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Biochemical Aspects of Fatty Liver
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
One of the most powerful alkylating agents is ethionine, an amino acid. It binds to liver ATP shortly after injection with production of the relatively stable adenosyl-S-ethionine (Farber and Corban, 1958; Farber and Popper, 1950). ATP becomes insufficient for both amino acid and fatty acid activation. According to Farber’s group, this is the most important reason to explain fatty liver and succeeds in increasing fat 5–6 h after injection, especially in female rats. Additional causes for fat accumulation are, however, ethylation of DNA, mRNA, rRNA, and tRNA, as effected by adenosyl-S-ethionine.
The Molecular Genetics OF DNA Methylation in Colorectal Cancer
Published in Leonard H. Augenlicht, Cell and Molecular Biology of Colon Cancer, 2019
Christman et al.20 demonstrated that ethionine can induce differentiation of erythroleukemic cells, probably through an effect on DNA methylation. Jones and Taylor21 demonstrated that 5-azacytidine (5-azaCR), which causes specific hypomethylation of DNA, leads to cell differentiation. C3H 10T1/2 cells, when treated with a brief course of 5-azacytidine, differentiate into chondrocytes, myoblasts, and adipocytes.21 Experiments using cloned gene constructs also support a specific role for DNA methylation in gene expression. Artificially methylated plasmid constructs are not efficiently transcribed even if incorporated into genomic DNA,22 and this difference appears to be mediated by changes in chromatin conformation.23
Choline, Methionine, Folate and Chemical Carcinogenesis
Published in Maryce M. Jacobs, Vitamins and Minerals in the Prevention and Treatment of Cancer, 2018
Adrianne E. Rogers, Steven H. Zeisel, Rizwan Akhtar
Chemical carcinogens can interfere with methyl group metabolism in animals fed complete diets. There have been observations of reduction of hepatic Adomet and early hypomethylation of oncogenes in rats fed a complete diet and given the hepatic carcinogen, diethylnitrosamine (DEN).36 DEN also perturbs hepatic folate metabolism.37 Another hepatic carcinogen, ethionine, seriously perturbs hepatic methyl metabolism.38 Direct interactions of carcinogens with methyl metabolism are of great interest since they provide other evidence of the importance of methyl metabolism in carcinogenesis and may be important in tissues other than liver.
Epigenetic regulation by gut microbiota
Published in Gut Microbes, 2022
Vivienne Woo, Theresa Alenghat
Immune cells similarly undergo broad histone modifications in response to microbial colonization. Non-mucosal mononuclear phagocytes (macrophages and dendritic cells) require microbial signals to epigenetically and transcriptionally activate genes involved in interferon (IFN) signaling and initiating normal T cell responses.61,62 Specifically, GF or antibiotic-treated mice have decreased H3K4me3 (activating) at genes involved in pro-inflammatory responses including type I IFNs and increased H3K27me3 (repressive) at metabolic pathways compared to microbiota-exposed cells. The microbiota further maintain this anti-inflammatory phenotype in macrophages through HDAC3-mediated histone deacetylation of the pro-inflammatory cytokine IL-12β.63 Similar changes in chromatin accessibility defined by differential H3K4me2 enrichment were shown at lineage-defining regulatory elements in innate lymphoid cells (ILCs) to favor an ILC3 phenotype over ILC1 or ILC2 in response to the microbiota.64 Ethionine was recently discovered as a novel microbiota-derived metabolite produced by the commensal bacterium Lactobacillus reuteri through a 2-carbon folate cycle.43 In agreement with previous reports that ethionine inhibits histone methylation,65 mass spectrometric analyses revealed that human monocytic THP-1 cells treated with ethionine preferentially incorporated ethyl groups into lysine residues of histone H3 (K9/K10/K26) instead of methyl groups. Moreover, ethionine-treated monocytes failed to activate NF-kB signaling or TNF-α expression in response to LPS treatment.43
Herbal and Natural Dietary Products: Upcoming Therapeutic Approach for Prevention and Treatment of Hepatocellular Carcinoma
Published in Nutrition and Cancer, 2021
Deepa S. Mandlik, Satish K. Mandlik
Ginger is a perennial plant and rhizome is the principal active part of it. In addition to being used as a condiment, ginger also has antioxidant, antiemetic, cell defence, and anticancer activity (69). The activity of ginger is attributed to its powerful active ingredients such as sesquiterpenoids, gingerols, shogaols, tannin, and anthocyanin (70). In a rat model, ginger has an enormous role in treating experimental cancer. The treatment of rats with ginger extract (50 mg/kg) daily, it lessened the α-fetoprotein (liver tumor marker) and growth factors levels (71). Ginger was observed to suppress cell proliferation in the HepG-2 cell line (72). 6-shogaol and 6-gingerol are the most common active constituents in ginger that displayed an anticancer activity against hepatoma cell line by triggering reactive oxygen species (ROS)-mediated caspase-dependent apoptosis and controls the matrix metalloproteinases (MMP)-9 and TIMP-1 expression (73). In-vitro experimentation of ginger extract on HepG2 cell lines at a concentration of 250 μg/ml has demonstrated important morphological improvements in HepG2 cell chromosomes. Administration of ginger extract in rats inhibits liver carcinogenesis by decreasing the levels of nuclear factor-қB (NF-қB) and TNF-α. Thus, ginger may act as an anti-inflammatory and anti-cancerous agent, which could be helpful in the treatment of liver cancer (74). In recent research, one month of ginger oil treatment reported hepato-protection by rising antioxidant enzymes superoxide dismutase, glutathione S-transferases and glutathione in the liver tissue of mice (75). Human HCC work has indicated that 6-shogaol induces apoptosis by controlling the unfolded protein response sensor protein kinase RNA-like endoplasmic reticulum kinase and eIF2α target via the signaling pathway of endoplasmic reticulum stress (76). It was found that 6-gingerol persuaded apoptosis of human HepG2 cells via the lysosomal-mitochondrial axis in which cathepsin D displayed a vital part in the apoptosis cycle. 6-Gingerol mediated release of cathepsin D from mitochondria preceding the production of reactive oxygen species and cytochrome c (77). By scavenging free radical formation and decreasing lipid peroxidation, ginger suppresses ethionine prompted hepatic carcinoma in a rodent model (78). The invasion and metastasis of hepatocellular carcinoma were efficiently prevented by 6-gingerol and 6-shogaol by inhibiting MMP-2/-9, uPA, MAPK, and PI3k/Akt pathways, along with down-regulating STAT3 and NF-қB activities (79).