Lephart Edwin D, Andrus Merritt B
1 Department of Physiology & Developmental Biology, Brigham Young University, Provo, UT 84602, USA.
2 The Neuroscience Center, Brigham Young University, Provo, UT 84602, USA.
Exp Biol Med (Maywood). 2017 Sep;242(15):1482-1489. doi: 10.1177/1535370217723628. Epub 2017 Jul 27.
Resveratrol (RV) is a polyphenolic compound naturally produced by plants. Polyphenolic compounds incorporated into medicinal products are beneficial but, RV is rapidly metabolized with an associated decline in biological activity. This study tested RV as the standard and compared five structurally modified RV analogs: butyrate, isobutyrate, palmitoate, acetate, and diacetate (to improve functionality) at 1% concentration(s) for 24 h in epiderm full thickness cultures by gene array/qPCR mRNA analysis. When silent mating type information regulation 2 homolog 1, extracellular elements (collagen1A1, 3A1, 4A1; elastin, tissue inhibitor of matrix metalloproteinase 1, fibrillin 1 laminin beta1 and matrix metalloproteinase 9), anti-aging and aging genes, inflammatory biomarkers (interleukin-1A [IL1A], IL1R2, IL-6 and IL-8), nerve growth factor, and the antioxidants (proliferating cell nuclear antigen, catalase, superoxide dismutase and metallothionein 1H/2H) were evaluated, ranking each from highest-to-lowest for gene expression: butyrate > isobutyrate > diacetate > acetate > palmitoate. This study showed that the butyrate and isobutyrate analogs are more biologically active compared to resveratrol and have potential use in topical applications to improve dermal and other health applications. Impact statement Resveratrol has been reported to have a wide variety of health benefits but its rapid metabolism especially after oral ingestion results in very low bioavailability. Notably, the first human skin gene expression study of resveratrol was not published until 2014. The purpose of this study was to determine if increased stability and biological activity could be obtained by modifying the chemical structure of natural (trans) resveratrol and quantifying human gene expression by qPCR of skin biomarkers that enhance dermal health. Five resveratrol analogs were synthesized that increased their lipophilic index to enhance tissue penetration and augment biological activities on the measured parameters that expand the current knowledge of structure/function relationships. The butyrate and isobutyrate modifications displayed gene expression values significantly above resveratrol and suggest that oral application of these and potentially other resveratrol analogs may yield similar results to improve stability and biological activity to benefit/address various disorders/diseases.
白藜芦醇（RV）是植物天然产生的一种多酚类化合物。纳入医药产品中的多酚类化合物有益处，但是，白藜芦醇代谢迅速，伴随生物活性下降。本研究以白藜芦醇作为标准物进行测试，并比较了五种结构修饰的白藜芦醇类似物：丁酸酯、异丁酸酯、棕榈酸酯、乙酸酯和二乙酸酯（为提高功能），在表皮全层培养物中以1%的浓度作用24小时，通过基因芯片/qPCR mRNA分析。当对沉默交配型信息调节2同源物1、细胞外成分（胶原蛋白1A1、3A1、4A1；弹性蛋白、基质金属蛋白酶1组织抑制剂、原纤蛋白1、层粘连蛋白β1和基质金属蛋白酶9）、抗衰老和衰老相关基因、炎症生物标志物（白细胞介素-1A [IL1A]、IL1R2、IL-6和IL-8）、神经生长因子以及抗氧化剂（增殖细胞核抗原、过氧化氢酶、超氧化物歧化酶和金属硫蛋白1H/2H）进行评估时，按照基因表达从高到低对每种物质进行排序：丁酸酯＞异丁酸酯＞二乙酸酯＞乙酸酯＞棕榈酸酯。本研究表明，与白藜芦醇相比，丁酸酯和异丁酸酯类似物具有更高的生物活性，在局部应用中具有改善皮肤及其他健康应用的潜在用途。影响声明据报道，白藜芦醇具有多种健康益处，但其代谢迅速，尤其是口服摄入后生物利用度极低。值得注意的是，关于白藜芦醇的首个人类皮肤基因表达研究直到2014年才发表。本研究的目的是确定通过修饰天然（反式）白藜芦醇的化学结构并通过对增强皮肤健康的皮肤生物标志物进行qPCR定量人类基因表达，是否能够提高其稳定性和生物活性。合成了五种白藜芦醇类似物，提高了它们的亲脂性指数以增强组织穿透力，并增强在所测参数上的生物活性，从而扩展了当前对结构/功能关系的认识。丁酸酯和异丁酸酯修饰显示出基因表达值显著高于白藜芦醇，这表明口服这些以及可能的其他白藜芦醇类似物可能会产生类似的结果，以提高稳定性和生物活性，从而有益于/应对各种疾病。
