Sulforaphane increases Nrf2 expression and protects alveolar epithelial cells against injury caused by cigarette smoke extract

Zhang, Jiao; Chang, Jiachen; Li, Jing; Nie, Dengmei; Cui, Huijuan; Guo, Dadong

doi:10.3892/mmr.2017.6700

Cited by 38 publications

(24 citation statements)

References 24 publications

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“…Acting through the Nrf2 pathway, sulforaphane inhibited 7,12-dimethylbenz(a)anthracene-induced skin tumorigenesis in mice [ 195 ]. At the same time, the Nrf2 pathway seems to be involved in the sulforaphane-mediated protection from apoptosis in different cellular models [ 196 , 197 ]. Oral administration of sulforaphane was able to inhibit DMBA-induced mammary carcinogenesis in rats [ 198 ].…”

Section: Nrf2-activating Phytochemicals: Senescence Inducers Senomentioning

confidence: 99%

Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy

Malavolta

Bracci

Santarelli

et al. 2018

Mediators of Inflammation

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The reactivation of senescence in cancer and the subsequent clearance of senescent cells are suggested as therapeutic intervention in the eradication of cancer. Several natural compounds that activate Nrf2 (nuclear factor erythroid-derived 2-related factor 2) pathway, which is involved in complex cytoprotective responses, have been paradoxically shown to induce cell death or senescence in cancer. Promoting the cytoprotective Nrf2 pathway may be desirable for chemoprevention, but it might be detrimental in later stages and advanced cancers. However, senolytic activity shown by some Nrf2-activating compounds could be used to target senescent cancer cells (particularly in aged immune-depressed organisms) that escape immunosurveillance. We herein describe in vitro and in vivo effects of fifteen Nrf2-interacting natural compounds (tocotrienols, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, silybin, phenethyl isothiocyanate, sulforaphane, triptolide, allicin, berberine, piperlongumine, fisetin, and phloretin) on cellular senescence and discuss their use in adjuvant cancer therapy. In light of available literature, it can be concluded that the meaning and the potential of adjuvant therapy with natural compounds in humans remain unclear, also taking into account the existence of few clinical trials mostly characterized by uncertain results. Further studies are needed to investigate the therapeutic potential of those compounds that display senolytic activity.

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Section: Nrf2-activating Phytochemicals: Senescence Inducers Senomentioning

confidence: 99%

Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy

Malavolta

Bracci

Santarelli

et al. 2018

Mediators of Inflammation

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“…To check for acute toxicity, the cells were incubated with tested agents for 3 hours. Standard toxicity assessment time was set to 24 hours, according to the literature [ 30 ].…”

Section: Methodsmentioning

confidence: 99%

Bardoxolone Methyl Displays Detrimental Effects on Endothelial Bioenergetics, Suppresses Endothelial ET-1 Release, and Increases Endothelial Permeability in Human Microvascular Endothelium

Szczęsny-Małysiak

Stojak

Campagna

et al. 2020

Oxidative Medicine and Cellular Longevity

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Nrf2 is a master regulator of antioxidant cellular defence, and agents activating the Nrf2 pathway have been tested in various diseases. However, unexpected side effects of cardiovascular nature reported for bardoxolone methyl in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease (the BEACON trial) still have not been fully explained. Here, we aimed to characterize the effects of bardoxolone methyl compared with other Nrf2 activators—dimethyl fumarate and L-sulforaphane—on human microvascular endothelium. Endothelial toxicity, bioenergetics, mitochondrial membrane potential, endothelin-1 (ET-1) release, endothelial permeability, Nrf2 expression, and ROS production were assessed in human microvascular endothelial cells (HMEC-1) incubated for 3 and 24 hours with 100 nM–5 μM of either bardoxolone methyl, dimethyl fumarate, or L-sulforaphane. Three-hour incubation with bardoxolone methyl (100 nM–5 μM), although not toxic to endothelial cells, significantly affected endothelial bioenergetics by decreasing mitochondrial membrane potential ( concentrations ≥ 3 μ M ), decreasing spare respiratory capacity ( concentrations ≥ 1 μ M ), and increasing proton leak ( concentrations ≥ 500 nM ), while dimethyl fumarate and L-sulforaphane did not exert such actions. Bardoxolone methyl at concentrations ≥ 3 μ M also decreased cellular viability and induced necrosis and apoptosis in the endothelium upon 24-hour incubation. In turn, endothelin-1 decreased permeability in endothelial cells in picomolar range, while bardoxolone methyl decreased ET-1 release and increased endothelial permeability even after short-term (3 hours) incubation. In conclusion, despite that all three Nrf2 activators exerted some beneficial effects on the endothelium, as evidenced by a decrease in ROS production, bardoxolone methyl, the most potent Nrf2 activator among the tested compounds, displayed a distinct endothelial profile of activity comprising detrimental effects on mitochondria and cellular viability and suppression of endothelial ET-1 release possibly interfering with ET-1–dependent local regulation of endothelial permeability.

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“…For example, the intravenous administration of 5 mg/kg of SFN in a rabbit model of ALI significantly decreased lung injury and increased serum levels of Nrf2, suggesting that Nrf2 activation can significantly improve ALI [32]. The incubation of cultured alveolar epithelial cells with 0.5 µM of SFN significantly reduced ROS production caused by cigarette smoke through a Nrf2-dependent pathway [30]. Furthermore, an analog of AA, 3-olaurylglyceryl ascorbate, can also activate the Nrf2 pathway, decreasing intracellular ROS in normal human epidermal keratinocytes cells [48].…”

Section: Antioxidants Are Effective In Mitigating Cellular Damage Andmentioning

confidence: 97%

“…Nrf2 has been reported to have a prophylactic effect in animals model of ALI induced by hyperoxia, cigarette smoke, and oleic acid [21,[30][31][32]. To determine whether SFN mitigates HALI by reducing hyperoxia-induced oxidative stress, macrophages were cultured under hyperoxic conditions and incubated with SFN.…”

Section: Sulforaphane Significantly Attenuates Hyperoxia-induced Oxidmentioning

confidence: 99%

Dietary Antioxidants Significantly Attenuate Hyperoxia-Induced Acute Inflammatory Lung Injury by Enhancing Macrophage Function via Reducing the Accumulation of Airway HMGB1

Patel

Dial

et al. 2020

IJMS

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Mechanical ventilation with hyperoxia is the major supportive measure to treat patients with acute lung injury and acute respiratory distress syndrome (ARDS). However, prolonged exposure to hyperoxia can induce oxidative inflammatory lung injury. Previously, we have shown that high levels of airway high-mobility group box 1 protein (HMGB1) mediate hyperoxia-induced acute lung injury (HALI). Using both ascorbic acid (AA, also known as vitamin C) and sulforaphane (SFN), an inducer of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), we tested the hypothesis that dietary antioxidants can mitigate HALI by ameliorating HMGB1-compromised macrophage function in phagocytosis by attenuating hyperoxia-induced extracellular HMGB1 accumulation. Our results indicated that SFN, which has been shown to attenute HALI in mice exposed to hyperoxia, dose-dependently restored hyperoxia-compromised macrophage function in phagocytosis (75.9 ± 3.5% in 0.33 µM SFN versus 50.7 ± 1.8% in dimethyl sulfoxide (DMSO) control, p < 0.05) by reducing oxidative stress and HMGB1 release from cultured macrophages (47.7 ± 14.7% in 0.33 µM SFN versus 93.1 ± 14.6% in DMSO control, p < 0.05). Previously, we have shown that AA enhances hyperoxic macrophage functions by reducing hyperoxia-induced HMGB1 release. Using a mouse model of HALI, we determined the effects of AA on hyperoxia-induced inflammatory lung injury. The i.p. administration of 50 mg/kg of AA to mice exposed to 72 h of ≥98% O2 significantly decreased hyperoxia-induced oxidative and nitrosative stress in mouse lungs. There was a significant decrease in the levels of airway HMGB1 (43.3 ± 12.2% in 50 mg/kg AA versus 96.7 ± 9.39% in hyperoxic control, p < 0.05), leukocyte infiltration (60.39 ± 4.137% leukocytes numbers in 50 mg/kg AA versus 100 ± 5.82% in hyperoxic control, p < 0.05) and improved lung integrity in mice treated with AA. Our study is the first to report that the dietary antioxidants, ascorbic acid and sulforaphane, ameliorate HALI and attenuate hyperoxia-induced macrophage dysfunction through an HMGB1-mediated pathway. Thus, dietary antioxidants could be used as potential treatments for oxidative-stress-induced acute inflammatory lung injury in patients receiving mechanical ventilation.

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Sulforaphane increases Nrf2 expression and protects alveolar epithelial cells against injury caused by cigarette smoke extract

Cited by 38 publications

References 24 publications

Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy

Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy

Bardoxolone Methyl Displays Detrimental Effects on Endothelial Bioenergetics, Suppresses Endothelial ET-1 Release, and Increases Endothelial Permeability in Human Microvascular Endothelium

Dietary Antioxidants Significantly Attenuate Hyperoxia-Induced Acute Inflammatory Lung Injury by Enhancing Macrophage Function via Reducing the Accumulation of Airway HMGB1

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