Topical Collection "Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment"

Editors

Collection Editor
Prof. Dr. Natalia Osna

Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
Website | E-Mail
Phone: 1-402-995-3735
Interests: hepatitis C, B and other viral hepatitis; alcoholic liver disease; innate immunity; antigen presentation; proteasome; autophagy; humanized mice (animal models for hepatitis study)
Collection Editor
Prof. Dr. Kusum Kharbanda

Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
Website | E-Mail
Phone: 402-995-3752
Interests: alcoholic liver disease; protein methylation; gut-liver axis in alcoholic liver disease; non-alcoholic steatohepatitis

Topical Collection Information

Dear Colleagues,

Alcohol consumption causes damage to various organs and systems. Liver is a primary target for the detrimental effects of alcohol since this substance of abuse is mainly metabolized by liver cells which express high levels of two major alcohol oxiding enzymes, alcohol dehydrogenase and CYP2E1. However, other organs, including brain, gut, pancreas, lungs, immune system are also affected by alcohol. Alcohol may also serve as a second hit for progression of viral infections, autoimmune diseases and cancer. Common mechanisms of alcohol-related organ injury include increases in oxidative stress, methylation impairments, posttranslational modifications of proteins, dysregulation of lipid metabolism and signal transduction pathways that ultimately affects cell survial and function. This Topical Collection will cover the pathobiology of alcohol-sensitive organ injury and the development of targeted treatment strategies.

We encourage you to share your data and thoughts in this broad field that clearly demonstrates how the harmful effects of alcohol contribute to disease initiation and progression in the liver, brain, gut, heart, lungs and other organs and tissues of the body.

Prof. Dr. Natalia Osna
Prof. Dr. Kusum Kharbanda
Collection Editors

Manuscript Submission Information

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Keywords

  • alcoholic liver disease (ALD)
  • steatohepatitis
  • fibrosis
  • cirhosis
  • parenhymal and non-parenhymal liver cells
  • brain
  • gut
  • lungs
  • immune responses
  • oxidative stress
  • methylation
  • viral infections
  • post-translational protein modifications
  • treatment of ALD

Published Papers (34 papers)

2017

Jump to: 2016, 2015

Open AccessReview Organ–Organ Crosstalk and Alcoholic Liver Disease
Biomolecules 2017, 7(3), 62; doi:10.3390/biom7030062
Received: 6 July 2017 / Revised: 10 August 2017 / Accepted: 11 August 2017 / Published: 16 August 2017
PDF Full-text (1721 KB) | HTML Full-text | XML Full-text
Abstract
Alcohol consumption is a common custom worldwide, and the toxic effects of alcohol on several target organs are well-understood. Given the poor prognosis of treating clinically-relevant alcoholic liver disease (ALD) (i.e., alcoholic hepatitis (AH) and cirrhosis), additional research is required to develop more
[...] Read more.
Alcohol consumption is a common custom worldwide, and the toxic effects of alcohol on several target organs are well-understood. Given the poor prognosis of treating clinically-relevant alcoholic liver disease (ALD) (i.e., alcoholic hepatitis (AH) and cirrhosis), additional research is required to develop more effective therapies. While the stages of ALD have been well-characterized, targeted therapies to prevent or reverse this process in humans are still needed. Better understanding of risk factors and mechanisms underlying disease progression can lead to the development of rational therapies to prevent or reverse ALD in the clinic. A potential area of targeted therapy for ALD may be organ–organ communication in the early stages of the disease. In contrast to AH and end-stage liver diseases, the involvement of multiple organs in the development of ALD is less understood. The impact of these changes on pathology to the liver and other organs may not only influence disease progression during the development of the disease, but also outcomes of end stages diseases. The purpose of this review is to summarize the established and proposed communication between the liver and other organ systems that may contribute to the development and progression of liver disease, as well as to other organs. Potential mechanisms of this organ–organ communication are also discussed. Full article
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Open AccessReview Alcohol and Cancer: Mechanisms and Therapies
Biomolecules 2017, 7(3), 61; doi:10.3390/biom7030061
Received: 10 July 2017 / Revised: 7 August 2017 / Accepted: 8 August 2017 / Published: 14 August 2017
PDF Full-text (792 KB) | HTML Full-text | XML Full-text
Abstract
Several scientific and clinical studies have shown an association between chronic alcohol consumption and the occurrence of cancer in humans. The mechanism for alcohol-induced carcinogenesis has not been fully understood, although plausible events include genotoxic effects of acetaldehyde, cytochrome P450 2E1 (CYP2E1)-mediated generation
[...] Read more.
Several scientific and clinical studies have shown an association between chronic alcohol consumption and the occurrence of cancer in humans. The mechanism for alcohol-induced carcinogenesis has not been fully understood, although plausible events include genotoxic effects of acetaldehyde, cytochrome P450 2E1 (CYP2E1)-mediated generation of reactive oxygen species, aberrant metabolism of folate and retinoids, increased estrogen, and genetic polymorphisms. Here, we summarize the impact of alcohol drinking on the risk of cancer development and potential underlying molecular mechanisms. The interactions between alcohol abuse, anti-tumor immune response, tumor growth, and metastasis are complex. However, multiple studies have linked the immunosuppressive effects of alcohol with tumor progression and metastasis. The influence of alcohol on the host immune system and the development of possible effective immunotherapy for cancer in alcoholics are also discussed here. The conclusive biological effects of alcohol on tumor progression and malignancy have not been investigated extensively using an animal model that mimics the human disease. This review provides insights into cancer pathogenesis in alcoholics, alcohol and immune interactions in different cancers, and scope and future of targeted immunotherapeutic modalities in patients with alcohol abuse. Full article
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Open AccessReview Alcohol, Adipose Tissue and Lipid Dysregulation
Biomolecules 2017, 7(1), 16; doi:10.3390/biom7010016
Received: 19 December 2016 / Accepted: 10 February 2017 / Published: 16 February 2017
Cited by 2 | PDF Full-text (987 KB) | HTML Full-text | XML Full-text
Abstract
Chronic alcohol consumption perturbs lipid metabolism as it increases adipose tissue lipolysis and leads to ectopic fat deposition within the liver and the development of alcoholic fatty liver disease. In addition to the recognition of the role of adipose tissue derived fatty acids
[...] Read more.
Chronic alcohol consumption perturbs lipid metabolism as it increases adipose tissue lipolysis and leads to ectopic fat deposition within the liver and the development of alcoholic fatty liver disease. In addition to the recognition of the role of adipose tissue derived fatty acids in liver steatosis, alcohol also impacts other functions of adipose tissue and lipid metabolism. Lipid balance in response to long‐term alcohol intake favors adipose tissue loss and fatty acid efflux as lipolysis is upregulated and lipogenesis is either slightly decreased or unchanged. Study of the lipolytic and lipogenic pathways has identified several regulatory proteins modulated by alcohol that contribute to these effects. Glucose tolerance of adipose tissue is also impaired by chronic alcohol due to decreased glucose transporter‐4 availability at the membrane. As an endocrine organ, white adipose tissue (WAT) releases several adipokines that are negatively modulated following chronic alcohol consumption including adiponectin, leptin, and resistin. When these effects are combined with the enhanced expression of inflammatory mediators that are induced by chronic alcohol, a proinflammatory state develops within WAT, contributing to the observed lipodystrophy. Lastly, while chronic alcohol intake may enhance thermogenesis of brown adipose tissue (BAT), definitive mechanistic evidence is currently lacking. Overall, both WAT and BAT depots are impacted by chronic alcohol intake and the resulting lipodystrophy contributes to fat accumulation in peripheral organs, thereby enhancing the pathological state accompanying chronic alcohol use disorder. Full article
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Open AccessReview Role of Protein Quality Control Failure in Alcoholic Hepatitis Pathogenesis
Biomolecules 2017, 7(1), 11; doi:10.3390/biom7010011
Received: 7 November 2016 / Revised: 26 January 2017 / Accepted: 30 January 2017 / Published: 8 February 2017
PDF Full-text (7456 KB) | HTML Full-text | XML Full-text
Abstract
The mechanisms of protein quality control in hepatocytes in cases of alcoholic hepatitis (AH) including ufmylation, FAT10ylation, metacaspase 1 (Mca1), ERAD (endoplasmic reticulum-associated degradation), JUNQ (juxta nuclear quality control), IPOD (insoluble protein deposit) autophagocytosis, and ER stress are reviewed. The Mallory–Denk body (MDB)
[...] Read more.
The mechanisms of protein quality control in hepatocytes in cases of alcoholic hepatitis (AH) including ufmylation, FAT10ylation, metacaspase 1 (Mca1), ERAD (endoplasmic reticulum-associated degradation), JUNQ (juxta nuclear quality control), IPOD (insoluble protein deposit) autophagocytosis, and ER stress are reviewed. The Mallory–Denk body (MDB) formation develops in the hepatocytes in alcoholic hepatitis as a consequence of the failure of these protein quality control mechanisms to remove misfolded and damaged proteins and to prevent MDB aggresome formation within the cytoplasm of hepatocytes. The proteins involved in the quality control pathways are identified, quantitated, and visualized by immunofluorescent antibody staining of liver biopsies from patients with AH. Quantification of the proteins are achieved by measuring the fluorescent intensity using a morphometric system. Ufmylation and FAT10ylation pathways were downregulated, Mca1 pathways were upregulated, autophagocytosis was upregulated, and ER stress PERK (protein kinase RNA-like endoplasmic reticulum kinase) and CHOP (CCAAT/enhancer-binding protein homologous protein) mechanisms were upregulated. In conclusion: Despite the upregulation of several pathways of protein quality control, aggresomes (MDBs) still formed in the hepatocytes in AH. The pathogenesis of AH is due to the failure of protein quality control, which causes balloon-cell change with MDB formation and ER stress. Full article
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Open AccessReview Key Events Participating in the Pathogenesis of Alcoholic Liver Disease
Biomolecules 2017, 7(1), 9; doi:10.3390/biom7010009
Received: 21 December 2016 / Accepted: 20 January 2017 / Published: 27 January 2017
PDF Full-text (1376 KB) | HTML Full-text | XML Full-text
Abstract
Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. It ranges from fatty liver to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma.The most prevalent forms of ALD are alcoholic fatty liver, alcoholic hepatitis (AH) and alcoholic cirrhosis, which frequently progress
[...] Read more.
Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. It ranges from fatty liver to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma.The most prevalent forms of ALD are alcoholic fatty liver, alcoholic hepatitis (AH) and alcoholic cirrhosis, which frequently progress as people continue drinking. ALD refers to a number of symptoms/deficits that contribute to liver injury. These include steatosis, inflammation, fibrosis and cirrhosis, which, when taken together, sequentially or simultaneously lead to significant disease progression. The pathogenesis of ALD, influenced by host and environmental factors, is currentlyonly partially understood. To date, lipopolysaccharide (LPS) translocation from the gut to the portal blood, aging, gender, increased infiltration and activation of neutrophils and bone marrow-derived macrophages along with alcohol plus iron metabolism, with its associated increase in reactive oxygen species (ROS), are all key events contributing to the pathogenesis of ALD. This review aimsto introduce the reader to the concept of alcohol‐mediated liver damage and the mechanisms driving injury. Full article
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2016

Jump to: 2017, 2015

Open AccessArticle Chronic Binge Alcohol Administration Dysregulates Hippocampal Genes Involved in Immunity and Neurogenesis in Simian Immunodeficiency Virus-Infected Macaques
Biomolecules 2016, 6(4), 43; doi:10.3390/biom6040043
Received: 15 September 2016 / Revised: 23 October 2016 / Accepted: 28 October 2016 / Published: 9 November 2016
PDF Full-text (2538 KB) | HTML Full-text | XML Full-text
Abstract
Alcohol use disorders (AUD) exacerbate neurocognitive dysfunction in Human Immunodeficiency Virus (HIV+) patients. We have shown that chronic binge alcohol (CBA) administration (13–14 g EtOH/kg/wk) prior to and during simian immunodeficiency virus (SIV) infection in rhesus macaques unmasks learning deficits in operant learning
[...] Read more.
Alcohol use disorders (AUD) exacerbate neurocognitive dysfunction in Human Immunodeficiency Virus (HIV+) patients. We have shown that chronic binge alcohol (CBA) administration (13–14 g EtOH/kg/wk) prior to and during simian immunodeficiency virus (SIV) infection in rhesus macaques unmasks learning deficits in operant learning and memory tasks. The underlying mechanisms of neurocognitive alterations due to alcohol and SIV are not known. This exploratory study examined the CBA-induced differential expression of hippocampal genes in SIV-infected (CBA/SIV+; n = 2) macaques in contrast to those of sucrose administered, SIV-infected (SUC/SIV+; n = 2) macaques. Transcriptomes of hippocampal samples dissected from brains obtained at necropsy (16 months post-SIV inoculation) were analyzed to determine differentially expressed genes. MetaCore from Thomson Reuters revealed enrichment of genes involved in inflammation, immune responses, and neurodevelopment. Functional relevance of these alterations was examined in vitro by exposing murine neural progenitor cells (NPCs) to ethanol (EtOH) and HIV trans-activator of transcription (Tat) protein. EtOH impaired NPC differentiation as indicated by decreased βIII tubulin expression. These findings suggest a role for neuroinflammation and neurogenesis in CBA/SIV neuropathogenesis and warrant further investigation of their potential contribution to CBA-mediated neurobehavioral deficits. Full article
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Open AccessReview Role of Transcription Factors in Steatohepatitis and Hypertension after Ethanol: The Epicenter of Metabolism
Biomolecules 2016, 6(3), 29; doi:10.3390/biom6030029
Received: 31 August 2015 / Revised: 25 May 2016 / Accepted: 8 June 2016 / Published: 24 June 2016
Cited by 4 | PDF Full-text (564 KB) | HTML Full-text | XML Full-text
Abstract
Chronic alcohol consumption induces multi-organ damage, including alcoholic liver disease (ALD), pancreatitis and hypertension. Ethanol and ethanol metabolic products play a significant role in the manifestation of its toxicity. Ethanol metabolizes to acetaldehyde and produces reduced nicotinamide adenine dinucleotide (NADH) by cytosolic alcohol
[...] Read more.
Chronic alcohol consumption induces multi-organ damage, including alcoholic liver disease (ALD), pancreatitis and hypertension. Ethanol and ethanol metabolic products play a significant role in the manifestation of its toxicity. Ethanol metabolizes to acetaldehyde and produces reduced nicotinamide adenine dinucleotide (NADH) by cytosolic alcohol dehydrogenase. Ethanol metabolism mediated by cytochrome-P450 2E1 causes oxidative stress due to increased production of reactive oxygen species (ROS). Acetaldehyde, increased redox cellular state and ROS activate transcription factors, which in turn activate genes for lipid biosynthesis and offer protection of hepatocytes from alcohol toxicity. Sterol regulatory element binding proteins (SREBPs) and peroxisome proliferator activated-receptors (PPARs) are two key lipogenic transcription factors implicated in the development of fatty liver in alcoholic and non-alcoholic steatohepatitis. SREBP-1 is activated in the livers of chronic ethanol abusers. An increase in ROS activates nuclear factor erythroid-2-related factor-2 (Nrf2) and hypoxia inducible factor (HIF) to provide protection to hepatocytes from ethanol toxicity. Under ethanol exposure, due to increased gut permeability, there is release of gram-negative bacteria-derived lipopolysaccharide (LPS) from intestine causing activation of immune response. In addition, the metabolic product, acetaldehyde, modifies the proteins in hepatocyte, which become antigens inviting auto-immune response. LPS activates macrophages, especially the liver resident macrophages, Kupffer cells. These Kupffer cells and circulating macrophages secrete various cytokines. The level of tumor necrosis factor-α (TNFα), interleukin-1beta (IL-1β), IL-6, IL-8 and IL-12 have been found elevated among chronic alcoholics. In addition to elevation of these cytokines, the peripheral iron (Fe2+) is also mobilized. An increased level of hepatic iron has been observed among alcoholics. Increased ROS, IL-1β, acetaldehyde, and increased hepatic iron, all activate nuclear factor-kappa B (NF-κB) transcription factor. Resolution of increased reactive oxygen species requires increased expression of genes responsible for dismutation of increased ROS which is partially achieved by IL-6 mediated activation of signal transducers and activators of transcription 3 (STAT3). In addition to these transcription factors, activator protein-1 may also be activated in hepatocytes due to its association with resolution of increased ROS. These transcription factors are central to alcohol-mediated hepatotoxicity. Full article
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Open AccessEditorial Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment
Biomolecules 2016, 6(2), 20; doi:10.3390/biom6020020
Received: 31 March 2016 / Accepted: 1 April 2016 / Published: 15 April 2016
Cited by 2 | PDF Full-text (161 KB) | HTML Full-text | XML Full-text
Abstract
Alcohol consumption causes damage to various organs and systems.[...] Full article
Open AccessArticle The Involvement of Acetaldehyde in Ethanol-Induced Cell Cycle Impairment
Biomolecules 2016, 6(2), 17; doi:10.3390/biom6020017
Received: 9 March 2016 / Revised: 9 March 2016 / Accepted: 24 March 2016 / Published: 31 March 2016
Cited by 1 | PDF Full-text (2217 KB) | HTML Full-text | XML Full-text
Abstract
Background: Hepatocytes metabolize the vast majority of ingested ethanol. This metabolic activity results in hepatic toxicity and impairs the ability of hepatocytes to replicate. Previous work by our group has shown that ethanol metabolism results in a G2/M cell cycle arrest. The intent
[...] Read more.
Background: Hepatocytes metabolize the vast majority of ingested ethanol. This metabolic activity results in hepatic toxicity and impairs the ability of hepatocytes to replicate. Previous work by our group has shown that ethanol metabolism results in a G2/M cell cycle arrest. The intent of these studies was to discern the roles of acetaldehyde and reactive oxygen, two of the major by-products of ethanol metabolism, in the G2/M cell cycle arrest. Methods: To investigate the role of ethanol metabolites in the cell cycle arrest, VA-13 and VL-17A cells were used. These are recombinant Hep G2 cells that express alcohol dehydrogenase or alcohol dehydrogenase and cytochrome P450 2E1, respectively. Cells were cultured with or without ethanol, lacking or containing the antioxidants N-acetylcysteine (NAC) or trolox, for three days. Cellular accumulation was monitored by the DNA content of the cultures. The accumulation of the cyclin-dependent kinase, Cdc2 in the inactive phosphorylated form (p-Cdc2) and the cyclin-dependent kinase inhibitor p21 were determined by immunoblot analysis. Results: Cultures maintained in the presence of ethanol demonstrated a G2/M cell cycle arrest that was associated with a reduction in DNA content and increased levels of p-Cdc2 and p21, compared with cells cultured in its absence. Inclusion of antioxidants in the ethanol containing media was unable to rescue the cells from the cell cycle arrest or these ethanol metabolism-mediated effects. Additionally, culturing the cells in the presence of acetaldehyde alone resulted in increased levels of p-Cdc2 and p21. Conclusions: Acetaldehyde produced during ethanol oxidation has a major role in the ethanol metabolism-mediated G2/M cell cycle arrest, and the concurrent accumulation of p21 and p-Cdc2. Although reactive oxygen species are thought to have a significant role in ethanol-induced hepatocellular damage, they may have a less important role in the inability of hepatocytes to replace dead or damaged cells. Full article
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Open AccessReview Multidisciplinary View of Alcohol Use Disorder: From a Psychiatric Illness to a Major Liver Disease
Biomolecules 2016, 6(1), 11; doi:10.3390/biom6010011
Received: 31 July 2015 / Revised: 16 December 2015 / Accepted: 27 December 2015 / Published: 15 January 2016
Cited by 3 | PDF Full-text (207 KB) | HTML Full-text | XML Full-text
Abstract
Alcohol use disorder is a significant health problem being a cause of increased morbidity and mortality worldwide. Alcohol-related illness has a relevant economic impact on the society and a negative influence on the life of patients and their family members. Psychosocial support might
[...] Read more.
Alcohol use disorder is a significant health problem being a cause of increased morbidity and mortality worldwide. Alcohol-related illness has a relevant economic impact on the society and a negative influence on the life of patients and their family members. Psychosocial support might be useful in the management of people affected by alcohol use disorder since psychiatric and pharmaceutical approaches show some limits. In fact, many drugs are accessible for the treatment of alcohol disorder, but only Baclofen is functional as an anti-craving drug in patients with advanced liver disease. The alcohol-related liver damage represents the most frequent cause of advanced liver disease in Europe, and it is the main cause of death among adults with high alcohol consumption. The multidisciplinary action of clinical-psychologists, psychiatrics and hepatologists, is essential in the management of patients with alcohol liver disease especially in the case of liver transplantation. In general, the multidisciplinary approach is necessary in prevention, in framing patients and in the treatment. More resources should be used in prevention and research with the main aim of decreasing the harmful alcohol consumption. Full article
Open AccessReview Alcoholic Liver Disease: Update on the Role of Dietary Fat
Biomolecules 2016, 6(1), 1; doi:10.3390/biom6010001
Received: 31 August 2015 / Revised: 23 November 2015 / Accepted: 7 December 2015 / Published: 6 January 2016
Cited by 12 | PDF Full-text (815 KB) | HTML Full-text | XML Full-text
Abstract
Alcoholic liver disease (ALD) spans a spectrum of liver pathology, including fatty liver, alcoholic steatohepatitis, and cirrhosis. Accumulating evidence suggests that dietary factors, including dietary fat, as well as alcohol, play critical roles in the pathogenesis of ALD. The protective effects of dietary
[...] Read more.
Alcoholic liver disease (ALD) spans a spectrum of liver pathology, including fatty liver, alcoholic steatohepatitis, and cirrhosis. Accumulating evidence suggests that dietary factors, including dietary fat, as well as alcohol, play critical roles in the pathogenesis of ALD. The protective effects of dietary saturated fat (SF) and deleterious effects of dietary unsaturated fat (USF) on alcohol-induced liver pathology are well recognized and documented in experimental animal models of ALD. Moreover, it has been demonstrated in an epidemiological study of alcoholic cirrhosis that dietary intake of SF was associated with a lower mortality rates, whereas dietary intake of USF was associated with a higher mortality. In addition, oxidized lipids (dietary and in vivo generated) may play a role in liver pathology. The understanding of how dietary fat contributes to the ALD pathogenesis will enhance our knowledge regarding the molecular mechanisms of ALD development and progression, and may result in the development of novel diet-based therapeutic strategies for ALD management. This review explores the relevant scientific literature and provides a current understanding of recent advances regarding the role of dietary lipids in ALD pathogenesis. Full article
Open AccessReview Guardian of Genetic Messenger-RNA-Binding Proteins
Biomolecules 2016, 6(1), 4; doi:10.3390/biom6010004
Received: 2 September 2015 / Revised: 2 December 2015 / Accepted: 4 December 2015 / Published: 6 January 2016
Cited by 2 | PDF Full-text (1036 KB) | HTML Full-text | XML Full-text
Abstract
RNA in cells is always associated with RNA-binding proteins that regulate all aspects of RNA metabolism including RNA splicing, export from the nucleus, RNA localization, mRNA turn-over as well as translation. Given their diverse functions, cells express a variety of RNA-binding proteins, which
[...] Read more.
RNA in cells is always associated with RNA-binding proteins that regulate all aspects of RNA metabolism including RNA splicing, export from the nucleus, RNA localization, mRNA turn-over as well as translation. Given their diverse functions, cells express a variety of RNA-binding proteins, which play important roles in the pathologies of a number of diseases. In this review we focus on the effect of alcohol on different RNA-binding proteins and their possible contribution to alcohol-related disorders, and discuss the role of these proteins in the development of neurological diseases and cancer. We further discuss the conventional methods and newer techniques that are employed to identify RNA-binding proteins. Full article
Open AccessArticle Moderate (2%, v/v) Ethanol Feeding Alters Hepatic Wound Healing after Acute Carbon Tetrachloride Exposure in Mice
Biomolecules 2016, 6(1), 5; doi:10.3390/biom6010005
Received: 4 September 2015 / Revised: 26 November 2015 / Accepted: 9 December 2015 / Published: 6 January 2016
Cited by 2 | PDF Full-text (9775 KB) | HTML Full-text | XML Full-text
Abstract
Wound healing consists of three overlapping phases: inflammation, proliferation, and matrix synthesis and remodeling. Prolonged alcohol abuse can cause liver fibrosis due to deregulated matrix remodeling. Previous studies demonstrated that moderate ethanol feeding enhances liver fibrogenic markers and frank fibrosis independent of differences
[...] Read more.
Wound healing consists of three overlapping phases: inflammation, proliferation, and matrix synthesis and remodeling. Prolonged alcohol abuse can cause liver fibrosis due to deregulated matrix remodeling. Previous studies demonstrated that moderate ethanol feeding enhances liver fibrogenic markers and frank fibrosis independent of differences in CCl4-induced liver injury. Our objective was to determine whether or not other phases of the hepatic wound healing response were affected by moderate ethanol after CCl4 exposure. Mice were fed moderate ethanol (2% v/v) for two days and then were exposed to CCl4 and euthanized 24–96 h later. Liver injury was not different between pair- and ethanol-fed mice; however, removal of necrotic tissue was delayed after CCl4-induced liver injury in ethanol-fed mice. Inflammation, measured by TNFα mRNA and protein and hepatic Ly6c transcript accumulation, was reduced and associated with enhanced hepatocyte apoptosis after ethanol feeding. Hepatocytes entered the cell cycle equivalently in pair- and ethanol-fed mice after CCl4 exposure, but hepatocyte proliferation was prolonged in livers from ethanol-fed mice. CCl4-induced hepatic stellate cell activation was increased and matrix remodeling was prolonged in ethanol-fed mice compared to controls. Taken together, moderate ethanol affected each phase of the wound healing response to CCl4. These data highlight previously unknown effects of moderate ethanol exposure on hepatic wound healing after acute hepatotoxicant exposure. Full article

2015

Jump to: 2017, 2016

Open AccessArticle In Vivo Acute on Chronic Ethanol Effects in Liver: A Mouse Model Exhibiting Exacerbated Injury, Altered Metabolic and Epigenetic Responses
Biomolecules 2015, 5(4), 3280-3294; doi:10.3390/biom5043280
Received: 13 August 2015 / Accepted: 17 November 2015 / Published: 20 November 2015
Cited by 6 | PDF Full-text (2491 KB) | HTML Full-text | XML Full-text
Abstract
Chronic alcoholics who also binge drink (i.e., acute on chronic) are prone to an exacerbated liver injury but its mechanism is not understood. We therefore investigated the in vivo effects of chronic and binge ethanol ingestion and compared to chronic ethanol
[...] Read more.
Chronic alcoholics who also binge drink (i.e., acute on chronic) are prone to an exacerbated liver injury but its mechanism is not understood. We therefore investigated the in vivo effects of chronic and binge ethanol ingestion and compared to chronic ethanol followed by three repeat binge ethanol on the liver of male C57/BL6 mice fed ethanol in liquid diet (4%) for four weeks followed by binge ethanol (intragastric administration, 3.5 g/kg body weight, three doses, 12h apart). Chronic followed by binge ethanol exacerbated fat accumulation, necrosis, decrease in hepatic SAM and SAM:SAH ratio, increase in adenosine levels, and elevated CYP2E1 levels. Histone H3 lysine acetylation (H3AcK9), dually modified phosphoacetylated histone H3 (H3AcK9/PS10), and phosphorylated H2AX increased after binge whereas phosphorylation of histone H3 ser 10 (H3S10) and H3 ser 28 (H3S28) increased after chronic ethanol-binge. Histone H3 lysine 4 and 9 dimethylation increased with a marked dimethylation in H3K9 in chronic ethanol binge group. Trimethylated histone H3 levels did not change. Nuclear levels of histone acetyl transferase GCN5 and histone deacetylase HDAC3 were elevated whereas phospho-CREB decreased in a distinctive manner. Taken together, acute on chronic ethanol ingestion caused amplification of liver injury and elicited characteristic profiles of histone modifications, metabolic alterations, and changes in nuclear protein levels. These findings demonstrate that chronic ethanol exposure renders liver more susceptible to repeat acute/binge ethanol induced acceleration of alcoholic liver disease. Full article
Open AccessArticle High Intrinsic Aerobic Capacity Protects against Ethanol-Induced Hepatic Injury and Metabolic Dysfunction: Study Using High Capacity Runner Rat Model
Biomolecules 2015, 5(4), 3295-3308; doi:10.3390/biom5043295
Received: 6 September 2015 / Accepted: 10 November 2015 / Published: 20 November 2015
Cited by 3 | PDF Full-text (409 KB) | HTML Full-text | XML Full-text
Abstract
Rats artificially selected over several generations for high intrinsic endurance/aerobic capacity resulting in high capacity runners (HCR) has been developed to study the links between high aerobic fitness and protection from metabolic diseases (Wisloff et al., Science, 2005). We have previously shown that
[...] Read more.
Rats artificially selected over several generations for high intrinsic endurance/aerobic capacity resulting in high capacity runners (HCR) has been developed to study the links between high aerobic fitness and protection from metabolic diseases (Wisloff et al., Science, 2005). We have previously shown that the HCR strain have elevated hepatic mitochondrial content and oxidative capacity. In this study, we tested if the elevated hepatic mitochondrial content in the HCR rat would provide “metabolic protection” from chronic ethanol-induced hepatic steatosis and injury. The Leiber-Decarli liquid diet with ethanol (7% v/v; HCR-E) and without (HCR-C) was given to HCR rats (n = 8 per group) from 14 to 20 weeks of age that were weight matched and pair-fed to assure isocaloric intake. Hepatic triglyceride (TG) content and macro- and microvesicular steatosis were significantly greater in HCR-E compared with HCR-C (p < 0.05). In addition, hepatic superoxide dismutase activity and glutathione levels were significantly (p < 0.05) reduced in the HCR-E rats. This hepatic phenotype also was associated with reduced total hepatic fatty acid oxidation (p = 0.03) and ß-hydroxyacyl-CoA dehydrogenase activity (p = 0.01), and reductions in microsomal triglyceride transfer protein and apoB-100 protein content (p = 0.01) in HCR-E animals. However, despite these documented hepatic alterations, ethanol ingestion failed to induce significant hepatic liver injury, including no changes in hepatic inflammation, or serum alanine amino transferase (ALTs), free fatty acids (FFAs), triglycerides (TGs), insulin, or glucose. High intrinsic aerobic fitness did not reduce ethanol-induced hepatic steatosis, but protected against ethanol-induced hepatic injury and systemic metabolic dysfunction in a high aerobic capacity rat model. Full article
Open AccessReview Role of microRNAs in Alcohol-Induced Multi-Organ Injury
Biomolecules 2015, 5(4), 3309-3338; doi:10.3390/biom5043309
Received: 29 August 2015 / Accepted: 16 November 2015 / Published: 20 November 2015
Cited by 11 | PDF Full-text (301 KB) | HTML Full-text | XML Full-text
Abstract
Alcohol consumption and its abuse is a major health problem resulting in significant healthcare cost in the United States. Chronic alcoholism results in damage to most of the vital organs in the human body. Among the alcohol-induced injuries, alcoholic liver disease is one
[...] Read more.
Alcohol consumption and its abuse is a major health problem resulting in significant healthcare cost in the United States. Chronic alcoholism results in damage to most of the vital organs in the human body. Among the alcohol-induced injuries, alcoholic liver disease is one of the most prevalent in the United States. Remarkably, ethanol alters expression of a wide variety of microRNAs that can regulate alcohol-induced complications or dysfunctions. In this review, we will discuss the role of microRNAs in alcoholic pancreatitis, alcohol-induced liver damage, intestinal epithelial barrier dysfunction, and brain damage including altered hippocampus structure and function, and neuronal loss, alcoholic cardiomyopathy, and muscle damage. Further, we have reviewed the role of altered microRNAs in the circulation, teratogenic effects of alcohol, and during maternal or paternal alcohol consumption. Full article
Open AccessArticle Alcohol and Apoptosis: Friends or Foes?
Biomolecules 2015, 5(4), 3193-3203; doi:10.3390/biom5043193
Received: 22 September 2015 / Revised: 4 November 2015 / Accepted: 9 November 2015 / Published: 19 November 2015
Cited by 8 | PDF Full-text (1068 KB) | HTML Full-text | XML Full-text
Abstract
Alcohol abuse causes 79,000 deaths stemming from severe organ damage in the United States every year. Clinical manifestations of long-term alcohol abuse on the cardiac muscle include defective contractility with the development of dilated cardiomyopathy and low-output heart failure; which has poor prognosis
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Alcohol abuse causes 79,000 deaths stemming from severe organ damage in the United States every year. Clinical manifestations of long-term alcohol abuse on the cardiac muscle include defective contractility with the development of dilated cardiomyopathy and low-output heart failure; which has poor prognosis with less than 25% survival for more than three years. In contrast, low alcohol consumption has been associated with reduced risk of cardiovascular disease, however the mechanism of this phenomenon remains elusive. The aim of this study was to determine the significance of apoptosis as a mediating factor in cardiac function following chronic high alcohol versus low alcohol exposure. Adult rats were provided 5 mM (low alcohol), 100 mM (high alcohol) or pair-fed non-alcohol controls for 4–5 months. The hearts were dissected, sectioned and stained with cresyl violet or immunohistochemically for caspase-3, a putative marker for apoptosis. Cardiomyocytes were isolated to determine the effects of alcohol exposure on cell contraction and relaxation. High alcohol animals displayed a marked thinning of the left ventricular wall combined with elevated caspase-3 activity and decreased contractility. In contrast, low alcohol was associated with increased contractility and decreased apoptosis suggesting an overall protective mechanism induced by low levels of alcohol exposure. Full article
Open AccessArticle Skin Immunization Obviates Alcohol-Related Immune Dysfunction
Biomolecules 2015, 5(4), 3009-3028; doi:10.3390/biom5043009
Received: 9 July 2015 / Revised: 21 September 2015 / Accepted: 30 September 2015 / Published: 6 November 2015
Cited by 1 | PDF Full-text (1841 KB) | HTML Full-text | XML Full-text
Abstract
Alcoholics suffer from immune dysfunction that can impede vaccine efficacy. If ethanol (EtOH)-induced immune impairment is in part a result of direct exposure of immune cells to EtOH, then reduced levels of exposure could result in less immune dysfunction. As alcohol ingestion results
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Alcoholics suffer from immune dysfunction that can impede vaccine efficacy. If ethanol (EtOH)-induced immune impairment is in part a result of direct exposure of immune cells to EtOH, then reduced levels of exposure could result in less immune dysfunction. As alcohol ingestion results in lower alcohol levels in skin than blood, we hypothesized that the skin immune network may be relatively preserved, enabling skin-targeted immunizations to obviate the immune inhibitory effects of alcohol consumption on conventional vaccines. We employed the two most common chronic EtOH mouse feeding models, the liver-damaging Lieber-DeCarli (LD) and liver-sparing Meadows-Cook (MC) diets, to examine the roles of EtOH and/or EtOH-induced liver dysfunction on alcohol related immunosuppression. Pair-fed mice were immunized against the model antigen ovalbumin (OVA) by DNA immunization or against flu by administering the protein-based influenza vaccine either systemically (IV, IM), directly to liver (hydrodynamic), or cutaneously (biolistic, ID). We measured resulting tissue EtOH levels, liver stress, regulatory T cell (Treg), and myeloid-derived suppressor cell (MDSC) populations. We compared immune responsiveness by measuring delayed-type hypersensitivity (DTH), antigen-specific cytotoxic T lymphocyte (CTL), and antibody induction as a function of delivery route and feeding model. We found that, as expected, and independent of the feeding model, EtOH ingestion inhibits DTH, CTL lysis, and antigen-specific total IgG induced by traditional systemic vaccines. On the other hand, skin-targeted vaccines were equally immunogenic in alcohol-exposed and non-exposed subjects, suggesting that cutaneous immunization may result in more efficacious vaccination in alcohol-ingesting subjects. Full article
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Open AccessReview Alcohol, Aldehydes, Adducts and Airways
Biomolecules 2015, 5(4), 2987-3008; doi:10.3390/biom5042987
Received: 29 July 2015 / Revised: 13 October 2015 / Accepted: 16 October 2015 / Published: 5 November 2015
Cited by 7 | PDF Full-text (775 KB) | HTML Full-text | XML Full-text
Abstract
Drinking alcohol and smoking cigarettes results in the formation of reactive aldehydes in the lung, which are capable of forming adducts with several proteins and DNA. Acetaldehyde and malondialdehyde are the major aldehydes generated in high levels in the lung of subjects with
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Drinking alcohol and smoking cigarettes results in the formation of reactive aldehydes in the lung, which are capable of forming adducts with several proteins and DNA. Acetaldehyde and malondialdehyde are the major aldehydes generated in high levels in the lung of subjects with alcohol use disorder who smoke cigarettes. In addition to the above aldehydes, several other aldehydes like 4-hydroxynonenal, formaldehyde and acrolein are also detected in the lung due to exposure to toxic gases, vapors and chemicals. These aldehydes react with nucleophilic targets in cells such as DNA, lipids and proteins to form both stable and unstable adducts. This adduction may disturb cellular functions as well as damage proteins, nucleic acids and lipids. Among several adducts formed in the lung, malondialdehyde DNA (MDA-DNA) adduct and hybrid malondialdehyde-acetaldehyde (MAA) protein adducts have been shown to initiate several pathological conditions in the lung. MDA-DNA adducts are pre-mutagenic in mammalian cells and induce frame shift and base-pair substitution mutations, whereas MAA protein adducts have been shown to induce inflammation and inhibit wound healing. This review provides an insight into different reactive aldehyde adducts and their role in the pathogenesis of lung disease. Full article
Open AccessReview Update on Alcoholic Hepatitis
Biomolecules 2015, 5(4), 2978-2986; doi:10.3390/biom5042978
Received: 6 September 2015 / Revised: 26 October 2015 / Accepted: 29 October 2015 / Published: 2 November 2015
Cited by 4 | PDF Full-text (78 KB) | HTML Full-text | XML Full-text
Abstract
Alcoholic liver disease is one of the most prevalent liver diseases worldwide, and a major cause of morbidity and mortality. Alcoholic hepatitis is a severe form of liver injury in patients with alcohol abuse, can present as an acute on chronic liver failure
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Alcoholic liver disease is one of the most prevalent liver diseases worldwide, and a major cause of morbidity and mortality. Alcoholic hepatitis is a severe form of liver injury in patients with alcohol abuse, can present as an acute on chronic liver failure associated with a rapid decline in liver synthetic function, and consequent increase in mortality. Despite therapy, about 30%–50% of patients with severe alcoholic hepatitis eventually die. The pathogenic pathways that lead to the development of alcoholic hepatitis are complex and involve oxidative stress, gut dysbiosis, and dysregulation of the innate and adaptive immune system with injury to the parenchymal cells and activation of hepatic stellate cells. As accepted treatment approaches are currently limited, a better understanding of the pathophysiology would be required to generate new approaches that improve outcomes. This review focuses on recent advances in the diagnosis, pathogenesis of alcoholic hepatitis and novel treatment strategies. Full article
Open AccessReview Chronic Ethanol Exposure: Pathogenesis of Pulmonary Disease and Dysfunction
Biomolecules 2015, 5(4), 2840-2853; doi:10.3390/biom5042840
Received: 30 July 2015 / Revised: 4 September 2015 / Accepted: 28 September 2015 / Published: 20 October 2015
Cited by 5 | PDF Full-text (95 KB) | HTML Full-text | XML Full-text
Abstract
Ethanol (EtOH) is the world’s most commonly used drug, and has been widely recognized as a risk factor for developing lung disorders. Chronic EtOH exposure affects all of the organ systems in the body and increases the risk of developing pulmonary diseases such
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Ethanol (EtOH) is the world’s most commonly used drug, and has been widely recognized as a risk factor for developing lung disorders. Chronic EtOH exposure affects all of the organ systems in the body and increases the risk of developing pulmonary diseases such as acute lung injury and pneumonia, while exacerbating the symptoms and resulting in increased mortality in many other lung disorders. EtOH and its metabolites inhibit the immune response of alveolar macrophages (AMs), increase airway leakage, produce damaging reactive oxygen species (ROS), and disrupt the balance of antioxidants/oxidants within the lungs. In this article, we review the role of EtOH exposure in the pathogenesis and progression of pulmonary disease. Full article
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Open AccessReview A Mechanistic Review of Mitophagy and Its Role in Protection against Alcoholic Liver Disease
Biomolecules 2015, 5(4), 2619-2642; doi:10.3390/biom5042619
Received: 11 July 2015 / Revised: 23 September 2015 / Accepted: 25 September 2015 / Published: 16 October 2015
Cited by 12 | PDF Full-text (208 KB) | HTML Full-text | XML Full-text
Abstract
Alcoholic liver disease (ALD) is a major health problem worldwide, and alcohol is well-known to cause mitochondrial damage, which exacerbates alcohol-induced liver injury and steatosis. No successful treatments are currently available for treating ALD. Therefore, a better understanding of mechanisms involved in regulation
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Alcoholic liver disease (ALD) is a major health problem worldwide, and alcohol is well-known to cause mitochondrial damage, which exacerbates alcohol-induced liver injury and steatosis. No successful treatments are currently available for treating ALD. Therefore, a better understanding of mechanisms involved in regulation of mitochondrial homeostasis in the liver and how these mechanisms may protect against alcohol-induced liver disease is needed for future development of better therapeutic options for ALD. Mitophagy is a key mechanism for maintaining mitochondrial homeostasis by removing damaged mitochondria, and mitophagy protects against alcohol-induced liver injury. Parkin, an E3 ubiquitin ligase, is well-known to induce mitophagy in in vitro models although Parkin-independent mechanisms for mitophagy induction also exist. In this review, we discuss the roles of Parkin and mitophagy in protection against alcohol-induced liver injury and steatosis. We also discuss Parkin-independent mechanisms for mitophagy induction, which have not yet been evaluated in the liver but may also potentially have a protective role against ALD. In addition to mitophagy, mitochondrial spheroid formation may also provide a novel mechanism of protection against ALD, but the role of mitochondrial spheroids in protection against ALD progression needs to be further explored. Targeting removal of damaged mitochondria by mitophagy or inducing formation of mitochondrial spheroids may be promising therapeutic options for treatment of ALD. Full article
Open AccessArticle Modulation of Intestinal Barrier and Bacterial Endotoxin Production Contributes to the Beneficial Effect of Nicotinic Acid on Alcohol-Induced Endotoxemia and Hepatic Inflammation in Rats
Biomolecules 2015, 5(4), 2643-2658; doi:10.3390/biom5042643
Received: 31 July 2015 / Revised: 21 September 2015 / Accepted: 23 September 2015 / Published: 16 October 2015
Cited by 3 | PDF Full-text (2143 KB) | HTML Full-text | XML Full-text
Abstract
Alcohol consumption causes nicotinic acid deficiency. The present study was undertaken to determine whether dietary nicotinic acid supplementation provides beneficial effects on alcohol-induced endotoxin signaling and the possible mechanisms at the gut-liver axis. Male Sprague-Dawley rats were pair-fed the Lieber-DeCarli liquid diets containing
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Alcohol consumption causes nicotinic acid deficiency. The present study was undertaken to determine whether dietary nicotinic acid supplementation provides beneficial effects on alcohol-induced endotoxin signaling and the possible mechanisms at the gut-liver axis. Male Sprague-Dawley rats were pair-fed the Lieber-DeCarli liquid diets containing ethanol or isocaloric maltose dextrin for eight weeks, with or without dietary supplementation with 750 mg/liter nicotinic acid. Chronic alcohol feeding elevated the plasma endotoxin level and activated hepatic endotoxin signaling cascade, which were attenuated by nicotinic acid supplementation. Alcohol consumption remarkably decreased the mRNA levels of claudin-1, claudin-5, and ZO-1 in the distal intestine, whereas nicotinic acid significantly up-regulated these genes. The concentrations of endotoxin, ethanol, and acetaldehyde in the intestinal contents were increased by alcohol exposure, and niacin supplementation reduced the intestinal endotoxin and acetaldehyde levels. Nicotinic acid supplementation upregulated the intestinal genes involved in aldehyde detoxification via transcriptional regulation. These results demonstrate that modulation of the intestinal barrier function and bacterial endotoxin production accounts for the inhibitory effects of nicotinic acid on alcohol-induced endotoxemia and hepatic inflammation. Full article
Open AccessArticle Autophagy Protects against CYP2E1/Chronic Ethanol-Induced Hepatotoxicity
Biomolecules 2015, 5(4), 2659-2674; doi:10.3390/biom5042659
Received: 7 May 2015 / Revised: 9 October 2015 / Accepted: 9 October 2015 / Published: 16 October 2015
Cited by 8 | PDF Full-text (4218 KB) | HTML Full-text | XML Full-text
Abstract
Autophagy is an intracellular pathway by which lysosomes degrade and recycle long-lived proteins and cellular organelles. The effects of ethanol on autophagy are complex but recent studies have shown that autophagy serves a protective function against ethanol-induced liver injury. Autophagy was found to
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Autophagy is an intracellular pathway by which lysosomes degrade and recycle long-lived proteins and cellular organelles. The effects of ethanol on autophagy are complex but recent studies have shown that autophagy serves a protective function against ethanol-induced liver injury. Autophagy was found to also be protective against CYP2E1-dependent toxicity in vitro in HepG2 cells which express CYP2E1 and in vivo in an acute alcohol/CYPE1-dependent liver injury model. The goal of the current report was to extend the previous in vitro and acute in vivo experiments to a chronic ethanol model to evaluate whether autophagy is also protective against CYP2E1-dependent liver injury in a chronic ethanol-fed mouse model. Wild type (WT), CYP2E1 knockout (KO) or CYP2E1 humanized transgenic knockin (KI), mice were fed an ethanol liquid diet or control dextrose diet for four weeks. In the last week, some mice received either saline or 3-methyladenine (3-MA), an inhibitor of autophagy, or rapamycin, which stimulates autophagy. Inhibition of autophagy by 3-MA potentiated the ethanol-induced increases in serum transaminase and triglyceride levels in the WT and KI mice but not KO mice, while rapamycin prevented the ethanol liver injury. Treatment with 3-MA enhanced the ethanol-induced fat accumulation in WT mice and caused necrosis in the KI mice; little or no effect was found in the ethanol-fed KO mice or any of the dextrose-fed mice. 3-MA treatment further lowered the ethanol-decrease in hepatic GSH levels and further increased formation of TBARS in WT and KI mice, whereas rapamycin blunted these effects of ethanol. Neither 3-MA nor rapamycin treatment affected CYP2E1 catalytic activity or content or the induction CYP2E1 by ethanol. The 3-MA treatment decreased levels of Beclin-1 and Atg 7 but increased levels of p62 in the ethanol-fed WT and KI mice whereas rapamycin had the opposite effects, validating inhibition and stimulation of autophagy, respectively. These results suggest that autophagy is protective against CYP2E1-dependent liver injury in a chronic ethanol-fed mouse model. We speculate that autophagy-dependent processes such as mitophagy and lipophagy help to minimize ethanol-induced CYP2E1-dependent oxidative stress and therefore the subsequent liver injury and steatosis. Attempts to stimulate autophagy may be helpful in lowering ethanol and CYP2E1-dependent liver toxicity. Full article
Open AccessReview Alcohol and the Intestine
Biomolecules 2015, 5(4), 2573-2588; doi:10.3390/biom5042573
Received: 1 September 2015 / Revised: 24 September 2015 / Accepted: 5 October 2015 / Published: 15 October 2015
Cited by 5 | PDF Full-text (107 KB) | HTML Full-text | XML Full-text
Abstract
Alcohol abuse is a significant contributor to the global burden of disease and can lead to tissue damage and organ dysfunction in a subset of alcoholics. However, a subset of alcoholics without any of these predisposing factors can develop alcohol-mediated organ injury. The
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Alcohol abuse is a significant contributor to the global burden of disease and can lead to tissue damage and organ dysfunction in a subset of alcoholics. However, a subset of alcoholics without any of these predisposing factors can develop alcohol-mediated organ injury. The gastrointestinal tract (GI) could be an important source of inflammation in alcohol-mediated organ damage. The purpose of review was to evaluate mechanisms of alcohol-induced endotoxemia (including dysbiosis and gut leakiness), and highlight the predisposing factors for alcohol-induced dysbiosis and gut leakiness to endotoxins. Barriers, including immunologic, physical, and biochemical can regulate the passage of toxins into the portal and systemic circulation. In addition, a host of environmental interactions including those influenced by circadian rhythms can impact alcohol-induced organ pathology. There appears to be a role for therapeutic measures to mitigate alcohol-induced organ damage by normalizing intestinal dysbiosis and/or improving intestinal barrier integrity. Ultimately, the inflammatory process that drives progression into organ damage from alcohol appears to be multifactorial. Understanding the role of the intestine in the pathogenesis of alcoholic liver disease can pose further avenues for pathogenic and treatment approaches. Full article
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Open AccessReview The Molecular Circadian Clock and Alcohol-Induced Liver Injury
Biomolecules 2015, 5(4), 2504-2537; doi:10.3390/biom5042504
Received: 31 July 2015 / Revised: 2 September 2015 / Accepted: 9 September 2015 / Published: 14 October 2015
Cited by 6 | PDF Full-text (541 KB) | HTML Full-text | XML Full-text
Abstract
Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the
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Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases. Full article
Open AccessReview Endoplasmic Reticulum Stress and Ethanol Neurotoxicity
Biomolecules 2015, 5(4), 2538-2553; doi:10.3390/biom5042538
Received: 5 August 2015 / Revised: 2 September 2015 / Accepted: 21 September 2015 / Published: 14 October 2015
Cited by 13 | PDF Full-text (520 KB) | HTML Full-text | XML Full-text
Abstract
Ethanol abuse affects virtually all organ systems and the central nervous system (CNS) is particularly vulnerable to excessive ethanol exposure. Ethanol exposure causes profound damages to both the adult and developing brain. Prenatal ethanol exposure induces fetal alcohol spectrum disorders (FASD) which is
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Ethanol abuse affects virtually all organ systems and the central nervous system (CNS) is particularly vulnerable to excessive ethanol exposure. Ethanol exposure causes profound damages to both the adult and developing brain. Prenatal ethanol exposure induces fetal alcohol spectrum disorders (FASD) which is associated with mental retardation and other behavioral deficits. A number of potential mechanisms have been proposed for ethanol-induced brain damage; these include the promotion of neuroinflammation, interference with signaling by neurotrophic factors, induction of oxidative stress, modulation of retinoid acid signaling, and thiamine deficiency. The endoplasmic reticulum (ER) regulates posttranslational protein processing and transport. The accumulation of unfolded or misfolded proteins in the ER lumen triggers ER stress and induces unfolded protein response (UPR) which are mediated by three transmembrane ER signaling proteins: pancreatic endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). UPR is initiated to protect cells from overwhelming ER protein loading. However, sustained ER stress may result in cell death. ER stress has been implied in various CNS injuries, including brain ischemia, traumatic brain injury, and aging-associated neurodegeneration, such as Alzheimer’s disease (AD), Huntington’s disease (HD), Amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD). However, effects of ethanol on ER stress in the CNS receive less attention. In this review, we discuss recent progress in the study of ER stress in ethanol-induced neurotoxicity. We also examine the potential mechanisms underlying ethanol-mediated ER stress and the interaction among ER stress, oxidative stress and autophagy in the context of ethanol neurotoxicity. Full article
Open AccessReview Potential Role of the Gut/Liver/Lung Axis in Alcohol-Induced Tissue Pathology
Biomolecules 2015, 5(4), 2477-2503; doi:10.3390/biom5042477
Received: 31 July 2015 / Revised: 11 September 2015 / Accepted: 21 September 2015 / Published: 30 September 2015
Cited by 3 | PDF Full-text (592 KB) | HTML Full-text | XML Full-text
Abstract
Both Alcoholic Liver Disease (ALD) and alcohol-related susceptibility to acute lung injury are estimated to account for the highest morbidity and mortality related to chronic alcohol abuse and, thus, represent a focus of intense investigation. In general, alcohol-induced derangements to both organs are
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Both Alcoholic Liver Disease (ALD) and alcohol-related susceptibility to acute lung injury are estimated to account for the highest morbidity and mortality related to chronic alcohol abuse and, thus, represent a focus of intense investigation. In general, alcohol-induced derangements to both organs are considered to be independent and are often evaluated separately. However, the liver and lung share many general responses to damage, and specific responses to alcohol exposure. For example, both organs possess resident macrophages that play key roles in mediating the immune/inflammatory response. Additionally, alcohol-induced damage to both organs appears to involve oxidative stress that favors tissue injury. Another mechanism that appears to be shared between the organs is that inflammatory injury to both organs is enhanced by alcohol exposure. Lastly, altered extracellular matrix (ECM) deposition appears to be a key step in disease progression in both organs. Indeed, recent studies suggest that early subtle changes in the ECM may predispose the target organ to an inflammatory insult. The purpose of this chapter is to review the parallel mechanisms of liver and lung injury in response to alcohol consumption. This chapter will also explore the potential that these mechanisms are interdependent, as part of a gut-liver-lung axis. Full article
Open AccessReview Impact of Alcohol on Glycemic Control and Insulin Action
Biomolecules 2015, 5(4), 2223-2246; doi:10.3390/biom5042223
Received: 23 May 2015 / Revised: 24 August 2015 / Accepted: 21 September 2015 / Published: 29 September 2015
Cited by 8 | PDF Full-text (645 KB) | HTML Full-text | XML Full-text
Abstract
Alcohol has profound effects on tissue and whole-body fuel metabolism which contribute to the increased morbidity and mortality in individuals with alcohol use disorder. This review focuses on the glucose metabolic effects of alcohol, primarily in the muscle, liver and adipose tissue, under
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Alcohol has profound effects on tissue and whole-body fuel metabolism which contribute to the increased morbidity and mortality in individuals with alcohol use disorder. This review focuses on the glucose metabolic effects of alcohol, primarily in the muscle, liver and adipose tissue, under basal postabsorptive conditions and in response to insulin stimulation. While there is a relatively extensive literature in this area, results are often discordant and extrapolating between models and tissues is fraught with uncertainty. Comparisons between data generated in experimental cell and animals systems will be contrasted with that obtained from human subjects as often times results differ. Further, the nutritional status is also an important component of the sometimes divergent findings pertaining to the effects of alcohol on the regulation of insulin and glucose metabolism. This work is relevant as the contribution of alcohol intake to the development or exacerbation of type 2 diabetes remains ill-defined and a multi-systems approach is likely needed as both alcohol and diabetes affect multiple targets within the body. Full article
Open AccessReview The Altered Hepatic Tubulin Code in Alcoholic Liver Disease
Biomolecules 2015, 5(3), 2140-2159; doi:10.3390/biom5032140
Received: 22 July 2015 / Revised: 21 August 2015 / Accepted: 24 August 2015 / Published: 18 September 2015
Cited by 2 | PDF Full-text (514 KB) | HTML Full-text | XML Full-text
Abstract
The molecular mechanisms that lead to the progression of alcoholic liver disease have been actively examined for decades. Because the hepatic microtubule cytoskeleton supports innumerable cellular processes, it has been the focus of many such mechanistic studies. It has long been appreciated that
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The molecular mechanisms that lead to the progression of alcoholic liver disease have been actively examined for decades. Because the hepatic microtubule cytoskeleton supports innumerable cellular processes, it has been the focus of many such mechanistic studies. It has long been appreciated that α-tubulin is a major target for modification by highly reactive ethanol metabolites and reactive oxygen species. It is also now apparent that alcohol exposure induces post-translational modifications that are part of the natural repertoire, mainly acetylation. In this review, the modifications of the “tubulin code” are described as well as those adducts by ethanol metabolites. The potential cellular consequences of microtubule modification are described with a focus on alcohol-induced defects in protein trafficking and enhanced steatosis. Possible mechanisms that can explain hepatic dysfunction are described and how this relates to the onset of liver injury is discussed. Finally, we propose that agents that alter the cellular acetylation state may represent a novel therapeutic strategy for treating liver disease. Full article
Open AccessReview Alcoholic Liver Disease: Role of Cytokines
Biomolecules 2015, 5(3), 2023-2034; doi:10.3390/biom5032023
Received: 3 July 2015 / Revised: 21 August 2015 / Accepted: 24 August 2015 / Published: 28 August 2015
Cited by 8 | PDF Full-text (91 KB) | HTML Full-text | XML Full-text
Abstract
The present review spans a broad spectrum of topics dealing with alcoholic liver disease (ALD), including clinical and translational research. It focuses on the role of the immune system and the signaling pathways of cytokines in the pathogenesis of ALD. An additional factor
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The present review spans a broad spectrum of topics dealing with alcoholic liver disease (ALD), including clinical and translational research. It focuses on the role of the immune system and the signaling pathways of cytokines in the pathogenesis of ALD. An additional factor that contributes to the pathogenesis of ALD is lipopolysaccharide (LPS), which plays a central role in the induction of steatosis, inflammation, and fibrosis in the liver. LPS derived from the intestinal microbiota enters the portal circulation, and is recognized by macrophages (Kupffer cells) and hepatocytes. In individuals with ALD, excessive levels of LPS in the liver affect immune, parenchymal, and non-immune cells, which in turn release various inflammatory cytokines and recruit neutrophils and other inflammatory cells. In this review, we elucidate the mechanisms by which alcohol contributes to the activation of Kupffer cells and the inflammatory cascade. The role of the stellate cells in fibrogenesis is also discussed. Full article
Open AccessReview Biomolecules and Biomarkers Used in Diagnosis of Alcohol Drinking and in Monitoring Therapeutic Interventions
Biomolecules 2015, 5(3), 1339-1385; doi:10.3390/biom5031339
Received: 9 April 2015 / Revised: 15 May 2015 / Accepted: 29 May 2015 / Published: 29 June 2015
Cited by 17 | PDF Full-text (228 KB) | HTML Full-text | XML Full-text
Abstract
Background: The quantitative, measurable detection of drinking is important for the successful treatment of alcohol misuse in transplantation of patients with alcohol disorders, people living with human immunodeficiency virus that need to adhere to medication, and special occupational hazard offenders, many of whom
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Background: The quantitative, measurable detection of drinking is important for the successful treatment of alcohol misuse in transplantation of patients with alcohol disorders, people living with human immunodeficiency virus that need to adhere to medication, and special occupational hazard offenders, many of whom continually deny drinking. Their initial misconduct usually leads to medical problems associated with drinking, impulsive social behavior, and drunk driving. The accurate identification of alcohol consumption via biochemical tests contributes significantly to the monitoring of drinking behavior. Methods: A systematic review of the current methods used to measure biomarkers of alcohol consumption was conducted using PubMed and Google Scholar databases (2010–2015). The names of the tests have been identified. The methods and publications that correlate between the social instruments and the biochemical tests were further investigated. There is a clear need for assays standardization to ensure the use of these biochemical tests as routine biomarkers. Findings: Alcohol ingestion can be measured using a breath test. Because alcohol is rapidly eliminated from the circulation, the time for detection by this analysis is in the range of hours. Alcohol consumption can alternatively be detected by direct measurement of ethanol concentration in blood or urine. Several markers have been proposed to extend the interval and sensitivities of detection, including ethyl glucuronide and ethyl sulfate in urine, phosphatidylethanol in blood, and ethyl glucuronide and fatty acid ethyl esters in hair, among others. Moreover, there is a need to correlate the indirect biomarker carbohydrate deficient transferrin, which reflects longer lasting consumption of higher amounts of alcohol, with serum γ-glutamyl transpeptidase, another long term indirect biomarker that is routinely used and standardized in laboratory medicine. Full article
Open AccessReview Advances and New Concepts in Alcohol-Induced Organelle Stress, Unfolded Protein Responses and Organ Damage
Biomolecules 2015, 5(2), 1099-1121; doi:10.3390/biom5021099
Received: 5 May 2015 / Revised: 23 May 2015 / Accepted: 26 May 2015 / Published: 3 June 2015
Cited by 12 | PDF Full-text (1017 KB) | HTML Full-text | XML Full-text
Abstract
Alcohol is a simple and consumable biomolecule yet its excessive consumption disturbs numerous biological pathways damaging nearly all organs of the human body. One of the essential biological processes affected by the harmful effects of alcohol is proteostasis, which regulates the balance between
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Alcohol is a simple and consumable biomolecule yet its excessive consumption disturbs numerous biological pathways damaging nearly all organs of the human body. One of the essential biological processes affected by the harmful effects of alcohol is proteostasis, which regulates the balance between biogenesis and turnover of proteins within and outside the cell. A significant amount of published evidence indicates that alcohol and its metabolites directly or indirectly interfere with protein homeostasis in the endoplasmic reticulum (ER) causing an accumulation of unfolded or misfolded proteins, which triggers the unfolded protein response (UPR) leading to either restoration of homeostasis or cell death, inflammation and other pathologies under severe and chronic alcohol conditions. The UPR senses the abnormal protein accumulation and activates transcription factors that regulate nuclear transcription of genes related to ER function. Similarly, this kind of protein stress response can occur in other cellular organelles, which is an evolving field of interest. Here, I review recent advances in the alcohol-induced ER stress response as well as discuss new concepts on alcohol-induced mitochondrial, Golgi and lysosomal stress responses and injuries. Full article
Open AccessArticle The Effect of Alcohol and Hydrogen Peroxide on Liver Hepcidin Gene Expression in Mice Lacking Antioxidant Enzymes, Glutathione Peroxidase-1 or Catalase
Biomolecules 2015, 5(2), 793-807; doi:10.3390/biom5020793
Received: 4 March 2015 / Revised: 22 April 2015 / Accepted: 27 April 2015 / Published: 6 May 2015
Cited by 4 | PDF Full-text (1040 KB) | HTML Full-text | XML Full-text
Abstract
This study investigates the regulation of hepcidin, the key iron-regulatory molecule, by alcohol and hydrogen peroxide (H2O2) in glutathione peroxidase-1 (gpx-1−/−) and catalase (catalase−/−) knockout mice. For alcohol studies, 10% ethanol was administered in the
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This study investigates the regulation of hepcidin, the key iron-regulatory molecule, by alcohol and hydrogen peroxide (H2O2) in glutathione peroxidase-1 (gpx-1−/−) and catalase (catalase−/−) knockout mice. For alcohol studies, 10% ethanol was administered in the drinking water for 7 days. Gpx-1−/− displayed significantly higher hepatic H2O2 levels than catalase−/− compared to wild-type mice, as measured by 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA). The basal level of liver hepcidin expression was attenuated in gpx-1−/− mice. Alcohol increased H2O2 production in catalase−/− and wild-type, but not gpx-1−/−, mice. Hepcidin expression was inhibited in alcohol-fed catalase−/− and wild-type mice. In contrast, alcohol elevated hepcidin expression in gpx-1−/− mice. Gpx-1−/− mice also displayed higher level of basal liver CHOP protein expression than catalase−/− mice. Alcohol induced CHOP and to a lesser extent GRP78/BiP expression, but not XBP1 splicing or binding of CREBH to hepcidin gene promoter, in gpx-1−/− mice. The up-regulation of hepatic ATF4 mRNA levels, which was observed in gpx-1−/− mice, was attenuated by alcohol. In conclusion, our findings strongly suggest that H2O2 inhibits hepcidin expression in vivo. Synergistic induction of CHOP by alcohol and H2O2, in the absence of gpx-1, stimulates liver hepcidin gene expression by ER stress independent of CREBH. Full article

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