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Lin HM, Zhang JR, Li MX, Hou H, Wang H, Huang Y. Cigarette smoking and alcohol-related liver disease. LIVER RESEARCH 2024; 8:237-245. [PMID: 39958918 PMCID: PMC11771264 DOI: 10.1016/j.livres.2024.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 08/27/2024] [Accepted: 12/04/2024] [Indexed: 02/18/2025]
Abstract
China is a major consumer of alcohol and tobacco. Tobacco and alcohol use are closely linked, with up to 90% of alcoholics having a history of tobacco use, and heavy smokers also tending to be alcoholics. Alcohol-related liver disease (ALD), one of the most common and serious complications of chronic alcohol intake, involving hepatic steatosis, hepatitis, hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC), has become one of the globally prevalent chronic diseases. An increasing number of studies have focused on the association between smoking and ALD and explored the mechanisms involved. Clinical evidence suggests that smoking has a negative impact on the incidence and severity of fatty liver disease, progression of liver fibrosis, development of HCC, prognosis of patients with advanced liver disease, and alcohol-related liver transplant recipients. The underlying mechanisms are complex and involve different pathophysiological pathways, including free radical exposure, endoplasmic reticulum stress, insulin resistance, and oncogenic signaling. This review discusses the deleterious effects of smoking on ALD patients and the possible underlying mechanisms at several levels. It emphasizes the importance of discouraging smoking among ALD patients. Finally, the pathogenic role of electronic cigarettes, which have emerged in recent years, is discussed, calling for an emphasis on social missions for young people.
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Affiliation(s)
- Hui-Min Lin
- Anhui Provincial Laboratory of Inflammatory and Immunity Disease, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
- Department of Pharmacy, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Jing-Rong Zhang
- Anhui Provincial Laboratory of Inflammatory and Immunity Disease, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Meng-Xue Li
- Anhui Provincial Laboratory of Inflammatory and Immunity Disease, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Hui Hou
- Department of Pharmacy, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Hua Wang
- Anhui Provincial Laboratory of Inflammatory and Immunity Disease, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Yan Huang
- Anhui Provincial Laboratory of Inflammatory and Immunity Disease, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
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Haque LY, Leggio L. Integrated and collaborative care across the spectrum of alcohol-associated liver disease and alcohol use disorder. Hepatology 2024; 80:1408-1423. [PMID: 38935926 PMCID: PMC11841743 DOI: 10.1097/hep.0000000000000996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 06/08/2024] [Indexed: 06/29/2024]
Abstract
The public health impact of alcohol-associated liver disease (ALD), a serious consequence of problematic alcohol use, and alcohol use disorder (AUD) is growing, with ALD becoming a major cause of alcohol-associated death overall and the leading indication for liver transplantation in the United States. Comprehensive care for ALD often requires treatment of AUD. Although there is a growing body of evidence showing that AUD treatment is associated with reductions in liver-related morbidity and mortality, only a minority of patients with ALD and AUD receive this care. Integrated and collaborative models that streamline both ALD and AUD care for patients with ALD and AUD are promising approaches to bridge this treatment gap and rely on multidisciplinary and interprofessional teams and partnerships. Here, we review the role of AUD care in ALD treatment, the effects of AUD treatment on liver-related outcomes, the impact of comorbid conditions such as other substance use disorders, obesity, and metabolic syndrome, and the current landscape of integrated and collaborative care for ALD and AUD in various treatment settings. We further review knowledge gaps and unmet needs that remain, including the role of precision medicine, the application of harm reduction approaches, the impact of health disparities, and the need for additional AUD treatment options, as well as further efforts to support implementation and dissemination.
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Affiliation(s)
- Lamia Y. Haque
- Department of Internal Medicine, Yale School of Medicine,
New Haven, Connecticut
- Yale Program in Addiction Medicine, Yale School of
Medicine, New Haven, Connecticut
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and
Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National
Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism,
National Institutes of Health, Baltimore and Bethesda, MD
- Center for Alcohol and Addiction Studies, Department of
Behavioral and Social Sciences, School of Public Health, Brown University,
Providence, RI
- Division of Addiction Medicine, Department of Medicine,
School of Medicine, Johns Hopkins University, Baltimore, MD
- Department of Neuroscience, Georgetown University Medical
Center, Washington, DC
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3
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de la Monte SM, Tong M. Dysregulated mTOR networks in experimental sporadic Alzheimer's disease. Front Cell Neurosci 2024; 18:1432359. [PMID: 39386180 PMCID: PMC11461251 DOI: 10.3389/fncel.2024.1432359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 08/29/2024] [Indexed: 10/12/2024] Open
Abstract
Background Beyond the signature amyloid-beta plaques and neurofibrillary tangles, Alzheimer's disease (AD) has been shown to exhibit dysregulated metabolic signaling through insulin and insulin-like growth factor (IGF) networks that crosstalk with the mechanistic target of rapamycin (mTOR). Its broad impact on brain structure and function suggests that mTOR is likely an important therapeutic target for AD. Objective This study characterizes temporal lobe (TL) mTOR signaling abnormalities in a rat model of sporadic AD neurodegeneration. Methods Long Evans rats were given intracerebroventricular injections of streptozotocin (ic-STZ) or saline (control), and 4 weeks later, they were administered neurobehavioral tests followed by terminal harvesting of the TLs for histopathological study and measurement of AD biomarkers, neuroinflammatory/oxidative stress markers, and total and phosphorylated insulin/IGF-1-Akt-mTOR pathway signaling molecules. Results Rats treated with ic-STZ exhibited significantly impaired performance on Rotarod (RR) and Morris Water Maze (MWM) tests, brain atrophy, TL and hippocampal neuronal and white matter degeneration, and elevated TL pTau, AβPP, Aβ, AChE, 4-HNE, and GAPDH and reduced ubiquitin, IL-2, IL-6, and IFN-γ immunoreactivities. In addition, ic-STZ reduced TL pY1135/1136-IGF-1R, Akt, PTEN, pS380-PTEN, pS2448-mTOR, p70S6K, pT412-p70S6K, p/T-pT412-p70S6K, p/T-Rictor, and p/T-Raptor. Conclusion Experimental ic-STZ-induced sporadic AD-type neurodegeneration with neurobehavioral dysfunctions associated with inhibition of mTOR signaling networks linked to energy metabolism, plasticity, and white matter integrity.
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Affiliation(s)
- Suzanne M. de la Monte
- Departments of Medicine, Pathology and Laboratory Medicine, Neurology, and Neurosurgery, Rhode Island Hospital, Women and Infants Hospital, The Alpert Medical School at Brown University, Providence, RI, United States
| | - Ming Tong
- Department of Medicine, Rhode Island Hospital, The Alpert Medical School at Brown University, Providence, RI, United States
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Homans C, Yalcin EB, Tong M, Gallucci G, Bautista D, Moriel N, de la Monte S. Therapeutic Effects of Myriocin in Experimental Alcohol-Related Neurobehavioral Dysfunction and Frontal Lobe White Matter Biochemical Pathology. JOURNAL OF BEHAVIORAL AND BRAIN SCIENCE 2022; 12:23-42. [PMID: 36815096 PMCID: PMC9942847 DOI: 10.4236/jbbs.2022.122003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background & Objective Chronic excessive alcohol consumption causes white matter degeneration with myelin loss and impaired neuronal conductivity. Subsequent rarefaction of myelin accounts for the sustained deficits in cognition, learning, and memory. Correspondingly, chronic heavy or repeated binge alcohol exposures in humans and experimental models alter myelin lipid composition leading to build-up of ceramides which can be neurotoxic and broadly inhibitory to brain functions. Methods This study examined the effects of chronic + binge alcohol exposures (8 weeks) and intervention with myriocin, a ceramide inhibitor, on neurobehavioral functions (Open Field, Novel Object Recognition, and Morris Water Maze tests) and frontal lobe white matter myelin lipid biochemical pathology in an adult Long-Evans rat model. Results The ethanol-exposed group had significant deficits in executive functions with increased indices of anxiety and impairments in spatial learning acquisition. Myriocin partially remediated these effects of ethanol while not impacting behavior in the control group. Ethanol-fed rats had significantly smaller brains with broadly reduced expression of sulfatides and reduced expression of two of the three sphingomyelins detected in frontal white matter. Myriocin partially resolved these effects corresponding with improvements in neurobehavioral function. Conclusion Therapeutic strategies that support cerebral white matter myelin expression of sulfatide and sphingomyelin may help remediate cognitive-behavioral dysfunction following chronic heavy alcohol consumption in humans.
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Affiliation(s)
- Camilla Homans
- Biotechnology Graduate Program, Brown University, Providence, RI, USA
| | - Emine B. Yalcin
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA,Liver Research Center, Department of Medicine, Rhode Island Hospital, Providence, RI, USA
| | - Ming Tong
- Liver Research Center, Department of Medicine, Rhode Island Hospital, Providence, RI, USA
| | - Gina Gallucci
- Liver Research Center, Department of Medicine, Rhode Island Hospital, Providence, RI, USA
| | - David Bautista
- Warren Alpert Medical School of Brown University, Providence, RI, USA,Brown University, Providence, RI, USA
| | - Natalia Moriel
- Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Suzanne de la Monte
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA,Warren Alpert Medical School of Brown University, Providence, RI, USA,Department of Pathology and Laboratory Medicine, Rhode Island Hospital, Women and Infants Hospital of Rhode Island, Providence VA Medical Center, Providence, RI, USA,
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Valutite DE, Semenov AV, Ostankova YV, Kozlov KV, Borisov AG, Nazarov VD, Totolian AA. Detection of drug resistance mutations of hepatitis C virus in patients with failure of the treatment with direct acting antivirals. JOURNAL OF MICROBIOLOGY, EPIDEMIOLOGY AND IMMUNOBIOLOGY 2021; 98:18-27. [DOI: 10.36233/0372-9311-47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
Background. The development of direct acting antivirals (DAAs) has spurred a revolution in treatment of patients with chronic hepatitis C. However, there are cases showing no response to treatment. In 5% of cases, the viral breakthrough is most likely caused by DAA resistance mutations in the hepatitis C virus genome.The purpose of the study is to detect drug resistance mutations of hepatitis C virus in patients with DAA treatment failure.Materials and methods. The study was performed on plasma samples from 3 patients diagnosed with chronic hepatitis C virus infection and demonstrating DAA virological treatment failure. All isolates had genotype 1b. Drug resistance mutations were detected by using direct sequencing of NS3, NS5A, and NS5B genome regions. The detection technique was developed at the Pasteur Research Institute of Epidemiology and Microbiology.Results. Drug resistance mutations were detected in all cases. By using the Geno2pheno [hcv] 0.92 tool, nucleotide substitutions were detected in different viral genome regions and presumably caused resistance or decreased sensitivity to antivirals both present and absent in the sofosbuvir + daclatasvir combination therapy. Antiviral treatment failure in patients with chronic hepatitis C is caused by drug resistance mutations.Conclusions. The developed technique is efficient for detection of drug resistance mutations in NS3, NS5A, and NS5B regions in cases of virological failure of DAA treatment.
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Investigation of Precise Molecular Mechanistic Action of Tobacco-Associated Carcinogen `NNK´ Induced Carcinogenesis: A System Biology Approach. Genes (Basel) 2019; 10:genes10080564. [PMID: 31357510 PMCID: PMC6723528 DOI: 10.3390/genes10080564] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 07/22/2019] [Accepted: 07/24/2019] [Indexed: 12/21/2022] Open
Abstract
Cancer is the second deadliest disease listed by the WHO. One of the major causes of cancer disease is tobacco and consumption possibly due to its main component, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). A plethora of studies have been conducted in the past aiming to decipher the association of NNK with other diseases. However, it is strongly linked with cancer development. Despite these studies, a clear molecular mechanism and the impact of NNK on various system-level networks is not known. In the present study, system biology tools were employed to understand the key regulatory mechanisms and the perturbations that will happen in the cellular processes due to NNK. To investigate the system level influence of the carcinogen, NNK rewired protein–protein interaction network (PPIN) was generated from 544 reported proteins drawn out from 1317 articles retrieved from PubMed. The noise was removed from PPIN by the method of modulation. Gene ontology (GO) enrichment was performed on the seed proteins extracted from various modules to find the most affected pathways by the genes/proteins. For the modulation, Molecular COmplex DEtection (MCODE) was used to generate 19 modules containing 115 seed proteins. Further, scrutiny of the targeted biomolecules was done by the graph theory and molecular docking. GO enrichment analysis revealed that mostly cell cycle regulatory proteins were affected by NNK.
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Alahmari AA, Sreekumar B, Patel V, Ashat M, Alexandre M, Uduman AK, Akinbiyi EO, Ceplenski A, Shugrue CA, Kolodecik TR, Tashkandi N, Messenger SW, Groblewski GE, Gorelick FS, Thrower EC. Cigarette toxin 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces experimental pancreatitis through α7 nicotinic acetylcholine receptors (nAChRs) in mice. PLoS One 2018; 13:e0197362. [PMID: 29870540 PMCID: PMC5988302 DOI: 10.1371/journal.pone.0197362] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 05/01/2018] [Indexed: 01/29/2023] Open
Abstract
Clinical studies have shown that cigarette smoking is a dose-dependent and independent risk factor for acute pancreatitis. Cigarette smoke contains nicotine which can be converted to the potent receptor ligand and toxin, NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone]. Previously, we have shown that NNK induces premature activation of pancreatic zymogens in rats, an initiating event in pancreatitis, and this activation is prevented by pharmacologic inhibition of nicotinic acetylcholine receptors (nAChR). In this study, we determined whether NNK mediates pancreatitis through the α7 isoform of nAChR using α7nAChR knockout mice. PCR analysis confirmed expression of non-neuronal α7nAChR in C57BL/6 (WT) mouse and human acinar cells. NNK treatment stimulated trypsinogen activation in acini from WT but not α7nAChR-/- mice. NNK also stimulated trypsinogen activation in human acini. To further confirm these findings, WT and α7nAChR-/- mice were treated with NNK in vivo and markers of pancreatitis were measured. As observed in acini NNK treatment induced trypsinogen activation in WT but not α7nAChR-/- mice. NNK also induced other markers of pancreatitis including pancreatic edema, vacuolization and pyknotic nuclei in WT but not α7nAChR-/- animals. NNK treatment led to increased neutrophil infiltration, a marker of inflammation, in WT mice and to a significantly lesser extent in α7nAChR-/- mice. We also examined downstream targets of α7nAChR activation and found that calcium and PKC activation are involved down stream of NNK stimulation of α7nAChR. In this study we used genetic deletion of the α7nAChR to confirm our previous inhibitor studies that demonstrated NNK stimulates pancreatitis by activating this receptor. Lastly, we demonstrate that NNK can also stimulate zymogen activation in human acinar cells and thus may play a role in human disease.
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Affiliation(s)
- A. A. Alahmari
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States of America
- Veterans Affairs Connecticut Healthcare, West Haven, CT, United States of America
| | - B. Sreekumar
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States of America
- Veterans Affairs Connecticut Healthcare, West Haven, CT, United States of America
| | - V. Patel
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States of America
- Veterans Affairs Connecticut Healthcare, West Haven, CT, United States of America
| | - M. Ashat
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States of America
- Veterans Affairs Connecticut Healthcare, West Haven, CT, United States of America
| | - M. Alexandre
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States of America
- Veterans Affairs Connecticut Healthcare, West Haven, CT, United States of America
| | - A. K. Uduman
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States of America
- Veterans Affairs Connecticut Healthcare, West Haven, CT, United States of America
| | - E. O. Akinbiyi
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States of America
- Veterans Affairs Connecticut Healthcare, West Haven, CT, United States of America
| | - A. Ceplenski
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States of America
- Veterans Affairs Connecticut Healthcare, West Haven, CT, United States of America
| | - C. A. Shugrue
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States of America
- Veterans Affairs Connecticut Healthcare, West Haven, CT, United States of America
| | - T. R. Kolodecik
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States of America
- Veterans Affairs Connecticut Healthcare, West Haven, CT, United States of America
| | - N. Tashkandi
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States of America
- Veterans Affairs Connecticut Healthcare, West Haven, CT, United States of America
| | - S. W. Messenger
- Department of Nutritional Sciences, University of Wisconsin, Madison, Wisconsin, United States of America
| | - G. E. Groblewski
- Department of Nutritional Sciences, University of Wisconsin, Madison, Wisconsin, United States of America
| | - F. S. Gorelick
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States of America
- Veterans Affairs Connecticut Healthcare, West Haven, CT, United States of America
- Department of Cell Biology, Yale University School of Medicine, New Haven, CT, United States of America
| | - E. C. Thrower
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States of America
- Veterans Affairs Connecticut Healthcare, West Haven, CT, United States of America
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Miguel-Hidalgo JJ. Molecular Neuropathology of Astrocytes and Oligodendrocytes in Alcohol Use Disorders. Front Mol Neurosci 2018; 11:78. [PMID: 29615864 PMCID: PMC5869926 DOI: 10.3389/fnmol.2018.00078] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 02/28/2018] [Indexed: 12/16/2022] Open
Abstract
Postmortem studies reveal structural and molecular alterations of astrocytes and oligodendrocytes in both the gray and white matter (GM and WM) of the prefrontal cortex (PFC) in human subjects with chronic alcohol abuse or dependence. These glial cellular changes appear to parallel and may largely explain structural and functional alterations detected using neuroimaging techniques in subjects with alcohol use disorders (AUDs). Moreover, due to the crucial roles of astrocytes and oligodendrocytes in neurotransmission and signal conduction, these cells are very likely major players in the molecular mechanisms underpinning alcoholism-related connectivity disturbances between the PFC and relevant interconnecting brain regions. The glia-mediated etiology of alcohol-related brain damage is likely multifactorial since metabolic, hormonal, hepatic and hemodynamic factors as well as direct actions of ethanol or its metabolites have the potential to disrupt distinct aspects of glial neurobiology. Studies in animal models of alcoholism and postmortem human brains have identified astrocyte markers altered in response to significant exposures to ethanol or during alcohol withdrawal, such as gap-junction proteins, glutamate transporters or enzymes related to glutamate and gamma-aminobutyric acid (GABA) metabolism. Changes in these proteins and their regulatory pathways would not only cause GM neuronal dysfunction, but also disturbances in the ability of WM axons to convey impulses. In addition, alcoholism alters the expression of astrocyte and myelin proteins and of oligodendrocyte transcription factors important for the maintenance and plasticity of myelin sheaths in WM and GM. These changes are concomitant with epigenetic DNA and histone modifications as well as alterations in regulatory microRNAs (miRNAs) that likely cause profound disturbances of gene expression and protein translation. Knowledge is also available about interactions between astrocytes and oligodendrocytes not only at the Nodes of Ranvier (NR), but also in gap junction-based astrocyte-oligodendrocyte contacts and other forms of cell-to-cell communication now understood to be critical for the maintenance and formation of myelin. Close interactions between astrocytes and oligodendrocytes also suggest that therapies for alcoholism based on a specific glial cell type pathology will require a better understanding of molecular interactions between different cell types, as well as considering the possibility of using combined molecular approaches for more effective therapies.
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Affiliation(s)
- José J Miguel-Hidalgo
- Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, United States
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Lu Y, Cederbaum AI. Cytochrome P450s and Alcoholic Liver Disease. Curr Pharm Des 2018; 24:1502-1517. [PMID: 29637855 PMCID: PMC6053342 DOI: 10.2174/1381612824666180410091511] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 03/30/2018] [Accepted: 04/06/2018] [Indexed: 12/19/2022]
Abstract
Alcohol consumption causes liver diseases, designated as Alcoholic Liver Disease (ALD). Because alcohol is detoxified by alcohol dehydrogenase (ADH), a major ethanol metabolism system, the development of ALD was initially believed to be due to malnutrition caused by alcohol metabolism in liver. The discovery of the microsomal ethanol oxidizing system (MEOS) changed this dogma. Cytochrome P450 enzymes (CYP) constitute the major components of MEOS. Cytochrome P450 2E1 (CYP2E1) in MEOS is one of the major ROS generators in liver and is considered to be contributive to ALD. Our labs have been studying the relationship between CYP2E1 and ALD for many years. Recently, we found that human CYP2A6 and its mouse analog CYP2A5 are also induced by alcohol. In mice, the alcohol induction of CYP2A5 is CYP2E1-dependent. Unlike CYP2E1, CYP2A5 protects against the development of ALD. The relationship of CYP2E1, CYP2A5, and ALD is a major focus of this review.
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Affiliation(s)
- Yongke Lu
- Department of Health Sciences, College of Public Health, East Tennessee State University
- Center of Excellence for Inflammation, Infectious Disease and Immunity, East Tennessee State University
| | - Arthur I. Cederbaum
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai
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Yalcin EB, Tong M, Gallucci G, de la Monte SM. Effects of Tobacco Nicotine-Derived Nitrosamine Ketone (NNK) Exposures on Brain Alcohol Metabolizing Enzyme Activities. Drug Metab Lett 2018; 12:117-124. [PMID: 29886839 PMCID: PMC9964543 DOI: 10.2174/1872312812666180611115418] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 05/22/2018] [Accepted: 05/28/2018] [Indexed: 01/30/2023]
Abstract
BACKGROUND The high levels of blood alcohol achieved with chronic plus binge alcohol exposures are somewhat reduced by co-administration of tobacco-specific Nicotine-Derived Nitrosamine Ketone (NNK) suggesting that NNK may alter alcohol metabolism. OBJECTIVE We examined ethanol and acetaldehyde-metabolizing enzyme activities and malondialdehyde adduct formation in rats exposed to ethanol (chronic + binge), NNK, or both. METHODS 4-week old Long Evans rats were fed liquid diets containing 0% or 26% caloric ethanol for 8 weeks. Ethanol-fed rats were binge-administered ethanol (2 g/kg; on Mondays, Wednesdays, and Fridays) by intraperitoneal (i.p.) injection, while control group administered saline in weeks 7 and 8 (n=12/group). Six rats from each group were administered i.p. injections of NNK (2 mg/kg) or saline on Tuesdays, Thursdays, and Saturdays of weeks 3 through 8. Alcohol dehydrogenase, catalase, and aldehyde dehydrogenase activities were measured using commercial assays. Cytochrome P450 mRNA levels (17 isoforms) were measured by quantitative reverse transcription-polymerase chain reaction. Malondialdehyde immunoreactivity was measured by enzyme-linked immunosorbent assay. RESULTS Dual exposures to ethanol and NNK significantly increased frontal lobe ADH activity relative to control (P=0.01) and ethanol only (P=0.04) treatments, and ALDH relative to control (P=0.02). In contrast, malondialdehyde-protein expression was not significantly altered by ethanol+NNK. Ethanol decreased CYP1A1 mRNA expression relative to control (P=0.02), and combined ethanol+NNK exposures decreased the expression of CYP1A1 (P=0.01) and CYP2C6 (P=0.03). CONCLUSION Dual exposures to ethanol and NNK increase brain ethanol metabolism and inhibit the expression of CYP450s that regulate xenobiotic metabolism.
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Affiliation(s)
- Emine B. Yalcin
- Liver Research Center, Division of Gastroenterology and Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI
| | - Ming Tong
- Liver Research Center, Division of Gastroenterology and Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI
| | - Gina Gallucci
- Liver Research Center, Division of Gastroenterology and Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI
| | - Suzanne M. de la Monte
- Liver Research Center, Division of Gastroenterology and Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI;,Departments of Neurology, Neurosurgery, and Pathology, Rhode Island Hospital and the Alpert Medical School of Brown University, USA,Address correspondence to this author at the Pierre Galletti Research Building, Rhode Island Hospital, 55 Claverick Street, Room 419, Providence, RI 02903. Tel: 401-444-7364; Fax: 401-444-2939;
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11
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Yalcin EB, McLean T, Tong M, de la Monte SM. Progressive white matter atrophy with altered lipid profiles is partially reversed by short-term abstinence in an experimental model of alcohol-related neurodegeneration. Alcohol 2017; 65:51-62. [PMID: 29084630 DOI: 10.1016/j.alcohol.2017.05.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 05/09/2017] [Accepted: 05/12/2017] [Indexed: 01/01/2023]
Abstract
Chronic ethanol exposure causes white matter (WM) atrophy and degeneration with major impairments in the structural integrity of myelin. Since myelin is composed of oligodendrocyte lipid-rich membranes, understanding the consequences and reversibility of alcohol-related oligodendrocyte dysfunction in relation to myelin structure could provide new insights into the pathogenesis of WM degeneration and potential strategies for treatment. Adult male Long Evans rats were pair-fed with isocaloric liquid diets containing 0% or 26% ethanol (caloric) for 3 or 8 weeks. During the last 2 weeks of feeding, the ethanol groups were binged with 2 g/kg of ethanol by intraperitoneal (i.p.) injection on Mondays, Wednesdays, and Fridays; controls were treated with i.p. saline. For recovery effects, at the 6-week time point, ethanol exposures were tapered over 2 days, and then discontinued, rendering the rats ethanol-free for 12 days. Anterior corpus callosum WM lipid ion profiles were analyzed using matrix-assisted laser desorption ionization-imaging mass spectrometry (MALDI-IMS) and correlated with histopathology. Ethanol exposures caused progressive atrophy and reductions in myelin staining intensity within the corpus callosum, whereas short-term recovery partially reversed those effects. MALDI-IMS demonstrated striking ethanol-associated alterations in WM lipid profiles characterized by reduced levels of phosphatidylinositols, phosphatidylserines, phosphatidylethanolamines, and sulfatides, and partial "normalization" of lipid expression with recovery. Ethanol exposure duration and recovery responses were further distinguished by heatmap hierarchical dendrogram and PCA plots. In conclusion, chronic+binge ethanol exposures caused progressive, partially reversible WM atrophy with myelin loss associated with reduced expression of WM phospholipids and sulfatides. The extent of WM lipid abnormalities suggests that ethanol broadly impairs molecular and biochemical functions regulating myelin synthesis, degradation, and maintenance in oligodendrocytes.
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Liang Z, Wu R, Xie W, Xie C, Wu J, Geng S, Li X, Zhu M, Zhu W, Zhu J, Huang C, Ma X, Xu W, Zhong C, Han H. Effects of Curcumin on Tobacco Smoke-induced Hepatic MAPK Pathway Activation and Epithelial-Mesenchymal Transition In Vivo. Phytother Res 2017; 31:1230-1239. [PMID: 28585748 DOI: 10.1002/ptr.5844] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 05/09/2017] [Accepted: 05/10/2017] [Indexed: 12/11/2022]
Abstract
Tobacco smoke is a major risk factor for hepatic cancer. Epithelial-mesenchymal transition (EMT) induced by tobacco smoke is crucially involved in the initiation and development of cancer. Mitogen-activated protein kinase (MAPK) pathways play important roles in tobacco smoke-associated carcinogenesis including EMT process. The chemopreventive effect of curcumin supplementation against cancers has been reported. In this study, we investigated the effects of tobacco smoke on MAPK pathway activation and EMT alterations, and then the preventive effect of curcumin was examined in the liver of BALB/c mice. Our results indicated that exposure of mice to tobacco smoke for 12 weeks led to activation of ERK1/2, JNK, p38 and ERK5 pathways as well as activator protein-1 (AP-1) proteins in liver tissue. Exposure of mice to tobacco smoke reduced the hepatic mRNA and protein expression of the epithelial markers, while the hepatic mRNA and protein levels of the mesenchymal markers were increased. Treatment of curcumin effectively attenuated tobacco smoke-induced activation of ERK1/2 and JNK MAPK pathways, AP-1 proteins and EMT alterations in the mice liver. Our data suggested the protective effect of curcumin in tobacco smoke-triggered MAPK pathway activation and EMT in the liver of BALB/c mice, thus providing new insights into the chemoprevention of tobacco smoke-associated hepatic cancer. Copyright © 2017 John Wiley & Sons, Ltd.
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Affiliation(s)
- Zhaofeng Liang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Rui Wu
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
- Chongchuanqu Market Supervision Administration, Nantong, 226006, China
| | - Wei Xie
- Institute of Food Safety and Assessment, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, 211166, China
| | - Chunfeng Xie
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Jieshu Wu
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Shanshan Geng
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Xiaoting Li
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Mingming Zhu
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Weiwei Zhu
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Jianyun Zhu
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Cong Huang
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Xiao Ma
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Wenrong Xu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Caiyun Zhong
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Hongyu Han
- Department of Clinical Nutrition, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, 510060, China
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13
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Gao B, Xu MJ, Bertola A, Wang H, Zhou Z, Liangpunsakul S. Animal Models of Alcoholic Liver Disease: Pathogenesis and Clinical Relevance. Gene Expr 2017; 17:173-186. [PMID: 28411363 PMCID: PMC5500917 DOI: 10.3727/105221617x695519] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Alcoholic liver disease (ALD), a leading cause of chronic liver injury worldwide, comprises a range of disorders including simple steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Over the last five decades, many animal models for the study of ALD pathogenesis have been developed. Recently, a chronic-plus-binge ethanol feeding model was reported. This model induces significant steatosis, hepatic neutrophil infiltration, and liver injury. A clinically relevant model of high-fat diet feeding plus binge ethanol was also developed, which highlights the risk of excessive binge drinking in obese/overweight individuals. All of these models recapitulate some features of the different stages of ALD and have been widely used by many investigators to study the pathogenesis of ALD and to test for therapeutic drugs/components. However, these models are somewhat variable, depending on mouse genetic background, ethanol dose, and animal facility environment. This review focuses on these models and discusses these variations and some methods to improve the feeding protocol. The pathogenesis, clinical relevance, and translational studies of these models are also discussed.
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Affiliation(s)
- Bin Gao
- *Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Ming-Jiang Xu
- *Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Adeline Bertola
- *Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
- †Université Côte d’Azur, INSERM, Centre Méditerranéen de Médecine Moléculaire, Nice, France
| | - Hua Wang
- *Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
- ‡Department of Oncology, The First Affiliated Hospital, Institute for Liver Diseases of Anhui Medical University, Hefei, P.R. China
| | - Zhou Zhou
- *Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Suthat Liangpunsakul
- §Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- ¶Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
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Papp-Peka A, Tong M, Kril JJ, De La Monte SM, Sutherland GT. The Differential Effects of Alcohol and Nicotine-Specific Nitrosamine Ketone on White Matter Ultrastructure. Alcohol Alcohol 2017; 52:165-171. [PMID: 28182194 PMCID: PMC6075461 DOI: 10.1093/alcalc/agw067] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Revised: 08/15/2016] [Accepted: 08/29/2016] [Indexed: 01/04/2023] Open
Abstract
Aims The chronic consumption of alcohol is known to result in neurodegeneration and impairment of cognitive function. Pathological and neuroimaging studies have confirmed that brain atrophy in alcoholics is mainly due to widespread white matter (WM) loss with neuronal loss restricted to specific regions, such as the prefrontal cortex. Neuroimaging studies of cigarette smokers also suggest that chronic inhalation of tobacco smoke leads to brain atrophy, although the neurotoxic component is unknown. As a high proportion of chronic alcoholics also smoke cigarettes it has been hypothesized that at least some alcohol-related brain damage is due to tobacco smoke exposure. Methods 39 Long Evans rats were subjected to 8 weeks exposure to alcohol and/or 5 weeks co-exposure to nicotine-specific nitrosamine ketone (NNK), a proxy for tobacco smoke. Their frontal WM was then assayed with transmission electron microscopy. Results NNK and ethanol co-exposure had a synergistic effect in decreasing myelinated fibre density. Furthermore, NNK treatment led to a greater reduction in myelin sheath thickness than ethanol whereas only the ethanol-treated animals showed a decrease in unmyelinated fibre density. Conclusion These data suggest that NNK causes WM degeneration, an effect that is exacerbated by alcohol, but unlike alcohol, it has little impact on the neuronal components of the brain.
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Affiliation(s)
- A Papp-Peka
- Charles Perkins Centre, Discipline of Pathology, School of Medical Sciences, The University of Sydney, Johns Hopkins Drive, Camperdown NSW 2050, Australia
| | | | - J J Kril
- Charles Perkins Centre, Discipline of Pathology, School of Medical Sciences, The University of Sydney, Johns Hopkins Drive, Camperdown NSW 2050, Australia
| | | | - G T Sutherland
- Charles Perkins Centre, Discipline of Pathology, School of Medical Sciences, The University of Sydney, Johns Hopkins Drive, Camperdown NSW 2050, Australia
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15
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Sinha-Hikim AP, Sinha-Hikim I, Friedman TC. Connection of Nicotine to Diet-Induced Obesity and Non-Alcoholic Fatty Liver Disease: Cellular and Mechanistic Insights. Front Endocrinol (Lausanne) 2017; 8:23. [PMID: 28239368 PMCID: PMC5300964 DOI: 10.3389/fendo.2017.00023] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 01/25/2017] [Indexed: 12/18/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) poses a serious health hazard affecting 20-40% of adults in the general population in the USA and over 70% of the obese and extremely obese people. In addition to obesity, nicotine is recognized as a risk factor for NAFLD, and it has been reported that nicotine can exaggerate obesity-induced hepatic steatosis. The development of NAFLD has serious clinical complications because of its potential progression from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. Multiple mechanisms can be involved in nicotine plus high-fat diet-induced (HFD) hepatic steatosis. Emerging evidence now suggests that nicotine exacerbates hepatic steatosis triggered by HFD, through increased oxidative stress and hepatocellular apoptosis, decreased phosphorylation (inactivation) of adenosine-5-monophosphate-activated protein kinase and, in turn, up-regulation of sterol response-element binding protein 1-c, fatty acid synthase, and activation of acetyl-coenzyme A-carboxylase, leading to increased hepatic lipogenesis. There is also growing evidence that chronic endoplasmic reticulum stress through regulation of several pathways leading to oxidative stress, inflammation, perturbed hepatic lipid homeostasis, apoptosis, and autophagy can induce hepatic steatosis and its progression to NASH. Evidence also suggests a central role of the gut microbiota in obesity and its related disorders, including NAFLD. This review explores the contribution of nicotine and obesity to the development of NAFLD and its molecular underpinning.
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Affiliation(s)
- Amiya P. Sinha-Hikim
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
- David Geffen School of Medicine at University of California, Los Angeles, CA, USA
| | - Indrani Sinha-Hikim
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
- David Geffen School of Medicine at University of California, Los Angeles, CA, USA
| | - Theodore C. Friedman
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
- David Geffen School of Medicine at University of California, Los Angeles, CA, USA
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16
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Yalcin EB, Tong M, de la Monte SM. Enzymatic Responses to Alcohol and Tobacco Nicotine-Derived Nitrosamine Ketone Exposures in Long Evans Rat Livers. AUSTIN LIVER 2016; 1:1003. [PMID: 29658012 PMCID: PMC5898820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
BACKGROUND Chronic feeding plus binge administration of ethanol causes very high blood alcohol concentrations. However, its co-administration with tobacco Nicotine-Derived Nitrosamine Ketone (NNK) results in somewhat lower blood alcohol levels, suggesting that NNK and therefore smoking, alters alcohol metabolism in the liver. To explore this hypothesis, we examined effects of ethanol and/or NNK exposures on the expression and activity levels of enzymes that regulate their metabolism in liver. METHODS This study utilized a 4-way model in which Long Evans rats were fed liquid diets containing 0% or 26% ethanol for 8 weeks, and respectively i.p injected with saline or 2 g/kg of ethanol 3 times/week during Weeks 7 and 8. The control and ethanol-exposed groups were each sub-divided and further i.p treated with 2 mg/kg of NNK or saline (3×/week) in Weeks 3-8. ADH, catalase and ALDH activities were measured using commercial kits. CYP450 mRNA levels (17 isoforms) were measured by qRT-PCR analysis. RESULTS Ethanol significantly increased hepatic ADH but not catalase or ALDH activity. NNK had no effect on ADH, ALDH, or catalase, but when combined with ethanol, it increased ADH activity above the levels measured in all other groups. Ethanol increased CYP2C7, while NNK increased CYP2B1 and CYP4A1mRNA levels relative to control. In contrast, dual ethanol + NNK exposures inhibited CYP2B1 and CYP4A1 expression relative to NNK. Conclusion: Dual exposures to ethanol and NNK increase hepatic ethanol metabolism, and ethanol and/or NNK exposures alter the expression of CYP450 isoforms that are utilized in NNK and fatty acid metabolism.
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Affiliation(s)
- E B Yalcin
- Liver Research Center, Division of Gastroenterology and Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, USA
| | - M Tong
- Liver Research Center, Division of Gastroenterology and Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, USA
| | - S M de la Monte
- Liver Research Center, Division of Gastroenterology and Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, USA
- Departments of Neurology, Neurosurgery and Pathology, Rhode Island Hospital and the Alpert Medical School of Brown University, USA
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17
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Deochand C, Tong M, Agarwal AR, Cadenas E, de la Monte SM. Tobacco Smoke Exposure Impairs Brain Insulin/IGF Signaling: Potential Co-Factor Role in Neurodegeneration. J Alzheimers Dis 2016; 50:373-86. [PMID: 26682684 DOI: 10.3233/jad-150664] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Human studies suggest tobacco smoking is a risk factor for cognitive impairment and neurodegeneration, including Alzheimer's disease (AD). However, experimental data linking tobacco smoke exposures to underlying mediators of neurodegeneration, including impairments in brain insulin and insulin-like growth factor (IGF) signaling in AD are lacking. OBJECTIVE This study tests the hypothesis that cigarette smoke (CS) exposures can impair brain insulin/IGF signaling and alter expression of AD-associated proteins. METHODS Adult male A/J mice were exposed to air for 8 weeks (A8), CS for 4 or 8 weeks (CS4, CS8), or CS8 followed by 2 weeks recovery (CS8+R). Gene expression was measured by qRT-PCR analysis and proteins were measured by multiplex bead-based or direct binding duplex ELISAs. RESULTS CS exposure effects on insulin/IGF and insulin receptor substrate (IRS) proteins and phosphorylated proteins were striking compared with the mRNA. The main consequences of CS4 or CS8 exposures were to significantly reduce insulin R, IGF-1R, IRS-1, and tyrosine phosphorylated insulin R and IGF-1R proteins. Paradoxically, these effects were even greater in the CS8+R group. In addition, relative levels of S312-IRS-1, which inhibits downstream signaling, were increased in the CS4, CS8, and CS8+R groups. Correspondingly, CS and CS8+R exposures inhibited expression of proteins and phosphoproteins required for signaling through Akt, PRAS40, and/or p70S6K, increased AβPP-Aβ, and reduced ASPH protein, which is a target of insulin/IGF-1 signaling. CONCLUSION Secondhand CS exposures caused molecular and biochemical abnormalities in brain that overlap with the findings in AD, and many of these effects were sustained or worsened despite short-term CS withdrawal.
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Affiliation(s)
- Chetram Deochand
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.,Divisions of Gastroenterology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.,Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Ming Tong
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.,Divisions of Gastroenterology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.,Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Amit R Agarwal
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
| | - Enrique Cadenas
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
| | - Suzanne M de la Monte
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.,Divisions of Gastroenterology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.,Divisions of Neuropathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.,Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.,Department of Pathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.,Department of Neurology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.,Department of Neurosurgery, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
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18
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Yalcin EB, Nunez K, Tong M, de la Monte SM. Differential Sphingolipid and Phospholipid Profiles in Alcohol and Nicotine-Derived Nitrosamine Ketone-Associated White Matter Degeneration. Alcohol Clin Exp Res 2016; 39:2324-33. [PMID: 26756797 DOI: 10.1111/acer.12909] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Accepted: 09/15/2015] [Indexed: 12/28/2022]
Abstract
BACKGROUND Alcohol-mediated neurodegeneration is associated with white matter (WM) atrophy due to targeting of myelin and oligodendrocytes. However, variability in disease severity suggests cofactors contribute to WM degeneration. We examined the potential cofactor role of the tobacco-specific nitrosamine, nicotine-derived nitrosamine ketone (NNK), because smoking causes WM atrophy and most heavy drinkers consume tobacco products. METHODS This 8-week study of Long Evans rats had 4 treatment groups: control; NNK-2 mg/kg, 3×/wk in weeks 3 to 8; ethanol (EtOH) (chronic-26% caloric + binge-2 g/kg, 3×/wk in weeks 7 to 8); and EtOH + NNK. Exposure effects on WM lipid biochemical profiles and in situ distributions were examined using matrix-assisted laser desorption/ionization imaging mass spectrometry and tandem mass spectrometry. RESULTS NNK mainly caused WM fiber degeneration and fiber loss, EtOH caused demyelination, and dual exposures had additive effects. EtOH and EtOH + NNK decreased WM (including corpus callosum) and/or gray matter (hypothalamus, cortex, medial temporal) levels of several phosphatidylserine, phosphatidylinositol, and sphingolipid (sulfatide [ST]) species, while NNK increased or had minimal effect on these lipids. EtOH + NNK had broader and larger inhibitory effects on phospholipids and ST than EtOH or NNK alone. Principal component analysis clustered control with NNK, and EtOH with EtOH + NNK groups, highlighting the independent EtOH- rather than NNK-driven responses. CONCLUSIONS Chronic EtOH exposures decreased several phospholipid and sphingolipid species in brain, while concomitant NNK exposures exacerbated these effects. These findings support our hypothesis that tobacco smoking is a pathogenic cofactor in alcohol-mediated WM degeneration.
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Affiliation(s)
- Emine B Yalcin
- Liver Research Center, Division of Gastroenterology, Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, Rhode Island.,Rhode Island Hospital and the Alpert Medical School of Brown University (EBY, MT, SMdlM), Providence, Rhode Island
| | | | - Ming Tong
- Liver Research Center, Division of Gastroenterology, Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, Rhode Island.,Rhode Island Hospital and the Alpert Medical School of Brown University (EBY, MT, SMdlM), Providence, Rhode Island
| | - Suzanne M de la Monte
- Liver Research Center, Division of Gastroenterology, Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, Rhode Island.,Rhode Island Hospital and the Alpert Medical School of Brown University (EBY, MT, SMdlM), Providence, Rhode Island.,Departments of Neurology, Neurosurgery and Pathology (SMdlM), Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, Rhode Island
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19
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Aizawa K, Liu C, Tang S, Veeramachaneni S, Hu KQ, Smith DE, Wang XD. Tobacco carcinogen induces both lung cancer and non-alcoholic steatohepatitis and hepatocellular carcinomas in ferrets which can be attenuated by lycopene supplementation. Int J Cancer 2016; 139:1171-81. [PMID: 27116542 PMCID: PMC5085066 DOI: 10.1002/ijc.30161] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 04/15/2016] [Indexed: 12/23/2022]
Abstract
Early epidemiologic studies have reported that tobacco smoking, which is causally associated with liver cancer, is an independent risk factor for non-alcoholic fatty liver diseases (NAFLD). Lycopene from tomatoes has been shown to be a potential preventive agent against NAFLD and hepatocellular carcinoma (HCC). In the present study, we investigated whether the tobacco carcinogen 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces lesions in both lungs and livers of ferrets with or without lycopene intervention. Male ferrets (6 groups, n = 8-10) were treated either with NNK (50 mg/kg BW, i.p., once a month for four consecutive months) or saline with or without dietary lycopene supplementation (2.2 and 6.6 mg/kg BW/day, respectively) for 26 weeks. Results demonstrate that NNK exposure results in higher incidences of lung tumors, HCC and steatohepatitis (which is characterized by severe inflammatory cell infiltration with concurrent fat accumulation in liver, hepatocellular ballooning degeneration and increased NF-κB expression), as well as elevations in bilirubin and AST levels in ferrets. Lycopene supplementation at two doses prevented NNK-induced expressions of α7 nicotinic acetylcholine receptor in the lung and NF-κB and CYP2E1 in the liver and attenuated the NNK-induced mortality and pathological lesions in both the lungs and livers of ferrets. The present study provided strong experimental evidence that the tobacco carcinogen NNK can induce both HCC and steatohepatitis in the ferrets and can be a useful model for studying tobacco carcinogen-associated NAFLD and liver cancer. Furthermore, lycopene could provide potential benefits against smoke carcinogen-induced pulmonary and hepatic injury.
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Affiliation(s)
- Koichi Aizawa
- Nutrition and Cancer Biology Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
- Nature & Wellness Research Department, Research & Development Division, Kagome Co., Ltd., Tochigi, Japan
| | - Chun Liu
- Nutrition and Cancer Biology Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
| | - Sanyuan Tang
- Nutrition and Cancer Biology Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
| | - Sudipta Veeramachaneni
- Nutrition and Cancer Biology Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
| | - Kang-Quan Hu
- Nutrition and Cancer Biology Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
| | - Donald E. Smith
- Comparative Biology Unit, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
| | - Xiang-Dong Wang
- Nutrition and Cancer Biology Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
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20
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Tong M, Andreani T, Krotow A, Gundogan F, de la Monte SM. Potential Contributions of the Tobacco Nicotine-Derived Nitrosamine Ketone to White Matter Molecular Pathology in Fetal Alcohol Spectrum Disorder. ACTA ACUST UNITED AC 2016; 3. [PMID: 28868525 PMCID: PMC5575815 DOI: 10.15436/2377-1348.16.729] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background Fetal alcohol spectrum disorder (FASD) is associated with long-term
deficits in cognitive and motor functions. Previous studies linked
neurodevelopmental abnormalities to increased oxidative stress and white
matter hypotrophy. However, similar effects occur with low-dose nitrosamine
exposures, alcohol abuse correlates with cigarette smoking, and tobacco
smoke contains tobacco-specific nitrosamines, including NNK. Hypothesis Tobacco smoke exposure is a co-factor in FASD. Design Long Evans rat pups were i.p. administered ethanol (2 g/kg) on
postnatal days (P) 2, 4, 6 and/or NNK (2 mg/kg) on P3, P5, and P7 to
simulate third trimester human exposures. Oligodendroglial
myelin-associated, neuroglial, and relevant transcription factor mRNA
transcripts were measured using targeted PCR arrays. Results Ethanol and NNK differentially altered the expression of immature and
mature oligodendroglial, neuronal and astrocytic structural and
plasticity-associated, and various transcription factor genes. NNK’s
effects were broader and more pronounced than ethanol’s, and
additive or synergistic effects of dual exposures impacted expression of all
four categories of genes investigated. Conclusion Developmental exposures to alcohol and NNK (via tobacco smoke)
contribute to sustained abnormalities in brain white matter structure and
function via distinct but overlapping alterations in the expression of genes
that regulate oligodendrocyte survival, maturation and function, neuroglial
structural integrity, and synaptic plasticity. The results support the
hypothesis that smoking may contribute to brain abnormalities associated
with FASD.
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Affiliation(s)
- Ming Tong
- Department of Medicine, Division of Gastroenterology, and the Liver Research Center Rhode Island Hospital, Providence, RI.,Warren Alpert Medical School of Brown University, Providence, RI
| | - Tomas Andreani
- Department of Medicine, Division of Gastroenterology, and the Liver Research Center Rhode Island Hospital, Providence, RI
| | | | - Fusun Gundogan
- Warren Alpert Medical School of Brown University, Providence, RI.,Department of Pathology, Women and Infants Hospital of Rhode Island, Providence, RI
| | - Suzanne M de la Monte
- Department of Medicine, Division of Gastroenterology, and the Liver Research Center Rhode Island Hospital, Providence, RI.,Warren Alpert Medical School of Brown University, Providence, RI.,Pathobiology Graduate Program, Brown University, Providence, RI.,Departments of Pathology and Neurology, and the Division of Neuropathology, Rhode Island Hospital, Providence, RI
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21
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Re E, Tong M, de la Monte SM. Tobacco Nitrosamine Exposures Contribute to Fetal Alcohol Spectrum Disorder Associated Cerebellar Dysgenesis. ACTA ACUST UNITED AC 2016; 8:10-21. [PMID: 29201262 PMCID: PMC5711469 DOI: 10.5539/ijb.v8n3p10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Variability in the phenotypic features and severity of fetal alcohol spectrum disorder (FASD) is not fully linked to alcohol dose. We hypothesize that FASD-type neurodevelopmental abnormalities may be caused by exposures to the tobacco-specific nitrosamine, NNK, since a high percentage of pregnant women who drink also smoke. In vitro experiments using PNET2 human cerebellar neuronal cultures examined ethanol and NNK effects on viability and mitochondrial function. Early postnatal rat cerebellar slice cultures were used to examine effects of ethanol and NNK on cerebellar histology and neuroglial and stress protein expression. Ethanol (50 mM) decreased viability and ATP content and increased mitochondrial mass, while NNK (100 μM or higher) selectively inhibited mitochondrial function. The slice culture studies demonstrated striking adverse effects of ethanol, NNK and ethanol+NNK exposures manifested by architectural disorganization of the cortex with relative reductions of internal granule cells, increases in external granule cells, and loss of Purkinje cells. Ethanol, NNK, and ethanol+NNK inhibited expression of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), and increased levels of 4-hydroxynonenal (HNE). In addition, ethanol increased activated Caspase 3, NNK decreased tau and phospho-tau, and ethanol+NNK inhibited expression of Aspartyl-β-hydroxylase (ASPH), which mediates neuronal migration. In conclusion, ethanol and NNK were shown to exert independent but overlapping adverse effects on cerebellar cortical development, neuronal viability, function, and neuroglial protein expression. These findings support our hypothesis that NNK exposures via tobacco smoking in pregnancy can contribute to FASD-associated neurodevelopmental abnormalities.
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Affiliation(s)
- Edward Re
- Warren Alpert Medical School of Brown University, Providence, RI
| | - Ming Tong
- Department of Medicine, Division of Gastroenterology, and Liver Research Center Rhode Island Hospital, Providence, RI.,Warren Alpert Medical School of Brown University, Providence, RI
| | - Suzanne M de la Monte
- Department of Medicine, Division of Gastroenterology, and Liver Research Center Rhode Island Hospital, Providence, RI.,Departments of Pathology, Neurology, and Neurosurgery, and the Division of Neuropathology, Rhode Island Hospital, Providence, RI.,Warren Alpert Medical School of Brown University, Providence, RI
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de la Monte SM, Tong M, Agarwal AR, Cadenas E. Tobacco Smoke-Induced Hepatic Injury with Steatosis, Inflammation, and Impairments in Insulin and Insulin-Like Growth Factor Signaling. ACTA ACUST UNITED AC 2016; 6. [PMID: 27525191 PMCID: PMC4979551 DOI: 10.4172/2161-0681.1000269] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Background Alcoholic liver disease (ALD) is associated with impairments in hepatic insulin and insulin-like growth factor (IGF) signaling through cell growth, survival, and metabolic pathways. Since not all heavy drinkers develop ALD, co-factors may be important. Epidemiologic data indicate that most heavy drinkers smoke tobacco and experimental data revealed that low-level nitrosamine exposures, including those from tobacco, can cause steatohepatitis with hepatic insulin/IGF resistance and exacerbate ALD. We hypothesize that cigarette smoke (CS) exposures also cause liver injury with impaired hepatic insulin/IGF signaling, and thereby contribute to ALD. Methods Adult male A/J mice were exposed to air for 8 weeks (A8), CS for 4 (CS4) or 8 (CS8) weeks, or CS for 8 weeks with 2 weeks recovery (CS8+R). Results CS exposures caused progressive liver injury with disruption of the normal hepatic chord architecture, lobular inflammation, apoptosis or necrosis, micro-steatosis, sinusoidal dilatation, and nuclear pleomorphism. Histopathological liver injury scores increased significantly from A8 to CS4 and then further to CS8 (P<0.0001). The mean histological grade was also higher in CS8+R relative to A8 (P<0.0001) but lower than in CS4, reflecting partial resolution of injury by CS withdrawal. CS exposures impaired insulin and IGF-1 signaling through IRS-1, Akt, GSK-3β, and PRAS40. Livers from CS8+R mice had normalized or elevated levels of insulin receptor, pYpY-Insulin-R, 312S-IRS-1, 473S-Akt, S9-GSK-3β, and pT246-PRAS40 relative to A8, CS4, or CS8, reflecting partial recovery. Conclusion CS-mediated liver injury and steatohepatitis with impairments in insulin/IGF signalling are reminiscent of the findings in ALD. Therefore, CS exposures (either first or second-hand) may serve as a co-factor in ALD. The persistence of several abnormalities following CS exposure cessation suggests that some aspects of CS-mediated hepatic metabolic dysfunction are not readily reversible.
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Affiliation(s)
- Suzanne M de la Monte
- Liver Research Center, Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, USA; Division of Neuropathology and Departments of Pathology, Neurology, and Neurosurgery, Rhode Island Hospital and the Alpert Medical School of Brown University, USA
| | - M Tong
- Liver Research Center, Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, USA
| | - A R Agarwal
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
| | - E Cadenas
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
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23
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Zabala V, Silbermann E, Re E, Andreani T, Tong M, Ramirez T, Gundogan F, de la Monte SM. Potential Co-Factor Role of Tobacco Specific Nitrosamine Exposures in the Pathogenesis of Fetal Alcohol Spectrum Disorder. GYNECOLOGY AND OBSTETRICS RESEARCH : OPEN JOURNAL 2016; 2:112-125. [PMID: 28845454 PMCID: PMC5570438 DOI: 10.17140/goroj-2-125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND Cerebellar developmental abnormalities in Fetal Alcohol Spectrum Disorder (FASD) are linked to impairments in insulin signaling. However, co-morbid alcohol and tobacco abuses during pregnancy are common. Since smoking leads to tobacco specific Nitrosamine (NNK) exposures which have been shown to cause brain insulin resistance, we hypothesized that neurodevelopmental abnormalities in FASD could be mediated by ethanol and/or NNK. METHODS Long Evans rat pups were intraperitoneal (IP) administered ethanol (2 g/kg) on postnatal days (P) 2, 4, 6 and/or NNK (2 mg/kg) on P3, P5, and P7 to simulate third trimester human exposures. The Cerebellar function, histology, insulin and Insulin-like Growth Factor (IGF) signaling, and neuroglial protein expression were assessed. RESULTS Ethanol, NNK and ethanol+NNK groups had significant impairments in motor function (rotarod tests), abnormalities in cerebellar structure (Purkinje cell loss, simplification and irregularity of folia, and altered white matter), signaling through the insulin and IGF-1 receptors, IRS-1, Akt and GSK-3β, and reduced expression of several important neuroglial proteins. Despite similar functional effects, the mechanisms and severity of NNK and ethanol+NNK induced alterations in cerebellar protein expression differed from those of ethanol. CONCLUSIONS Ethanol and NNK exert independent but overlapping adverse effects on cerebellar development, function, insulin signaling through cell survival, plasticity, metabolic pathways, and neuroglial protein expression. The results support the hypothesis that tobacco smoke exposure can serve as a co-factor mediating long-term effects on brain structure and function in FASD.
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Affiliation(s)
- Valerie Zabala
- Molecular Pharmacology and Physiology Graduate Program, Brown University, Providence, RI, USA
| | | | - Edward Re
- Alpert Medical School of Brown University, Providence, RI, USA
| | - Tomas Andreani
- Graduate Program in Neuroscience, Northwestern University, Chicago, IL, USA
| | - Ming Tong
- Liver Research Center, Division of Gastroenterology and Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA
| | | | - Fusun Gundogan
- Department of Pathology, Women and Infants Hospital of Rhode Island, Alpert Medical School of Brown University, Providence, RI, USA
| | - Suzanne M. de la Monte
- Departments of Neurology, Neurosurgery, and Pathology, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA
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24
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Yalcin E, de la Monte S. Tobacco nitrosamines as culprits in disease: mechanisms reviewed. J Physiol Biochem 2016; 72:107-20. [PMID: 26767836 PMCID: PMC4868960 DOI: 10.1007/s13105-016-0465-9] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 01/05/2016] [Indexed: 12/29/2022]
Abstract
The link between tobacco abuse and cancer is well-established. However, emerging data indicate that toxins in tobacco smoke cause cellular injury due to enhanced toxic/metabolic effects of metabolites, disruption of intracellular signaling mechanisms, and formation of DNA, protein, and lipid adducts that impair function and promote oxidative stress and inflammation. These effects of smoking, which are largely non-carcinogenic, can be produced by tobacco-specific nitrosamines and their metabolites. These factors could account for the increased rates of neurodegeneration and insulin resistance diseases among smokers. Herein, we review nicotine and tobacco-specific nitrosamine metabolism, mechanisms of adduct formation, DNA damage, mutagenesis, and potential mechanisms of disease.
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Affiliation(s)
- Emine Yalcin
- Departments of Pathology (Neuropathology), Neurology, and Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, 55 Claverick Street, Room 419, Providence, RI, 02903, USA
| | - Suzanne de la Monte
- Departments of Pathology (Neuropathology), Neurology, and Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, 55 Claverick Street, Room 419, Providence, RI, 02903, USA.
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25
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Bertino G, Ardiri A, Proiti M, Rigano G, Frazzetto E, Demma S, Ruggeri MI, Scuderi L, Malaguarnera G, Bertino N, Rapisarda V, Di Carlo I, Toro A, Salomone F, Malaguarnera M, Bertino E, Malaguarnera M. Chronic hepatitis C: This and the new era of treatment. World J Hepatol 2016; 8:92-106. [PMID: 26807205 PMCID: PMC4716531 DOI: 10.4254/wjh.v8.i2.92] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 09/29/2015] [Accepted: 12/18/2015] [Indexed: 02/06/2023] Open
Abstract
Over the last years it has started a real revolution in the treatment of chronic hepatitis C. This occurred for the availability of direct-acting antiviral agents that allow to reach sustained virologic response in approximately 90% of cases. In the near future further progress will be achieved with the use of pan-genotypic drugs with high efficacy but without side effects.
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26
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Nunez K, Kay J, Krotow A, Tong M, Agarwal AR, Cadenas E, de la Monte SM. Cigarette Smoke-Induced Alterations in Frontal White Matter Lipid Profiles Demonstrated by MALDI-Imaging Mass Spectrometry: Relevance to Alzheimer's Disease. J Alzheimers Dis 2016; 51:151-63. [PMID: 26836183 PMCID: PMC5575809 DOI: 10.3233/jad-150916] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Meta-analysis has shown that smokers have significantly increased risks for Alzheimer's disease (AD), and neuroimaging studies showed that smoking alters white matter (WM) structural integrity. OBJECTIVE Herein, we characterize the effects of cigarette smoke (CS) exposures and withdrawal on WM myelin lipid composition using matrix assisted laser desorption and ionization-imaging mass spectrometry (MALDI-IMS). METHODS Young adult male A/J mice were exposed to air (8 weeks; A8), CS (4 or 8 weeks; CS4, CS8), or CS8 followed by 2 weeks recovery (CS8 + R). Frontal lobe WM was examined for indices of lipid and protein oxidation and lipid profile alterations by MALDI-IMS. Lipid ions were identified by MS/MS with the LIPID MAPS prediction tools database. Inter-group comparisons were made using principal component analysis and R-generated heatmap. RESULTS CS increased lipid and protein adducts such that higher levels were present in CS8 compared with CS4 samples. CS8 + R reversed CS8 effects and normalized the levels of oxidative stress. MALDI-IMS demonstrated striking CS-associated alterations in WM lipid profiles characterized by either reductions or increases in phospholipids (phosphatidylinositol, phosphatidylserine, phosphatidylcholine, or phosphatidylethanolamine) and sphingolipids (sulfatides), and partial reversal of CS's inhibitory effects with recovery. The heatmap hierarchical dendrogram and PCA distinguished CS exposure, duration, and withdrawal effects on WM lipid profiles. CONCLUSION CS-mediated WM degeneration is associated with lipid peroxidation, protein oxidative injury, and alterations in myelin lipid composition, including shifts in phospholipids and sphingolipids needed for membrane integrity, plasticity, and intracellular signaling. Future goals are to delineate WM abnormalities in AD using MALDI-IMS, and couple the findings with MRI-mass spectroscopy to improve in vivo diagnostics and early detection of brain biochemical responses to treatment.
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Affiliation(s)
- Kavin Nunez
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Molecular Pharmacology, Physiology, and Biotechnology, Providence, RI, USA
| | - Jared Kay
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Departments of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Alexander Krotow
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Pathobiology Graduate Programs at Brown University, Providence, RI, USA
| | - Ming Tong
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Departments of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Amit R. Agarwal
- The Department of Pharmacology Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
| | - Enrique Cadenas
- The Department of Pharmacology Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
| | - Suzanne M. de la Monte
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Divisions of Gastroenterology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Divisions of Neuropathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Departments of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Departments of Pathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Departments of Neurology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Departments of Neurosurgery, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
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27
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Yu R, Deochand C, Krotow A, Leão R, Tong M, Agarwal AR, Cadenas E, de la Monte SM. Tobacco Smoke-Induced Brain White Matter Myelin Dysfunction: Potential Co-Factor Role of Smoking in Neurodegeneration. J Alzheimers Dis 2016; 50:133-48. [PMID: 26639972 PMCID: PMC5577392 DOI: 10.3233/jad-150751] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Meta-analysis studies showed that smokers have increased risk for developing Alzheimer's disease (AD) compared with non-smokers, and neuroimaging studies revealed that smoking damages white matter structural integrity. OBJECTIVE The present study characterizes the effects of side-stream (second hand) cigarette smoke (CS) exposures on the expression of genes that regulate oligodendrocyte myelin-synthesis, maturation, and maintenance and neuroglial functions. METHODS Adult male A/J mice were exposed to air (8 weeks; A8), CS (4 or 8 weeks; CS4, CS8), or CS8 followed by 2 weeks recovery (CS8 + R). The frontal lobes were used for histology and qRT-PCR analysis. RESULTS Luxol fast blue, Hematoxylin and Eosin stained histological sections revealed CS-associated reductions in myelin staining intensity and narrowing of the corpus callosum. CS exposures broadly decreased mRNA levels of immature and mature oligodendrocyte myelin-associated, neuroglial, and oligodendrocyte-related transcription factors. These effects were more prominent in the CS8 compared with CS4 group, suggesting that molecular abnormalities linked to white matter atrophy and myelin loss worsen with duration of CS exposure. Recovery normalized or upregulated less than 25% of the suppressed genes; in most cases, inhibition of gene expression was either sustained or exacerbated. CONCLUSION CS exposures broadly inhibit expression of genes needed for myelin synthesis and maintenance. These adverse effects often were not reversed by short-term CS withdrawal. The results support the hypothesis that smoking contributes to white matter degeneration, and therefore could be a key risk factor for a number of neurodegenerative diseases, including AD.
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Affiliation(s)
- Rosa Yu
- Liver Research Center, Divisions of Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Gastroenterology and Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Chetram Deochand
- Liver Research Center, Divisions of Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Gastroenterology and Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Molecular Pharmacology and Physiology Graduate Program at Brown University, Providence, RI, USA
| | - Alexander Krotow
- Molecular Pharmacology and Physiology Graduate Program at Brown University, Providence, RI, USA
| | - Raiane Leão
- Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Ming Tong
- Liver Research Center, Divisions of Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Gastroenterology and Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Amit R. Agarwal
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
| | - Enrique Cadenas
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
| | - Suzanne M. de la Monte
- Liver Research Center, Divisions of Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Gastroenterology and Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Neuropathology, and Departments of Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Pathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Neurology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
- Neurosurgery, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
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28
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Tong M, Yu R, Silbermann E, Zabala V, Deochand C, de la Monte SM. Differential Contributions of Alcohol and Nicotine-Derived Nitrosamine Ketone (NNK) to White Matter Pathology in the Adolescent Rat Brain. Alcohol Alcohol 2015; 50:680-9. [PMID: 26373813 DOI: 10.1093/alcalc/agv102] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Accepted: 08/17/2015] [Indexed: 12/30/2022] Open
Abstract
AIM Epidemiologic studies have demonstrated high rates of smoking among alcoholics, and neuroimaging studies have detected white matter atrophy and degeneration in both smokers and individuals with alcohol-related brain disease (ARBD). These findings suggest that tobacco smoke exposure may be a co-factor in ARBD. The present study examines the differential and additive effects of tobacco-specific nitrosamine (NNK) and ethanol exposures on the structural and functional integrity of white matter in an experimental model. METHODS Adolescent Long Evans rats were fed liquid diets containing 0 or 26% ethanol for 8 weeks. In weeks 3-8, rats were treated with nicotine-derived nitrosamine ketone (NNK) (2 mg/kg, 3×/week) or saline by i.p. injection. In weeks 7-8, the ethanol group was binge-administered ethanol (2 g/kg; 3×/week). RESULTS Ethanol, NNK and ethanol + NNK caused striking degenerative abnormalities in white matter myelin and axons, with accompanying reductions in myelin-associated glycoprotein expression. Quantitative RT-PCR targeted array and heatmap analyses demonstrated that ethanol modestly increased, whereas ethanol + NNK sharply increased expression of immature and mature oligodendroglial genes, and that NNK increased immature but inhibited mature oligodendroglial genes. In addition, NNK modulated expression of neuroglial genes in favor of growth cone collapse and synaptic disconnection. Ethanol- and NNK-associated increases in FOXO1, FOXO4 and NKX2-2 transcription factor gene expression could reflect compensatory responses to brain insulin resistance in this model. CONCLUSION Alcohol and tobacco exposures promote ARBD by impairing myelin synthesis, maturation and integrity via distinct but overlapping mechanisms. Public health measures to reduce ARBD should target both alcohol and tobacco abuses.
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Affiliation(s)
- Ming Tong
- Department of Medicine, Division of Gastroenterology, and the Liver Research Center, Rhode Island Hospital, Providence, RI, USA Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Rosa Yu
- Departments of Pathology and Neurology, and the Division of Neuropathology, Rhode Island Hospital, Providence, RI, USA
| | | | - Valerie Zabala
- Molecular Pharmacology and Physiology Graduate Program, Brown University, Providence, RI, USA
| | - Chetram Deochand
- Biotechnology Graduate Program, Brown University, Providence, RI, USA
| | - Suzanne M de la Monte
- Department of Medicine, Division of Gastroenterology, and the Liver Research Center, Rhode Island Hospital, Providence, RI, USA Warren Alpert Medical School of Brown University, Providence, RI, USA Departments of Pathology and Neurology, and the Division of Neuropathology, Rhode Island Hospital, Providence, RI, USA
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