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Two coordination polymers (CPs), [Zn5(L)2(phen)5](1) and [Cd2(HL)(2,2-bpy)(H2O)3](2), were synthesized by using 2',3,3',5,5'-Diphenyl ether pentacarboxylic acid (H5L), phenanthroline (phen), and 2,2'-bipyridine (2,2'-bpy) under hydrothermal conditions. The L5- ligand adopts the µ6-к2: к2: к1: к1: к1: к1 mode in 1 and the µ5-к2: к2: к2: к2: к1 mode in 2. Sensing experiments show that 1 and 2 are fluorescence probes with high sensitivity and rapid detection of nitro explosives, antibiotics, and pesticides. In order to verify the ability of 2 to detect FLU in actual samples, we performed a spiked recovery experiment in green pepper water. The spiked recoveries were 97.77-101.18 %. Interestingly, because H5L is not completely deprotonated in 2, there is abundant hydrogen bonding, which makes the fluorescence quenching rate higher and the detection limit lower. The possible fluorescence quenching mechanism of 1 and 2 can be explained by their UV-VIS absorption spectra and orbital energy levels.
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This paper concerns complete synchronization (CS) problem of discrete-time fractional-order BAM neural networks (BAMNNs) with leakage and discrete delays. Firstly, on the basis of Caputo fractional difference theory and nabla l-Laplace transform, two equations about the nabla sum are strictly proved. Secondly, two extended Halanay inequalities that are suitable for discrete-time fractional difference inequations with arbitrary initial time and multiple types of delays are introduced. In addition, through applying Caputo fractional difference theory and combining with inequalities gained from this paper, some sufficient CS criteria of discrete-time fractional-order BAMNNs with leakage and discrete delays are established under adaptive controller. Finally, one numerical simulation is utilized to certify the effectiveness of the obtained theoretical results.
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BACKGROUND: Several population pharmacokinetic (PopPK) models of caffeine in preterm infants have been published, but the extrapolation of these models to facilitate model-informed precision dosing (MIPD) in clinical practice is uncertain. This study aimed to comprehensively evaluate their predictive performance using an external, independent dataset. METHODS: Data used for external evaluation were based on an independent cohort of preterm infants. Currently available PopPK models for caffeine in preterm infants were identified and re-established. Prediction- and simulation-based diagnostics were used to assess model predictability. The influence of prior information was assessed using Bayesian forecasting. RESULTS: 120 plasma samples from 76 preterm infants were included in the evaluation dataset. Twelve PopPK models of caffeine in preterm infants were re-established based on our previously published study. Although two models showed superior predictive performance, none of the 12 PopPK models met all the clinical acceptance criteria of these external evaluation items. Besides, the external predictive performances of most models were unsatisfactory in prediction- and simulation-based diagnostics. Nevertheless, the application of Bayesian forecasting significantly improved the predictive performance, even with only one prior observation. CONCLUSIONS: Two models that included the most covariates had the best predictive performance across all external assessments. Inclusion of different covariates, heterogeneity of preterm infant characteristics, and different study designs influenced predictive performance. Thorough evaluation is needed before these PopPK models can be implemented in clinical practice. The implementation of MIPD for caffeine in preterm infants could benefit from the combination of PopPK models and Bayesian forecasting as a helpful tool.
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Constructing amorphous/crystalline heterophase structure with high porosity is a promising strategy to effectively tailor the physicochemical properties of electrode materials and further improve the electrochemical performance of supercapacitors. Here, the porous C-doped NiO (C-NiO) with amorphous/crystalline heterophase grown on NF was prepared using NF as Ni source via a self-sacrificial template method. Calcining the self-sacrificial NiC2O4 template at a suitable temperature (400 °C) was beneficial to the formation of porous heterophase structure with abundant cavities and cracks, resulting in high electrical conductivity and rich ion/electron-transport channels. The density functional theory (DFT) calculations further verified that in-situ C-doping could modulate the electronic structure and enhance the OH- adsorption capability. The unique porous amorphous/crystalline heterophase structure greatly accelerated electrons/ions transfer and Faradaic reaction kinetic, which effectively improved the charge storage. The C-NiO calcined at 400 °C (C-NiO(400)) displayed a markedly enhanced specific charge, outstanding rate property and excellent cycling stability. Furthermore, the hybrid supercapacitor assembled by C-NiO(400) and active carbon achieved a high energy density of 49.0 Wh kg-1 at 800 W kg-1 and excellent cycle stability (90.9 % retention at 5 A/g after 10 000 cycles). This work provided a new strategy for designing amorphous/crystalline heterophase electrode materials in high-performance energy storage.
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Infertility has gradually become a global health concern, and evidence suggests that exposure to environmental endocrine-disrupting chemicals (EDCs) represent one of the key causes of infertility. Benzo(a)pyrene (BaP) is a typical EDC that is widespread in the environment. Previous studies have detected BaP in human urine, semen, cervical mucus, oocytes and follicular fluid, resulting in reduced fertility and irreversible reproductive damage. However, the mechanisms underlying the effects of gestational BaP exposure on offspring fertility in male mice have not been fully explored. In this study, pregnant mice were administered BaP at doses of 0, 5, 10 and 20 mg/kg/day via gavage from Days 7.5 to 12.5 of gestation. The results revealed that BaP exposure during pregnancy disrupted the structural integrity of testicular tissue, causing a disorganized arrangement of spermatogenic cells, compromised sperm quality, elevated levels of histone modifications and increased apoptosis in the testicular tissue of F1 male mice. Furthermore, oxidative stress was also increased in the testicular tissue of F1 male mice. BaP activated the AhR/ERα signaling pathway, affected H3K4me3 expression and induced apoptosis in testicular tissue. AhR and Cyp1a1 were overexpressed, and the expression of key molecules in the antioxidant pathway, including Keap1 and Nrf2, was reduced. The combined effects of these molecules led to apoptosis in testicular tissues, damaging and compromising sperm quality. This impairment in testicular cells further contributed to compromised testicular tissues, ultimately impacting the reproductive health of F1 male mice.
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Apoptosis , Benzo(a)pireno , Estrés Oxidativo , Animales , Benzo(a)pireno/toxicidad , Masculino , Femenino , Ratones , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Embarazo , Testículo/efectos de los fármacos , Testículo/metabolismo , Disruptores Endocrinos/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Células Germinativas/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Exposición Materna/efectos adversos , Histonas/metabolismo , Código de Histonas/efectos de los fármacosRESUMEN
BACKGROUND: Corynebacterium striatum (C. striatum), a common skin and mucosal colonizer, is increasingly considered as an opportunistic pathogen causing bloodstream infections (BSIs). This study aims to investigate the clinical features and outcomes of C. striatum-BSI. METHODS: We included hospitalized cases with C. striatum-positive blood cultures from January 2014 to June 2022 and classified them into C. striatum-BSI group and contamination group; Clinical characteristics, treatments, and outcomes were compared between the C. striatum-BSI group and contamination group, Methicillin-resistant Staphylococcus aureus (MRSA)-BSI and Methicillin-resistant Staphylococcus epidermidis (MRSE)-BSI. RESULTS: Fifty-three patients with positive C. striatum blood cultures were identified. Among them, 25 patients were classified as C. striatum-BSI, with 21 as contamination cases. And 62 cases of MRSA-BSI and 44 cases of MRSE-BSI were identified. Compared to the contaminated group, the C. striatum-BSI group had a shorter time to positivity of blood cultures (27.0 h vs. 42.5 h, P = 0.011). C. striatum-BSI group had a longer time to positivity (27 h) when compared to both the MRSA (20 h) and MRSE groups (19 h) (p < 0.05). Appropriate therapy within 24 h of BSI onset was significantly lower in the C. striatum group (28%) compared to the MRSA (64.5%) and MRSE (65.9%) groups (p < 0.005). The 28-day mortality was higher in the C. striatum group (52.0%) compared to the MRSA (25.8%) and MRSE (18.2%) groups. CONCLUSIONS: Given the distinct characteristics of C. striatum-BSI, including a longer time to positivity than other Gram-positive bacteria and higher mortality rates, we suggest prescribing early appropriate antibiotics if C. striatum-BSI is suspected.
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Bacteriemia , Infecciones por Corynebacterium , Corynebacterium , Staphylococcus aureus Resistente a Meticilina , Humanos , Corynebacterium/aislamiento & purificación , Corynebacterium/clasificación , Corynebacterium/genética , Masculino , Femenino , Persona de Mediana Edad , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Infecciones por Corynebacterium/microbiología , Infecciones por Corynebacterium/tratamiento farmacológico , Bacteriemia/microbiología , Bacteriemia/tratamiento farmacológico , Bacteriemia/mortalidad , Anciano , Staphylococcus epidermidis/aislamiento & purificación , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/mortalidad , Infecciones Estafilocócicas/tratamiento farmacológico , Adulto , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Estudios Retrospectivos , Anciano de 80 o más AñosRESUMEN
De novo purine synthesis metabolism plays a crucial role in tumor cell survival and malignant progression. However, the specific impact of this metabolic pathway on chemoresistance in ovarian cancer remains unclear. This study aims to elucidate the influence of de novo purine synthesis on chemoresistance in ovarian cancer and its underlying regulatory mechanisms. We analyzed metabolic differences between chemosensitive and chemoresistant ovarian cancer tissues using mass spectrometry-based metabolomics. Cell growth, metabolism, chemoresistance, and DNA damage repair characteristics were assessed in vitro using cell line models. Tumor growth and chemoresistance were assessed in vivo using ovarian cancer xenograft tumors. Intervention of purines and NEK6-mediated purine metabolism on chemoresistance was investigated at multiple levels. Chemoresistant ovarian cancers exhibited higher purine abundance and NEK6 expression. Inhibiting NEK6 led to decreased de novo purine synthesis, resulting in diminished chemoresistance in ovarian cancer cells. Mechanistically, NEK6 directly interacted with FOXO3, contributing to the phosphorylation of FOXO3 at S7 through its kinase activity, thereby inhibiting its nuclear translocation. Nuclear FOXO3 promoted FBXW7 transcription, leading to c-MYC ubiquitination and suppression of de novo purine synthesis. Paeonol, by inhibiting NEK6, suppressed de novo purine synthesis and enhanced chemosensitivity. The NEK6-mediated reprogramming of de novo purine synthesis emerges as a critical pathway influencing chemoresistance in ovarian cancer. Paeonol exhibits the potential to interfere with NEK6, thereby inhibiting chemoresistance.
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Resistencia a Antineoplásicos , Proteína Forkhead Box O3 , Quinasas Relacionadas con NIMA , Neoplasias Ováricas , Proteínas Proto-Oncogénicas c-myc , Purinas , Femenino , Humanos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Proteína Forkhead Box O3/metabolismo , Proteína Forkhead Box O3/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Purinas/farmacología , Purinas/metabolismo , Línea Celular Tumoral , Animales , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Quinasas Relacionadas con NIMA/metabolismo , Quinasas Relacionadas con NIMA/genética , Ratones , Ratones Desnudos , Núcleo Celular/metabolismo , Proteína 7 que Contiene Repeticiones F-Box-WD/metabolismo , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
BACKGROUND: Pharmacogenetics/pharmacogenomics (PGx) focuses on the genetic variation that causes the heterogeneity of pharmacokinetics and drug response among individuals and has the potential to predict individual efficacy and/or side effects. This study aims to investigate and understand the implementation of genetic testing for the personalized medication (GTPM) in children's hospitals in Mainland China. METHODS: A survey was conducted on 50 children's hospitals from 31 provinces, municipalities, and autonomous regions across Mainland China, and statistical analysis and recommendations were made. RESULTS: Questionnaire response was rate of 76.0% (38/50). Data from 15 hospitals conducting GTPM were included in this study, but only 6 hospitals had offered PGx tests for no less than five drug-related genes, and only 5 hospitals had covered more than ten drugs, which was a small scale overall. 20.0% of the laboratories did not conduct internal quality control, and 33.3% did not participate in inter-laboratory quality assessment. 46.7% of the practitioners did not receive external training. The primary goal for GTPM was to optimize drug dosage in the 15 hospitals, while the main challenge for GTPM was the implementation cost. CONCLUSION: Although GTPM in pediatrics has made major progress in Mainland China in recent years, there were still various problems in terms of software, hardware configuration, personnel allocation, business scale, quality control, and result interpretation. This requires joint efforts of health administration, medical insurance departments, researchers, and hospitals to promote and improve GTPM.
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Medicina de Precisión , Humanos , China , Niño , Medicina de Precisión/métodos , Encuestas y Cuestionarios , Pruebas de Farmacogenómica , Hospitales Pediátricos , Farmacogenética , Pueblos del Este de AsiaRESUMEN
BACKGROUND: To investigate the peripapillary retinal nerve fibre layer (RNFL) thickness changes and analyse factors associated with visual recovery of G11778A Leber hereditary optic neuropathy (LHON) patients. METHODS: Patients diagnosed with G11778A LHON between July 2017 and December 2020 in Tongji hospital were included in this follow-up study. Patients were grouped according to disease duration. Variations in the RNFL thickness in each quadrant at different disease stages were characterised using optical coherence tomography. According to the absence or presence of significant visual acuity improvements, LHON patients of disease duration ≥ 6 months were divided into two groups. A bivariate logistic regression model was constructed to analyse the potential factors associated with spontaneous visual recovery. RESULTS: This study included 56 G11778A LHON patients (112 eyes) and 25 healthy controls (50 eyes), with a mean follow-up of 5.25 ± 1.42 months. All quadrants and mean RNFL thicknesses of LHON patients first increased and then decreased, except for the temporal RNFL. As the disease progressed, RNFL thinning slowed; however, gradual RNFL thinning occurred. Logistic regression revealed that baseline best corrected visual acuity was related to spontaneous visual recovery of LHON patients with disease duration ≥ 6 months. CONCLUSION: The pattern of RNFL involvement could be helpful in the differential diagnosis of LHON and other optic neuropathies. LHON patients with better vision are more likely to experience some degree of spontaneous visual acuity recovery after the subacute phase.
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Fibras Nerviosas , Atrofia Óptica Hereditaria de Leber , Células Ganglionares de la Retina , Tomografía de Coherencia Óptica , Agudeza Visual , Humanos , Atrofia Óptica Hereditaria de Leber/fisiopatología , Atrofia Óptica Hereditaria de Leber/diagnóstico , Masculino , Femenino , Fibras Nerviosas/patología , Células Ganglionares de la Retina/patología , Tomografía de Coherencia Óptica/métodos , Estudios de Seguimiento , Adulto , Agudeza Visual/fisiología , Adulto Joven , Disco Óptico/patología , Disco Óptico/diagnóstico por imagen , Adolescente , Persona de Mediana Edad , Estudios Retrospectivos , Campos Visuales/fisiologíaRESUMEN
Transition-metal selenides have been extensively studied as promising electrode materials for supercapacitors. Engineering amorphous/crystalline heterostructures is an effective strategy to improve rich active sites for accelerating redox reaction kinetics but still lacks exploration. In this study, an amorphous/crystalline heterostructure was designed and constructed by selenizing the self-sacrificial template NiMnS to generate amorphous Mn/polycrystalline Ni0.85Se-NiSe2 heterophase via the phase transformation from metal sulfide into metal selenide. The synergy of the complementary multi-components and amorphous/polycrystalline heterophase could enrich electron/ion-transport channels and expose abundant active sites, which accelerated electron/ion transfer and Faradaic reaction kinetics during charging/discharging. As expected, the optimal NiMnSe exhibited a high specific charge (1389.1 C g-1 at 1 A g-1), a good rate capability, and an excellent lifespan (88.9% retention). Moreover, the fabricated NiMnSe//activated carbon device achieved a long cycle life and energy density of 48.0 W h kg-1 at 800 W kg-1, shedding light on the potential for use in practical applications, such as electrochemical energy-storage devices.
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Background/Aims: Recent studies revealed that patients with persistent aminotransferase elevations after antiviral treatment had higher risk of hepatic events; yet its underlying causes remain unclear. Our study aimed to investigate the etiologies of persistent aminotransferase elevations in patients treated with nucleos(t)ide analogs (NAs). Materials and Methods: A retrospective study was conducted on chronic hepatitis B (CHB) patients who had been receiving NA treatment for over a year and had an aminotransferase level greater than 40 IU/mL (more than twice, with a 3-month interval) and subsequently underwent a liver biopsy. Results: The study group included 46 patients (34 males) with a mean age of 44.8 ± 20.3 years (range: 24-71 years).The average dura- tion of NA therapy was 3.7 years (1.1-10.6 years). The etiologies of persistant transaminase elevation were categorized into 4 groups: patients with low hepatitis B virus (HBV) viral load (LVL, n = 11); concurrent non-alcoholic fatty liver disease (NAFLD, n = 12); concurrent other liver diseases (OLD, n = 12); and unknown liver dysfunction (ULD, n = 11). The proportion of G ≥ 2 inflammation was significantly higher in the LVL group (90.9%) compared to NAFLD (33.3%), OLD (50%), and ULD (27.2%) groups (P = .012). The hepatitis B e-antigen (HBeAg)-positive group exhibited a younger age (34.5 ± 10.2 vs. 48.1 ± 9.4 years, P < .001), a lower proportion of fibrosis F ≥ 2 (36.3% vs. 77.1%, P = .012), and a higher prevalence of detectable HBV DNA (54.5% vs.14.2%, P = .00632) compared to the HBeAg-negative group. Conclusion: The etiology of persistent aminotransferase elevations in CHB patients undergoing NAs treatment warrants investigation. Besides the commonly observed NAFLD and low HBV viral load, concurrent presence of other liver diseases requires elucidation.The proportion of G≥2 inflammation was higher in the LVL group.
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Alanina Transaminasa , Antivirales , Hepatitis B Crónica , Carga Viral , Humanos , Masculino , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/sangre , Hepatitis B Crónica/virología , Femenino , Persona de Mediana Edad , Adulto , Estudios Retrospectivos , Antivirales/uso terapéutico , Antivirales/efectos adversos , Anciano , Adulto Joven , Alanina Transaminasa/sangre , Virus de la Hepatitis B , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico , Nucleósidos/uso terapéuticoRESUMEN
BACKGROUND: Considerable interindividual variability for the pharmacokinetics of caffeine in preterm infants has been demonstrated, emphasizing the importance of personalized dosing. This study aimed to develop and apply a repository of currently published population pharmacokinetic (PopPK) models of caffeine in preterm infants to facilitate model-informed precision dosing (MIPD). RESEARCH DESIGN AND METHODS: Literature search was conducted using PubMed, Embase, Scopus, and Web of Science databases. Relevant publications were screened, and their quality was assessed. PopPK models were reestablished to develop the model repository. Covariate effects were evaluated and the concentration-time profiles were simulated. An online simulation and calculation tool was developed as an instance. RESULTS: Twelve PopPK models were finally included in the repository. Preterm infants' age and body size, especially the postnatal age and current weight, were identified as the most clinically critical covariates. Simulated blood concentration-time profiles across these models were comparable. Caffeine citrate-dose regimen should be adjusted according to the age and body size of preterm infants. The developed online tool can be used to facilitate clinical decision-making. CONCLUSIONS: The first developed repository of PopPK models for caffeine in preterm infants has a wide range of potential applications in the MIPD of caffeine.
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BACKGROUND: Puerarin is an isoflavone compound isolated from the roots of a leguminous plant, the wild kudzu. Various functional activities of this compound in multiple diseases have been reported. However, the effect and mechanism of puerarin in improving blood pressure remain non-elucidated. PURPOSE: The current study was designed to assess the preventive effects of puerarin on the onset and progression of hypertension and to verify the hypothesis that puerarin alleviates blood pressure by inhibiting the ROS/TLR4/NLRP3 inflammasome signaling pathway in the hypothalamic paraventricular nucleus (PVN) of salt-induced prehypertensive rats. METHODS: Male Dahl salt-sensitive rats were fed low NaCl salt (3% in drinking water) for the control (NS) group or 8% (HS) to induce prehypertension. Each batch was divided into two group and treated by bilateral PVN microinjection with either artificial cerebrospinal fluid or puerarin through a micro-osmotic pump for 6 weeks. The mean arterial pressure (MAP) was recorded, and samples were collected and analyzed. RESULTS: We concluded that puerarin significantly prevented the elevation of blood pressure and effectively alleviated the increase in heart rate caused by high salt. Norepinephrine (NE) in the plasma of salt-induced prehypertensive rats also decreased upon puerarin chronic infusion. Additionally, analysis of the PVN sample revealed that puerarin pretreatment decreased the positive cells and gene level of TLR4 (Toll-like receptor 4), NLRP3, Caspase-1 p10, NOX2, MyD88, NOX4, and proinflammatory cytokines in the PVN. Puerarin pretreatment also decreased NF-κBp65 activity, inhibited oxidative stress, and alleviated inflammatory responses in the PVN. CONCLUSION: We conclude that puerarin alleviated blood pressure via inhibition of the ROS/TLR4/NLRP3 inflammasome signaling pathway in the PVN, suggesting the therapeutic potential of puerarin in the prevention of hypertension.
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Presión Sanguínea , Inflamasomas , Isoflavonas , Proteína con Dominio Pirina 3 de la Familia NLR , Núcleo Hipotalámico Paraventricular , Especies Reactivas de Oxígeno , Transducción de Señal , Receptor Toll-Like 4 , Animales , Masculino , Ratas , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Hipertensión/inducido químicamente , Hipertensión/tratamiento farmacológico , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Isoflavonas/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Prehipertensión/tratamiento farmacológico , Ratas Endogámicas Dahl , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Cloruro de Sodio Dietético , Receptor Toll-Like 4/metabolismoRESUMEN
Functional materials with organic/inorganic composites as the main matrix and rare earth ion complexes as the guest have shown a very broad application prospect for antibiotic sensors. However, Eu3+-complex often relies on a single fluorescence response signal, which is susceptible to changes in the detection environment and cannot simultaneously detect and remove tetracycline (TC). Herein, green fluorescent covalent two-dimensional organic framework (COF-TD) is synthesized, followed by modification of Eu3+ to synthesize COF-TD@Eu3+. In the ratiometric sensor, Eu3+ serves as the recognition site and specific response probe for TC, while COF-TD is the fluorescence reference and carrier for Eu3+. Due to the antenna effect, TC enhances the red fluorescence of Eu3+, while the green fluorescence of COF-TD remains almost stable. Based on the change of fluorescence intensity and fluorescence color from green to red, the efficient ratiometric sensing can be finished in 1 min. The developed method shows high sensitivity with a detection limit of 0.3 µM and high selectivity to TC which makes the method applicable to detect TC in traditional Chinese medicine preparations. In addition, due to the high specific surface area of COFs and specific adsorption sites, COF-TD@Eu3+ also shows good performance for TC removal. The findings show that the maximum adsorption capacity is 137.3 mg g-1 and the adsorption equilibrium is reached in 30 min. Smartphone assisted COF-TD@Eu3+ for both ratiometric fluorescence detection and detecting the absorption of TC is proposed for the first time. The molecular cryptosteganography that transforms the selective response of COF-TD@Eu3+ to binary strings is anticipated to advance utilization of nanomaterials in logic sensing and information safety.
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Europio , Colorantes Fluorescentes , Límite de Detección , Estructuras Metalorgánicas , Espectrometría de Fluorescencia , Tetraciclina , Europio/química , Estructuras Metalorgánicas/química , Tetraciclina/análisis , Tetraciclina/química , Adsorción , Espectrometría de Fluorescencia/métodos , Colorantes Fluorescentes/química , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/química , Antibacterianos/análisis , Antibacterianos/química , FluorescenciaRESUMEN
BACKGROUND: Immune thrombocytopenia (ITP) is a prevalent autoimmune bleeding disorder, with the primary objective of treatment being the prevention of bleeding. Clinical investigations have indicated that individuals with ITP face an elevated risk of thrombosis, and the occurrence of thromboembolic events in ITP patients can be attributed to a multitude of factors. However, establishing a definitive causal relationship between ITP and thrombosis remains challenging. METHODS: A two-sample Mendelian randomization (MR) study utilizing summary data from FinnGen consortium and UK Biobank was undertaken to investigate the causal association between ITP and thrombosis. The primary analysis employed the inverse-variance weighted (IVW) method, while supplementary analyses were conducted using the MR-Egger, weighted median, and MR-PRESSO approaches. RESULTS: Based on IVW method, there was a statistically significant but small positive correlation between ITP and thrombosis. Specifically, ITP patients exhibited a suggestive positive correlation with myocardial infarction and deep-vein thrombosis. However, our investigation did not identify any causal relationship between ITP and cerebral infarction, arterial embolism, other arterial embolisms, pulmonary embolism, thrombophlebitis, or portal vein thrombosis. Sensitivity analyses further confirmed the accuracy and robustness of these findings. CONCLUSIONS: This study presents empirical support for the causal relationship between ITP and thrombosis. It is important to note that a diminished platelet count does not serve as a preventive measure against thrombus formation. Consequently, when managing a newly diagnosed ITP patient, clinicians need to be aware that there is a slight elevation in the risk of thrombosis during treatment.
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Análisis de la Aleatorización Mendeliana , Púrpura Trombocitopénica Idiopática , Trombosis , Humanos , Púrpura Trombocitopénica Idiopática/epidemiología , Púrpura Trombocitopénica Idiopática/complicaciones , Púrpura Trombocitopénica Idiopática/genética , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/sangre , Trombosis/epidemiología , Trombosis/etiología , Trombosis/diagnóstico , Trombosis/genética , Factores de RiesgoRESUMEN
OBJECTIVES: To determine the pharmacological impact of hesperidin, the main component of Citri Reticulatae Pericarpium, on depressive behavior and elucidate the mechanism by which hesperidin treats depression, focusing on the gut-brain axis. METHODS: Fifty-four Sprague Dawley male rats were randomly allocated to 6 groups using a random number table, including control, model, hesperidin, probiotics, fluoxetine, and Citri Reticulatae Pericarpium groups. Except for the control group, rats in the remaining 5 groups were challenged with chronic unpredictable mild stress (CUMS) for 21 days and housed in single cages. The sucrose preference test (SPT), immobility time in the forced swim test (FST), and number in the open field test (OFT) were performed to measure the behavioral changes in the rats. Enzyme-linked immunosorbent assay was used to determine the levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) in brain tissue, and the histopathology was performed to evaluate the changes of colon tissue, together with sequencing of the V3-V4 regions of 16S rRNA gene on feces to explore the changes of intestinal flora in the rats. RESULTS: Compared to the control group, the rats in the model group showed notable reductions in body weight, SPF, and number in OFT (P<0.01). Hesperidin was found to ameliorate depression induced by CUMS, as seen by improvements in body weight, SPT, immobility time in FST, and number in OFT (P<0.05 or P<0.01). Regarding neurotransmitters, it was found that at a dose of 50 mg/kg hesperidin treatment upregulated the levels of 5-HT and BDNF in depressed rats (P<0.05). Compared to the control group, the colon tissue of the model group exhibited greater inflammatory cell infiltration, with markedly reduced numbers of goblet cells and crypts and were significantly improved following treatment with hesperidin. Simultaneously, the administration of hesperidin demonstrated a positive impact on the gut microbiome of rats treated with CUMS, such as Shannon index increased and Simpson index decreased (P<0.01), while the abundance of Pseudomonadota and Bacteroidota increased in the hesperidin-treated group (P<0.05). CONCLUSION: The mechanism responsible for the beneficial effects of hesperidin on depressive behavior in rats may be related to inhibition of the expressions of BDNF and 5-HT and preservation of the gut microbiota.
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The d-amino acid oxidase (DAAO) is pivotal in obtaining optically pure l-glufosinate (l-PPT) by converting d-glufosinate (d-PPT) to its deamination product. We screened and designed a Rasamsonia emersonii DAAO (ReDAAO), making it more suitable for oxidizing d-PPT. Using Caver 3.0, we delineated three substrate binding pockets and, via alanine scanning, identified nearby key residues. Pinpointing key residues influencing activity, we applied virtual saturation mutagenesis (VSM), and experimentally validated mutants which reduced substrate binding energy. Analysis of positive mutants revealed elongated side-chain prevalence in substrate binding pocket periphery. Although computer-aided approaches can rapidly identify advantageous mutants and guide further design, the mutations obtained in the first round may not be suitable for combination with other advantageous mutations. Therefore, each round of combination requires reasonable iteration. Employing VSM-assisted screening multiple times and after four rounds of combining mutations, we ultimately obtained a mutant, N53V/F57Q/V94R/V242R, resulting in a mutant with a 5097% increase in enzyme activity compared to the wild type. It provides valuable insights into the structural determinants of enzyme activity and introduces a novel rational design procedure.
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D-Aminoácido Oxidasa , Ingeniería de Proteínas , D-Aminoácido Oxidasa/genética , D-Aminoácido Oxidasa/metabolismo , D-Aminoácido Oxidasa/química , Ingeniería de Proteínas/métodos , Especificidad por Sustrato , Mutagénesis , Mutagénesis Sitio-Dirigida/métodos , Aminobutiratos/metabolismo , Modelos Moleculares , Mutación , Sitios de UniónRESUMEN
Gut flora is considered to modulate lipid transport from the intestine into the bloodstream, and thus may potentially participate in the development of GDM. Although previous studies have shown that the intestinal microbiota influences lipid transport and metabolism in GDM, the precise mechanisms remain elusive. To address this, we used a high-fat diet (HFD)-induced GDM mouse model and conducted 16s rRNA sequencing and fecal metabolomics to assess gut microbial community shifts and associated metabolite changes. Western blot, ELISA, and chromatin immunoprecipitation (ChIP) were utilized to elucidate how gut microbiota affect intestinal lipid transport and the insulin sensitivity of hepatic, adipose, and skeletal muscle tissues. We found that HFD impaired the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) in pregnant mice. 16s rRNA sequencing demonstrated profound compositional changes, especially in the relative abundances of Firmicutes and Bacteroidetes. Metabolomics analysis presented a decline in the concentration of short-chain fatty acids (SCFAs) in the GDM group. Western blot analyses showed an upregulation of HDAC3 and a concurrent reduction in H3K27 acetylation in the intestine. ChIP-qPCR showed that PPAR-γ was inhibited, which in turn activated lipid-transporter CD36. ELISA and insulin signaling pathway detection in insulin-target organs showed high concentrations of circulating fatty acids and triglycerides and insulin resistance in insulin-target organs. Our results suggest that gut microbiota is closely associated with the development of GDM, partly because decreased gut flora-associated SCFAs activate CD36 by suppressing the HDAC3-H3K27ac-PPAR-γ axis to transport excessive fatty acids and triglycerides into blood circulation, thereby dysregulating the insulin sensitivity of insulin target organs.
Asunto(s)
Diabetes Gestacional , Dieta Alta en Grasa , Ácidos Grasos Volátiles , Microbioma Gastrointestinal , Histona Desacetilasas , Metabolismo de los Lípidos , Ratones Endogámicos C57BL , PPAR gamma , Animales , Femenino , Embarazo , Diabetes Gestacional/metabolismo , Histona Desacetilasas/metabolismo , Ácidos Grasos Volátiles/metabolismo , PPAR gamma/metabolismo , Ratones , Dieta Alta en Grasa/efectos adversos , Histonas/metabolismo , Resistencia a la InsulinaRESUMEN
Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.