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Pharmacologic Induction of Epidermal Melanin and Protection Against Sunburn in a Humanized Mouse Model
Published on: September 7, 2013
Silibinin prevents ultraviolet radiation-caused skin damages in SKH-1 hairless mice via a decrease in thymine dimer
Sivanandhan Dhanalakshmi1, G U Mallikarjuna, Rana P Singh
1Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Abstract:
Non-melanoma skin cancer (NMSC) accounts for >1 million new cases each year in the US alone suggesting that more approaches are needed for its prevention and control. Earlier studies by us have shown that silymarin (a crude form of biologically active silibinin with some other isomers), isolated from milk thistle, affords strong protection against ultraviolet (UV) radiation-induced NMSC in SKH-1 hairless mice; however, the molecular mechanisms of its efficacy are not known. Here, we assessed the effect of silibinin on UV-induced DNA damage and p53-p21/Cip1 accumulation, and their roles in UV-induced cell proliferation and apoptosis in SKH-1 hairless mouse epidermis. Topical application of silibinin prior to, or immediately after, UV irradiation resulted in a very strong protective effect against UV-induced thymine dimer positive cells in epidermis accounting for 76-85% (P < 0.001) inhibition. In other studies, silibinin treatment resulted in a further up-regulation of p53 by approximately 1.6-fold (P < 0.001) together with an increase ( approximately 2-fold, P < 0.001) in p21/Cip1 protein levels. Proliferative cell nuclear antigen staining showed that silibinin pre- or post-topical application significantly inhibits (40-52 and 20-40%, respectively, P < 0.001) UV-induced epidermal cell proliferation. In addition, silibinin strongly decreased UV-caused terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic/sunburn cell formation (P < 0.001). These findings suggest that silibinin affords strong protection against UV-induced damage in epidermis by a decrease in thymine dimer positive cells and an up-regulation of p53-p21/Cip1 possibly leading to an inhibition in both cell proliferation and apoptosis. Comparable effects of silibinin following its pre- or post-UV application suggest that mechanisms other than sunscreen effect are operational in silibinin efficacy against UV-caused skin damages.
Insights
Silibinin from milk thistle significantly protects against UV radiation damage by reducing DNA damage and regulating cell growth pathways. This milk thistle extract shows promise for preventing non-melanoma skin cancer.
Area of Science:
- Dermatology
- Molecular Biology
- Photoprotection
Background:
- Non-melanoma skin cancer (NMSC) is a prevalent health concern, necessitating novel prevention strategies.
- Silymarin, derived from milk thistle, has demonstrated protective effects against UV-induced NMSC in mouse models, but its mechanisms remain unclear.
Purpose of the Study:
- To investigate the molecular mechanisms underlying silibinin's photoprotective effects against UV radiation.
- To assess silibinin's impact on UV-induced DNA damage, p53-p21/Cip1 pathway, cell proliferation, and apoptosis in mouse epidermis.
Main Methods:
- Topical application of silibinin to SKH-1 hairless mice before or after UV irradiation.
- Assessment of thymine dimer formation, p53 and p21/Cip1 protein levels, and cell proliferation markers (PCNA).
- Evaluation of apoptosis using TUNEL staining.
Main Results:
- Silibinin significantly inhibited UV-induced thymine dimer formation by 76-85%.
- Silibinin upregulated p53 (1.6-fold) and p21/Cip1 (2-fold) protein levels.
- Silibinin reduced UV-induced epidermal cell proliferation (20-52%) and apoptosis (sunburn cells).
Conclusions:
- Silibinin provides substantial protection against UV-induced skin damage by reducing DNA damage and modulating the p53-p21/Cip1 pathway.
- These effects lead to inhibition of both cell proliferation and apoptosis, suggesting mechanisms beyond simple UV absorption.
- Silibinin's efficacy, regardless of application timing relative to UV exposure, highlights its potential as a preventative agent for UV-induced skin damage.
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