ]. The PPARγ expression was reported to be downregulated in the psoriatic skin of mice, and DDH1 dose dependently could restore the gene expression [ 13 ]. In vitro experimental models of psoriasis showed that the expression of other PPARs (PPARa) was also decreased in the skin, while PPARb and PPARd expressions were increased [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

The Model of PPARγ-Downregulated Signaling in Psoriasis

et al. 2020

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Interactions of genes in intersecting signaling pathways, as well as environmental influences, are required for the development of psoriasis. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor and transcription factor which inhibits the expression of many proinflammatory genes. We tested the hypothesis that low levels of PPARγ expression promote the development of psoriatic lesions. We combined experimental results and network functional analysis to reconstruct the model of PPARγ-downregulated signaling in psoriasis. We hypothesize that the expression of IL17, STAT3, FOXP3, and RORC and FOSL1 genes in psoriatic skin is correlated with the level of PPARγ expression, and they belong to the same signaling pathway that regulates the development of psoriasis lesion.

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Ascorbic acid derivative DDH-1 ameliorates psoriasis-like skin lesions in mice by suppressing inflammatory cytokine expression

Cited by 14 publications

References 14 publications

Loss of the Epigenetic Mark 5-hmC in Psoriasis: Implications for Epidermal Stem Cell Dysregulation

Loss of the Epigenetic Mark 5-hmC in Psoriasis: Implications for Epidermal Stem Cell Dysregulation

Loss of Methylation Modification Marks the Presence of Psoriasis

The Model of PPARγ-Downregulated Signaling in Psoriasis

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