Topical application of an amygdalin analogue reduces inflammation and keratinocyte proliferation in a psoriasis mouse model

Gago-López, Nuria; Arnal, Carmen Lagunas; Pérez, Juan J.; Wagner, Erwin F.

doi:10.1111/exd.14390

Cited by 18 publications

(13 citation statements)

References 43 publications

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“…Keratinocytes also release cytokines such as IL-23, TNF-α and TSLP (Thymic stromal lymphopoietin). These mediators stimulate immune cells to produce cytokines that, in turn, intensify the inflammatory state by inducing keratinocyte proliferation [18]. IL-22 exhibits a strong hyperproliferative effect on keratinocytes.…”

Section: Discussionmentioning

confidence: 99%

The Unknown Role of Periostin in Psoriatic Epidermal Hyperplasia

Wojciechowska,

Ścibior,

Betyna-Białek

et al. 2023

IJMS

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Psoriasis is an inflammatory skin disease that affects 1–2% of the general population. The pathomechanism is based on type 1 immunological reactions. Hyperplasia of the epidermis in psoriasis is a result of disrupted epidermal architecture due to increased synthesis and expression of extracellular matrix proteins. In our study, we analyzed the involvement of periostin (POSTN) in the pathogenesis of psoriasis, as one of the extracellular matrix proteins belonging to the fasciclin family. The study group consisted of 70 patients with psoriasis, while the control group comprised 30 healthy individuals. The serum concentrations of POSTN, Il-6, Il-17, Il-22, TNF-α and IFN-γ were measured in all participants. The severity of psoriasis was determined using the PASI (Psoriasis Area and Severity Index) score. The presence of POSTN in biopsy samples of 50 patients was assessed using the direct immunofluorescence method. The results were subjected to statistical analysis. The serum concentrations of POSTN, Il-6, Il-17, Il-22, TNF-α and IFN-γ in the study group are significantly higher than in the control group. Positive correlation has been demonstrated between the PASI score and the investigated cytokines, but not with POSTN. There was no statistically significant correlation between the POSTN level and the cytokines levels. POSTN deposits were localized in the epidermis in 66% of patients with psoriasis. The role of POSTN in the pathogenesis of psoriasis remains unclear. The mechanisms inducing the synthesis and expression of POSTN in psoriatic skin are not yet fully understood. Further research is needed to enhance our understanding of the mechanism underlying epidermal hyperplasia in psoriasis.

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Section: Discussionmentioning

confidence: 99%

The Unknown Role of Periostin in Psoriatic Epidermal Hyperplasia

Wojciechowska,

Ścibior,

Betyna-Białek

et al. 2023

IJMS

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“…The cream formulation was prepared as previously reported, 15 which contains a mixing of oily phase and aqueous phase. The oily phase contains 10% white mineral oils, 6% light liquid paraffin, 10% PEG‐8 beeswax, 6% glyceryl caprylate, 4% cetyl alcohol, 3% hydrogenated palm and 3% lauroyl PEG‐32 glycerides.…”

Section: Methodsmentioning

confidence: 99%

Topical application of TOPK inhibitor OTS514 suppresses psoriatic progression by inducing keratinocytes cell cycle arrest and apoptosis

Fan-dian

Lü

et al. 2023

Experimental Dermatology

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T‐LAK cell‐oriented protein kinase (TOPK) potently promotes malignant proliferation of tumour cells and is considered as a maker of tumour progression. Psoriasis is a common inflammatory skin disease characterized by abnormal proliferation of keratinocytes. However, the role of TOPK in psoriasis has not been well elucidated. This study aims to investigate the expression and role of TOPK in psoriasis, and the role of TOPK inhibitor in psoriasis attenuation. Gene Expression Omnibus datasets derived from psoriasis patients and psoriatic model mice were screened for analysis. Skin specimens from psoriasis patients were collected for TOPK immunohistochemical staining to investigate the expression and localization of TOPK. Next, psoriatic mice model was established to further confirm TOPK expression pattern. Then, TOPK inhibitor was applied to investigate the role of TOPK in psoriasis progression. Finally, cell proliferation assay, apoptosis assay and cell cycle analysis were performed to investigate the potential mechanism involved. Our study showed that TOPK was upregulated in the lesions of both psoriasis patients and psoriatic model mice, and TOPK levels were positively associated with psoriasis progression. TOPK was upregulated in psoriatic lesions and expressed predominantly by epidermal keratinocytes. In addition, TOPK levels in epidermal keratinocytes were positively correlated with epidermal hyperplasia. Furthermore, topical application of TOPK inhibitor OTS514 obviously alleviated disease severity and epidermal hyperplasia. Mechanismly, inhibiting TOPK induces G2/M phase arrest and apoptosis of keratinocytes, thereby attenuating epidermal hyperplasia and disease progression. Collectively, this study identifies that upregulation of TOPK in keratinocytes promotes psoriatic progression, and inhibiting TOPK attenuates epidermal hyperplasia and psoriatic progression.

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“…interleukin [IL]-6 and tumour necrosis factor [TNF]-α) to amplify inflammation. 1,4 Biologics targeting IL-23, IL-17 and TNF-α are effective for patients with psoriasis. 5,6 However, some patients fail to respond and are likely to develop drug resistance gradually or relapse when the treatment is stopped.…”

Section: Introductionmentioning

confidence: 99%

“…S100A8/9 and LL37) and other inflammatory mediators (e.g. interleukin [IL]‐6 and tumour necrosis factor [TNF]‐α) to amplify inflammation 1,4 . Biologics targeting IL‐23, IL‐17 and TNF‐α are effective for patients with psoriasis 5,6 .…”

Section: Introductionmentioning

confidence: 99%

Serine deficiency exacerbates psoriatic skin inflammation by regulating S‐adenosyl methionine‐dependentDNAmethylation andNF‐κBsignalling activation in keratinocytes

Meng,

Liu,

Yao

et al. 2023

Acad Dermatol Venereol

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BackgroundSerine metabolism is crucial for tumor oncogenesis and immune responses. S‐adenosyl methionine (SAM), a methyl donor, is typically derived from serine‐driven one‐carbon metabolism. However, the involvement of serine metabolism in psoriatic skin inflammation remains unclear.ObjectivesTo investigate the association between serine metabolism and psoriatic skin inflammation.MethodsClinical samples were collected from patients with psoriasis and the expression of serine biosynthesis enzymes was evaluated. The HaCaT human keratinocyte cell line was transfected with small interfering RNA (siRNA) of key enzyme or treated with inhibitors. RNA sequencing and DNA methylation assays were performed to elucidate the mechanisms underlying serine metabolism‐regulated psoriatic keratinocyte inflammation An imiquimod (IMQ)‐induced psoriasis mouse model was established to determine the effect of the SAM administration on psoriatic skin inflammation.ResultsThe expression of serine synthesis pathway enzymes, including the first rate‐limiting enzyme in serine biosynthesis, phosphoglycerate dehydrogenase (PHGDH), was downregulated in the epidermal lesions of patients with psoriasis compared with that in healthy controls. Suppressing PHGDH in keratinocytes promoted the production of proinflammatory cytokines and enrichment of psoriatic‐related signaling pathways, including the tumor necrosis factor‐alpha (TNF‐α) signaling pathway, interleukin (IL)‐17 signaling pathway, and NF‐κB signaling pathway. In particular, PHGDH inhibition markedly promoted the secretion of IL‐6 in keratinocytes with or without IL‐17A, IL‐22, IL‐1α, oncostatin M, and TNF‐α (mix) stimulation. Mechanistically, PHGDH inhibition upregulated the expression of IL‐6 by inhibiting SAM‐dependent DNA methylation at the promoter and increasing the binding of myocyte enhancer factor 2A. Furthermore, PHGDH inhibition increased the secretion of IL‐6 by increasing the activation of NF‐κB via SAM inhibition. SAM treatment effectively alleviated IMQ‐induced psoriasis‐like skin inflammation in mice.ConclusionsOur study revealed the crucial role of PHGDH in antagonizing psoriatic skin inflammation and indicated that targeting serine metabolism may represent a novel therapeutic strategy for treating psoriasis.

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Topical application of an amygdalin analogue reduces inflammation and keratinocyte proliferation in a psoriasis mouse model

Cited by 18 publications

References 43 publications

The Unknown Role of Periostin in Psoriatic Epidermal Hyperplasia

The Unknown Role of Periostin in Psoriatic Epidermal Hyperplasia

Topical application of TOPK inhibitor OTS514 suppresses psoriatic progression by inducing keratinocytes cell cycle arrest and apoptosis

Serine deficiency exacerbates psoriatic skin inflammation by regulating S‐adenosyl methionine‐dependentDNAmethylation andNF‐κBsignalling activation in keratinocytes

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