Phloroglucinol Inhibits Oxidative-Stress-Induced Cytotoxicity in C2C12 Murine Myoblasts through Nrf-2-Mediated Activation of HO-1

Abstract

Phloroglucinol is a class of polyphenolic compounds containing aromatic phenyl rings and is known to have various pharmacological activities. Recently, we reported that this compound isolated from Ecklonia cava, a brown alga belonging to the family Laminariaceae, has potent antioxidant activity in human dermal keratinocytes. In this study, we evaluated whether phloroglucinol could protect against hydrogen peroxide (H2O2)-induced oxidative damage in murine-derived C2C12 myoblasts. Our results revealed that phloroglucinol suppressed H2O2-induced cytotoxicity and DNA damage while blocking the production of reactive oxygen species. We also found that phloroglucinol protected cells from the induction of apoptosis associated with mitochondrial impairment caused by H2O2 treatment. Furthermore, phloroglucinol enhanced the phosphorylation of nuclear factor-erythroid-2 related factor 2 (Nrf2) as well as the expression and activity of heme oxygenase-1 (HO-1). However, such anti-apoptotic and cytoprotective effects of phloroglucinol were greatly abolished by the HO-1 inhibitor, suggesting that phloroglucinol could increase the Nrf2-mediated activity of HO-1 to protect C2C12 myoblasts from oxidative stress. Taken together, our results indicate that phloroglucinol has a strong antioxidant activity as an Nrf2 activator and may have therapeutic benefits for oxidative-stress-mediated muscle disease.

The Ocean’s Pharmacy: Health Discoveries in Marine Algae

“…Many algal compounds exert their antioxidant effect by increasing the activity of endogenous antioxidant enzymes like SOD, CAT, and GPx [34], decreasing ROS production [35,36], and/or decreasing the expression of iNOS, leading to a decreased production of NO [37]. In skeletal myoblasts, algal compounds (phloroglucinol and Indole-6-carboxaldehyde) exerted antioxidant effects by regulating oxidative stress-induced apoptosis, mainly by decreasing mitochondrial dysfunction and modulating apoptosis-regulatory factors (e.g., caspases, Bcl-2, Bax, and cytochrome c) [38,39]. Some algal compounds (e.g., from Ecklonia cava and Sargassum thunbergii) were also able to decrease oxidative stress responses by modulating the signaling pathways, mainly by downregulating AMP-activated protein kinase (AMPK) and NF-κB, and upregulating Nrf2/ARE/HO-1/AKT pathways [38][39][40].…”

Bilirubin Concentration in Follicular Fluid Is Increased in Infertile Females, Correlates with Decreased Antioxidant Levels and Increased Nitric Oxide Metabolites, and Negatively Affects Outcome Measures of In Vitro Fertilization

“…As previously mentioned, intracellular heme catabolism is mainly dependen activity of HOx, the enzymes catalyzing the rate-limiting reaction of heme degr HO exists in two isoforms: heme oxygenase 1 (HO-1) and heme oxygenase 2 Whilst HO-2 is constitutively expressed in all human tissues (although in d amounts), HO-1 is the inducible isoenzyme that can be found in a lower number o [16,17]. The expression of HO-1 is modulated by that of the nuclear factor eryt related factor 2 (Nrf2), activating the cell defense systems (including HO-1) a variety of stressors [18][19][20]. Pathological conditions causing oxidative/nitrosativ inflammation and mitochondrial malfunctioning are capable of activating the Nr axis as a cell/tissue protective response to increase the probability of cell/tissue to the stressor.…”

“…Whilst HO-2 is constitutively expressed in all human tissues (although in different amounts), HO-1 is the inducible isoenzyme that can be found in a lower number of tissues [ 16 , 17 ]. The expression of HO-1 is modulated by that of the nuclear factor erythroid-2-related factor 2 (Nrf2), activating the cell defense systems (including HO-1) against a variety of stressors [ 18 , 19 , 20 ]. Pathological conditions causing oxidative/nitrosative stress, inflammation and mitochondrial malfunctioning are capable of activating the Nrf2/HO-1 axis as a cell/tissue protective response to increase the probability of cell/tissue to survive the stressor.…”

Oxidative Stress and Skeletal Muscle Function

“…Park et al have demonstrated that the polyphenol Phloroglucinol showed strong antioxidant activity, protecting C2C12 muscle cells from H 2 O 2 -induced oxidative stress. Like other polyphenols, this molecule has been shown to enhance Nrf2/HO-1 signaling activity, thus activating the antioxidant enzymatic cellular system [ 8 ]. This cell defense mechanism is particularly important because it allows cells to adapt and better defend themselves against oxidative stress.…”