23 results on '"Seddek AL"'
Search Results
2. Acetaminophen overdose causes a breach of the blood-bile barrier in mice but not in rats.
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Hassan R, Hobloss Z, Myllys M, González D, Begher-Tibbe B, Reinders J, Friebel A, Hoehme S, Abdelmageed N, Abbas AA, Seddek AL, Morad SAF, Hengstler JG, and Ghallab A
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- Mice, Rats, Humans, Male, Animals, Bile metabolism, Chromatography, Liquid, Rats, Wistar, Tandem Mass Spectrometry, Liver metabolism, Hepatocytes metabolism, Mice, Inbred C57BL, Tight Junction Proteins metabolism, Acetaminophen toxicity, Acetaminophen metabolism, Chemical and Drug Induced Liver Injury pathology
- Abstract
Acetaminophen (APAP) is known to cause a breach of the blood-bile barrier in mice that, via a mechanism called futile bile acid (BA) cycling, increases BA concentrations in hepatocytes above cytotoxic thresholds. Here, we compared this mechanism in mice and rats, because both species differ massively in their susceptibility to APAP and compared the results to available human data. Dose and time-dependent APAP experiments were performed in male C57BL6/N mice and Wistar rats. The time course of BA concentrations in liver tissue and in blood was analyzed by MALDI-MSI and LC-MS/MS. APAP and its derivatives were measured in the blood by LC-MS. APAP-induced liver damage was analyzed by histopathology, immunohistochemistry, and by clinical chemistry. In mice, a transient increase of BA in blood and in peri-central hepatocytes preceded hepatocyte death. The BA increase coincided with oxidative stress in liver tissue and a compromised morphology of bile canaliculi and immunohistochemically visualized tight junction proteins. Rats showed a reduced metabolic activation of APAP compared to mice. However, even at very high doses that caused cell death of hepatocytes, no increase of BA concentrations was observed neither in liver tissue nor in the blood. Correspondingly, no oxidative stress was detectable, and the morphology of bile canaliculi and tight junction proteins remained unaltered. In conclusion, different mechanisms cause cell death in rats and mice, whereby oxidative stress and a breach of the blood-bile barrier are seen only in mice. Since transient cholestasis also occurs in human patients with APAP overdose, mice are a clinically relevant species to study APAP hepatotoxicity but not rats., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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3. Inhibition of the renal apical sodium dependent bile acid transporter prevents cholemic nephropathy in mice with obstructive cholestasis.
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Ghallab A, González D, Strängberg E, Hofmann U, Myllys M, Hassan R, Hobloss Z, Brackhagen L, Begher-Tibbe B, Duda JC, Drenda C, Kappenberg F, Reinders J, Friebel A, Vucur M, Turajski M, Seddek AL, Abbas T, Abdelmageed N, Morad SAF, Morad W, Hamdy A, Albrecht W, Kittana N, Assali M, Vartak N, van Thriel C, Sous A, Nell P, Villar-Fernandez M, Cadenas C, Genc E, Marchan R, Luedde T, Åkerblad P, Mattsson J, Marschall HU, Hoehme S, Stirnimann G, Schwab M, Boor P, Amann K, Schmitz J, Bräsen JH, Rahnenführer J, Edlund K, Karpen SJ, Simbrunner B, Reiberger T, Mandorfer M, Trauner M, Dawson PA, Lindström E, and Hengstler JG
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- Humans, Mice, Animals, Kidney metabolism, Bile Acids and Salts metabolism, Liver metabolism, Bile Ducts metabolism, Sodium, Cholestasis complications, Cholestasis metabolism, Symporters metabolism, Kidney Diseases, Liver Diseases metabolism, Carrier Proteins, Membrane Glycoproteins, Organic Anion Transporters, Sodium-Dependent
- Abstract
Background & Aims: Cholemic nephropathy (CN) is a severe complication of cholestatic liver diseases for which there is no specific treatment. We revisited its pathophysiology with the aim of identifying novel therapeutic strategies., Methods: Cholestasis was induced by bile duct ligation (BDL) in mice. Bile flux in kidneys and livers was visualized by intravital imaging, supported by MALDI mass spectrometry imaging and liquid chromatography-tandem mass spectrometry. The effect of AS0369, a systemically bioavailable apical sodium-dependent bile acid transporter (ASBT) inhibitor, was evaluated by intravital imaging, RNA-sequencing, histological, blood, and urine analyses. Translational relevance was assessed in kidney biopsies from patients with CN, mice with a humanized bile acid (BA) spectrum, and via analysis of serum BAs and KIM-1 (kidney injury molecule 1) in patients with liver disease and hyperbilirubinemia., Results: Proximal tubular epithelial cells (TECs) reabsorbed and enriched BAs, leading to oxidative stress and death of proximal TECs, casts in distal tubules and collecting ducts, peritubular capillary leakiness, and glomerular cysts. Renal ASBT inhibition by AS0369 blocked BA uptake into TECs and prevented kidney injury up to 6 weeks after BDL. Similar results were obtained in mice with humanized BA composition. In patients with advanced liver disease, serum BAs were the main determinant of KIM-1 levels. ASBT expression in TECs was preserved in biopsies from patients with CN, further highlighting the translational potential of targeting ASBT to treat CN., Conclusions: BA enrichment in proximal TECs followed by oxidative stress and cell death is a key early event in CN. Inhibiting renal ASBT and consequently BA enrichment in TECs prevents CN and systemically decreases BA concentrations., Impact and Implications: Cholemic nephropathy (CN) is a severe complication of cholestasis and an unmet clinical need. We demonstrate that CN is triggered by the renal accumulation of bile acids (BAs) that are considerably increased in the systemic blood. Specifically, the proximal tubular epithelial cells of the kidney take up BAs via the apical sodium-dependent bile acid transporter (ASBT). We developed a therapeutic compound that blocks ASBT in the kidneys, prevents BA overload in tubular epithelial cells, and almost completely abolished all disease hallmarks in a CN mouse model. Renal ASBT inhibition represents a potential therapeutic strategy for patients with CN., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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4. Increased sinusoidal export of drug glucuronides is a compensative mechanism in liver cirrhosis of mice.
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Fendt R, Ghallab A, Myllys M, Hofmann U, Hassan R, Hobloss Z, González D, Brackhagen L, Marchan R, Edlund K, Seddek AL, Abdelmageed N, Blank LM, Schlender JF, Holland CH, Hengstler JG, and Kuepfer L
- Abstract
Rationale: Liver cirrhosis is known to affect drug pharmacokinetics, but the functional assessment of the underlying pathophysiological alterations in drug metabolism is difficult. Methods: Cirrhosis in mice was induced by repeated treatment with carbon tetrachloride for 12 months. A cocktail of six drugs was administered, and parent compounds as well as phase I and II metabolites were quantified in blood, bile, and urine in a time-dependent manner. Pharmacokinetics were modeled in relation to the altered expression of metabolizing enzymes. In discrepancy with computational predictions, a strong increase of glucuronides in blood was observed in cirrhotic mice compared to vehicle controls. Results: The deviation between experimental findings and computational simulations observed by analyzing different hypotheses could be explained by increased sinusoidal export and corresponded to increased expression of export carriers ( Abcc3 and Abcc4 ). Formation of phase I metabolites and clearance of the parent compounds were surprisingly robust in cirrhosis, although the phase I enzymes critical for the metabolism of the administered drugs in healthy mice, Cyp1a2 and Cyp2c29 , were downregulated in cirrhotic livers. RNA-sequencing revealed the upregulation of numerous other phase I metabolizing enzymes which may compensate for the lost CYP isoenzymes. Comparison of genome-wide data of cirrhotic mouse and human liver tissue revealed similar features of expression changes, including increased sinusoidal export and reduced uptake carriers. Conclusion: Liver cirrhosis leads to increased blood concentrations of glucuronides because of increased export from hepatocytes into the sinusoidal blood. Although individual metabolic pathways are massively altered in cirrhosis, the overall clearance of the parent compounds was relatively robust due to compensatory mechanisms., Competing Interests: Author J-FS was employed by the company Bayer AG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fendt, Ghallab, Myllys, Hofmann, Hassan, Hobloss, González, Brackhagen, Marchan, Edlund, Seddek, Abdelmageed, Blank, Schlender, Holland, Hengstler and Kuepfer.)
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- 2023
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5. Vinpocetine protects against chloroquine-induced cardiotoxicity by mitigating oxidative stress.
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Abdelmageed N, Twafik WA, Morad OA, Haridy M, Hassan R, Ahmed M, El-Zorba HY, El-Banna HA, Seddek AL, Ghallab A, and Morad SAF
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- Animals, Mice, Cardiotoxicity prevention & control, SARS-CoV-2, COVID-19 Drug Treatment, Hydroxychloroquine toxicity, Hydroxychloroquine therapeutic use, Oxidative Stress, Chloroquine toxicity, COVID-19
- Abstract
Chloroquine (CQ) and hydroxychloroquine (HCQ) are classical antimalarial drugs, and recently have been used for other applications including coronavirus disease 2019 (COVID-19). Although they are considered safe, cardiomyopathy may associate CQ and HCQ applications particularly at overdoses. The goal of the present study was to evaluate the potential protective effect of the nootropic agent vinpocetine against CQ and HCQ adverse effects with a specific focus on the heart. For this purpose, a mouse model of CQ (0.5 up to 2.5 g/kg)/HCQ (1 up to 2 g/kg) toxicity was used, and the effect of vinpocetine was evaluated by survival, biochemical, as well as histopathological analyses. Survival analysis revealed that CQ and HCQ caused dose-dependent lethality, which was prevented by co-treatment with vinpocetine (100 mg/kg, oral or intraperitoneal). To gain deeper understanding, a dose of 1 g/kg CQ-which did not cause death within the first 24 h after administration-was applied with and without vinpocetine administration (100 mg/kg, intraperitoneal). The CQ vehicle group showed marked cardiotoxicity as evidenced by significant alterations of blood biomarkers including troponione-1, creatine phosphokinase (CPK), creatine kinase-myocardial band (CK-MB), ferritin, and potassium levels. This was confirmed at the tissue level by massive alteration of the heart tissue morphology and coincided with massive oxidative stress. Interestingly, co-administration of vinpocetine strongly ameliorated CQ-induced alterations and restored the antioxidant-defense system of the heart. These data suggest that vinpocetine could be used as an adjuvant therapy together with CQ/HCQ applications., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2023
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6. Cognitive Functions, Neurotransmitter Alterations, and Hippocampal Microstructural Changes in Mice Caused by Feeding on Western Diet.
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Custodio RJP, Hobloss Z, Myllys M, Hassan R, González D, Reinders J, Bornhorst J, Weishaupt AK, Seddek AL, Abbas T, Friebel A, Hoehme S, Getzmann S, Hengstler JG, van Thriel C, and Ghallab A
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- Animals, Mice, Cognition, Brain, Diet, Western adverse effects, Fatty Liver
- Abstract
Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is the most common chronic liver disease in Western countries. It is becoming increasingly evident that peripheral organ-centered inflammatory diseases, including liver diseases, are linked with brain dysfunctions. Therefore, this study aims to unravel the effect of MASLD on brain histology, cognitive functions, and neurotransmitters. For this purpose, mice fed for 48 weeks on standard (SD) or Western diet (WD) were evaluated by behavioral tests, followed by sacrifice and analysis of the liver-brain axis including histopathology, immunohistochemistry, and biochemical analyses. Histological analysis of the liver showed features of Metabolic Dysfunction-Associated Steatohepatitis (MASH) in the WD-fed mice including lipid droplet accumulation, inflammation, and fibrosis. This was accompanied by an elevation of transaminase and alkaline phosphatase activities, increase in inflammatory cytokine and bile acid concentrations, as well as altered amino acid concentrations in the blood. Interestingly, compromised blood capillary morphology coupled with astrogliosis and microgliosis were observed in brain hippocampus of the WD mice, indicating neuroinflammation or a disrupted neurovascular unit. Moreover, attention was impaired in WD-fed mice along with the observations of impaired motor activity and balance, enhanced anxiety, and stereotyped head-twitch response (HTR) behaviors. Analysis of neurotransmitters and modulators including dopamine, serotonin, GABA, glutamate, and acetylcholine showed region-specific dysregulation in the brain of the WD-fed mice. In conclusion, the induction of MASH in mice is accompanied by the alteration of cellular morphology and neurotransmitter expression in the brain, associated with compromised cognitive functions.
- Published
- 2023
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7. Inhibition of cytochrome P450 enhances the nephro- and hepatotoxicity of ochratoxin A.
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Hassan R, González D, Hobloss Z, Brackhagen L, Myllys M, Friebel A, Seddek AL, Marchan R, Cramer B, Humpf HU, Hoehme S, Degen GH, Hengstler JG, and Ghallab A
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- Animals, Mice, Lipocalin-2, Carbon Tetrachloride, Acetaminophen toxicity, Alanine Transaminase, Cytochrome P-450 Enzyme System metabolism, Biomarkers, Aspartate Aminotransferases, Mycotoxins, Liver Diseases, Chemical and Drug Induced Liver Injury etiology
- Abstract
The mycotoxin ochratoxin A (OTA) is a contaminant in food that causes nephrotoxicity and to a minor degree hepatotoxicity. Recently, we observed that OTA induces liver damage preferentially to the cytochrome P450 (CYP)-expressing pericentral lobular zone, similar to hepatotoxic substances known to be metabolically toxified by CYP, such as acetaminophen or carbon tetrachloride. To investigate whether CYP influences OTA toxicity, we used a single dose of OTA (7.5 mg/kg; intravenous) with and without pre-treatment with the pan CYP-inhibitor 1-aminobenzotriazole (ABT) 2 h before OTA administration. Blood, urine, as well as liver and kidney tissue samples were collected 24 h after OTA administration for biochemical and histopathological analyses. Inhibition of CYPs by ABT strongly increased the nephro- and hepatotoxicity of OTA. The urinary kidney damage biomarkers kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) were increased > 126-fold and > 20-fold, respectively, in mice treated with ABT and OTA compared to those receiving OTA alone. The blood biomarkers of liver damage, alanine transaminase (ALT) and aspartate transaminase (AST) both increased > 21- and 30-fold, respectively, when OTA was administered to ABT pre-treated mice compared to the effect of OTA alone. Histological analysis of the liver revealed a pericentral lobular damage induced by OTA despite CYP-inhibition by ABT. Administration of ABT alone caused no hepato- or nephrotoxicity. Overall, the results presented are compatible with a scenario where CYPs mediate the detoxification of OTA, yet the mechanisms responsible for the pericental liver damage pattern still remain to be elucidated., (© 2022. The Author(s).)
- Published
- 2022
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8. Hypoalbuminemia affects the spatio-temporal tissue distribution of ochratoxin A in liver and kidneys: consequences for organ toxicity.
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Hassan R, Friebel A, Brackhagen L, Hobloss Z, Myllys M, González D, Albrecht W, Mohammed ESI, Seddek AL, Marchan R, Cadenas C, Cramer B, Humpf HU, Hartl L, Simbrunner B, Reiberger T, Trauner M, Hoehme S, Degen GH, Hengstler JG, and Ghallab A
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- Animals, Kidney metabolism, Liver metabolism, Mice, Serum Albumin metabolism, Tissue Distribution, Hypoalbuminemia metabolism, Mycotoxins metabolism, Ochratoxins chemistry
- Abstract
Hypoalbuminemia (HA) is frequently observed in systemic inflammatory diseases and in liver disease. However, the influence of HA on the pharmacokinetics and toxicity of compounds with high plasma albumin binding remained insufficiently studied. The 'lack-of-delivery-concept' postulates that HA leads to less carrier mediated uptake of albumin bound substances into hepatocytes and to less glomerular filtration; in contrast, the 'concept-of-higher-free-fraction' argues that increased concentrations of non-albumin bound compounds facilitate hepatocellular uptake and enhance glomerular filtration. To address this question, we performed intravital imaging on livers and kidneys of anesthetized mice to quantify the spatio-temporal tissue distribution of the mycotoxin ochratoxin A (OTA) based on its auto-fluorescence in albumin knockout and wild-type mice. HA strongly enhanced the uptake of OTA from the sinusoidal blood into hepatocytes, followed by faster secretion into bile canaliculi. These toxicokinetic changes were associated with increased hepatotoxicity in heterozygous albumin knockout mice for which serum albumin was reduced to a similar extent as in patients with severe hypoalbuminemia. HA also led to a shorter half-life of OTA in renal capillaries, increased glomerular filtration, and to enhanced uptake of OTA into tubular epithelial cells. In conclusion, the results favor the 'concept-of-higher-free-fraction' in HA; accordingly, HA causes an increased tissue uptake of compounds with high albumin binding and increased organ toxicity. It should be studied if this concept can be generalized to all compounds with high plasma albumin binding that are substrates of hepatocyte and renal tubular epithelial cell carriers., (© 2022. The Author(s).)
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- 2022
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9. Colchicine overdose impairs the capacity of Kupffer cells to clear foreign particles and endotoxins.
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Hassan R, Myllys M, Brackhagen L, Hobloss Z, González D, Seddek AL, Friebel A, Hoehme S, Marchan R, Trauner M, Hengstler JG, and Ghallab A
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- Animals, Anti-Inflammatory Agents pharmacology, Colchicine metabolism, Colchicine toxicity, Cytokines metabolism, Endothelial Cells metabolism, Endotoxins, Humans, Mice, Tubulin metabolism, Kupffer Cells, Lipopolysaccharides toxicity
- Abstract
Colchicine is an anti-inflammatory drug with a narrow therapeutic index. Its binding to tubulin prevents microtubule polymerization; however, little is known about how depolymerization of microtubules interferes with the phagocytosis function of Kupffer cells (KC). Here, we applied functional intravital imaging techniques to investigate the influence of microtubule disruption by colchicine on KC morphology, as well as its capacity to clear foreign particles and bacterial lipopolysaccharide (LPS) in anesthetized mice. Intravital imaging of KC in healthy mice showed the typical elongated morphology, localization at the luminal side of the sinusoidal endothelial cells, and moving cell protrusions. In contrast, at colchicine doses of 1 mg/kg and higher (intraperitoneal), KC appeared roundish with strongly reduced protrusions and motility. To study the functional consequences of these alterations, we analyzed the capacity of KC to phagocytose fluorescent nanospheres (100 nm-size) and LPS. After tail vein injection, the nanospheres formed aggregates of up to ~ 5 µm moving along the sinusoidal bloodstream. In controls, the nanosphere aggregates were rapidly captured by the Kupffer cell protrusions, followed by an internalization process that lasted up to 10 min. Similar capture events and internalization processes were observed after the administration of fluorescently labeled LPS. In contrast, capture and internalization of both nanospheres and LPS by KC were strongly reduced in colchicine-treated mice. Reduced phagocytosis of LPS was accompanied by aggravated production of inflammatory cytokines. Since 0.4 mg/kg colchicine in mice has been reported to be bio-equivalent to human therapeutic doses, the here-observed adverse effects on KC occurred at doses only slightly above those used clinically, and may be critical for patients with endotoxemia due to a leaky gut-blood barrier., (© 2022. The Author(s).)
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- 2022
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10. Interruption of bile acid uptake by hepatocytes after acetaminophen overdose ameliorates hepatotoxicity.
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Ghallab A, Hassan R, Hofmann U, Friebel A, Hobloss Z, Brackhagen L, Begher-Tibbe B, Myllys M, Reinders J, Overbeck N, Sezgin S, Zühlke S, Seddek AL, Murad W, Brecklinghaus T, Kappenberg F, Rahnenführer J, González D, Goldring C, Copple IM, Marchan R, Longerich T, Vucur M, Luedde T, Urban S, Canbay A, Schreiter T, Trauner M, Akakpo JY, Olyaee M, Curry SC, Sowa JP, Jaeschke H, Hoehme S, and Hengstler JG
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- Acetaminophen metabolism, Acetylcysteine pharmacology, Animals, Bile Acids and Salts metabolism, Hepatocytes metabolism, Humans, Liver metabolism, Mice, Mice, Inbred C57BL, Chemical and Drug Induced Liver Injury drug therapy, Chemical and Drug Induced Liver Injury metabolism, Chemical and Drug Induced Liver Injury prevention & control, Drug Overdose
- Abstract
Background & Aims: Acetaminophen (APAP) overdose remains a frequent cause of acute liver failure, which is generally accompanied by increased levels of serum bile acids (BAs). However, the pathophysiological role of BAs remains elusive. Herein, we investigated the role of BAs in APAP-induced hepatotoxicity., Methods: We performed intravital imaging to investigate BA transport in mice, quantified endogenous BA concentrations in the serum of mice and patients with APAP overdose, analyzed liver tissue and bile by mass spectrometry and MALDI-mass spectrometry imaging, assessed the integrity of the blood-bile barrier and the role of oxidative stress by immunostaining of tight junction proteins and intravital imaging of fluorescent markers, identified the intracellular cytotoxic concentrations of BAs, and performed interventions to block BA uptake from blood into hepatocytes., Results: Prior to the onset of cell death, APAP overdose causes massive oxidative stress in the pericentral lobular zone, which coincided with a breach of the blood-bile barrier. Consequently, BAs leak from the bile canaliculi into the sinusoidal blood, which is then followed by their uptake into hepatocytes via the basolateral membrane, their secretion into canaliculi and repeated cycling. This, what we termed 'futile cycling' of BAs, led to increased intracellular BA concentrations that were high enough to cause hepatocyte death. Importantly, however, the interruption of BA re-uptake by pharmacological NTCP blockage using Myrcludex B and Oatp knockout strongly reduced APAP-induced hepatotoxicity., Conclusions: APAP overdose induces a breach of the blood-bile barrier which leads to futile BA cycling that causes hepatocyte death. Prevention of BA cycling may represent a therapeutic option after APAP intoxication., Lay Summary: Only one drug, N-acetylcysteine, is approved for the treatment of acetaminophen overdose and it is only effective when given within ∼8 hours after ingestion. We identified a mechanism by which acetaminophen overdose causes an increase in bile acid concentrations (to above toxic thresholds) in hepatocytes. Blocking this mechanism prevented acetaminophen-induced hepatotoxicity in mice and evidence from patients suggests that this therapy may be effective for longer periods after ingestion compared to N-acetylcysteine., Competing Interests: Conflict of interest S.U. is holder and inventor on patents protecting Myrcludex B (Hepcludex/bulevirtide). All other authors declare that they have no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
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11. Transcriptomic Cross-Species Analysis of Chronic Liver Disease Reveals Consistent Regulation Between Humans and Mice.
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Holland CH, Ramirez Flores RO, Myllys M, Hassan R, Edlund K, Hofmann U, Marchan R, Cadenas C, Reinders J, Hoehme S, Seddek AL, Dooley S, Keitel V, Godoy P, Begher-Tibbe B, Trautwein C, Rupp C, Mueller S, Longerich T, Hengstler JG, Saez-Rodriguez J, and Ghallab A
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- Animals, Chronic Disease, Down-Regulation, Humans, Mice, Species Specificity, Up-Regulation, Disease Models, Animal, Gene Expression Profiling, Liver Diseases genetics, Transcriptome
- Abstract
Mouse models are frequently used to study chronic liver diseases (CLDs). To assess their translational relevance, we quantified the similarity of commonly used mouse models to human CLDs based on transcriptome data. Gene-expression data from 372 patients were compared with data from acute and chronic mouse models consisting of 227 mice, and additionally to nine published gene sets of chronic mouse models. Genes consistently altered in humans and mice were mapped to liver cell types based on single-cell RNA-sequencing data and validated by immunostaining. Considering the top differentially expressed genes, the similarity between humans and mice varied among the mouse models and depended on the period of damage induction. The highest recall (0.4) and precision (0.33) were observed for the model with 12-months damage induction by CCl
4 and by a Western diet, respectively. Genes consistently up-regulated between the chronic CCl4 model and human CLDs were enriched in inflammatory and developmental processes, and mostly mapped to cholangiocytes, macrophages, and endothelial and mesenchymal cells. Down-regulated genes were enriched in metabolic processes and mapped to hepatocytes. Immunostaining confirmed the regulation of selected genes and their cell type specificity. Genes that were up-regulated in both acute and chronic models showed higher recall and precision with respect to human CLDs than exclusively acute or chronic genes. Conclusion: Similarly regulated genes in human and mouse CLDs were identified. Despite major interspecies differences, mouse models detected 40% of the genes significantly altered in human CLD. The translational relevance of individual genes can be assessed at https://saezlab.shinyapps.io/liverdiseaseatlas/., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)- Published
- 2022
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12. Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression.
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Ghallab A, Myllys M, Friebel A, Duda J, Edlund K, Halilbasic E, Vucur M, Hobloss Z, Brackhagen L, Begher-Tibbe B, Hassan R, Burke M, Genc E, Frohwein LJ, Hofmann U, Holland CH, González D, Keller M, Seddek AL, Abbas T, Mohammed ESI, Teufel A, Itzel T, Metzler S, Marchan R, Cadenas C, Watzl C, Nitsche MA, Kappenberg F, Luedde T, Longerich T, Rahnenführer J, Hoehme S, Trauner M, and Hengstler JG
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- Animals, Disease Models, Animal, Disease Progression, Liver metabolism, Mice, Mice, Inbred C57BL, Carcinoma, Hepatocellular pathology, Diet, Western adverse effects, Liver Neoplasms pathology, Non-alcoholic Fatty Liver Disease metabolism
- Abstract
Mouse models of non-alcoholic fatty liver disease (NAFLD) are required to define therapeutic targets, but detailed time-resolved studies to establish a sequence of events are lacking. Here, we fed male C57Bl/6N mice a Western or standard diet over 48 weeks. Multiscale time-resolved characterization was performed using RNA-seq, histopathology, immunohistochemistry, intravital imaging, and blood chemistry; the results were compared to human disease. Acetaminophen toxicity and ammonia metabolism were additionally analyzed as functional readouts. We identified a sequence of eight key events: formation of lipid droplets; inflammatory foci; lipogranulomas; zonal reorganization; cell death and replacement proliferation; ductular reaction; fibrogenesis; and hepatocellular cancer. Functional changes included resistance to acetaminophen and altered nitrogen metabolism. The transcriptomic landscape was characterized by two large clusters of monotonously increasing or decreasing genes, and a smaller number of 'rest-and-jump genes' that initially remained unaltered but became differentially expressed only at week 12 or later. Approximately 30% of the genes altered in human NAFLD are also altered in the present mouse model and an increasing overlap with genes altered in human HCC occurred at weeks 30-48. In conclusion, the observed sequence of events recapitulates many features of human disease and offers a basis for the identification of therapeutic targets.
- Published
- 2021
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13. Subcellular spatio-temporal intravital kinetics of aflatoxin B 1 and ochratoxin A in liver and kidney.
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Ghallab A, Hassan R, Myllys M, Albrecht W, Friebel A, Hoehme S, Hofmann U, Seddek AL, Braeuning A, Kuepfer L, Cramer B, Humpf HU, Boor P, Degen GH, and Hengstler JG
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- Animals, Cytochrome P-450 Enzyme System metabolism, Half-Life, Hepatocytes metabolism, Male, Mice, Mice, Inbred C57BL, Microscopy methods, Spatio-Temporal Analysis, Tissue Distribution, Aflatoxin B1 pharmacokinetics, Kidney metabolism, Liver metabolism, Ochratoxins pharmacokinetics
- Abstract
Local accumulation of xenobiotics in human and animal tissues may cause adverse effects. Large differences in their concentrations may exist between individual cell types, often due to the expression of specific uptake and export carriers. Here we established a two-photon microscopy-based technique for spatio-temporal detection of the distribution of mycotoxins in intact kidneys and livers of anesthetized mice with subcellular resolution. The mycotoxins ochratoxin A (OTA, 10 mg/kg b.w.) and aflatoxin B
1 (AFB1 , 1.5 mg/kg b.w.), which both show blue auto-fluorescence, were analyzed after intravenous bolus injections. Within seconds after administration, OTA was filtered by glomeruli, and enriched in distal tubular epithelial cells (dTEC). A striking feature of AFB1 toxicokinetics was its very rapid uptake from sinusoidal blood into hepatocytes (t1/2 ~ 4 min) and excretion into bile canaliculi. Interestingly, AFB1 was enriched in the nuclei of hepatocytes with zonal differences in clearance. In the cytoplasm of pericentral hepatocytes, the half-life (t1/2 ~ 63 min) was much longer compared to periportal hepatocytes of the same lobules (t1/2 ~ 9 min). In addition, nuclear AFB1 from periportal hepatocytes cleared faster compared to the pericentral region. These local differences in AFB1 clearance may be due to the pericentral expression of cytochrome P450 enzymes that activate AFB1 to protein- and DNA-binding metabolites. In conclusion, the present study shows that large spatio-temporal concentration differences exist within the same tissues and its analysis may provide valuable additional information to conventional toxicokinetic studies.- Published
- 2021
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14. Vinpocetine-based therapy is an attractive strategy against oxidative stress-induced hepatotoxicity in vitro by targeting Nrf2/HO-1 pathway.
- Author
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Abdelmageed N, Twafik WA, Seddek AL, and Morad SAF
- Abstract
Vinpocetine (Vin), a synthetic-derivative of Vincamine, monoterpenoid indole alkaloid, has been reported to have various medicinal benefits. The purpose of our study was to investigate the pivotal role of "nuclear factor erythroid 2-related factor-2" (Nrf2)-mediated antioxidant protection of Vin against H
2 O2 and paracetamol (APAP)-induced liver toxicity. For this purpose, a normal human hepatic cell line (L02 cells) was incubated with cytotoxic concentrations of H2 O2 or APAP in the presence or absence of Vin. To evaluate the responses, MTS Cell Viability assay, immunoblotting, biochemical assays, and molecular docking approach were used. Viability analysis showed that treatment of L02 cells with Vin prevented the cytotoxicity induced by H2 O2 and APAP. It was evidenced by the fact that Vin dumped H2 O2- and APAP-cytotoxicity and reactive oxygen species (ROS) generation. The immunoblotting analysis shows that Vin increased Nrf2 expression along with the expression of target protein, heme oxygenase-1 (HO-1), and increased intracellular glutathione (GSH) level. Interestingly, we found that Vin could protect the protein expression-level of Nrf2, which indicated the prospective interaction between Vin and Keap1 protein. Additionally, molecular docking-study revealed that Vin competed with Nrf2 for Keap1-binding site, with hydrogen and stearic interactions. Collectively, Vin effectively protects against H2 O2 and APAP-induced cytotoxicity via executing Nrf2-mediated restoration of antioxidative/oxidative balance. Meanwhile, Vin interrupts protein-protein interaction between Nrf2 and Keap1, which might also contribute to decrease Nrf2 degradation and stabilize protein expression. Thus, Vin-based adjuvant therapy may represent a smart drug regimen to mitigate drug-induced oxidative stress and liver injuries., (Copyright © 2021 Abdelmageed et al.)- Published
- 2021
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15. Modelling of liver regeneration after hepatectomy.
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Seddek AL and Hassan R
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- 2020
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16. Fluoride: no evidence of developmental neurotoxicity due to current exposure levels in Europe.
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Seddek AL and Ghallab A
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- Age Factors, Animals, Dose-Response Relationship, Drug, Europe, Humans, Nervous System growth & development, Neurotoxicity Syndromes physiopathology, No-Observed-Adverse-Effect Level, Risk Assessment, Cariostatic Agents adverse effects, Fluorides adverse effects, Nervous System drug effects, Neurotoxicity Syndromes etiology
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- 2020
- Full Text
- View/download PDF
17. Future perspectives of DILI prediction in vitro.
- Author
-
Ghallab A and Seddek AL
- Subjects
- Humans, Chemical and Drug Induced Liver Injury
- Published
- 2019
- Full Text
- View/download PDF
18. Highlight report: the need of 'fit-for-purpose' controls for cell lines used in toxicity assays.
- Author
-
Hassan R, Ghallab A, and Seddek AL
- Subjects
- Cell Line, Genetic Drift, Hazardous Substances
- Published
- 2018
- Full Text
- View/download PDF
19. Highlight report: Protection of cholestatic livers by shunting of bile from canaliculi to sinusoids.
- Author
-
Abbass T, Murad W, and Seddek AL
- Published
- 2018
- Full Text
- View/download PDF
20. Hepatic zonation of toxic metabolite formation: perspectives of matrix-assisted laser desorption mass spectrometry imaging.
- Author
-
Murad W, Abbass T, and Seddek AL
- Subjects
- Animals, Mice, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Acetaminophen, Liver
- Published
- 2018
- Full Text
- View/download PDF
21. Erratum to: Highlight report: co-cultures of hepatocytes and macrophages for hepatotoxicity testing.
- Author
-
Seddek AL and Abbas AA
- Published
- 2017
- Full Text
- View/download PDF
22. Highlight report: co-cultures of hepatocytes and macrophages for hepatotoxicity testing.
- Author
-
Seddek AL and Abbas AA
- Subjects
- Cells, Cultured, Chemical and Drug Induced Liver Injury, Humans, Macrophages, Coculture Techniques, Hepatocytes
- Published
- 2017
- Full Text
- View/download PDF
23. Extract from Calotropis procera latex activates murine macrophages.
- Author
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Seddek Al, Mahmoud ME, Shiina T, Hirayama H, Iwami M, Miyazawa S, Nikami H, Takewaki T, and Shimizu Y
- Subjects
- Animals, Cell Line, Cell Movement drug effects, Cells, Cultured, Macrophages cytology, Macrophages metabolism, Male, Mice, Nitric Oxide metabolism, Nitric Oxide Synthase Type II antagonists & inhibitors, Nitric Oxide Synthase Type II genetics, Reverse Transcriptase Polymerase Chain Reaction, Calotropis chemistry, Macrophages drug effects, Plant Extracts chemistry, Plant Extracts pharmacology
- Abstract
Calotropis procera latex has long been used in traditional medicines. Extracts from C. procera latex have been reported to have various pharmacological actions, including protection from myocardial infarction, hepatoprotective action, antitumor activity, antinociceptive, and pro- and anti-inflammatory actions. To evaluate the immunomodulatory functions of the water-soluble C. procera extract (CPE), we investigated its ability to activate macrophages-effector cells in inflammatory and immune responses. Intraperitoneal injection of CPE in mice (2 mg/mouse) induced migration of macrophages to the intraperitoneal cavity, confirming the proinflammatory effects of water-soluble CPE. The direct effects of CPE on macrophages were then assessed by measuring the production of nitric oxide (NO) as an indicator for macrophage activation. Addition of CPE (1-10 microg/ml) to the culture medium of the murine monocyte/macrophage cell line RAW264.7 caused an increase in NO production in a time- and dose-dependent manner. CPE-elicited NO production was blocked by application of an inhibitor of inducible nitric oxide synthase (iNOS). Expression of iNOS mRNA was induced by treatment of cultured macrophages with CPE. Injection of CPE in mice also resulted in an increase in plasma NO level. The results suggest that CPE activates macrophages and facilitates NO production via up-regulation of iNOS gene expression.
- Published
- 2009
- Full Text
- View/download PDF
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