Abstract
Based on the antioxidative effect of resveratrol (RES) in mitigating reactive oxygen species (ROS) production through the induction of nuclear factor-erythroid 2-related factor-2 (Nrf2)/heme oxigenase-1 (HO-1) signaling pathway, we investigated whether the protective activity of RES against ROS-mediated cytotoxicity is mediated by intracellular carbon monoxide (CO), a product of HO-1 activity, in ultraviolet B (UVB)-irradiated human keratinocyte HaCaT cells. The cells were exposed to UVB radiation following treatment with RES and/or CO-releasing molecule-2 (CORM-2). RES and/or CORM-2 upregulated HO-1 protein expression, accompanied by a gradual reduction of UVB-induced intracellular ROS levels. CORM-2 reduced intracellular ROS in the presence of tin protoporphyrin IX, an HO-1 inhibitor, indicating that the cytoprotection observed was mediated by intracellular CO and not by HO-1 itself. Moreover, CORM-2 decreased RES-stimulated mitochondrial quantity and respiration and increased the cytosolic protein expressions of radical-scavenging superoxide dismutases, SOD1 and SOD2. Taken together, our observations suggest that RES and intracellular CO act independently, at least partly, in attenuating cellular oxidative stress by promoting antioxidant enzyme expressions and inhibiting mitochondrial respiration in UVB-exposed keratinocytes.
Highlights
The human skin represents high vulnerability to external hazards, such as ultraviolet radiation (UV) from the sun, air pollutants, cigarette smoke, and other factors [1] and undergoes dynamic self-renewal and orchestrated repair processes [2,3,4]
The fundamental understanding that intracellular carbon monoxide (CO) mainly originates from the enzymatic activity of heme oxigenase-1 (HO-1) depicts the possibility that RES might exert its cytoprotective effect through HO-1/CO
Results presented in this study strengthen previous evidence that both RES and intracellular CO participate in cell signaling through modulation of mitochondrial function and antioxidant response leading to the elimination of intracellular reactive oxygen species (ROS)
Summary
The human skin represents high vulnerability to external hazards, such as ultraviolet radiation (UV) from the sun, air pollutants, cigarette smoke, and other factors [1] and undergoes dynamic self-renewal and orchestrated repair processes [2,3,4]. Normal metabolic processes concomitantly generate oxidants, more commonly known as the electrophilic reactive oxygen species (ROS), which are closely regulated by the elaborate antioxidant network to maintain cellular redox homeostasis [5]. Resveratrol (RES) exemplified nuclear factor-erythroid 2-related factor-2 (Nrf2)-activating capacity and promotes transcription of antioxidant enzymes including heme oxygenase-1 (HO-1) [15], which closely controls the cellular redox balance [16]. Biliverdin [32,33], we hypothesized that RES potentially regulates cellular adaptive response via intracellular CO production in human skin (Figure S1). The current work was undertaken to investigate the potential role of intracellular CO in maintaining cellular homeostasis by upregulating the stress-inducible antioxidant enzymes to stimulate cellular detoxification and maintain redox balance in human skin cells
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