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Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To analyze the DTA (, , ) mutations in patients with myeloproliferative neoplasms (MPN), and preliminarily explore their correlation with thromboembolism.
OBJECTIVE
To analyze the DTA (, , ) mutations in patients with myeloproliferative neoplasms (MPN), and preliminarily explore their correlation with thromboembolism.
METHODS
Clinical characteristics of 62 patients diagnosed de novo MPN at Central Hospital Affiliated to Shandong First Medical University from September 2016 to September 2022 were retrospectively analyzed. Next-generation sequencing was used to detect 35 MPN-related genes, and the DTA mutations in MPN patients and their relationship with thromboembolic events were analyzed.
RESULTS
75.8% (47/62) of the patients presented pathogenic non-driver mutations, and the mean number of pathogenic non-driver mutations per patient was 1.08. Among them, the most frequently mutated non-driver genes were (38.7%, 24/62), (9.7%, 6/62) and (6.5%, 4/62). The presence of DTA gene mutations was 50% (31/62) in the total MPN patients, and mainly accompanied by driver mutations. The mutation rate of DTA in patients aged ≥60 years was significantly higher than that in patients <60 years old ( =0.039). The incidence of thromboembolism in patients with DTA mutation was 58.1% (18/31), which was significantly higher than that in patients without DTA mutation (19.4%, 6/31) ( =0.002). The gene mutation rate in MPN patients with thromboembolism was 66.7% (16/24), which was significantly higher than that in patients without thromboembolism (21.1%, 8/38) ( =0.00).
CONCLUSION
Patients with MPN have a higher incidence of DTA mutations, which are mainly accompanied by driver gene mutations. The incidence of thromboembolism in MPN patients with DTA mutations is higher than that in patients without DTA mutations. Especially, the elderly (≥60 years) essential thrombocythemia(ET) and polycythemia vera(PV) patients with mutation should be vigilant for thromboembolic events.
Topics: Humans; Mutation; Dioxygenases; Middle Aged; Myeloproliferative Disorders; Thromboembolism; Retrospective Studies; Proto-Oncogene Proteins; DNA-Binding Proteins; Repressor Proteins; DNA Methyltransferase 3A; DNA (Cytosine-5-)-Methyltransferases; Male; Female; High-Throughput Nucleotide Sequencing
PubMed: 38926973
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.025 -
Cell Death & Disease Jun 2024Advances in functional studies on epigenetic regulators have disclosed the vital roles played by diverse histone lysine demethylases (KDMs), ranging from normal... (Review)
Review
Advances in functional studies on epigenetic regulators have disclosed the vital roles played by diverse histone lysine demethylases (KDMs), ranging from normal development to tumorigenesis. Most of the KDMs are Jumonji C domain-containing (JMJD) proteins. Many of these KDMs remove methyl groups from histone tails to regulate gene transcription. There are more than 30 known KDM proteins, which fall into different subfamilies. Of the many KDM subfamilies, KDM3 (JMJD1) proteins specifically remove dimethyl and monomethyl marks from lysine 9 on histone H3 and other non-histone proteins. Dysregulation of KDM3 proteins leads to infertility, obesity, metabolic syndromes, heart diseases, and cancers. Among the KDM3 proteins, KDM3A has been largely studied in cancers. However, despite a number of studies pointing out their importance in tumorigenesis, KDM3B and KDM3C are relatively overlooked. KDM3B and KDM3C show context-dependent functions, showing pro- or anti-tumorigenic abilities in different cancers. Thus, this review provides a thorough understanding of the involvement of KDM3B and KDMC in oncology that should be helpful in determining the role of KDM3 proteins in preclinical studies for development of novel pharmacological methods to overcome cancer.
Topics: Humans; Jumonji Domain-Containing Histone Demethylases; Epigenesis, Genetic; Carcinogenesis; Animals; Neoplasms
PubMed: 38926399
DOI: 10.1038/s41419-024-06850-z -
Discovery Medicine Jun 2024Genetic mutations play a crucial role in the development and progression of myelodysplastic syndromes (MDS), impacting the immune microenvironment and influencing the...
BACKGROUND
Genetic mutations play a crucial role in the development and progression of myelodysplastic syndromes (MDS), impacting the immune microenvironment and influencing the choice of treatment regimen, as well as the efficacy and prognosis of patients. The objective of this study was to examine variations in hematological and immunological characteristics associated with common gene mutations in MDS patients and establish a foundation for the precise treatment of MDS.
METHODS
The hematological, immunological, and other clinical features of 71 recently diagnosed MDS patients from January 1, 2019, to July 31, 2023, were retrospectively analyzed. These patients were categorized based on their gene mutations, and the variances in hematological and immunological characteristics among distinct groups were compared.
RESULTS
Hematological variances were observed among different gene mutation groups. Specifically, platelet counts in the splicing factor 3B subunit 1 () mutation group were notably higher compared to the wild-type group ( = 0.009). Conversely, in the additional sex combs like 1 () mutation groups, monocyte ratios were significantly elevated in comparison to the wild-type group ( = 0.046), and in the ten-eleven translocation 2 () mutation group, lymphocyte ratios were significantly lower ( = 0.022). Additionally, the leukocyte ( = 0.005), neutrophil ratio ( = 0.002), and lymphocyte ratio ( = 0.001) were significantly higher in the Runt-related transcription factor 1 () mutation group. Regarding immunological distinctions, the Natural Killer (NK) cell ratio demonstrated a significant increase in the mutation group ( = 0.005). Moreover, the mutation group exhibited a significantly higher Interleukin-8 (IL-8) level ( = 0.017). In contrast, the U2 small nuclear RNA auxiliary factor 1 () group displayed significantly lower levels of IL-1β ( = 0.033), IL-10 ( = 0.033), and Tumour Necrosis Factor-α (TNF-α) ( = 0.009).
CONCLUSION
Distinct variations exist in the immune microenvironment of MDS associated with different genetic mutations. Further studies are imperative to delve into the underlying mechanisms that drive these differences.
Topics: Humans; Myelodysplastic Syndromes; Mutation; Female; Male; Middle Aged; Aged; RNA Splicing Factors; Retrospective Studies; Adult; Dioxygenases; Aged, 80 and over; DNA-Binding Proteins; Phosphoproteins; Killer Cells, Natural; Core Binding Factor Alpha 2 Subunit; Platelet Count; Repressor Proteins
PubMed: 38926115
DOI: 10.24976/Discov.Med.202436185.119 -
Trends in Biochemical Sciences Jun 2024Jumonji C domain-containing (JMJD) proteins are found in bacteria, fungi, animals, and plants. They belong to the 2-oxoglutarate-dependent oxygenase superfamily and are... (Review)
Review
Jumonji C domain-containing (JMJD) proteins are found in bacteria, fungi, animals, and plants. They belong to the 2-oxoglutarate-dependent oxygenase superfamily and are endowed with various enzymatic activities, including demethylation of histones and hydroxylation of non-histone proteins. Many JMJD proteins are involved in the epigenetic control of gene expression, yet they also modulate a myriad other cellular processes. In this review we focus on the 33 human JMJD proteins and their established and controversial catalytic properties, survey their epigenetic and non-epigenetic functions, emphasize their contribution to sex-specific disease differences, and highlight how they sense metabolic changes. All this underlines not only their key roles in development and homeostasis, but also that JMJD proteins are destined to become drug targets in multiple diseases.
PubMed: 38926050
DOI: 10.1016/j.tibs.2024.06.009 -
Biological & Pharmaceutical Bulletin 2024Unknown interactions between drugs remain the limiting factor for clinical application of drugs, and the induction and inhibition of drug-metabolizing CYP enzymes are...
Unknown interactions between drugs remain the limiting factor for clinical application of drugs, and the induction and inhibition of drug-metabolizing CYP enzymes are considered the key to examining the drug-drug interaction (DDI). In this study, using human HepaRG cells as an in vitro model system, we analyzed the potential DDI based on the expression levels of CYP3A4 and CYP1A2. Rifampicin and omeprazole, the potent inducers for CYP3A4 and CYP1A2, respectively, induce expression of the corresponding CYP enzymes at both the mRNA and protein levels. We noticed that, in addition to inducing CYP1A2, omeprazole induced CYP3A4 mRNA expression in HepaRG cells. However, unexpectedly, CYP3A4 protein expression levels were not increased after omeprazole treatment. Concurrent administration of rifampicin and omeprazole showed an inhibitory effect of omeprazole on the CYP3A4 protein expression induced by rifampicin, while its mRNA induction remained intact. Cycloheximide chase assay revealed increased CYP3A4 protein degradation in the cells exposed to omeprazole. The data presented here suggest the potential importance of broadening the current DDI examination beyond conventional transcriptional induction and enzyme-activity inhibition tests to include post-translational regulation analysis of CYP enzyme expression.
Topics: Omeprazole; Humans; Cytochrome P-450 CYP3A; Rifampin; RNA, Messenger; Drug Interactions; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP1A2; Cell Line
PubMed: 38925922
DOI: 10.1248/bpb.b24-00161 -
Microbial Biotechnology Jun 2024Pharmaceuticals are of increasing environmental concern as they emerge and accumulate in surface- and groundwater systems around the world, endangering the overall... (Review)
Review
Pharmaceuticals are of increasing environmental concern as they emerge and accumulate in surface- and groundwater systems around the world, endangering the overall health of aquatic ecosystems. Municipal wastewater discharge is a significant vector for pharmaceuticals and their metabolites to enter surface waters as humans incompletely absorb prescription drugs and excrete up to 50% into wastewater, which are subsequently incompletely removed during wastewater treatment. Microalgae present a promising target for improving wastewater treatment due to their ability to remove some pollutants efficiently. However, their inherent metabolic pathways limit their capacity to degrade more recalcitrant organic compounds such as pharmaceuticals. The human liver employs enzymes to break down and absorb drugs, and these enzymes are extensively researched during drug development, meaning the cytochrome P450 enzymes responsible for metabolizing each approved drug are well studied. Thus, unlocking or increasing cytochrome P450 expression in endogenous wastewater microalgae could be a cost-effective strategy to reduce pharmaceutical loads in effluents. Here, we discuss the challenges and opportunities associated with introducing cytochrome P450 enzymes into microalgae. We anticipate that cytochrome P450-engineered microalgae can serve as a new drug removal method and a sustainable solution that can upgrade wastewater treatment facilities to function as "mega livers".
Topics: Microalgae; Cytochrome P-450 Enzyme System; Wastewater; Pharmaceutical Preparations; Water Purification; Water Pollutants, Chemical; Humans; Biodegradation, Environmental
PubMed: 38925623
DOI: 10.1111/1751-7915.14515 -
PloS One 2024Despite Antiplatelet therapy (APT), cardiovascular patients undergoing revascularisation remain at high risk for thrombotic events. Individual response to APT varies... (Observational Study)
Observational Study
BACKGROUND
Despite Antiplatelet therapy (APT), cardiovascular patients undergoing revascularisation remain at high risk for thrombotic events. Individual response to APT varies substantially, resulting in insufficient protection from thrombotic events due to high on-treatment platelet reactivity (HTPR) in ≤40% of patients. Individual variation in platelet response impairs APT guidance on a single patient level. Unfortunately, little is known about individual platelet response to APT over time, timing for accurate residual platelet reactivity measurement, or the optimal test to monitor residual platelet reactivity.
AIMS
To investigate residual platelet reactivity variability over time in individual patients undergoing carotid endarterectomy (CEA) treated with clopidogrel.
METHODS
Platelet reactivity was determined in patients undergoing CEA in a prospective, single-centre, observational study using the VerifyNow (change in turbidity from ADP-induced binding to fibrinogen-coated beads), the VASP assay (quantification of phosphorylation of vasodilator-stimulated phosphoprotein), and a flow-cytometry-based assay (PACT) at four perioperative time points. Genotyping identified slow (CYP2C19*2 and CYP2C19*3) and fast (CYP2C19*17) metabolisers.
RESULTS
Between December 2017 and November 2019, 50 patients undergoing CEA were included. Platelet reactivity measured with the VerifyNow (p = < .001) and VASP (p = .029) changed over time, while the PACT did not. The VerifyNow identified patients changing HTRP status after surgery. The VASP identified patients changing HTPR status after eight weeks (p = .018). CYP2C19 genotyping identified 13 slow metabolisers.
CONCLUSION
In patients undergoing CEA, perioperative platelet reactivity measurements fluctuate over time with little agreement between platelet reactivity assays. Consequently, HTPR status of individual patients measured with the VerifyNow and VASP assay changed over time. Therefore, generally used perioperative platelet reactivity measurements seem unreliable for adjusting perioperative APT strategy.
Topics: Humans; Male; Female; Aged; Pilot Projects; Blood Platelets; Prospective Studies; Endarterectomy, Carotid; Platelet Aggregation Inhibitors; Clopidogrel; Platelet Function Tests; Middle Aged; Perioperative Period; Cytochrome P-450 CYP2C19; Vascular Surgical Procedures; Platelet Activation; Aged, 80 and over; Cell Adhesion Molecules; Microfilament Proteins
PubMed: 38924073
DOI: 10.1371/journal.pone.0304800 -
Chemical Biology & Drug Design Jun 2024The environmental factor aryl hydrocarbon receptor (AhR), a key protein connecting the external environmental signals (e.g., environmental endocrine disruptor TCDD) to...
The environmental factor aryl hydrocarbon receptor (AhR), a key protein connecting the external environmental signals (e.g., environmental endocrine disruptor TCDD) to internal cellular processes, is involved in the activation of peripheral macrophages and inflammatory response in human body. Thus, there is widespread interest in finding compounds to anti-inflammatory response in macrophages by targeting human AhR. Here, ensemble docking based-virtual screening was first used to screen a library (~200,000 compounds) against human AhR ligand binding domain (LBD) and 25 compounds were identified as potential inhibitors. Then, 9 out of the 25 ligands were found to down-regulate the mRNA expression of CYP1A1 (a downstream gene of AhR signaling) in AhR overexpressing macrophages. The most potent compound AE-411/41415610 was selected for further study and found to reduce both mRNA and protein expressions level of CYP1A1 in mouse peritoneal macrophage. Moreover, protein chip signal pathway analysis indicated that AE-411/41415610 play a role in regulating JAK-STAT and AKT-mTOR pathways. In sum, the discovered hits with novel scaffolds provided a starting point for future design of more effective AhR-targeted lead compounds to regulate CYP1A1 expression of inflammatory peritoneal macrophages.
Topics: Receptors, Aryl Hydrocarbon; Cytochrome P-450 CYP1A1; Animals; Ligands; Mice; Humans; Molecular Docking Simulation; Signal Transduction; Macrophages; Macrophages, Peritoneal; Inflammation; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Binding Sites
PubMed: 38923686
DOI: 10.1111/cbdd.14572 -
Angewandte Chemie (International Ed. in... Jun 2024In animals limiting oxygen upregulates hypoxia-inducible factor (HIF) promoting a metabolic shift towards glycolysis. Factor inhibiting HIF (FIH) is an asparaginyl...
In animals limiting oxygen upregulates hypoxia-inducible factor (HIF) promoting a metabolic shift towards glycolysis. Factor inhibiting HIF (FIH) is an asparaginyl hydroxylase that regulates HIF function by reducing its interaction with histone acetyl transferases. HIF levels are negatively regulated by the HIF prolyl hydroxylases (PHDs), which like FIH, are 2-oxoglutarate(2OG) oxygenases. Genetic loss of FIH promotes both glycolysis and aerobic metabolism. FIH has multiple non-HIF substrates making it challenging to connect its biochemistry with physiology. A structure-mechanism guided approach identified a highly potent in vivo active FIH inhibitor, ZG-2291, binding of which promotes a conformational flip of a catalytically important tyrosine, enabling selective inhibition of FIH over other JmjC subfamily 2OG oxygenases. Consistent with genetic studies, ZG-2291 promotes thermogenesis and ameliorates symptoms of obesity and metabolic dysfunction in ob/ob mice. The results reveal ZG-2291 as a useful probe for the physiological functions of FIH and identify FIH inhibition as a promising strategy for obesity treatment.
PubMed: 38923188
DOI: 10.1002/anie.202410438 -
Toxins Jun 2024Physiologically based pharmacokinetic (PBPK) models were utilized to investigate potential interactions between aflatoxin B1 (AFB1) and efavirenz (EFV), a non-nucleoside...
Physiologically based pharmacokinetic (PBPK) models were utilized to investigate potential interactions between aflatoxin B1 (AFB1) and efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor drug and inducer of several CYP enzymes, including CYP3A4. PBPK simulations were conducted in a North European Caucasian and Black South African population, considering different dosing scenarios. The simulations predicted the impact of EFV on AFB1 metabolism via CYP3A4 and CYP1A2. In vitro experiments using human liver microsomes (HLM) were performed to verify the PBPK predictions for both single- and multiple-dose exposures to EFV. Results showed no significant difference in the formation of AFB1 metabolites when combined with EFV (0.15 µM) compared to AFB1 alone. However, exposure to 5 µM of EFV, mimicking chronic exposure, resulted in increased CYP3A4 activity, affecting metabolite formation. While co-incubation with EFV reduced the formation of certain AFB1 metabolites, other outcomes varied and could not be fully attributed to CYP3A4 induction. Overall, this study provides evidence that EFV, and potentially other CYP1A2/CYP3A4 perpetrators, can impact AFB1 metabolism, leading to altered exposure to toxic metabolites. The results emphasize the importance of considering drug interactions when assessing the risks associated with mycotoxin exposure in individuals undergoing HIV therapy in a European and African context.
Topics: Aflatoxin B1; Humans; Benzoxazines; Alkynes; Cyclopropanes; Microsomes, Liver; Drug Interactions; Models, Biological; Reverse Transcriptase Inhibitors; Male; Cytochrome P-450 CYP3A; Adult; Female; Cytochrome P-450 CYP1A2; Middle Aged; Young Adult; White People
PubMed: 38922153
DOI: 10.3390/toxins16060259