-
Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Dec 2023
Topics: Humans; Leukemia, Promyelocytic, Acute; Tretinoin
PubMed: 38503533
DOI: 10.3760/cma.j.issn.0253-2727.2023.12.016 -
Frontiers in Pharmacology 2024The toxicity of arsenic is widely recognized globally, mainly harming human health by polluting water, soil, and food. However, its formulations can also be used for... (Review)
Review
The toxicity of arsenic is widely recognized globally, mainly harming human health by polluting water, soil, and food. However, its formulations can also be used for the clinical treatment of diseases such as leukemia and tumors. Arsenic has been used as a drug in China for over 2,400 years, with examples such as the arsenic-containing drug realgar mentioned in Shennong's Herbal Classic. We have reviewed references on arsenic over the past thirty years and found that research has mainly focused on clinical, pharmacological, and toxicological aspects. The finding showed that in clinical practice, arsenic trioxide is mainly used in combination with all-trans retinoic acid (ATRA) at a dose of 10 mg/d for the treatment of acute promyelocytic leukemia (APL); realgar can be used to treat acute promyelocytic leukemia, myelodysplastic syndrome, and lymphoma. In terms of pharmacology, arsenic mainly exerts anti-tumor effects. The dosage range of the action is 0.01-80 μmol/L, and the concentration of arsenic in most studies does not exceed 20 μmol/L. The pharmacological effects of realgar include antiviral activity, inhibition of overactivated lactate dehydrogenase, and resistance to malaria parasites. In terms of toxicity, arsenic is toxic to multiple systems in a dose-dependent manner. For example, 5 μmol/L sodium arsenite can induce liver oxidative damage and promote the expression of pro-inflammatory factors, and 15 μmol/L sodium arsenite induces myocardial injury; when the concentration is higher, it is more likely to cause toxic damage.
PubMed: 38495096
DOI: 10.3389/fphar.2024.1338725 -
Biochemistry and Cell Biology =... Jun 2024Neutrophil myeloperoxidase/HO/chloride system is a key mechanism to control pathogen infection. This enzyme, myeloperoxidase, plays a pivotal role in the arsenal of...
Neutrophil myeloperoxidase/HO/chloride system is a key mechanism to control pathogen infection. This enzyme, myeloperoxidase, plays a pivotal role in the arsenal of azurophilic granules that are released through degranulation upon neutrophil activation, which trigger local hypochlorous acid production. Myeloperoxidase gene encodes a protein precursor named promyeloperoxidase that arbors a propeptide that gets cleaved later during secretory routing in post-endoplasmic reticulum compartments. Although evidence suggested that this processing event was performed by one or different enzymes from the proprotein convertases family, the identity of this enzyme was never investigated. In this work, the naturally producing myeloperoxidase promyelocytic cell line HL-60 was used to investigate promyeloperoxidase cleavage during granulocytic differentiation in response to proprotein convertase inhibitors decanoyl-RVKR-chloromethylketone and hexa-d-arginine. Stable PC knockdown of endogenously expressed proprotein convertases, furin and PC7, was achieved using lentiviral delivery of shRNAs. None of the knockdown cell line could reproduce the effect of the pan-proprotein convertases inhibitor decanoyl-RVKR-chloromethylketone that accumulated intracellular promyeloperoxidase stores in HL-60 cells, therefore illustrating that both furin and PC7 redundantly process this proprotein.
Topics: Humans; HL-60 Cells; Furin; Peroxidase; Granulocytes; Cell Differentiation; Subtilisins; Enzyme Precursors; Amino Acid Chloromethyl Ketones
PubMed: 38484367
DOI: 10.1139/bcb-2023-0339 -
Cureus Feb 2024Alcoholic hepatitis (AH) is a clinicopathologic illness caused by excessive alcohol abuse and is a precursor of cirrhosis. The leukemoid reaction (LR) is characterized...
Alcoholic hepatitis (AH) is a clinicopathologic illness caused by excessive alcohol abuse and is a precursor of cirrhosis. The leukemoid reaction (LR) is characterized by a strikingly raised granulocyte count of 40,000-50,000 cells/mm. The LR usually suggests an acute inflammatory reaction. It is usually mistaken for chronic myeloid leukemia. The initial phase of leukocytosis occurs due to the releasing of cells from the bone marrow with more immature cells, causing a left upper shift in the ratio of immature to mature neutrophils and macrophages. The LR is usually seen in cases of leukemia but is rare to present in alcohol hepatitis. Excessive alcohol use causes AH in persons with or without underlying chronic liver disease. In severe AH, leukemoid responses have been associated with very poor prognosis and short-term mortality. We describe a case of a 35-year-old male with severe AH with an LR.
PubMed: 38481914
DOI: 10.7759/cureus.54039 -
Experimental and Therapeutic Medicine Apr 2024Toll-like receptor 2 (TLR2) is an important sensor for innate immune cells, including neutrophils, for the recognition of pathogen infection. Lipoteichoic acid (LTA), a...
Toll-like receptor 2 (TLR2) is an important sensor for innate immune cells, including neutrophils, for the recognition of pathogen infection. Lipoteichoic acid (LTA), a cell wall component of gram-positive bacteria, is a TLR2 ligand. LTA-induced TLR2 signaling pathways are well established in neutrophils. However, experimental studies regarding transcriptional regulation and the molecular mechanisms in primary human neutrophils are limited due to their short lifespan. The promyelocytic leukemia cell line, HL-60, can differentiate into a neutrophil-like phenotype following treatment with dimethyl sulfoxide. The aim of the present study was to investigate whether differentiated HL-60 (dHL-60) cells induced a similar gene expression profile upon LTA treatment as that previously determined for primary human neutrophils. After 4 or 24 h of LTA treatment, undifferentiated HL-60 (uHL-60) and dHL-60 cells were collected for RNA sequencing. The results demonstrated that hundreds of identical differentially expressed genes (DEGs) were observed in 1 and 10 µg/ml LTA-treated dHL-60 cells following 4 and 24 h of incubation, while almost no DEGs between LTA-treated HL-60 and dHL-60 cells were observed. Using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses (KEGG), it was noted that the pathways of shared DEGs between the 1 and 10 µg/ml LTA-treated dHL-60 cells at both time points were significantly enriched in immune and inflammatory response-related pathways, such as cellular response to tumor necrosis factor, interleukin-1, interferon γ, neutrophil chemotaxis, the NF-κB signaling pathway and the Toll-like receptor signaling pathway. In addition, when comparing the effect of 1 and 10 µg/ml LTA treatment on dHL60 cells, it was found that all enriched GO and KEGG pathways were associated with the TLR signaling pathways of neutrophils. The results of the present study provided important information for the implementation of mRNA profiling in LTA-treated dHL-60 cells and may indicate the feasibility of using dHL-60 cells as a research model for TLR2 signaling in human neutrophils.
PubMed: 38476893
DOI: 10.3892/etm.2024.12446 -
Cell Death Discovery Mar 2024Ubiquitin-specific peptidase 22 (USP22) is a deubiquitinating enzyme (DUB) that underlies tumorigenicity, proliferation, cell death and differentiation through...
Ubiquitin-specific peptidase 22 (USP22) is a deubiquitinating enzyme (DUB) that underlies tumorigenicity, proliferation, cell death and differentiation through deubiquitination of histone and non-histone targets. Ubiquitination determines stability, localization and functions of cell fate proteins and controls cell-protective signaling pathways to surveil cell cycle progression. In a variety of carcinomas, lymphomas and leukemias, ubiquitination regulates the tumor-suppressive functions of the promyelocytic leukemia protein (PML), but PML-specific DUBs, DUB-controlled PML ubiquitin sites and the functional consequences of PML (de)ubiquitination remain unclear. Here, we identify USP22 as regulator of PML and the oncogenic acute promyelocytic leukemia (APL) fusion PML-RARα protein stability and identify a destabilizing role of PML residue K394. Additionally, loss of USP22 upregulates interferon (IFN) and IFN-stimulated gene (ISG) expression in APL and induces PML-RARα stabilization and a potentiation of the cell-autonomous sensitivity towards all-trans retinoic acid (ATRA)-mediated differentiation. Our findings imply USP22-dependent surveillance of PML-RARα stability and IFN signaling as important regulator of APL pathogenesis, with implications for viral mimicry, differentiation and cell fate regulation in other leukemia subtypes.
PubMed: 38467608
DOI: 10.1038/s41420-024-01894-8 -
Hamostaseologie Mar 2024Despite enormous improvement in the management of patients with acute promyelocytic leukemia (APL), the distinctive coagulopathy observed at presentation in affected...
Despite enormous improvement in the management of patients with acute promyelocytic leukemia (APL), the distinctive coagulopathy observed at presentation in affected patients is often life-threatening. While hemorrhagic manifestations are well known and described in this setting, APL-related thromboses are underappreciated. Data regarding this complication are scarce showing variable incidence. Furthermore, risk factors for thrombosis are inconsistent and unreliable; so, differentiation of increased risk of hemorrhage from an increased thrombotic risk is quite difficult in the absence of adequate predictive scores. Besides, prophylactic use of anticoagulants and recombinant thrombomodulin are a matter of ongoing debate. Also, due to the common feature of thrombocytopenia and other hemorrhagic risks, patients with APL are excluded from trials analyzing anticoagulant prophylaxis in cancers; so, data from prospective trials are lacking. A detailed analysis of thrombotic risks in APL with the development of a reliable risk stratification model is needed to further improve the care of APL patients.
PubMed: 38467145
DOI: 10.1055/a-2238-4782 -
Frontiers in Oncology 2024Acute promyelocytic leukemia (APL) with fusion gene is a distinct variant of acute myeloid leukemia. According to the different break sites of the gene, there are...
BACKGROUND
Acute promyelocytic leukemia (APL) with fusion gene is a distinct variant of acute myeloid leukemia. According to the different break sites of the gene, there are three transcripts: Long (bcr1), Variant (bcr2) and Short (bcr3).
METHODS
We retrospectively analyzed 82 APL cases with short isoform.
RESULTS
A total of 384 patients with APL were seen, of which 85(22.14%) had short isoform (bcr3) and 82 met the inclusion criteria. The median age was 33.5 years (range, 2-72 years). The incidences of hemorrhage in the intermediate- and high-risk group were higher, but only the incidence between medium and low risk differed statistically (, and the incidences of fever, fatigue, splenomegaly, and lymph node enlargement and differentiation syndrome (DS in those groups were not statistically significant (>0.05). gene mutation rate and the mortality rate of the high-risk group were significantly higher than that of other groups (=0.040 and =0.004, 0.041 and =0.037, respectively). The mortality rate was lowest (4.26%) in the group treated with ATRA combined with arsenic and anthracycline. The 3-year OS and the 3-year DFS of the low and intermediate-risk group were better (=0.019 and =0.017, respectively).
CONCLUSIONS
ATRA combined with arsenic and anthracycline had significant impact on outcomes in APL with short isoform.
PubMed: 38450185
DOI: 10.3389/fonc.2024.1342671 -
Neuron May 2024Glucocorticoids are important for proper organ maturation, and their levels are tightly regulated during development. Here, we use human cerebral organoids and mice to...
Glucocorticoids are important for proper organ maturation, and their levels are tightly regulated during development. Here, we use human cerebral organoids and mice to study the cell-type-specific effects of glucocorticoids on neurogenesis. We show that glucocorticoids increase a specific type of basal progenitors (co-expressing PAX6 and EOMES) that has been shown to contribute to cortical expansion in gyrified species. This effect is mediated via the transcription factor ZBTB16 and leads to increased production of neurons. A phenome-wide Mendelian randomization analysis of an enhancer variant that moderates glucocorticoid-induced ZBTB16 levels reveals causal relationships with higher educational attainment and altered brain structure. The relationship with postnatal cognition is also supported by data from a prospective pregnancy cohort study. This work provides a cellular and molecular pathway for the effects of glucocorticoids on human neurogenesis that relates to lasting postnatal phenotypes.
Topics: Neurogenesis; Humans; Animals; Mice; Glucocorticoids; Cerebral Cortex; Female; Promyelocytic Leukemia Zinc Finger Protein; Pregnancy; Neurons; Organoids; Gene Expression Regulation, Developmental; Neural Stem Cells; Male
PubMed: 38442714
DOI: 10.1016/j.neuron.2024.02.005 -
Heliyon Mar 2024is a recently reported fusion gene associated with acute promyelocytic leukemia (APL), caused by the integration of torque teno mini virus (TTMV) genomic fragments into...
is a recently reported fusion gene associated with acute promyelocytic leukemia (APL), caused by the integration of torque teno mini virus (TTMV) genomic fragments into the second intron of the gene. Currently, there have been only six documented cases, with clinical presentations showing significant variability. Although initial responses to all-trans retinoic acid (ATRA) treatment may be observed in patients with ::-APL, the overall prognosis remains unfavorable among infrequent reported cases. This article presents a pediatric case that manifested as ::-negative APL with central nervous system involvement at onset. The patient experienced both intramedullary and extramedullary relapse one year after undergoing allogeneic hematopoietic stem cell transplantation. Upon identification as ::-APL and subsequent administration of two rounds of ATRA-based treatment, the patient rapidly developed multiple ligand-binding domain mutations and demonstrated extensive resistance to ATRA and various other therapeutic interventions. Additionally, the patient experienced mutant clone expansion and progressed MYC-targeted gene activation. This case represents the first documentation of extramedullary involvement at both the initial diagnosis and relapse stages, emphasizing the intricate clinical features and challenges associated with the rapid accumulation of multiple ATRA-resistant mutations in ::-APL, characterizing it as a distinct and complex sub-entity of atypical APL.
PubMed: 38434265
DOI: 10.1016/j.heliyon.2024.e27107