Reduction of Cell Proliferation by Acute C2H6O Exposure (original) (raw)

Reduction of cell proliferation by acute alcohol (ethanol: C 2 H 6 O) exposure

Cancers, 2021

Endogenous acetaldehyde production from the metabolism of ingested alcohol exposes hematopoietic progenitor cells to increased genotoxic risk. To develop possible therapeutic strategies to prevent or reverse alcohol abuse effects, it would be critical to determine the temporal progression of acute ethanol toxicity on progenitor cell numbers and proliferative status. We followed the variation of the cell proliferation rate in bone marrow and spleen in response to acute ethanol intoxication in the MITO-Luc mouse, in which NF-Y-dependent cell proliferation can be assessed in vivo by non-invasive bioluminescent imaging. One week after ethanol administration, bioluminescent signals in bone marrow and spleen decreased below the level corresponding to physiological proliferation, and they progressively resumed to pre-treatment values in approximately 4 weeks. Boosting acetaldehyde catabolism by administration of an aldehyde dehydrogenase activity activator or administration of polyphenols with antioxidant activity partially restored bone marrow cells’ physiological proliferation. These results indicate that in this mouse model, bioluminescent alteration reﬂects the reduction of the physiological proliferation rate of bone marrow progenitor cells due to the toxic effect of aldehydes generated by alcohol oxidation. In summary, this study presents a novel view of the impact of acute alcohol intake on bone marrow cell proliferation in vivo.

Stem cells under the influence of alcohol: effects of ethanol consumption on stem/progenitor cells

Cellular and Molecular Life Sciences, 2019

Stem cells drive embryonic and fetal development. In several adult tissues, they retain the ability to self-renew and differentiate into a variety of specialized cells, thus contributing to tissue homeostasis and repair throughout life span. Alcohol consumption is associated with an increased risk for several diseases and conditions. Growing and developing tissues are particularly vulnerable to alcohol’s influence, suggesting that stem- and progenitor-cell function could be affected. Accordingly, recent studies have revealed the possible relevance of alcohol exposure in impairing stem-cell properties, consequently affecting organ development and injury response in different tissues. Here, we review the main studies describing the effects of alcohol on different types of progenitor/stem cells including neuronal, hepatic, intestinal and adventitial progenitor cells, bone-marrow-derived stromal cell, dental pulp, embryonic and hematopoietic stem cells, and tumor initiating cells. A better understanding of the nature of the cellular damage induced by chronic and episodic heavy (binge) drinking is critical for the improvement of current therapeutic strategies designed to treat patients suffering from alcohol-related disorders.

EFFECTS OF ETHANOL ON MOUSE EMBRYONIC STEM CELL DIFFERENTIATION Original Article

International Journal of Pharmacy and Pharmaceutical Sciences, 2015

Objective: Chronic alcohol consumption during gestation causes fetal malformations, termed fetal alcohol syndrome (FAS). We conducted the present study to clarify the mechanism underlying alcohol consumption-induced malformations. Methods: First, the effects of ethanol on the viability of cell lines, such as EB3 (undifferentiated mouse embryonic stem (ES) cells), 3T3-Swiss albino, Neuro-2a, NCTC Clone 1469, and UBE6T-15, were determined. Furthermore, ethanol-induced cell death patterns were analyzed by the annexin V-Cy3.18 (AnnCy3) immune fluorescent method. Second, the effects of ethanol on ES cell differentiation were assessed by the embryoid body (EB) model. The formation of an EB, accompanied by spontaneous pulsation derived from EB3 cells, was monitored. EB3 cells were cultured in hanging drops of media containing 0-5% ethanol for 8 days. We then analyzed the EB formation grade by counting the EBs accompanied by spontaneous pulsation in four categories and by monitoring the expression of differentiation marker genes: connexin43, GATA4, c-kit, α-SMA, and Oct-3/4. Results: EB3 cells were more sensitive to alcohol than the other four cell lines, and that ethanol-induced death of EB3 cells matched the apoptosis pattern. There were no obvious differences in the formation rates of EBs with pulsation among all ethanol-treated groups. However, c-kit gene expression was significantly decreased in the EBs treated with 3 and 5% ethanol, in comparison to the control EBs. Conclusion: Collectively, the present study suggested that ES cells are more sensitive to ethanol than differentiated cells, and that ethanol-induced down regulation of c-kit expression might be involved in alcohol-induced malformations.

Effects of Ethanol on Mouse Embryonic Stem Cell Differentiation

International Journal of Pharmacy and Pharmaceutical Sciences, 2015

Alcohol Disrupts Human Liver Stem/Progenitor Cell Proliferation and Differentiation

Journal of stem cell research & therapy, 2014

Excessive alcohol consumption injures the liver resulting in various liver diseases including liver cirrhosis. Advanced liver disease continues to be a major challenge to human health. Liver stem/progenitor cells (LSPCs) are tissue specific precursors with a distinct capacity of multi-lineage differentiation. These precursor cells may play an important role in the process of tissue injury repair and pathological transition of liver structures. At the present time, knowledge about the effect of alcohol on LSPC function during the development of alcoholic liver disease remains absent. This study was conducted to investigate changes in LSPC activity of proliferation and differentiation following alcohol exposure. The disruption of cell signaling mechanisms underlying alcohol-induced alteration of LSPC activities was also examined. Primary and immortalized human liver stem cells (HL1-1 cells and HL1-hT1 cells, respectively) were cultured in media optimized for cell proliferation and hep...

Ethanol-Induced Apoptosis and Oxidative Stress in Hepatocytes

Alcoholism-clinical and Experimental Research, 1996

This short review focuses on ethanol-induced oxidative stress and hepatocyte apoptosis. Apoptosis is increasingly recognized as a fundamental biological process that impacts on an early development, maturation, and acquisition of disease states of multicellular organisms. Although the occurrence of apoptosis has been identiied for many decades, relatively recent acceptance of this principle is evidenced by remarkable increases in special conferences and presentations on this topic as well as its rapidly expanding volume of scientific literature. Oxidative stress is well recognized to be a key step in the pathogenesis of ethanol-associated liver injury. Ethanol administration induces an increase in lipid peroxidation either by enhancing the production of oxygen reactive species and/or by decreasing the level of endogenous antioxidants. Studies in our laboratory using a confocal laser scanning microscopic system strongly suggest that agents which inhibit ethanol-induced oxidative stress effectively attenuate hepatocyte death, i.e., apoptosis and necrosis. In addition, our investigations demonstrated that inhibitors of intracellular antioxidants exaggerate ethanol-associated hepatocyte apoptosis. Although the detailed mechanism still remains unknown, it is conceivable that an oxidant-dependent mechanism is largely involved in the process for ethanol-induced hepatocyte apoptosis.

Modulation of liver-specific cellular response to ethanol in vitro in hep G2 cells

Toxicology in vitro : an international journal published in association with BIBRA, 1998

The aim of this study was to investigate in vitro in a human hepatoblastoma cell line, Hep G2, the effect of ethanol (EtOH) toxicity. The ultrastructural changes were assessed by performing quantitative light and transmission electron microscopy. The second objective of this study was to define further EtOH-induced biochemical changes associated with mitochondrial function. In comparison with controls, after exposure to 80 mm EtOH cells showed: a threefold increase in length of mitochondria; proliferation, vesiculation and dilatation of smooth endoplasmic reticulum, and twofold increases in the size of lipid droplets and in their number/cell. Exposure of cells to two doses of EtOH augmented the ultrastructural alterations observed after a single dose. Cytoviability, assessed by metabolism of methylxanthine dye decreased significantly by (P < 0.0001) to 68% of the control after one dose and was further reduced after the second dose of EtOH (P < 0.001). Succinate dehydrogenase a...

Human embryonic stem cell model of ethanol-mediated early developmental toxicity

Experimental Neurology, 2012

Background: Fetal alcohol syndrome is an important clinical problem. Human embryonic stem cells (hESC) have not been widely used to study developmental alcohol toxicity. Here we document the phenotype of hESC exposed to clinically-relevant, low dose ethanol (20 mM). Methods: All cultures were maintained in 3% O 2 to reflect normal physiologic conditions. Undifferentiated hESC were expanded with basic fibroblast growth factor (bFGF), with or without ethanol, then differentiated without ethanol. Proliferation and apoptosis in response to ethanol were assayed, and PCR used to examine expression of GABA receptor subunits. Whole cell patch clamping was used to examine GABA A receptor function in undifferentiated hESC. Immunocytochemistry and western blotting were used to follow differentiation of early neurons, astrocytes, and oligodendrocytes, Principal findings: Exposure to 20 mM ethanol resulted in larger colonies of undifferentiated hESC despite an increase in apoptosis, because proliferation of the undifferentiated cells (and neuroblasts) was significantly increased. Differentiation of hESC (following a week of ethanol exposure) resulted in decreased expression of GFAP (by western) compared to unexposed cells, suggesting that astrocyte differentiation was reduced, while markers of oligodendrocyte and neuron differentiation were unchanged. At the message level, undifferentiated hESC express all GABA A receptor subunits, but functional receptors were not found by whole cell patch clamping. Conclusion: Our results in hESC suggest a complex mix of ethanol-induced phenotypic changes when ethanol exposure occurs very early in development. Not only increased apoptosis, but inappropriate proliferation and loss of trophic astrocytes could result from low-dose ethanol exposure very early in development. More generally, these studies support a role for hESC in developing hypotheses and focusing questions to complement animal studies of developmental toxicities.

Comparative study of the damage produced by acute ethanol and acetaldehyde treatment in a human fetal hepatic cell line

Toxicology, 1997

The effects of acute ethanol and acetaldehyde treatment on cell proliferation, cell adhesion capacity, neutral red incorporation into lysosomes, glutathione content, protein sulfhydryl compounds, lipid peroxidation, inner mitochondrial membrane integrity (MTT test), lactate dehydrogenase activity (LDH) and ultrastructural alterations were investigated in a human fetal hepatic cell line (WRL-68 cells). WRL-68 cells were used, due to the fact that, although this cell line expresses some hepatic characteristics, it does not express alcohol dehydrogenase or cytochrome P450 activity, so it could be a good model to study the effect of the toxic agents per se. Cells were exposed during 120 min with 200 mM ethanol or 10 mM acetaldehyde. Under these conditions, cells presented 100% viability and no morphological alteration was observed by light microscopy. Acetaldehyde-treated cells reduced their proliferative capacity drastically while the ethanol-treated ones presented no difference with control cells. Cell adhesion to substrate, measured as time required to adhere to the substrate and time required to detach from the substrate, was diminished in acetaldehyde WRL-68-treated cells. Cytotoxicity measures as neutral red and MTT test showed that acetaldehydetreated cells presented more damage than ethanol-treated ones. Cellular respiratory capacity was compromised by acetaldehyde treatment due to 40% less oxygen consumption than control cells. Lipid peroxidation values, measured as malondialdehyde production, were higher in ethanol-treated WRL-68 cells (127%) than in acetaldehyde-treated ones (60%) to control cell values. Lactate dehydrogenase activity (LDH) in extracellular media of ethanol-treated cells presented the highest values. GSH content was reduced 95% and thiol protein content was diminished severely in acetaldehyde-treated cells. Transmission electron microscopy showed more ultrastructural alterations in cells treated with acetaldehyde. The results indicate that acetaldehyde, like ethanol, produced damage at cellular level, although more damage could be observed in acetaldehyde WRL-68-treated cells. 0 1997 Elsevier Science Ireland Ltd.

Effects of long term ethanol consumption mediated oxidative stress on neovessel generation in liver

Toxicology Mechanisms and Methods, 2012

Angiogenesis, the growth of new blood vessels, is essential during tissue repair. Though most molecular mechanisms of angiogenesis are common to the liver and other organs, there was no report available whether alcoholic liver disease also causes angiogenesis. In this study, we examined the effects of long term ethanol (1.6 g/kg body weight/ day) consumption on angiogenic responses in the liver of male Wistar strain albino rats (16-18 weeks old, weighing 200-220 g) up to 36 weeks. Chronic ethanol consumption was associated with not only elevated oxidative stress, and altered cytokines expression, but also developed large von Willebrand factor, fibrosis and activation of matrix metalloproteinases. Moreover, vascular endothelial growth factor-receptor 2 (VEGF-R2, fetal liver kinase 1: Flk-1/KDR) expression and neovessel generation in the rat liver were noted after 36 weeks of ethanol consumption. Thus our study provides novel evidence that long-term ethanol consumption is associated with angiogenesis through delicate and coordinated action of a variety of mediators.

Reduction of Cell Proliferation by Acute C2H6O Exposure (original) (raw)

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