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Cited by 411Advanced Glycation End Products researchPotato Plant ResearchGenetics, Aging, and Longevity in Model Organisms

Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury

Open access
Rungratanawanich, Wiramon, Qu, Ying, Wang, Xin, Essa, Musthafa Mohamed, Song, Byoung-Joon·2021·Experimental & Molecular Medicine
DOI 10.1038/s12276-021-00561-7PMC PMC8080618
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Abstract

Advanced glycation end products (AGEs) are potentially harmful and heterogeneous molecules derived from nonenzymatic glycation. The pathological implications of AGEs are ascribed to their ability to promote oxidative stress, inflammation, and apoptosis. Recent studies in basic and translational research have revealed the contributing roles of AGEs in the development and progression of various aging-related pathological conditions, such as diabetes, cardiovascular complications, gut microbiome-associated illnesses, liver or neurodegenerative diseases, and cancer. Excessive chronic and/or acute binge consumption of alcohol (ethanol), a widely consumed addictive substance, is known to cause more than 200 diseases, including alcohol use disorder (addiction), alcoholic liver disease, and brain damage. However, despite the considerable amount of research in this area, the underlying molecular mechanisms by which alcohol abuse causes cellular toxicity and organ damage remain to be further characterized. In this review, we first briefly describe the properties of AGEs: their formation, accumulation, and receptor interactions. We then focus on the causative functions of AGEs that impact various aging-related diseases. We also highlight the biological connection of AGE–alcohol–adduct formations to alcohol-mediated tissue injury. Finally, we describe the potential translational research opportunities for treatment of various AGE- and/or alcohol-related adduct-associated disorders according to the mechanistic insights presented.

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Written from the paper’s full text.

TL;DR

This review describes how advanced glycation end products (AGEs) form endogenously and exogenously, accumulate, interact with RAGE and other receptors, and contribute to aging-related diseases and alcohol-mediated multiorgan injury. It also proposes biological connections between AGEs, alcohol metabolites, and adduct formation, with translational strategies to reduce AGE burden.

Key findings

  • AGEs are heterogeneous, irreversible products of nonenzymatic glycation that promote oxidative stress, inflammation, apoptosis, and tissue injury; AGE–RAGE signaling is implicated in diabetes, cardiovascular disease, kidney disease, obesity, osteoporosis, cancer, gut microbiome-associated disease, neurodegenerative disease, and liver disease.
  • Alcohol consumption causes more than 200 diseases and injuries worldwide; in the United States alone, more than 250 billion dollars are lost annually due to alcoholism-related disorders and consequences.
  • Less than 30% of dietary AGEs are absorbed in the intestine after ingestion, and less than 15% are excreted in urine and feces, suggesting the remaining unabsorbed AGEs are degraded by gut microorganisms.
  • Alcohol metabolism via CYP2E1 can generate reactive metabolites and adducts, including acetaldehyde (AA), malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), MAA adducts, hydroxyethyl radicals, and AA-AGE adducts; AA-AGE formation is observed after chronic alcohol exposure and is linked to RAGE expression, oxidative stress, steatosis, apoptosis, and ALD/AFLD.
  • In the brain under normal conditions, cerebral catalase accounts for more than 60% of ethanol oxidation; CYP2E1 has a higher Km (~10 mM for ethanol) than ADH (Km <1 mM for ethanol) and is inducible by ethanol.
  • Cooking methods affect dietary AGEs: boiling or stewing meat can reduce AGE contents to one-half of that prepared by broiling, and marinating meat with acidic ingredients such as lemon juice or vinegar can decrease dietary AGEs produced during high-heat cooking by as much as 50%.

Methods

  • Narrative review of basic and translational literature on AGE formation, accumulation, receptor interactions, aging-related diseases, alcohol metabolism, adduct formation, and translational applications.
  • Synthesizes evidence from experimental animal models, cell culture models, human samples, autopsied tissues, and clinical/observational studies; includes summary tables (Table 1, Table 2) and figures (Fig. 1, Fig. 2).
  • Main analysis is qualitative mechanistic synthesis; no systematic review protocol, meta-analysis, or primary data collection is reported.

Limitations

  • The paper states that the underlying molecular mechanisms by which alcohol exerts cellular toxicity and organ damage remain to be further characterized.
  • The paper notes that several roles of AGEs, alcohol, and adducts in specific organs need further study, including heart, gut, pancreas, serum, erythrocytes, and testis; it also states that plasma AGE differences in Alzheimer’s and Parkinson’s disease are sex-dependent and require careful interpretation.
  • Evident from the text: this is a narrative review without systematic search or quantitative synthesis, and many proposed preventive compounds have not been specifically evaluated for AGE-associated adduct formation.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s12276-021-00561-7

Cites

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Statistics

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Claims the paper makes

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  • Premisecitation

    The pathological implications of AGEs are ascribed to their ability to promote oxidative stress, inflammation, and apoptosis.

    “The pathological implications of AGEs are ascribed to their ability to promote oxidative stress, inflammation, and apoptosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Uribarri, J. et al. Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress, and aging. J. Gerontol. A Biol. Sci. Med Sci. 62, 427–433 (2007). source

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  • Premisecitation

    Advanced glycation end products (AGEs) are potentially harmful heterogeneous molecules derived from nonenzymatic glycation.

    “Advanced glycation end products (AGEs) are potentially harmful and heterogeneous molecules derived from nonenzymatic glycation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Goldberg, T. et al. Advanced glycoxidation end products in commonly consumed foods. J. Am. Dietetic Assoc. 104, 1287–1291 (2004). source

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    • cites [2] Henning, C. & Glomb, M. A. Pathways of the Maillard reaction under physiological conditions. Glycoconj. J. 33, 499–512 (2016). source

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  • Premisecitation

    AGEs can be formed endogenously or provided by exogenous sources under normal and pathological conditions.

    “AGEs can be formed endogenously or provided by exogenous sources under normal and pathological conditions1,2.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Goldberg, T. et al. Advanced glycoxidation end products in commonly consumed foods. J. Am. Dietetic Assoc. 104, 1287–1291 (2004). source

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    • cites [2] Henning, C. & Glomb, M. A. Pathways of the Maillard reaction under physiological conditions. Glycoconj. J. 33, 499–512 (2016). source

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  • Premisecitation

    AGEs contribute to the development and progression of various aging-related pathological conditions, including diabetes, cardiovascular complications, gut microbiome-associated illnesses, liver or neurodegenerative diseases, and cancer.

    “Recent studies in basic and translational research have revealed the contributing roles of AGEs in the development and progression of various aging-related pathological conditions, such as diabetes, cardiovascular complications, gut microbiome-associated illnesses, liver or neurodegenerative diseases, and cancer.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Byun, K. et al. Advanced glycation end-products produced systemically and by macrophages: a common contributor to inflammation and degenerative diseases. Pharmacol. Therapeutics 177, 44–55 (2017). source

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    • cites [5] Abate, G., Marziano, M., Rungratanawanich, W., Memo, M. & Uberti, D. Nutrition and AGE-ing: focusing on Alzheimer’s disease. Oxid. Med. Cell. Longev. 2017, 1–10 (2017). source

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  • Premisecitation

    Dietary AGE formation depends on temperature, water content, pH status, and cooking time and method.

    “This formation of dietary AGEs depends on various factors, such as (1) temperature. e.g., the food browning process; (2) water content. e.g., dry-heat cooking; (3) pH status, e.g., food processing at high pH; and (4) cooking time and method, e.g., long-term cooking or storage and frying or broiling.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Abate, G., Marziano, M., Rungratanawanich, W., Memo, M. & Uberti, D. Nutrition and AGE-ing: focusing on Alzheimer’s disease. Oxid. Med. Cell. Longev. 2017, 1–10 (2017). source

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    • cites [19] Luevano-Contreras, C. & Chapman-Novakofski, K. Dietary advanced glycation end products and aging. Nutrients 2, 1247–1265 (2010). source

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  • Classified as probably not a substantial claim. 9
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  • The quote only partly states this claim. 3

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    Premisecitation

    Excessive chronic and/or acute binge consumption of alcohol causes more than 200 diseases, including alcohol use disorder, alcoholic liver disease, and brain damage.

    “Excessive chronic and/or acute binge consumption of alcohol (ethanol), a widely consumed addictive substance, is known to cause more than 200 diseases, including alcohol use disorder (addiction), alcoholic liver disease, and brain damage.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Jamal, M. et al. in Neuroscience of Alcohol (ed Victor R. Preedy) 39–46 (Academic Press, 2019).

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    • cites [7] NIAAA. Alcohol Facts and Statistics. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) https://www.niaaa.nih.gov/sites/default/files/AlcoholFactsAndStats.pdf (2020).

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    Premisecitation

    Persistently high blood glucose, often observed in type 2 diabetes, increases the substrate reservoir for AGE formation and activates protein kinase C and NADPH oxidases, producing ROS.

    “For example, persistently high blood glucose, often observed in people with type 2 diabetes, increases the reservoir of substrate for accelerating AGE formation and activates protein kinase C and NADPH oxidases, producing ROS13,18.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [13] Peppa, M., Uribarri, J. & Vlassara, H. Glucose, advanced glycation end products, and diabetes complications: what is new and what works. Clin. Diabetes 21, 186 (2003). source

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    • cites [18] Yan, S. F., Ramasamy, R. & Schmidt, A. M. Mechanisms of disease: advanced glycation end-products and their receptor in inflammation and diabetes complications. Nat. Clin. Pract. Endocrinol. Metab. 4, 285–293 (2008). source

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    Premisecitation

    Elevated oxidative stress can stimulate AGE accumulation, while AGE activation can increase oxidative stress, creating a synergistic feed-forward loop.

    “Additionally, elevated oxidative stress can act as a catalyst to stimulate AGE accumulation, while activation of AGEs can increase oxidative stress, creating a synergistic feed-forward loop to accelerate pathophysiological conditions2–4.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] Henning, C. & Glomb, M. A. Pathways of the Maillard reaction under physiological conditions. Glycoconj. J. 33, 499–512 (2016). source

      Not checked in the free run.

    • cites [3] Uribarri, J. et al. Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress, and aging. J. Gerontol. A Biol. Sci. Med Sci. 62, 427–433 (2007). source

      Not checked in the free run.

    • cites [4] Byun, K. et al. Advanced glycation end-products produced systemically and by macrophages: a common contributor to inflammation and degenerative diseases. Pharmacol. Therapeutics 177, 44–55 (2017). source

      Not checked in the free run.

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    Premisecitation

    Exogenous AGEs include dietary AGEs and cigarette smoke.

    “Exogenous AGEs include dietary AGEs (e.g., foods and beverages such as soft drinks containing high fructose corn sirup and/or sugar) and cigarette smoke.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Abate, G., Marziano, M., Rungratanawanich, W., Memo, M. & Uberti, D. Nutrition and AGE-ing: focusing on Alzheimer’s disease. Oxid. Med. Cell. Longev. 2017, 1–10 (2017). source

      Not checked in the free run.

    • cites [19] Luevano-Contreras, C. & Chapman-Novakofski, K. Dietary advanced glycation end products and aging. Nutrients 2, 1247–1265 (2010). source

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    Premisecitation

    Factors promoting AGE formation include excessive and/or prolonged alcohol consumption, cigarette smoking, high fat/caloric diets and/or extensively processed food, renal status, homeostatic imbalance, inflammation, hyperglycemia, and oxidative stress.

    “These factors include excessive and/or prolonged alcohol consumption, cigarette smoking, the intake of high fat/caloric diets and/or extensively processed food, renal status, homeostatic imbalance, inflammation, hyperglycemia, and oxidative stress2–4.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] Henning, C. & Glomb, M. A. Pathways of the Maillard reaction under physiological conditions. Glycoconj. J. 33, 499–512 (2016). source

      Not checked in the free run.

    • cites [3] Uribarri, J. et al. Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress, and aging. J. Gerontol. A Biol. Sci. Med Sci. 62, 427–433 (2007). source

      Not checked in the free run.

    • cites [4] Byun, K. et al. Advanced glycation end-products produced systemically and by macrophages: a common contributor to inflammation and degenerative diseases. Pharmacol. Therapeutics 177, 44–55 (2017). source

      Not checked in the free run.

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    Premisecitation

    Cigarette smoke contains reactive glycation products, which can increase AGE accumulation in the tissues and circulating blood of smokers.

    “In addition to dietary AGEs, cigarette smoke is found to contain reactive glycation products, which can increase AGE accumulation in the tissues and circulating blood of smokers23.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Cerami, C. et al. Tobacco smoke is a source of toxic reactive glycation products. Proc. Natl Acad. Sci. USA 94, 13915–13920 (1997). source

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    Premisecitation

    AGEs can bind to proteins with short half-lives such as serum albumin, thereby activating RAGEs and inducing inflammatory responses followed by protein dysfunction and cell damage.

    “In addition to long-lived proteins, AGEs can bind to proteins with short half-lives such as serum albumin, thereby activating RAGEs and inducing inflammatory responses followed by protein dysfunction and cell damage34.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Rondeau, P. & Bourdon, E. The glycation of albumin: structural and functional impacts. Biochimie 93, 645–658 (2011). source

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    Premisecitation

    RAGE is a multiligand cell surface receptor in the immunoglobulin superfamily.

    “A RAGE is a multiligand cell surface receptor in the immunoglobulin superfamily35.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Sessa, L. et al. The receptor for advanced glycation end-products (RAGE) is only present in mammals, and belongs to a family of cell adhesion molecules (CAMs). PloS One 9, e86903 (2014). source

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    Premisecitation

    Under pathological conditions, RAGEs can be upregulated and participate in various aging-related pathophysiologies.

    “However, under pathological conditions, RAGEs can be upregulated and participate in various aging-related pathophysiologies, such as adult-onset type 2 diabetes mellitus (DM), cardiovascular disorders, myocardial infarction, chronic kidney failure, pancreatitis, cancer, Alzheimer’s disease (AD), Parkinson’s disease (PD), hepatic fibrosis, and alcohol-mediated tissue injury37,38.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Chaudhuri, J. et al. The role of advanced glycation end products in aging and metabolic diseases: bridging association and causality. Cell Metab. 28, 337–352 (2018). source

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    • cites [38] Wautier, M.-P., Guillausseau, P.-J. & Wautier, J.-L. Activation of the receptor for advanced glycation end products and consequences on health. Diabetes Metab. Syndrome: Clin. Res. Rev. 11, 305–309 (2017). source

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    Premisecitation

    AGEs stimulate mitochondrial ROS production and JNK and NADPH oxidase activity to induce mitochondrial dysfunction and oxidative stress.

    “AGEs also stimulate mitochondrial ROS production and c-Jun N-terminal protein kinase (JNK) and NADPH oxidase activity to induce mitochondrial dysfunction and oxidative stress51–53.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [51] Sergi, D. et al. Mitochondrial (Dys)function and insulin resistance: from pathophysiological molecular mechanisms to the impact of diet. Front. Physiol. 10, 1–20 (2019). source

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    • cites [52] Lin, N., Zhang, H. & Su, Q. Advanced glycation end-products induce injury to pancreatic beta cells through oxidative stress. Diabetes Metab. 38, 250–257 (2012). source

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    • cites [53] Song, B. J. et al. Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications. Redox Biol. 3, 109–123 (2014). source

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    Premisecitation

    RAGE binds diverse ligands such as S100 proteins, amyloid-β peptides, prions, and HMGB1, which alter cellular functions and contribute to various pathophysiologies.

    “In addition to an AGE, a RAGE binds diverse ligands, such as members of the S100 protein family, amyloid-β peptides (Aβ), prions, and high-mobility group protein B1 (HMGB1), which alter cellular functions and contribute to various pathophysiologies42–44.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [42] Dhumale, S. S., Waghela, B. N. & Pathak, C. Quercetin protects necrotic insult and promotes apoptosis by attenuating the expression of RAGE and its ligand HMGB1 in human breast adenocarcinoma cells. IUBMB Life 67, 361–373 (2015). source

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    • cites [43] Donato, R. RAGE: a single receptor for several ligands and different cellular responses: the case of certain S100 proteins. Curr. Mol. Med. 7, 711–724 (2007). source

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    • cites [44] Jeong, J. et al. Soluble RAGE attenuates AngII-induced endothelial hyperpermeability by disrupting HMGB1-mediated crosstalk between AT1R and RAGE. Exp. Mol. Med. 51, 1–15 (2019). source

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    Premisecitation

    Chronic hyperglycemia in diabetes exhibits elevated AGE formation, serum AGE levels, RAGE expression, and AGE-RAGE interactions, leading to increased oxidative stress, insulin resistance, inflammation, pancreatic β-cell dysfunction with apoptosis, and diabetic complications.

    “Chronic hyperglycemia, frequently observed in experimental models and human diabetes, exhibits elevated AGE formation, serum AGE levels, RAGE expression, and AGE-RAGE interactions. Consequently, these changes lead to increased oxidative stress, insulin resistance, inflammation, pancreatic β-cell dysfunction with apoptosis, and eventually diabetic complications, including retinopathy, neuropathy, c”
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    • cites [47] Roshandel, D. et al. DNA methylation age calculators reveal association with diabetic neuropathy in type 1 diabetes. Clin. Epigenetics 12, 1–16 (2020). source

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    • cites [48] Le Bagge, S., Fotheringham, A. K., Leung, S. S. & Forbes, J. M. Targeting the receptor for advanced glycation end products (RAGE) in type 1 diabetes. Med. Res. Rev. 1–20, https://doi.org/10.1002/med.21654 (2020). source

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    • cites [49] Egana-Gorrono, L. et al. Receptor for advanced glycation end products (RAGE) and mechanisms and therapeutic opportunities in diabetes and cardiovascular disease: insights from human subjects and animal models. Front. Cardiovasc. Med. 7, 1–15 (2020). source

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    • cites [50] Yang, P., Feng, J., Peng, Q., Liu, X. & Fan, Z. Advanced glycation end products: potential mechanism and therapeutic target in cardiovascular complications under diabetes. Oxid. Med. Cell. Longev. 2019, 1–12 (2019).

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    Premisecitation

    Activation of these proteins usually increases oxidative stress and inflammation, which promotes RAGE expression in a positive feed-forward loop, contributing to chronic disease development.

    “Activation of these proteins usually increases oxidative stress and inflammation that, in turn, promotes RAGE expression in a positive feed-forward loop, contributing to chronic disease development39–41.”
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    • cites [39] Senatus, L. M. & Schmidt, A. M. The AGE-RAGE axis: implications for age-associated arterial diseases. Front. Genet. 8, 1–10 (2017). source

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    • cites [40] Xue, J. et al. The receptor for advanced glycation end products (RAGE) specifically recognizes methylglyoxal-derived AGEs. Biochemistry 53, 3327–3335 (2014). source

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    • cites [41] Bongarzone, S., Savickas, V., Luzi, F. & Gee, A. D. Targeting the receptor for advanced glycation endproducts (RAGE): a medicinal chemistry perspective. J. Medicinal Chem. 60, 7213–7232 (2017). source

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    Premisecitation

    In humans, serum contains AGE peptides and free AGE adducts; AGE peptides are filtered by renal glomeruli and reabsorbed by proximal convoluted tubules and eliminated in urine as free AGE adducts.

    “In humans, serum contains AGE peptides and free AGE adducts. AGE peptides are generally filtered by renal glomeruli and further reabsorbed by proximal convoluted tubules and eliminated from the body in the form of free AGE adducts in the urine66,67.”
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    • cites [66] Rabbani, N. & Thornalley, P. J. Advanced glycation end products in the pathogenesis of chronic kidney disease. Kidney Int. 93, 803–813 (2018). source

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    • cites [67] Bettiga, A. et al. The Modern Western Diet Rich in Advanced Glycation End-Products (AGEs): an overview of its impact on obesity and early progression of renal pathology. Nutrients 11, E1748 (2019). source

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    Premisecitation

    Accumulation and exposure to AGEs exacerbate oxidative stress and inflammation and initiate the oxidation of LDLs, which are harmful to cardiovascular function.

    “The accumulation and exposure to AGEs exacerbate oxidative stress and inflammation and initiate the oxidation of low-density lipoproteins (LDLs), which are harmful to cardiovascular function.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [55] Uribarri, J. et al. Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. Diabetes Care 34, 1610–1616 (2011). source

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    • cites [56] Xu, J. et al. Involvement of advanced glycation end products in the pathogenesis of diabetic retinopathy. Cell. Physiol. Biochem. 48, 705–717 (2018). source

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    • cites [57] Lim, M. et al. Induction of apoptosis of Beta cells of the pancreas by advanced glycation end-products, important mediators of chronic complications of diabetes mellitus. Ann. N. Y. Acad. Sci. 1150, 311–315 (2008). source

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    • cites [59] Goldin, A., Beckman, J. A., Schmidt, A. M. & Creager, M. A. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation 114, 597–605 (2006). source

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    Premisecitation

    Restriction of dietary AGEs can reduce and/or reverse these effects by enhancing insulin sensitivity and upregulating AGE-R1 and SIRT1 while suppressing NF-κB, TNF-α, leptin, and serum AGEs in type 2 DM.

    “Restriction of dietary AGEs can reduce and/or reverse these effects by enhancing insulin sensitivity and upregulating AGE-R1 and SIRT1 expression while suppressing NF-κB, tumor necrosis factor-alpha (TNF-α), leptin, and serum AGEs in type 2 DM55.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Uribarri, J. et al. Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. Diabetes Care 34, 1610–1616 (2011). source

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    Premisecitation

    The AGE-RAGE interaction instigates pericyte apoptosis, vascular inflammation and permeability, and blood-tissue barrier breakdown.

    “In addition, the AGE-RAGE interaction further instigates pericyte apoptosis, vascular inflammation and permeability, and blood-tissue barrier breakdown56.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Xu, J. et al. Involvement of advanced glycation end products in the pathogenesis of diabetic retinopathy. Cell. Physiol. Biochem. 48, 705–717 (2018). source

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    Premisecitation

    AGEs can be produced in renal mesangial cells and induce expression of MCP-1.

    “In addition, AGEs can be produced in renal mesangial cells and induce the expression of monocyte chemoattractant protein-1 (MCP-1).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [70] Frimat, M. et al. Kidney, heart and brain: three organs targeted by ageing and glycation. Clin. Sci. 131, 1069–1092 (2017). source

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    • cites [71] Kumar Pasupulati, A., Chitra, P. S. & Reddy, G. B. Advanced glycation end products mediated cellular and molecular events in the pathology of diabetic nephropathy. Biomol. Concepts 7, 293–309 (2016). source

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    Premisecitation

    Increased circulating AGEs can accumulate in renal glomeruli and enhance collagen and laminin production in the extracellular matrix together with proximal tubular senescence, oxidative stress, and inflammatory processes.

    “Increased circulating AGEs can accumulate in the renal glomeruli and enhance collagen and laminin production in the extracellular matrix together with proximal tubular senescence, oxidative stress, and inflammatory processes66.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Rabbani, N. & Thornalley, P. J. Advanced glycation end products in the pathogenesis of chronic kidney disease. Kidney Int. 93, 803–813 (2018). source

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    Premisecitation

    Adipose tissues produce molecular RAGE ligands such as HMGB-1 and RAGE-inducible molecules such as MCP-1 and IL-6; upon RAGE interaction, these bound molecules activate their own production in adipose tissues, suggesting a causal role of RAGE signaling in the inflammatory pathway.

    “Adipose tissues also produce molecular RAGE ligands (such as HMGB-1) and RAGE-inducible molecules (e.g., MCP-1 and IL-6). Upon RAGE interaction, these bound molecules activate their own production in adipose tissues, suggesting a causal role of RAGE signaling in the inflammatory pathway49,67.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [49] Egana-Gorrono, L. et al. Receptor for advanced glycation end products (RAGE) and mechanisms and therapeutic opportunities in diabetes and cardiovascular disease: insights from human subjects and animal models. Front. Cardiovasc. Med. 7, 1–15 (2020). source

      Not checked in the free run.

    • cites [67] Bettiga, A. et al. The Modern Western Diet Rich in Advanced Glycation End-Products (AGEs): an overview of its impact on obesity and early progression of renal pathology. Nutrients 11, E1748 (2019). source

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    Premisecitation

    Endogenous AGEs can be trapped and accumulated in adipose tissues, and AGE accumulation can be prevented by RAGE inhibition.

    “In addition to dietary AGEs, endogenous AGEs can be trapped and accumulated in adipose tissues, and AGE accumulation can be prevented by RAGE inhibition77.”
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    • cites [77] Gaens, K. H. et al. Nepsilon-(carboxymethyl)lysine-receptor for advanced glycation end product axis is a key modulator of obesity-induced dysregulation of adipokine expression and insulin resistance. Arteriosclerosis, Thrombosis, Vasc. Biol. 34, 1199–1208 (2014). source

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    Aggregated AGEs activate JNK, IKK, NF-κB, and TNF-α pathways to trigger hypothalamic insulin and leptin resistance, resulting in hypothalamic dysfunction, imbalanced energy control, and elevated food consumption and body weight with obesity and metabolic syndromes.

    “Aggregated AGEs can activate the JNK, Iκ-B kinase (IKK), NF-κB, and TNF-α pathways to trigger hypothalamic insulin and leptin resistance, resulting in hypothalamic dysfunction, imbalanced energy control, and subsequently elevated food consumption and body weight with obesity and metabolic syndromes78.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Sergi, D., Boulestin, H., Campbell, F. M. & Williams, L. M. The role of dietary advanced glycation end products in metabolic dysfunction. Mol. Nutr. Food Res. e1900934, https://doi.org/10.1002/mnfr.201900934 (2020). source

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    Premisecitation

    The AGE-RAGE interaction augments production of proinflammatory cytokines and suppresses osteoblast differentiation via the Wnt, PI3K, and ERK1/2 signaling pathways.

    “The interaction of AGE-RAGE augments the production of proinflammatory cytokines and suppresses osteoblast differentiation via the Wnt, PI3K, and ERK1/2 signaling pathways83.”
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    • cites [83] Li, G., Xu, J. & Li, Z. Receptor for advanced glycation end products inhibits proliferation in osteoblast through suppression of Wnt, PI3K and ERK signaling. Biochem. Biophys. Res. Commun. 423, 684–689 (2012). source

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    Premisecitation

    Binding of AGEs to RAGE triggers extracellular matrix glycation, NADPH oxidase activity, local hypoxia, VEGF expression, and NF-κB activation to produce oxidative stress and inflammation, supporting the cancer microenvironment and promoting tumoral angiogenesis and proliferation.

    “The binding of AGEs to RAGE triggers extracellular matrix glycation, NADPH oxidase activity, local hypoxia, VEGF expression, and NF-κB activation to produce oxidative stress and inflammation, supporting the cancer microenvironment and promoting tumoral angiogenesis and proliferation32,87.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [32] Rojas, A., Anazco, C., Gonzalez, I. & Araya, P. Extracellular matrix glycation and receptor for advanced glycation end-products activation: a missing piece in the puzzle of the association between diabetes and cancer. Carcinogenesis 39, 515–521 (2018). source

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    • cites [87] Foster, D. et al. AGE metabolites: a biomarker linked to cancer disparity? Cancer Epidemiol. Biomark. Prev. 23, 2186–2191 (2014). source

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    Premisecitation

    In bone, accumulated AGEs can increase osteoclast generation while decreasing osteoblast growth and differentiation.

    “In bone, accumulated AGEs can increase osteoclast generation while decreasing osteoblast growth and differentiation.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [80] Okazaki, K. et al. Advanced glycation end products (AGEs), but not high glucose, inhibit the osteoblastic differentiation of mouse stromal ST2 cells through the suppression of osterix expression, and inhibit cell growth and increasing cell apoptosis. Calcif. Tissue Int. 91, 286–296 (2012). source

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    • cites [81] Liu, J. et al. AGEs induce apoptosis in rat osteoblast cells by activating the caspase-3 signaling pathway under a high-glucose environment in vitro. Appl. Biochem. Biotechnol. 178, 1015–1027 (2016). source

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    • cites [82] Zhu, S. Y. et al. Advanced oxidation protein products induce pre-osteoblast apoptosis through a nicotinamide adenine dinucleotide phosphate oxidase-dependent, mitogen-activated protein kinases-mediated intrinsic apoptosis pathway. Aging Cell 17, 1–15 (2018). source

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    Premisecitation

    The intestinal microbiota produces deglycating enzymes to digest AGEs, which are utilized for energy production.

    “The intestinal microbiota produces deglycating enzymes to digest AGEs, which are utilized for energy production.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Qu, W. et al. Dietary advanced glycation end products modify gut microbial composition and partially increase colon permeability in rats. Mol. Nutr. Food Res. 61, 1–14 (2017). source

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    Premisecitation

    Less than 30% of dietary AGEs are absorbed in the intestine after ingestion, and less than 15% are excreted in urine and feces.

    “In the body, less than 30% of dietary AGEs are absorbed in the intestine after ingestion, and less than 15% are excreted in urine and feces, leading to a hypothesis that the remaining unabsorbed AGEs are degraded by gut microorganisms97.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97] Tuohy, K. M. et al. Metabolism of Maillard reaction products by the human gut microbiota–implications for health. Mol. Nutr. Food Res. 50, 847–857 (2006). source

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    Premisecitation

    Elevated accumulation of AGEs can enhance gut barrier dysfunction, intestinal permeability, and bacterial translocation by stimulating production and release of proinflammatory cytokines, potentially toxic metabolites, and bacterial products, causing intestinal epithelial cell damage, contributing to systemic endotoxemia, inflammation, and multiorgan injury.

    “Elevated accumulation of AGEs can enhance gut barrier dysfunction, intestinal permeability, and bacterial translocation by stimulating the production and release of proinflammatory cytokines, potentially toxic metabolites and bacterial products, as well as causing intestinal epithelial cell damage, contributing to systemic endotoxemia, inflammation, and multiorgan injury98.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Qu, W. et al. Dietary advanced glycation end products modify gut microbial composition and partially increase colon permeability in rats. Mol. Nutr. Food Res. 61, 1–14 (2017). source

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    Premisecitation

    The gut microbiota plays a critical role in regulating body function by producing diverse metabolites and influencing the gut-liver-brain axis and immune system pathways.

    “The gut microbiota plays a critical role in regulating body function by producing diverse metabolites and influencing the gut-liver-brain axis and other pathways, such as immune system pathways.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [95] Gentile, C. L. & Weir, T. L. The gut microbiota at the intersection of diet and human health. Science 362, 776–780 (2018). source

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    • cites [96] Dinan, T. G. & Cryan, J. F. Gut-brain axis in 2016: brain-gut-microbiota axis - mood, metabolism and behaviour. Nat. Rev. Gastroenterol. Hepatol. 14, 69–70 (2017). source

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    Premisecitation

    Oxidative stress can be generated due to AGE formation in the brain; this feed-forward process creates a vicious cycle that exacerbates oxidative damage with subsequent initiation and progression of neurodegenerative diseases.

    “Oxidative stress can also be generated due to AGE formation in the brain. This feed-forward process creates a vicious cycle that exacerbates oxidative damage with the subsequent initiation and progression of neurodegenerative diseases4,103.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Byun, K. et al. Advanced glycation end-products produced systemically and by macrophages: a common contributor to inflammation and degenerative diseases. Pharmacol. Therapeutics 177, 44–55 (2017). source

      Not checked in the free run.

    • cites [103] Srikanth, V. et al. Advanced glycation endproducts and their receptor RAGE in Alzheimer’s disease. Neurobiol. Aging 32, 763–777 (2011). source

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  • May combine two claims.

    Premisecitation

    After binding with S100, RAGE contributes to epithelial-mesenchymal cell transition and cell migration, which is associated with tumor invasion and metastasis in cervical cancer and osteosarcomas.

    “After binding with S100, RAGE also contributes to the epithelial-mesenchymal cell transition and cell migration, which is associated with tumor invasion and metastasis in cervical cancer and osteosarcomas, suggesting a contributing role for RAGE in tumor malignancy92.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Kataoka, K. et al. S100A7 promotes the migration and invasion of osteosarcoma cells via the receptor for advanced glycation end products. Oncol. Lett. 3, 1149–1153 (2012). source

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    Premisecitation

    HMGB1 and Aβ can bind RAGEs to activate the NF-κB, ERK1/2, p38, JNK, PI3K, JAK/STAT pathways, leading to neuronal cell death and neurodegeneration.

    “In addition to AGEs and AGE adducts, HMGB1 and Aβ can bind RAGEs to activate the NF-κB, ERK1/2, p38, JNK, PI3K, Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways, leading to neuronal cell death and neurodegeneration112.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] Bortolotto, V. & Grilli, M. Every cloud has a silver lining: proneurogenic effects of abeta oligomers and HMGB-1 via activation of the RAGE-NF-kappaB axis. CNS Neurol. Disord. Drug Targets 16, 1066–1079 (2017). source

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    Premisecitation

    Accumulation of AGEs and the AGE-RAGE interaction greatly induce reactive gliosis and the NF-κB proinflammatory pathway, leading to cellular stress, activated gliosis, and eventually neuronal degeneration.

    “Additionally, the accumulation of AGEs and the AGE-RAGE interaction greatly induce reactive gliosis and the NF-κB proinflammatory pathway, leading to cellular stress, activated gliosis, and eventually neuronal degeneration105.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] Wang, C.-Y. et al. Trientine reduces BACE1 activity and mitigates amyloidosis via the AGE/RAGE/NF-κB pathway in a transgenic mouse model of Alzheimer’s disease. Antioxid. Redox Signal 19, 2024–2039 (2013). source

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  • May combine two claims.

    Premisecitation

    Activated microglial cells produce and secrete AGE-albumin to induce RAGE expression in neurons and promote neuronal cell death, contributing to neurodegenerative disorders.

    “Activated microglial cells produce and secrete AGE-albumin to induce RAGE expression in neurons and promote neuronal cell death, thereby contributing to neurodegenerative disorders4,108.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Byun, K. et al. Advanced glycation end-products produced systemically and by macrophages: a common contributor to inflammation and degenerative diseases. Pharmacol. Therapeutics 177, 44–55 (2017). source

      Not checked in the free run.

    • cites [108] Byun, K. et al. Activated microglial cells synthesize and secrete AGE-albumin. Anat. Cell Biol. 45, 47–52 (2012). source

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    Premisecitation

    The AGE-albumin adduct is one of the most abundant AGE-protein adducts in the brain, confirmed by mass spectral analysis, and causes RAGE overexpression in primary neurons in human AD brains.

    “One of the most abundant AGE-protein adducts in the brain is the AGE-albumin adduct, which was confirmed by mass spectral analysis, and causes RAGE overexpression in primary neurons in human AD brains.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [111] Byun, K. et al. Induction of neuronal death by microglial AGE-albumin: implications for Alzheimer’s disease. PloS One 7, 1–11 (2012). source

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  • May combine two claims.

    Premisecitation

    AGEs suppress SIRT1 expression and stimulate iNOS and caspase-3 to enhance neuronal apoptosis and/or degeneration with elevated gliosis.

    “AGEs also suppress SIRT1 expression and stimulate inducible nitric oxide synthase (iNOS) and caspase-3 to enhance neuronal apoptosis and/or degeneration with elevated gliosis110.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [110] Wong, A. et al. Advanced glycation endproducts co-localize with inducible nitric oxide synthase in Alzheimer’s disease. Brain Res. 920, 32–40 (2001). source

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  • May combine two claims.

    Premisecitation

    Aβ is produced by the AGE-albumin-RAGE interaction, which in turn supports AGE-albumin adduct formation in a positive feed-forward cycle.

    “Aβ is also produced by the AGE-albumin-RAGE interaction, which in turn supports AGE-albumin adduct formation in a positive feed-forward cycle.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Byun, K. et al. Induction of neuronal death by microglial AGE-albumin: implications for Alzheimer’s disease. PloS One 7, 1–11 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Accumulated AGEs can accelerate the formation of Aβ, tau, and APP and induce hyperphosphorylation of tau and cross-linking of AGE-Aβ, leading to an increase in these aggregates.

    “Accumulated AGEs can accelerate the formation of Aβ, tau, and amyloid precursor protein (APP) and induce the hyperphosphorylation of tau and the cross-linking of AGE-Aβ, leading to an increase in these aggregates109.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] Chen, K., Maley, J. & Yu, P. H. Potential inplications of endogenous aldehydes in beta-amyloid misfolding, oligomerization and fibrillogenesis. J. Neurochem. 99, 1413–1424 (2006). source

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  • May combine two claims.

    Premisecitation

    Endogenous and exogenous AGEs provoke the initiation and progression of NAFLD, and dietary AGEs from fructose- or sucrose-enriched diets and/or soft drinks can worsen liver fibrosis faster than endogenous AGEs.

    “Endogenous and exogenous AGEs provoke the initiation and progression of NAFLD.”
    • Also stated in: § AGEs and liver diseases · plain
      “However, consumption of dietary AGEs from sources such as fructose- or sucrose-enriched diets and/or soft drinks can worsen liver fibrosis faster than consumption of endogenous AGEs.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [55] Uribarri, J. et al. Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. Diabetes Care 34, 1610–1616 (2011). source

      Not checked in the free run.

    • cites [56] Xu, J. et al. Involvement of advanced glycation end products in the pathogenesis of diabetic retinopathy. Cell. Physiol. Biochem. 48, 705–717 (2018). source

      Not checked in the free run.

    • cites [57] Lim, M. et al. Induction of apoptosis of Beta cells of the pancreas by advanced glycation end-products, important mediators of chronic complications of diabetes mellitus. Ann. N. Y. Acad. Sci. 1150, 311–315 (2008). source

      Not checked in the free run.

    • cites [124] Leung, C. et al. Dietary glycotoxins exacerbate progression of experimental fatty liver disease. J. Hepatol. 60, 832–838 (2014). source

      Not checked in the free run.

    • cites [125] Rolo, A. P., Teodoro, J. S. & Palmeira, C. M. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic. Biol. Med. 52, 59–69 (2012). source

      Not checked in the free run.

    • cites [126] Jiang, J. X. et al. Advanced glycation endproducts induce fibrogenic activity in nonalcoholic steatohepatitis by modulating TNF-alpha-converting enzyme activity in mice. Hepatology 58, 1339–1348 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AGEs cross-linked with α-synuclein are present in PD brains and result in aggregation of α-synuclein toxic oligomers.

    “AGEs cross-linked with α-synuclein are also present in PD brains, resulting in the aggregation of α-synuclein toxic oligomers115,116.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [115] Guerrero, E., Vasudevaraju, P., Hegde, M. L., Britton, G. B. & Rao, K. S. Recent advances in alpha-synuclein functions, advanced glycation, and toxicity: implications for Parkinson’s disease. Mol. Neurobiol. 47, 525–536 (2013). source

      Not checked in the free run.

    • cites [116] Munch, G. et al. Crosslinking of alpha-synuclein by advanced glycation endproducts–an early pathophysiological step in Lewy body formation? J. Chem. Neuroanat. 20, 253–257 (2000). source

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  • May combine two claims.

    Premisecitation

    The liver eliminates circulating AGEs using liver sinusoidal endothelial cells and Kupffer cells, and this function declines during aging and in various liver diseases, resulting in accumulation of AGEs or their aggregates.

    “It is involved in the catabolism and elimination of circulating AGEs using liver sinusoidal endothelial cells and Kupffer cells.”
    • Also stated in: § AGEs and liver diseases · plain
      “This function of the liver declines during the aging process and in various liver diseases, resulting in the accumulation of AGEs or their aggregates120,121.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [120] Sebekova, K., Kupcova, V., Schinzel, R. & Heidland, A. Markedly elevated levels of plasma advanced glycation end products in patients with liver cirrhosis - amelioration by liver transplantation. J. Hepatol. 36, 66–71 (2002). source

      Not checked in the free run.

    • cites [121] Fernando, D. H., Forbes, J. M., Angus, P. W. & Herath, C. B. Development and progression of non-alcoholic fatty liver disease: the role of advanced glycation end products. Int. J. Mol. Sci. 20, 1–19 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Aggregation of AGEs decreases GSH, SIRT1, and TIMP3 and increases oxidative stress and inflammation, promoting inflammatory liver injury and fibrosis in experimental animal models and NAFLD patients.

    “The aggregation of AGEs decreases the levels of the most important cellular antioxidant peptides, glutathione (GSH), SIRT1, and tissue inhibitor of metalloproteinase 3 (TIMP3), accompanied by increased oxidative stress and inflammation, promoting inflammatory liver injury and fibrosis in experimental animal models and NAFLD patients55–57,124–126.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [55] Uribarri, J. et al. Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. Diabetes Care 34, 1610–1616 (2011). source

      Not checked in the free run.

    • cites [56] Xu, J. et al. Involvement of advanced glycation end products in the pathogenesis of diabetic retinopathy. Cell. Physiol. Biochem. 48, 705–717 (2018). source

      Not checked in the free run.

    • cites [57] Lim, M. et al. Induction of apoptosis of Beta cells of the pancreas by advanced glycation end-products, important mediators of chronic complications of diabetes mellitus. Ann. N. Y. Acad. Sci. 1150, 311–315 (2008). source

      Not checked in the free run.

    • cites [124] Leung, C. et al. Dietary glycotoxins exacerbate progression of experimental fatty liver disease. J. Hepatol. 60, 832–838 (2014). source

      Not checked in the free run.

    • cites [125] Rolo, A. P., Teodoro, J. S. & Palmeira, C. M. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic. Biol. Med. 52, 59–69 (2012). source

      Not checked in the free run.

    • cites [126] Jiang, J. X. et al. Advanced glycation endproducts induce fibrogenic activity in nonalcoholic steatohepatitis by modulating TNF-alpha-converting enzyme activity in mice. Hepatology 58, 1339–1348 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AGE-albumin is the most abundant AGE product in the human PD brain and is synthesized by activated microglial cells.

    “AGE-albumin, the most abundant AGE product in the human PD brain, is synthesized by activated microglial cells.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119] Bayarsaikhan, E. et al. Microglial AGE-albumin is critical for neuronal death in Parkinson’s disease: a possible implication for theranostics. Int. J. Nanomed. 10(Spec Iss), 281–292 (2015).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RAGE interacts with S100 in PD brains, activating NF-κB and TNF-α signaling pathways to promote dopaminergic neuronal death and subsequent neurodegeneration.

    “Moreover, RAGE can interact with S100 in PD brains, activating the NF-κB and TNF-α signaling pathways to promote dopaminergic neuronal death and subsequent neurodegeneration in PD117,118.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [117] Sathe, K. et al. S100B is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-alpha pathway. Brain J. Neurol. 135, 3336–3347 (2012). source

      Not checked in the free run.

    • cites [118] Abdelsalam, R. M. & Safar, M. M. Neuroprotective effects of vildagliptin in rat rotenone Parkinson’s disease model: role of RAGE-NFkappaB and Nrf2-antioxidant signaling pathways. J. Neurochem. 133, 700–707 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Ethanol metabolism primarily occurs in the liver in three major steps: ethanol oxidation to acetaldehyde, acetaldehyde metabolism to acetate, and acetate catabolism to H2O and CO2.

    “Ethanol metabolism primarily occurs in the liver in three major steps: (1) ethanol oxidation to acetaldehyde, (2) acetaldehyde metabolism to acetate, and (3) acetate catabolism to H2O and CO2132–134.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [132] Purohit, V., Gao, B. & Song, B. J. Molecular mechanisms of alcoholic fatty liver. Alcohol. Clin. Exp. Res. 33, 191–205 (2009). source

      Not checked in the free run.

    • cites [133] Thiele, G. M., Klassen, L. W. & Tuma, D. J. Formation and immunological properties of aldehyde-derived protein adducts following alcohol consumption. Methods Mol. Biol. 447, 235–257 (2008). source

      Not checked in the free run.

    • cites [134] Zakhari, S. Overview: how is alcohol metabolized by the body? Alcohol Res. Health. 29, 245–254 (2006).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RAGE amounts are increased in HCC liver compared with hepatitis and healthy liver, and serum AGE amounts are higher in HCC than in NASH and healthy liver specimens.

    “Increased amounts of RAGE are also observed in the liver of hepatocellular carcinoma (HCC), and its level is significantly greater than it is liver affected by hepatitis and healthy liver specimens.”
    • Also stated in: § AGEs and liver diseases · plain
      “The amounts of serum AGEs are also higher in HCC than in NASH and healthy liver specimens.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [129] Hiwatashi, K. et al. A novel function of the receptor for advanced glycation end-products (RAGE) in association with tumorigenesis and tumor differentiation of HCC. Ann. Surg. Oncol. 15, 923–933 (2008). source

      Not checked in the free run.

    • cites [130] Takino, J., Yamagishi, S. & Takeuchi, M. Glycer-AGEs-RAGE signaling enhances the angiogenic potential of hepatocellular carcinoma by upregulating VEGF expression. World J. Gastroenterol. 18, 1781–1788 (2012). source

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    • cites [131] Yang, Y. et al. Pioglitazone, a PPARgamma agonist, inhibits growth and invasion of human hepatocellular carcinoma via blockade of the rage signaling. Mol. Carcinog. 54, 1584–1595 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In HCC, AGE-RAGE interaction is associated with angiogenesis and tumor proliferation and invasion, which are ameliorated by RAGE inhibition.

    “In HCC, the AGE-RAGE interaction is associated with angiogenesis and tumor proliferation and invasion, which are ameliorated by RAGE inhibition.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [129] Hiwatashi, K. et al. A novel function of the receptor for advanced glycation end-products (RAGE) in association with tumorigenesis and tumor differentiation of HCC. Ann. Surg. Oncol. 15, 923–933 (2008). source

      Not checked in the free run.

    • cites [130] Takino, J., Yamagishi, S. & Takeuchi, M. Glycer-AGEs-RAGE signaling enhances the angiogenic potential of hepatocellular carcinoma by upregulating VEGF expression. World J. Gastroenterol. 18, 1781–1788 (2012). source

      Not checked in the free run.

    • cites [131] Yang, Y. et al. Pioglitazone, a PPARgamma agonist, inhibits growth and invasion of human hepatocellular carcinoma via blockade of the rage signaling. Mol. Carcinog. 54, 1584–1595 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Accumulated AGEs and AGE-RAGE interactions in liver cells augment ROS generation and MAPK/NF-κB activation, leading to inflammatory cell death in the parenchyma and tissue remodeling during fibrosis.

    “Accumulated AGEs and AGE-RAGE interactions in these cells augment the generation of ROS and the activation of MAPK and NF-κB pathways, leading to inflammatory cell death in the parenchyma and tissue remodeling processes during fibrosis127,128.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [127] Fehrenbach, H., Weiskirchen, R., Kasper, M. & Gressner, A. M. Up-regulated expression of the receptor for advanced glycation end products in cultured rat hepatic stellate cells during transdifferentiation to myofibroblasts. Hepatology 34, 943–952 (2001). source

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    • cites [128] Leung, C. et al. Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease. World J. Gastroenterol. 22, 8026–8040 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Ethanol is absorbed via simple diffusion in the small intestine into the blood and rapidly circulates throughout the body.

    “Upon consumption, ethanol is absorbed via simple diffusion in the small intestine into the blood and rapidly circulates throughout the body6.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Jamal, M. et al. in Neuroscience of Alcohol (ed Victor R. Preedy) 39–46 (Academic Press, 2019).

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Treatment with an antioxidant can halt AA-AGE adduct formation, supporting that AA-AGE adducts can be generated from a Schiff base product similar to AA adducts and AGEs.

    “However, treatment with an antioxidant can halt AA-AGE adduct formation, supporting the idea that AA-AGE adducts can be generated from a Schiff base product similar to AA adducts and AGEs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [168] Freeman, T. L. et al. Recent advances in alcohol-induced adduct formation. Alcohol. Clin. Exp. Res. 29, 1310–1316 (2005). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cytosolic ADH is a major enzyme that catalyzes oxidative metabolism of ethanol to acetaldehyde by using NAD+ converted to NADH.

    “Cytosolic ADH is a major enzyme that catalyzes the oxidative metabolism of ethanol to acetaldehyde by using the cofactor nicotinamide adenine dinucleotide (NAD+) converted to NADH132–134.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [132] Purohit, V., Gao, B. & Song, B. J. Molecular mechanisms of alcoholic fatty liver. Alcohol. Clin. Exp. Res. 33, 191–205 (2009). source

      Not checked in the free run.

    • cites [133] Thiele, G. M., Klassen, L. W. & Tuma, D. J. Formation and immunological properties of aldehyde-derived protein adducts following alcohol consumption. Methods Mol. Biol. 447, 235–257 (2008). source

      Not checked in the free run.

    • cites [134] Zakhari, S. Overview: how is alcohol metabolized by the body? Alcohol Res. Health. 29, 245–254 (2006).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After chronic and/or large amounts of ethanol intake, CYP2E1 is involved in ethanol metabolism through an NADPH-dependent pathway; CYP2E1 expression and activity are usually induced by ethanol and other substances such as dietary fats, and this induction contributes to alcohol- and nonalcohol-induced pathophysiology.

    “After chronic and/or large amounts of ethanol intake, CYP2E1, the major component of the microsomal ethanol oxidizing system (MEOS) with a higher km (~10 mM for ethanol) than that of ADH (km <1 mM for ethanol), is also involved in ethanol metabolism through an NADPH-dependent pathway.”
    • Also stated in: § Alcohol metabolism (see summary in Fig. 1) · plain
      “In contrast to those of ADH and catalase, CYP2E1 expression and activity are usually induced by ethanol and other substances, such as dietary fats.”
    • Also stated in: § Alcohol metabolism (see summary in Fig. 1) · plain
      “The induction and activation of CYP2E1, in turn, contribute to alcohol- and nonalcohol-induced pathophysiology136–144.”
    Quote in the paperNot a substantial claim0 of 9 sources checked
    • cites [136] Yun, J.-W. et al. Binge alcohol promotes hypoxic liver injury through a CYP2E1–HIF-1α-dependent apoptosis pathway in mice and humans. Free Radic. Biol. Med. 77, 183–194 (2014). source

      Not checked in the free run.

    • cites [137] Jeong, K.-S. et al. Cytochrome P450 2E1 (CYP2E1)-dependent production of a 37-kDa acetaldehyde–protein adduct in the rat liver. Arch. Biochem. Biophys. 384, 81–87 (2000). source

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    • cites [138] Cederbaum, A. I., Lu, Y. & Wu, D. Role of oxidative stress in alcohol-induced liver injury. Arch. Toxicol. 83, 519–548 (2009). source

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    • cites [139] Abdelmegeed, M. A. et al. Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis. J. Hepatol. 57, 860–866 (2012). source

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    • cites [140] Knockaert, L., Descatoire, V., Vadrot, N., Fromenty, B. & Robin, M. A. Mitochondrial CYP2E1 is sufficient to mediate oxidative stress and cytotoxicity induced by ethanol and acetaminophen. Toxicol. Vitro 25, 475–484 (2011). source

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    • cites [141] Leung, T. M. & Nieto, N. CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease. J. Hepatol. 58, 395–398 (2013). source

      Not checked in the free run.

    • cites [142] Song, B. J., Akbar, M., Jo, I., Hardwick, J. P. & Abdelmegeed, M. A. Translational implications of the alcohol-metabolizing enzymes, including cytochrome P450-2E1, in alcoholic and nonalcoholic liver disease. Adv. Pharmacol. 74, 303–372 (2015). source

      Not checked in the free run.

    • cites [143] Seitz, H. K. The role of cytochrome P4502E1 in the pathogenesis of alcoholic liver disease and carcinogenesis. Chem. Biol. Interact. 316, 108918 (2020). source

      Not checked in the free run.

    • cites [144] Song, B. J. et al. Contributing roles of CYP2E1 and other cytochrome P450 isoforms in alcohol-related tissue injury and carcinogenesis. Adv. Exp. Med. Biol. 1164, 73–87 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AA-AGE adducts are observed after chronic alcohol exposure, exhibit similar properties to AGE adducts cross-linked with sugar molecules, and are different from MAA adducts formed by AA and MDA interactions.

    “The formation of AA-AGE adducts can be observed after chronic alcohol exposure.”
    • Also stated in: § Alcohol metabolism (see summary in Fig. 1) · plain
      “These AA-AGE adducts exhibit similar properties (e.g., brown color and polymerization) as the AGE adducts cross-link with sugar molecules, and they are different from MAA adducts formed by AA and MDA interactions.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [168] Freeman, T. L. et al. Recent advances in alcohol-induced adduct formation. Alcohol. Clin. Exp. Res. 29, 1310–1316 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Catalase may participate in ethanol oxidation in the presence of H2O2 but appears to play no major role in hepatic ethanol metabolism under physiological conditions due to limited H2O2 supply.

    “Catalase present in peroxisomes may participate in ethanol oxidation in the presence of H2O2132–134, although this enzyme appears to play no major role in hepatic ethanol metabolism under physiological conditions due to the limited supply of H2O2135.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [132] Purohit, V., Gao, B. & Song, B. J. Molecular mechanisms of alcoholic fatty liver. Alcohol. Clin. Exp. Res. 33, 191–205 (2009). source

      Not checked in the free run.

    • cites [133] Thiele, G. M., Klassen, L. W. & Tuma, D. J. Formation and immunological properties of aldehyde-derived protein adducts following alcohol consumption. Methods Mol. Biol. 447, 235–257 (2008). source

      Not checked in the free run.

    • cites [134] Zakhari, S. Overview: how is alcohol metabolized by the body? Alcohol Res. Health. 29, 245–254 (2006).

      Not checked in the free run.

    • cites [135] Lieber, C. S. Microsomal ethanol-oxidizing system (MEOS): the first 30 years (1968-1998)–a review. Alcohol. Clin. Exp. Res. 23, 991–1007 (1999).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acetaldehyde is converted to acetate by mitochondrial ALDH2 in humans, and CYP2E1 also takes part in this step with NADPH as a cofactor.

    “In the second step, acetaldehyde is converted to acetate due to the low km (for acetaldehyde) mitochondrial aldehyde dehydrogenase 2 isozyme (ALDH2) in humans145.”
    • Also stated in: § Alcohol metabolism (see summary in Fig. 1) · plain
      “Notably, CYP2E1 also takes part in this step with NADPH acting as a cofactor to convert acetaldehyde to acetate146.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [145] Klyosov, A. A., Rashkovetsky, L. G., Tahir, M. K. & Keung, W. M. Possible role of liver cytosolic and mitochondrial aldehyde dehydrogenases in acetaldehyde metabolism. Biochemistry 35, 4445–4456 (1996). source

      Not checked in the free run.

    • cites [146] Kunitoh, S. et al. Acetaldehyde as well as ethanol is metabolized by human CYP2E1. J. Pharmacol. Exp. Therapeutics 280, 527–532 (1997).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CYP2E1 is widely expressed throughout the brain, such as in the cerebral cortex, hippocampus, and cerebellum; brain CYP2E1 is inducible by ethanol and may play a key role in cerebral ethanol metabolism, especially after chronic and/or binge alcohol intake.

    “In contrast, CYP2E1 is widely expressed throughout the brain, such as in the cerebral cortex, hippocampus, and cerebellum.”
    • Also stated in: § Alcohol metabolism (see summary in Fig. 1) · hedged
      “Similar to that in the liver, brain CYP2E1 is also inducible by ethanol and may therefore play a key role in cerebral ethanol metabolism, especially after chronic and/or binge alcohol intake151–155.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [151] Hansson, T., Tindberg, N., Ingelman-Sundberg, M. & Kohler, C. Regional distribution of ethanol-inducible cytochrome P450 IIE1 in the rat central nervous system. Neuroscience 34, 451–463 (1990). source

      Not checked in the free run.

    • cites [152] Yadav, S., Dhawan, A., Singh, R. L., Seth, P. K. & Parmar, D. Expression of constitutive and inducible cytochrome P450 2E1 in rat brain. Mol. Cell. Biochem. 286, 171–180 (2006). source

      Not checked in the free run.

    • cites [153] Upadhya, S. C., Tirumalai, P. S., Boyd, M. R., Mori, T. & Ravindranath, V. Cytochrome P4502E (CYP2E) in brain: constitutive expression, induction by ethanol and localization by fluorescence in situ hybridization. Arch. Biochem Biophys. 373, 23–34 (2000). source

      Not checked in the free run.

    • cites [154] Anandatheerthavarada, H. K. et al. Induction of brain cytochrome P-450IIE1 by chronic ethanol treatment. Brain Res. 601, 279–285 (1993). source

      Not checked in the free run.

    • cites [155] Montoliu, C., Valles, S., Renau-Piqueras, J. & Guerri, C. Ethanol-induced oxygen radical formation and lipid peroxidation in rat brain: effect of chronic alcohol consumption. J. Neurochem. 63, 1855–1862 (1994). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Acetate produced is further degraded to CO2 and H2O, ending the final step of ethanol oxidation in the liver.

    “Finally, the acetate that is produced is further degraded to CO2 and H2O, ending the final step of ethanol oxidation in the liver132–134.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [132] Purohit, V., Gao, B. & Song, B. J. Molecular mechanisms of alcoholic fatty liver. Alcohol. Clin. Exp. Res. 33, 191–205 (2009). source

      Not checked in the free run.

    • cites [133] Thiele, G. M., Klassen, L. W. & Tuma, D. J. Formation and immunological properties of aldehyde-derived protein adducts following alcohol consumption. Methods Mol. Biol. 447, 235–257 (2008). source

      Not checked in the free run.

    • cites [134] Zakhari, S. Overview: how is alcohol metabolized by the body? Alcohol Res. Health. 29, 245–254 (2006).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The role of CYP2E1 in brain ethanol metabolism and its association with alcohol-mediated oxidative neuronal injury and aging-related AD and PD have been suggested.

    “The role of CYP2E1 in brain ethanol metabolism and its association with alcohol-mediated oxidative neuronal injury155–160 and aging-related AD and PD161 have also been suggested.”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [155] Montoliu, C., Valles, S., Renau-Piqueras, J. & Guerri, C. Ethanol-induced oxygen radical formation and lipid peroxidation in rat brain: effect of chronic alcohol consumption. J. Neurochem. 63, 1855–1862 (1994). source

      Not checked in the free run.

    • cites [156] Montoliu, C. et al. Ethanol increases cytochrome P4502E1 and induces oxidative stress in astrocytes. J. Neurochem. 65, 2561–2570 (1995). source

      Not checked in the free run.

    • cites [157] Brzezinski, M. R., Boutelet-Bochan, H., Person, R. E., Fantel, A. G. & Juchau, M. R. Catalytic activity and quantitation of cytochrome P-450 2E1 in prenatal human brain. J. Pharmacol. Exp. Therapeutics 289, 1648–1653 (1999).

      Not checked in the free run.

    • cites [158] Haorah, J., Knipe, B., Leibhart, J., Ghorpade, A. & Persidsky, Y. Alcohol-induced oxidative stress in brain endothelial cells causes blood-brain barrier dysfunction. J. Leukoc. Biol. 78, 1223–1232 (2005). source

      Not checked in the free run.

    • cites [159] Zhong, Y. et al. Induction of brain CYP2E1 by chronic ethanol treatment and related oxidative stress in hippocampus, cerebellum, and brainstem. Toxicology 302, 275–284 (2012). source

      Not checked in the free run.

    • cites [160] Valencia-Olvera, A. C., Moran, J., Camacho-Carranza, R., Prospero-Garcia, O. & Espinosa-Aguirre, J. J. CYP2E1 induction leads to oxidative stress and cytotoxicity in glutathione-depleted cerebellar granule neurons. Toxicol. Vitro 28, 1206–1214 (2014). source

      Not checked in the free run.

    • cites [161] Peng, B. et al. Role of alcohol drinking in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Int. J. Mol. Sci. 21, https://doi.org/10.3390/ijms21072316 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cerebral ADH plays very little or virtually no role in ethanol metabolism in the brain compared to its hepatic isoform, whereas cerebral catalase acts as the main oxidizing enzyme, accounting for more than 60% of ethanol oxidation in the brain under normal conditions.

    “Cerebral ADH plays very little or virtually no role in ethanol metabolism in the brain compared to its action by its hepatic isoform.”
    • Also stated in: § Alcohol metabolism (see summary in Fig. 1) · plain
      “However, cerebral catalase acts as the main oxidizing enzyme, accounting for more than 60% of ethanol oxidation in the brain under normal conditions147.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Zimatkin, S. M., Pronko, S. P., Vasiliou, V., Gonzalez, F. J. & Deitrich, R. A. Enzymatic mechanisms of ethanol oxidation in the brain. Alcohol. Clin. Exp. Res. 30, 1500–1505 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Remaining unmetabolized ethanol, acetaldehyde, and acetate can be distributed to many other organs, including heart, lung, kidney, pancreas, and brain, causing damage in various peripheral tissues and neurobehavioral effects caused by damage to the brain.

    “Furthermore, the remaining unmetabolized ethanol, acetaldehyde, and acetate can be distributed to many other organs, including the heart, lung, kidney, pancreas, and brain, causing damage in various peripheral tissues and neurobehavioral effects caused by damage to the brain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Ethanol oxidizing enzymes are functional in the brain and include ADH, catalase, CYP2E1, and ALDH2, which make different contributions.

    “Similar to the liver, ethanol oxidizing enzymes are also functional in the brain and include ADH, catalase, CYP2E1, and ALDH2, which make different contributions.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Zimatkin, S. M., Pronko, S. P., Vasiliou, V., Gonzalez, F. J. & Deitrich, R. A. Enzymatic mechanisms of ethanol oxidation in the brain. Alcohol. Clin. Exp. Res. 30, 1500–1505 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Interactions between acetaldehyde or MDA and cellular proteins lead to formation of MAA adducts, which are highly stable and resistant to rapid degradation; increased MAA adducts from alcohol exposure stimulate protein dysfunction and immune-induced tissue injury through interactions with TLR-3, TLR-6, calpain, collagen alpha-1 (XII) chain, procollagen type XIV alpha-1, protocadherin beta, or补体成分.

    “Interactions between acetaldehyde or MDA and cellular proteins lead to the formation of MAA adducts, which are highly stable and resistant to rapid degradation178,179.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain
      “Increased levels of MAA adducts from alcohol exposure stimulate protein dysfunction and immune-induced tissue injury through interactions with Toll-like receptor-3 (TLR-3), TLR-6, calpain, collagen alpha-1 (XII) chain, procollagen type XIV alpha-1, protocadherin beta, or complement component proteins167,180.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [178] Tuma, D. J., Thiele, G. M., Xu, D., Klassen, L. W. & Sorrell, M. F. Acetaldehyde and malondialdehyde react together to generate distinct protein adducts in the liver during long-term ethanol administration. Hepatology 23, 872–880 (1996). source

      Not checked in the free run.

    • cites [179] McCaskill, M. L. et al. Hybrid malondialdehyde and acetaldehyde protein adducts form in the lungs of mice exposed to alcohol and cigarette smoke. Alcohol. Clin. Exp. Res. 35, 1106–1113 (2011). source

      Not checked in the free run.

    • cites [167] Tuma, D. J. & Casey, C. A. Dangerous byproducts of alcohol breakdown–focus on adducts. Alcohol Res. Health. 27, 285–290 (2003).

      Not checked in the free run.

    • cites [180] Patel, V. B., Worrall, S., Emery, P. W. & Preedy, V. R. Protein adduct species in muscle and liver of rats following acute ethanol administration. Alcohol Alcohol. 40, 485–493 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MDA and 4-HNE are reactive lipid peroxides with short half-lives that can form covalent adducts with various proteins and nucleic acids in the body.

    “MDA and 4-HNE are reactive lipid peroxides with short half-lives that can form covalent adducts with various proteins and nucleic acids in the body.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [172] Doorn, J. A., Hurley, T. D. & Petersen, D. R. Inhibition of human mitochondrial aldehyde dehydrogenase by 4-hydroxynon-2-enal and 4-oxonon-2-enal. Chem. Res. Toxicol. 19, 102–110 (2006). source

      Not checked in the free run.

    • cites [173] Galligan, J. J. et al. Oxidative stress-mediated aldehyde adduction of GRP78 in a mouse model of alcoholic liver disease: functional independence of ATPase activity and chaperone function. Free Radic. Biol. Med. 73, 411–420 (2014). source

      Not checked in the free run.

    • cites [174] Sampey, B. P., Stewart, B. J. & Petersen, D. R. Ethanol-induced modulation of hepatocellular extracellular signal-regulated kinase-1/2 activity via 4-hydroxynonenal. J. Biol. Chem. 282, 1925–1937 (2007). source

      Not checked in the free run.

    • cites [175] Shearn, C. T. et al. Increased carbonylation of the lipid phosphatase PTEN contributes to Akt2 activation in a murine model of early alcohol-induced steatosis. Free Radic. Biol. Med. 65, 680–692 (2013). source

      Not checked in the free run.

    • cites [176] Shearn, C. T., Backos, D. S., Orlicky, D. J., Smathers-McCullough, R. L. & Petersen, D. R. Identification of 5’ AMP-activated kinase as a target of reactive aldehydes during chronic ingestion of high concentrations of ethanol. J. Biol. Chem. 289, 15449–15462 (2014). source

      Not checked in the free run.

    • cites [177] Hartley, D. P. & Petersen, D. R. Co-metabolism of ethanol, ethanol-derived acetaldehyde, and 4-hydroxynonenal in isolated rat hepatocytes. Alcohol. Clin. Exp. Res. 21, 298–304 (1997). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondrial ALDH2 is the final enzyme for converting acetaldehyde to acetate, although acetaldehyde is locally produced in the brain due to its very limited ability to cross the blood-brain barrier.

    “Finally, mitochondrial ALDH2 is the final enzyme for converting acetaldehyde to acetate148, although acetaldehyde is locally produced in the brain due to its very limited ability to cross the BBB162.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [148] Deng, X.-s & Deitrich, R. A. Putative role of brain acetaldehyde in ethanol addiction. Curr. Drug Abus. Rev. 1, 3–8 (2008). source

      Not checked in the free run.

    • cites [162] Zimatkin, S. M. Histochemical study of aldehyde dehydrogenase in the rat CNS. J. Neurochem. 56, 1–11 (1991). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Formation of adduct proteins can prolong protein half-lives and accumulate as aggregated proteins; AA adduct formation and ubiquitin conjugation may compete for common lysine residues, so when lysine residues are occupied by reactive acetaldehyde, lipid aldehydes, AGEs, or AA, adducts persist and may aggregate due to lack of free lysine for ubiquitin conjugation and proteolysis.

    “The formation of adduct proteins can prolong protein half-lives and accumulate as aggregated proteins.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · hedged
      “Therefore, when lysine residues are already occupied by reactive acetaldehyde, lipid aldehydes, AGEs, or AA, adducts persist for extended periods of time and may end up as aggregated proteins due to the lack of free lysine needed for ubiquitin conjugation and subsequent proteolysis.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [182] Song, B. J. Ethanol-inducible cytochrome P450 (CYP2E1): biochemistry, molecular biology and clinical relevance: 1996 update. Alcohol. Clin. Exp. Res. 20, 138a–146a (1996). source

      Not checked in the free run.

    • cites [183] Song, B. J., Veech, R. L., Park, S. S., Gelboin, H. V. & Gonzalez, F. J. Induction of rat hepatic N-nitrosodimethylamine demethylase by acetone is due to protein stabilization. J. Biol. Chem. 264, 3568–3572 (1989). source

      Not checked in the free run.

    • cites [184] Roberts, B. J., Shoaf, S. E., Jeong, K. S. & Song, B. J. Induction of CYP2E1 in liver, kidney, brain and intestine during chronic ethanol administration and withdrawal: Evidence that CYP2E1 possesses a rapid phase half-life of 6 hours or less. Biochem. Biophys. Res. Commun. 205, 1064–1071 (1994). source

      Not checked in the free run.

    • cites [185] Abdelmegeed, M. A., Moon, K.-H., Chen, C., Gonzalez, F. J. & Song, B.-J. Role of cytochrome P450 2E1 in protein nitration and ubiquitin-mediated degradation during acetaminophen toxicity. Biochem. Pharmacol. 79, 57–66 (2010). source

      Not checked in the free run.

    • cites [186] Roberts, B. J., Song, B. J., Soh, Y., Park, S. S. & Shoaf, S. E. Ethanol induces CYP2E1 by protein stabilization. Role of ubiquitin conjugation in the rapid degradation of CYP2E1. J. Biol. Chem. 270, 29632–29635 (1995). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Ethanol intake can induce 4-HNE to interact with mitochondrial, ER, and cytosolic proteins, inactivating them and resulting in accumulation of lipid aldehydes, ER stress, mitochondrial dysfunction, cell signaling alteration, and potentially multitissue injury.

    “For instance, ethanol intake can induce 4-HNE to interact with cytochrome C oxidase (complex IV) and ALDH2 in the mitochondria, GRP78 and disulfide isomerase in the ER, and ERK1/2, phosphatase and tensin homolog (PTEN), AMP-activated protein kinase (AMPK), and gamma-glutamylcysteine synthetase (GCS) in the cytosol.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain
      “These adduct formations inactivate their target proteins and result in the accumulation of lipid aldehydes, ER stress, mitochondrial dysfunction, cell signaling alteration, and potentially multitissue injury172–177.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [172] Doorn, J. A., Hurley, T. D. & Petersen, D. R. Inhibition of human mitochondrial aldehyde dehydrogenase by 4-hydroxynon-2-enal and 4-oxonon-2-enal. Chem. Res. Toxicol. 19, 102–110 (2006). source

      Not checked in the free run.

    • cites [173] Galligan, J. J. et al. Oxidative stress-mediated aldehyde adduction of GRP78 in a mouse model of alcoholic liver disease: functional independence of ATPase activity and chaperone function. Free Radic. Biol. Med. 73, 411–420 (2014). source

      Not checked in the free run.

    • cites [174] Sampey, B. P., Stewart, B. J. & Petersen, D. R. Ethanol-induced modulation of hepatocellular extracellular signal-regulated kinase-1/2 activity via 4-hydroxynonenal. J. Biol. Chem. 282, 1925–1937 (2007). source

      Not checked in the free run.

    • cites [175] Shearn, C. T. et al. Increased carbonylation of the lipid phosphatase PTEN contributes to Akt2 activation in a murine model of early alcohol-induced steatosis. Free Radic. Biol. Med. 65, 680–692 (2013). source

      Not checked in the free run.

    • cites [176] Shearn, C. T., Backos, D. S., Orlicky, D. J., Smathers-McCullough, R. L. & Petersen, D. R. Identification of 5’ AMP-activated kinase as a target of reactive aldehydes during chronic ingestion of high concentrations of ethanol. J. Biol. Chem. 289, 15449–15462 (2014). source

      Not checked in the free run.

    • cites [177] Hartley, D. P. & Petersen, D. R. Co-metabolism of ethanol, ethanol-derived acetaldehyde, and 4-hydroxynonenal in isolated rat hepatocytes. Alcohol. Clin. Exp. Res. 21, 298–304 (1997). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ALDH1B and other isoforms may be involved in acetaldehyde metabolism in rodents.

    “In contrast, ALDH1B and other isoforms may be involved in acetaldehyde metabolism in rodents145,147,163.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [145] Klyosov, A. A., Rashkovetsky, L. G., Tahir, M. K. & Keung, W. M. Possible role of liver cytosolic and mitochondrial aldehyde dehydrogenases in acetaldehyde metabolism. Biochemistry 35, 4445–4456 (1996). source

      Not checked in the free run.

    • cites [147] Zimatkin, S. M., Pronko, S. P., Vasiliou, V., Gonzalez, F. J. & Deitrich, R. A. Enzymatic mechanisms of ethanol oxidation in the brain. Alcohol. Clin. Exp. Res. 30, 1500–1505 (2006). source

      Not checked in the free run.

    • cites [163] Stagos, D. et al. Aldehyde dehydrogenase 1B1: molecular cloning and characterization of a novel mitochondrial acetaldehyde-metabolizing enzyme. Drug Metab. Dispos. 38, 1679–1687 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AA adducts are formed by interaction of acetaldehyde with certain amino acids including lysine, cysteine, and aromatic amino acids; these amino acids in different proteins may exert unequal preference for AA adduct formation; proteins commonly bound include erythrocyte membrane proteins, hemoglobin, tubulin, lipoproteins, albumin, and collagen.

    “Acetaldehyde adducts (AA adducts) are formed by the interaction of acetaldehyde, a direct metabolite of ethanol oxidation and a human carcinogen, with certain amino acids, including lysine, cysteine, and aromatic amino acids.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain
      “The proteins commonly bound to acetaldehyde to produce AA adducts include membrane proteins of the red blood cells (erythrocytes), hemoglobin (oxygen transport), tubulin (cellular structure), lipoproteins (lipid transport), albumin (blood), and collagen (connective tissue)167,169,180.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [167] Tuma, D. J. & Casey, C. A. Dangerous byproducts of alcohol breakdown–focus on adducts. Alcohol Res. Health. 27, 285–290 (2003).

      Not checked in the free run.

    • cites [169] Worrall, S., de Jersey, J. & Wilce, P. A. Comparison of the formation of proteins modified by direct and indirect ethanol metabolites in the liver and blood of rats fed the lieber–de carli liquid diet. Alcohol Alcohol. 35, 164–170 (2000). source

      Not checked in the free run.

    • cites [180] Patel, V. B., Worrall, S., Emery, P. W. & Preedy, V. R. Protein adduct species in muscle and liver of rats following acute ethanol administration. Alcohol Alcohol. 40, 485–493 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AA adducts are produced in two separate pathways: the first forms AA adducts with specific amino acids and N-ethyl amino acid groups under reducing conditions; the second is AA adduct synthesis under nonreducing conditions, with initial Schiff base formation followed by rearrangements to yield diverse AA adducts.

    “AA adducts are produced in two separate pathways that yield two different types of adducts, depending on the existing conditions.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain
      “In the second pathway, the initial step is the formation of a Schiff base adduct followed by several rearrangements and reactions to yield diverse AA adducts168.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [168] Freeman, T. L. et al. Recent advances in alcohol-induced adduct formation. Alcohol. Clin. Exp. Res. 29, 1310–1316 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Direct exposure of AA-AGE adducts to cortical neurons triggers ROS generation, leading to oxidative stress and consequently neuronal apoptosis and degeneration in a dose-dependent manner; these effects can be prevented by NAC or anti-AA-AGE antibody, suggesting a direct role for AA-AGE adducts in generating oxidative stress-induced neurotoxicity.

    “In neurons, direct exposure of AA-AGE adducts to cortical neurons triggers ROS generation, leading to oxidative stress and consequently neuronal apoptosis and degeneration in a dose-dependent manner.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · hedged
      “These effects can be prevented by treatment with the antioxidant N-acetylcysteine (NAC) or a neutralizing anti-AA-AGE antibody, suggesting a direct role for AA-AGE adducts in generating oxidative stress-induced neurotoxicity199.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [199] Takeuchi, M. et al. Neurotoxicity of acetaldehyde-derived advanced glycation end products for cultured cortical neurons. J. Neuropathol. Exp. Neurol. 62, 486–496 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ethanol intake or exposure can induce and accelerate AGE production in the brain; aggregation of cross-linked AGEs further upregulates RAGE expression and activation, contributing to diverse outcomes with neurobehavioral impairment, as observed in people with AUD.

    “In addition to cerebral AA-protein adducts, ethanol intake or exposure can induce and accelerate AGE production in the brain.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain
      “Aggregation of cross-linked AGEs further upregulates RAGE expression and activation, contributing to diverse outcomes with neurobehavioral impairment, as observed in people with AUD190.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [190] Nakamura, K. et al. Acetaldehyde adducts in the brain of alcoholics. Arch. Toxicol. 77, 591–593 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acetaldehyde can interact with dopamine to produce AA-DA adducts, including salsolinol, a neurotoxin and potent stimulant in alcohol, which is involved in the pathogenesis of AUD and PD.

    “Furthermore, acetaldehyde can interact with dopamine (DA) to produce AA-DA adducts, including salsolinol, a neurotoxin and potent stimulant in alcohol, which is involved in the pathogenesis of AUD and PD194,195.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [194] Smith, S. L., Jennett, R. B., Sorrell, M. F. & Tuma, D. J. Acetaldehyde substoichiometrically inhibits bovine neurotubulin polymerization. J. Clin. Investig. 84, 337–341 (1989). source

      Not checked in the free run.

    • cites [195] Deehan, G. A. Jr, Hauser, S. R., Wilden, J. A., Truitt, W. A. & Rodd, Z. A. Elucidating the biological basis for the reinforcing actions of alcohol in the mesolimbic dopamine system: the role of active metabolites of alcohol. Front. Behav. Neurosci. 7, 1–13 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Daily alcohol exposure for ten consecutive days instigates microglial activation to synthesize and secrete AGE-albumin adducts in the hippocampus and entorhinal cortex of the rat brain; accumulated AGE-albumin adducts increase RAGE expression and activate MAPK (JNK and p38K)-dependent cell death to promote inflammation, apoptosis, and neuronal damage, attenuated by soluble RAGE and chemical AGE

    “Daily alcohol exposure for ten consecutive days also instigated microglial activation to synthesize and secrete AGE-albumin adducts in the hippocampus and entorhinal cortex of the rat brain.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain
      “Accumulated AGE-albumin adducts increase the expression of RAGE and activate the MAPK (JNK and p38K)-dependent cell death pathway to promote inflammation, apoptosis, and neuronal damage, which are significantly attenuated by treatment with soluble RAGE and chemical AGE inhibitors200.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [200] Byun, K. et al. Microglial AGE-albumin is critical in promoting alcohol-induced neurodegeneration in rats and humans. PloS one 9, e104699 (2014). source

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  • May combine two claims. The quote only partly states this claim.

    Interpretationcitation

    Acetaldehyde in the brain alters DNA integrity and neuronal viability; it can form AA-DNA adducts in the brain and peripheral blood leukocytes of people with AUD since ethanol, acetaldehyde, and lipid aldehydes such as MDA and 4-HNE can inhibit DNA repair enzymes; dual mechanisms of elevated AA-DNA adducts and suppressed DNA repair may contribute to genetic instability and DNA mutations, promoting

    “The presence of acetaldehyde in the brain also alters DNA integrity and neuronal viability.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · hedged
      “The dual mechanisms of simultaneously elevated AA-DNA adducts and suppressed DNA repair systems following alcohol intake may contribute to genetic instability and DNA mutations, promoting neurological pathologies192,197,198.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [53] Song, B. J. et al. Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications. Redox Biol. 3, 109–123 (2014). source

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    • cites [192] Heymann, H. M., Gardner, A. M. & Gross, E. R. Aldehyde-induced DNA and protein adducts as biomarker tools for alcohol use disorder. Trends Mol. Med 24, 144–155 (2018). source

      Not checked in the free run.

    • cites [197] Lamarche, F., Gonthier, B., Signorini, N., Eysseric, H. & Barret, L. Impact of ethanol and acetaldehyde on DNA and cell viability of cultured neurones. Cell Biol. Toxicol. 20, 361–374 (2004). source

      Not checked in the free run.

    • cites [198] Tong, M. et al. Acetaldehyde-mediated neurotoxicity: relevance to fetal alcohol spectrum disorders. Oxid. Med. Cell. Longev. 2011, e213286 (2011). source

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  • May combine two claims.

    Interpretationcitation

    Excessive alcohol exposure increases oxidative stress and levels of reactive acetaldehyde and lipid aldehydes with simultaneous decrease in defensive molecules and detoxification enzymes including GSH and ALDH2, leading to accumulation of acetaldehyde adducts and possibly AGEs in the brain, which has a much lower detoxification capacity than the liver.

    “Excessive alcohol exposure increases oxidative stress and the levels of reactive acetaldehyde and lipid aldehydes with a simultaneous decrease in defensive molecules and detoxification enzymes, including GSH and ALDH253,172,177.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · hedged
      “These changes subsequently lead to the accumulation of acetaldehyde adducts and possibly AGEs in the brain, which has a much lower detoxification capacity than the liver, as previously mentioned102.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [53] Song, B. J. et al. Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications. Redox Biol. 3, 109–123 (2014). source

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    • cites [172] Doorn, J. A., Hurley, T. D. & Petersen, D. R. Inhibition of human mitochondrial aldehyde dehydrogenase by 4-hydroxynon-2-enal and 4-oxonon-2-enal. Chem. Res. Toxicol. 19, 102–110 (2006). source

      Not checked in the free run.

    • cites [177] Hartley, D. P. & Petersen, D. R. Co-metabolism of ethanol, ethanol-derived acetaldehyde, and 4-hydroxynonenal in isolated rat hepatocytes. Alcohol. Clin. Exp. Res. 21, 298–304 (1997). source

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    • cites [102] de la Monte, S. M. & Kril, J. J. Human alcohol-related neuropathology. Acta Neuropathol. 127, 71–90 (2014). source

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  • May combine two claims.

    Premisecitation

    Ethanol ingestion upregulates RAGE expression in the orbitofrontal cortex and increases levels of oxidative stress, HMGB1, TLR-4, neuroimmune markers, and proinflammatory cytokines in the brain.

    “Moreover, ethanol ingestion also upregulates RAGE expression in the orbitofrontal cortex and increases the levels of oxidative stress, HMGB1, TLR-4, neuroimmune markers, and proinflammatory cytokines in the brain201.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [201] Vetreno, R. P., Qin, L. & Crews, F. T. Increased receptor for advanced glycation end product expression in the human alcoholic prefrontal cortex is linked to adolescent drinking. Neurobiol. Dis. 59, 52–62 (2013). source

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  • May combine two claims.

    Interpretationcitation

    Aggregation of AA-protein adducts can enhance neuronal damage and degeneration in different brain regions, suggesting a critical role for AA-protein adducts in promoting brain damage and pathophysiology associated with chronic alcohol consumption.

    “Additionally, the aggregation of these AA-protein adducts can enhance neuronal damage and degeneration in different brain regions190,196.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · hedged
      “These findings suggest a critical role for AA-protein adducts in promoting brain damage and pathophysiology associated with chronic alcohol consumption.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [190] Nakamura, K. et al. Acetaldehyde adducts in the brain of alcoholics. Arch. Toxicol. 77, 591–593 (2003). source

      Not checked in the free run.

    • cites [196] Iwahashi, K. et al. [Acetaldehyde adducts in the cerebral cortex of ethanol-fed mice]. Nihon Arukoru Yakubutsu Igakkai zasshi 32, 489–494 (1997)..

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic exposure to alcohol enhances RAGE expression, ROS generation, Nrf2, TLR-4, GFAP, Iba1, and lipid peroxidation, resulting in neuroinflammation, neuronal apoptosis, and memory impairment.

    “Additionally, chronic exposure to alcohol enhances RAGE expression, ROS generation, nuclear factor erythroid 2–related factor 2 (Nrf2), TLR-4, glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba1), and lipid peroxidation, resulting in neuroinflammation, neuronal apoptosis, and memory impairment202.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [202] Ikram, M. et al. Natural dietary supplementation of curcumin protects mice brains against ethanol-induced oxidative stress-mediated neurodegeneration and memory impairment via Nrf2/TLR4/RAGE signaling. Nutrients 11, E1082 (2019). source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    AA-protein adducts are widely present in the brains of alcohol-exposed rodents or people with AUD; after alcohol consumption they are rapidly produced in the cerebral cortex primarily with mitochondrial proteins and localized in white matter, deep layers of the frontal cortex, and molecular layer of the cerebellum; they also form AA-tubulin adducts causing microtubule malformation and cytoskeletal

    “AA-protein adducts are widely present in the brains of alcohol-exposed rodents or people with alcohol use disorder (AUD)189–192.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain
      “AA-protein adducts are also formed with cytosolic proteins, including tubulins, known as AA-tubulin adducts, resulting in microtubule malformation and the cytoskeletal dysfunction of nerve cells193,194.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [189] Rintala, J. et al. Evidence of acetaldehyde-protein adduct formation in rat brain after lifelong consumption of ethanol. Alcohol Alcohol. 35, 458–463 (2000). source

      Not checked in the free run.

    • cites [190] Nakamura, K. et al. Acetaldehyde adducts in the brain of alcoholics. Arch. Toxicol. 77, 591–593 (2003). source

      Not checked in the free run.

    • cites [191] Upadhya, S. C. & Ravindranath, V. Detection and localization of protein-acetaldehyde adducts in rat brain after chronic ethanol treatment. Alcohol. Clin. Exp. Res. 26, 856–863 (2002). source

      Not checked in the free run.

    • cites [192] Heymann, H. M., Gardner, A. M. & Gross, E. R. Aldehyde-induced DNA and protein adducts as biomarker tools for alcohol use disorder. Trends Mol. Med 24, 144–155 (2018). source

      Not checked in the free run.

    • cites [193] Tuma, D. J., Smith, S. L. & Sorrell, M. F. Acetaldehyde and microtubules. Ann. N. Y. Acad. Sci. 625, 786–792 (1991). source

      Not checked in the free run.

    • cites [194] Smith, S. L., Jennett, R. B., Sorrell, M. F. & Tuma, D. J. Acetaldehyde substoichiometrically inhibits bovine neurotubulin polymerization. J. Clin. Investig. 84, 337–341 (1989). source

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  • May combine two claims.

    Interpretationreasoning

    Chronic and excessive alcohol consumption can alter brain structure and function, causing behavioral, emotional, and intellectual abnormalities, including alcohol tolerance and addiction, emotional dysregulation, and executive, neurocognitive, and motor dysfunctions with neuroinflammation and/or neurodegeneration.

    “Chronic and excessive alcohol consumption can alter brain structure and function, causing behavioral, emotional, and intellectual abnormalities.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain
      “These neurobehavioral changes include the development of alcohol tolerance and addiction, emotional dysregulation, and executive, neurocognitive, and motor dysfunctions with neuroinflammation and/or neurodegeneration.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    After ethanol intake, AA, MDA, and 4-HNE adducts are produced rapidly in the hepatic centrilobular zone, sinusoids, and HSCs as well as on the hepatocyte surface; their amounts are markedly elevated in the early phase of ALD, suggesting a role in initial development and progression of ALD.

    “After ethanol intake, AA, MDA, and 4-HNE adducts are produced rapidly in the hepatic centrilobular zone (zone III), sinusoids, and HSCs as well as on the hepatocyte surface in the liver.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · hedged
      “The amounts of these adducts are also markedly elevated in the early phase of alcoholic liver disease (ALD) in the presence or absence of clinical or histological signs216–219, suggesting their role in the initial development and progression of ALD.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [216] Niemela, O. et al. Early alcoholic liver injury: formation of protein adducts with acetaldehyde and lipid peroxidation products, and expression of CYP2E1 and CYP3A. Alcohol. Clin. Exp. Res. 22, 2118–2124 (1998). source

      Not checked in the free run.

    • cites [217] Ronis, M. J. et al. Increased 4-hydroxynonenal protein adducts in male GSTA4-4/PPAR-alpha double knockout mice enhance injury during early stages of alcoholic liver disease. Am. J. Physiol. Gastrointest. liver Physiol. 308, G403–G415 (2015). source

      Not checked in the free run.

    • cites [218] Fritz, K. S. & Petersen, D. R. Exploring the biology of lipid peroxidation-derived protein carbonylation. Chem. Res Toxicol. 24, 1411–1419 (2011). source

      Not checked in the free run.

    • cites [219] Shearn, C. T., Reigan, P. & Petersen, D. R. Inhibition of hydrogen peroxide signaling by 4-hydroxynonenal due to differential regulation of Akt1 and Akt2 contributes to decreases in cell survival and proliferation in hepatocellular carcinoma cells. Free Radic. Biol. Med. 53, 1–11 (2012). source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    MAA adducts are found in HSCs, liver sinusoidal endothelial cells, and Kupffer cells in ALD models; they stimulate transformation of HSCs into activated myofibroblasts, resulting in elevated production of profibrotic factors such as PDGF, and can induce proinflammatory cytokines such as TNF-α, IL-12, IL-18, and MIF.

    “In addition to individual AA and MDA adducts, MAA adducts (AA-MDA-protein hybrid adducts) are found in HSCs, liver sinusoidal endothelial cells, and Kupffer cells in ALD models.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [220] Mello, T., Ceni, E., Surrenti, C. & Galli, A. Alcohol induced hepatic fibrosis: role of acetaldehyde. Mol. Asp. Med. 29, 17–21 (2008). source

      Not checked in the free run.

    • cites [221] Wang, J.-H., Batey, R.-G. & George, J. Role of ethanol in the regulation of hepatic stellate cell function. World J. Gastroenterol. 12, 6926–6932 (2006). source

      Not checked in the free run.

    • cites [222] Ceni, E., Mello, T. & Galli, A. Pathogenesis of alcoholic liver disease: role of oxidative metabolism. World J. Gastroenterol. 20, 17756–17772 (2014). source

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    • cites [223] Willis, M. S., Klassen, L. W., Tuma, D. J., Sorrell, M. F. & Thiele, G. M. Adduction of soluble proteins with malondialdehyde-acetaldehyde (MAA) induces antibody production and enhances T-cell proliferation. Alcohol. Clin. Exp. Res. 26, 94–106 (2002). source

      Not checked in the free run.

    • cites [224] Willis, M. S., Klassen, L. W., Tuma, D. J. & Thiele, G. M. Malondialdehyde-acetaldehyde-haptenated protein induces cell death by induction of necrosis and apoptosis in immune cells. Int. Immunopharmacol. 2, 519–535 (2002). source

      Not checked in the free run.

    • cites [225] Willis, M. S., Thiele, G. M., Tuma, D. J. & Klassen, L. W. T cell proliferative responses to malondialdehyde-acetaldehyde haptenated protein are scavenger receptor mediated. Int. Immunopharmacol. 3, 1381–1399 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Ethanol consumption stimulates formation of AA-AGE in the liver; increased AA-AGE adduct formation and accumulation are positively correlated with progression of ALD, as indicated by hepatic fat accumulation and steatohepatitis, which are reversibly ameliorated by alcohol abstinence.

    “Ethanol consumption stimulates the formation of AA-AGE in the liver.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · hedged
      “Increased AA-AGE adduct formation and accumulation were positively correlated with the progression of ALD, as indicated by hepatic fat accumulation and steatohepatitis, which are reversibly ameliorated by alcohol abstinence215.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [215] Hayashi, N. et al. Acetaldehyde-derived advanced glycation end-products promote alcoholic liver disease. PloS One 8, e70034 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In hepatic Kupffer cells, 4-HNE adducts are present and activate infiltration of neutrophils into the liver, leading to activation of HSCs and an inflammatory cytokine response; these findings indicate a contributing role of MAA and 4-HNE adducts in promoting the hepatic immune response associated with ALD development.

    “In hepatic Kupffer cells, 4-HNE adducts are also present and activate the infiltration of neutrophils into the liver, leading to the activation of HSCs and an inflammatory cytokine response226–228.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · hedged
      “These findings indicate a contributing role of MAA and 4-HNE adducts in promoting the hepatic immune response associated with ALD development.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [226] Fritz, K. S. & Petersen, D. R. An overview of the chemistry and biology of reactive aldehydes. Free Radic. Biol. Med. 59, 85–91 (2013). source

      Not checked in the free run.

    • cites [227] Galligan, J. J. et al. Protein carbonylation in a murine model for early alcoholic liver disease. Chem. Res. Toxicol. 25, 1012–1021 (2012). source

      Not checked in the free run.

    • cites [228] Mottaran, E. et al. Lipid peroxidation contributes to immune reactions associated with alcoholic liver disease. Free Radic. Biol. Med. 32, 38–45 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic and/or excessive alcohol intake can cause ARDS and other types of pulmonary dysfunction characterized by reduced air exchange rates with increased lung epithelial barrier dysfunction, possibly through increased oxidative stress and MDA and 4-HNE adducts.

    “Chronic and/or excessive alcohol intake can cause acute respiratory distress syndrome (ARDS) and other types of pulmonary dysfunction characterized by reduced air exchange rates with increased lung epithelial barrier dysfunction, possibly through increased oxidative stress and MDA and 4-HNE adducts164,234.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [164] Sapkota, M. & Wyatt, A. T. Alcohol, aldehydes, adducts and airways. Biomolecules 5, 2987–3008 (2015). source

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    • cites [234] Gauthier, T. W. et al. Fetal alcohol exposure impairs alveolar macrophage function via decreased glutathione availability. Pediatr. Res. 57, 76–81 (2005). source

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    Premisecitation

    Adducts derived from HER are detected in the liver and localized in microsomes and plasma membranes of hepatocytes and are inducible by alcohol exposure.

    “Finally, adducts derived from HER are also detected in the liver and localized in the microsomes and plasma membranes of hepatocytes and are inducible by alcohol exposure229,230.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [229] Moncada, C., Torres, V., Varghese, G., Albano, E. & Israel, Y. Ethanol-derived immunoreactive species formed by free radical mechanisms. Mol. Pharmacol. 46, 786–791 (1994).

      Not checked in the free run.

    • cites [230] Clot, P. et al. Plasma membrane hydroxyethyl radical adducts cause antibody-dependent cytotoxicity in rat hepatocytes exposed to alcohol. Gastroenterology 113, 265–276 (1997). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Alcohol ingestion enhances AGE synthesis and plasma AGEs in the circulation, especially in the portal and hepatic veins of cirrhotic livers; elevated AGE levels support AGE-protein adduct formation accompanied by decreased albumin turnover in plasma.

    “Alcohol ingestion also enhances AGE synthesis and plasma AGEs in the circulation, especially in the portal and hepatic veins of cirrhotic livers.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain
      “Elevated AGE levels support AGE-protein adduct formation accompanied by decreased albumin turnover in plasma232.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [232] Ahmed, N. et al. Increased protein glycation in cirrhosis and therapeutic strategies to prevent it. Ann. N. Y. Acad. Sci. 1043, 718–724 (2005). source

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  • May combine two claims.

    Interpretationcitation

    HSCs directly exposed to AA-AGE adducts can enhance RAGE expression, ROS generation, and oxidative stress to promote hepatocyte ballooning, apoptosis, and steatosis, suggesting a role for AA-AGE adducts in the pathogenesis of AFLD.

    “HSCs directly exposed to AA-AGE adducts can enhance RAGE expression, ROS generation, and oxidative stress to promote hepatocyte ballooning, apoptosis, and steatosis231.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · hedged
      “These findings suggest a role for AA-AGE adducts in the pathogenesis of AFLD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [231] Takeuchi, M.et al. Toxic AGE (TAGE) theory for the pathophysiology of the onset/progression of NAFLD and ALD. Nutrients 9, 634 (2017).. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In advanced ALD with cirrhosis, 4-HNE and MDA adducts are found in greater amounts than in nonalcoholic liver cirrhosis and normal liver, suggesting involvement of 4-HNE and MDA adducts in promoting advanced ALD.

    “In advanced ALD with cirrhosis, 4-HNE and MDA adducts are also found in greater amounts than in nonalcoholic liver cirrhosis and normal liver139,228, suggesting the involvement of 4-HNE and MDA adducts in promoting advanced ALD.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [139] Abdelmegeed, M. A. et al. Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis. J. Hepatol. 57, 860–866 (2012). source

      Not checked in the free run.

    • cites [228] Mottaran, E. et al. Lipid peroxidation contributes to immune reactions associated with alcoholic liver disease. Free Radic. Biol. Med. 32, 38–45 (2002). source

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  • May combine two claims.

    Interpretationcitation

    AGE-protein adducts can accumulate as aggregated proteins in cells, leading to activation of Kupffer and HSCs in the liver and microglial cells in the brain followed by parenchymal cell death, suggesting involvement of AGEs in the progression of ALD and alcohol-mediated multiorgan injury.

    “Additionally, AGE-protein adducts can accumulate as aggregated proteins in the cells, leading to the activation of Kupffer and HSCs in the liver and microglial cells in the brain followed by parenchymal cell death (e.g., hepatocytes and neurons, respectively), suggesting the involvement of AGEs in the progression of ALD and alcohol-mediated multiorgan injury233.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [233] Grune, T. Oxidized protein aggregates: formation and biological effects. Free Radic. Biol. Med. 150, 120–124 (2020). source

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    Premisecitation

    Excessive alcohol consumption is known to cause testis dysfunction and degeneration, possibly by increasing oxidative stress; alcohol intake can induce RAGE overexpression in the testis, and prolonged ethanol exposure stimulates RAGE activation to produce oxidative stress and inflammatory mediators, leading to testicular dysfunction and degeneration.

    “Excessive alcohol consumption is known to cause testis dysfunction and degeneration, possibly by increasing oxidative stress.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain
      “Prolonged ethanol exposure stimulates RAGE activation to produce oxidative stress and inflammatory mediators, leading to testicular dysfunction and degeneration259.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [259] Giannessi, F. et al. Chronic alcohol administration causes expression of calprotectin and RAGE altering the distribution of zinc ions in mouse testis. Syst. Biol. Reprod. Med. 61, 18–25 (2015). source

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    Premisecitation

    After alcohol consumption, AA adducts are produced in blood erythrocytes and are correlated with the incidence of fetal alcohol spectrum disorders (FASDs).

    “After alcohol consumption, AA adducts are produced in blood erythrocytes and are also correlated with the incidence of fetal alcohol spectrum disorders (FASDs)257,258.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [257] Niemela, O. & Israel, Y. Hemoglobin-acetaldehyde adducts in human alcohol abusers. Lab. Investig. 67, 246–252 (1992).

      Not checked in the free run.

    • cites [258] Niemelä, O., Halmesmäki, E. & Ylikorkala, O. Hemoglobin-acetaldehyde adducts are elevated in women carrying alcohol-damaged fetuses. Alcohol. Clin. Exp. Res. 15, 1007–1010 (1991). source

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  • May combine two claims.

    Premisecitation

    Excessive alcohol intake is known to cause leaky gut with increased intestinal cell permeability and endotoxemia, possibly via increased CYP2E1 and oxidative stress.

    “Excessive alcohol intake is known to cause leaky gut with increased intestinal cell permeability and endotoxemia, possibly via increased CYP2E1 and oxidative stress245–248.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [245] Abdelmegeed, M. A. et al. CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis. Free Radic. Biol. Med. 65, 1238–1245 (2013). source

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    • cites [246] Forsyth, C. B., Voigt, R. M. & Keshavarzian, A. Intestinal CYP2E1: a mediator of alcohol-induced gut leakiness. Redox Biol. 3, 40–46 (2014). source

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    • cites [247] Cho, Y. E. & Song, B. J. Pomegranate prevents binge alcohol-induced gut leakiness and hepatic inflammation by suppressing oxidative and nitrative stress. Redox Biol. 18, 266–278 (2018). source

      Not checked in the free run.

    • cites [248] Cho, Y. E., Yu, L. R., Abdelmegeed, M. A., Yoo, S. H. & Song, B. J. Apoptosis of enterocytes and nitration of junctional complex proteins promote alcohol-induced gut leakiness and liver injury. J. Hepatol. 69, 142–153 (2018). source

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  • May combine two claims.

    Premisecitation

    Excessive alcohol consumption is known to cause cardiac dysfunction with reduced blood ejection force and volume, possibly by augmenting oxidative stress, increasing levels of MDA and 4-HNE adducts, and suppressing ALDH2 activity.

    “Excessive alcohol consumption is known to cause cardiac dysfunction with reduced blood ejection force and volume, possibly by augmenting oxidative stress, increasing the levels of MDA and 4-HNE adducts and suppressing ALDH2 activity241,242.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [241] Chen, C. H. et al. Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science 321, 1493–1495 (2008). source

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    • cites [242] Zhang, Y. & Ren, J. ALDH2 in alcoholic heart diseases: molecular mechanism and clinical implications. Pharmacol. Therapeutics 132, 86–95 (2011). source

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    Premisecitation

    Ethanol intake is known to increase the amounts of MDA adducts and AGEs in the serum; the amounts of MDA adducts are more positively correlated with AGE concentrations than with blood glucose levels.

    “Ethanol intake is known to increase the amounts of MDA adducts and AGEs in the serum.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain
      “The amounts of MDA adducts are more positively correlated with AGE concentrations than with blood glucose levels256.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [256] Gopal, V. R. & Indira, M. Investigations on the correlation of advanced glycated end products (AGE) associated fluorescence with blood glucose and oxidative stress in ethanol-administered diabetic rats. Exp. Toxicol. Pathol. 62, 157–162 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ethanol intake stimulates MAA adduct formation in the lung; elevated MAA adducts are found in bronchoalveolar lavage fluids of chronically alcohol-exposed animals and people with AUD; MAA adducts bind SR-A on lung macrophages to activate inflammatory processes, impede wound healing of bronchial epithelial cells, and activate PKC-mediated release of IL-8.

    “Ethanol intake stimulates MAA adduct formation in the lung.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain
      “MAA adducts bind scavenger receptor A (SR-A) on lung macrophages to activate inflammatory processes in airway epithelial cells236.”
    • Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain
      “The formation of MAA adducts also impedes the wound healing process of bronchial epithelial cells and activates PKC-mediated release of IL-8 in the lung.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [179] McCaskill, M. L. et al. Hybrid malondialdehyde and acetaldehyde protein adducts form in the lungs of mice exposed to alcohol and cigarette smoke. Alcohol. Clin. Exp. Res. 35, 1106–1113 (2011). source

      Not checked in the free run.

    • cites [235] Sapkota, M. et al. Malondialdehyde–acetaldehyde (MAA) protein adducts are found exclusively in the lungs of smokers with alcohol use disorders and are associated with systemic anti-MAA antibodies. Alcohol. Clin. Exp. Res. 41, 2093–2099 (2017). source

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    • cites [236] Wyatt, T. A., Kharbanda, K. K., Tuma, D. J., Sisson, J. H. & Spurzem, J. R. Malondialdehyde–acetaldehyde adducts decrease bronchial epithelial wound repair. Alcohol 36, 31–40 (2005). source

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    • cites [237] Berger, J. P. et al. Malondialdehyde-acetaldehyde (MAA) adducted proteins bind to scavenger receptor A in airway epithelial cells. Alcohol 48, 493–500 (2014). source

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    • cites [238] Duryee, M. J. et al. Scavenger receptors on sinusoidal liver endothelial cells are involved in the uptake of aldehyde-modified proteins. Mol. Pharm. 68, 1423–1430 (2005). source

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    Premisecitation

    Rice (Oryza sativa L.) and blueberry exhibit antiglycation activities.

    “such rice (Oryza sativa L.), and blueberry, exhibit antiglycation activities.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [265] Premakumara, G. A. S., Abeysekera, W. K. S. M., Ratnasooriya, W. D., Chandrasekharan, N. V. & Bentota, A. P. Antioxidant, anti-amylase and anti-glycation potential of brans of some Sri Lankan traditional and improved rice (Oryza sativa L.) varieties. J. Cereal Sci. 58, 451–456 (2013). source

      Not checked in the free run.

    • cites [266] Dearlove, R. P., Greenspan, P., Hartle, D. K., Swanson, R. B. & Hargrove, J. L. Inhibition of protein glycation by extracts of culinary herbs and spices. J. Med. Food 11, 275–281 (2008). source

      Not checked in the free run.

    • cites [267] Yeh, W. J., Hsia, S. M., Lee, W. H. & Wu, C. H. Polyphenols with antiglycation activity and mechanisms of action: a review of recent findings. J. Food Drug Anal. 25, 84–92 (2017). source

      Not checked in the free run.

    • cites [268] Chen, H., Virk, M. S. & Chen, F. Phenolic acids inhibit the formation of advanced glycation end products in food simulation systems depending on their reducing powers and structures. Int. J. Food Sci. Nutr. 67, 400–411 (2016). source

      Not checked in the free run.

    • cites [269] Ma, H. et al. Evaluation of polyphenol anthocyanin-enriched extracts of blackberry, black raspberry, blueberry, cranberry, red raspberry, and strawberry for free radical scavenging, reactive carbonyl species trapping, anti-glycation, anti-β-amyloid aggregation, and microglial neuroprotective effects. Int. J. Mol. Sci. 19, 1–19 (2018). source

      Not checked in the free run.

    • cites [270] Daiponmak, W., Senakun, C. & Siriamornpun, S. Antiglycation capacity and antioxidant activities of different pigmented Thai rice. Int. J. Food Sci. Technol. 49, 1805–1810 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    AGEs can be produced endogenously and exogenously.

    “AGEs can be produced endogenously and exogenously.”
    • Also stated in: § Concluding remarks (see overview in Fig. 2) · plain
      “AGEs can be produced endogenously and exogenously.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Polyphenols such as gallic acid, flavonoids, anthocyanin, and ferulic acid attenuate protein glycation and prevent the biosynthesis of AGEs.

    “These foods are rich in polyphenols such as gallic acid, flavonoids, anthocyanin, and ferulic acid, which attenuate protein glycation and prevent the biosynthesis of AGEs265–270.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [265] Premakumara, G. A. S., Abeysekera, W. K. S. M., Ratnasooriya, W. D., Chandrasekharan, N. V. & Bentota, A. P. Antioxidant, anti-amylase and anti-glycation potential of brans of some Sri Lankan traditional and improved rice (Oryza sativa L.) varieties. J. Cereal Sci. 58, 451–456 (2013). source

      Not checked in the free run.

    • cites [266] Dearlove, R. P., Greenspan, P., Hartle, D. K., Swanson, R. B. & Hargrove, J. L. Inhibition of protein glycation by extracts of culinary herbs and spices. J. Med. Food 11, 275–281 (2008). source

      Not checked in the free run.

    • cites [267] Yeh, W. J., Hsia, S. M., Lee, W. H. & Wu, C. H. Polyphenols with antiglycation activity and mechanisms of action: a review of recent findings. J. Food Drug Anal. 25, 84–92 (2017). source

      Not checked in the free run.

    • cites [268] Chen, H., Virk, M. S. & Chen, F. Phenolic acids inhibit the formation of advanced glycation end products in food simulation systems depending on their reducing powers and structures. Int. J. Food Sci. Nutr. 67, 400–411 (2016). source

      Not checked in the free run.

    • cites [269] Ma, H. et al. Evaluation of polyphenol anthocyanin-enriched extracts of blackberry, black raspberry, blueberry, cranberry, red raspberry, and strawberry for free radical scavenging, reactive carbonyl species trapping, anti-glycation, anti-β-amyloid aggregation, and microglial neuroprotective effects. Int. J. Mol. Sci. 19, 1–19 (2018). source

      Not checked in the free run.

    • cites [270] Daiponmak, W., Senakun, C. & Siriamornpun, S. Antiglycation capacity and antioxidant activities of different pigmented Thai rice. Int. J. Food Sci. Technol. 49, 1805–1810 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The preventive effects of all these dietary compounds on AGE-associated adduct formation have not been specifically evaluated.

    “although the preventive effects of all these dietary compounds on AGE-associated adduct formation have not been specifically evaluated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Naturally occurring CYP2E1 inhibitors and synthetic compounds can prevent alcohol-induced oxidative stress and the formation of various adducts, including AA adducts and AA-MAA adducts.

    “can prevent alcohol-induced oxidative stress and the formation of various adducts, including AA adducts137 and AA-MAA adducts53,285”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [137] Jeong, K.-S. et al. Cytochrome P450 2E1 (CYP2E1)-dependent production of a 37-kDa acetaldehyde–protein adduct in the rat liver. Arch. Biochem. Biophys. 384, 81–87 (2000). source

      Not checked in the free run.

    • cites [53] Song, B. J. et al. Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications. Redox Biol. 3, 109–123 (2014). source

      Not checked in the free run.

    • cites [285] Zimmerman, M. C. et al. Direct antioxidant properties of methotrexate: inhibition of malondialdehyde-acetaldehyde-protein adduct formation and superoxide scavenging. Redox Biol. 13, 588–593 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    The accumulation of AGEs and the interaction of AGE-RAGE play causative roles in various aging-related diseases and alcohol-mediated tissue injuries by interfering with cell signaling pathways and forming adducts with cellular macromolecules, contributing to their inactivation and pathophysiology in many tissues/organs.

    “The accumulation of AGEs and the interaction of AGE-RAGE play causative roles in various aging-related diseases and alcohol-mediated tissue injuries by interfering with cell signaling pathways and forming adducts with cellular macromolecules, contributing to their inactivation and pathophysiology in many tissues/organs.”
    • Also stated in: § Concluding remarks (see overview in Fig. 2) · plain
      “The accumulation of AGEs and the interaction of AGE-RAGE play causative roles in various aging-related diseases and alcohol-mediated tissue injuries by interfering with cell signaling pathways and forming adducts with cellular macromolecules, contributing to their inactivation and pathophysiology in many tissues/organs.”
    Quote in the paperNot a substantial claim
102 of 102

  • The paper relies on this without support.

    The underlying molecular mechanisms by which alcohol abuse causes cellular toxicity and organ damage remain to be further characterized.

    “However, despite the considerable amount of research in this area, the underlying molecular mechanisms by which alcohol abuse causes cellular toxicity and organ damage remain to be further characterized.”

  • The paper relies on this without support.

    Water content, cooking method, temperature and time, and food pH determine the final amount of AGEs.

    “In addition, the water content, cooking method, temperature and time, and food pH are crucial to the final amount of AGEs.”

  • The paper relies on this without support.

    Findings from experimental rodent and cell culture models about CYP2E1 and adduct formation apply to human alcohol-mediated tissue injury.

    “as demonstrated in experimental rodent and cell culture models137,180,216,273”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting effects of AGEs on osteoblast apoptosis

    Minor

    Table 1 lists decreased osteoblast apoptosis as a consequence of AGEs, but the osteoporosis section says chronic AGE accumulation induces osteoblast apoptosis.

1 of 1

Cites

1 retracted

Flagged first, then by citations

6 of the 320 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Jamal, M. et al. in Neuroscience of Alcohol (ed Victor R. Preedy) 39–46 (Academic Press, 2019).

Cited by

Sorted by citations

Related

Authors
Rungratanawanich, W., Qu, Y., Wang, X., Essa, M. M., & Song, B.-J.
Affiliations
  • National Institutes of Health (US)
  • Brigham and Women's Hospital (US)
  • Sultan Qaboos University (OM)
Corresponding author
  • Rungratanawanich, Wiramon
  • Song, Byoung-Joon
ORCID
Venue
Experimental & Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2021-02
Volume
53
Issue
2
Pages
168-188
ISSN
  • 1226-3613 (ISSN-L)
  • 2092-6413
DOI
10.1038/s12276-021-00561-7
PMC
PMC8080618
OpenAlex
W3126459824
Semantic Scholar
4364cdbe970626483a51513d5376cd8c84d30cb3
Cited by
411
References
320
Citations by year
2026: 75 · 2025: 108 · 2024: 74 · 2023: 65 · 2022: 61 · 2021: 28
FWCI
7.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Experimental & Molecular Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Intramural fund of National Institute of Alcohol Abuse and Alcoholism.
  • Department of Neurobiology, Harvard Medical School (Wang)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Potato Plant Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
advanced glycation end products, glycation, AGE receptor, age-related diseases, binge drinking, oxidative stress, inflammation, apoptosis, diabetes mellitus, cardiovascular disease, gut microbiota, alcoholic liver disease, neurodegenerative diseases, cancer, cytotoxicity
MeSH terms
Receptor for Advanced Glycation End Products, Aging, Ethanol, Animals, Disease Susceptibility, Extracellular Space, Gene Expression Regulation, Humans, Organ Specificity, Protein Processing, Post-Translational, Lipid Peroxidation, Biomarkers, Glycation End Products, Advanced, Oxidative Stress, Intracellular Space

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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