RESUMEN
The almost simultaneous emergence of major animal phyla during the early Cambrian shaped modern animal biodiversity. Reconstructing evolutionary relationships among such closely spaced branches in the animal tree of life has proven to be a major challenge, hindering understanding of early animal evolution and the fossil record. This is particularly true in the species-rich and highly varied Mollusca where dramatic inconsistency among paleontological, morphological, and molecular evidence has led to a long-standing debate about the group's phylogeny and the nature of dozens of enigmatic fossil taxa. A critical step needed to overcome this issue is to supplement available genomic data, which is plentiful for well-studied lineages, with genomes from rare but key lineages, such as Scaphopoda. Here, by presenting chromosome-level genomes from both extant scaphopod orders and leveraging complete genomes spanning Mollusca, we provide strong support for Scaphopoda as the sister taxon of Bivalvia, revitalizing the morphology-based Diasoma hypothesis originally proposed 50 years ago. Our molecular clock analysis confidently dates the split between Bivalvia and Scaphopoda at ~520 Ma, prompting a reinterpretation of controversial laterally compressed Early Cambrian fossils, including Anabarella, Watsonella, and Mellopegma, as stem diasomes. Moreover, we show that incongruence in the phylogenetic placement of Scaphopoda in previous phylogenomic studies was due to ancient incomplete lineage sorting (ILS) that occurred during the rapid radiation of Conchifera. Our findings highlight the need to consider ILS as a potential source of error in deep phylogeny reconstruction, especially in the context of the unique nature of the Cambrian Explosion.
Asunto(s)
Bivalvos , Animales , Filogenia , Biodiversidad , Movimiento Celular , Suplementos DietéticosRESUMEN
Progressive multifocal leukoencephalopathy (PML) is a demyelinating infection of the immunosuppressed brain, mediated by the gliotropic polyomavirus JCV. JCV replicates in human glial progenitor cells and astrocytes, which undergo viral T antigen-triggered mitosis, enabling viral replication. We asked if JCV spread might therefore be accelerated by glial proliferation. Using both in vitro analysis and a human glial chimeric mouse model of JCV infection, we found that dividing human astrocytes supported JCV propagation to a substantially greater degree than did mitotically quiescent cells. Accordingly, bulk and single cell RNA-sequence analysis revealed that JCV-infected glia differentially manifested cell cycle-linked disruption of both DNA damage response and transcriptional regulatory pathways. In vivo, JCV infection of humanized glial chimeras was greatly accentuated by cuprizone-induced demyelination and its associated mobilization of GPCs. Importantly, in vivo infection triggered the death of uninfected as well as infected glia, reflecting significant bystander death. Together, these data suggest that JCV propagation in PML may be accelerated by glial cell division. As such, the accentuated glial proliferation attending disease-associated demyelination may provide an especially favorable environment for JCV propagation, thus potentiating oligodendrocytic bystander death and further accelerating demyelination in susceptible hosts.
RESUMEN
BACKGROUND: Methadone maintenance treatment (MMT) is effective for managing opioid use disorder, but adverse effects mean that optimal therapy occurs with the lowest dose that controls opioid craving. OBJECTIVE: To assess the efficacy of acupuncture versus sham acupuncture on methadone dose reduction. DESIGN: Multicenter, 2-group, randomized, sham-controlled trial. (Chinese Clinical Trial Registry: ChiCTR2200058123). SETTING: 6 MMT clinics in China. PARTICIPANTS: Adults aged 65 years or younger with opioid use disorder who attended clinic daily and had been using MMT for at least 6 weeks. INTERVENTION: Acupuncture or sham acupuncture 3 times a week for 8 weeks. MEASUREMENTS: The 2 primary outcomes were the proportion of participants who achieved a reduction in methadone dose of 20% or more compared with baseline and opioid craving, which was measured by the change from baseline on a 100-mm visual analogue scale (VAS). RESULTS: Of 118 eligible participants, 60 were randomly assigned to acupuncture and 58 were randomly assigned to sham acupuncture (2 did not receive acupuncture). At week 8, more patients reduced their methadone dose 20% or more with acupuncture than with sham acupuncture (37 [62%] vs. 16 [29%]; risk difference, 32% [97.5% CI, 13% to 52%]; P < 0.001). In addition, acupuncture was more effective in decreasing opioid craving than sham acupuncture with a mean difference of -11.7 mm VAS (CI, -18.7 to -4.8 mm; P < 0.001). No serious adverse events occurred. There were no notable differences between study groups when participants were asked which type of acupuncture they received. LIMITATION: Fixed acupuncture protocol limited personalization and only 12 weeks of follow-up after stopping acupuncture. CONCLUSION: Eight weeks of acupuncture were superior to sham acupuncture in reducing methadone dose and decreasing opioid craving. PRIMARY FUNDING SOURCE: National Natural Science Foundation of China.
RESUMEN
Aspergillus fumigatus (A. fumigatus) is one of the common pathogens of fungal keratitis. Fungal growth and invasion cause excessive inflammation and corneal damage, leading to severe vision loss. Neutrophils are the primary infiltrating cells critical for fungal clearance. Cathelicidin [LL-37 in humans and cathelicidin-related antimicrobial peptide (CRAMP) in mice], a natural antimicrobial peptide, can directly inhibit the growth of many pathogens and regulate immune responses. However, the role of cathelicidin and its effect on neutrophils in A. fumigatus keratitis remain unclear. By establishing A. fumigatus keratitis mouse models, we found that cathelicidin was increased in A. fumigatus keratitis. It could reduce fungal loads, lower clinical scores, and improve corneal transparency. Restriction of CRAMP on fungal proliferation was largely counteracted in CD18-/- mice, in which neutrophils cannot migrate into infected sites. When WT neutrophils were transferred into CD18-/- mice, corneal fungal loads were distinctly reduced, indicating that neutrophils are vital for CRAMP-mediated resistance. Furthermore, cathelicidin promoted neutrophils to phagocytose and degrade conidia both in vitro and in vivo. CXC chemokine receptor 2 (CXCR2) was reported to be a functional receptor of LL-37 on neutrophils. CXCR2 antagonist SB225002 or phospholipase C (PLC) inhibitor U73122 weakened LL-37-induced phagocytosis. Meanwhile, LL-37 induced PLC γ phosphorylation, which was attenuated by SB225002. SB225002 or the autophagy inhibitors Bafilomycin-A1 and 3-Methyladenine weakened LL-37-induced degradation of conidia. Transmission electron microscopy (TEM) observed that LL-37 increased autophagosomes in Aspergillus-infected neutrophils. Consistently, LL-37 elevated autophagy-associated protein expressions (Beclin-1 and LC3-II), but this effect was weakened by SB225002. Collectively, cathelicidin reduces fungal loads and improves the prognosis of A. fumigatus keratitis. Both in vitro and in vivo, cathelicidin promotes neutrophils to phagocytose and degrade conidia. LL-37/CXCR2 activates PLC γ to amplify neutrophils' phagocytosis and induces autophagy to eliminate intracellular conidia.
Asunto(s)
Aspergillus fumigatus , Queratitis , Compuestos de Fenilurea , Humanos , Animales , Ratones , Neutrófilos , Antifúngicos/metabolismo , Catelicidinas , Fosfolipasa C gamma/metabolismo , Queratitis/microbiología , Pronóstico , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Imbalanced immune responses are involved in developing preeclampsia (PE). We wish to explore the expression and potential changes of immune checkpoint molecules TIGIT, CD226 and CD155 in PE patients. METHODS: The expression of the immune checkpoint molecules TIGIT, CD226 and CD155 in different lymphocyte subpopulations was determined by flow cytometry in 24 patients with PE and compared to 24 healthy pregnant women of the same gestational age as the controls.âSerum CD155 was detected by ELISA in the patients with PE compared to controls. RESULTS: The percentages of CD4+ and CD8+ T lymphocytes in the peripheral blood of PE patients were not significantly different from those of the controls, whereas the regulatory T cells (Tregs) in PE patients were significantly lower than those in controls (6.43 ± 1.77% vs. 7.48 ± 1.71%, P = 0.0420). The expression of TIGIT and CD226 showed different percentages on CD4+ T cells, CD8+ T cells and Treg cells. However, the difference in the percentages of TIGIT, CD226 on these T cells between the two groups was not statistically significant. The level of CD155 in peripheral serum of PE patients was 6.64 ± 1.79 ng/ml, which was not significantly different from that in the control group 5.61 ± 1.77 ng/ml, P = 0.0505. The present results demonstrate that TIGIT, CD226 and CD155 are not present at altered immune conditions in the peripheral blood of patients with PE, compared with normal pregnant women. CONCLUSION: The immune checkpoint molecules TIGIT, CD226 and CD155 are not abnormally expressed in PE patients.
Asunto(s)
Linfocitos T CD8-positivos , Preeclampsia , Humanos , Embarazo , Femenino , Proteínas de Punto de Control Inmunitario/metabolismo , Preeclampsia/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Receptores Inmunológicos/metabolismoRESUMEN
Genomic epidemiology is important to study the COVID-19 pandemic, and more than two million severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomic sequences were deposited into public databases. However, the exponential increase of sequences invokes unprecedented bioinformatic challenges. Here, we present the Coronavirus GenBrowser (CGB) based on a highly efficient analysis framework and a node-picking rendering strategy. In total, 1,002,739 high-quality genomic sequences with the transmission-related metadata were analyzed and visualized. The size of the core data file is only 12.20 MB, highly efficient for clean data sharing. Quick visualization modules and rich interactive operations are provided to explore the annotated SARS-CoV-2 evolutionary tree. CGB binary nomenclature is proposed to name each internal lineage. The pre-analyzed data can be filtered out according to the user-defined criteria to explore the transmission of SARS-CoV-2. Different evolutionary analyses can also be easily performed, such as the detection of accelerated evolution and ongoing positive selection. Moreover, the 75 genomic spots conserved in SARS-CoV-2 but non-conserved in other coronaviruses were identified, which may indicate the functional elements specifically important for SARS-CoV-2. The CGB was written in Java and JavaScript. It not only enables users who have no programming skills to analyze millions of genomic sequences, but also offers a panoramic vision of the transmission and evolution of SARS-CoV-2.
Asunto(s)
COVID-19/epidemiología , COVID-19/virología , Vigilancia en Salud Pública/métodos , SARS-CoV-2/genética , Programas Informáticos , Navegador Web , Biología Computacional/métodos , Análisis Mutacional de ADN , Bases de Datos Genéticas , Genoma Viral , Genómica , Humanos , Epidemiología Molecular/métodos , Anotación de Secuencia Molecular , MutaciónRESUMEN
PURPOSE: To determine the antifungal, anti-inflammatory and neuroprotective effects of resveratrol (RES) in Aspergillus fumigatus (A. fumigatus) keratitis. METHODS: Cytotoxicity assay and Draize eye assay were performed to assess the toxicity of RES. The antifungal effect of RES was assessed by minimal inhibitory concentration, scanning or transmission electron microscopy, propidium iodide uptake assay, and Calcofluor white staining. Phosphorylation of p38 MAPK, mRNA and protein levels of Dectin-1 and related inflammatory factors were measured by qRT-PCR, ELISA and Western blot in vitro and in vivo. Clinical score, HE staining, plate count, and myeloperoxidase test were used to observe the progress of fungal keratitis. IF staining, qRT-PCR, and the Von Frey test were selected to assess the neuroprotective effects of RES. RESULTS: RES suppressed A. fumigatus hyphae growth and altered hyphae morphology in vitro. RES decreased the expression of Dectin-1, IL-1ß and TNF-α, as well as p38 MAPK phosphorylation expression, and also decreased clinical scores, reduced inflammatory cell infiltration and neutrophil activity, and decreased fungal load. RES also protected corneal basal nerve fibers, down-regulated mechanosensitivity thresholds, and increased the mRNA levels of CGRP and TRPV-1.. CONCLUSION: These evidences revealed that RES could exert antifungal effects on A. fumigatus and ameliorate FK through suppressing the Dectin-1/p38 MAPK pathway to down-regulate IL-1ß, IL-6, etc. expression and play protective effect on corneal nerves.
Asunto(s)
Antiinflamatorios , Aspergillus fumigatus , Queratitis , Lectinas Tipo C , Fármacos Neuroprotectores , Resveratrol , Proteínas Quinasas p38 Activadas por Mitógenos , Aspergillus fumigatus/efectos de los fármacos , Lectinas Tipo C/metabolismo , Queratitis/tratamiento farmacológico , Queratitis/metabolismo , Queratitis/microbiología , Resveratrol/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Fármacos Neuroprotectores/farmacología , Antiinflamatorios/farmacología , Ratones , Aspergilosis/tratamiento farmacológico , Aspergilosis/metabolismo , Antifúngicos/farmacología , Masculino , Transducción de Señal/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Córnea/efectos de los fármacos , Córnea/metabolismoRESUMEN
PURPOSE: Aspergillus fumigatus (A. fumigatus) keratitis is a type of infectious corneal disease that significantly impairs vision. The objective of this study is to evaluate the therapeutic potential of chelerythrine (CHE) on A. fumigatus keratitis. METHODS: The antifungal activity of CHE was assessed through various tests including the minimum inhibitory concentration test, scanning electron microscopy, transmission electron microscopy, propidium iodide uptake test and plate count. Neutrophil infiltration and activity were assessed using immunofluorescence staining and the myeloperoxidase test. RT-PCR, western blotting assay, and ELISA were performed to measure the expression levels of proinflammatory cytokines (IL-1ß and IL-6), NF-E2-related factor (Nrf2), heme oxygenase-1 (HO-1), and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), as well as to determine the ratio of phosphorylated-p38 (p-p38) mitogen-activated protein kinase (MAPK) to p38 MAPK. RESULTS: In vitro, CHE inhibited the growth of A. fumigatus conidia, reduced fungal hyphae survival, and prevented fungal biofilm formation. In vivo, CHE reduced the severity of A. fumigatus keratitis and exhibited an excellent anti-inflammatory effect by blocking neutrophil infiltration. Furthermore, CHE decreased the expression levels of proinflammatory cytokines and LOX-1 at both mRNA and protein levels, while also decreasing the p-p38 MAPK/p38 MAPK ratio. Additionally, CHE increased the expression levels of Nrf2 and HO-1. CONCLUSION: CHE provides protection against A. fumigatus keratitis through multiple mechanisms, including reducing fungal survival, inducing anti-inflammatory effects, enhancing Nrf2 and HO-1 expression, and suppressing the signaling pathway of LOX-1/p38 MAPK.
RESUMEN
Fungal keratitis (FK) is a highly blinding infectious corneal disease caused by pathogenic fungi. Candida albicans (C. albicans) is one of the main pathogens of fungal keratitis. Extracellular vesicles (EVs), lipid bilayer compartments released by almost all living cells, including fungi, have garnered attention for their role in pathogenic microbial infection and host immune responses in recent years. Studies have reported that pretreating the host with fungal EVs can reduce the inflammatory response of the host when attacked by fungi and reduce the lethality of fungal infection. However, there are no studies that have evaluated whether C. albicans EVs can modulate the inflammatory response associated with C. albicans keratitis. Our study revealed that C. albicans EVs could activate the polymorphonuclear cells (PMNs) and promote their secretion of proinflammatory cytokines and nitric oxide (NO), enhance their phagocytic and fungicidal abilities against C. albicans. C. albicans EVs also induced a proinflammatory response in RAW264.7 cells, which was characterized by increased production of inflammatory cytokines and elevated expression of the chemokine CCL2. Similarly, stimulation of C. albicans EVs to RAW264.7 cells also enhanced the phagocytosis and killing ability of cells against C. albicans. Besides, in our in vivo experiments, after receiving subconjunctival injection of C. albicans EVs, C57BL/6 mice were infected with C. albicans. The results demonstrated that pre-exposure to C. albicans EVs could effectively diminish the severity of keratitis, reduce fungal load and improve prognosis. Overall, we conclude that C. albicans EVs can modulate the function of immune cells and play a protective role in C. albicans keratitis.
Asunto(s)
Vesículas Extracelulares , Queratitis , Animales , Ratones , Candida albicans/fisiología , Ratones Endogámicos C57BL , Queratitis/microbiología , CitocinasRESUMEN
Fungal keratitis (FK) is an infectious keratopathy can cause serious damage to vision. Its severity is related to the virulence of fungus and response of inflammatory. Rosmarinic acid (RA) extracted from Rosmarinus officinalis exhibits antioxidant, anti-inflammatory and anti-viral properties. The aim of this study was to investigate the effect of RA on macrophage autophagy and its therapeutic effect on FK. In this study, we demonstrated that RA reduced expression of proinflammatory cytokine, lessened the recruitment of inflammatory cells in FK. The relative contents of autophagy markers, such as LC3 and Beclin-1, were significantly up-regulated in RAW 264.7 cells and FK. In addition, RA restored mitochondrial membrane potential (MMP) of macrophage to normal level. RA not only reduced the production of intracellular reactive oxygen species (ROS) but also mitochondria ROS (mtROS) in macrophage. At the same time, RA induced macrophage to M2 phenotype and down-regulated the mRNA expression of IL-6, IL-1ß, TNF-α. All the above effects could be offset by the autophagy inhibitor 3-Methyladenine (3-MA). Besides, RA promote phagocytosis of RAW 264.7 cells and inhibits spore germination, biofilm formation and conidial adherence, suggesting a potential therapeutic role for RA in FK.
Asunto(s)
Aspergilosis , Aspergillus fumigatus , Autofagia , Cinamatos , Depsidos , Infecciones Fúngicas del Ojo , Macrófagos , Especies Reactivas de Oxígeno , Ácido Rosmarínico , Depsidos/farmacología , Animales , Autofagia/efectos de los fármacos , Ratones , Aspergilosis/tratamiento farmacológico , Aspergilosis/microbiología , Aspergilosis/metabolismo , Infecciones Fúngicas del Ojo/microbiología , Infecciones Fúngicas del Ojo/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/microbiología , Cinamatos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Queratitis/microbiología , Queratitis/tratamiento farmacológico , Queratitis/metabolismo , Modelos Animales de Enfermedad , Células RAW 264.7 , Citocinas/metabolismo , Fagocitosis/efectos de los fármacosRESUMEN
This study aims to investigate sex differences and risk factors for self-reported suicide attempts among Chinese Han middle-aged patients with first-episode drug-naïve (FEDN) anxious depression (AD). A total of 1796 patients with FEDN major depressive disorder were enrolled in this study, including 341 middle-aged patients with AD. We compared the prevalence, demographics, and clinical characteristics of suicide attempts between male and female patients with FEDN middle-aged AD. We also explored the risk factors for self-reported suicide attempts in this population using binary logistic regression analysis. The male/female ratio was 91/250 and the age of onset was 51.50 ± 4.13. Our results showed that there were no significant sex differences in the prevalence of self-reported suicide attempts in middle-aged patients with FEDN AD. However, we did find significant differences in several demographic and clinical characteristics between self-reported suicide attempters and non-suicide attempters. Moreover, severe anxiety, measured by the Hamilton Anxiety Rating Scale score, was identified as a risk factor for self-reported suicide attempts in female middle-aged AD patients. Additionally, elevated thyroid peroxidase antibody (TPOAb) levels were linked to self-reported suicide attempts in male AD patients. Our findings suggest that there are no significant sex differences in the prevalence of self-reported suicide attempts in this population, but there may be sex-specific risk factors for self-reported suicide attempts in middle-aged AD. Clinical psychiatrists need to pay attention to thyroid hormone levels in middle-aged anxious depression.
RESUMEN
Ferroptosis is an iron-dependent death mode mediated by the aggregation of lipid peroxides and lipid-reactive oxygen species. It is characterized by iron-dependent lipid peroxide accumulation accompanied by oxidoreductase deficiency. Pancreatic beta cell dysfunction and insulin resistance are two major causes of type 2 diabetes mellitus (T2DM). Iron accumulation and metabolism may play a role in the development of T2DM. The molecular mechanism of ß cell apoptosis and iron death in T2DM were reviewed. In addition, we discuss recent insights on the relationship between the trace element iron and apoptosis of ß cells in T2DM.
Asunto(s)
Diabetes Mellitus Tipo 2 , Ferroptosis , Humanos , Vitamina D , Vitaminas , Transducción de Señal , Hierro , Peróxidos Lipídicos , Especies Reactivas de OxígenoRESUMEN
The study investigated the influences of pure H2 and O2 introduction, simulating gases produced from the electrokinetic-enhanced bioremediation (EK-Bio), on TCE degradation, and the dynamic changes of the indigenous microbial communities. The dissolved hydrogen (DH) and oxygen (DO) concentrations ranged from 0.2 to 0.7 mg/L and 2.6 to 6.6 mg/L, respectively. The biological analysis was conducted by 16S rRNA sequencing and functional gene analyses. The results showed that the H2 introduction enhanced TCE degradation, causing a 90.4% TCE removal in the first 4 weeks, and 131.1 µM was reduced eventually. Accordingly, cis-dichloroethylene (cis-DCE) was produced as the only product. The following three ways should be responsible for this promoted TCE degradation. Firstly, the high DH rapidly reduced the oxidation-reduction potential (ORP) value to around -500 mV, beneficial to TCE microbial dechlorination. Secondly, the high DH significantly changed the community and promoted the enrichment of TCE anaerobic dechlorinators, such as Sulfuricurvum, Sulfurospirillum, Shewanella, Geobacter, and Desulfitobacterium, and increased the abundance of dechlorination gene pceA. Thirdly, the high DH promoted preferential TCE dechlorination and subsequent sulfate reduction. However, TCE bio-remediation did not occur in a high DO environment due to the reduced aerobic function or lack of functional bacteria or co-metabolic substrate. The competitive dissolved organic carbon (DOC) consumption and unfriendly microbe-microbe interactions also interpreted the non-degradation of TCE in the high DO environment. These results provided evidence for the mechanism of EK-Bio. Providing anaerobic obligate dechlorinators, and aerobic metabolic bacteria around the electrochemical cathodes and anodes, respectively, or co-metabolic substrates to the anode can be feasible methods to promote remediation of TCE-contaminated shallow aquifer under EK-Bio technology.
Asunto(s)
Tricloroetileno , Biodegradación Ambiental , Tricloroetileno/análisis , Tricloroetileno/metabolismo , ARN Ribosómico 16S , Bacterias/metabolismo , Hidrógeno/análisis , Hidrógeno/metabolismo , Oxígeno/análisis , Oxígeno/metabolismoRESUMEN
BACKGROUND: The high costs of innovative anticancer drugs hinder a number of cancer patients' access to these drugs in China. To address this problem, in 2018, the medical insurance access negotiation (MIAN) policy was implemented, when the prices of 17 innovative anticancer drugs were successfully negotiated and they were therefore included in the reimbursement list. This study aimed to explore the impact of the MIAN policy on the utilization of innovative anticancer drugs. METHODS: With monthly data on drug expenditures and defined daily doses (DDDs) of each innovative anticancer drug from January 2017 to December 2019, interrupted time series analysis was employed to estimate both the instant (change in the level of outcome) and long-term (change in trends of outcomes) impacts of the MIAN policy on drug utilization in terms of drug expenditures and DDDs. Our sample consists of 12 innovative anticancer drugs. RESULTS: From January 2017 to December 2019, the monthly drug expenditures and DDDs of 12 innovative anticancer drugs increased by about 573% (from US$8,931,809.30 to US$51,138,331.09) and 1400% (from 47,785 to 668,754), respectively. Overall, the implementation of the MIAN policy led to instant substantial increases of US$8,734,414 in drug expenditures and 158,192.5 in DDDs. Moreover, a sharper upward trend over time was reported, with increases of US$2,889,078 and 38,715.3 in the monthly growth rates of drug expenditures and DDDs, respectively. Regarding individual innovative anticancer drugs, the most prominent instant change and trend change in drug utilization were found for osimertinib, crizotinib, and ibrutinib. In contrast, the utilization of pegaspargase was barely affected by the MIAN policy. CONCLUSIONS: The MIAN policy has effectively promoted the utilization of innovative anticancer drugs. To ensure the continuity of the effects and eliminate differentiation, supplementary measures should be carried out, such as careful selection of drugs for medical insurance negotiations, a health technology assessment system and a multichannel financing mechanism.
Asunto(s)
Antineoplásicos , Seguro , Nitrosaminas , Humanos , Negociación , Análisis de Series de Tiempo Interrumpido , Gastos en Salud , Antineoplásicos/uso terapéutico , China , Costos de los MedicamentosRESUMEN
XL092 is a potent ATP-competitive inhibitor of multiple receptor tyrosine kinases that is undergoing clinical development for the treatment of lung cancer. In this study, an LC triple quadrupole mass spectrometry method was established to measure XL092 in monkey plasma. A Waters ACQUITY UPLC BEH C18 column was used for chromatographic separation. The mobile phase consisted of water containing 0.1% formic acid and acetonitrile with a gradient elution at the flow rate of 0.4 mL/min. Multiple reaction monitoring mode was used for quantitative analysis of XL092 in positive electrospray ionization. In the concentration range of 0.5-1000 ng/mL, XL092 showed excellent linearity in monkey plasma with a correlation coefficient greater than 0.995 (r > 0.995). The lowest limit of quantification was 0.5 ng/mL. The intra- and inter-day relative standard deviations were <9.99%, while the relative error ranged from -12.50% to 8.10%. The mean recovery was over 82.51%. XL092 was stable in monkey plasma after storage under certain conditions. The validated method was demonstrated to be selective, sensitive, and reliable, and has been successfully applied to the pharmacokinetic study of XL092 in monkey plasma. XL092 showed moderate short half-life (~3.81 h) and good oral bioavailability (80%).
Asunto(s)
Espectrometría de Masas en Tándem , Animales , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodos , Modelos Lineales , Masculino , Cromatografía Liquida/métodos , Límite de Detección , Sensibilidad y Especificidad , Cromatografía Líquida de Alta Presión/métodos , Macaca fascicularis , Estabilidad de MedicamentosRESUMEN
Elderly patients infected with severe acute respiratory syndrome coronavirus 2 are at higher risk of severe clinical manifestation, extended hospitalization, and increased mortality. Those patients are more likely to experience persistent symptoms and exacerbate the condition of basic diseases with long COVID-19 syndrome. However, the molecular mechanisms underlying severe COVID-19 in the elderly patients remain unclear. Our study aims to investigate the function of the interaction between disease-characteristic genes and immune cell infiltration in patients with severe COVID-19 infection. COVID-19 datasets (GSE164805 and GSE180594) and aging dataset (GSE69832) were obtained from the Gene Expression Omnibus database. The combined different expression genes (DEGs) were subjected to Gene Ontology (GO) functional enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Diseases Ontology functional enrichment analysis, Gene Set Enrichment Analysis, machine learning, and immune cell infiltration analysis. GO and KEGG enrichment analyses revealed that the eight DEGs (IL23A, PTGER4, PLCB1, IL1B, CXCR1, C1QB, MX2, ALOX12) were mainly involved in inflammatory mediator regulation of TRP channels, coronavirus disease-COVID-19, and cytokine activity signaling pathways. Three-degree algorithm (LASSO, SVM-RFE, KNN) and correlation analysis showed that the five DEGs up-regulated the immune cells of macrophages M0/M1, memory B cells, gamma delta T cell, dendritic cell resting, and master cell resisting. Our study identified five hallmark genes that can serve as disease-characteristic genes and target immune cells infiltrated in severe COVID-19 patients among the elderly population, which may contribute to the study of pathogenesis and the evaluation of diagnosis and prognosis in aging patients infected with severe COVID-19.
RESUMEN
SCO-267 is a potent G-protein-coupled receptor 40 agonist that is undergoing clinical development for the treatment of type 2 diabetes mellitus. The current work was undertaken to investigate the bioactivation potential of SCO-267 in vitro and in vivo. Three SCO-267-derived glutathione (GSH) conjugates (M1-M3) were found both in rat and human liver microsomal incubations supplemented with GSH and nicotinamide adenine dinucleotide phosphate. Two GSH conjugates (M1-M2) together with two N-acetyl-cysteine conjugates (M4-M5) were detected in the bile of rats receiving SCO-267 at 10 mg/kg. The identified conjugates suggested the generation of quinone-imine and ortho-quinone intermediates. CYP3A4 was demonstrated to primarily catalyze the bioactivation of SCO-267. In addition, SCO-267 concentration-, time-, and NADPH-dependently inactivated CYP3A in human liver microsomes using testosterone as a probe substrate, along with KI and kinact values of 4.91 µM and 0.036 min-1 , respectively. Ketoconazole (a competitive inhibitor of CYP3A) displayed no significant protective effect on SCO-267-induced CYP3A inactivation. However, inclusion of GSH showed significant protection. These findings revealed that SCO-267 undergoes a facile CYP3A4-catalyzed bioactivation with the generation of quinone-imine and ortho-quinone intermediates, which were assumed to be involved in SCO-267 induced CYP3A inactivation. These findings provide further insight into the bioactivation pathways involved in the generation of reactive, potentially toxic metabolites of SCO-267. Further studies are needed to evaluate the influence of SCO-267 metabolism on the safety of this drug in vivo.
Asunto(s)
Benzoquinonas , Citocromo P-450 CYP3A , Diabetes Mellitus Tipo 2 , Piperidinas , Piridinas , Humanos , Ratas , Animales , Citocromo P-450 CYP3A/metabolismo , Activación Metabólica , Diabetes Mellitus Tipo 2/metabolismo , Quinonas/metabolismo , Iminas/metabolismo , Microsomas Hepáticos/metabolismo , Glutatión/metabolismoRESUMEN
BACKGROUND: Despite the increasing emphasis on rehabilitation training after orthopedic surgery, little is known about the pain caused by the procedure itself. Clinical practice is driven by beliefs in pain management. AIMS: This study aimed to explore the perspective of pain management during rehabilitation training after orthopedic trauma in China and its influencing factors from different perspectives in traditional Chinese medicine and Western medicine, respectively. DESIGN: A phenomenological qualitative study involving semi-structured interviews. SETTINGS: ⯠METHODS: A qualitative study was conducted with 16 medical workers working in the Rehabilitation Medicine Department in eastern China from July 2022-February 2023. A directed method to thematic analysis was used to code the transcribed data and identify themes. RESULTS: Four main themes emerged. (1) Inconsistent perspectives and practice: Chinese doctors majoring in Western medicine felt sympathy, helpless, and had a lack of knowledge and misconception about pain. Traditional Chinese medicine deemed that pain is a protective mechanism and attached importance to holism and unique means. (2) Consistent outcome: Insufficient pain management will have a series of negative consequences for patients' recovery, forming a vicious cycle. (3) Expectations: Though they are not optimistic about traditional analgesics, enhancement, cooperation and ideal analgesic methods still be expressed, and (4) Concept transformation: Conducting nitrous oxide is a process not only to promote analgesic technology but also to promote the awareness and concept of pain management. CONCLUSIONS: Our study emphasized that medical workers should be aware of the importance of pain management at the same time while treating the disability. The study provides insight into pain management experiences within different educational backgrounds. The findings enable professionals to recognize the importance of pain management and its influencing factors to provide feasible and effective pain management strategies.
Asunto(s)
Manejo del Dolor , Investigación Cualitativa , Humanos , Manejo del Dolor/métodos , Manejo del Dolor/normas , Masculino , Femenino , Adulto , China , Persona de Mediana Edad , Medicina Tradicional China/métodos , Medicina Tradicional China/normas , Procedimientos Ortopédicos/métodos , Entrevistas como Asunto/métodos , Cirugía de Cuidados IntensivosRESUMEN
Neurodevelopmental disorders in children have become a significant global public health concern, impacting child health worldwide. In China, the current intervention model for high-risk infants involves early diagnosis and early treatment. However, in recent years, overseas studies have explored novel preventive early intervention strategies for neurodevelopmental disorders in high-risk infants, achieving promising results. This article provides a comprehensive review of the optimal timing, methods, and intervention models of the preventive early intervention strategies for neurodevelopmental disorders in high-risk infants. The aim is to enhance the awareness and knowledge of healthcare professionals regarding preventive early intervention strategies for neurodevelopmental disorders in high-risk infants, facilitate clinical research and application of such interventions in China, and ultimately reduce the incidence of neurodevelopmental disorders in this high-risk population.
Asunto(s)
Trastornos del Neurodesarrollo , Lactante , Niño , Humanos , Trastornos del Neurodesarrollo/prevención & control , Trastornos del Neurodesarrollo/epidemiología , Intervención Educativa Precoz , Factores de Riesgo , ChinaRESUMEN
Obesity is widely recognized as a major global health problem caused by a chronic energy imbalance resulting from a combination of excess caloric intake and insufficient energy expenditure. Excessive energy intake and physical inactivity are traditional risk factors for obesity. Obesity is a risk factor for many diseases, including hypertension, diabetes and tumours. Recent studies have found a strong link between ferroptosis and obesity. Ferroptosis is an iron-dependent regulated cell death caused by iron overload and reactive oxygen species-dependent excessive accumulation of lipid peroxidation. Ferroptosis is involved in many biological processes, such as amino acid metabolism, iron metabolism and lipid metabolism. Some potential strategies to reduce the adverse effects of ferroptosis on obesity are suggested and future research priorities are highlighted.