The Experts below are selected from a list of 1410 Experts worldwide ranked by ideXlab platform

Georg T. Wondrak - One of the best experts on this subject based on the ideXlab platform.

  • Activation of NRF2 by topical apocarotenoid treatment mitigates radiation-induced dermatitis
    Redox Biology, 2020
    Co-Authors: Cody J. Schmidlin, Montserrat Rojo De La Vega, Donna D Zhang, Jessica Perer, Georg T. Wondrak
    Abstract:

    Radiation therapy is a frontline treatment option for cancer patients; however, the effects of radiotherapy on non-tumor tissue (e.g. radiation-induced dermatitis) often worsen patient quality of life. Previous studies have implicated the importance of redox balance in preventing dermatitis, specifically in reference to modulation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) signaling pathway. Due to the cytoprotective functions of transcriptional target genes of NRF2, we investigated how modulation of NRF2 expression could affect DNA damage, oxidative stress, and cell viability in response to radiotherapy. Specifically, it was noted that NRF2 knockdown sensitized human skin keratinocytes to ionizing radiation; likewise, genetic ablation of NRF2 in vivo increased radiosensitivity of murine epidermis. Oppositely, pharmacological induction of NRF2 via the apocarotenoid Bixin lowered markers of DNA damage and oxidative stress, while preserving viability in irradiated keratinocytes. Mechanistic studies indicated that topical pretreatment using Bixin as an NRF2 activator antagonized initial DNA damage by raising cellular glutathione levels. Additionally, topical application of Bixin prevented radiation-induced dermatitis, epidermal thickening, and oxidative stress in the skin of SKH1 mice. Overall, these data indicate that NRF2 is critical for mitigating the harmful skin toxicities associated with ionizing radiation, and that topical upregulation of NRF2 via Bixin could prevent radiation-induced dermatitis.

  • Image_1.tiff
    2018
    Co-Authors: Montserrat Rojo De La Vega, Donna D Zhang, Georg T. Wondrak
    Abstract:

    Environmental exposure to solar ultraviolet (UV) radiation causes acute photodamage, premature aging, and skin cancer, attributable to UV-induced genotoxic, oxidative, and inflammatory stress. The transcription factor NRF2 [nuclear factor erythroid 2 (E2)-related factor 2] is the master regulator of the cellular antioxidant response protecting skin against various environmental stressors including UV radiation and electrophilic pollutants. NRF2 in epidermal keratinocytes can be activated using natural chemopreventive compounds such as the apocarotenoid Bixin, an FDA-approved food additive and cosmetic ingredient from the seeds of the achiote tree (Bixa orellana). Here, we tested the feasibility of topical use of Bixin for NRF2-dependent skin photoprotection in two genetically modified mouse models [SKH1 and C57BL/6J (Nrf2+/+ versus Nrf2-/-)]. First, we observed that a Bixin formulation optimized for topical NRF2 activation suppresses acute UV-induced photodamage in Nrf2+/+ but not Nrf2-/- SKH1 mice, a photoprotective effect indicated by reduced epidermal hyperproliferation and oxidative DNA damage. Secondly, it was demonstrated that topical Bixin suppresses PUVA (psoralen + UVA)-induced hair graying in Nrf2+/+ but not Nrf2-/- C57BL/6J mice. Collectively, this research provides the first in vivo evidence that topical application of Bixin can protect against UV-induced photodamage and PUVA-induced loss of hair pigmentation through NRF2 activation. Topical NRF2 activation using Bixin may represent a novel strategy for human skin photoprotection, potentially complementing conventional sunscreen-based approaches.

  • Topical Bixin Confers NRF2-Dependent Protection Against Photodamage and Hair Graying in Mouse Skin
    Frontiers Media S.A., 2018
    Co-Authors: Montserrat Rojo De La Vega, Georg T. Wondrak, Donna D Zhang
    Abstract:

    Environmental exposure to solar ultraviolet (UV) radiation causes acute photodamage, premature aging, and skin cancer, attributable to UV-induced genotoxic, oxidative, and inflammatory stress. The transcription factor NRF2 [nuclear factor erythroid 2 (E2)-related factor 2] is the master regulator of the cellular antioxidant response protecting skin against various environmental stressors including UV radiation and electrophilic pollutants. NRF2 in epidermal keratinocytes can be activated using natural chemopreventive compounds such as the apocarotenoid Bixin, an FDA-approved food additive and cosmetic ingredient from the seeds of the achiote tree (Bixa orellana). Here, we tested the feasibility of topical use of Bixin for NRF2-dependent skin photoprotection in two genetically modified mouse models [SKH1 and C57BL/6J (Nrf2+/+ versus Nrf2-/-)]. First, we observed that a Bixin formulation optimized for topical NRF2 activation suppresses acute UV-induced photodamage in Nrf2+/+ but not Nrf2-/- SKH1 mice, a photoprotective effect indicated by reduced epidermal hyperproliferation and oxidative DNA damage. Secondly, it was demonstrated that topical Bixin suppresses PUVA (psoralen + UVA)-induced hair graying in Nrf2+/+ but not Nrf2-/- C57BL/6J mice. Collectively, this research provides the first in vivo evidence that topical application of Bixin can protect against UV-induced photodamage and PUVA-induced loss of hair pigmentation through NRF2 activation. Topical NRF2 activation using Bixin may represent a novel strategy for human skin photoprotection, potentially complementing conventional sunscreen-based approaches

  • targeting nrf2 for improved skin barrier function and photoprotection focus on the achiote derived apocarotenoid Bixin
    Nutrients, 2017
    Co-Authors: Montserrat Rojo De La Vega, Donna D Zhang, Andrea Krajisnik, Georg T. Wondrak
    Abstract:

    The transcription factor NRF2 (nuclear factor-E2-related factor 2) orchestrates major cellular defense mechanisms including phase-II detoxification, inflammatory signaling, DNA repair, and antioxidant response. Recent studies strongly suggest a protective role of NRF2-mediated gene expression in the suppression of cutaneous photodamage induced by solar UV (ultraviolet) radiation. The apocarotenoid Bixin, a Food and Drug Administration (FDA)-approved natural food colorant (referred to as ‘annatto’) originates from the seeds of the achiote tree native to tropical America, consumed by humans since ancient times. Use of achiote preparations for skin protection against environmental insult and for enhanced wound healing has long been documented. We have recently reported that (i) Bixin is a potent canonical activator of the NRF2-dependent cytoprotective response in human skin keratinocytes; that (ii) systemic administration of Bixin activates NRF2 with protective effects against solar UV-induced skin damage; and that (iii) Bixin-induced suppression of photodamage is observable in Nrf2+/+ but not in Nrf2−/− SKH-1 mice confirming the NRF2-dependence of Bixin-induced antioxidant and anti-inflammatory effects. In addition, Bixin displays molecular activities as sacrificial antioxidant, excited state quencher, PPAR (peroxisome proliferator-activated receptor) α/γ agonist, and TLR (Toll-like receptor) 4/NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) antagonist, all of which might be relevant to the enhancement of skin barrier function and environmental stress protection. Potential skin photoprotection and photochemoprevention benefits provided by topical application or dietary consumption of this ethno-pharmacologically validated phytochemical originating from the Americas deserves further preclinical and clinical examination.

  • the apocarotenoid Bixin protects mouse skin against uv induced damage in an nrf2 dependent manner
    Free Radical Biology and Medicine, 2017
    Co-Authors: Montserrat Rojo De La Vega, Georg T. Wondrak, Donna D Zhang
    Abstract:

    Skin barrier function and integrity can be impaired as a result of exposure to environmental stressors, including solar ultra violet (UV) radiation. UV induces oxidative stress, inflammation, premature ageing, and cancer. Therefore, there is a need to find effective and safe strategies to protect the skin from these deleterious effects. An effective strategy to prevent UV damage involves activation of the transcription factor nuclear factor-E2-related factor 2 (NRF2) to induce cellular stress responses and damage repair. We recently characterized the apocarotenoid Bixin, and FDA-approved natural food colorant from the seeds of the achiote tree (Bixa orellana), as a safe and potent NRF2 activator. In this study, we tested the feasibility of enhancing NRF2-dependent skin protection using a topical Bixin formulation in a model for acute UV-induced skin damage and UV-induced hair graying. Nrf2+/+ and Nrf2-/- SKH-I hairless mice (acute skin damage) or C57BL/6J mice (hair graying) were treated twice with a topical Bixin formulation 48 h and 24 h before exposure to UV. Skin tissues were harvested at 24 h (acute skin damage) or 2 weeks (hair graying) post-exposure and analyzed by immunoblotting and immunohistochemistry. We observed that Bixin activated cutaneous expression of NRF2 and its target genes, and limited photodamage in Nrf2+/+ but not Nrf2-/- mice. Moreover, Bixin reduced inflammation, oxidative damage, and apoptosis in the epidermis of Nrf2+/+ SKH-I mice. Consistently, Bixin prevented UV-induced hair graying in Nrf2+/+ C57BL/6J mice. These results suggest that Bixin-based interventions may be useful for NRF2-dependent skin protection against environmental insults.

Ivonne M C M Rietjens - One of the best experts on this subject based on the ideXlab platform.

  • combining in vitro data and physiologically based kinetic modeling facilitates reverse dosimetry to define in vivo dose response curves for Bixin and crocetin induced activation of pparγ in humans
    Molecular Nutrition & Food Research, 2020
    Co-Authors: Suparmi Suparmi, Laura H J De Haan, A Spenkelink, Jochem Louisse, Karsten Beekmann, Ivonne M C M Rietjens
    Abstract:

    Scope It is investigated whether at realistic dietary intake Bixin and crocetin could induce peroxisome proliferator-activated receptor γ (PPARγ)-mediated gene expression in humans using a combined in vitro-in silico approach. Methods and results Concentration-response curves obtained from in vitro PPARγ-reporter gene assays are converted to in vivo dose-response curves using physiologically based kinetic modeling-facilitated reverse dosimetry, from which the benchmark dose levels resulting in a 50% effect above background level (BMD50 ) are predicted and subsequently compared to dietary exposure levels. Bixin and crocetin activated PPARγ-mediated gene transcription in a concentration-dependent manner with similar potencies. Due to differences in kinetics, the predicted BMD50 values for in vivo PPARγ activation are about 30-fold different, amounting to 115 and 3505 mg kg bw-1 for crocetin and Bixin, respectively. Human dietary and/or supplemental estimated daily intakes may reach these BMD50 values for crocetin but not for Bixin, pointing at better possibilities for in vivo PPARγ activation by crocetin. Conclusion Based on a combined in vitro-in silico approach, it is estimated whether at realistic dietary intakes plasma concentrations of Bixin and crocetin are likely to reach concentrations that activate PPARγ-mediated gene expression, without the need for a human intervention study.

Suparmi Suparmi - One of the best experts on this subject based on the ideXlab platform.

  • Combining In Vitro Data and Physiologically Based Kinetic Modeling Facilitates Reverse Dosimetry to Define In Vivo Dose–Response Curves for Bixin- and Crocetin-Induced Activation of PPARγ in Humans
    2020
    Co-Authors: Suparmi Suparmi, Laura Haan, Spenkelink Albertus, Louisse Jochem, Beekmann Karsten, Rietjens, Ivonne M.c.m.
    Abstract:

    Scope: It is investigated whether at realistic dietary intake Bixin and crocetin could induce peroxisome proliferator-activated receptor γ (PPARγ)-mediated gene expression in humans using a combined in vitro–in silico approach. Methods and results: Concentration–response curves obtained from in vitro PPARγ-reporter gene assays are converted to in vivo dose–response curves using physiologically based kinetic modeling-facilitated reverse dosimetry, from which the benchmark dose levels resulting in a 50% effect above background level (BMD50) are predicted and subsequently compared to dietary exposure levels. Bixin and crocetin activated PPARγ-mediated gene transcription in a concentration-dependent manner with similar potencies. Due to differences in kinetics, the predicted BMD50 values for in vivo PPARγ activation are about 30-fold different, amounting to 115 and 3505 mg kg bw−1 for crocetin and Bixin, respectively. Human dietary and/or supplemental estimated daily intakes may reach these BMD50 values for crocetin but not for Bixin, pointing at better possibilities for in vivo PPARγ activation by crocetin. Conclusion: Based on a combined in vitro–in silico approach, it is estimated whether at realistic dietary intakes plasma concentrations of Bixin and crocetin are likely to reach concentrations that activate PPARγ-mediated gene expression, without the need for a human intervention study.

  • combining in vitro data and physiologically based kinetic modeling facilitates reverse dosimetry to define in vivo dose response curves for Bixin and crocetin induced activation of pparγ in humans
    Molecular Nutrition & Food Research, 2020
    Co-Authors: Suparmi Suparmi, Laura H J De Haan, A Spenkelink, Jochem Louisse, Karsten Beekmann, Ivonne M C M Rietjens
    Abstract:

    Scope It is investigated whether at realistic dietary intake Bixin and crocetin could induce peroxisome proliferator-activated receptor γ (PPARγ)-mediated gene expression in humans using a combined in vitro-in silico approach. Methods and results Concentration-response curves obtained from in vitro PPARγ-reporter gene assays are converted to in vivo dose-response curves using physiologically based kinetic modeling-facilitated reverse dosimetry, from which the benchmark dose levels resulting in a 50% effect above background level (BMD50 ) are predicted and subsequently compared to dietary exposure levels. Bixin and crocetin activated PPARγ-mediated gene transcription in a concentration-dependent manner with similar potencies. Due to differences in kinetics, the predicted BMD50 values for in vivo PPARγ activation are about 30-fold different, amounting to 115 and 3505 mg kg bw-1 for crocetin and Bixin, respectively. Human dietary and/or supplemental estimated daily intakes may reach these BMD50 values for crocetin but not for Bixin, pointing at better possibilities for in vivo PPARγ activation by crocetin. Conclusion Based on a combined in vitro-in silico approach, it is estimated whether at realistic dietary intakes plasma concentrations of Bixin and crocetin are likely to reach concentrations that activate PPARγ-mediated gene expression, without the need for a human intervention study.

Donna D Zhang - One of the best experts on this subject based on the ideXlab platform.

  • Activation of NRF2 by topical apocarotenoid treatment mitigates radiation-induced dermatitis
    Redox Biology, 2020
    Co-Authors: Cody J. Schmidlin, Montserrat Rojo De La Vega, Donna D Zhang, Jessica Perer, Georg T. Wondrak
    Abstract:

    Radiation therapy is a frontline treatment option for cancer patients; however, the effects of radiotherapy on non-tumor tissue (e.g. radiation-induced dermatitis) often worsen patient quality of life. Previous studies have implicated the importance of redox balance in preventing dermatitis, specifically in reference to modulation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) signaling pathway. Due to the cytoprotective functions of transcriptional target genes of NRF2, we investigated how modulation of NRF2 expression could affect DNA damage, oxidative stress, and cell viability in response to radiotherapy. Specifically, it was noted that NRF2 knockdown sensitized human skin keratinocytes to ionizing radiation; likewise, genetic ablation of NRF2 in vivo increased radiosensitivity of murine epidermis. Oppositely, pharmacological induction of NRF2 via the apocarotenoid Bixin lowered markers of DNA damage and oxidative stress, while preserving viability in irradiated keratinocytes. Mechanistic studies indicated that topical pretreatment using Bixin as an NRF2 activator antagonized initial DNA damage by raising cellular glutathione levels. Additionally, topical application of Bixin prevented radiation-induced dermatitis, epidermal thickening, and oxidative stress in the skin of SKH1 mice. Overall, these data indicate that NRF2 is critical for mitigating the harmful skin toxicities associated with ionizing radiation, and that topical upregulation of NRF2 via Bixin could prevent radiation-induced dermatitis.

  • Image_1.tiff
    2018
    Co-Authors: Montserrat Rojo De La Vega, Donna D Zhang, Georg T. Wondrak
    Abstract:

    Environmental exposure to solar ultraviolet (UV) radiation causes acute photodamage, premature aging, and skin cancer, attributable to UV-induced genotoxic, oxidative, and inflammatory stress. The transcription factor NRF2 [nuclear factor erythroid 2 (E2)-related factor 2] is the master regulator of the cellular antioxidant response protecting skin against various environmental stressors including UV radiation and electrophilic pollutants. NRF2 in epidermal keratinocytes can be activated using natural chemopreventive compounds such as the apocarotenoid Bixin, an FDA-approved food additive and cosmetic ingredient from the seeds of the achiote tree (Bixa orellana). Here, we tested the feasibility of topical use of Bixin for NRF2-dependent skin photoprotection in two genetically modified mouse models [SKH1 and C57BL/6J (Nrf2+/+ versus Nrf2-/-)]. First, we observed that a Bixin formulation optimized for topical NRF2 activation suppresses acute UV-induced photodamage in Nrf2+/+ but not Nrf2-/- SKH1 mice, a photoprotective effect indicated by reduced epidermal hyperproliferation and oxidative DNA damage. Secondly, it was demonstrated that topical Bixin suppresses PUVA (psoralen + UVA)-induced hair graying in Nrf2+/+ but not Nrf2-/- C57BL/6J mice. Collectively, this research provides the first in vivo evidence that topical application of Bixin can protect against UV-induced photodamage and PUVA-induced loss of hair pigmentation through NRF2 activation. Topical NRF2 activation using Bixin may represent a novel strategy for human skin photoprotection, potentially complementing conventional sunscreen-based approaches.

  • Topical Bixin Confers NRF2-Dependent Protection Against Photodamage and Hair Graying in Mouse Skin
    Frontiers Media S.A., 2018
    Co-Authors: Montserrat Rojo De La Vega, Georg T. Wondrak, Donna D Zhang
    Abstract:

    Environmental exposure to solar ultraviolet (UV) radiation causes acute photodamage, premature aging, and skin cancer, attributable to UV-induced genotoxic, oxidative, and inflammatory stress. The transcription factor NRF2 [nuclear factor erythroid 2 (E2)-related factor 2] is the master regulator of the cellular antioxidant response protecting skin against various environmental stressors including UV radiation and electrophilic pollutants. NRF2 in epidermal keratinocytes can be activated using natural chemopreventive compounds such as the apocarotenoid Bixin, an FDA-approved food additive and cosmetic ingredient from the seeds of the achiote tree (Bixa orellana). Here, we tested the feasibility of topical use of Bixin for NRF2-dependent skin photoprotection in two genetically modified mouse models [SKH1 and C57BL/6J (Nrf2+/+ versus Nrf2-/-)]. First, we observed that a Bixin formulation optimized for topical NRF2 activation suppresses acute UV-induced photodamage in Nrf2+/+ but not Nrf2-/- SKH1 mice, a photoprotective effect indicated by reduced epidermal hyperproliferation and oxidative DNA damage. Secondly, it was demonstrated that topical Bixin suppresses PUVA (psoralen + UVA)-induced hair graying in Nrf2+/+ but not Nrf2-/- C57BL/6J mice. Collectively, this research provides the first in vivo evidence that topical application of Bixin can protect against UV-induced photodamage and PUVA-induced loss of hair pigmentation through NRF2 activation. Topical NRF2 activation using Bixin may represent a novel strategy for human skin photoprotection, potentially complementing conventional sunscreen-based approaches

  • targeting nrf2 for improved skin barrier function and photoprotection focus on the achiote derived apocarotenoid Bixin
    Nutrients, 2017
    Co-Authors: Montserrat Rojo De La Vega, Donna D Zhang, Andrea Krajisnik, Georg T. Wondrak
    Abstract:

    The transcription factor NRF2 (nuclear factor-E2-related factor 2) orchestrates major cellular defense mechanisms including phase-II detoxification, inflammatory signaling, DNA repair, and antioxidant response. Recent studies strongly suggest a protective role of NRF2-mediated gene expression in the suppression of cutaneous photodamage induced by solar UV (ultraviolet) radiation. The apocarotenoid Bixin, a Food and Drug Administration (FDA)-approved natural food colorant (referred to as ‘annatto’) originates from the seeds of the achiote tree native to tropical America, consumed by humans since ancient times. Use of achiote preparations for skin protection against environmental insult and for enhanced wound healing has long been documented. We have recently reported that (i) Bixin is a potent canonical activator of the NRF2-dependent cytoprotective response in human skin keratinocytes; that (ii) systemic administration of Bixin activates NRF2 with protective effects against solar UV-induced skin damage; and that (iii) Bixin-induced suppression of photodamage is observable in Nrf2+/+ but not in Nrf2−/− SKH-1 mice confirming the NRF2-dependence of Bixin-induced antioxidant and anti-inflammatory effects. In addition, Bixin displays molecular activities as sacrificial antioxidant, excited state quencher, PPAR (peroxisome proliferator-activated receptor) α/γ agonist, and TLR (Toll-like receptor) 4/NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) antagonist, all of which might be relevant to the enhancement of skin barrier function and environmental stress protection. Potential skin photoprotection and photochemoprevention benefits provided by topical application or dietary consumption of this ethno-pharmacologically validated phytochemical originating from the Americas deserves further preclinical and clinical examination.

  • the apocarotenoid Bixin protects mouse skin against uv induced damage in an nrf2 dependent manner
    Free Radical Biology and Medicine, 2017
    Co-Authors: Montserrat Rojo De La Vega, Georg T. Wondrak, Donna D Zhang
    Abstract:

    Skin barrier function and integrity can be impaired as a result of exposure to environmental stressors, including solar ultra violet (UV) radiation. UV induces oxidative stress, inflammation, premature ageing, and cancer. Therefore, there is a need to find effective and safe strategies to protect the skin from these deleterious effects. An effective strategy to prevent UV damage involves activation of the transcription factor nuclear factor-E2-related factor 2 (NRF2) to induce cellular stress responses and damage repair. We recently characterized the apocarotenoid Bixin, and FDA-approved natural food colorant from the seeds of the achiote tree (Bixa orellana), as a safe and potent NRF2 activator. In this study, we tested the feasibility of enhancing NRF2-dependent skin protection using a topical Bixin formulation in a model for acute UV-induced skin damage and UV-induced hair graying. Nrf2+/+ and Nrf2-/- SKH-I hairless mice (acute skin damage) or C57BL/6J mice (hair graying) were treated twice with a topical Bixin formulation 48 h and 24 h before exposure to UV. Skin tissues were harvested at 24 h (acute skin damage) or 2 weeks (hair graying) post-exposure and analyzed by immunoblotting and immunohistochemistry. We observed that Bixin activated cutaneous expression of NRF2 and its target genes, and limited photodamage in Nrf2+/+ but not Nrf2-/- mice. Moreover, Bixin reduced inflammation, oxidative damage, and apoptosis in the epidermis of Nrf2+/+ SKH-I mice. Consistently, Bixin prevented UV-induced hair graying in Nrf2+/+ C57BL/6J mice. These results suggest that Bixin-based interventions may be useful for NRF2-dependent skin protection against environmental insults.

Montserrat Rojo De La Vega - One of the best experts on this subject based on the ideXlab platform.

  • Activation of NRF2 by topical apocarotenoid treatment mitigates radiation-induced dermatitis
    Redox Biology, 2020
    Co-Authors: Cody J. Schmidlin, Montserrat Rojo De La Vega, Donna D Zhang, Jessica Perer, Georg T. Wondrak
    Abstract:

    Radiation therapy is a frontline treatment option for cancer patients; however, the effects of radiotherapy on non-tumor tissue (e.g. radiation-induced dermatitis) often worsen patient quality of life. Previous studies have implicated the importance of redox balance in preventing dermatitis, specifically in reference to modulation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) signaling pathway. Due to the cytoprotective functions of transcriptional target genes of NRF2, we investigated how modulation of NRF2 expression could affect DNA damage, oxidative stress, and cell viability in response to radiotherapy. Specifically, it was noted that NRF2 knockdown sensitized human skin keratinocytes to ionizing radiation; likewise, genetic ablation of NRF2 in vivo increased radiosensitivity of murine epidermis. Oppositely, pharmacological induction of NRF2 via the apocarotenoid Bixin lowered markers of DNA damage and oxidative stress, while preserving viability in irradiated keratinocytes. Mechanistic studies indicated that topical pretreatment using Bixin as an NRF2 activator antagonized initial DNA damage by raising cellular glutathione levels. Additionally, topical application of Bixin prevented radiation-induced dermatitis, epidermal thickening, and oxidative stress in the skin of SKH1 mice. Overall, these data indicate that NRF2 is critical for mitigating the harmful skin toxicities associated with ionizing radiation, and that topical upregulation of NRF2 via Bixin could prevent radiation-induced dermatitis.

  • Image_1.tiff
    2018
    Co-Authors: Montserrat Rojo De La Vega, Donna D Zhang, Georg T. Wondrak
    Abstract:

    Environmental exposure to solar ultraviolet (UV) radiation causes acute photodamage, premature aging, and skin cancer, attributable to UV-induced genotoxic, oxidative, and inflammatory stress. The transcription factor NRF2 [nuclear factor erythroid 2 (E2)-related factor 2] is the master regulator of the cellular antioxidant response protecting skin against various environmental stressors including UV radiation and electrophilic pollutants. NRF2 in epidermal keratinocytes can be activated using natural chemopreventive compounds such as the apocarotenoid Bixin, an FDA-approved food additive and cosmetic ingredient from the seeds of the achiote tree (Bixa orellana). Here, we tested the feasibility of topical use of Bixin for NRF2-dependent skin photoprotection in two genetically modified mouse models [SKH1 and C57BL/6J (Nrf2+/+ versus Nrf2-/-)]. First, we observed that a Bixin formulation optimized for topical NRF2 activation suppresses acute UV-induced photodamage in Nrf2+/+ but not Nrf2-/- SKH1 mice, a photoprotective effect indicated by reduced epidermal hyperproliferation and oxidative DNA damage. Secondly, it was demonstrated that topical Bixin suppresses PUVA (psoralen + UVA)-induced hair graying in Nrf2+/+ but not Nrf2-/- C57BL/6J mice. Collectively, this research provides the first in vivo evidence that topical application of Bixin can protect against UV-induced photodamage and PUVA-induced loss of hair pigmentation through NRF2 activation. Topical NRF2 activation using Bixin may represent a novel strategy for human skin photoprotection, potentially complementing conventional sunscreen-based approaches.

  • Topical Bixin Confers NRF2-Dependent Protection Against Photodamage and Hair Graying in Mouse Skin
    Frontiers Media S.A., 2018
    Co-Authors: Montserrat Rojo De La Vega, Georg T. Wondrak, Donna D Zhang
    Abstract:

    Environmental exposure to solar ultraviolet (UV) radiation causes acute photodamage, premature aging, and skin cancer, attributable to UV-induced genotoxic, oxidative, and inflammatory stress. The transcription factor NRF2 [nuclear factor erythroid 2 (E2)-related factor 2] is the master regulator of the cellular antioxidant response protecting skin against various environmental stressors including UV radiation and electrophilic pollutants. NRF2 in epidermal keratinocytes can be activated using natural chemopreventive compounds such as the apocarotenoid Bixin, an FDA-approved food additive and cosmetic ingredient from the seeds of the achiote tree (Bixa orellana). Here, we tested the feasibility of topical use of Bixin for NRF2-dependent skin photoprotection in two genetically modified mouse models [SKH1 and C57BL/6J (Nrf2+/+ versus Nrf2-/-)]. First, we observed that a Bixin formulation optimized for topical NRF2 activation suppresses acute UV-induced photodamage in Nrf2+/+ but not Nrf2-/- SKH1 mice, a photoprotective effect indicated by reduced epidermal hyperproliferation and oxidative DNA damage. Secondly, it was demonstrated that topical Bixin suppresses PUVA (psoralen + UVA)-induced hair graying in Nrf2+/+ but not Nrf2-/- C57BL/6J mice. Collectively, this research provides the first in vivo evidence that topical application of Bixin can protect against UV-induced photodamage and PUVA-induced loss of hair pigmentation through NRF2 activation. Topical NRF2 activation using Bixin may represent a novel strategy for human skin photoprotection, potentially complementing conventional sunscreen-based approaches

  • targeting nrf2 for improved skin barrier function and photoprotection focus on the achiote derived apocarotenoid Bixin
    Nutrients, 2017
    Co-Authors: Montserrat Rojo De La Vega, Donna D Zhang, Andrea Krajisnik, Georg T. Wondrak
    Abstract:

    The transcription factor NRF2 (nuclear factor-E2-related factor 2) orchestrates major cellular defense mechanisms including phase-II detoxification, inflammatory signaling, DNA repair, and antioxidant response. Recent studies strongly suggest a protective role of NRF2-mediated gene expression in the suppression of cutaneous photodamage induced by solar UV (ultraviolet) radiation. The apocarotenoid Bixin, a Food and Drug Administration (FDA)-approved natural food colorant (referred to as ‘annatto’) originates from the seeds of the achiote tree native to tropical America, consumed by humans since ancient times. Use of achiote preparations for skin protection against environmental insult and for enhanced wound healing has long been documented. We have recently reported that (i) Bixin is a potent canonical activator of the NRF2-dependent cytoprotective response in human skin keratinocytes; that (ii) systemic administration of Bixin activates NRF2 with protective effects against solar UV-induced skin damage; and that (iii) Bixin-induced suppression of photodamage is observable in Nrf2+/+ but not in Nrf2−/− SKH-1 mice confirming the NRF2-dependence of Bixin-induced antioxidant and anti-inflammatory effects. In addition, Bixin displays molecular activities as sacrificial antioxidant, excited state quencher, PPAR (peroxisome proliferator-activated receptor) α/γ agonist, and TLR (Toll-like receptor) 4/NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) antagonist, all of which might be relevant to the enhancement of skin barrier function and environmental stress protection. Potential skin photoprotection and photochemoprevention benefits provided by topical application or dietary consumption of this ethno-pharmacologically validated phytochemical originating from the Americas deserves further preclinical and clinical examination.

  • the apocarotenoid Bixin protects mouse skin against uv induced damage in an nrf2 dependent manner
    Free Radical Biology and Medicine, 2017
    Co-Authors: Montserrat Rojo De La Vega, Georg T. Wondrak, Donna D Zhang
    Abstract:

    Skin barrier function and integrity can be impaired as a result of exposure to environmental stressors, including solar ultra violet (UV) radiation. UV induces oxidative stress, inflammation, premature ageing, and cancer. Therefore, there is a need to find effective and safe strategies to protect the skin from these deleterious effects. An effective strategy to prevent UV damage involves activation of the transcription factor nuclear factor-E2-related factor 2 (NRF2) to induce cellular stress responses and damage repair. We recently characterized the apocarotenoid Bixin, and FDA-approved natural food colorant from the seeds of the achiote tree (Bixa orellana), as a safe and potent NRF2 activator. In this study, we tested the feasibility of enhancing NRF2-dependent skin protection using a topical Bixin formulation in a model for acute UV-induced skin damage and UV-induced hair graying. Nrf2+/+ and Nrf2-/- SKH-I hairless mice (acute skin damage) or C57BL/6J mice (hair graying) were treated twice with a topical Bixin formulation 48 h and 24 h before exposure to UV. Skin tissues were harvested at 24 h (acute skin damage) or 2 weeks (hair graying) post-exposure and analyzed by immunoblotting and immunohistochemistry. We observed that Bixin activated cutaneous expression of NRF2 and its target genes, and limited photodamage in Nrf2+/+ but not Nrf2-/- mice. Moreover, Bixin reduced inflammation, oxidative damage, and apoptosis in the epidermis of Nrf2+/+ SKH-I mice. Consistently, Bixin prevented UV-induced hair graying in Nrf2+/+ C57BL/6J mice. These results suggest that Bixin-based interventions may be useful for NRF2-dependent skin protection against environmental insults.