Bioactive compounds (BCs) are known to exhibit antioxidant, anti-inflammatory, and anti-cancer properties by regulating the cellular redox balance and histone acetylation state. BCs can control chronic oxidative states caused by dietary stress, i.e., alcohol, high-fat, or high-glycemic diet, and adjust the redox balance to recover physiological conditions. Unique functions of BCs to scavenge reactive oxygen species (ROS) can resolve the redox imbalance due to the excessive generation of ROS. The ability of BCs to regulate the histone acetylation state contributes to the activation of transcription factors involved in immunity and metabolism against dietary stress. The protective properties of BCs are mainly ascribed to the roles of sirtuin 1 (SIRT1) and nuclear factor erythroid 2–related factor 2 (NRF2). As a histone deacetylase (HDAC), SIRT1 modulates the cellular redox balance and histone acetylation state by mediating ROS generation, regulating nicotinamide adenine dinucleotide (NAD+)/NADH ratio, and activating NRF2 in metabolic progression. In this study, the unique functions of BCs against diet-induced inflammation, oxidative stress, and metabolic dysfunction have been considered by focusing on the cellular redox balance and histone acetylation state. This work may provide evidence for the development of effective therapeutic agents from BCs.

Kim HJ, et al. Nutr Res Pract. 2018 Dec;12(6):503-511. https://doi.org/10.4162/nrp.2018.12.6.503

Inflammation, an innate immune response mediated by macrophages, has been a hallmark leading to the pathophysiology of diseases. In this study, we examined the inhibitory effects of ginsenoside compound K (CK) on lipopolysaccharide (LPS)-induced inflammation and metabolic alteration in RAW 264.7 macrophages by regulating sirtuin 1 (SIRT1) and histone deacetylase 4 (HDAC4). LPS suppressed SIRT1 while promoting HDAC4 expression, accompanied by increases in cellular reactive oxygen species accumulation and pro-inflammatory gene expression; however, the addition of CK elicited the opposite effects. CK ameliorated the LPS-induced increase in glycolytic genes and abrogated the LPS-altered genes engaged in the NAD+ salvage pathway. LPS decreased basal, maximal, and non-mitochondrial respiration, reducing ATP production and proton leak in macrophages, which were abolished by CK. SIRT1 inhibition augmented Hdac4 expression along with increased LPS-induced inflammatory and glycolytic gene expression, while decreasing genes that regulate mitochondrial biogenesis; however, its activation resulted in the opposite effects. Inhibition of HDAC4 enhanced Sirt1 expression and attenuated the LPS-induced inflammatory gene expression. In conclusion, CK exerted anti-inflammatory and antioxidant properties with the potential to counteract the alterations of energy metabolism, including glycolysis and mitochondrial respiration, through activating SIRT1 and repressing HDAC4 in LPS-stimulated macrophages.

Kim B, et al. Nutr Res Pract. 2021 Jun;15(3):279-293. https://doi.org/10.4162/nrp.2021.15.3.279

Black elderberry (Sambucus Nigar) with high polyphenol content has been reported to have a hypolipidemic effect, but its underlying mechanisms have not been well characterized. In the present study, we investigated the effects of polyphenol-rich black elderberry (BEE) on oxidative stress and hepatic lipid metabolism. The total antioxidant activity of BEE was evaluated. The expression of genes for lipid metabolism was measured in 50 or 100 μg/mL of BEE-treated HepG2 cells. The mRNA and protein levels of genes for cholesterol metabolisms, i.e., sterol regulatory element-binding protein 2, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and low-density lipoprotein receptor, were decreased by BEE. There was marked induction of genes for high-density lipoprotein metabolism, i.e., scavenger receptor class B type 1and ATP-binding cassette (ABC) transporter A1 in BEE-treated cells. The expression of canalicular efflux transporter for hepatic cholesterol and bile acids, such as ABCG5/G8 and ABCB11, was significantly increased by BEE treatment. There was no alteration of the lipogenic genes, whereas BEE significantly decreased the expression of genes for fatty acid oxidation. BEE significantly altered the expression of histone deacetylase and sirtuins. These data suggest that the hypocholesterolemic effects of BEE may be attributed to the alteration of genes for hepatic cholesterol synthesis and flux.