The innate immune response in the central nervous system (CNS) participates in both synaptic plasticity and neural damage. Emerging evidence from human and animal studies supports the role of the neuroimmune system response in many actions of ethanol (EtOH) on the CNS. Research studies have shown that alcohol stimulates brain immune cells, microglia, and astrocytes, by activating innate immune receptors Toll-like receptors (TLRs) and NOD-like receptors (inflammasome NLRs) triggering signaling pathways, which culminate in the production of pro-inflammatory cytokines and chemokines that lead to neuroinflammation. This review focuses on evidence that indicates the participation of TLRs and the inflammasome NLRs signaling response in many effects of EtOH on the CNS, such as neuroinflammation associated with brain damage, cognitive and behavioral dysfunction, and adolescent brain development alterations. It also reviews findings that indicate the role of TLR4-dependent signaling immune molecules in alcohol consumption, reward, and addiction. The research data suggest that overactivation of TLR4 or NLRs increases pro-inflammatory cytokines and mediators to cause neural damage in the cerebral cortex and hippocampus, while modest TLR4 activation, along with the generation of certain cytokines and chemokines in specific brain areas (e.g., amygdala, ventral tegmental area), modulate neurotransmission, alcohol drinking, and alcohol rewards. Elimination of TLR4 and NLRP3 abolishes many neuroimmune effects of EtOH. Despite much progress being made in this area, there are some research gaps and unanswered questions that this review discusses. Finally, potential therapies that target neuroimmune pathways to treat neuropathological and behavioral consequences of alcohol abuse are also evaluated.
{"title":"Impact of the Innate Immune Response in the Actions of Ethanol on the Central Nervous System.","authors":"J. Montesinos, S. Alfonso-Loeches, C. Guerri","doi":"10.1111/acer.13208","DOIUrl":"https://doi.org/10.1111/acer.13208","url":null,"abstract":"The innate immune response in the central nervous system (CNS) participates in both synaptic plasticity and neural damage. Emerging evidence from human and animal studies supports the role of the neuroimmune system response in many actions of ethanol (EtOH) on the CNS. Research studies have shown that alcohol stimulates brain immune cells, microglia, and astrocytes, by activating innate immune receptors Toll-like receptors (TLRs) and NOD-like receptors (inflammasome NLRs) triggering signaling pathways, which culminate in the production of pro-inflammatory cytokines and chemokines that lead to neuroinflammation. This review focuses on evidence that indicates the participation of TLRs and the inflammasome NLRs signaling response in many effects of EtOH on the CNS, such as neuroinflammation associated with brain damage, cognitive and behavioral dysfunction, and adolescent brain development alterations. It also reviews findings that indicate the role of TLR4-dependent signaling immune molecules in alcohol consumption, reward, and addiction. The research data suggest that overactivation of TLR4 or NLRs increases pro-inflammatory cytokines and mediators to cause neural damage in the cerebral cortex and hippocampus, while modest TLR4 activation, along with the generation of certain cytokines and chemokines in specific brain areas (e.g., amygdala, ventral tegmental area), modulate neurotransmission, alcohol drinking, and alcohol rewards. Elimination of TLR4 and NLRP3 abolishes many neuroimmune effects of EtOH. Despite much progress being made in this area, there are some research gaps and unanswered questions that this review discusses. Finally, potential therapies that target neuroimmune pathways to treat neuropathological and behavioral consequences of alcohol abuse are also evaluated.","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"29 1","pages":"2260-2270"},"PeriodicalIF":3.2,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88458082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Ganesan, L. Poluektova, D. Tuma, K. Kharbanda, N. Osna
BACKGROUND Alcohol consumption exacerbates the pathogenesis of hepatitis C virus (HCV) infection and worsens disease outcomes. The exact reasons are not clear yet, but they might be partially attributed to the ability of alcohol to further suppress the innate immunity. Innate immunity is known to be already decreased by HCV in liver cells. METHODS In this study, we aimed to explore the mechanisms of how alcohol metabolism dysregulates IFNα signaling (STAT1 phosphorylation) in HCV+ hepatoma cells. To this end, CYP2E1+ Huh7.5 cells were infected with HCV and exposed to the acetaldehyde (Ach) generating system (AGS). RESULTS Continuously produced Ach suppressed IFNα-induced STAT1 phosphorylation, but increased the level of a protease, USP18 (both measured by Western blot), which interferes with IFNα signaling. Induction of USP18 by Ach was confirmed in primary human hepatocyte cultures and in livers of ethanol-fed HCV transgenic mice. Silencing of USP18 by specific siRNA attenuated the pSTAT1 suppression by Ach. The mechanism by which Ach down-regulates pSTAT1 is related to an enhanced interaction between IFNαR2 and USP18 that finally dysregulates the cross talk between the IFN receptor on the cell surface and STAT1. Furthermore, Ach decreases ISGylation of STAT1 (protein conjugation of a small ubiquitin-like modifier, ISG15, Western blot), which preserves STAT1 activation. Suppressed ISGylation leads to an increase in STAT1 K48 polyubiquitination which allows pSTAT1 degrading by proteasome. CONCLUSIONS We conclude that Ach disrupts IFNα-induced STAT1 phosphorylation by the up-regulation of USP18 to block the innate immunity protection in HCV-infected liver cells, thereby contributing to HCV-alcohol pathogenesis. This, in part, may explain the mechanism of HCV-infection exacerbation/progression in alcohol-abusing patients.
{"title":"Acetaldehyde Disrupts Interferon Alpha Signaling in Hepatitis C Virus-Infected Liver Cells by Up-Regulating USP18.","authors":"M. Ganesan, L. Poluektova, D. Tuma, K. Kharbanda, N. Osna","doi":"10.1111/acer.13226","DOIUrl":"https://doi.org/10.1111/acer.13226","url":null,"abstract":"BACKGROUND\u0000Alcohol consumption exacerbates the pathogenesis of hepatitis C virus (HCV) infection and worsens disease outcomes. The exact reasons are not clear yet, but they might be partially attributed to the ability of alcohol to further suppress the innate immunity. Innate immunity is known to be already decreased by HCV in liver cells.\u0000\u0000\u0000METHODS\u0000In this study, we aimed to explore the mechanisms of how alcohol metabolism dysregulates IFNα signaling (STAT1 phosphorylation) in HCV+ hepatoma cells. To this end, CYP2E1+ Huh7.5 cells were infected with HCV and exposed to the acetaldehyde (Ach) generating system (AGS).\u0000\u0000\u0000RESULTS\u0000Continuously produced Ach suppressed IFNα-induced STAT1 phosphorylation, but increased the level of a protease, USP18 (both measured by Western blot), which interferes with IFNα signaling. Induction of USP18 by Ach was confirmed in primary human hepatocyte cultures and in livers of ethanol-fed HCV transgenic mice. Silencing of USP18 by specific siRNA attenuated the pSTAT1 suppression by Ach. The mechanism by which Ach down-regulates pSTAT1 is related to an enhanced interaction between IFNαR2 and USP18 that finally dysregulates the cross talk between the IFN receptor on the cell surface and STAT1. Furthermore, Ach decreases ISGylation of STAT1 (protein conjugation of a small ubiquitin-like modifier, ISG15, Western blot), which preserves STAT1 activation. Suppressed ISGylation leads to an increase in STAT1 K48 polyubiquitination which allows pSTAT1 degrading by proteasome.\u0000\u0000\u0000CONCLUSIONS\u0000We conclude that Ach disrupts IFNα-induced STAT1 phosphorylation by the up-regulation of USP18 to block the innate immunity protection in HCV-infected liver cells, thereby contributing to HCV-alcohol pathogenesis. This, in part, may explain the mechanism of HCV-infection exacerbation/progression in alcohol-abusing patients.","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"17 1","pages":"2329-2338"},"PeriodicalIF":3.2,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85059240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
1 The Formation, Elimination, Interpretation and Future Research Needs of Phosphatidylethanol 2 (PEth) for Research Studies and Clinical Practice 4 Judith A. Hahn, PhD 5 University of California, San Francisco 7 Raymond F. Anton, MD 8 Medical University of South Carolina 10 Martin A. Javors, PhD 11 University of Texas Health Science Center, San Antonio 13 Address correspondence to: 14 Judith A. Hahn, PhD 15 University of California, San Francisco 16 550 16 th St. 3 rd floor 17 San Francisco, CA 94143 18 Phone: 415-476-5815 19 e-mail: judy.hahn@ucsf.edu 21 Funding: NIAAA K24AA022586 (Hahn), NIAAA U01AA020776 (Hahn), NIAAA K05AA017435 22 (Anton), R01AA022361 (Javors)
1磷脂酰乙醇的形成、消除、解释和未来研究需求2 (PEth)的研究和临床实践4 Judith A. Hahn博士5加州大学旧金山分校7 Raymond F. Anton医学博士8南卡罗来纳医科大学10 Martin A. Javors博士11德克萨斯大学圣安东尼奥分校健康科学中心13地址通信:14 Judith A. Hahn, PhD 15 California University, San Francisco 16 550 16 th St. 3 floor 17 San Francisco, CA 94143 18电话:415-476-5815 19 e-mail: judy.hahn@ucsf.edu 21资助:NIAAA K24AA022586 (Hahn)， NIAAA U01AA020776 (Hahn)， NIAAA K05AA017435 22 (Anton)， R01AA022361 (Javors)
{"title":"The Formation, Elimination, Interpretation, and Future Research Needs of Phosphatidylethanol for Research Studies and Clinical Practice.","authors":"J. Hahn, R. Anton, M. Javors","doi":"10.1111/acer.13213","DOIUrl":"https://doi.org/10.1111/acer.13213","url":null,"abstract":"1 The Formation, Elimination, Interpretation and Future Research Needs of Phosphatidylethanol 2 (PEth) for Research Studies and Clinical Practice 4 Judith A. Hahn, PhD 5 University of California, San Francisco 7 Raymond F. Anton, MD 8 Medical University of South Carolina 10 Martin A. Javors, PhD 11 University of Texas Health Science Center, San Antonio 13 Address correspondence to: 14 Judith A. Hahn, PhD 15 University of California, San Francisco 16 550 16 th St. 3 rd floor 17 San Francisco, CA 94143 18 Phone: 415-476-5815 19 e-mail: judy.hahn@ucsf.edu 21 Funding: NIAAA K24AA022586 (Hahn), NIAAA U01AA020776 (Hahn), NIAAA K05AA017435 22 (Anton), R01AA022361 (Javors)","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"15 1","pages":"2292-2295"},"PeriodicalIF":3.2,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82458977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Recent research into the pathophysiology of alcohol use disorder suggests that the behavioral and physical manifestations of AUD are produced by hierarchical dysfunction at the cellular, synaptic, and circuit levels. Synaptic and circuit function are highly dependent upon the activity and function of astrocytes. Therefore, dysregulation of astrocytic function may compromise synaptic activity and produce maladaptive modifications of circuit strength. In this commentary, we discuss the extensive crosstalk between neurons and astrocytes that determine synaptic strength and bioenergetic integrity, expounding upon the extensive interactions between glutamatergic neurotransmission and cellular metabolism. Furthermore, we discuss how dysregulation of astrocyte function in AUD may alter astrocyte function and compromise both excitatory neurotransmission and CNS bioenergetics.
{"title":"Disruption of Integrated Neuronal and Astrocytic Signaling Contributes to Alcohol Use Disorder.","authors":"D. Lindberg, D. Choi","doi":"10.1111/acer.13227","DOIUrl":"https://doi.org/10.1111/acer.13227","url":null,"abstract":"Recent research into the pathophysiology of alcohol use disorder suggests that the behavioral and physical manifestations of AUD are produced by hierarchical dysfunction at the cellular, synaptic, and circuit levels. Synaptic and circuit function are highly dependent upon the activity and function of astrocytes. Therefore, dysregulation of astrocytic function may compromise synaptic activity and produce maladaptive modifications of circuit strength. In this commentary, we discuss the extensive crosstalk between neurons and astrocytes that determine synaptic strength and bioenergetic integrity, expounding upon the extensive interactions between glutamatergic neurotransmission and cellular metabolism. Furthermore, we discuss how dysregulation of astrocyte function in AUD may alter astrocyte function and compromise both excitatory neurotransmission and CNS bioenergetics.","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"21 1","pages":"2309-2311"},"PeriodicalIF":3.2,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85517716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Reproducibility of Experiments with Laboratory Animals: What Should We Do Now?","authors":"J. Crabbe","doi":"10.1111/acer.13228","DOIUrl":"https://doi.org/10.1111/acer.13228","url":null,"abstract":"","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"11 1","pages":"2305-2308"},"PeriodicalIF":3.2,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85192409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. A. McGinn, Rod I. Paulsen, Christy A. Itoga, Muhammad A Farooq, Jonathan E Reppel, K. Edwards, Annie M. Whitaker, N. Gilpin, Scott Edwards
BACKGROUND Nicotine use increases alcohol drinking, suggesting that the combination of these drugs may produce synergistic effects in activating reward circuitry. Alternatively, use of either of these drugs may facilitate the development of cross-tolerance to the other to promote intake escalation. METHODS In this study, adult male Wistar rats were chronically exposed to room air or chronic, intermittent nicotine vapor, which has been shown to produce symptoms of nicotine dependence as evidenced by elevated nicotine self-administration and a host of somatic and motivational withdrawal symptoms. We examined regional neuroadaptations in nicotine-experienced versus nonexperienced animals, focusing on changes in phosphorylation of the AMPA glutamate channel subunit GluA1 in reward-related brain regions as excitatory neuroadaptations are heavily implicated in both alcohol and nicotine addiction. RESULTS During withdrawal, nicotine exposure and alcohol challenge (1 g/kg) interactively produced neuroadaptations in GluA1 phosphorylation in a brain region-dependent manner. Alcohol robustly increased protein kinase A-mediated phosphorylation of GluA1 at serine 845 in multiple regions. However, this neuroadaptation was largely absent in 3 areas (dorsomedial prefrontal cortex, dorsal striatum, and central amygdala) in nicotine-experienced animals. This interactive effect suggests a molecular tolerance to alcohol-stimulated phosphorylation of GluA1 in the context of nicotine dependence. CONCLUSIONS Nicotine may modify the rewarding or reinforcing effects of alcohol by altering glutamate signaling in a region-specific manner, thereby leading to increased drinking in heavy smokers.
{"title":"Withdrawal from Chronic Nicotine Exposure Produces Region-Specific Tolerance to Alcohol-Stimulated GluA1 Phosphorylation.","authors":"M. A. McGinn, Rod I. Paulsen, Christy A. Itoga, Muhammad A Farooq, Jonathan E Reppel, K. Edwards, Annie M. Whitaker, N. Gilpin, Scott Edwards","doi":"10.1111/acer.13258","DOIUrl":"https://doi.org/10.1111/acer.13258","url":null,"abstract":"BACKGROUND\u0000Nicotine use increases alcohol drinking, suggesting that the combination of these drugs may produce synergistic effects in activating reward circuitry. Alternatively, use of either of these drugs may facilitate the development of cross-tolerance to the other to promote intake escalation.\u0000\u0000\u0000METHODS\u0000In this study, adult male Wistar rats were chronically exposed to room air or chronic, intermittent nicotine vapor, which has been shown to produce symptoms of nicotine dependence as evidenced by elevated nicotine self-administration and a host of somatic and motivational withdrawal symptoms. We examined regional neuroadaptations in nicotine-experienced versus nonexperienced animals, focusing on changes in phosphorylation of the AMPA glutamate channel subunit GluA1 in reward-related brain regions as excitatory neuroadaptations are heavily implicated in both alcohol and nicotine addiction.\u0000\u0000\u0000RESULTS\u0000During withdrawal, nicotine exposure and alcohol challenge (1 g/kg) interactively produced neuroadaptations in GluA1 phosphorylation in a brain region-dependent manner. Alcohol robustly increased protein kinase A-mediated phosphorylation of GluA1 at serine 845 in multiple regions. However, this neuroadaptation was largely absent in 3 areas (dorsomedial prefrontal cortex, dorsal striatum, and central amygdala) in nicotine-experienced animals. This interactive effect suggests a molecular tolerance to alcohol-stimulated phosphorylation of GluA1 in the context of nicotine dependence.\u0000\u0000\u0000CONCLUSIONS\u0000Nicotine may modify the rewarding or reinforcing effects of alcohol by altering glutamate signaling in a region-specific manner, thereby leading to increased drinking in heavy smokers.","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"1 1","pages":"2537-2547"},"PeriodicalIF":3.2,"publicationDate":"2016-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84841440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Melanie Tran, Zhihong Yang, S. Liangpunsakul, Li Wang
BACKGROUND Chronic ethanol (EtOH) consumption causes alcoholic liver disease (ALD), and disruption of the circadian system facilitates the development of ALD. Small heterodimer partner (SHP) is a nuclear receptor and critical regulator of hepatic lipid metabolism. This study aimed at depicting circadian metabolomes altered by chronic EtOH-plus-binge and Shp deficiency using high-throughput metabolomics. METHODS Wild-type (WT) C57BL/6 and Shp-/- mice were fed the control diet (CD) or Lieber-DeCarli EtOH liquid diet (ED) for 10 days followed by a single bout of maltose (CD + M) or EtOH (ED + E) binge on the 11th day. Serum and liver were collected over a 24-hour light/dark (LD) cycle at Zeitgeber time ZT12, ZT18, ZT0, and ZT6, and metabolomics was performed using gas chromatography-mass spectrometry. RESULTS A total of 110 metabolites were identified in liver and of those 80 were also present in serum from pathways of carbohydrates, lipids, pentose phosphate, amino acids, nucleotides, and tricarboxylic acid cycle. In the liver, 91% of metabolites displayed rhythmicity with ED + E, whereas in the serum, only 87% were rhythmic. Bioinformatics analysis identified unique metabolome patterns altered in WT CD + M, WT ED + E, Shp-/- CD + M, and Shp-/- ED + E groups. Specifically, metabolites from the nucleotide and amino acid pathway (ribose, glucose-6-phosphate, glutamic acid, aspartic acid, and sedoheptulose-7-P) were elevated in Shp-/- CD + M mice during the dark cycle, whereas metabolites including N-methylalanine, 2-hydroxybutyric acid, and 2-hydroxyglutarate were elevated in WT ED + E mice during the light cycle. The rhythmicity and abundance of other individual metabolites were also significantly altered by both control and EtOH diets. CONCLUSIONS Metabolomics provides a useful means to identify unique metabolites altered by chronic EtOH-plus-binge.
背景:慢性乙醇(EtOH)消耗导致酒精性肝病(ALD)，昼夜节律系统的破坏促进了ALD的发展。小异二聚体(SHP)是一种核受体，是肝脏脂质代谢的重要调节因子。本研究旨在利用高通量代谢组学描述慢性etoh +暴食和Shp缺乏所改变的昼夜节律代谢组学。方法野生型(WT) C57BL/6和Shp-/-小鼠分别饲喂对照饲粮(CD)或lieberman - decarli EtOH液体饲粮(ED) 10 d，第11天饲喂麦芽糖(CD + M)或EtOH (ED + E)单次暴食。在Zeitgeber时间ZT12、ZT18、ZT0和ZT6的24小时光/暗(LD)周期内收集血清和肝脏，并采用气相色谱-质谱法进行代谢组学分析。结果在肝脏中鉴定出110种sa代谢物，其中80种代谢物也存在于血清碳水化合物、脂质、戊糖磷酸、氨基酸、核苷酸和三羧酸循环途径中。在肝脏中，91%的代谢物表现出ED + E节律性，而在血清中，只有87%的代谢物表现出节律性。生物信息学分析确定了WT CD + M、WT ED + E、Shp-/- CD + M和Shp-/- ED + E组中独特的代谢组模式。具体来说，Shp-/- CD + M小鼠的核苷酸和氨基酸途径的代谢物(核糖、葡萄糖-6-磷酸、谷氨酸、天冬氨酸和sedoheptulose-7-P)在黑暗周期中升高，而WT ED + E小鼠的代谢物包括n -甲基丙氨酸、2-羟基丁酸和2-羟基戊二酸在光照周期中升高。其他个体代谢物的节律性和丰度也被对照组和EtOH饮食显著改变。结论代谢组学提供了一种有效的方法来鉴定慢性etoh +暴食所改变的独特代谢物。
{"title":"Metabolomics Analysis Revealed Distinct Cyclic Changes of Metabolites Altered by Chronic Ethanol-Plus-Binge and Shp Deficiency.","authors":"Melanie Tran, Zhihong Yang, S. Liangpunsakul, Li Wang","doi":"10.1111/acer.13257","DOIUrl":"https://doi.org/10.1111/acer.13257","url":null,"abstract":"BACKGROUND\u0000Chronic ethanol (EtOH) consumption causes alcoholic liver disease (ALD), and disruption of the circadian system facilitates the development of ALD. Small heterodimer partner (SHP) is a nuclear receptor and critical regulator of hepatic lipid metabolism. This study aimed at depicting circadian metabolomes altered by chronic EtOH-plus-binge and Shp deficiency using high-throughput metabolomics.\u0000\u0000\u0000METHODS\u0000Wild-type (WT) C57BL/6 and Shp-/- mice were fed the control diet (CD) or Lieber-DeCarli EtOH liquid diet (ED) for 10 days followed by a single bout of maltose (CD + M) or EtOH (ED + E) binge on the 11th day. Serum and liver were collected over a 24-hour light/dark (LD) cycle at Zeitgeber time ZT12, ZT18, ZT0, and ZT6, and metabolomics was performed using gas chromatography-mass spectrometry.\u0000\u0000\u0000RESULTS\u0000A total of 110 metabolites were identified in liver and of those 80 were also present in serum from pathways of carbohydrates, lipids, pentose phosphate, amino acids, nucleotides, and tricarboxylic acid cycle. In the liver, 91% of metabolites displayed rhythmicity with ED + E, whereas in the serum, only 87% were rhythmic. Bioinformatics analysis identified unique metabolome patterns altered in WT CD + M, WT ED + E, Shp-/- CD + M, and Shp-/- ED + E groups. Specifically, metabolites from the nucleotide and amino acid pathway (ribose, glucose-6-phosphate, glutamic acid, aspartic acid, and sedoheptulose-7-P) were elevated in Shp-/- CD + M mice during the dark cycle, whereas metabolites including N-methylalanine, 2-hydroxybutyric acid, and 2-hydroxyglutarate were elevated in WT ED + E mice during the light cycle. The rhythmicity and abundance of other individual metabolites were also significantly altered by both control and EtOH diets.\u0000\u0000\u0000CONCLUSIONS\u0000Metabolomics provides a useful means to identify unique metabolites altered by chronic EtOH-plus-binge.","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"39 1","pages":"2548-2556"},"PeriodicalIF":3.2,"publicationDate":"2016-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87091043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tatsuo Inamine, An-Ming Yang, Lirui Wang, Kuei-Chuan Lee, C. Llorente, B. Schnabl
BACKGROUND Chronic alcohol abuse is associated with intestinal dysbiosis and bacterial translocation. Translocated commensal bacteria contribute to alcoholic liver disease. Secretory immunoglobulin A (IgA) in the intestine binds bacteria and prevents bacterial translocation. METHODS To investigate the functional role of IgA in ethanol (EtOH)-induced liver disease in mice, we subjected wild type (WT) and IgA-deficient littermate mice to Lieber-DeCarli models of chronic EtOH administration and the model of chronic and binge EtOH feeding (the NIAAA model). RESULTS Chronic EtOH feeding increased systemic levels of IgA, while fecal IgA was reduced in C57BL/6 WT mice. WT and Iga-/- littermate mice showed similar liver injury, steatosis, and inflammation following 4 weeks of EtOH feeding or chronic and binge EtOH feeding. IgA deficiency did not affect intestinal absorption or hepatic metabolism of EtOH. Pretreatment with ampicillin elevated intestinal IgA in WT littermate mice. Despite increased intestinal IgA, WT littermate mice exhibited a similar degree of liver disease compared with Iga-/- mice after 7 weeks of EtOH feeding. Interestingly, bacterial translocation to mesenteric lymph nodes was increased in Iga-/- mice fed an isocaloric diet, but was the same after EtOH feeding relative to WT littermate mice. The absence of intestinal IgA was associated with increased intestinal and plasma IgM in Iga-/- mice after EtOH feeding. CONCLUSIONS Our findings indicate that absence of IgA does not affect the development of alcoholic liver disease in mice. Loss of intestinal IgA is compensated by increased levels of intestinal IgM, which likely limits bacterial translocation after chronic EtOH administration.
{"title":"Genetic Loss of Immunoglobulin A Does Not Influence Development of Alcoholic Steatohepatitis in Mice.","authors":"Tatsuo Inamine, An-Ming Yang, Lirui Wang, Kuei-Chuan Lee, C. Llorente, B. Schnabl","doi":"10.1111/acer.13239","DOIUrl":"https://doi.org/10.1111/acer.13239","url":null,"abstract":"BACKGROUND\u0000Chronic alcohol abuse is associated with intestinal dysbiosis and bacterial translocation. Translocated commensal bacteria contribute to alcoholic liver disease. Secretory immunoglobulin A (IgA) in the intestine binds bacteria and prevents bacterial translocation.\u0000\u0000\u0000METHODS\u0000To investigate the functional role of IgA in ethanol (EtOH)-induced liver disease in mice, we subjected wild type (WT) and IgA-deficient littermate mice to Lieber-DeCarli models of chronic EtOH administration and the model of chronic and binge EtOH feeding (the NIAAA model).\u0000\u0000\u0000RESULTS\u0000Chronic EtOH feeding increased systemic levels of IgA, while fecal IgA was reduced in C57BL/6 WT mice. WT and Iga-/- littermate mice showed similar liver injury, steatosis, and inflammation following 4 weeks of EtOH feeding or chronic and binge EtOH feeding. IgA deficiency did not affect intestinal absorption or hepatic metabolism of EtOH. Pretreatment with ampicillin elevated intestinal IgA in WT littermate mice. Despite increased intestinal IgA, WT littermate mice exhibited a similar degree of liver disease compared with Iga-/- mice after 7 weeks of EtOH feeding. Interestingly, bacterial translocation to mesenteric lymph nodes was increased in Iga-/- mice fed an isocaloric diet, but was the same after EtOH feeding relative to WT littermate mice. The absence of intestinal IgA was associated with increased intestinal and plasma IgM in Iga-/- mice after EtOH feeding.\u0000\u0000\u0000CONCLUSIONS\u0000Our findings indicate that absence of IgA does not affect the development of alcoholic liver disease in mice. Loss of intestinal IgA is compensated by increased levels of intestinal IgM, which likely limits bacterial translocation after chronic EtOH administration.","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"55 1","pages":"2604-2613"},"PeriodicalIF":3.2,"publicationDate":"2016-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76413495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Nociceptin Receptor as a Target to Treat Alcohol Use Disorder: Challenges in Advancing Medications Development.","authors":"R. Litten","doi":"10.1111/acer.13222","DOIUrl":"https://doi.org/10.1111/acer.13222","url":null,"abstract":"","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"34 1","pages":"2299-2304"},"PeriodicalIF":3.2,"publicationDate":"2016-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74053315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Luli R. Akinfiresoye, Clive Miranda, D. Lovinger, P. N'Gouemo
BACKGROUND Cyclic AMP-dependent protein kinase A (PKA) signaling is a key target for the action of alcohol and may therefore play a role in the pathophysiology of alcohol withdrawal seizures (AWSs). Here, we investigated the role of PKA activity with respect to increased seizure susceptibility in rats that were subjected to alcohol withdrawal. METHODS Adult male Sprague Dawley rats received 3 daily doses of ethanol (EtOH) (or vehicle) for 4 consecutive days. Rats were then tested for susceptibility to acoustically evoked AWSs 3, 24, and 48 hours after the last alcohol dose. In separate experiments, the inferior colliculus (IC) was collected at these same time points from rats subjected to alcohol withdrawal and control rats following alcohol withdrawal. PKA activity, catalytic Cα (PKACα ) protein, regulatory RIIα (PKARIIα ) protein, and RIIβ (PKARIIβ ) protein were measured in the IC. Lastly, in situ pharmacological studies were performed to evaluate whether inhibiting PKA activity in the IC suppressed AWSs. RESULTS In the EtOH-treated group, AWSs were observed at the 24-hour time point, but not at the 3-hour or 48-hour time points. In the IC, PKA activity was significantly higher both 3 hours (i.e., before AWS susceptibility) and 24 hours after the last alcohol dose (when AWS susceptibility peaked) than in control rats. Consistent with these findings, protein levels of the PKACα subunit were significantly increased in the IC both 3 and 24 hours after the last alcohol dose. Lastly, in situ inhibition of PKA activity within the IC suppressed AWSs. CONCLUSIONS The increase in PKA activity and PKACα protein expression in the IC preceded the occurrence of AWSs, and inhibiting PKA activity within the IC suppressed acoustically evoked AWSs. Together, these findings suggest that altered PKA activity plays a key role in the pathogenesis of AWSs.
{"title":"Alcohol Withdrawal Increases Protein Kinase A Activity in the Rat Inferior Colliculus.","authors":"Luli R. Akinfiresoye, Clive Miranda, D. Lovinger, P. N'Gouemo","doi":"10.1111/acer.13223","DOIUrl":"https://doi.org/10.1111/acer.13223","url":null,"abstract":"BACKGROUND\u0000Cyclic AMP-dependent protein kinase A (PKA) signaling is a key target for the action of alcohol and may therefore play a role in the pathophysiology of alcohol withdrawal seizures (AWSs). Here, we investigated the role of PKA activity with respect to increased seizure susceptibility in rats that were subjected to alcohol withdrawal.\u0000\u0000\u0000METHODS\u0000Adult male Sprague Dawley rats received 3 daily doses of ethanol (EtOH) (or vehicle) for 4 consecutive days. Rats were then tested for susceptibility to acoustically evoked AWSs 3, 24, and 48 hours after the last alcohol dose. In separate experiments, the inferior colliculus (IC) was collected at these same time points from rats subjected to alcohol withdrawal and control rats following alcohol withdrawal. PKA activity, catalytic Cα (PKACα ) protein, regulatory RIIα (PKARIIα ) protein, and RIIβ (PKARIIβ ) protein were measured in the IC. Lastly, in situ pharmacological studies were performed to evaluate whether inhibiting PKA activity in the IC suppressed AWSs.\u0000\u0000\u0000RESULTS\u0000In the EtOH-treated group, AWSs were observed at the 24-hour time point, but not at the 3-hour or 48-hour time points. In the IC, PKA activity was significantly higher both 3 hours (i.e., before AWS susceptibility) and 24 hours after the last alcohol dose (when AWS susceptibility peaked) than in control rats. Consistent with these findings, protein levels of the PKACα subunit were significantly increased in the IC both 3 and 24 hours after the last alcohol dose. Lastly, in situ inhibition of PKA activity within the IC suppressed AWSs.\u0000\u0000\u0000CONCLUSIONS\u0000The increase in PKA activity and PKACα protein expression in the IC preceded the occurrence of AWSs, and inhibiting PKA activity within the IC suppressed acoustically evoked AWSs. Together, these findings suggest that altered PKA activity plays a key role in the pathogenesis of AWSs.","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"8 1","pages":"2359-2367"},"PeriodicalIF":3.2,"publicationDate":"2016-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83495761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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