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Global Medical Genetics Jun 2024Myelodysplastic syndrome (MDS) is a malignant clonal disorder of hematopoietic stem cells which is characterized by morphologic dysplasia. However, the pathological...
Myelodysplastic syndrome (MDS) is a malignant clonal disorder of hematopoietic stem cells which is characterized by morphologic dysplasia. However, the pathological characteristics of megakaryocytes (MKs) in MDS patients with gene mutation are not well established. Bone marrow MK specimens from 104 patients with primary MDS were evaluated, and all patients were distributed into two groups according to gene mutation associated with functional MKs. The morphologic and cellular characteristics of MKs and platelets were recorded and compared. The more frequently mutated genes in MDS patients were (11.54%), (8.65%), (5.77%), and the most common point mutation was p.(R307H) and p.(Q43P). Patients with MK mutation showed a decrease in adenosine diphosphate-induced platelet aggregation, high proportion of CD34 CD61 MKs (10.00 vs. 4.00%, = 0.012), and short overall survival (33.15 vs. 40.50 months, = 0.013). Further, patients with a higher percent of CD34 CD61 MKs (≧20.00%) had lower platelet counts (36.00 × 10 /L vs. 88.50 × 10 /L, = 0.015) and more profound emperipolesis ( = 0.001). By analyzing RNA-sequencing of MKs, differentially expressed mRNA was involved in physiological processes including platelet function and platelet activation, especially for MDS patients with high percent of CD34 CD61 MKs. The high levels of expression of CD62P, CXCL10, and S100A9 mRNA, shown by RNA sequencing, were validated by PCR assay. High proportion of CD34 CD61 MKs was a poor prognostic factor in MDS patients with MK mutation. CD62P, CXCL10, and S100A9 may be the potential targets to evaluate the molecular link between gene defects and platelet function.
PubMed: 38860162
DOI: 10.1055/s-0044-1787752 -
Journal of Visualized Experiments : JoVE May 2024Peripheral mononuclear cells (PBMCs) exhibit robust changes in mitochondrial respiratory capacity in response to health and disease. While these changes do not always...
Peripheral mononuclear cells (PBMCs) exhibit robust changes in mitochondrial respiratory capacity in response to health and disease. While these changes do not always reflect what occurs in other tissues, such as skeletal muscle, these cells are an accessible and valuable source of viable mitochondria from human subjects. PBMCs are exposed to systemic signals that impact their bioenergetic state. Thus, expanding our tools to interrogate mitochondrial metabolism in this population will elucidate mechanisms related to disease progression. Functional assays of mitochondria are often limited to using respiratory outputs following maximal substrate, inhibitor, and uncoupler concentrations to determine the full range of respiratory capacity, which may not be achievable in vivo. The conversion of adenosine diphosphate (ADP) to adenosine triphosphate (ATP) by ATP-synthase results in a decrease in mitochondrial membrane potential (mMP) and an increase in oxygen consumption. To provide a more integrated analysis of mitochondrial dynamics, this article describes the use of high-resolution fluorespirometry to measure the simultaneous response of oxygen consumption and mitochondrial membrane potential (mMP) to physiologically relevant concentrations of ADP. This technique uses tetramethylrhodamine methylester (TMRM) to measure mMP polarization in response to ADP titrations following maximal hyperpolarization with complex I and II substrates. This technique can be used to quantify how changes in health status, such as aging and metabolic disease, affect the sensitivity of mitochondrial response to energy demand in PBMCs, T-cells, and monocytes from human subjects.
Topics: Humans; Membrane Potential, Mitochondrial; Leukocytes, Mononuclear; Rhodamines; Adenosine Diphosphate; Oxygen Consumption; Mitochondria; Fluorescent Dyes
PubMed: 38856231
DOI: 10.3791/66863 -
World Journal of Emergency Medicine 2024Chlorfenapyr is used to kill insects that are resistant to organophosphorus insecticides. Chlorfenapyr poisoning has a high mortality rate and is difficult to treat.... (Review)
Review
BACKGROUND
Chlorfenapyr is used to kill insects that are resistant to organophosphorus insecticides. Chlorfenapyr poisoning has a high mortality rate and is difficult to treat. This article aims to review the mechanisms, clinical presentations, and treatment strategies for chlorfenapyr poisoning.
DATA RESOURCES
We conducted a review of the literature using PubMed, Web of Science, and SpringerLink from their beginnings to the end of October 2023. The inclusion criteria were systematic reviews, clinical guidelines, retrospective studies, and case reports on chlorfenapyr poisoning that focused on its mechanisms, clinical presentations, and treatment strategies. The references in the included studies were also examined to identify additional sources.
RESULTS
We included 57 studies in this review. Chlorfenapyr can be degraded into tralopyril, which is more toxic and reduces energy production by inhibiting the conversion of adenosine diphosphate to adenosine triphosphate. High fever and altered mental status are characteristic clinical presentations of chlorfenapyr poisoning. Once it occurs, respiratory failure occurs immediately, ultimately leading to cardiac arrest and death. Chlorfenapyr poisoning is difficult to treat, and there is no specific antidote.
CONCLUSION
Chlorfenapyr is a new pyrrole pesticide. Although it has been identified as a moderately toxic pesticide by the World Health Organization (WHO), the mortality rate of poisoned patients is extremely high. There is no specific antidote for chlorfenapyr poisoning. Therefore, based on the literature review, future efforts to explore rapid and effective detoxification methods, reconstitute intracellular oxidative phosphorylation couplings, identify early biomarkers of chlorfenapyr poisoning, and block the conversion of chlorfenapyr to tralopyril may be helpful for emergency physicians in the diagnosis and treatment of this disease.
PubMed: 38855374
DOI: 10.5847/wjem.j.1920-8642.2024.046 -
BMC Pharmacology & Toxicology Jun 2024Antiplatelet therapy is an important factor influencing the postterm patency rate of carotid artery stenting (CAS). Clopidogrel is a platelet aggregation inhibitor...
Antiplatelet therapy is an important factor influencing the postterm patency rate of carotid artery stenting (CAS). Clopidogrel is a platelet aggregation inhibitor mediated by the adenosine diphosphate receptor and is affected by CYP2C19 gene polymorphisms in vivo. When the CYP2C19 gene has a nonfunctional mutation, the activity of the encoded enzyme will be weakened or lost, which directly affects the metabolism of clopidogrel and ultimately weakens its antiplatelet aggregation ability. Therefore, based on network pharmacology, analyzing the influence of CYP2C19 gene polymorphisms on the antiplatelet therapeutic effect of clopidogrel after CAS is highly important for the formulation of individualized clinical drug regimens. The effect of the CYP2C19 gene polymorphism on the antiplatelet aggregation of clopidogrel after CAS was analyzed based on network pharmacology. A total of 100 patients with ischemic cerebrovascular disease who were confirmed by the neurology department and required CAS treatment were studied. CYP2C19 genotyping was performed on all patients via a gene chip. All patients were classified into the wild-type (WT) group (*1/*1), heterozygous mutation (HTM) group (CYP2C19*1/*2, CYP2C19*1/*3), and homozygous mutation (HMM) group (CYP2C19*2/*2, CYP2C19*2/*3, and CYP2C19*3/*3). High-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) was used to detect the blood concentration of clopidogrel and the plasma clopidogrel clearance (CL) rate in different groups of patients before and after clopidogrel treatment. The platelet aggregation rate of patients with different genotypes was measured by turbidimetry. The incidences of clopidogrel resistance (CR) and stent thrombosis in different groups after three months of treatment were analyzed. The results showed that among the different CYP2C19 genotypes, patients from the HTM group accounted for the most patients, while patients from the HTM group accounted for the least patients. Similarly, the clopidogrel CL of patients in the HMM group was lower than that of patients in the WT group and HTM group (P < 0.01). The platelet inhibition rate of patients in the HMM group was evidently inferior to that of patients in the WT group and HTM group (P < 0.01). The incidence of CR and stent thrombosis in the WT group was notably lower than that in the HTM and HMM groups (P < 0.01). These results indicate that the CYP2C19 gene can affect CR occurrence and stent thrombosis after CAS by influencing clopidogrel metabolism and platelet count.
Topics: Humans; Cytochrome P-450 CYP2C19; Clopidogrel; Platelet Aggregation Inhibitors; Stents; Male; Female; Platelet Aggregation; Aged; Middle Aged; Polymorphism, Genetic; Ticlopidine; Genotype; Carotid Arteries
PubMed: 38845014
DOI: 10.1186/s40360-024-00750-w -
Molecular Cell Jun 2024The Tn7 family of transposons is notable for its highly regulated integration mechanisms, including programmable RNA-guided transposition. The targeting pathways rely on...
The Tn7 family of transposons is notable for its highly regulated integration mechanisms, including programmable RNA-guided transposition. The targeting pathways rely on dedicated target selection proteins from the TniQ family and the AAA+ adaptor TnsC to recruit and activate the transposase at specific target sites. Here, we report the cryoelectron microscopy (cryo-EM) structures of TnsC bound to the TniQ domain of TnsD from prototypical Tn7 and unveil key regulatory steps stemming from unique behaviors of ATP- versus ADP-bound TnsC. We show that TnsD recruits ADP-bound dimers of TnsC and acts as an exchange factor to release one protomer with exchange to ATP. This loading process explains how TnsC assembles a heptameric ring unidirectionally from the target site. This unique loading process results in functionally distinct TnsC protomers within the ring, providing a checkpoint for target immunity and explaining how insertions at programmed sites precisely occur in a specific orientation across Tn7 elements.
Topics: Cryoelectron Microscopy; DNA Transposable Elements; Adenosine Triphosphate; Transposases; Adenosine Diphosphate; Protein Binding; Bacterial Proteins; Models, Molecular; Protein Multimerization; Binding Sites
PubMed: 38834067
DOI: 10.1016/j.molcel.2024.05.012 -
ASAIO Journal (American Society For... Jun 2024Impaired primary hemostasis and dysregulated angiogenesis, known as a two-hit hypothesis, are associated with gastrointestinal (GI) bleeding in patients with...
The Impact of Acute Exercise on Hemostasis and Angiogenesis Mediators in Patients With Continuous-Flow Left Ventricular Assist Devices: A Prospective Observational Pilot Study.
Impaired primary hemostasis and dysregulated angiogenesis, known as a two-hit hypothesis, are associated with gastrointestinal (GI) bleeding in patients with continuous-flow left ventricular assist devices (CF-LVADs). Exercise is known to influence hemostasis and angiogenesis in healthy individuals; however, little is known about the effect in patients with CF-LVADs. The objective of this prospective observational study was to determine whether acute exercise modulates two-hit hypothesis mediators associated with GI bleeding in patients with a CF-LVAD. Twenty-two patients with CF-LVADs performed acute exercise either on a cycle ergometer for approximately 10 minutes or on a treadmill for 30 minutes. Blood samples were taken pre- and post-exercise to analyze hemostatic and angiogenic biomarkers. Acute exercise resulted in an increased platelet count (p < 0.00001) and platelet function (induced by adenosine diphosphate, p = 0.0087; TRAP-6, p = 0.0005; ristocetin, p = 0.0009). Additionally, high-molecular-weight vWF multimers (p < 0.00001), vWF collagen-binding activity (p = 0.0012), factor VIII (p = 0.034), angiopoietin-1 (p = 0.0026), and vascular endothelial growth factor (p = 0.0041) all increased after acute exercise. This pilot work demonstrates that acute exercise modulated two-hit hypothesis mediators associated with GI bleeding in patients with CF-LVADs.
PubMed: 38833540
DOI: 10.1097/MAT.0000000000002246 -
Heliyon Jun 2024The significance of novel anti-tumor pharmaceuticals in the treatment of gynecological tumors is growing, but there is no consensus regarding the optimal drug delivery...
OBJECTIVE
The significance of novel anti-tumor pharmaceuticals in the treatment of gynecological tumors is growing, but there is no consensus regarding the optimal drug delivery strategy for gynecological tumors. This study seeks to investigate the treatment models of novel anti-tumor drugs in patients with gynecological cancer in China over the past five years, with a particular emphasis on the trend and rationality of their use.
METHOD
We conducted a cross-sectional analysis of data from a China Medical Association-supervised hospital prescription analysis cooperation initiative. The data was derived from prescriptions written for patients diagnosed with cancer between January 2017 and December 2021. The required information for patients was extracted. Our study included 2308 patients that were diagnosed as gynecological tumors which were treated with novel antineoplastic targeted drugs. Patients were categorized by age and region. Then, the selection, application, and indications of the most essential treatment pharmaceuticals were investigated. We evaluated anti-tumor prescription information based on the recommended drug labeling protocol and the most recent domestic and international guidelines.Excel 2013 and SPSS (version 25; SPSS Inc., Chicago, IL, United States) were utilized to conduct statistical analysis.In addition,we also used Sankey diagram to evalute the relation between novel antineoplastic targeted drugs and corresponding diagnoses.
RESULT
The top three cities for the 2308 patients included in this study were Guangzhou (28.51%), Hangzhou (21.79%), and Beijing (20.06%). In the past five years, the average age of medication patients was 55.61-year-old, with 37.86% of women aged of 51-60. Each patient's primary treatment regimens were statistically analyzed, yielding a total of 16 single-drug and combination-drug primary treatment regimens. Bevacizumab, Olaparib, Trastuzumab, Apatinib, and Arotinib were the top five treatment strategies. The maximum proportion, up to 0.74%, was attributed to the combination of human epidermal growth factor receptor-2 inhibitor (HER2i), including Trastuzumab and Parostuzumab. Vascular endothelial growth factor receptor inhibitor (VEGFRi), including Bevacizumab and Apatinib was the most frequently prescribed medication for outpatients in major cities across the country. According to the 5-year change in time, poly adenosine diphosphate ribose polymerase inhibitor (PARPi) rated first in terms of usage, with Olaparib ranking first with the highest concentration of 33.44% and Niraparib ranking second overall with the fastest growth in 2021. The quantity of VEGFRi variants utilized was the greatest, and their proportion of total usage increased annually. The top five drugs by total drug costs were Bevacizumab, Carelizumab, Olaparib, Trastuzumab, and Apatinib. However, the top five drugs by per capita drug cost were Olaparib + Bevacizumab, Bevacizumab + Sidilimab, Arrotinib + Olaparib, Olaparib, and Patuzumab + Trastuzumab.
CONCLUSION
The incidence rate of gynecological tumor patients rises with age, and the cost of drug treatment has risen annually over the past five years, which is also related to the rising incidence rate of tumors in recent years. Bevacizumab rates first in the drug treatment scheme for the application of novel anti-tumor targeted drugs, which may be related to the widespread use of VEGFRi drugs in gynecological and reproductive tumors. Breast cancer and adenocarcinoma are at the top of the female cancer incidence spectrum, which may explain why HER2i multi-drug combination regimen rates highest among multi-drug combination regimens. Future research may concentrate on how novel anti-tumor targeted drugs can minimize the economic burden and maximize the benefits of patient treatment for patients with gynecological cancer.
PubMed: 38832281
DOI: 10.1016/j.heliyon.2024.e31371 -
Nature Communications May 2024The human AAA-ATPase Bcs1L translocates the fully assembled Rieske iron-sulfur protein (ISP) precursor across the mitochondrial inner membrane, enabling respiratory...
The human AAA-ATPase Bcs1L translocates the fully assembled Rieske iron-sulfur protein (ISP) precursor across the mitochondrial inner membrane, enabling respiratory Complex III assembly. Exactly how the folded substrate is bound to and released from Bcs1L has been unclear, and there has been ongoing debate as to whether subunits of Bcs1L act in sequence or in unison hydrolyzing ATP when moving the protein cargo. Here, we captured Bcs1L conformations by cryo-EM during active ATP hydrolysis in the presence or absence of ISP substrate. In contrast to the threading mechanism widely employed by AAA proteins in substrate translocation, subunits of Bcs1L alternate uniformly between ATP and ADP conformations without detectable intermediates that have different, co-existing nucleotide states, indicating that the subunits act in concert. We further show that the ISP can be trapped by Bcs1 when its subunits are all in the ADP-bound state, which we propose to be released in the apo form.
Topics: Adenosine Triphosphate; Hydrolysis; Cryoelectron Microscopy; Electron Transport Complex III; Humans; Adenosine Diphosphate; ATPases Associated with Diverse Cellular Activities; Iron-Sulfur Proteins; Protein Conformation; Protein Folding; Models, Molecular; Protein Transport
PubMed: 38821922
DOI: 10.1038/s41467-024-49029-y -
Journal of Neurosurgery May 2024Concern about thromboembolic events after flow diversion (FD) warrants dual antiplatelet therapy for 3 to 6 months. Platelet function tests are routinely performed prior...
OBJECTIVE
Concern about thromboembolic events after flow diversion (FD) warrants dual antiplatelet therapy for 3 to 6 months. Platelet function tests are routinely performed prior to the procedure to detect clopidogrel responsiveness, as resistance is associated with CYP2C19 gene polymorphisms. This study aimed to identify optimal cutoff values in light transmission aggregometry (LTA) for clopidogrel and aspirin as predictive indicators of thromboembolic complications.
METHODS
The authors conducted a retrospective analysis of aneurysms treated with FD between 2013 and 2023 at a single academic institution. Patients with LTA data for adenosine diphosphate (ADP) and arachidonic acid (ARA) were included, excluding those with aborted procedures. Receiver operating characteristic curves were plotted for ADP and ARA assays to determine optimal cutoff values.
RESULTS
A total of 442 patients harboring 552 aneurysms treated in 485 procedures were selected for this analysis. Complete and near-complete aneurysm occlusion on the last radiological follow-up was achieved in 81.8% of aneurysms in a median last imaging follow-up of 13.9 months. A good functional outcome (modified Rankin Scale score ≤ 2) was achieved in 96.3% of patients on the last follow-up. Thromboembolic complications occurred in 4.9% of procedures, and intracranial hemorrhagic complications in 1.9%. For the ADP assay, a value ≥ 40% reached a sensitivity of 82.1% and a specificity of 42.9% with a positive likelihood ratio (LR) of 1.50. For the ARA assay, a value ≥ 13.5% reached a sensitivity of 82.1% and a specificity of 45.6% with a positive LR of 1.51.
CONCLUSIONS
This study analyzed the largest FD-treated cohort in which optimal LTA platelet function thresholds for clopidogrel were evaluated and is the first to assess LTA values for aspirin. The authors found that values ≥ 40% for clopidogrel and ≥ 13.5% for aspirin were optimal for predicting thromboembolic complications after FD in treating aneurysms.
PubMed: 38820610
DOI: 10.3171/2024.3.JNS2487 -
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue Apr 2024AMP-activated protein kinase (AMPK) is a widely distributed and evolutionarily conserved serine/threonine protein kinase present in eukaryotic cells. In regulating... (Review)
Review
AMP-activated protein kinase (AMPK) is a widely distributed and evolutionarily conserved serine/threonine protein kinase present in eukaryotic cells. In regulating cellular energy metabolism, AMPK plays an extremely important role as an energy metabolic kinase. When the body is in a low energy state, AMPK is activated in response to changes in intracellular adenine nucleotide levels and is bound to adenosine monophosphate (AMP) or adenosine diphosphate (ADP). Activated AMPK regulates various metabolic processes, including lipid and glucose metabolism and cellular autophagy. AMPK directly promotes autophagy by phosphorylating autophagy-related proteins in the mammalian target of rapamycin complex 1 (mTORC1), serine/threonine protein kinase-dysregulated 51-like kinase 1 (ULK1) and type III phosphatidylinositol 3-kinase-vacuolar protein-sorting 34 (PIK3C3-VPS34) complexes. AMPK also indirectly promotes autophagy by regulating the expression of downstream autophagy-related genes of transcription factors such as forkhead box O3 (FOXO3), lysosomal function transcription factor EB (TFEB) and bromodomain protein 4 (BRD4). AMPK also regulates mitochondrial autophagy, induces the division of damaged mitochondria and promotes the transfer of the autophagic response to damaged mitochondria. Another function of AMPK is to regulate mitochondrial health by stimulating mitochondrial biogenesis and participating in various aspects of mitochondrial homeostasis regulation. This review discusses the specific regulation of mitochondrial biology and internal environmental homeostasis by AMPK signaling channels as central to the cellular response to energy stress and regulation of mitochondria, highlighting the key role of AMPK in regulating cellular autophagy and mitochondrial autophagy, as well as advances in research on the regulation of mitochondrial homeostasis.
Topics: Autophagy; AMP-Activated Protein Kinases; Humans; Mitochondria; Homeostasis; Signal Transduction; Animals; Energy Metabolism; Mechanistic Target of Rapamycin Complex 1
PubMed: 38813640
DOI: 10.3760/cma.j.cn121430-20230302-00132