Chemical Distance Measurement and System Pharmacology Approach Uncover the Novel Protective Effects of Biotransformed Ginsenoside C-Mc against UVB-Irradiated Photoaging

Abstract

Long-term exposure to ultraviolet light induces photoaging and may eventually increase the risk of skin carcinogenesis. Rare minor ginsenosides isolating from traditional medicine Panax (ginseng) have shown biomedical efficacy as antioxidation and antiphotodamage agents. However, due to the difficulty of component extraction and wide variety of ginsenoside, the identification of active antiphotoaging ginsenoside remains a huge challenge. In this study, we proposed a novel in silico approach to identify potential compound against photoaging from 82 ginsenosides. Specifically, we calculated the shortest distance between unknown and known antiphotoaging ginsenoside set in the chemical space and applied chemical structure similarity assessment, drug-likeness screening, and ADMET evaluation for the candidates. We highlighted three rare minor ginsenosides (C-Mc, Mx, and F2) that possess high potential as antiphotoaging agents. Among them, C-Mc deriving from American ginseng (Panax quinquefolius L.) was validated by wet-lab experimental assays and showed significant antioxidant and cytoprotective activity against UVB-induced photodamage in human dermal fibroblasts. Furthermore, system pharmacology analysis was conducted to explore the therapeutic targets and molecular mechanisms through integrating global drug-target network, high quality photoaging-related gene profile from multiomics data, and skin tissue-specific expression protein network. In combination with in vitro assays, we found that C-Mc suppressed MMP production through regulating the MAPK/AP-1/NF-κB pathway and expedited collagen synthesis via the TGF-β/Smad pathway, as well as enhanced the expression of Nrf2/ARE to hold a balance of endogenous oxidation. Overall, this study offers an effective drug discovery framework combining in silico prediction and in vitro validation, uncovering that ginsenoside C-Mc has potential antiphotoaging properties and might be a novel natural agent for use in oral drug, skincare products, or functional food.

Role of Phytochemicals in Skin Photoprotection via Regulation of Nrf2

“…Ginsenosides, triterpene saponins, are major bioactive compounds responsible for pharmacological activities of Panax (ginseng), which has traditionally been used to treat and prevent various conditions associated with aging including skin aging. Previous studies demonstrated that the rare minor ginsenosides (C-Mc and Mx), which may act as potential antiphotoaging compounds, suppressed MMP production via regulating MAPK/AP-1/NF-κB pathway and promoted collagen production via the TGF-β/Smad pathway in association with upregulation of Nrf2 signaling in UVB-irradiated human dermal fibroblasts ( Liu et al, 2018 ; Liu et al, 2022 ).…”

Myconoside and Calceolarioside E Restrain UV-Induced Skin Photoaging by Activating NRF2-Mediated Defense Mechanisms

“…Oxidative stress and inflammation have a close interaction that leads to the progression of photoaging under UVR exposure. Oxidative stress is involved in collagen degradation in the skin, and inflammation stimulates epidermal thickening and reduces collagen contents in the epidermis and dermis [1,5,7,22,[59][60][61][62]. The MAPK family of kinases are major regulators involved in cell apoptosis and inflammatory responses that trigger the phosphorylation of c-Fos, c-Jun, and JunD proteins (AP-1 complex), leading to collagen degradation via upregulation of MMP-1, -3, and -9 [1,[5][6][7]54,55,[59][60][61][62].…”

“…Oxidative stress is involved in collagen degradation in the skin, and inflammation stimulates epidermal thickening and reduces collagen contents in the epidermis and dermis [1,5,7,22,[59][60][61][62]. The MAPK family of kinases are major regulators involved in cell apoptosis and inflammatory responses that trigger the phosphorylation of c-Fos, c-Jun, and JunD proteins (AP-1 complex), leading to collagen degradation via upregulation of MMP-1, -3, and -9 [1,[5][6][7]54,55,[59][60][61][62]. Activation of specific MAPK inhibitors, such as JNK and P38/MAPK, by blocking the Smad 3/4 complex has been suggested to suppress TGF-β expression, thereby impairing collagen syn-thesis [5,11,[59][60][61][62].…”

Puerariae lobatae radix protects against UVB-induced skin aging via antagonism of REV-ERBα in mice

“…p21 and p53 are anti-oncogenes that promote cell senescence ( Chen Q. et al, 2020 ), and are also regarded as markers of skin aging. In fact, measurements of SOD activity, MDA/HYP levels, and Mmp-1/p21/p53 expression have been widely performed to assess aging and to screen anti-aging agents ( Sharpless, 2015 ; Lee et al, 2016 ; Sun et al, 2018 ; Li et al, 2022 ; Liu et al, 2022 ).…”