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  1. Book ; Online: Autophagy and Related Transcription Factors in Liver and Gut Diseases

    Eid, Nabil / Thomes, Paul / Menon, Manoj B. / Zeng, Tao / Raimundo, Nuno / Fernandez-Checa, Jose C. / Wang, Lin

    2020  

    Keywords Science: general issues ; Pharmacology ; Autophagy ; Lipophagy ; Liver ; Gut ; Diseases
    Size 1 electronic resource (109 pages)
    Publisher Frontiers Media SA
    Document type Book ; Online
    Note English ; Open Access
    HBZ-ID HT021230328
    ISBN 9782889635467 ; 2889635465
    Database ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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  2. Book: Unternehmer in der Region Aachen - zwischen Maas und Rhein

    Thomes, Paul

    (Rheinisch-westfälische Wirtschaftsbiographien ; 19.2015 ; Veröffentlichungen der Historischen Kommission für Westfalen ; N.F., 28)

    2015  

    Author's details hrsg. von Paul Thomes
    Series title Rheinisch-westfälische Wirtschaftsbiographien ; 19.2015
    Veröffentlichungen der Historischen Kommission für Westfalen ; N.F., 28
    Language German
    Size XV, 235 S., Ill.
    Publisher Aschendorff
    Publishing place Münster
    Document type Book
    ISBN 9783402131077 ; 3402131072
    Database Former special subject collection: coastal and deep sea fishing

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  3. Article ; Online: Ethanol Exposure to Ethanol-Oxidizing HEPG2 Cells Induces Intracellular Protein Aggregation.

    Thomes, Paul G / Rensch, Gage / Casey, Carol A / Donohue, Terrence M

    Cells

    2023  Volume 12, Issue 7

    Abstract: Background: Aggresomes are collections of intracellular protein aggregates. In liver cells of patients with alcoholic hepatitis, aggresomes appear histologically as cellular inclusions known as Mallory-Denk (M-D) bodies. The proteasome is a ... ...

    Abstract Background: Aggresomes are collections of intracellular protein aggregates. In liver cells of patients with alcoholic hepatitis, aggresomes appear histologically as cellular inclusions known as Mallory-Denk (M-D) bodies. The proteasome is a multicatalytic intracellular protease that catalyzes the degradation of both normal (native) and abnormal (misfolded and/or damaged) proteins. The enzyme minimizes intracellular protein aggregate formation by rapidly degrading abnormal proteins before they form aggregates. When proteasome activity is blocked, either by specific inhibitors or by intracellular oxidants (e.g., peroxynitrite, acetaldehyde), aggresome formation is enhanced. Here, we sought to verify whether inhibition of proteasome activity by ethanol exposure enhances protein aggregate formation in VL-17A cells, which are recombinant, ethanol-oxidizing HepG2 cells that express both alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1).
    Methods: We exposed ethanol-non-oxidizing HepG2 cells (
    Results: After we exposed VL-17A cells to increasing doses of ethanol for 24 h or 72 h, 20S proteasome activity declined in response to rising ethanol concentrations. After 24 h of ethanol exposure, aggresome numbers in VL-17A cells were 1.8-fold higher than their untreated controls at all ethanol concentrations employed. After 72 h of ethanol exposure, mean aggresome numbers were 2.5-fold higher than unexposed control cells. The mean aggregate size in all ethanol-exposed VL-17A cells was significantly higher than in unexposed control cells but was unaffected by the duration of ethanol exposure. Co-exposure of cells to EtOH and rapamycin, the latter an autophagy activator, completely prevented EtOH-induced aggresome formation. In the livers of patients with alcohol-induced hepatitis (AH), the staining intensity of aggresomes was 2.2-fold higher than in the livers of patients without alcohol use disorder (AUD).
    Conclusions: We conclude that ethanol-induced proteasome inhibition in ethanol-metabolizing VL-17A hepatoma cells causes accumulation of protein aggregates. Notably, autophagy activation removes such aggregates. The significance of these findings is discussed.
    MeSH term(s) Humans ; Ethanol/pharmacology ; Ethanol/metabolism ; Hep G2 Cells ; Protein Aggregates ; Cytochrome P-450 CYP2E1/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Hepatitis
    Chemical Substances Ethanol (3K9958V90M) ; Protein Aggregates ; Cytochrome P-450 CYP2E1 (EC 1.14.13.-) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
    Language English
    Publishing date 2023-03-26
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells12071013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Multiomics Approach Captures Hepatic Metabolic Network Altered by Chronic Ethanol Administration

    Sakallioglu, Isin Tuna / Tripp, Bridget / Kubik, Jacy / Casey, Carol A. / Thomes, Paul / Powers, Robert

    Biology (Basel). 2022 Dec. 23, v. 12, no. 1

    2022  

    Abstract: Using a multiplatform and multiomics approach, we identified metabolites, lipids, proteins, and metabolic pathways that were altered in the liver after chronic ethanol administration. A functional enrichment analysis of the multiomics dataset revealed ... ...

    Abstract Using a multiplatform and multiomics approach, we identified metabolites, lipids, proteins, and metabolic pathways that were altered in the liver after chronic ethanol administration. A functional enrichment analysis of the multiomics dataset revealed that rats treated with ethanol experienced an increase in hepatic fatty acyl content, which is consistent with an initial development of steatosis. The nuclear magnetic resonance spectroscopy (NMR) and liquid chromatography–mass spectrometry (LC-MS) metabolomics data revealed that the chronic ethanol exposure selectively modified toxic substances such as an increase in glucuronidation tyramine and benzoyl; and a depletion in cholesterol-conjugated glucuronides. Similarly, the lipidomics results revealed that ethanol decreased diacylglycerol, and increased triacylglycerol, sterol, and cholesterol biosynthesis. An integrated metabolomics and lipidomics pathway analysis showed that the accumulation of hepatic lipids occurred by ethanol modulation of the upstream lipid regulatory pathways, specifically glycolysis and glucuronides pathways. A proteomics analysis of lipid droplets isolated from control EtOH-fed rats and a subsequent functional enrichment analysis revealed that the proteomics data corroborated the metabolomic and lipidomic findings that chronic ethanol administration altered the glucuronidation pathway.
    Keywords biochemical pathways ; biosynthesis ; cholesterol ; data collection ; diacylglycerols ; ethanol ; glycolysis ; lipidomics ; liquid chromatography ; liver ; mass spectrometry ; metabolites ; multiomics ; nuclear magnetic resonance spectroscopy ; proteomics ; toxicity ; triacylglycerols ; tyramine
    Language English
    Dates of publication 2022-1223
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article ; Online
    ZDB-ID 2661517-4
    ISSN 2079-7737
    ISSN 2079-7737
    DOI 10.3390/biology12010028
    Database NAL-Catalogue (AGRICOLA)

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  5. Article: Multiomics Approach Captures Hepatic Metabolic Network Altered by Chronic Ethanol Administration.

    Sakallioglu, Isin Tuna / Tripp, Bridget / Kubik, Jacy / Casey, Carol A / Thomes, Paul / Powers, Robert

    Biology

    2022  Volume 12, Issue 1

    Abstract: Using a multiplatform and multiomics approach, we identified metabolites, lipids, proteins, and metabolic pathways that were altered in the liver after chronic ethanol administration. A functional enrichment analysis of the multiomics dataset revealed ... ...

    Abstract Using a multiplatform and multiomics approach, we identified metabolites, lipids, proteins, and metabolic pathways that were altered in the liver after chronic ethanol administration. A functional enrichment analysis of the multiomics dataset revealed that rats treated with ethanol experienced an increase in hepatic fatty acyl content, which is consistent with an initial development of steatosis. The nuclear magnetic resonance spectroscopy (NMR) and liquid chromatography-mass spectrometry (LC-MS) metabolomics data revealed that the chronic ethanol exposure selectively modified toxic substances such as an increase in glucuronidation tyramine and benzoyl; and a depletion in cholesterol-conjugated glucuronides. Similarly, the lipidomics results revealed that ethanol decreased diacylglycerol, and increased triacylglycerol, sterol, and cholesterol biosynthesis. An integrated metabolomics and lipidomics pathway analysis showed that the accumulation of hepatic lipids occurred by ethanol modulation of the upstream lipid regulatory pathways, specifically glycolysis and glucuronides pathways. A proteomics analysis of lipid droplets isolated from control EtOH-fed rats and a subsequent functional enrichment analysis revealed that the proteomics data corroborated the metabolomic and lipidomic findings that chronic ethanol administration altered the glucuronidation pathway.
    Language English
    Publishing date 2022-12-23
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2661517-4
    ISSN 2079-7737
    ISSN 2079-7737
    DOI 10.3390/biology12010028
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Book ; Online ; Thesis: Reziprozität von Struktur-Akteurs-Beziehungen und ihr Einfluss auf die Transformation einer Branche

    Peters, Robert [Verfasser] / Thomes, Paul [Akademischer Betreuer] / Piller, Frank T. [Akademischer Betreuer]

    Eine longitudinale Analyse der Aachener Nadelindustrie in drei Beiträgen

    2022  

    Author's details Robert Peters ; Paul Thomes, Frank Thomas Piller
    Keywords Wirtschaft ; Economics
    Subject code sg330
    Language German
    Publisher Universitätsbibliothek der RWTH Aachen
    Publishing place Aachen
    Document type Book ; Online ; Thesis
    Database Digital theses on the web

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  7. Book ; Online ; Thesis: Kulturelle Werteidentität als Erfolgsfaktor bei der Internalisierung von externen Effekten vor dem Hintergrund der historischen Entwicklung der institutionellen Rahmenbedingungen am Fallbeispiel des philippinischen Bergbaus seit dem 15. Jahrhundert

    Gatzweiler, Birgit [Verfasser] / Thomes, Paul [Akademischer Betreuer] / Lorz, Oliver [Akademischer Betreuer]

    2022  

    Author's details Birgit Gatzweiler ; Paul Thomes, Jens Oliver Lorz
    Keywords Wirtschaft ; Economics
    Subject code sg330
    Language German
    Publisher Universitätsbibliothek der RWTH Aachen
    Publishing place Aachen
    Document type Book ; Online ; Thesis
    Database Digital theses on the web

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  8. Article: mTOR signaling regulates aberrant epithelial cell proliferative and migratory behaviors characteristic of airway mucous metaplasia in asthma.

    Kudrna, Katrina / Staab, Elizabeth B / Eilers, Evan / Thomes, Paul / Maurya, Shailendra / Brody, Steven L / Wyatt, Todd A / Bailey, Kristina L / Dickinson, John D

    bioRxiv : the preprint server for biology

    2024  

    Abstract: In asthma, the airway epithelium is hyperplastic, hypertrophied, and lined with numerous large MUC5AC-containing goblet cells (GC). Furthermore, the normal epithelial architecture is disorganized with numerous, what we here describe as, ectopic goblet ... ...

    Abstract In asthma, the airway epithelium is hyperplastic, hypertrophied, and lined with numerous large MUC5AC-containing goblet cells (GC). Furthermore, the normal epithelial architecture is disorganized with numerous, what we here describe as, ectopic goblet cells (eGC) deep within the thickened epithelial layer disconnected from the lumenal surface. mTOR is a highly conserved pathway that regulates cell size and proliferation. We hypothesized that the balance between mTOR and autophagy signaling regulates key features of the asthma epithelial layer. Airway histological sections from subjects with asthma had increased frequency of eGC and increased levels of mTOR phosphorylation target-Ribosomal S6. Using human airway epithelial cells (hAECs) with IL-13 stimulation and timed withdrawal to stimulate resolution, we found that multiple key downstream phosphorylation targets downstream from the mTOR complex were increased during early IL-13-mediated mucous metaplasia, and then significantly declined during resolution. The IL-13-mediated changes in mTOR signaling were paralleled by morphologic changes with airway epithelial hypertrophy, hyperplasia, and frequency of eGC. We then examined the relationship between mTOR and autophagy using mice deficient in autophagy protein Atg16L1. Despite having increased cytoplasmic mucins, mouse AECs from Atg16L1 deficient mice had no significant difference in mTOR downstream signaling. mTOR inhibition with rapamycin led to a loss of IL-13-mediated epithelial hypertrophy, hyperplasia, ectopic GC distribution, and reduction in cytoplasmic MUC5AC levels. mTOR inhibition was also associated with a reduction in aberrant IL-13-mediated hAEC proliferation and migration. Our findings demonstrate that mTOR signaling is associated with mucous metaplasia and is crucial to the disorganized airway epithelial structure and function characteristic of muco-obstructive airway diseases such as asthma.
    Graphical abstract key concepts: The airway epithelium in asthma is disorganized and characterized by cellular proliferation, aberrant migration, and goblet cell mucous metaplasia.mTOR signaling is a dynamic process during IL-13-mediated mucous metaplasia, increasing with IL-13 stimulation and declining during resolution.mTOR signaling is strongly increased in the asthmatic airway epithelium.mTOR signaling is associated with the development of key features of the metaplastic airway epithelium including cell proliferation and ectopic distribution of goblet cells and aberrant cellular migration.Inhibition of mTOR leads to decreased epithelial hypertrophy, reduced ectopic goblet cells, and cellular migration.
    Language English
    Publishing date 2024-02-14
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.02.12.579905
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Role of Early Growth Response-1 in the Development of Alcohol-Induced Steatosis.

    Thomes, Paul G / Donohue, Terrence M

    Current molecular pharmacology

    2015  Volume 10, Issue 3, Page(s) 179–185

    Abstract: Here, we describe research on the involvement of the transcription factor, Early Growth Response- 1 (Egr-1) in alcohol-induced liver injury, specifically, fatty liver (steatosis), one of the earliest and most frequent signs of liver injury that occurs ... ...

    Abstract Here, we describe research on the involvement of the transcription factor, Early Growth Response- 1 (Egr-1) in alcohol-induced liver injury, specifically, fatty liver (steatosis), one of the earliest and most frequent signs of liver injury that occurs after heavy drinking. Egr-1 is a ubiquitous transcription factor found in nearly all cell types. However, because the liver is the principal site of ethanol oxidation, it sustains the greatest damage from alcohol abuse. Thus, this review focuses on how alcohol consumption causes changes in the hepatic expression of Egr-1, which, in turn causes downstream alterations in the expression of other genes to cause liver pathology. Ironically, while such changes in Egr-1 expression clearly favor steatosis and even fibrosis development, the absence of Egr-1 expression can actually exacerbate liver injury after excessive alcohol consumption or after exposure to other hepatotoxins. The existing literature on Egr-1 is extensive. Here, we confine our initial description of Egr-1 to its principal molecular characteristics, its biological functions, and its involvement in certain pathologies that are either directly or obliquely related to alcoholic liver disease. We describe experimental data that clearly implicate Egr-1 function in alcohol-induced steatosis and fibrosis, showing that ethanol-elicited regulation of Egr-1 expression depends on the generation of acetaldehyde and that the absence of Egr-1 diminishes alcohol-induced triglyceride accumulation. Overall, the existing evidence for the involvement of Egr-1 as a key link in alcohol-induced liver disease is strong. The evidence underscores the potential role of Egr-1 and several other transcription factors as therapeutic targets in the alleviation of alcoholic liver disease, which, even after decades of treatment options, still remains difficult to manage in the clinic.
    MeSH term(s) Acetaldehyde/metabolism ; Animals ; Autophagy ; Early Growth Response Protein 1/genetics ; Early Growth Response Protein 1/metabolism ; Gene Expression Regulation ; Humans ; Lipolysis ; Liver Diseases, Alcoholic/metabolism ; Liver Diseases, Alcoholic/pathology ; Signal Transduction
    Chemical Substances Early Growth Response Protein 1 ; Acetaldehyde (GO1N1ZPR3B)
    Language English
    Publishing date 2015-08-13
    Publishing country United Arab Emirates
    Document type Journal Article ; Review
    ISSN 1874-4702
    ISSN (online) 1874-4702
    DOI 10.2174/1874467208666150817112529
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Crohn's Disease Patients Uniquely Contain Inflammatory Responses to Flagellin in a CD4 Effector Memory Subset.

    Morgan, Nadine N / Duck, Lennard W / Wu, Jiongru / Rujani, Mahmud / Thomes, Paul G / Elson, Charles O / Mannon, Peter J

    Inflammatory bowel diseases

    2022  Volume 28, Issue 12, Page(s) 1893–1903

    Abstract: Background: Specific microbial antigens stimulate production of antibodies indicative of the aberrant immune response in Crohn's disease (CD). We tested for T cell reactivity linkage to B cell responses and now report on the prevalence, functionality, ... ...

    Abstract Background: Specific microbial antigens stimulate production of antibodies indicative of the aberrant immune response in Crohn's disease (CD). We tested for T cell reactivity linkage to B cell responses and now report on the prevalence, functionality, and phenotypic differences of flagellin-specific T cells among CD patients, ulcerative colitis (UC) patients, and control subjects and association with clinical features and flagellin seropositivity within CD patients.
    Methods: Sera from non-inflammatory bowel disease control subjects, CD patients, and UC patients were probed for antibody reactivity to gut bacterial recombinant flagellin antigens. Peripheral blood mononuclear cells were measured for flagellin antigen (CBir1, A4 Fla2, FlaX) or control (Candida albicans, and CytoStim) reactivity analyzed by flow cytometry for CD154 and cytokine expression on CD4+ T cells. Supernatants from post-flagellin-stimulated and unstimulated cells were used to measure effects on epithelial barrier function.
    Results: CD patients had a significantly higher percentage of flagellin-specific CD154+ CD4+ cells that have an effector memory T helper 1 and T helper 17 phenotype compared with UC patients and healthy control subjects. There was a positive correlation between the frequency of flagellin-specific CD154+ CD4+ effector memory T cells and serum levels of anti-flagellin immunoglobulin G in the CD patients. In addition, A4 Fla2-reactive T cells from active CD patients produced cytokines that can decrease barrier function in a gut epithelium.
    Conclusions: These findings demonstrate a Crohn's-associated flagellin-reactive CD4 cell subset distinct from UC patients and control subjects. There is a link between these cells and flagellin seropositivity. This CD4 cell subset could reflect a particular endophenotype of CD, leading to novel insight into its pathology and treatment.
    MeSH term(s) Humans ; Crohn Disease/pathology ; Flagellin ; Leukocytes, Mononuclear ; Colitis, Ulcerative/complications ; Antigens, Bacterial ; Antibodies ; Cytokines
    Chemical Substances Flagellin (12777-81-0) ; Antigens, Bacterial ; Antibodies ; Cytokines
    Language English
    Publishing date 2022-08-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1340971-2
    ISSN 1536-4844 ; 1078-0998
    ISSN (online) 1536-4844
    ISSN 1078-0998
    DOI 10.1093/ibd/izac146
    Database MEDical Literature Analysis and Retrieval System OnLINE

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