Abstract
Heme oxygenase (HO)-1 is a detoxifying phase II enzyme that plays a role in both inflammatory and oxidative stress responses. Curdrania tricuspidata is widespread throughout East Asia and is used as a therapeutic agent in traditional medicine. We investigated whether treatment with sixteen flavonoid or xanthone compounds from C. tricuspidata could induce HO-1 expression in HT22 hippocampal cells, RAW264.7 macrophage, and BV2 microglia. In these compounds, kuwanon C showed the most remarkable HO-1 expression effects. In addition, treatment with kuwanon C reduced cytoplasmic nuclear erythroid 2-related factor (Nrf2) expression and increased Nrf2 expression in the nucleus. Significant inhibition of glutamate-induced oxidative injury and induction of reactive oxygen species (ROS) occurred when HT22 hippocampal cells were pretreated with kuwanon C. The levels of inflammatory mediator and cytokine, which increased following lipopolysaccharide (LPS) stimulation, were suppressed in RAW264.7 macrophage and BV2 microglia after kuwanon C pretreatment. Kuwanon C also attenuated p65 DNA binding and translocation into the nucleus in LPS-induced RAW264.7 and BV2 cells. The anti-inflammatory, anti-neuroinflammatory, and neuroprotective effects of kuwanon C were reversed when co-treatment with HO-1 inhibitor of tin protoporphyrin-IX (SnPP). These results suggest that the neuroprotective and anti-inflammatory effects of kuwanon C are regulated by HO-1 expression.
Highlights
Heme oxygenase (HO) catalyzes the degradation of heme and is found in three isoforms: HO-1, -2, and -3
This study focused on identifying biomarkers that regulate the expression of HO-1 in three cell lines of neurodegenerative and inflammatory disease model: the immortalized murine hippocampal neuronal cell line HT22, the murine-derived macrophage cell line RAW264.7, and the immortalized murine microglia cell line BV2
Because HO-1 and Nrf2 are known to be critical to the regulation of oxidative damage and inflammation in most cell types [4], we examined whether antioxidative and anti-inflammatory effects were directly related to the modification of their expression by testing the effects of kuwanon C in the presence of an HO-1 inhibitor
Summary
Heme oxygenase (HO) catalyzes the degradation of heme and is found in three isoforms: HO-1, -2, and -3. HO-1 is a 32 kDa protein induced by diverse stimuli, including inflammatory cytokine expression and oxidative stress. HO-2 is a 36 kDa protein that commonly acts as an important constitutively expressed enzyme, and HO-3 is a 33 kDa protein important for heme sensing [1,2]. HO-1 is a detoxifying phase II enzyme that plays a critical role in both inflammatory and oxidative responses. HO-1-mediated degradation of heme generates carbon monoxide (CO), biliverdin, and iron, which are believed to facilitate several cytoprotective responses against oxidative stress [3]. Nuclear erythroid 2-related factor (Nrf2) regulates the expression of various cytoprotective genes, including HO-1. Nrf is known to serve an essential function in both the xenobiotic and oxidative stress responses, fulfilling a critical protective function in several organs, including the kidney, liver, nervous system, and lungs [4]
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