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The Journal of Toxicological Sciences 2024This study was conducted as part of an investigation into the cause of vesnarinone-associated agranulocytosis. When HL-60 cells were exposed to vesnarinone for 48 hr,...
This study was conducted as part of an investigation into the cause of vesnarinone-associated agranulocytosis. When HL-60 cells were exposed to vesnarinone for 48 hr, little cytotoxicity was observed, although reduced glutathione (GSH) content decreased in a concentration-dependent manner. Significant cytotoxicity and reactive oxygen species (ROS) production were observed when intracellular GSH content was reduced by treatment with L-buthionine-(S, R)-sulphoximine. The involvement of myeloperoxidase (MPO) metabolism was suggested, as when HL-60 cells were exposed to a reaction mixture of vesnarinone-MPO/HO/Cl, cytotoxicity was also observed. In contrast, the presence of GSH (1 mM) protected against these cytotoxic effects. Liquid chromatography-mass spectrometry analysis of the MPO/HO/Cl reaction mixture revealed that vesnarinone was converted into two metabolites, (4-(3,4-dimethoxybenzoyl)piperazine [Metabolite 1: M1] and 1-chloro-4-(3,4-dimethoxybenzoyl)piperazine [Metabolite 2: M2]). M2 was identified as the N-chloramine form, a reactive metabolite of M1. Interestingly, M2 was converted to M1, which was accompanied by the conversion of GSH to oxidized GSH (GSSG). Furthermore, when HL-60 cells were exposed to synthetic M1 and M2 for 24 hr, M2 caused dose-dependent cytotoxicity, whereas M1 did not. Cells were protected from M2-derived cytotoxicity by the presence of GSH. In conclusion, we present the first demonstration of the cytotoxic effects and ROS production resulting from the MPO/HO/Cl metabolic reaction of vesnarinone and newly identified the causative metabolite, M2, as the N-chloramine metabolite of M1, which induces cytotoxicity in HL-60 cells. Moreover, a protective role of GSH against the cytotoxicity was revealed. These findings suggest a possible nonimmunological cause of vesnarinone agranulocytosis.
Topics: Humans; Chloramines; Glutathione; HL-60 Cells; Hydrogen Peroxide; Reactive Oxygen Species; Agranulocytosis; Antineoplastic Agents; Chlorides; Piperazines; Pyrazines; Quinolines
PubMed: 38432956
DOI: 10.2131/jts.49.95 -
Annals of Hematology Jun 2024
Topics: Humans; Biomarkers, Tumor; Leukemia, Promyelocytic, Acute; Leukocytes, Mononuclear
PubMed: 38427058
DOI: 10.1007/s00277-024-05673-4 -
Leukemia Jul 2024Differentiation therapy has proven to be a success story for patients with acute promyelocytic leukemia. However, the remaining subtypes of acute myeloid leukemia (AML)... (Review)
Review
Differentiation therapy has proven to be a success story for patients with acute promyelocytic leukemia. However, the remaining subtypes of acute myeloid leukemia (AML) are treated with cytotoxic chemotherapies that have limited efficacy and a high likelihood of resistance. As differentiation arrest is a hallmark of AML, there is increased interest in developing differentiation-inducing agents to enhance disease-free survival. Here, we provide a comprehensive review of current reports and future avenues of nucleic acid therapeutics for AML, focusing on the use of targeted nucleic acid drugs to promote differentiation. Specifically, we compare and discuss the precision of small interfering RNA, small activating RNA, antisense oligonucleotides, and aptamers to modulate gene expression patterns that drive leukemic cell differentiation. We delve into preclinical and clinical studies that demonstrate the efficacy of nucleic acid-based differentiation therapies to induce leukemic cell maturation and reduce disease burden. By directly influencing the expression of key genes involved in myeloid maturation, nucleic acid therapeutics hold the potential to induce the differentiation of leukemic cells towards a more mature and less aggressive phenotype. Furthermore, we discuss the most critical challenges associated with developing nucleic acid therapeutics for myeloid malignancies. By introducing the progress in the field and identifying future opportunities, we aim to highlight the power of nucleic acid therapeutics in reshaping the landscape of myeloid leukemia treatment.
Topics: Humans; Cell Differentiation; Leukemia, Myeloid, Acute; Nucleic Acids; Animals; Leukemia, Myeloid; RNA, Small Interfering; Oligonucleotides, Antisense
PubMed: 38424137
DOI: 10.1038/s41375-024-02191-0 -
Ecancermedicalscience 2023Chemotherapy-induced thrombocytopenia (CIT) is an arduous complication of chemotherapy to be dealt with, and there are many unmet needs in this field to be addressed on...
INTRODUCTION
Chemotherapy-induced thrombocytopenia (CIT) is an arduous complication of chemotherapy to be dealt with, and there are many unmet needs in this field to be addressed on the global front. We have conducted this study to contribute to the understanding of existing knowledge gaps of CIT management and highlight the direction to focus future investigations.
METHODS
This was an academic single-institution report on a cross-sectional study evaluating CIT management practices using platelet (PLT) transfusions by haematologists and oncologists in Armenia.
RESULTS
Physicians' opinions differed significantly when it came to defining thrombocytopenia by PLT levels. 13.2% of those surveyed considered thrombocytopenia to be when PLT counts fall below 180 × 10/L, 42.1% defined thrombocytopenia to have a PLT threshold of 150 × 10/L, 15.8% and 21.0% specialists setting their thresholds at 140 × 10/L and 100 × 10/L, respectively.All physicians managed CIT by performing PLT transfusions for prophylactic purposes (i.e., when PLT count falls below a certain threshold) with none of them transfusing PLTs only on-demand to address active bleeding. 73.3% haematologists (adult), 57.1% medical oncologists, and 50% paediatricians deemed 10 × 10/L as the threshold PLT count for transfusing afebrile patients with haematologic malignancies (besides acute promyelocytic leukaemia (APL)) and solid tumours.PLT products availability varied among the respondents, with only 53% of them responding that they had 24/7 access.
CONCLUSION
CIT is a complication of interest to physicians worldwide and has not been resolved yet. This is the first conducted survey regarding CIT and the initial step for further research.
PubMed: 38414967
DOI: 10.3332/ecancer.2023.1627 -
Atherosclerosis Apr 2024Atherosclerosis is a chronic lipid-driven inflammatory disease largely influenced by hemodynamics. Neutrophil extracellular trap (NET)-mediated inflammation plays an...
BACKGROUND AND AIMS
Atherosclerosis is a chronic lipid-driven inflammatory disease largely influenced by hemodynamics. Neutrophil extracellular trap (NET)-mediated inflammation plays an important role in atherosclerosis. However, little is known about the relationship between low shear stress (LSS) and NET generation, as well as the underlying mechanism.
METHODS
We induced LSS by partial ligation of the left carotid artery in high-fat diet-fed male ApoE mice. To further validate the direct relationship between LSS and NET formation invitro, differentiated human promyelocytic leukemia HL-60 cells and bone marrow-derived neutrophils were suspended in fluid flow under normal or low shear stress using a parallel-plate flow chamber system.
RESULTS
Four weeks after surgery, ligated carotid arteries had more lipid deposition, larger plaque area, and increased NET formation than unligated arteries. Inhibition of NETosis could significantly reduce plaque formation in ApoE mice. Invitro, LSS could promote NET generation directly through downregulation of Piezo1, a mechanosensitive ion channel. Downregulation of Piezol could activate neutrophils and promote NETosis in static conditions. Conversely, Yoda1-evoked activation of Piezo1 attenuated LSS-induced NETosis. Mechanistically, downregulation of Piezo1 resulted in decreased Ca influx and increased histone deacetylase 2 (HDAC2), which increased reactive oxygen species levels and led to NETosis. LSS-induced NET generation also promoted apoptosis and adherence of endothelial cells.
CONCLUSION
LSS directly promotes NETosis through the Piezo1-HDAC2 axis in atherosclerosis progression. This study uncovers the essential role of Piezo1-mediated mechanical signaling in NET generation and plaque formation, which provides a promising therapeutic strategy for atherosclerosis.
Topics: Animals; Humans; Male; Mice; Apolipoproteins E; Atherosclerosis; Endothelial Cells; Extracellular Traps; Ion Channels; Lipids
PubMed: 38412763
DOI: 10.1016/j.atherosclerosis.2024.117473 -
Nucleus (Austin, Tex.) Dec 2024Promyelocytic leukemia (PML) nuclear bodies, membrane-less organelles in the nucleus, play a crucial role in cellular homeostasis. These dynamic structures result from... (Review)
Review
Promyelocytic leukemia (PML) nuclear bodies, membrane-less organelles in the nucleus, play a crucial role in cellular homeostasis. These dynamic structures result from the assembly of scaffolding PML proteins and various partners. Recent crystal structure analyses revealed essential self-interacting domains, while liquid-liquid phase separation contributes to their formation. PML bodies orchestrate post-translational modifications, particularly stress-induced SUMOylation, impacting target protein functions. Serving as hubs in multiple signaling pathways, they influence cellular processes like senescence. Dysregulation of PML expression contributes to diseases, including cancer, highlighting their significance. Therapeutically, PML bodies are promising targets, exemplified by successful acute promyelocytic leukemia treatment with arsenic trioxide and retinoic acid restoring PML bodies. Understanding their functions illuminates both normal and pathological cellular physiology, guiding potential therapies. This review explores recent advancements in PML body biogenesis, biochemical activity, and their evolving biological roles.
Topics: Humans; Promyelocytic Leukemia Nuclear Bodies; Nuclear Proteins; Promyelocytic Leukemia Protein; Transcription Factors; Leukemia, Promyelocytic, Acute
PubMed: 38411156
DOI: 10.1080/19491034.2024.2321265 -
MBio Apr 2024The fate of herpesvirus genomes following entry into different cell types is thought to regulate the outcome of infection. For the Herpes simplex virus 1 (HSV-1), latent...
Single-genome analysis reveals a heterogeneous association of the herpes simplex virus genome with H3K27me2 and the reader PHF20L1 following infection of human fibroblasts.
UNLABELLED
The fate of herpesvirus genomes following entry into different cell types is thought to regulate the outcome of infection. For the Herpes simplex virus 1 (HSV-1), latent infection of neurons is characterized by association with repressive heterochromatin marked with Polycomb silencing-associated lysine 27 methylation on histone H3 (H3K27me). However, whether H3K27 methylation plays a role in repressing lytic gene expression in non-neuronal cells is unclear. To address this gap in knowledge, and with consideration that the fate of the viral genome and outcome of HSV-1 infection could be heterogeneous, we developed an assay to quantify the abundance of histone modifications within single viral genome foci of infected fibroblasts. Using this approach, combined with bulk epigenetic techniques, we were unable to detect any role for H3K27me3 during HSV-1 lytic infection of fibroblasts. By contrast, we could detect the lesser studied H3K27me2 on a subpopulation of viral genomes, which was consistent with a role for H3K27 demethylases in promoting lytic gene expression. In addition, viral genomes co-localized with the H3K27me2 reader protein PHF20L1, and this association was enhanced by inhibition of the H3K27 demethylases UTX and JMJD3. Notably, targeting of H3K27me2 to viral genomes was enhanced following infection with a transcriptionally defective virus in the absence of Promyelocytic leukemia nuclear bodies. Collectively, these studies implicate a role for H3K27me2 in fibroblast-associated HSV genome silencing in a manner dependent on genome sub-nuclear localization and transcriptional activity.
IMPORTANCE
Investigating the potential mechanisms of gene silencing for DNA viruses in different cell types is important to understand the differential outcomes of infection, particularly for viruses like herpesviruses that can undergo distinct types of infection in different cell types. In addition, investigating chromatin association with viral genomes informs on the mechanisms of epigenetic regulation of DNA processes. However, there is a growing appreciation for heterogeneity in the outcome of infection at the single cell, and even single viral genome, level. Here we describe a novel assay for quantifying viral genome foci with chromatin proteins and show that a portion of genomes are targeted for silencing by H3K27me2 and associate with the reader protein PHF20L1. This study raises important questions regarding the mechanism of H3K27me2-specific targeting to viral genomes, the contribution of epigenetic heterogeneity to herpesvirus infection, and the role of PHF20L1 in regulating the outcome of DNA virus infection.
Topics: Humans; Chromatin; Chromosomal Proteins, Non-Histone; Epigenesis, Genetic; Fibroblasts; Herpes Simplex; Herpesvirus 1, Human
PubMed: 38411116
DOI: 10.1128/mbio.03278-23 -
Materials (Basel, Switzerland) Feb 2024A series of unsymmetrical phenyl -carbonyl selenides with -amido function substituted on the nitrogen atom with chiral alkyl groups was obtained. The compounds form a...
A series of unsymmetrical phenyl -carbonyl selenides with -amido function substituted on the nitrogen atom with chiral alkyl groups was obtained. The compounds form a series of enantiomeric and diastereomeric pairs and present the first examples of this type of chiral Se derivatives. All obtained selenides were further evaluated as antioxidants and anticancer agents to define the influence of the particular stereochemistry of the attached functional groups on the bioactivity of the molecules. The highest HO reduction potential was observed for -(-2-hydroxy-1-indanyl)-2-((2-oxopropyl)selanyl)benzamide, and the best radical scavenging properties for -(-1-hydroxy-2-butanyl)-2-((2-oxopropyl)selanyl)benzamide. Also, both enantiomers of the -(1-hydroxy-2-butanyl) selenide expressed the highest cytotoxic potential towards human promyelocytic leukemia HL-60 cell line with similar IC values 14.4 ± 0.5 and 16.2 ± 1.1 µM, respectively. On the other hand, breast cancer cell line MCF-7 was most sensitive to -(()-(-)-1-hydroxy-2-butanyl)- 2-((2-oxopropyl)selanyl)benzamide (IC50 of 35.7 ± 0.6 µM). The structure-activity dependence of the obtained Se derivatives was discussed, and the most potent compounds were selected.
PubMed: 38399148
DOI: 10.3390/ma17040899 -
Journal of Clinical Medicine Feb 2024Triterpenoids, such as ganoderic acid, and polysaccharides, including β-D-glucans, α-D-glucans, and α-D-mannans, are the main secondary metabolites of the medicinal... (Review)
Review
Triterpenoids, such as ganoderic acid, and polysaccharides, including β-D-glucans, α-D-glucans, and α-D-mannans, are the main secondary metabolites of the medicinal fungus . There is evidence of the effects of ganoderic acid in hematological malignancies, whose mechanisms involve the stimulation of immune response, the macrophage-like differentiation, the activation of MAP-K pathway, an IL3-dependent cytotoxic action, the induction of cytoprotective autophagy, and the induction of apoptosis. In fact, this compound has been tested in twenty-six different human cancer cell types and has shown an anti-proliferative activity, especially in leukemia, lymphoma, and myeloma lines. Moreover, research clarified the capability of molecules from to induce mitochondrial damage in acute promyelocytic leukemia cells, without cytotoxic effects in normal mononuclear cells. Active lipids extracted from the spores of this fungus have also been shown to induce apoptosis mediated by downregulation of P-Akt and upregulation of caspases-3, -8, and -9. Among in vivo studies, a study in BALB/c mice injected with WEHI-3 leukemic cells suggested that treatment with promotes differentiation of T- and B-cell precursors, phagocytosis by PBMCs, and NK cell activity. Our review presents data revealing the possibility of employing in hematological malignancies and incorporating it into clinical practice.
PubMed: 38398467
DOI: 10.3390/jcm13041153 -
International Journal of Molecular... Feb 2024Acute myeloid leukemia (AML) is an aggressive malignancy characterized by rapid growth and uncontrolled proliferation of undifferentiated myeloid cells. Metabolic...
Enhanced Expression of Glycolytic Enzymes and Succinate Dehydrogenase Complex Flavoprotein Subunit A by Mesothelin Promotes Glycolysis and Mitochondrial Respiration in Myeloblasts of Acute Myeloid Leukemia.
Acute myeloid leukemia (AML) is an aggressive malignancy characterized by rapid growth and uncontrolled proliferation of undifferentiated myeloid cells. Metabolic reprogramming is commonly observed in the bone marrow of AML patients, as leukemia cells require increased ATP supply to support disease progression. In this study, we examined the potential role of mesothelin as a metabolic modulator in myeloid cells in AML. Mesothelin is a well-known marker of solid tumors that promotes cancer cell proliferation and survival. We initially analyzed alterations in mesothelin expression in the myeloblast subpopulations, defined as SSC-Alow/CD45dim, obtained from the bone marrow of AML patients using flow cytometry. Our results showed overexpression of mesothelin in 34.8% of AML patients. Subsequently, metabolic changes in leukemia cells were evaluated by comparing the oxygen consumption rates (OCR) of bone marrow samples derived from adult AML patients. Notably, a higher OCR was observed in the mesothelin-positive compared to the mesothelin-low and non-expressing groups. Treatment with recombinant human mesothelin protein enhanced OCR and increased the mRNA expression of glycolytic enzymes and mitochondrial complex II in KG1α AML cells. Notably, siRNA targeting mesothelin in KG1α cells led to the reduction of glycolysis-related gene expression but had no effect on the mitochondrial complex gene. The collective results demonstrate that mesothelin induces metabolic changes in leukemia cells, facilitating the acquisition of a rapid supply of ATP for proliferation in AML. Therefore, the targeting of mesothelin presents a potentially promising approach to mitigating the progression of AML through the inhibition of glycolysis and mitochondrial respiration in myeloid cells.
Topics: Adult; Humans; Mesothelin; Granulocyte Precursor Cells; Succinate Dehydrogenase; Cell Line, Tumor; Leukemia, Myeloid, Acute; Cell Proliferation; Respiration; Glycolysis; Adenosine Triphosphate
PubMed: 38396817
DOI: 10.3390/ijms25042140