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Nature Reviews. Cardiology Jul 2023Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme involved in the detoxification of alcohol-derived acetaldehyde and endogenous aldehydes. The inactivating... (Review)
Review
Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme involved in the detoxification of alcohol-derived acetaldehyde and endogenous aldehydes. The inactivating ALDH2 rs671 polymorphism, present in up to 8% of the global population and in up to 50% of the East Asian population, is associated with increased risk of cardiovascular conditions such as coronary artery disease, alcohol-induced cardiac dysfunction, pulmonary arterial hypertension, heart failure and drug-induced cardiotoxicity. Although numerous studies have attributed an accumulation of aldehydes (secondary to alcohol consumption, ischaemia or elevated oxidative stress) to an increased risk of cardiovascular disease (CVD), this accumulation alone does not explain the emerging protective role of ALDH2 rs671 against ageing-related cardiac dysfunction and the development of aortic aneurysm or dissection. ALDH2 can also modulate risk factors associated with atherosclerosis, such as cholesterol biosynthesis and HDL biogenesis in hepatocytes and foam cell formation and efferocytosis in macrophages, via non-enzymatic pathways. In this Review, we summarize the basic biology and the clinical relevance of the enzymatic and non-enzymatic, tissue-specific roles of ALDH2 in CVD, and discuss the future directions in the research and development of therapeutic strategies targeting ALDH2. A thorough understanding of the complex roles of ALDH2 in CVD will improve the diagnosis, management and prognosis of patients with CVD who harbour the ALDH2 rs671 polymorphism.
Topics: Humans; Cardiovascular Diseases; Aldehyde Dehydrogenase, Mitochondrial; Polymorphism, Genetic; Coronary Artery Disease; Aldehydes; Ethanol
PubMed: 36781974
DOI: 10.1038/s41569-023-00839-5 -
Journal of Gastroenterology and... Aug 2023Alcoholic liver disease (ALD), which is a leading cause of morbidity and mortality worldwide, covers a large spectrum of liver injuries ranging from simple steatosis to... (Review)
Review
Alcoholic liver disease (ALD), which is a leading cause of morbidity and mortality worldwide, covers a large spectrum of liver injuries ranging from simple steatosis to steatohepatitis, advanced fibrosis, cirrhosis, and hepatocellular carcinoma. The pathogenesis of ALD includes genetic and epigenetic alterations, oxidative stress, acetaldehyde-mediated toxicity and cytokine and chemokine-induced inflammation, metabolic reprogramming, immune damage, and dysbiosis of the gut microbiota. This review discusses the progress in the pathogenesis and molecular mechanism of ALD, which could provide evidence for further research on the potential therapeutic strategies targeting these pathways.
Topics: Humans; Ethanol; Liver Diseases, Alcoholic; Liver; Carcinoma, Hepatocellular; Liver Neoplasms
PubMed: 37423758
DOI: 10.1111/jgh.16282 -
Journal of Gastroenterology and... Aug 2023Alcohol consumption is a major cause of cirrhosis and hepatocellular carcinoma (HCC). The prevalence of alcohol-associated hepatocellular carcinoma (aHCC) varies... (Review)
Review
Alcohol consumption is a major cause of cirrhosis and hepatocellular carcinoma (HCC). The prevalence of alcohol-associated hepatocellular carcinoma (aHCC) varies worldwide but is highest in Eastern Europe. Alcohol is the second fastest-growing cause of age-standardized liver cancer mortality with tumors more often diagnosed outside surveillance protocols and at a more advanced stage. Risk factors for aHCC include greater amounts of alcohol consumption, sex, and certain genetic polymorphisms. Smoking, concomitant liver disease, obesity, and diabetes act synergistically in increasing the risk of HCC in alcohol-associated liver disease. Alcohol-related hepatocarcinogenesis results from the complex interactions of several mechanistic pathways. Although not completely understood, underlying mechanisms include acetaldehyde-related hepatotoxicity, oxidative stress, activation of the innate immune system, and alterations of the host microbiome.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Ethanol; Risk Factors; Liver Diseases, Alcoholic; Alcohol Drinking; Carcinogenesis
PubMed: 37263779
DOI: 10.1111/jgh.16248 -
Food Chemistry Aug 2023The reactions between malondialdehyde and 2,5-dimethylresorcinol, orcinol, olivetol, and alkylresocinols were studied in an attempt to investigate both if this lipid...
The reactions between malondialdehyde and 2,5-dimethylresorcinol, orcinol, olivetol, and alkylresocinols were studied in an attempt to investigate both if this lipid oxidation product is trapped by phenolics analogously to other reactive carbonyls and to elucidate the chemical structures of the produced adducts. After being formed, malondialdehyde is both partially fractionated to acetaldehyde and oligomerized into dimers and trimers. All these compounds react with phenolics producing three main kinds of derivatives: 5(or 7)-alkyl-7(or 5)-hydroxy-4-methyl-4H-chromene-3-carbaldehydes, 7-alkyl-9-hydroxy-6H-2,6-methanobenzo[d][1,3]dioxocine-5-carbaldehydes, and 4-(3-formylphenyl)-7-hydroxy-4H-chromene-3-carbaldehydes. A total of twenty-four adducts were isolated by semipreparative high-performance liquid chromatography (HPLC) and characterized by mono- and bi-dimensional nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). Reaction pathways to explain the formation of all these compounds are proposed. Obtained results show that phenolics can trap malondialdehyde producing stable derivatives. The function(s) that such derivatives can play in foods remain(s) to be elucidated.
Topics: Malondialdehyde; Phenols; Acetaldehyde; Food; Magnetic Resonance Spectroscopy
PubMed: 36933433
DOI: 10.1016/j.foodchem.2023.135915 -
International Review of Neurobiology 2024The mesolimbic dopamine pathway plays a major role in drug reinforcement and is likely involved also in the development of drug addiction. Ethanol, like most addictive...
The mesolimbic dopamine pathway plays a major role in drug reinforcement and is likely involved also in the development of drug addiction. Ethanol, like most addictive drugs, acutely activates the mesolimbic dopamine system and releases dopamine, and ethanol-associated stimuli also appear to trigger dopamine release. In addition, chronic exposure to ethanol reduces the baseline function of the mesolimbic dopamine system. The molecular mechanisms underlying ethanol´s interaction with this system remain, however, to be unveiled. Here research on the actions of ethanol in the mesolimbic dopamine system, focusing on the involvement of cystein-loop ligand-gated ion channels, opiate receptors, gastric peptides and acetaldehyde is briefly reviewed. In summary, a great complexity as regards ethanol´s mechanism(s) of action along the mesolimbic dopamine system has been revealed. Consequently, several new targets and possibilities for pharmacotherapies for alcohol use disorder have emerged.
Topics: Humans; Dopamine; Ethanol; Brain; Alcoholism; Alcohol Drinking
PubMed: 38555117
DOI: 10.1016/bs.irn.2024.02.003 -
International Journal of General... 2023Alcoholic liver disease (ALD)-one of the most common liver diseases - involves a wide range of disorders, including asymptomatic hepatic steatosis, alcoholic hepatitis... (Review)
Review
Alcoholic liver disease (ALD)-one of the most common liver diseases - involves a wide range of disorders, including asymptomatic hepatic steatosis, alcoholic hepatitis (AH), liver fibrosis, and cirrhosis. Alcohol consumption induces a weakened gut barrier and changes in the composition of the gut microbiota. The presence of CYP2E1 and its elevated levels in the gastrointestinal tract after alcohol exposure lead to elevated levels of ROS and acetaldehyde, inducing inflammation and oxidative damage in the gut. At the same time, the influx of harmful molecules such as the bacterial endotoxin LPS and peptidogly from gut dysbiosis can induce intestinal inflammation and oxidative damage, further compromising the intestinal mucosal barrier. In this process, various oxidative stress-mediated post-translational modifications (PTMs) play an important role in the integrity of the barrier, eg, the presence of acetaldehyde will result in the sustained phosphorylation of several paracellular proteins (occludin and zona occludens-1), which can lead to intestinal leakage. Eventually, persistent oxidative stress, LPS infiltration and hepatocyte damage through the enterohepatic circulation will lead to hepatic stellate cell activation and hepatic fibrosis. In addition, probiotics, prebiotics, synbiotics, fecal microbial transplantation (FMT), bioengineered bacteria, gut-restricted FXR agonists and others are promising therapeutic approaches that can alter gut microbiota composition to improve ALD. In the future, there will be new challenges to study the interactions between the genetics of individuals with ALD and their gut microbiome, to provide personalized interventions targeting the gut-liver axis, and to develop better techniques to measure microbial communities and metabolites in the body.
PubMed: 37641627
DOI: 10.2147/IJGM.S420195 -
Scientific Reports Sep 2023E-cigarettes are now very popular in the world. Compared to traditional cigarettes, e-cigarettes are often considered safer and healthier. However, their safety remains...
E-cigarettes are now very popular in the world. Compared to traditional cigarettes, e-cigarettes are often considered safer and healthier. However, their safety remains controversial and requires further research and regulation. In this study, we aimed to understand the possible hazards to humans of four compounds (formaldehyde, acetaldehyde, acrolein, and acetone) and seven heavy metals (arsenic, cadmium, manganese, lead, copper, nickel, and chromium) contained in e-cigarette liquids and aerosols and perform a health risk assessment. We searched PubMed, CNKI, and other databases for relevant literature to obtain data on organic compounds and heavy metals in e-cigarette liquids and aerosols, and conducted acute, chronic, and carcinogenic risk assessments of various chemicals by different exposure routes. This study showed that exposure to four organic compounds and seven heavy metals in e-cigarette aerosols and e-liquids can cause varying levels of health risks in humans through different routes, with the inhalation route posing a higher overall risk than dermal exposure and oral intake. Various chemicals at high exposure doses can produce health risks beyond the acceptable range. E-cigarette designers must improve their products by changing the composition of the e-liquid and controlling the power of the device to reduce the health effects on humans.
Topics: Humans; Carcinogens; Electronic Nicotine Delivery Systems; Carcinogenesis; Metals, Heavy; Arsenic
PubMed: 37749131
DOI: 10.1038/s41598-023-43112-y -
Frontiers in Immunology 2023Post-translational protein modifications with malondialdehyde-acetaldehyde (MAA) and citrulline (CIT) are implicated in the pathogenesis of rheumatoid arthritis (RA)....
Citrullinated and malondialdehyde-acetaldehyde modified fibrinogen activates macrophages and promotes an aggressive synovial fibroblast phenotype in patients with rheumatoid arthritis.
OBJECTIVE
Post-translational protein modifications with malondialdehyde-acetaldehyde (MAA) and citrulline (CIT) are implicated in the pathogenesis of rheumatoid arthritis (RA). Although precise mechanisms have not been elucidated, macrophage-fibroblast interactions have been proposed to play a central role in the development and progression of RA. The purpose of our study was to evaluate the downstream effects of macrophage released soluble mediators, following stimulation with fibrinogen (FIB) modified antigens, on human fibroblast-like synoviocytes (HFLS).
METHODS
PMA-treated U-937 monocytes (Mϕ) and macrophage-differentiated peripheral blood mononuclear cells (MP) were stimulated with FIB, FIB-MAA, FIB-CIT, or FIB-MAA-CIT. HFLS-RA cells were stimulated directly with FIB antigens or with supernatants (SN) from macrophages (Mϕ-SN or MP-SN) stimulated with FIB antigens. Genes associated with an aggressive HFLS phenotype, extracellular matrix proteins, and activated signaling pathways were evaluated.
RESULTS
HFLS-RA cells treated with Mϕ-SN and Mϕ-SN demonstrated significant increases in mRNA expression of genes associated with an aggressive phenotype at 24-h as compared to direct stimulation with the same antigens. Similar results were obtained using MP-SN. Cellular morphology was altered and protein expression of vimentin (p<0.0001 vs. Mϕ-SN) and type II collagen (p<0.0001) were significantly increased in HFLS-RA cells treated with any of the Mϕ-SN generated following stimulation with modified antigens. Phosphorylation of JNK, Erk1/2, and Akt were increased most substantially in HFLS-RA treated with Mϕ-SN (p<0.05 vs Mϕ-SN). These and other data suggested the presence of PDGF-BB in Mϕ-SN. Mϕ-SN contained the highest concentration of PDGF-BB (p<0.0001 vs. Mϕ-SN) followed by Mϕ-SN then Mϕ-SN. HFLS-RA cells treated with PDGF-BB showed similar cellular morphology to the Mϕ-SN generated following stimulation with modified FIB, as well as the increased expression of vimentin, type II collagen, and the phosphorylation of JNK, Erk1/2 and Akt signaling molecules.
CONCLUSION
Together, these findings support the hypothesis that in response to MAA-modified and/or citrullinated fibrinogen, macrophages release soluble factors including PDGF-BB that induce fibroblast activation and promote an aggressive fibroblast phenotype. These cellular responses were most robust following macrophage activation with dually modified fibrinogen, compared to single modification alone, providing novel insights into the combined role of multiple post-translational protein modifications in the development of RA.
Topics: Humans; Fibrinogen; Vimentin; Becaplermin; Collagen Type II; Leukocytes, Mononuclear; Proto-Oncogene Proteins c-akt; Hemostatics; Macrophages; Fibroblasts; Acetaldehyde; Arthritis, Rheumatoid
PubMed: 37654483
DOI: 10.3389/fimmu.2023.1203548 -
Communications Chemistry Sep 2023Electrochemical conversion of organic compounds holds promise for advancing sustainable synthesis and catalysis. This study explored electrochemical carbonyl...
Electrochemical conversion of organic compounds holds promise for advancing sustainable synthesis and catalysis. This study explored electrochemical carbonyl hydrogenation on single-site M-N-C (Metal Nitrogen-doped Carbon) catalysts using formaldehyde, acetaldehyde, and acetone as model reactants. We strive to correlate and understand the selectivity dependence on the nature of the metal centers. Density Functional Theory calculations revealed similar binding energetics for carbonyl groups through oxygen-down or carbon-down adsorption due to oxygen and carbon scaling. Fe-N-C exhibited specific oxyphilicity and could selectively reduce aldehydes to hydrocarbons. By contrast, the carbophilic Co-N-C selectively converted acetaldehyde and acetone to ethanol and 2-propanol, respectively. We claim that the oxyphilicity of the active sites and consequent adsorption geometry (oxygen-down vs. carbon-down) are crucial in controlling product selectivity. These findings offer mechanistic insights into electrochemical carbonyl hydrogenation and can guide the development of efficient and sustainable electrocatalytic valorization of biomass-derived compounds.
PubMed: 37777576
DOI: 10.1038/s42004-023-01008-y -
The EMBO Journal Nov 2023The large intestine harbors microorganisms playing unique roles in host physiology. The beneficial or detrimental outcome of host-microbiome coexistence depends largely...
The large intestine harbors microorganisms playing unique roles in host physiology. The beneficial or detrimental outcome of host-microbiome coexistence depends largely on the balance between regulators and responder intestinal CD4 T cells. We found that ulcerative colitis-like changes in the large intestine after infection with the protist Blastocystis ST7 in a mouse model are associated with reduction of anti-inflammatory Treg cells and simultaneous expansion of pro-inflammatory Th17 responders. These alterations in CD4 T cells depended on the tryptophan metabolite indole-3-acetaldehyde (I3AA) produced by this single-cell eukaryote. I3AA reduced the Treg subset in vivo and iTreg development in vitro by modifying their sensing of TGFβ, concomitantly affecting recognition of self-flora antigens by conventional CD4 T cells. Parasite-derived I3AA also induces over-exuberant TCR signaling, manifested by increased CD69 expression and downregulation of co-inhibitor PD-1. We have thus identified a new mechanism dictating CD4 fate decisions. The findings thus shine a new light on the ability of the protist microbiome and tryptophan metabolites, derived from them or other sources, to modulate the adaptive immune compartment, particularly in the context of gut inflammatory disorders.
Topics: Animals; Mice; Gastrointestinal Microbiome; Eukaryota; Tryptophan; T-Lymphocytes, Regulatory; Microbiota
PubMed: 37743772
DOI: 10.15252/embj.2022112963