The Nrf2-inducers tanshinone I and dihydrotanshinone protect human skin cells and reconstructed human skin against solar simulated UV

Tao, Shasha; Justiniano, Rebecca; Zhang, Donna D.; Wondrak, Georg T.

doi:10.1016/j.redox.2013.10.004

Cited by 89 publications

(80 citation statements)

References 58 publications

(91 reference statements)

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“…In cells treated with CA, ubiquitination of Nrf2 decreased dramatically compared to untreated control. Likewise, SF or tBHQ also decreased Nrf2 ubiquitination, consistent with the known attenuation of ubiquitination by these Nrf2 inducers (40, 41). Following these experiments, the half-life of endogenous Nrf2 protein and its modulation by CA exposure was measured in HCT116 cells (Fig.…”

Section: Resultssupporting

confidence: 79%

Nrf2-Dependent Suppression of Azoxymethane/Dextran Sulfate Sodium–Induced Colon Carcinogenesis by the Cinnamon-Derived Dietary Factor Cinnamaldehyde

Long

Tao

Vega

et al. 2015

Cancer Prevention Research

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The progressive nature of colorectal cancer (CRC) and poor prognosis associated with the metastatic phase of the disease create an urgent need for the development of more efficacious strategies targeting colorectal carcinogenesis. Cumulative evidence suggests that the redox-sensitive transcription factor Nrf2 (nuclear factor-E2-related factor 2), a master regulator of the cellular antioxidant defence, represents a promising molecular target for CRC chemoprevention. Recently, we have identified cinnamon, the ground bark of Cinnamomum aromaticum (cassia cinnamon) and Cinnamomum verum (Ceylon cinnamon), as a rich dietary source of the Nrf2 inducer cinnamaldehyde (CA) eliciting the Nrf2-regulated antioxidant response in human epithelial colon cells, conferring cytoprotection against electrophilic and genotoxic insult. Here, we have explored the molecular mechanism underlying CA-induced Nrf2 activation in colorectal epithelial cells and have examined the chemopreventive potential of CA in a murine CRC model comparing Nrf2+/+ and Nrf2−/− mice. In HCT116 cells, CA caused a Keap1-C151-dependent increase in Nrf2 protein half-life via blockage of ubiquitination with upregulation of cytoprotective Nrf2 target genes and elevation of cellular glutathione. After optimizing colorectal Nrf2 activation and target gene expression by dietary CA-supplementation regimens, we demonstrated that CA suppresses AOM/DSS-induced inflammatory colon carcinogenesis with modulation of molecular markers of colorectal carcinogenesis. Dietary suppression of CRC using CA supplementation was achieved in Nrf2+/+ but not in Nrf2−/− mice confirming the Nrf2-dependence of CA-induced chemopreventive effects. Taken together, our data suggest feasibility of CRC suppression by dietary CA, an FDA-approved food additive derived from the third most consumed spice in the world.

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Section: Resultssupporting

confidence: 79%

Nrf2-Dependent Suppression of Azoxymethane/Dextran Sulfate Sodium–Induced Colon Carcinogenesis by the Cinnamon-Derived Dietary Factor Cinnamaldehyde

Long

Tao

Vega

et al. 2015

Cancer Prevention Research

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“…Equal amounts of mRNA were used to generate cDNA using the M-MLV Reverse Transcriptase synthesis kit according to the manufacturer’s instructions (Promega). RT-PCR and primer sequences of NRF2 , KEAP1 , GCLM , AKR1C1 and GAPDH were described previously to evaluate mRNA expression using the LightCycler 480 system (Roche) [21, 43]. Quantification of cDNA amount for mouse Nrf2 , Keap1 , Gclm , and Akr1c1 in each skin tissue sample was performed using the KAPA SYBR FAST qPCR Kit (Kapa Biosystems).…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies strongly suggest a protective role of NRF2-mediated gene expression in the suppression of cutaneous photodamage induced by solar UV radiation, and NRF2 activation has been shown to protect cutaneous keratinocytes and fibroblasts against the cytotoxic effects of UVA and UVB [9, 11-21]. Importantly, recent research performed in SKH-1 mice documents that constitutive genetic NRF2 activation protects mice against acute photodamage and photocarcinogenesis [22].…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, recent research performed in SKH-1 mice documents that constitutive genetic NRF2 activation protects mice against acute photodamage and photocarcinogenesis [22]. Therefore, pharmacological modulation of NRF2 has now attracted considerable attention as a novel approach to skin photoprotection [19, 21, 23]. Indeed, protection of primary human keratinocytes from UVB-induced cell death by novel drug-like NRF2 activators has been reported, a photoprotective effect attributed in part to NRF2-dependent elevation of cellular glutathione levels [20, 24, 25].…”

Section: Introductionmentioning

confidence: 99%

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Systemic administration of the apocarotenoid bixin protects skin against solar UV-induced damage through activation of NRF2

Tao

Park

Vega

et al. 2015

Free Radical Biology and Medicine

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Exposure to solar ultraviolet (UV) radiation is a causative factor in skin photodamage and carcinogenesis, and an urgent need exists for improved molecular photoprotective strategies different from (or synergistic with) photon absorption. Recent studies suggest a photoprotective role of cutaneous gene expression orchestrated by the transcription factor NRF2 (nuclear factor-E2-related factor 2). Here we have explored the molecular mechanism underlying carotenoid-based systemic skin photoprotection in SKH-1 mice and provide genetic evidence that photoprotection achieved by the FDA-approved apocarotenoid and food additive bixin depends on NRF2 activation. Bixin activates NRF2 through the critical Cys-151 sensor residue in KEAP1, orchestrating a broad cytoprotective response in cultured human keratinocytes as revealed by antioxidant gene expression array analysis. Following dose optimization studies for cutaneous NRF2 activation by systemic administration of bixin, feasibility of bixin-based suppression of acute cutaneous photodamage from solar UV exposure was investigated in Nrf2+/+ versus Nrf2−/− SKH-1 mice. Systemic administration of bixin suppressed skin photodamage, attenuating epidermal oxidative DNA damage and inflammatory responses in Nrf2+/+ but not in Nrf2−/− mice, confirming the NRF2-dependence of bixin-based cytoprotection. Taken together, these data demonstrate feasibility of achieving NRF2-dependent cutaneous photoprotection by systemic administration of the apocarotenoid bixin, a natural food additive consumed worldwide.

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“…Chronic exposure of mammalian skin to UV radiation induces a number of biological alterations that are directly or indirectly involved in the development of skin cancer and photoaging [1], [2].…”

Section: Introductionmentioning

confidence: 99%

Time-dependent effect of rutin on skin fibroblasts membrane disruption following UV radiation

et al. 2017

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Chronic exposure of the skin to solar UV radiation induces a number of biological alterations, including a redox imbalance; therefore, there is an urgent need for skin cells protective compounds. The aim of this study was to determine the effects of natural, previously extensively examined, polyphenol with antioxidant properties – rutin, on UV-induced skin fibroblasts membrane disruption. Accordingly, fibroblasts exposed to UVA and UVB irradiation were incubated with rutin (12 h before and/or up to 24 h after irradiation), and the structural and metabolic changes were examined. Rutin penetration through the fibroblast phospholipid bilayer was aided by UVA-induced bilitranslocase activity 2–4 h after irradiation, while UVB irradiation led to enhanced phospholipid peroxidation and higher membrane permeability to facilitate the interaction of rutin with phospholipids. Lipidomic analysis revealed that 4 h of rutin treatment also partially prevented UVA/B-induced increase in phosphatidylethanolamine and phosphatidylcholine level, as well as their membrane localization, which resulted in an enhanced zeta potential in the cells and liposomes. Moreover, rutin 2 h following irradiation, in a various degree, prevented the increased in phospholipase A2 activity and ROS generation, and partially protected against the reduction of arachidonic and linoleic acids level and the lipid peroxidation product 4-hydroxynonenal level increase. Rutin effectively prevented against decrease in glutathione peroxidase, glutathione and vitamins E and C activities/levels, particularly 2 h following UVA irradiation.In conclusion, highest skin fibroblasts membrane level of rutin occurred in 2–4 h following UVA/B-radiation results in its strongest effect on biomembrane structure and functions and cellular antioxidant system irrespective of the radiation type.

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The Nrf2-inducers tanshinone I and dihydrotanshinone protect human skin cells and reconstructed human skin against solar simulated UV

Cited by 89 publications

References 58 publications

Nrf2-Dependent Suppression of Azoxymethane/Dextran Sulfate Sodium–Induced Colon Carcinogenesis by the Cinnamon-Derived Dietary Factor Cinnamaldehyde

Nrf2-Dependent Suppression of Azoxymethane/Dextran Sulfate Sodium–Induced Colon Carcinogenesis by the Cinnamon-Derived Dietary Factor Cinnamaldehyde

Systemic administration of the apocarotenoid bixin protects skin against solar UV-induced damage through activation of NRF2

Time-dependent effect of rutin on skin fibroblasts membrane disruption following UV radiation

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