Author: Faizan Bhat, Mohammad ; Bhat, Mohammad Faizan ; Dekker, Frank J ; Kristín Einarsdóttir, Helga ; Sundberg, Lotta-Riina ; Marjomäki, Varpu ; Einarsdóttir, Helga Kristín ; Dekker, Frank J. ; Srdanović, Sonja

Innate immunity plays an important role in host defense against pathogenic infections. It involves macrophage polarization into either the pro-inflammatory M1 or the anti-inflammatory M2 phenotype, influencing immune stimulation or suppression, respectively. Epigenetic changes during immune reactions contribute to long-term innate immunity imprinting on macrophage polarization. It is becoming increasingly evident that epigenetic modulators, such as histone deacetylase (HDAC) inhibitors (HDACi), enable the enhancement of innate immunity by tailoring macrophage polarization in response to immune stressors. In this review, we summarize current literature on the impact of HDACi and other epigenetic modulators on the functioning of macrophages during diseases that have a strong immune component, such as infections. Depending on the disease context and the chosen therapeutic intervention, HDAC1, HDAC2, HDAC3, HDAC6, or HDAC8 are particularly important in influencing macrophage polarization towards either M1 or M2 phenotypes. We anticipate that therapeutic strategies based on HDAC epigenetic mechanisms will provide a unique approach to boost immunity against disease challenges, including resistant infections.

01 Jun 2024·Translational Oncology

New insights into possible HDAC inhibitor resistance in DLBCL - Comment on 'defining cellular responses to HDAC-selective inhibitors reveals that efficient targeting of HDAC3 is required to elicit cytotoxicity and overcome naïve resistance to pan-HDACi in diffuse large B cell lymphoma' by Havas et al.

Article

Author: Neureiter, Daniel ; Bekric, Dino ; Kiesslich, Tobias ; Mayr, Christian

A review.Over the past decades, the role of epigenetics and the related processes of histone acetylation (HAT) and histone deacetylation (HDAC) in human solid tumors and haematol. malignancies has been extensively studied in vitro and in vivo in order to identify new therapeutic options.Nevertheless, new approaches are being pursued to increase the therapeutic efficacy of such HDAC inhibitors alone or in combination with standard treatment regimens in various.Human malignancies.The lymphoma type of DLBCL is one of the most common forms of non-Hodgkin's lymphoma, representing an aggressive disease with an urgent need for therapy.The characteristics of these cases diagnosed with DLBCL are highly heterogeneous in terms of morphol., immunohistochem. and mol. phenotype, genetic features and their biol. pathways, which are associated with different prognosis as well as outcome due to the possibility of treatment failure to the standard chemotherapy protocol with R-CHOP immunochemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone).In particular, the HDAC6 and HDAC9-Bcl6 complex is often aberrant in DLBC, providing evidence for a pathogenic role in DLBCL.The HDAC inhibitors Vorinostat (SAHA), Belinostat (PXD101), Mocetinostat used in clin. trials as monotherapy for the DLBCL achieve only sobering overall response rate (ORR) up to 5.6% for Vorinostat, 10.5% for ORR for Belinostat and 18.9% for Mocetinostat.

01 Mar 2024·Science of The Total Environment

Neurotoxic effects induced by flunitrazepam and its metabolites in zebrafish: Oxidative stress, apoptosis, and histone hypoacetylation

Article

Author: Huang, Rui ; Lin, Wenting ; Qin, Yingjun ; Ren, Yuan ; Huang, Yajing ; Han, Xing ; Li, Kan

Benzodiazepines (BZDs) have been widely detected in aquatic environments, but their neurotoxic effects and potential mechanisms are still unclear. This study focuses on flunitrazepam (FLZ) and its metabolite, 7-aminoflunitrazepam (7-FLZ), as representative psychotropic BZD. We investigated their neurotoxic effects on adult zebrafish following a 30-day exposure to environmentally relevant concentrations. The findings reveal that exposure to these drugs induces anxiety-like and aggressive behaviors in zebrafish. Additionally, notable morphological damage to brain tissue and mitochondrial structures was observed. Through TUNEL staining, an increase in apoptotic cells was detected in the brain tissue of the exposed group, accompanied by marked elevations in ROS and caspase-3/9 levels. The upregulation of apoptosis-related genes Bax, p53, and Bcl-2 confirmed the occurrence of apoptosis. Furthermore, exposure to the drugs resulted in decreased acetylation levels of brain histones H3 and H4. The upregulation of histone deacetylation enzyme genes (HDAC1, HDAC3, HDAC4, and HDAC6) supported this result. Molecular docking results suggest that compared to 7-FLZ, FLZ has a higher binding affinity with HDAC3 and HDAC4, explaining why it causes lower histone acetylation levels. This study in zebrafish elucidates the neurotoxicity and molecular mechanisms induced by FLZ and 7-FLZ, which is significant for further understanding the impact of BZDs on human health and assessing their ecological risks.

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