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      The in vitro and in vivo depigmenting activity of pterostilbene through induction of autophagy in melanocytes and inhibition of UVA-irradiated α-MSH in keratinocytes via Nrf2-mediated antioxidant pathways

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          Abstract

          Pterostilbene (Pt) is a natural polyphenol found in blueberries and several grape varieties. Pt's pharmacological importance was well documented. Nevertheless, the depigmenting effects are not demonstrated. We evaluated the Pt's depigmenting effects through autophagy induction in B16F10 cells and inhibition of UVA (3 J/cm 2)-irradiated α-MSH in keratinocyte HaCaT cells via Nrf2-mediated antioxidant pathways. Pt (2.5–5μM) attenuated ROS production and downregulated the POMC/α-MSH pathway in HaCaT cells. The conditioned medium-derived from UVA-irradiated HaCaT pretreated with Pt suppressed melanogenesis in B16F10 through MITF-CREB-tyrosinase pathway downregulation. Interestingly, Pt-induced HaCaT autophagy was revealed by enhanced LC3-II accumulation, p62/SQSTM1 activation, and AVO formation. Pt significantly decreased melanosome gp100 but increased LC3-II levels in HaCaT cells exposed to B16F10-derived melanin. Pt activated and facilitated the Nrf2 antioxidant pathway in HaCaT cells leading to increased HO-1, γ-GCLC, and NQO-1 antioxidant protein expression. ERK, AMPK, and ROS pathways mediate the Nrf2 activation. However, Nrf2 knockdown suppressed Pt's antioxidant ability leading to uncontrolled ROS and α-MSH levels after UVA-irradiation suggested the essentiality of the Nrf2 pathway. Moreover, in α-MSH-stimulated B16F10 cells, Pt (10–30 μM) downregulated the MC1R, MITF, tyrosinase, TRP-1/-2, and melanin expression. Further, Pt showed potent anti-melanogenic effects through autophagy induction mechanism in B16F10 cells, verified by increased LC3-II/p62 levels, AVO formation, and Beclin-1/Bcl-2 ratio, decreased ATG4B levels and PI3K/AKT/mTOR pathway. Transmission electron microscopy provided direct evidence by showing autophagosomes engulfing melanosomes following Pt treatment in α-MSH-stimulated B16F10 cells. Moreover, Pt-induced anti-melanogenic activity through the downregulation of CREB-MITF pathway-mediated TRP-1/-2, tyrosinase expressions, melanosome formation, and melanin synthesis was substantially reversed due to 3-MA (autophagy inhibitor) pretreatment or LC3 silencing in B16F10 cells. In vivo results also confirmed that Pt-inhibited tyrosinase expression/activity and endogenous pigmentation in the zebrafish model. Therefore, pterostilbene is a potent skin-whitening and antioxidant agent and could be used in skin-whitening formulations as a topical applicant.

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          Highlights

          • •

            Pt inhibits ROS-mediated POMC/α-MSH pathway in UVA-irradiated HaCaT cells.

          • •

            Pt activates Nrf2-mediated HO-1, γ-GCLC, and NQO-1 expression in HaCaT cells.

          • •

            Pt-induces autophagy in B16F10 cells leading to melanogenesis inhibition.

          • •

            Pt-mediates anti-melanogenic mechanisms in α-MSH-stimulated B16F10 cells.

          • •

            Pt-inhibits tyrosinase expression and endogenous pigmentation in zebrafish model.

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          The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1.

          Masaaki Komatsu, Hirofumi Kurokawa, Satoshi Waguri … (2010)
          Impaired selective turnover of p62 by autophagy causes severe liver injury accompanied by the formation of p62-positive inclusions and upregulation of detoxifying enzymes. These phenotypes correspond closely to the pathological conditions seen in human liver diseases, including alcoholic hepatitis and hepatocellular carcinoma. However, the molecular mechanisms and pathophysiological processes in these events are still unknown. Here we report the identification of a novel regulatory mechanism by p62 of the transcription factor Nrf2, whose target genes include antioxidant proteins and detoxification enzymes. p62 interacts with the Nrf2-binding site on Keap1, a component of Cullin-3-type ubiquitin ligase for Nrf2. Thus, an overproduction of p62 or a deficiency in autophagy competes with the interaction between Nrf2 and Keap1, resulting in stabilization of Nrf2 and transcriptional activation of Nrf2 target genes. Our findings indicate that the pathological process associated with p62 accumulation results in hyperactivation of Nrf2 and delineates unexpected roles of selective autophagy in controlling the transcription of cellular defence enzyme genes.
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            The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation.

            Holly K. Bryan, Adedamola Olayanju, Christopher E. Goldring … (2013)
            The transcription factor Nrf2 (NF-E2-related factor 2) plays a vital role in maintaining cellular homeostasis, especially upon the exposure of cells to chemical or oxidative stress, through its ability to regulate the basal and inducible expression of a multitude of antioxidant proteins, detoxification enzymes and xenobiotic transporters. In addition, Nrf2 contributes to diverse cellular functions including differentiation, proliferation, inflammation and lipid synthesis and there is an increasing association of aberrant expression and/or function of Nrf2 with pathologies including cancer, neurodegeneration and cardiovascular disease. The activity of Nrf2 is primarily regulated via its interaction with Keap1 (Kelch-like ECH-associated protein 1), which directs the transcription factor for proteasomal degradation. Although it is generally accepted that modification (e.g. chemical adduction, oxidation, nitrosylation or glutathionylation) of one or more critical cysteine residues in Keap1 represents a likely chemico-biological trigger for the activation of Nrf2, unequivocal evidence for such a phenomenon remains elusive. An increasing body of literature has revealed alternative mechanisms of Nrf2 regulation, including phosphorylation of Nrf2 by various protein kinases (PKC, PI3K/Akt, GSK-3β, JNK), interaction with other protein partners (p21, caveolin-1) and epigenetic factors (micro-RNAs -144, -28 and -200a, and promoter methylation). These and other processes are potentially important determinants of Nrf2 activity, and therefore may contribute to the maintenance of cellular homeostasis. Here, we dissect evidence supporting these Keap1-dependent and -independent mechanisms of Nrf2 regulation. Furthermore, we highlight key knowledge gaps in this important field of biology, and suggest how these may be addressed experimentally. Copyright © 2012 Elsevier Inc. All rights reserved.
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              p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription.

              Michael T. McMahon, Ashish Jain, Terje Johansen … (2010)
              The p62/SQSTM1 (sequestosome 1) protein, which acts as a cargo receptor for autophagic degradation of ubiquitinated targets, is up-regulated by various stressors. Induction of the p62 gene by oxidative stress is mediated by NF-E2-related factor 2 (NRF2) and, at the same time, p62 protein contributes to the activation of NRF2, but hitherto the mechanisms involved were not known. Herein, we have mapped an antioxidant response element (ARE) in the p62 promoter that is responsible for its induction by oxidative stress via NRF2. Chromatin immunoprecipitation and gel mobility-shift assays verified that NRF2 binds to this cis-element in vivo and in vitro. Also, p62 docks directly onto the Kelch-repeat domain of Kelch-like ECH-associated protein 1 (KEAP1), via a motif designated the KEAP1 interacting region (KIR), thereby blocking binding between KEAP1 and NRF2 that leads to ubiquitylation and degradation of the transcription factor. The KIR motif in p62 is located immediately C-terminal to the LC3-interacting region (LIR) and resembles the ETGE motif utilized by NRF2 for its interaction with KEAP1. KIR is required for p62 to stabilize NRF2, and inhibition of KEAP1 by p62 occurs from a cytoplasmic location within the cell. The LIR and KIR motifs cannot be engaged simultaneously by LC3 and KEAP1, but because p62 is polymeric the interaction between KEAP1 and p62 leads to accumulation of KEAP1 in p62 bodies, which is followed by autophagic degradation of KEAP1. Our data explain how p62 contributes to activation of NRF2 target genes in response to oxidative stress through creating a positive feedback loop.
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                Author and article information

                Contributors
                You-Cheng Hseu
                Yugandhar Vudhya Gowrisankar
                Li-Wei Wang
                Yan-Zhen Zhang
                Xuan-Zao Chen
                Pei-Jane Huang
                Hung-Rong Yen
                Hsin-Ling Yang
                Journal
                Journal ID (nlm-ta): Redox Biol
                Journal ID (iso-abbrev): Redox Biol
                Title: Redox Biology
                Publisher: Elsevier
                ISSN (Electronic): 2213-2317
                Publication date PMC-release: 19 May 2021
                Publication date Collection: August 2021
                Publication date (Electronic): 19 May 2021
                Volume: 44
                Electronic Location Identifier: 102007
                Affiliations
                [a ]Department of Cosmeceutics, College of Pharmacy, China Medical University, Taichung 40402, Taiwan
                [b ]Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan
                [c ]Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan
                [d ]Research Center of Chinese Herbal Medicine, China Medical University, Taichung 40402, Taiwan
                [e ]Department of Medical Research, China Medical University Hospital, Taichung 40402, Taiwan
                [f ]School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan
                [g ]Institute of Nutrition, College of Health Care, China Medical University, Taichung 40402, Taiwan
                Author notes
                [∗ ]Corresponding author. Institute of Nutrition, College of Health Care, China Medical University, Shui-Nan Campus, No.100, Sec.1 Jingmao Road, Beitun District, Taichung City 40402, Taiwan. hlyang@ 123456mail.cmu.edu.tw
                [∗∗ ]Corresponding author. Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan. hungrongyen@ 123456gmail.com
                Article
                Publisher Item ID: S2213-2317(21)00165-8 Publisher ID: 102007
                DOI: 10.1016/j.redox.2021.102007
                PMC ID: 8167190
                PubMed ID: 34049220
                SO-VID: 65e9d0d8-af88-490b-a730-137560c98764
                Copyright © © 2021 The Authors. Published by Elsevier B.V.
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 31 March 2021
                Date revision received : 26 April 2021
                Date accepted : 10 May 2021
                Categories
                Subject: Research Paper

                Keywords: pterostilbene,ros,anti-melanogenesis,nrf2,autophagy
                Data availability:
                Keywords: pterostilbene, ros, anti-melanogenesis, nrf2, autophagy

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