Profile of Class I Histone Deacetylases (HDAC) by Human Dendritic Cells after Alcohol Consumption and In Vitro Alcohol Treatment and Their Implication in Oxidative Stress: Role of HDAC Inhibitors Trichostatin A and Mocetinostat

Abstract

Epigenetic mechanisms have been shown to play a role in alcohol use disorders (AUDs) and may prove to be valuable therapeutic targets. However, the involvement of histone deacetylases (HDACs) on alcohol-induced oxidative stress of human primary monocyte-derived dendritic cells (MDDCs) has not been elucidated. In the current study, we took a novel approach combining ex vivo, in vitro and in silico analyses to elucidate the mechanisms of alcohol-induced oxidative stress and role of HDACs in the periphery. ex vivo and in vitro analyses of alcohol-modulation of class I HDACs and activity by MDDCs from self-reported alcohol users and non-alcohol users was performed. Additionally, MDDCs treated with alcohol were assessed using qRT-PCR, western blot, and fluorometric assay. The functional effects of alcohol-induce oxidative stress were measured in vitro using PCR array and in silico using gene expression network analysis. Our findings show, for the first time, that MDDCs from self-reported alcohol users have higher levels of class I HDACs compare to controls and alcohol treatment in vitro differentially modulates HDACs expression. Further, HDAC inhibitors (HDACi) blocked alcohol-induction of class I HDACs and modulated alcohol-induced oxidative stress related genes expressed by MDDCs. In silico analysis revealed new target genes and pathways on the mode of action of alcohol and HDACi. Findings elucidating the ability of alcohol to modulate class I HDACs may be useful for the treatment of alcohol-induced oxidative damage and may delineate new potential immune-modulatory mechanisms.

Novel detection of post-translational modifications in human monocyte-derived dendritic cells after chronic alcohol exposure: Role of inflammation regulator H4K12ac

“…Another possible explanation for the enhancement of inflammatory cytokines is interactions between EtOH and NU9056; as we have previously reported in the case of co-treatment of MDDCs with mocetinostat and EtOH, which resulted in the exacerbation of production of oxidative stress related genes 8 . Histone modifications and inflammatory cytokine regulation have been correlated with oxidative and cellular stress as previously reported 53 – 55 .…”

“…Buffy Coats are commercially available and each buffy coat represents one N in our experiments. Monocytes were isolated from buffy coats and MDDCs were differentiated as previously described by us 8 .…”

“…Chronic alcohol use, one of the leading causes of morbidity, may result in addiction, which is intrinsically related to brain behavior and neuronal remodeling 6 . Recently, researchers have begun to investigate the epigenetic effects of alcohol abuse; however, most studies have been conducted in the hepatic 2 or neuronal regions 7 , 8 as recently reviewed by us 9 . Besides the vast amount of literature regarding the effects of alcohol abuse on the liver and CNS, alcohol is also known to affect the human immune system by modulating both the innate and adaptive components of the immune system 10 .…”

Phenethyl Isothiocyanate Suppresses Stemness in the Chemo- and Radio-Resistant Triple-Negative Breast Cancer Cell Line MDA-MB-231/IR Via Downregulation of Metadherin

“…As shown in Figure 2b, the MDA-MB-231/IR cells exhibited higher GSH levels. Correlating with these results, there was increased expression of antioxidant genes [42] such as NAD(P)H quinone oxidoreductase 1 (NQO1), glutamate-cysteine ligase catalytic subunit (GCLC), glutamate-cysteine ligase modifier subunit (GCLM), thioredoxin reductase 1 (TXNRD1), sulfiredoxin 1 (SRXN1), and microsomal glutathione S-transferase 3 (MQST3) ( Figure 2c). These results demonstrate that, in contrast to MDA-MB-231 cells, MDA-MB-231/IR cells maintained low ROS levels due to their higher expression of ROS scavengers.…”

Epigenetic mechanisms of alcoholism and stress-related disorders

“…The involvement of specific HDAC isoforms in alcohol dependence and exposure was investigated in several studies. Recently, results on human primary monocyte-derived dendritic cells, derived from alcohol users, demonstrated that class I HDAC gene expression and protein levels were significantly higher compared to the controls (Agudelo et al, 2016). Another in vitro study revealed that alcohol induced a dose-dependent increase of HDAC2 expression (Agudelo et al, 2011).…”