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Reham Hassan

About Reham Hassan:

PhD student

SEEK ID: https://seek.lisym.org/people/53

Location: Germany

Expertise: liver metabolism, non parenchymal cells, Liver injury and regeneration

Tools: RNA analysis, Mouse surgery, Immunohistochemistry, confocal microscopy

ORCID: https://orcid.org/0000-0002-6569-7676

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LiSyM network

This comprises the whole LiSyM network

Public web page: http://www.lisym.org

Model Guided Pharmacotherapy In Chronic Liver Disease (LiSyM-MGP)

Approach:
– Systems modeling of hepatic metabolism in liver diseases
– Control mechanisms of liver regeneration

Public web page: Not specified

Influence of Liver Fibrosis on Lobular Zonation
Model Guided Pharmacotherapy In Chronic Liver Disease (LiSyM-MGP)

Abstract (Expand)

Little is known about how liver fibrosis influences lobular zonation. To address this question, we used three mouse models of liver fibrosis, repeated CCl4 administration for 2, 6 and 12 months to … induce pericentral damage, as well as bile duct ligation (21 days) and mdr2−/− mice to study periportal fibrosis. Analyses were performed by RNA-sequencing, immunostaining of zonated proteins and image analysis. RNA-sequencing demonstrated a significant enrichment of pericentral genes among genes downregulated by CCl4; vice versa, periportal genes were enriched among the upregulated genes. Immunostaining showed an almost complete loss of pericentral proteins, such as cytochrome P450 enzymes and glutamine synthetase, while periportal proteins, such as arginase 1 and CPS1 became expressed also in pericentral hepatocytes. This pattern of fibrosis-associated ‘periportalization’ was consistently observed in all three mouse models and led to complete resistance to hepatotoxic doses of acetaminophen (200 mg/kg). Characterization of the expression response identified the inflammatory pathways TGFβ, NFκB, TNFα, and transcription factors NFKb1, Stat1, Hif1a, Trp53, and Atf1 among those activated, while estrogen-associated pathways, Hnf4a and Hnf1a, were decreased. In conclusion, liver fibrosis leads to strong alterations of lobular zonation, where the pericentral region adopts periportal features. Beside adverse consequences, periportalization supports adaptation to repeated doses of hepatotoxic compounds.

Authors: Ahmed Ghallab, Maiju Myllys, Christian Holland, Ayham Zaza, Walaa Murad, Reham Hassan, Yasser A Ahmed, Tahany Abbas, Eman Abdelrahim, Annika Schneider, Madlen Matz-Soja, Joerg Reinders, Rolf Gebhardt, Theresa Hildegard Wirtz, Maximilian Hatting, Dirk Drasdo, Julio Saez-Rodriguez, Christian Trautwein, Jan Hengstler

Date Published: 1st Dec 2019

Journal: Cells

Bile micro-infarcts in cholestasis are initiated by rupture of the apical hepatocyte membrane and cause shunting of bile to sinusoidal blood
Model Guided Pharmacotherapy In Chronic Liver Disease (LiSyM-MGP)

Abstract

Not specified

Authors: Ahmed Ghallab, Ute Hofmann, Selahaddin Sezgin, Nachiket Vartak, Reham Hassan, Ayham Zaza, Patricio Godoy, Kai Markus Schneider, Georgia Guenther, Yasser A Ahmed, Aya A Abbas, Verena Keitel, Lars Kuepfer, Steven Dooley, Frank Lammert, Christian Trautwein, Michael Spiteller, Dirk Drasdo, Alan F Hofmann, Peter Jansen, Jan Hengstler, Raymond Reif

Date Published: 13th Aug 2018

Journal: HEP

Spatio-temporal visualization of the distribution of acetaminophen as well as its metabolites and adducts in mouse livers by MALDI MSI
Model Guided Pharmacotherapy In Chronic Liver Disease (LiSyM-MGP)

Abstract (Expand)

Acetaminophen (APAP) is one of the most intensively studied compounds that causes hepatotoxicity in the pericentral region of the liver lobules. However, spatio-temporal information on the distribution … of APAP, its metabolites and GSH adducts in the liver tissue is not yet available. Here, we addressed the question, whether APAP-GSH adducts and GSH depletion show a zonated pattern and whether the distribution of APAP and its glucuronide as well as sulfate conjugates in liver lobules are zonated. For this purpose, a matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) technique was established, where the MSI images were superimposed onto CYP2E1 immunostained tissue. A time-dependent analysis (5, 15, 30, 60, 120, 240, 480 min) after intraperitoneal administration of 300 mg/kg APAP and a dose-dependent analysis (56 up to 500 mg APAP/kg) at 30 min were performed. The results demonstrate that the MALDI MSI technique allows the assignment of compounds and their metabolites to specific lobular zones. APAP-GSH adducts and GSH depletion occurred predominantly in the CYP2E1-positive zone of the liver, although GSH also decreased in the periportal region. In contrast, the parent compound, APAP sulfate and APAP glucuronide did not show a zonated pattern and tissue concentrations showed a similar time course as the corresponding analyses were performed with blood from the portal and liver veins. In conclusion, the present study is in agreement with the concept that pericentral CYPs form NAPQI that in the same cell binds to and depletes GSH but a lower level of GSH adducts is also observed in the periportal region. The results also provide further evidence of the recently published concept of 'aggravated loss of clearance capacity' according to which also liver tissue that survives intoxication may transiently show decreased metabolic capacity.

Authors: Selahaddin Sezgin, Reham Hassan, Sebastian Zühlke, Lars Kuepfer, Jan Hengstler, Michael Spiteller, Ahmed Ghallab

Date Published: 23rd Jul 2018

Journal: Arch Toxicol

Adverse outcome pathways: opportunities, limitations and open questions.
Model Guided Pharmacotherapy In Chronic Liver Disease (LiSyM-MGP)

Abstract (Expand)

Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory … purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field.

Authors: M. Leist, Ahmed Ghallab, R. Graepel, R. Marchan, Reham Hassan, S. H. Bennekou, A. Limonciel, M. Vinken, S. Schildknecht, T. Waldmann, E. Danen, B. van Ravenzwaay, H. Kamp, I. Gardner, P. Godoy, F. Y. Bois, A. Braeuning, R. Reif, F. Oesch, Dirk Drasdo, Stefan Hoehme, M. Schwarz, T. Hartung, T. Braunbeck, J. Beltman, H. Vrieling, F. Sanz, A. Forsby, D. Gadaleta, C. Fisher, J. Kelm, D. Fluri, G. Ecker, B. Zdrazil, A. Terron, P. Jennings, B. van der Burg, Steven Dooley, A. H. Meijer, E. Willighagen, M. Martens, C. Evelo, E. Mombelli, O. Taboureau, A. Mantovani, B. Hardy, B. Koch, S. Escher, C. van Thriel, C. Cadenas, D. Kroese, B. van de Water, Jan Hengstler

Date Published: 19th Oct 2017

Journal: Arch Toxicol

Physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage
Model Guided Pharmacotherapy In Chronic Liver Disease (LiSyM-MGP)

Abstract

Not specified

Authors: Andrea Schenk, Ahmed Ghallab, Ute Hofmann, Reham Hassan, Michael Schwarz, Andreas Schuppert, Lars Ole Schwen, Albert Braeuning, Donato Teutonico, Jan Hengstler, Lars Kuepfer

Date Published: 1st Dec 2017

Journal: Sci Rep

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