Phosphodiesterase 7A inhibitor ASB16165 impairs proliferation of keratinocytes in vitro and in vivo

Goto, Megumi; Kadoshima-Yamaoka, Kumiko; Murakawa, Masao; Yoshioka, Ryosuke; Tanaka, Yoshitaka; Inoue, Hidekazu; Murafuji, Hidenobu; Kanki, Satomi; Hayashi, Yasuhiko; Nagahira, Kazuhiro; Ogata, Atsuto; Nakatsuka, Takashi; Fukuda, Yoshiaki

doi:10.1016/j.ejphar.2010.01.024

Cited by 21 publications

(14 citation statements)

References 27 publications

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“…Our studies suggest that direct cAMP stimulation inhibits the proliferation of primary keratinocytes, in agreement with previous findings by others . Instead, our data suggest that one or more soluble cAMP‐induced factors derived from fibroblasts, likely Kgf or Fgf10, mediates forskolin‐induced keratinocyte proliferation.…”

Section: Discussionsupporting

confidence: 92%

Pigment‐independent cAMP‐mediated epidermal thickening protects against cutaneous UV injury by keratinocyte proliferation

Scott

Christian

Kesler

et al. 2012

Experimental Dermatology

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The epidermis increases pigmentation and epidermal thickness in response to ultraviolet exposure to protect against UV-associated carcinogenesis; however, the contribution of epidermal thickness has been debated. In a humanized skin mouse model that maintains interfollicular epidermal melanocytes, we found that forskolin, a small molecule that directly activates adenylyl cyclase and promotes cAMP generation, up-regulated epidermal eumelanin accumulation in fair-skinned melanocortin-1-receptor (Mc1r)-defective animals. Forskolin-induced pigmentation was associated with a reproducible expansion of epidermal thickness irrespective of melanization or the presence of epidermal melanocytes. Rather, forskolin-enhanced epidermal thickening was mediated through increased keratinocyte proliferation, indirectly through secreted factor(s) from cutaneous fibroblasts. We identified keratinocyte growth factor (Kgf) as a forskolin-induced fibroblast-derived cytokine that promoted keratinocyte proliferation, as forskolin induced Kgf expression both in the skin and in primary fibroblasts. Lastly, we found that even in the absence of pigmentation, forskolin-induced epidermal thickening significantly diminished the amount of UVA and UVB that passed through whole skin and reduced the amount of UVB-associated epidermal sunburn cells. These findings suggest the possibility of pharmacologic-induced epidermal thickening as a novel UV-protective therapeutic intervention, particularly for individuals with defects in pigmentation and adaptive melanization.

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Section: Discussionsupporting

confidence: 92%

Pigment‐independent cAMP‐mediated epidermal thickening protects against cutaneous UV injury by keratinocyte proliferation

Scott

Christian

Kesler

et al. 2012

Experimental Dermatology

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“…The expression of PDE7A is elevated in pro-inflammatory and immune cells, supporting the role of PdE7A as a therapeutic target for inflammation disorders (28). A recent study indicated that the PDE7A-specific inhibitor ASB16165 suppresses keratinocyte proliferation on TPA-induced skin inflammation (29).…”

Section: Discussionmentioning

confidence: 94%

The tumor-suppressive microRNA-1/133a cluster targets PDE7A and inhibits cancer cell migration and invasion in endometrial cancer

Yamamoto

Nishikawa

Chiyomaru

et al. 2015

International Journal of Oncology

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In developed countries, endometrial cancer (EC) is the most common malignancy among women. Unopposed estrogen therapy, obesity, nulliparity, diabetes mellitus and arterial hypertension have been linked to an increased risk of EC. However, the molecular mechanisms of EC oncogenesis and metastasis have not yet been fully elucidated. Our recent studies of microRNA (miRNA) expression signatures revealed that the microRNA-1/133a (miR‑1/133a) cluster is frequently downregulated in various types of human cancers. However, the functional role of the miR‑1/133a cluster in EC cells is still unknown. Thus, the aim of this study was to investigate the functional significance of the miR‑1/133a cluster and its regulated molecular targets, with an emphasis on the contributions of miR‑1/133a to EC oncogenesis and metastasis. We found that the expression levels of miR‑1 and miR‑133a were significantly reduced in EC tissues. Moreover, restoration of mature miR‑1 or miR‑133a miRNAs significantly inhibited cancer cell migration and invasion, suggesting that these clustered miRNAs act as tumor suppressors. Prediction of miRNA targets revealed that phosphodiesterase 7A (PDE7A) was a potential target gene regulated by both miR‑1 and miR‑133a. PDE7A was confirmed to be overexpressed in EC clinical specimens and silencing of PDE7A significantly inhibited cancer cell migration and invasion. Our data demonstrated that downregulation of the miR‑1/133a cluster promoted cancer cell migration and invasion via overexpression of PDE7A in EC cells. Elucidation of the molecular networks regulated by tumor-suppressive miRNAs will provide insights into the molecular mechanisms of EC oncogenesis and metastasis.

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“…The TPA-induced mouse ear skin inflammation model, as described previously, was employed with minor modifications [37,38]. Briefly, 20 µL of TPA solution (125 µg/mL in acetone) was applied topically on the mice ear on days 0, 2, 4, 6, 8, and 10.…”

Section: Generation Of Tpa-induced Psoriasis-like Mouse Modelmentioning

confidence: 99%

Super Critical Fluid Extracted Fatty Acids from Withania somnifera Seeds Repair Psoriasis-Like Skin Lesions and Attenuate Pro-Inflammatory Cytokines (TNF-α and IL-6) Release

et al. 2020

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(1) Background: Withania somnifera Dunal (Ashwagandha) is a widely used medicinal herb in traditional medicinal systems with extensive research on various plant parts. Surprisingly, seeds of W. somnifera have never been investigated for their therapeutic potential. (2) Methods: W. somnifera seeds were extracted for fatty acids (WSSO) using super critical fluid extraction, and was analyzed by gas chromatography. Its therapeutic potential in psoriasis-like skin etiologies was investigated using a 12-O tetradecanoyl phorbol 13-acetate (TPA)-induced psoriatic mouse model. Psoriatic inflammation along with psoriatic lesions and histopathological scores were recorded. WSSO was also tested on murine macrophage (RAW264.7), human epidermoid (A431), and monocytic (THP-1) cells, stimulated with TPA or lipo poly-saccharide (LPS) to induce pro-inflammatory cytokine (IL-6 and TNF-α) release. NFκB promoter activity was also measured by luciferase reporter assay. (3) Results: Topical application of WSSO with concurrent oral doses significantly reduced inflammation-induced edema, and repaired psoriatic lesions and associated histopathological scores. Inhibition of pro-inflammatory cytokines release was observed in WSSO-treated A431 and THP-1 cells, along with reduced NFκB expression. WSSO also inhibited reactive nitrogen species (RNS) in LPS-stimulated RAW264.7 cells. (4) Conclusion: Here we show that the fatty acids from W. somnifera seeds have strong anti-inflammatory properties, along with remarkable therapeutic potential on psoriasis-like skin etiologies.

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Phosphodiesterase 7A inhibitor ASB16165 impairs proliferation of keratinocytes in vitro and in vivo

Cited by 21 publications

References 27 publications

Pigment‐independent cAMP‐mediated epidermal thickening protects against cutaneous UV injury by keratinocyte proliferation

Pigment‐independent cAMP‐mediated epidermal thickening protects against cutaneous UV injury by keratinocyte proliferation

The tumor-suppressive microRNA-1/133a cluster targets PDE7A and inhibits cancer cell migration and invasion in endometrial cancer

Super Critical Fluid Extracted Fatty Acids from Withania somnifera Seeds Repair Psoriasis-Like Skin Lesions and Attenuate Pro-Inflammatory Cytokines (TNF-α and IL-6) Release

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