Dataset Information

Fernblock® Upregulates NRF2 Antioxidant Pathway and Protects Keratinocytes from PM2.5-Induced Xenotoxic Stress.

ABSTRACT: Humans in modern industrial and postindustrial societies face sustained challenges from environmental pollutants, which can trigger tissue damage from xenotoxic stress through different mechanisms. Thus, the identification and characterization of compounds capable of conferring antioxidant effects and protection against these xenotoxins are warranted. Here, we report that the natural extract of Polypodium leucotomos named Fernblock®, known to reduce aging and oxidative stress induced by solar radiations, upregulates the NRF2 transcription factor and its downstream antioxidant targets, and this correlates with its ability to reduce inflammation, melanogenesis, and general cell damage in cultured keratinocytes upon exposure to an experimental model of fine pollutant particles (PM2.5). Our results provide evidence for a specific molecular mechanism underpinning the protective activity of Fernblock® against environmental pollutants and potentially other sources of oxidative stress and damage-induced aging.

SUBMITTER: Delgado-Wicke P

PROVIDER: S-EPMC7181013 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Fernblock® Upregulates NRF2 Antioxidant Pathway and Protects Keratinocytes from PM<sub>2.5</sub>-Induced Xenotoxic Stress.

Delgado-Wicke Pablo P Rodríguez-Luna Azahara A Ikeyama Yoshifumi Y Honma Yoichi Y Kume Toshiaki T Gutierrez María M Lorrio Silvia S Juarranz Ángeles Á González Salvador S

Oxidative medicine and cellular longevity 20200414

Humans in modern industrial and postindustrial societies face sustained challenges from environmental pollutants, which can trigger tissue damage from xenotoxic stress through different mechanisms. Thus, the identification and characterization of compounds capable of conferring antioxidant effects and protection against these xenotoxins are warranted. Here, we report that the natural extract of <i>Polypodium leucotomos</i> named Fernblock®, known to reduce aging and oxidative stress induced by s ...[more]

PMID: 32377294

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Project description:Previous studies have shown that long-term exposure to fine particulate matter (PM2.5) increases the morbidity and mortality of pulmonary diseases such as asthma, chronic obstructive pulmonary disease and pulmonary emphysema. Oxidative stress and inflammation play key roles in pulmonary damage caused by PM2.5. Nuclear factor erythroid 2-related factor 2 (Nrf2) could regulate the expression of antioxidant and anti-inflammatory genes and is pivotal for protection against PM2.5-induced oxidative stress. In this study, a real-ambient exposure system was constructed with the outdoor ambient air in north China. Wild-type (WT) and Nrf2-/- (KO) mice were exposed to the real-ambient system for six weeks. After PM2.5 exposure, our data showed that the levels of inflammatory factors and malondialdehyde were significantly increased in WT and KO mice. Moreover, the lung function and pathological phenotype of the WT mice were altered but there was no obvious change in the Nrf2-/- mice. To further explore the potential molecular mechanisms, we performed RNA-sequencing. The RNA-sequence analysis results showed that the CYP450 pathway in the first ten pathways of KEGG was related to the metabolism of PM2.5. In WT and KO mice, the expression of CYP2E1 in the CYP450 pathway showed opposite trends after PM2.5 exposure. The data showed that the expression of the CYP2E1 gene in WT-PM mice increased while it decreased in KO-PM; the expression of the CYP2E1 protein showed a similar trend. CYP2E1 is primarily distributed in the endoplasmic reticulum (ER) where it could metabolize various exogenous substances attached to PM2.5 and produce highly toxic oxidation products closely related to ER stress. Consistently, the expression level of GRP94, a biomarker of ER stress, was increased in WT mice and reduced in KO mice under PM2.5 exposure. Persistent ER stress is a mechanism that causes lung damage under PM2.5 exposure. Nrf2 facilitates lung injury during PM2.5 exposure and CYP2E1 metabolism is involved in this process.

Project description:This study evaluated the effects of elevated homocysteine (Hcy) on the oxidative stress response in retinal Müller glial cells. Elevated Hcy has been implicated in retinal diseases including glaucoma and optic neuropathy, which are characterized by retinal ganglion cell (RGC) loss. To understand the mechanisms of Hcy-induced RGC loss, in vitro and in vivo models have been utilized. In vitro isolated RGCs are quite sensitive to elevated Hcy levels, while in vivo murine models of hyperhomocysteinemia (HHcy) demonstrate a more modest RGC loss (∼20%) over a period of many months. This differential response to Hcy between isolated cells and the intact retina suggests that the retinal milieu invokes mechanisms that buffer excess Hcy. Oxidative stress has been implicated as a mechanism of Hcy-induced neuron loss and NRF2 is a transcription factor that plays a major role in regulating cytoprotective responses to oxidative stress. In the present study we investigated whether HHcy upregulates NRF2-mediated stress responses in Müller cells, the chief retinal glial cell responsible for providing trophic support to retinal neurons. Primary Müller cells were exposed to L-Hcy-thiolactone [50μM-10mM] and assessed for viability, reactive oxygen species (ROS), and glutathione (GSH) levels. Gene/protein levels of Nrf2 and levels of NRF2-regulated antioxidants (NQO1, CAT, SOD2, HMOX1, GPX1) were assessed in Hcy-exposed Müller cells. Unlike isolated RGCs, isolated Müller cells are viable over a wide range of Hcy concentrations [50 μM - 1 mM]. Moreover, when exposed to elevated Hcy, Müller cells demonstrate decreased oxidative stress and decreased ROS levels. GSH levels increased by ∼20% within 24 h exposure to Hcy. Molecular analyses revealed 2-fold increase in Nrf2 expression. Expression of antioxidant genes Nqo1, Cat, Sod2, Hmox1, Gpx1 increased significantly. The consequences of Hcy exposure were evaluated also in Müller cells harvested from Nrf2-/- mice. In contrast to WT Müller cells, in which oxidative stress decreased upon exposure to Hcy, the Nrf2-/- Müller cells showed a significant increase in oxidative stress. Our data suggest that at least during early stages of Hhcy, a cytoprotective response may be in place, mediated in part by NRF2 in Müller cells.

Project description:IntroductionDespite the London Underground (LU) handling on average 2.8 million passenger journeys per day, the characteristics and potential health effects of the elevated concentrations of metal-rich PM2.5 found in this subway system are not well understood.MethodsSpatial monitoring campaigns were carried out to characterise the health-relevant chemical and physical properties of PM2.5 across the LU network, including diurnal and day-to-day variability and spatial distribution (above ground, depth below ground and subway line). Population-weighted station PM2.5 rankings were produced to understand the relative importance of concentrations at different stations and on different lines.ResultsThe PM2.5 mass in the LU (mean 88 μg m-3, median 28 μg m-3) was greater than at ambient background locations (mean 19 μg m-3, median 14 μg m-3) and roadside environments in central London (mean 22 μg m-3, median 14 μg m-3). Concentrations varied between lines and locations, with the deepest and shallowest submerged lines being the District (median 4 μg m-3) and Victoria (median 361 μg m-3 but up to 885 μg m-3). Broadly in agreement with other subway systems around the world, sampled LU PM2.5 comprised 47% iron oxide, 7% elemental carbon, 11% organic carbon, and 14% metallic and mineral oxides. Although a relationship between line depth and air quality inside the tube trains was evident, there were clear influences relating to the distance from cleaner outside air and the exchange with cabin air when the doors open. The passenger population-weighted exposure analysis demonstrated a method to identify stations that should be prioritised for remediation to improve air quality.ConclusionPM2.5 concentrations in the LU are many times higher than in other London transport Environments. Failure to include this environment in epidemiological studies of the relationship between PM2.5 and health in London is therefore likely to lead to a large exposure misclassification error. Given the significant contribution of underground PM2.5 to daily exposure, and the differences in composition compared to urban PM2.5, there is a clear need for well-designed studies to better understand the health effects of underground exposure.

Dataset Information

Fernblock® Upregulates NRF2 Antioxidant Pathway and Protects Keratinocytes from PM2.5-Induced Xenotoxic Stress.

Publications

Fernblock® Upregulates NRF2 Antioxidant Pathway and Protects Keratinocytes from PM<sub>2.5</sub>-Induced Xenotoxic Stress.

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