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Effects and Molecular Mechanisms of 4-methylimidazole on Skin Aging
Skin aging,Caramel color,4-methylimidazole,Senescence,Sirtuin6,
|Publication Year :||2019|
|Abstract:||近年許多研究證實皮膚老化與許多慢性疾病具有密切之關連。皮膚老化可經由內源性與外源性因子調控；此外，食物與食品添加物亦可影響皮膚老化進程。焦糖色素為常用於食品產業中著色用途之食品添加物，其製程中生成的4-甲基咪唑(4-methylimidazole, 4-MEI)，可能對人體健康造成影響，如：癌症。然而，目前對於4-MEI是否影響皮膚老化進程仍待釐清。因此，本篇研究欲探討4-MEI於皮膚老化之影響及作用機制。本研究模式分為體外細胞試驗與動物實驗，評估4-MEI對於皮膚老化相關蛋白表現量與皮膚表徵的影響。實驗結果顯示，人類真皮纖維母細胞株Hs68，經4-MEI處理後，隨劑量與時間增加，老化相關半乳醣苷酶(senescence-associated beta-galactosidase)表現上升，基質金屬蛋白酶(matrix metalloproteinases, MMPs) 中MMP2與MMP9蛋白表現量顯著增加，第四型膠原蛋白表現量顯著下降，而Sirtuin6 (SIRT6)蛋白表現量顯著降低，此外，大量表現SIRT6可回復4-MEI造成之半乳醣苷酶活性上升以及老化相關蛋白(MMP2, MMP9與TIMP1)表現等現象。接續探討4-MEI對於動物體內皮膚老化現象，本研究選用Balb/c無毛鼷鼠，每日以頸背部皮下單次注射1 g/kg body weight (b.w.) D-半乳糖 (D-galactose, D-gal)，連續給予八週誘導老化；第五週開始每日單次管餵80 mg/kg b.w. 4-MEI，連續給予四週後再將動物犧牲進行試驗。結果顯示，與對照組及D-gal誘導老化組相比較，D-gal誘導老化並餵食4-MEI組之皮膚皺紋生成量更多，且真皮層厚度具有下降趨勢，真皮層中膠原纖維排列稀疏且不規則，血清與真皮層Nε-carboxymethyl-lysine (CML)含量上升。綜合上述，本研究發現4-MEI可抑制SIRT6蛋白表現，促進MMPs蛋白表現，進而分解膠原蛋白，影響皮膚細胞外基質結構組成；而於Balb/c無毛鼷鼠模式，4-MEI加速老化的進程，於真皮層變薄，膠原纖維排列稀疏與CML含量增加等現象，另SIRT6於4-MEI致皮膚老化之確切分子機制仍待探討。|
Skin aging has been reported to be positively related with various chronic diseases. Aging skin occurs from intrinsic and extrinsic factors. Additionally, dietary food or food additives may cause skin aging. Caramel color is one of widely used food additives and its major harmful ingredient 4-methylimidazole (4-MEI) produced from caramel processing has been reported to exhibit potential toxic or carcinogenic effects to human. However, the relationship between skin aging and 4-MEI still remains unknown. The purpose of this study is to investigate effects and the potential molecular mechanisms of 4-MEI on skin aging. Hs68 human dermal fibroblasts and D-galactose-induced aging mice model were used to evaluate effects of 4-MEI on skin aging-related protein expressions and skin morphology. As expected, 4-MEI treatment significantly induced the activity of senescence-associated beta-galactosidase at a dose- and time-dependent manner in Hs68 cells. Moreover, 4-MEI also increased protein levels of matrix metalloproteinases -2 and -9 in Hs68 cells while the level of type IV collagen was gradually decreased. Furthermore, protein expressions of sirtuin6 (SIRT6), a senescence-related signal, was significantly suppressed by 4-MEI. Besides, overexpression of SIRT6 attenuated 4-MEI-induced cellular senescence and protein expressions of skin aging-related biomarkers (MMP2, MMP9 and TIMP1). In the D-galactose-induced aging mice model, mice of D-galactose-treated groups were daily received subcutaneous injections of 1000 mg/kg D-galactose for eight weeks. At the fifth week, mice of 4-methylimidazole-treated groups were administrated with or without 80 mg/kg 4-methylimidazole once a day by oral gavage for 4 consecutive weeks. As shown, dermal thickness and dermis collagen integrity were respectively reduced and altered in D-galactose-induced aging mice with 4-MEI administration. Nε-carboxymethyl-lysine (CML) levels of serum and skin were both increased in D-galactose+4-MEI group. In summary, 4-MEI accelerates protein expressions of skin aging-related biomarkers and signals in Hs68 cells, and promotes skin aging in D-galactose induced aging mice. However, further experiments are required to investigate the role of SIRT6 in 4-MEI-promoted skin aging.
|Appears in Collections:||食品安全與健康研究所|
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