Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications

In the paper

“Similar numbers of oxidatively-modified mitochondrial proteins were also identified by mass-spectral analysis in mice with I/R injury [38] and rats exposed to 3,4-methylenedioxymethamphetamine (MDMA) [39].”

What the sources say

• Not checked yetcites [38] Moon, 2008, Oxidative inactivation of key mitochondrial proteins leads to dysfunction and injury in hepatic ischemia reperfusion, Gastroenterology source
• Not checked yetcites [39] Moon, 2008, Mechanism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-mediated mitochondrial dysfunction in rat liver, Proteomics source

In the paper

“The rates of protein oxidation in CYP2E1-containing E47-HepG2 hepatoma cells [36] exhibited a dose- and time- dependent pattern in response to alcohol as well as the presence of CYP2E1 [37].”

What the sources say

• Not checked yetcites [37] Suh, 2004, Identification of oxidized mitochondrial proteins in alcohol-exposed human hepatoma cells and mouse liver, Proteomics source

In the paper

“In fact, mass-spectral analysis revealed that more than 87 mitochondrial and 60 cytosolic proteins were oxidatively-modified in alcohol-exposed rodents [34], [35].”

What the sources say

• Not checked yetcites [34] Moon, 2006, Inactivation of oxidized and S-nitrosylated mitochondrial proteins in alcoholic fatty liver of rats, Hepatology (Baltimore, Md.) source
• Not checked yetcites [35] Kim, 2006, Increased oxidation and degradation of cytosolic proteins in alcohol-exposed mouse liver and hepatoma cells, Proteomics source

In the paper

“Treatment with NAC completely protected the liver from the APAP-induced necrotic injury measured by increased serum transaminase activities and liver histology.”

What the sources say

• Not checked yetcites [94] Abdelmegeed, 2013, Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury, Free Radical Biology and Medicine source

In the paper

“Furthermore, NAC ameliorated the inactivation of the five critical enzymes via preventing Tyr nitration, as evidenced by immunoprecipitation with a specific antibody to each protein followed by immunoblot with anti-3-NT antibody.”

What the sources say

• Not checked yetcites [94] Abdelmegeed, 2013, Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury, Free Radical Biology and Medicine source

In the paper

“Furthermore, oxidative modification of the active site Cys residue of peroxiredoxin 1 (Prx1) and inactivation was observed in alcohol-exposed mice [47].”

What the sources say

• Not checked yetcites [47] Bae, 2011, Concerted action of sulfiredoxin and peroxiredoxin I protects against alcohol-induced oxidative injury in mouse liver, Hepatology (Baltimore, Md.) source

In the paper

“In fact, after immunoaffinity purification followed by mass-spectral analysis, we demonstrated that more than 70 mitochondrial proteins and 30 cytosolic proteins were nitrated in APAP-exposed mice [94].”

What the sources say

• Not checked yetcites [94] Abdelmegeed, 2013, Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury, Free Radical Biology and Medicine source

In the paper

“Our results showed that pro-apoptotic Bax in the cytosol can be phosphorylated (activated) by p-JNK and/or p-p38K, resulting in its conformational change with exposure of the C-terminal membrane domain.”

What the sources say

• Not checked yetcites [129] Kim, 2006, JNK- and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells, Journal of Biological Chemistry source

In the paper

“Our results revealed that Thr167 of Bax was phosphorylated before it was translocated to mitochondria to stimulate mitochondria-dependent apoptosis [129].”

What the sources say

• Not checked yetcites [129] Kim, 2006, JNK- and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells, Journal of Biological Chemistry source

In the paper

“By using immunoprecipitation with anti-Ac-Lys antibody followed by mass spectral analysis, 91 acetylated mitochondrial proteins were recently identified in alcohol exposed mice [152].”

What the sources say

• Not checked yetcites [152] Fritz, 2012, Mitochondrial acetylome analysis in a mouse model of alcohol-induced liver injury utilizing SIRT3 knockout mice, Journal of Proteome Research source

In the paper

“In fact, the average levels of MDA- and HNE-protein adducts in 50 alcoholic cirrhosis patients were significantly higher than those in a similar number of patients with nonalcoholic cirrhosis or healthy individuals [180].”

What the sources say

• Not checked yetcites [180] Mottaran, 2002, Lipid peroxidation contributes to immune reactions associated with alcoholic liver disease, Free Radical Biology and Medicine source

In the paper

“If one of these amino acids serves as the active site or is located near the active site of certain enzymes, it is highly likely that oxidative modifications of these amino acids can result in their inactivation, as shown by the oxidation and/or S-nitrosylation of Cys residues including the active site Cys in the mitochondrial aldehyde dehydrogenase (ALDH2) [34] and 3-keto-acyl CoA-thiolase (thiol”

What the sources say

• Not checked yetcites [34] Moon, 2006, Inactivation of oxidized and S-nitrosylated mitochondrial proteins in alcoholic fatty liver of rats, Hepatology (Baltimore, Md.) source

In the paper

“The number of oxidatively-modified mitochondrial proteins we characterized may represent a small fraction of the estimated number of 1100–1400 total mitochondrial proteins [40], [41].”

What the sources say

• Not checked yetcites [40] Pagliarini, 2008, A mitochondrial protein compendium elucidates complex I disease biology, Cell source
• Not checked yetcites [41] Calvo, 2010, The mitochondrial proteome and human disease, Annual Review of Genomics and Human Genetics source

In the paper

“These results indicate that ALDH2 and other ALDH isozymes, which contain the highly conserved active site Cys residue, can be reversibly modulated by S-nitrosylation under increased nitroxidative stress, as reviewed [42].”

What the sources say

• Not checked yetcites [42] Song, 2011, Post-translational modifications of mitochondrial aldehyde dehydrogenase and biomedical implications, Journal of Proteomics source

In the paper

“However, we believe that the actual number of oxidized proteins could be significantly higher than the proteins originally reported [34], [38], [39], because of the technical limitations in the identification and purification of oxidized proteins and detection methods, especially for those proteins expressed in low abundance, as previously discussed [26], [33].”

What the sources say

• Not checked yetcites [26] Song, 2013, Increased nitroxidative stress promotes mitochondrial dysfunction in alcoholic and nonalcoholic fatty liver disease, Oxidative Medicine and Cellular Longevity source
• Not checked yetcites [33] Song, 2010, A simple method to systematically study oxidatively modified proteins in biological samples and its applications, Methods in Enzymology source

In the paper

“However, chronic and/or binge alcohol, high fat diets, tobacco smoking, or certain hepatotoxic drugs can directly damage the mitochondrial ETC, producing greater amounts of ROS leaked from the ETS [24], [25], [26], [27].”

What the sources say

• Not checked yetcites [24] Pessayre, 2012, Central role of mitochondria in drug-induced liver injury, Drug Metabolism Reviews source
• Not checked yetcites [25] Yuan, 2013, Mechanisms of drug-induced liver injury, Clinics in Liver Disease source
• Not checked yetcites [26] Song, 2013, Increased nitroxidative stress promotes mitochondrial dysfunction in alcoholic and nonalcoholic fatty liver disease, Oxidative Medicine and Cellular Longevity source

In the paper

“Oxidative modification and suppression of ALDH2 in alcohol-exposed rodents were consistently observed by other groups [44], [45].”

What the sources say

• Not checked yetcites [44] Venkatraman, 2004, Oxidative modification of hepatic mitochondria protein thiols: effect of chronic alcohol consumption, American Journal of Physiology. Gastrointestinal and Liver Physiology source
• Not checked yetcites [45] Venkatraman, 2004, Modification of the mitochondrial proteome in response to the stress of ethanol-dependent hepatotoxicity, Journal of Biological Chemistry source

In the paper

“Hepatic mitochondrial abnormalities are observed in both alcoholic fatty liver disease (AFLD) [4], [5], [6], nonalcoholic fatty liver disease (NAFLD) [7], [8], [9] and acute liver injury.”

What the sources say

• Not checked yetcites [4] Hoek, 2002, Alcohol and mitochondria: a dysfunctional relationship, Gastroenterology source
• Not checked yetcites [5] Mantena, 2008, Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases, Free Radical Biology & Medicine source
• Not checked yetcites [6] Wu, 2009, Oxidative stress and alcoholic liver disease, Seminars in Liver Disease source

In the paper

“In addition, acute or sub-chronic exposure to various hepatotoxic compounds, including clinically-used drugs, such as acetaminophen (APAP) [18], [19], [20], a major ingredient of Tylenol®, an anti-breast cancer agent tamoxifen [21], an anti-retroviral drug zidovudine (AZT) [22] and antidepressants [23], can cause mitochondrial dysfunction, contributing to”

What the sources say

• Not checked yetcites [18] Cover, 2005, Peroxynitrite-induced mitochondrial and endonuclease-mediated nuclear DNA damage in acetaminophen hepatotoxicity, Journal of Pharmacology and Experimental Therapeutics source
• Not checked yetcites [21] Ribeiro, 2014, Mitochondria: the gateway for tamoxifen-induced liver injury, Toxicology source
• Not checked yetcites [22] Banerjee, 2013, Zidovudine (AZT) and hepatic lipid accumulation: implication of inflammation, oxidative and endoplasmic reticulum stress mediators, PloS One source

In the paper

“Without proper counter-balance by various cellular anti-oxidants, the persistent imbalance in cellular redox states result in decreased levels of mitochondrial antioxidants including mitochondrial glutathione (mtGSH), which serves as a critical determinant between toxic damage and cellular protection [30].”

What the sources say

• Not checked yetcites [30] Von Montfort, 2012, Mitochondrial GSH determines the toxic or therapeutic potential of superoxide scavenging in steatohepatitis, Journal of Hepatology source

In the paper

“For instance, NO-dependent inhibition of the mitochondrial respiration was monitored in both AFLD and NAFLD [86], [87], [88], [89], [90].”

What the sources say

• Not checked yetcites [86] McKim, 2003, Inducible nitric oxide synthase is required in alcohol-induced liver injury: studies with knockout mice, Gastroenterology source
• Not checked yetcites [87] Venkatraman, 2003, Chronic alcohol consumption increases the sensitivity of rat liver mitochondrial respiration to inhibition by nitric oxide, Hepatology (Baltimore, Md.) source
• Not checked yetcites [88] Venkatraman, 2004, The role of iNOS in alcohol-dependent hepatotoxicity and mitochondrial dysfunction in mice, Hepatology (Baltimore, Md.) source

In the paper

“These two PTMs can lead to alterations of both protein structure and function, contributing to increased cell and tissue injury.”

In the paper

“For instance, reversible oxidation of Cys residues of mitochondrial NADH-dependent ubiquinone oxidoreductase (complex I), ALDH2, and Prx3 seem to be protective, despite temporary inactivation, against further tissue damage from irreversible hyper-oxidation of Cys to Cys-sulfinic acid (Cys-SO2) and Cys-sulfonic acid (Cys-SO3) followed by proteolytic degradation [67], [68], as in the case of I/R”

What the sources say

• Not checked yetcites [67] Grek, 2013, Causes and consequences of cysteine S-glutathionylation, Journal of Biological Chemistry source
• Not checked yetcites [68] Gould, 2013, Regulation of protein function and signaling by reversible cysteine S-nitrosylation, Journal of Biological Chemistry source

In the paper

“Hepatic necrosis highly correlated with the areas of nitrated proteins [91].”

What the sources say

• Not checked yetcites [91] Hinson, 1998, Nitrotyrosine-protein adducts in hepatic centrilobular areas following toxic doses of acetaminophen in mice, Chemical Research in Toxicology source

In the paper

“In fact, these phenomena could explain the decreased levels of ALDH2 activity in alcoholic individuals, as discussed [34], [42].”

What the sources say

• Not checked yetcites [34] Moon, 2006, Inactivation of oxidized and S-nitrosylated mitochondrial proteins in alcoholic fatty liver of rats, Hepatology (Baltimore, Md.) source
• Not checked yetcites [42] Song, 2011, Post-translational modifications of mitochondrial aldehyde dehydrogenase and biomedical implications, Journal of Proteomics source

In the paper

“Similar modifications and inactivation of active site Cys residues in thiolase and possibly other enzymes in the β-oxidation pathway of fatty acids are likely to lead to fat accumulation observed in alcohol-exposed rodents [34], in MDMA-exposed rats [39] as well as in mouse liver following I/R injury [38].”

What the sources say

• Not checked yetcites [34] Moon, 2006, Inactivation of oxidized and S-nitrosylated mitochondrial proteins in alcoholic fatty liver of rats, Hepatology (Baltimore, Md.) source
• Not checked yetcites [39] Moon, 2008, Mechanism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-mediated mitochondrial dysfunction in rat liver, Proteomics source
• Not checked yetcites [38] Moon, 2008, Oxidative inactivation of key mitochondrial proteins leads to dysfunction and injury in hepatic ischemia reperfusion, Gastroenterology source

In the paper

“Since Prx1 was determined to be localized on the cytosolic side of the endoplasmic reticulum (ER) and interacts with CYP2E1 [47], it is likely that this oxidative inactivation of Prx1 contributes to increased ROS production and fatty liver following alcohol exposure.”

What the sources say

• Not checked yetcites [47] Bae, 2011, Concerted action of sulfiredoxin and peroxiredoxin I protects against alcohol-induced oxidative injury in mouse liver, Hepatology (Baltimore, Md.) source

In the paper

“Taken together, mitochondrial DNA mutation and/or deletion may lead to abnormal expression or deletion of some of the ETC components, contributing to mitochondrial respiratory dysfunction and more leakage of ROS/RNS.”

In the paper

“As described thus far, oxidative modifications of Cys residues in many cellular proteins are associated with inactivation or suppression of the activity of modified target proteins.”

In the paper

“Indeed, mitochondrial DNA is extremely sensitive to oxidative/nitrative damage due to (A) its location closer to the inner mitochondrial membrane; (B) the relatively low amount of histone, anti-oxidant enzymes, and mtGSH, and (C) the low levels of polyamines and DNA repair enzymes [78], [79].”

What the sources say

• Not checked yetcites [78] Wan, 2004, Acetoaminophen-induced accumulation of 8-oxodeoxyguanosine through reduction of Ogg1 DNA repair enzyme in C6 glioma cells, Experimental and Molecular Medicine source
• Not checked yetcites [79] Begriche, 2006, Mitochondrial dysfunction in Nash: causes, consequences and possible means to prevent it, Mitochondrion source

In the paper

“Thus, protein nitration serves as one of the critical causal factors in APAP-induced acute liver damage usually observed at later time points.”

What the sources say

• Not checked yetcites [94] Abdelmegeed, 2013, Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury, Free Radical Biology and Medicine source

In the paper

“CYP2E1, one of the main enzymes involved in APAP metabolism, seems to play a critical role in APAP-induced protein nitration and liver injury [93].”

What the sources say

• Not checked yetcites [93] Abdelmegeed, 2010, Role of cytochrome P450 2E1 in protein nitration and ubiquitin-mediated degradation during acetaminophen toxicity, Biochemical Pharmacology source

In the paper

“However, Cys residues in the adducts with reactive metabolites or lipid peroxides cannot be restored even in the presence of a strong reducing agent DTT and thus are considered irreversible, as discussed [26], [33].”

What the sources say

• Not checked yetcites [26] Song, 2013, Increased nitroxidative stress promotes mitochondrial dysfunction in alcoholic and nonalcoholic fatty liver disease, Oxidative Medicine and Cellular Longevity source
• Not checked yetcites [33] Song, 2010, A simple method to systematically study oxidatively modified proteins in biological samples and its applications, Methods in Enzymology source

In the paper

“Based on the conserved redox-sensitive Cys residues among the multiple isoforms [47], [48], [49], many Prx enzymes could be also oxidatively-modified and inactivated, contributing to elevated levels of oxidative stress.”

What the sources say

• Not checked yetcites [47] Bae, 2011, Concerted action of sulfiredoxin and peroxiredoxin I protects against alcohol-induced oxidative injury in mouse liver, Hepatology (Baltimore, Md.) source
• Not checked yetcites [48] Rhee, 2012, Peroxiredoxin functions as a peroxidase and a regulator and sensor of local peroxides, Journal of Biological Chemistry source
• Not checked yetcites [49] Rhee, 2011, Multiple functions of peroxiredoxins: peroxidases, sensors and regulators of the intracellular messenger H2O2, and protein chaperones, Antioxidants and Redox Signaling source

In the paper

“In contrast, JNK2 plays a dominant role in APAP-induced acute liver injury since JNK2-null mice are resistant to acute hepatotoxicity [113], suggesting that this area needs further clarification.”

What the sources say

• Not checked yetcites [113] Gunawan, 2006, C-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity, Gastroenterology source

In the paper

“Indeed, the suppressed activities of anti-oxidant enzymes such as SOD2 and Gpx would certainly interfere with the cellular anti-oxidant abilities.”

In the paper

“For instance, both JNK1 and JNK2 seem to be important in alcohol-induced fatty liver injury [111], while JNK1 seems critical in hepatotoxicity caused by co-treatment of pyrazole and TNFα [127].”

What the sources say

• Not checked yetcites [127] Wang, 2011, Hepatotoxicity mediated by pyrazole (cytochrome P450 2E1) plus tumor necrosis factor alpha treatment occurs in c-Jun N-terminal kinase 2-/- but not in c-Jun N-terminal kinase 1−/− mice, Hepatology (Baltimore, Md.) source

In the paper

“The inactivation of MAPK-phosphatases leads to activation of various stress-activated JNK and p38K [104], [105].”

What the sources say

• Not checked yetcites [104] Kamata, 2005, Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases, Cell source
• Not checked yetcites [105] Heneberg, 2005, Regulation of cys-based protein tyrosine phosphatases via reactive oxygen and nitrogen species in mast cells and basophils, Current Medicinal Chemistry source

In the paper

“Based on our results, we expect similar results of mitochondrial dysfunction and tissue injury with other conditions such as I/R injury [38] and LPS treatment [96], which caused extensive protein nitration.”

What the sources say

• Not checked yetcites [38] Moon, 2008, Oxidative inactivation of key mitochondrial proteins leads to dysfunction and injury in hepatic ischemia reperfusion, Gastroenterology source
• Not checked yetcites [96] Yoo, 2011, Lack of PPARα exacerbates lipopolysaccharide-induced liver toxicity through STAT1 inflammatory signaling and increased oxidative/nitrosative stress, Toxicology Letters source

In the paper

“The effects of peroxynitrite on nitration of Tyr or Trp and S-nitrosylation of Cys likely depend on cellular status of antioxidants, various microenvironments including surface exposure, peptide loop structure, local charge groups, and the presence of competing amino acids nearby (e.g., Cys near the potentially-nitrated Trp or Tyr), as suggested [98].”

What the sources say

• Not checked yetcites [98] Bregere, 2008, Detection and characterization of in vivo nitration and oxidation of tryptophan residues in proteins, Methods in Enzymology source

In the paper

“Furthermore, inactivation of thiolase likely leads to the inhibition of the β-oxidation of fatty acids with increased hepatic fat accumulation or inefficient supply of an alternative energy (e.g., ketone bodies produced from fat degradation).”

In the paper

“It is important to mention that the inactivation of many nitrated proteins can result from the nitration of Tyr residue in the active site, leading to interference of the protein’s catalytic activity.”

In the paper

“For instance, both JNK1 and JNK2 seem to be important in alcohol-induced fatty liver injury [111], while JNK1 seems critical in hepatotoxicity caused by co-treatment of pyrazole and TNFα [127].”

What the sources say

• Not checked yetcites [111] Yang, 2012, Cytochrome P4502E1, oxidative stress, JNK, and autophagy in acute alcohol-induced fatty liver, Free Radical Biology and Medicine source

In the paper

“When the active p-JNK is translocated to mitochondria, it can phosphorylate many mitochondrial proteins such as ATP synthase β subunit, α-KGDH, PDH E1α and β subunits, which were phosphorylated by the recombinant JNK, as shown in an in vitro study using bioenergetically competent mitochondria [135].”

What the sources say

• Not checked yetcites [135] Schroeter, 2003, C-Jun N-terminal kinase (JNK)-mediated modulation of brain mitochondria function: new target proteins for JNK signalling in mitochondrion-dependent apoptosis, Biochemical Journal source

In the paper

“Inactivation of AMPK is known to be associated with AFLD and NAFLD or acute liver injury, as reviewed [13].”

What the sources say

• Not checked yetcites [13] Purohit, 2009, Molecular mechanisms of alcoholic fatty liver, Alcoholism, Clinical and Experimental Research source

In the paper

“In contrast, AMPK can be suppressed by alcohol [137] or other agents such as high fat diet [138] and APAP [139].”

What the sources say

• Not checked yetcites [137] You, 2004, The role of AMP-activated protein kinase in the action of ethanol in the liver, Gastroenterology source
• Not checked yetcites [138] Singhal, 2013, RLIP76 protein knockdown attenuates obesity due to a high-fat diet, Journal of Biological Chemistry source
• Not checked yetcites [139] Saberi, 2014, Protein kinase C (PKC) participates in acetaminophen hepatotoxicity through c-jun-N-terminal kinase (JNK)-dependent and -independent signaling pathways, Hepatology (Baltimore, Md.) source

In the paper

“In addition, activation of JNK was positively related to high fat diet-induced insulin resistance and metabolic syndrome [119], [121], [122], [123].”

What the sources say

• Not checked yetcites [119] Solinas, 2006, Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates, Proceedings of the National Academy of Sciences of the United States of America source
• Not checked yetcites [121] Schattenberg, 2005, Hepatocyte CYP2E1 overexpression and steatohepatitis lead to impaired hepatic insulin signaling, Journal of Biological Chemistry source
• Not checked yetcites [122] Schattenberg, 2006, JNK1 but not JNK2 promotes the development of steatohepatitis in mice, Hepatology (Baltimore, Md.) source

In the paper

“In addition, activated p-JNK is known to translocate to mitochondria to initiate MPT change and damage following exposure to hepatotoxic agents including APAP [115], [116], [130], [131].”

What the sources say

• Not checked yetcites [115] Hanawa, 2008, Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury, Journal of Biological Chemistry source
• Not checked yetcites [116] Win, 2011, C-Jun N-terminal kinase (JNK)-dependent acute liver injury from acetaminophen or tumor necrosis factor (TNF) requires mitochondrial sab protein expression in mice, Journal of Biological Chemistry source
• Not checked yetcites [130] Kharbanda, 2000, Translocation of SAPK/JNK to mitochondria and interaction with Bcl-x(L) in response to DNA damage, Journal of Biological Chemistry source

In the paper

“Furthermore, persistent activation of JNK and/or p38K is positively associated with various liver diseases such as steatohepatitis and I/R injury [122], [123], [124], [125], suggesting the clinical importance of JNK and p38K in human disease states, as reviewed [126].”

What the sources say

• Not checked yetcites [122] Schattenberg, 2006, JNK1 but not JNK2 promotes the development of steatohepatitis in mice, Hepatology (Baltimore, Md.) source
• Not checked yetcites [123] Tuncman, 2006, Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance, Proceedings of the National Academy of Sciences of the United States of America source
• Not checked yetcites [124] Gao, 2011, Sirtuin 1 (SIRT1) protein degradation in response to persistent c-Jun N-terminal kinase 1 (JNK1) activation contributes to hepatic steatosis in obesity, Journal of Biological Chemistry source

In the paper

“Under increased nitroxidative stress, stress-activated MAPKs can be stimulated partly through inhibition of phosphoprotein phosphatases.”

In the paper

“Taken together, CYP2E1 is critically involved in JNK activation and cell death caused by those hepatotoxic CYP2E1 substrates.”

In the paper

“In fact, acute exposure to many hepatotoxic agents including alcohol [110], [111], APAP [112], [113], [114], [115], [116], arachidonic acid [117], 4-HNE and carbon tetrachloride [118], palmitic acid [119], and troglitazone [120] significantly activated JNK (p-JNK) and/or p38K (p-p38K), contributing to toxicity in a variety of cells.”

What the sources say

• Not checked yetcites [110] Lee, 2005, Pro- and anti-apoptotic roles of c-Jun N-terminal kinase (JNK) in ethanol and acetaldehyde exposed rat hepatocytes, European Journal of Pharmacology source
• Not checked yetcites [111] Yang, 2012, Cytochrome P4502E1, oxidative stress, JNK, and autophagy in acute alcohol-induced fatty liver, Free Radical Biology and Medicine source
• Not checked yetcites [112] Bae, 2001, Acetaminophen induces apoptosis of C6 glioma cells by activating the c-Jun NH(2)-terminal protein kinase-related cell death pathway, Molecular Pharmacology source

In the paper

“For instance, acetylation of long-chain fatty acyl-CoA dehydrogenase, one of the four enzymes involved in the mitochondrial fat oxidation pathway, causes its inactivation, leading to fat accumulation [154], [155].”

What the sources say

• Not checked yetcites [154] Hirschey, 2010, SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation, Nature source
• Not checked yetcites [155] Hirschey, 2011, SIRT3 regulates mitochondrial protein acetylation and intermediary metabolism, Cold Spring Harbor Symposia on Quantitative Biology source

In the paper

“In the case of binge alcohol-induced gut leakiness, CYP2E1-mediated increased oxidative stress plays an important role, since treatment with an antioxidant NAC or a CYP2E1 inhibitor chlormethiazole significantly prevented gut leakiness and liver injury.”

What the sources say

• Not checked yetcites [238] Abdelmegeed, 2013, CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis, Free Radical Biology and Medicine source

In the paper

“In addition to lipid peroxide-related protein adducts, recent data suggest that sugar moiety-related protein adduct such as advanced glycation end products (AGEs) can be produced by high fat or excessive alcohol exposure or under pathological states such as diabetes, cardiovascular diseases and Alzheimer's disease, as recently reviewed [190], [191], [192], [193].”

What the sources say

• Not checked yetcites [190] Daffu, 2013, Radical roles for RAGE in the pathogenesis of oxidative stress in cardiovascular diseases and beyond, International Journal of Molecular Sciences source
• Not checked yetcites [191] Ott, 2014, Role of advanced glycation end products in cellular signaling, Redox Biology source
• Not checked yetcites [192] Niforou, 2014, Molecular chaperones and proteostasis regulation during redox imbalance, Redox Biology source

In the paper

“Earlier reports also showed that chronic alcohol exposure suppressed the activities and protein amounts of sirtuin 1, 3 and 5 isoforms [142], [143], [144], [145], [149], [150], in a CYP2E1-independent manner [144].”

What the sources say

• Not checked yetcites [142] You, 2008, Involvement of mammalian sirtuin 1 in the action of ethanol in the liver, American Journal of Physiology: Gastrointestinal and Liver Physiology
• Not checked yetcites [143] Lieber, 2008, Effect of chronic alcohol consumption on hepatic SIRT1 and PGC-1alpha in rats, Biochemical and Biophysical Research Communications source
• Not checked yetcites [144] Picklo, 2008, Ethanol intoxication increases hepatic N-lysyl protein acetylation, Biochemical and Biophysical Research Communications source

In the paper

“We have thus far briefly described five major types of PTMs that promote mitochondrial dysfunction, fat accumulation, inflammation and hepatic injury in alcoholic and nonalcoholic substances (Fig. 1).”

In the paper

“They showed that the active site Cys301 of ALDH2 [173] and Cys280 in the critical Zn binding site of sirtuin 3 [151] were covalently modified with 4-HNE, leading to their inactivation.”

What the sources say

• Not checked yetcites [173] Doorn, 2006, Inhibition of human mitochondrial aldehyde dehydrogenase by 4-hydroxynon-2-enal and 4-oxonon-2-enal, Chemical Research in Toxicology source
• Not checked yetcites [151] Fritz, 2011, 4-hydroxynonenal inhibits SIRT3 via thiol-specific modification, Chemical Research in Toxicology source

In the paper

“binge alcohol exposure [232], [233], [234], [235], [236], [237], [238], [239] and nonalcoholic substances including fructose [240], [241], [242] are known to promote gut leakiness, contributing to more severe inflammatory liver disease.”

What the sources say

• Not checked yetcites [240] Spruss, 2009, Dietary fructose and intestinal barrier: potential risk factor in the pathogenesis of nonalcoholic fatty liver disease, Journal of Nutritional Biochemistry source
• Not checked yetcites [241] Spruss, 2012, Metformin protects against the development of fructose-induced steatosis in mice: role of the intestinal barrier function, Laboratory Investigation: a Journal of Technical Methods and Pathology source
• Not checked yetcites [242] Ritze, 2014, Lactobacillus rhamnosus GG protects against non-alcoholic fatty liver disease in mice, PloS One source

In the paper

“Recent results showed that highly-reactive lipid peroxides including 4-HNE and 4-ONE, despite their extremely short half-lives, can suppress the activities of many mitochondrial proteins likely through adduct formation with a few amino acids such as Cys, His, Arg, and Lys of target proteins [168].”

What the sources say

• Not checked yetcites [168] Fritz, 2013, An overview of the chemistry and biology of reactive aldehydes, Free Radical Biology and Medicine source

In the paper

“binge alcohol exposure [232], [233], [234], [235], [236], [237], [238], [239] and nonalcoholic substances including fructose [240], [241], [242] are known to promote gut leakiness, contributing to more severe inflammatory liver disease.”

What the sources say

• Not checked yetcites [232] Zhong, 2010, The role of zinc deficiency in alcohol-induced intestinal barrier dysfunction, American Journal of Physiology. Gastrointestinal and Liver Physiology source
• Not checked yetcites [240] Spruss, 2009, Dietary fructose and intestinal barrier: potential risk factor in the pathogenesis of nonalcoholic fatty liver disease, Journal of Nutritional Biochemistry source
• Not checked yetcites [242] Ritze, 2014, Lactobacillus rhamnosus GG protects against non-alcoholic fatty liver disease in mice, PloS One source

In the paper

“In addition, high fat feeding can suppress the activities of mitochondrial sirtuin 3 and other isoforms, thus increasing the number of acetylated proteins.”

In the paper

“binge alcohol exposure [232], [233], [234], [235], [236], [237], [238], [239] and nonalcoholic substances including fructose [240], [241], [242] are known to promote gut leakiness, contributing to more severe inflammatory liver disease.”

What the sources say

• Not checked yetcites [232] Zhong, 2010, The role of zinc deficiency in alcohol-induced intestinal barrier dysfunction, American Journal of Physiology. Gastrointestinal and Liver Physiology source
• Not checked yetcites [233] Kirpich, 2012, The type of dietary fat modulates intestinal tight junction integrity, gut permeability, and hepatic Toll-like receptor expression in a mouse model of alcoholic liver disease, Alcoholism, Clinical and Experimental Research source
• Not checked yetcites [234] Dunagan, 2012, Acetaldehyde disrupts tight junctions in Caco-2 cell monolayers by a protein phosphatase 2A-dependent mechanism, American Journal of Physiology. Gastrointestinal and Liver Physiology source

In the paper

“These promising results from different laboratories suggest that mitochondria-targeted antioxidants are more effective against elevated nitroxidative stress than untargeted natural antioxidants.”