Epigenetic histone modifications in a clinically relevant rat model of chronic ethanol-binge-mediated liver injury

Purpose

Ethanol binge augments liver injury after chronic ethanol consumption in humans, but the mechanism behind the enhanced liver injury by ethanol binge is not known. In this study we used a clinically relevant rat model in which liver injury is amplified by binge after chronic ethanol treatment and investigated the importance of histone modifications.

Methods

Eight-week-old Sprague-Dawley rats were fed ethanol in a liquid diet for 4 weeks. Control rats were fed an isocaloric liquid diet. This was followed by three binge administrations of ethanol (intragastric 5 g/kg body weight, 12 h apart). In the control, ethanol was replaced by water. Four hours after the last binge administration, liver samples were analyzed for histone modifications and parameters of liver injury.

Results

Chronic ethanol administration alone caused an increase in histone H3 ser10 and ser28 (H3S10 or S28) phosphorylation, and binge ethanol reduced their levels. Levels of dually modified phosphoacetylated histone H3 (H3AcK9/PS10) increased after acute binge ethanol and remained same after chronic ethanol binge. In contrast, histone H3 lysine-9 acetylation (H3AcK9) was not increased after chronic ethanol but increased significantly after acute binge and chronic ethanol binge. Increase in histone acetylation was accompanied by increased phospho-ERK1/2 in the nuclear extracts. Increased acetylation after chronic ethanol binge was also accompanied by increased protein levels of GCN5 histone acetyl transferase and a modest increase in HDAC3 in the nucleus. Histone lysine-9 dimethylation was significantly increased after chronic ethanol binge. Chronic ethanol binge also resulted in a decrease in the SAM:SAH ratio with a relative decrease of SAM levels and a corresponding increase in SAH levels.

Conclusions

Ethanol binge after chronic ethanol altered the profile of site-specific histone modifications and may underlie the mechanism of augmented liver injury by chronic-ethanol-binge-treated rats.

     

The emerging role of olanzapine in paediatric CINV control: A review

Chemotherapy-induced nausea and vomiting (CINV) is a serious side effect of chemotherapy that negatively impacts the quality of life of oncological patients and is associated with the emetogenic risk specific to administered chemotherapy. Current practice guidelines on the use of antiemetics in CINV include the option of adding olanzapine to antiemetic regimens in the management of adult CINV. The use of olanzapine in pediatric CINV has been restricted to children with poor CINV control. Research on the use of olanzapine in pediatric CINV has been limited. The aim of this review was to evaluate current evidence on the effective and safe antiemetic use of olanzapine in pediatric CINV of any type following chemotherapy of any emetogenicity. Ovid MEDLINE, Embase, CENTRAL databases were searched for any literature on the use of olanzapine in pediatric CINV published from 2015 to 2022. Studies that reported on the olanzapine-containing antiemetic regimen in peadiatric CINV control specifically were included. Search restrictions were placed on research published in English. The search generated 43 records that were assessed for eligibility. Out of 10 identified eligible studies a third were RCT. Findings of this review suggest that adding olanzapine to antiemetic regimen in pediatric CINV control is a worthwhile consideration. Further research is needed to establish the efficacy and safety of antiemetic olanzapine use in pediatric CINV.     

Epigenetic regulation of N6-methyladenosine modifications in obesity

Obesity is a serious health issue in the world and is related to a higher risk of suffering metabolic diseases. Understanding the molecular basis of obesity is critical to identify new targets to treat obesity and obesity-associated metabolic diseases. N6-methyladenosine (m6A) modification is the most common form of ribonucleic acid modification, which has attracted increasing interest of researchers in recent years, as it is reported that m6A has vital functions in diseases and everyday life activities. Recent studies showed that m6A modification was decreased in obese adipose tissue, and appeared to play a regulatory role in many obesity-associated biological processes, including adipogenesis, lipid metabolism and insulin resistance. In this review, we discussed the emerging advances in m6A modification in obesity to provide a novel therapeutic strategy for fighting against obesity.     

Epigenetic mechanisms in non-alcoholic fatty liver disease: An emerging field

Non-alcoholic fatty liver disease (NAFLD) is an emerging health concern in both developed and non-developed world, encompassing from simple steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis and liver cancer. Incidence and prevalence of this disease are increasing due to the socioeconomic transition and change to harmful diet. Currently, gold standard method in NAFLD diagnosis is liver biopsy, despite complications and lack of accuracy due to sampling error. Further, pathogenesis of NAFLD is not fully understood, but is well-known that obesity, diabetes and metabolic derangements played a major role in disease development and progression. Besides, gut microbioma and host genetic and epigenetic background could explain considerable interindividual variability. Knowledge that epigenetics, heritable events not caused by changes in DNA sequence, contribute to development of diseases has been a revolution in the last few years. Recently, evidences are accumulating revealing the important role of epigenetics in NAFLD pathogenesis and in NASH genesis. Histone modifications, changes in DNA methylation and aberrant profiles or microRNAs could boost development of NAFLD and transition into clinical relevant status. PNPLA3 genotype GG has been associated with a more progressive disease and epigenetics could modulate this effect. The impact of epigenetic on NAFLD progression could deserve further applications on therapeutic targets together with future non-invasive methods useful for the diagnosis and staging of NAFLD.     

Melatonin: data consistent with a role in controlling ovarian function

FSH and LH excretion were correlated with melatonin excretion in consecutive daily urines obtained from a normal adult female (27 days), a normal 11-year-old girl (28 days), and an 8-year-old girl with idiopathic sexual precocity (30 days). Additionally pregnanediol-3-glucuronide (PG) excretion was determined in the urines of the adult female. Gonadotropin and PG excretion patterns of the adult female were those associated with a normal menstrual cycle. Excretion of melatonin, mean +/- SD, (11.3 +/- 2.7 vs 4.7 +/- 1.4 ng/h, p less than 0.005) was greater and PG (38.3 +/- 81 vs 124.2 +/- 46.7 ug/h, p less than 0.005) was less during the first 13 days as compared to the subsequent 14 days. Gonadotropin and melatonin excretions correlated positively (first 13 days FSH, r = 0.828; rs = 0.815 and LH, r = 0.816; rs = 0.905, p less than 0.005 and subsequent 14 days FSH, r = 0.607; rs = 0.685, p less than 0.025 and LH, r = 0.490, p less than 0.05; rs = 0.638, p less than 0.025). Excretion of PG and melatonin did not correlate during the first 13 days. However, during the subsequent 14 days they correlated negatively (r = -0.679, p less than 0.005; rs = -0.620, p less than 0.025). During the 28-day period the gonadotropin and melatonin excretion patterns of the 11-year-old girl showed random fluctuations and correlated positively (FSH, r = 0.669; rs = 0.631 and LH, r = 0.690; rs = 0.695, p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)     

Histone deacetylases (HDAC)-induced histone modifications in the amygdala: a role in rapid tolerance to the anxiolytic effects of ethanol

Background: Rapid tolerance to the anxiolytic effects of ethanol appears to be an important factor in the development of alcoholism. Here, we investigated the involvement of amygdaloid histone deacetylases (HDAC)‐induced epigenetic changes in rapid ethanol tolerance (RET). Methods: RET in rats was induced by 2 ethanol injections administered 24 hours apart. Both ethanol‐tolerant and control rats were treated with the HDAC inhibitor, trichostatin A (TSA), and anxiety‐like behaviors were measured. HDAC activity, histone (H3 and H4) acetylation, and neuropeptide Y (NPY) expression in the amygdala of these rats were also measured. Results: A single ethanol exposure was able to produce an anxiolytic response, inhibit amygdaloid HDAC activity, and increase both histone acetylation and NPY expression (mRNA and protein levels) in the central nucleus of amygdala (CeA) and medial nucleus of amygdala (MeA) of rats. In contrast, 2 exposures of the same dose of ethanol (24 hours apart) neither elicited a similar anxiolytic response nor modulated HDAC activity, histone acetylation, or NPY expression in the amygdala. However, exposure to a higher dose of ethanol on the second day was able to produce an anxiolytic response and also inhibit amygdaloid HDAC activity. TSA treatment caused the reversal of RET by inhibiting HDAC activity, thereby increasing histone acetylation and NPY expression in the CeA and MeA. Conclusions: Cellular tolerance to the initial acute ethanol‐induced inhibition of HDAC activity and the subsequent upregulation of histone acetylation and NPY expression in the amygdala may be involved in the mechanisms underlying rapid tolerance to the anxiolytic effects of ethanol.     

The emerging role of adipokines as mediators of cardiovascular function: physiologic and clinical perspectives

Interest in the biology of white adipose tissue has increased dramatically since the discovery of leptin in 1994. The identification of the product of the gene obese (ob) threw light on the role of adipose tissue in the physiopathology of obesity-related diseases and spurred the identification of numerous other adipokines, many of a proinflammatory nature. It has become increasingly evident that white adipose tissue-derived cytokines mediate between obesity-related exogenous factors (nutrition and lifestyle) and the molecular events that lead to metabolic syndrome, inflammation, and cardiovascular diseases. Here we review recent adipokine research, with particular attention to the roles of adiponectin, leptin, resistin, visfatin, apelin, omentin, and chemerin in such conditions.     

Ovarian steroid receptors and their role in ovarian function

The steroidogenic pathway within the ovary gives rise to progestins, androgens and oestrogens, all of which act via specific nuclear receptors to regulate reproductive function and maintain fertility. The precise role of oestrogen in the ovary remains to be elucidated, hence the data presented here which arises from studies designed to resolve this issue. Oestrogens signal via two receptor subtypes ERalpha and ERbeta, both of which are present in the ovary. ERbeta, the most abundant mRNA, is primarily expressed by GC where it transduces signals from ovarian-derived and exogenous oestrogens. Specific roles for each of the ERs in the ovary have yet to be established, despite ER knockout studies indicating both are required for normal function. The ArKO mouse is a model of oestrogen insufficiency. These mice are infertile as a result of arrested folliculogenesis (at the antral stage) and a failure to ovulate. Trans/re-differentiation of somatic cells in the ovary gives rise to Sertoli cell-like and Leydig cell-like cells within abnormal follicular structures. Disruption to the balance of sex steroids in the ovary is likely to facilitate this phenotype. Future studies will focus on the regulation of somatic cell differentiation, assigning roles to individual ERs and establishing definitive targets of oestrogen action in the ovary.     

Epigenetic control of tumor angiogenesis

The term “epigenetic” is used to refer to heritable alterations in chromatin that are not due to changes in DNA sequence. Different growth factors and vascular genes mediate the angiogenic process, which is regulated by epigenetic states of genes. The aim of this article is to analyze the role of epigenetic mechanisms in the control and regulation of tumor angiogenetic processes. The reversibility of epigenetic events in contrast to genetic aberrations makes them potentially suitable for therapeutic intervention. In this context, DNA methyltransferase (DNMT) and HDAC inhibitors indirectly—via the tumor cells—exhibit angiostatic effects in vivo, and inhibition of miRNAs can contribute to the development of novel anti‐angiogenesis therapies.