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OBJECTIVE: The aim of this study was to assess right atrial (RA) function, including RA phase strain, via speckle-tracking echocardiography (STE) in a cohort of systemic lupus erythematosus (SLE) patients with pulmonary arterial hypertension (PAH) and in particular to explore the relationship between RA phase strain and the occurrence of cardiovascular events. METHODS: STE analyses of RA function were evaluated in patients with SLE-PAH and in 33 healthy control subjects. Clinical associations, serum biomarkers, echocardiographic data, survival times, and adverse cardiovascular events were evaluated. RESULTS: A total of 66 patients with SLE-PAH were enrolled; they were divided into two groups based on the occurrence of adverse clinical events. RA phase strain was significantly reduced in patients with events than in patients without events. The endpoint was defined as the combined outcome of all-cause mortality, right heart failure, and rehospitalization due to disease progression. During a mean follow-up of 17.2 ± 9.9 months, 23 patients (35%) reached the endpoint. Compared with patients with RA reservoir strain (RASr) ≥33.45%, patients with RASr < 33.45% had more adverse long-term outcomes (log rank p < .0001). RASr was independently associated with adverse clinical outcomes according to multivariate analysis (p = .010). CONCLUSION: Our data suggest that RA function has prognostic value for SLE-PAH patients, and strain analysis revealed that the worse the RA function is, the worse the prognosis.

Asunto(s)

Ecocardiografía , Atrios Cardíacos , Lupus Eritematoso Sistémico , Humanos , Femenino , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/fisiopatología , Masculino , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/fisiopatología , Pronóstico , Ecocardiografía/métodos , Persona de Mediana Edad , Adulto , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/complicaciones , Hipertensión Arterial Pulmonar/etiología , Hipertensión Arterial Pulmonar/sangre , Función del Atrio Derecho/fisiología , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/etiología , Estudios de Seguimiento

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The phytohormone abscisic acid (ABA) is an important regulator of plant growth, but its potential participation in the process of in vitro shoot regeneration has not to date been reported. Here, we found that ABA appeared to inhibit in vitro shoot regeneration. ABA represses the formation of stem cell niches, thereby reducing the shoot regeneration by localizing the expression of WUSCHEL (WUS). During in vitro shoot regeneration, enrichment of H3K9ac in the specific region of WUS is a necessary event for its activation which could be inhibited by exogenous ABA. These findings reveal the potential function, as well as the possible way of ABA in regulating de novo shoot regeneration in Arabidopsis.

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Background: Ovarian cancer has brought serious threats to female health. CCAAT/enhancer binding proteins (C/EBPs) are key transcription factors involved in ovarian cancer. Therefore, comprehensive profiling C/EBPs in ovarian cancer is needed. Methods: A comprehensive analysis concerning C/EBPs in ovarian cancer was performed. Firstly, detailed expression of C/EBP family members was integrally retrieved and then confirmed using immunohistochemistry. The regulatory effects and transcription regulatory functions of C/EBPs were studied by using regulatory network analysis and enrichment analysis. Using survival analysis, receiver operating characteristic curve analysis, and target-disease association analysis, the predictive prognostic value of C/EBPs on survival and drug responsiveness was systematically evaluated. The effects of C/EBPs on tumor immune infiltration were also assessed. Results: Ovarian cancer tissues expressed increased CEBPA, CEBPB, and CEBPG but decreased CEBPD when compared with normal control tissues. The overall alteration frequency of C/EBPs in ovarian cancer was approaching 30%. C/EBP family members formed a reciprocal regulatory network involving carcinogenesis and had pivotal transcription regulatory functions. C/EBPs could affect survival of ovarian cancer and correlated with poor survival outcomes (OS: HR = 1.40, P = .0053 and PFS: HR = 1.41, P = .0036). Besides, expression of CEBPA, CEBPB, CEBPD, and CEBPE could predict platinum and taxane responsiveness of ovarian cancer. C/EBPs also affected immune infiltration of ovarian cancer. Conclusions: C/EBPs were closely involved in ovarian cancer and exerted multiple biological functions. C/EBPs could be exploited as prognostic and predictive biomarkers in ovarian cancer.

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AIMS: Type 2 diabetes mellitus (T2DM) is related to an increased risk of postoperative cognitive dysfunction (POCD), which may be caused by neuronal hyperexcitability. Astrocyte glutamate transporter 1 (GLT-1) plays a crucial role in regulating neuron excitability. We investigated if T2DM would magnify the increased neuronal excitability induced by anesthesia/surgery (A/S) and lead to POCD in young adult mice, and if so, determined whether these effects were associated with GLT-1 expression. METHODS: T2DM model was induced by high fat diet (HFD) and injecting STZ. Then, we evaluated the spatial learning and memory of T2DM mice after A/S with the novel object recognition test (NORT) and object location test (OLT). Western blotting and immunofluorescence were used to analyze the expression levels of GLT-1 and neuronal excitability. Oxidative stress reaction and neuronal apoptosis were detected with SOD2 expression, MMP level, and Tunel staining. Hippocampal functional synaptic plasticity was assessed with long-term potentiation (LTP). In the intervention study, we overexpressed hippocampal astrocyte GLT-1 in GFAP-Cre mice. Besides, AAV-Camkllα-hM4Di-mCherry was injected to inhibit neuronal hyperexcitability in CA1 region. RESULTS: Our study found T2DM but not A/S reduced GLT-1 expression in hippocampal astrocytes. Interestingly, GLT-1 deficiency alone couldn't lead to cognitive decline, but the downregulation of GLT-1 in T2DM mice obviously enhanced increased hippocampal glutamatergic neuron excitability induced by A/S. The hyperexcitability caused neuronal apoptosis and cognitive impairment. Overexpression of GLT-1 rescued postoperative cognitive dysfunction, glutamatergic neuron hyperexcitability, oxidative stress reaction, and apoptosis in hippocampus. Moreover, chemogenetic inhibition of hippocampal glutamatergic neurons reduced oxidative stress and apoptosis and alleviated postoperative cognitive dysfunction. CONCLUSIONS: These findings suggest that the adult mice with type 2 diabetes are at an increased risk of developing POCD, perhaps due to the downregulation of GLT-1 in hippocampal astrocytes, which enhances increased glutamatergic neuron excitability induced by A/S and leads to oxidative stress reaction, and neuronal apoptosis.

Asunto(s)

Astrocitos , Diabetes Mellitus Tipo 2 , Regulación hacia Abajo , Transportador 2 de Aminoácidos Excitadores , Hipocampo , Ratones Endogámicos C57BL , Complicaciones Cognitivas Postoperatorias , Animales , Transportador 2 de Aminoácidos Excitadores/metabolismo , Transportador 2 de Aminoácidos Excitadores/biosíntesis , Transportador 2 de Aminoácidos Excitadores/genética , Astrocitos/metabolismo , Complicaciones Cognitivas Postoperatorias/etiología , Complicaciones Cognitivas Postoperatorias/metabolismo , Hipocampo/metabolismo , Ratones , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones Transgénicos

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Rationale: Extrachromosomal circular DNA is a hallmark of cancer, but its role in shaping the genome heterogeneity of urothelial bladder carcinoma (UBC) remains poorly understood. Here, we comprehensively analyzed the features of extrachromosomal circular DNA in 80 UBC patients. Methods: We performed whole-genome/exome sequencing (WGS/WES), Circle-Seq, single-molecule real-time (SMRT) long-read sequencing of circular DNA, and RNA sequencing (RNA-Seq) on 80 pairs of tumor and AT samples. We used our newly developed circular DNA analysis software, Circle-Map++ to detect small extrachromosomal circular DNA from Circle-Seq data. Results: We observed a high load and significant heterogeneity of extrachromosomal circular DNAs in UBC, including numerous single-locus and complex chimeric circular DNAs originating from different chromosomes. This includes highly chimeric circular DNAs carrying seven oncogenes and circles from nine chromosomes. We also found that large tumor-specific extrachromosomal circular DNAs could influence genome-wide gene expression, and are detectable in time-matched urinary sediments. Additionally, we found that the extrachromosomal circular DNA correlates with hypermutation, copy number variation, oncogene amplification, and clinical outcome. Conclusions: Overall, our study provides a comprehensive extrachromosomal circular DNA map of UBC, along with valuable data resources and bioinformatics tools for future cancer and extrachromosomal circular DNA research.

Asunto(s)

Variaciones en el Número de Copia de ADN , ADN Circular , Neoplasias de la Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/genética , Humanos , ADN Circular/genética , Variaciones en el Número de Copia de ADN/genética , Secuenciación Completa del Genoma/métodos , Heterogeneidad Genética , Masculino , Femenino , Secuenciación del Exoma/métodos , Anciano , Mutación/genética

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In this study, the PVA/starch blend films were prepared by dry melting method. The microstructure showed that the starch existed in the continuous PVA matrix in granular structure. When the amount of starch was 30 wt%, the tensile strength increased from 12.8 to 14.7 MPa, and the elastic modulus increased from 15.4 to 20.5 MPa, and the water absorption increased by about 2 %. The addition of starch increased the Tmax by 8.1-29.64 °C compared to pure PVA. Considering the mechanical, hydrophilic and optical properties of the blend films, PVA/starch at 7:3 was the most promising packaging material. Notably, the blend films exhibit great reusability and renewability. Overall, these findings highlight the potential of PVA/starch blend films as environmentally friendly materials with enhanced properties.

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Alzheimer's disease (AD, also known as dementia) has become a serious global health problem along with population aging, and neuroinflammation is the underlying cause of cognitive impairment in the brain. Nowadays, the development of multitarget anti-AD drugs is considered to be one effective approach. Imidazolylacetophenone oxime ethers or esters (IOEs) were multifunctional agents with neuroinflammation inhibition, metal chelation, antioxidant and neuroprotection properties against Alzheimer's disease. In this study, IOEs derivatives 1-8 were obtained by structural modifications of the oxime and imidazole groups, and the SARs showed that (Z)-oxime ether (derivative 2) had stronger anti-neuroinflammatory and neuroprotective ability than (E)-congener. Then, IOEs derivatives 9-30 were synthesized based on target-directed ligands and activity-based groups hybridization strategy. In vitro anti-AD activity screening revealed that some derivatives exhibited potentially multifunctional effects, among which derivative 28 exhibited the strongest inhibitory activity on NO production with EC50 value of 0.49 µM, and had neuroprotective effects on 6-OHDA-induced cell damage and RSL3-induced ferroptosis. The anti-neuroinflammatory mechanism showed that 28 could inhibit the release of pro-inflammatory factors PGE2 and TNF-α, down-regulate the expression of iNOS and COX-2 proteins, and promote the polarization of BV-2 cells from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. In addition, 28 can dose-dependently inhibit acetylcholinesterase (AChE) and Aß42 aggregation. Moreover, the selected nuclide [18F]-labeled 28 was synthesized to explore its biodistribution by micro-PET/CT, of which 28 can penetrate the blood-brain barrier (BBB). These results shed light on the potential of 28 as a new multifunctional candidate for AD treatment.

Asunto(s)

Acetofenonas , Enfermedad de Alzheimer , Diseño de Fármacos , Imidazoles , Fármacos Neuroprotectores , Oximas , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Oximas/química , Oximas/farmacología , Oximas/síntesis química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/síntesis química , Animales , Relación Estructura-Actividad , Imidazoles/farmacología , Imidazoles/química , Imidazoles/síntesis química , Acetofenonas/química , Acetofenonas/farmacología , Acetofenonas/síntesis química , Estructura Molecular , Humanos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Acetilcolinesterasa/metabolismo , Relación Dosis-Respuesta a Droga , Ratas , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química

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A new convenient method for identifying colorant compounds (CCs) in food matrices was developed using high-performance liquid chromatography with a diode array detector and quadrupole-time-of-flight mass spectrometer (HPLC-DAD-Q/TOF-MS) combined with theoretical calculations. A model sample containing three typical CCs was completely separated via HPLC-DAD. The obtained 3D ultraviolet-visible (UV-vis) spectra revealed the maximum absorption wavelengths (MAWs) of all CCs (yellow, 430 nm; red, 520 nm; blue, 620 nm) in the range of 400-800 nm, and their colors were determined based on their MAWs. Temporary structures of the CCs were obtained using Q/TOF-MS analysis. Theoretical calculations were then performed to obtain the theoretical MAWs and colors of the CCs according to their calculated UV-vis spectra based on temporary structures. The structures of the CCs were confirmed without the need for authoritative standards by comparing the consistency between their experimental and theoretical MAWs and colors. This method is particularly suitable for identifying CCs or compounds with UV-Vis absorption, including new compounds, compounds for which standards are difficult to obtain, and known compounds without reporting relevant molecular information.

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Simultaneous detection of the dynamic distribution of long-chain fatty acid ethyl esters (LCFAEEs) during Baijiu distillation is crucial for optimizing its flavor and health attributes. In this study, we synthesized a simple, cost-effective Fe3O4@NH2 adsorbent to simultaneously extract eight LCFAEEs from Baijiu. Through density functional theory and adsorption experiments, we elucidated 1,6-hexanediamine as a surface modifier, with the -NH2 groups providing adsorption sites for the LCFAEEs via hydrogen-bonding interactions and van der Waals forces. Additionally, we established the magnetic solid-phase extraction-GC-MS extraction technique combined with stable isotope dilution analysis to analyze LCFAEEs. This method revealed the dynamic distribution patterns of LCFAEEs during strong aroma-type Baijiu (SAB) distillation. We observed that the concentrations of the eight LCFAEEs gradually decreased with prolonged distillation and were significantly correlated with ethanol concentration. To ensure optimal flavor and clarity in SAB, it is recommended to select the heart-stage base Baijiu with an alcohol content of 58%-63%.

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Alzheimer disease (AD) is a prevalent neurodegenerative disorder that affects synapses and leads to progressive cognitive decline. The role of N-methyl-D-aspartic acid (NMDA) receptors in the pathogenesis of AD is well-established as they contribute to excitotoxicity and neurodegeneration in the pathological process of extrasynaptic glutamate concentration. However, the therapeutic potential of the NMDA receptor antagonist memantine in rescuing synaptic damage is limited. Research indicates that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors also play a significant role in AD. Abnormal transcription, expression, and localization of AMPA receptors lead to synaptic dysfunction and damage, contributing to early cognitive impairment in AD patients. Understanding the impact of AMPA receptors on AD pathogenesis and exploring the potential for the development of AMPA receptor-targeting drugs are crucial. This review aims to consolidate recent research findings on AMPA receptors in AD, elucidate the current state of AMPA receptor research and lay the foundation for future basic research and drug development.

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Acute kidney injury (AKI) is a major public health problem worldwide that still lacks effective treatments. Recent studies have suggested that ferroptosis is a key mediator of AKI due to its activation of lipid peroxidation. Therefore, we hypothesized that antiferroptosis agents might be a novel potential therapeutic strategy for AKI. Herein, we demonstrated that liquiritigenin (LG), an active ingredient of liquorice, improves renal function by inhibiting vitamin K epoxide reductase complex subunit 1 (VKORC1)-mediated ferroptosis, both in vivo and in vitro. In a folic acid-induced murine AKI model, after a single pre-treatment intravenous injection, LG markedly alleviated the loss of renal function through suppressing ferroptosis induced by iron accumulation. LG prevented mitochondrial morphological changes and upregulated glutathione and glutathione peroxidase 4 levels, while downregulating malonaldehyde and divalent iron levels. An in vitro RNA-sequence analysis suggested that the protective role of LG may involve upregulation of VKORC1. Moreover, knockdown of VKORC1 diminished the renal protective and antiferroptosis roles of LG. Collectively, our findings demonstrated that LG protected against AKI by inhibiting VKORC1-mediated ferroptosis. This suggests that inhibiting ferroptosis might be a novel therapeutic approach in the future.

RESUMEN

When IL-1 receptor antagonist (IL-1rn) is knocked out, mice have shown strain background dependent and major QTL regulated susceptibility to spontaneously inflammatory arthritis disease (SAD). The impact on bone properties resulting from the interactions of IL-1rn, genomic background strains, and the QTL locus, is unknown. Bone properties in the four specifically bred mouse strains with mutation of IL-1rn and variations in genomic components were investigated with high-resolution MicroCT and genomic analytical tools. Two congenic mouse strains were also measured to evaluate the influence on bone properties by a QTL in the region in chromosome 1. Our results reveal that several bone phenotypes, including bone mineral density (BMD), bone volume, tibial length, and cortical thickness of the tibia are different between wild type and IL-1rn knockout mice in both Balb/c and DBA/1 backgrounds, but IL-1rn knockout affects BMD differently between the two mouse strains. The absence of IL-1rn decreases BMD in Balb/c mice but increases BMD in DBA/1-/- mice compared to their respective wild type counterparts. A QTL transferred from the Balb/c genetic background which affects arthritis in congenic strains appears to also regulate BMD. While several genes, including Ctsg and Prg2, may affect BMD, Ifi202b is the most favored candidate gene for regulating BMD as well as SAD. In conclusion, the previously mentioned bone phenotypes are each influenced in different ways by the loss of IL-1ra when considered in mice from varying genomic backgrounds.

Asunto(s)

Densidad Ósea , Proteína Antagonista del Receptor de Interleucina 1 , Ratones Noqueados , Sitios de Carácter Cuantitativo , Animales , Ratones , Densidad Ósea/genética , Proteína Antagonista del Receptor de Interleucina 1/genética , Proteína Antagonista del Receptor de Interleucina 1/deficiencia , Ratones Endogámicos BALB C , Huesos/metabolismo , Huesos/diagnóstico por imagen , Huesos/patología , Ratones Endogámicos DBA , Masculino , Fenotipo , Microtomografía por Rayos X , Enfermedades Autoinflamatorias Hereditarias

RESUMEN

BACKGROUND: Pediatric patients undergoing liver transplantation are particularly susceptible to complications arising from intraoperative fluid management strategies. Conventional liberal fluid administration has been challenged due to its association with increased perioperative morbidity. This study aimed to assess the impact of intraoperative high-volume fluid therapy on pediatric patients who are undergoing living donor liver transplantation (LDLT). METHODS: Conducted at the Children's Hospital of Chongqing Medical University from March 2018 to April 2021, this retrospective study involved 90 pediatric patients divided into high-volume and non-high-volume fluid administration groups based on the 80th percentile of fluid administered. We collected the perioperative parameters and postoperative information of two groups. Multivariable logistic regression was utilized to assess the association between estimated blood loss (EBL) and high-volume FA. Kaplan-Meier survival analysis was used to compare patient survival after pediatric LDLT. RESULTS: Patients in the high-volume FA group received a higher EBL and longer length of stay than that in the non-high-volume FA group. Multivariate logistic regression analysis indicated that hours of maintenance fluids and fresh frozen plasma were significantly associated risk factors for the occurrence of EBL during pediatric LDLT. In addition, survival analysis showed no significant differences in one-year mortality between the groups. CONCLUSIONS: High-volume fluid administration during LDLT is linked with poorer intraoperative and postoperative outcomes among pediatric patients. These findings underscore the need for more conservative fluid management strategies in pediatric liver transplantations to enhance recovery and reduce complications.

Asunto(s)

Fluidoterapia , Cuidados Intraoperatorios , Trasplante de Hígado , Donadores Vivos , Humanos , Masculino , Femenino , Fluidoterapia/métodos , Estudios Retrospectivos , Preescolar , Niño , Cuidados Intraoperatorios/métodos , Lactante , Resultado del Tratamiento , Pérdida de Sangre Quirúrgica/estadística & datos numéricos , Tiempo de Internación/estadística & datos numéricos , Adolescente

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Despite recent studies implicating liquid-like biomolecular condensates in diverse cellular processes, many biomolecular condensates exist in a solid-like state, and their function and regulation are less understood. We show that the tumor suppressor Merlin, an upstream regulator of the Hippo pathway, localizes to both cell junctions and medial apical cortex in Drosophila epithelia, with the latter forming solid-like condensates that activate Hippo signaling. Merlin condensation required phosphatidylinositol-4-phosphate (PI4P)-mediated plasma membrane targeting and was antagonistically controlled by Pez and cytoskeletal tension through plasma membrane PI4P regulation. The solid-like material properties of Merlin condensates are essential for physiological function and protect the condensates against external perturbations. Collectively, these findings uncover an essential role for solid-like condensates in normal physiology and reveal regulatory mechanisms for their formation and disassembly.

Asunto(s)

Condensados Biomoleculares , Proteínas de Drosophila , Drosophila melanogaster , Vía de Señalización Hippo , Neurofibromina 2 , Animales , Membrana Celular/metabolismo , Drosophila melanogaster/metabolismo , Drosophila melanogaster/genética , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Uniones Intercelulares/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Neurofibromina 2/metabolismo , Neurofibromina 2/genética , Fosfatos de Fosfatidilinositol/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Condensados Biomoleculares/metabolismo

RESUMEN

In the present study, the in vivo absorption and fecal excretion of a purified fraction of polysaccharides from the fruits of Lycium barbarum L. (LBPs-4) in rats were investigated by labelling LBPs-4 with fluorescein isothiocyanate (FITC). It was found that the fluorescent labeled LBPs-4 (LBPs-4-FITC) was not detected in the plasma within 24 h following the administration of a single dose of LBPs-4-FITC (100 mg/kg of body weight) to rats, indicating that LBPs-4 was hardly absorbed in its prototype form. Instead, a smaller fragment dissociated from LBPs-4-FITC was observed in feces and was accumulated in a time-dependent manner, suggesting that LBPs-4 was excreted into the feces with a form of degradation. Meanwhile, we observed that LBPs-4-FTIC could modulate the fecal bacterial community profile via increasing the relative abundances of Bacteroides ovatus and Alistipes and promote the production of acetic acid. Furthermore, the monoculture experiment confirmed that LBPs-4 could be metabolized into smaller fragment by B. ovatus, producing acetic acid. Collectively, our study provides information on the destiny of LBPs-4 after oral administration: non-absorbed but moved to the large intestine and catabolized by gut microbiota, especially B. ovatus.

Asunto(s)

Heces , Frutas , Lycium , Polisacáridos , Animales , Heces/química , Lycium/química , Ratas , Frutas/química , Polisacáridos/química , Masculino , Microbioma Gastrointestinal/efectos de los fármacos , Ratas Sprague-Dawley

RESUMEN

Osteogenesis is tightly coupled with angiogenesis spatiotemporally. Previous studies have demonstrated that type H blood vessel formed by endothelial cells with high expression of CD31 and Emcn (CD31hi Emcnhi ECs) play a crucial role in bone regeneration. The mechanism of the molecular communication around CD31hi Emcnhi ECs and bone mesenchymal stem cells (BMSCs) in the osteogenic microenvironment is unclear. This study indicates that exosomes from bone mesenchymal stem cells with 7 days osteogenic differentiation (7D-BMSCs-exo) may promote CD31hi Emcnhi ECs angiogenesis, which was verified by tube formation assay, qRT-PCR, Western blot, immunofluorescence staining and µCT assays etc. in vitro and in vivo. Furthermore, by exosomal miRNA microarray and WGCNA assays, we identified downregulated miR-150-5p as the most relative hub gene coupling osteogenic differentiation and type H blood vessel angiogenesis. With bioinformatics assays, dual luciferase reporter experiments, qRT-PCR and Western blot assays, SOX2(SRY-Box Transcription Factor 2) was confirmed as a novel downstream target gene of miR-150-5p in exosomes, which might be a pivotal mechanism regulating CD31hi Emcnhi ECs formation. Additionally, JC-1 immunofluorescence staining, Western blot and seahorse assay results showed that the overexpression of SOX2 could shift metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis to enhance the CD31hi Emcnhi ECs formation. The PI3k/Akt signaling pathway might play a key role in this process. In summary, BMSCs in osteogenic differentiation might secrete exosomes with low miR-150-5p expression to induce type H blood vessel formation by mediating SOX2 overexpression in ECs. These findings might reveal a molecular mechanism of osteogenesis coupled with type H blood vessel angiogenesis in the osteogenic microenvironment and provide a new therapeutic target or cell-free remedy for osteogenesis impaired diseases.

Asunto(s)

Diferenciación Celular , Células Endoteliales , Exosomas , Células Madre Mesenquimatosas , MicroARNs , Neovascularización Fisiológica , Osteogénesis , MicroARNs/genética , MicroARNs/metabolismo , Exosomas/metabolismo , Osteogénesis/genética , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Diferenciación Celular/genética , Neovascularización Fisiológica/genética , Animales , Células Endoteliales/metabolismo , Células Endoteliales/citología , Ratones , Humanos , Células Cultivadas , Transducción de Señal , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/genética , Factores de Transcripción SOXB1/metabolismo , Factores de Transcripción SOXB1/genética , Reprogramación Metabólica , Angiogénesis

RESUMEN

Acute kidney injury (AKI) is a prevalent and potentially life-threatening complication characterized by a high incidence and mortality. A large number of studies have emphasized the role of ferroptosis in AKI. Moreover, FBXW7, a ubiquitin ligase, has been implicated in acute organ injury. Analysis of the GEO database (GSE98622) revealed increased FBXW7 mRNA levels in the kidney following ischemia‒reperfusion (IR). However, the role of FBXW7 in AKI has not been elucidated. Therefore, this study aimed to investigate the role of FBXW7 in IR-AKI and its underlying mechanisms. Here, we found that IR could induce AKI and increase FBXW7 expression, while the ferroptosis inhibitor Fer-1 alleviated AKI and decreased FBXW7 expression. Furthermore, we treated HK-2 cells with hypoxia for 12 h and reoxygenation for 4 h (H12R4) to simulate IR-AKI and investigated the impact of modulating FBXW7 expression on ferroptosis by employing ferroptosis-related agonists or inhibitors. Our findings revealed that H12R4 induced HK2 ferroptosis and increased the expression of FBXW7. FBXW7 overexpression in control cells exacerbated erastin-induced ferroptosis, and FBXW7 knockdown inhibited ferroptosis in H12R4-treated cells. Mechanistically, we confirmed that FBXW7 can bind to GPX4, a key molecule that inhibits ferroptosis. The half-life of the GPX4 protein decreased after FBXW7 overexpression, GPX4 ubiquitination increased after H12R4, and GPX4 degradation decreased after FBXW7 knockdown. In conclusion, our results indicated that FBXW7 plays an important role in the development of IR-AKI by promoting ferroptosis through the downregulation of GPX4 expression. This study provides new insight into FBXW7 as a potential target for treating AKI.

RESUMEN

Therapeutic drug monitoring (TDM) of imatinib (IM) in cancer therapy offers the potential to improve treatment efficacy while minimizing toxicity. There was a significant correlation between unbound concentration and clinical response and toxicity, compared with total plasma concentrations, and the quantification of unbound IM and its metabolite, N-desmethyl imatinib (NDI) are of interest for TDM. However, traditional unbound drug separation methods have shortcomings, especially are susceptible to non-specific binding (NSB) of drugs to the polymer-constructed components of filter membranes, which are difficult to avoid at present. Hence it is necessary to developed a reliable separation method for the analysis of the unbound fraction of IM and NDI in TDM. We developed and validated an hollow fiber solid phase microextraction (HF-SPME) method coupled with high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) that to measure unbound IM and NDI concentration in human plasma. It used the NSB phenomenon and solve the NSB problem. The preparation procedure only involves a common vortex and ultrasonication without dilution of samples and modification of membrane. A total of 50 chronic myeloid leukemia (CML) patients were enrolled in our study. The relationship between the unbound and total concentrations for IM and NDI, as well as the concentration ratios of NDI to IM in 50 clinical plasma samples were investigated. The extraction recovery is high to 95.5-106 % with validation parameters for the methodological results were all excellent. There were both a poor linear relationship between the unbound and total concentrations for IM (r2=0.504) and NDI (r2=0.201) in 50 clinical plasma samples. The unbound concentration ratios of NDI to IM varied widely in CML patients. The determination of unbound IM and NDI concentration is meaningful and necessary. The developed HF-SPME method is simple, accurate and precise that could be used to measure unbound IM and NDI concentration in clinical TDM.

Asunto(s)

Monitoreo de Drogas , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Microextracción en Fase Sólida , Espectrometría de Masas en Tándem , Humanos , Mesilato de Imatinib/sangre , Mesilato de Imatinib/farmacocinética , Microextracción en Fase Sólida/métodos , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas en Tándem/métodos , Monitoreo de Drogas/métodos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Femenino , Masculino , Persona de Mediana Edad , Adulto , Reproducibilidad de los Resultados

RESUMEN

OBJECTIVE: To compare the safety and clinical efficacy of freehand and 3D printing navigation template assisted screw placement in patients with old odontoid fractures of typeⅡ. METHODS: Total of 38 patients with old odontoid fractures of typeⅡwere treated from November 2018 to December 2022, all of which presented as chronic neck pain. According to the different methods of screw insertion into the pedicle, the patients were divided into a navigation template group and a freehand group. In the navigation template group, there were 17 patients including 9 males and 8 females with an average age of (51.30±13.20) years old, disease duration was (22.18±7.59) months. In the freehand group, there 21 patients including 7 males and 14 females with an average age of (49.46±11.92) years old, disease duration was (19.52±9.17) months. The intraoperative blood loss, operation time, and postoperative drainage output were recorded and compared between two groups. The accuracy of screw placement was evaluated by CT scan. Before operation and 1 year after operation, cervical pain was assessed by visual analogue scale(VAS), neurological changes were evaluated by the Japanese Orthopaedic Association (JOA) score, and the degree of spinal cord injury was assessed by the American Spinal Injury Association (ASIA) injury scale. RESULTS: All patients were followed up for (25.31±1.21) months. The operation time of template group (112.00±20.48) min had significantly shorter than that of the freehand group(124.29±15.24) min(P<0.05), while there were no significant differences between two groups in terms of intraoperative blood loss, postoperative drainage, and hospital stay(P>0.05). At 1 year after operation, in template group and freehand group, the VAS [(2.88±0.86), (2.90±0.83)] and JOA [(14.94±1.82), (14.62±2.19)] improved with preoperative [VAS(4.71±0.92), (4.86±0.79) and JOA (12.18±2.30), (11.95±2.31)](P<0.05), with no significant difference between two groups (P>0.05). No significant improvement was observed in ASIA grading in either group at 1 year after operation(P>0.05), and there was no significant difference between two groups(P>0.05). The template group had significantly better accuracy of screw placement in the pedicle of the axis than the freehand group (P<0.05), while no significant difference was observed between two groups in the accuracy of screw placement in the pedicle of the atlas (P>0.05). CONCLUSION: In the treatment of typeⅡold odontoid fractures with posterior pedicle screw fixation, 3D printing navigation template screw placement can significantly shorten the operation time, achieve similar clinical efficacy as free-hand screw placement, and significantly improve the accuracy of screw placement in the pedicle of the axis.

Asunto(s)

Apófisis Odontoides , Tornillos Pediculares , Impresión Tridimensional , Fracturas de la Columna Vertebral , Humanos , Femenino , Masculino , Apófisis Odontoides/lesiones , Apófisis Odontoides/cirugía , Persona de Mediana Edad , Fracturas de la Columna Vertebral/cirugía , Fijación Interna de Fracturas/métodos , Adulto , Anciano , Cirugía Asistida por Computador/métodos

RESUMEN

Purpose: This study aims to investigate patient characteristics with lens zonular ligament abnormalities in Acute Primary Angle Closure (APAC), identifying related risk factors, and evaluating the efficacy of Pilocarpine, a miotic agent. Design: Retrospective case-control study. Methods: Conducted as a retrospective case-control study at Hebei Provincial Eye Hospital from January 1, 2019, to December 31, 2021, the study included APAC cases undergoing ultrasound phacoemulsification with or without glaucoma surgery. Zonular ligament status was determined by intraoperative indicators such as lens equator visibility post-mydriasis and anterior capsule wrinkling during capsulorhexis. Patients were categorized into APAC and APAC with Lens Subluxation (APACLS) groups. Demographic details, Central Anterior Chamber Depth (ACD), Axial Length (AL), ACD difference between eyes (ACDD), Lens Thickness (LT), Lens Position (LP), and Relative Lens Position (RLP) were recorded and compared. Pilocarpine's impact on intraocular pressure reduction was assessed. Statistical analysis involved bilateral t-tests (for normally distributed data comparing both eyes in each group), non-parametric tests (for comparing two groups with non-normally distributed data), binary logistic regression, and Receiver Operating Characteristic (ROC) curve analysis for cutoff value determination related to zonular abnormalities. Results: The APAC and APACLS groups showed no significant difference in age of onset (70.11 ± 8.67 years vs. 70.11 ± 8.67 years, P = 0.159) or axial length of the eye (22.35 ± 0.64 mm vs. 22.36 ± 0.78 mm, P = 0.929). In the APACLS group, LT was greater (5.24 ± 0.37 mm vs. 5.01 ± 0.36 mm, P = 0.011), ACD was shallower (1.42 ± 0.24 mm vs. 1.69 ± 0.24 mm, P = 0.000), and ACDD was larger (0.38 ± 0.22 mm vs. 0.18 ± 0.18 mm, P = 0.000). The LP was lower (4.04 ± 0.32 vs. 4.20 ± 0.22, P = 0.013), and RLP was also lower (0.18 ± 0.02 vs. 0.19 ± 0.01, P = 0.015) in the APACLS group. A shallow ACD and a large ACDD were identified as risk factors associated with lens zonular abnormalities in the affected eyes (ACD OR value 63.97, P = 0.027; ACDD OR value 0.029, P = 0.027). Using ROC curve analysis, the cutoff value for ACDD was determined to be 0.375 mm, and for ACD, it was 1.6 mm. After pupil constriction with Pilocarpine eye drops, the proportion of patients whose intraocular pressure normalized was 75.36 % (52/69) in the APAC group and 71.43 % (25/35) in the APACLS group. Conclusion: ACD and ACDD in the affected eye are indicative of increased risk for APACLS. An ACD <1.6 mm and ACDD >0.375 mm should prompt consideration of zonular ligament abnormalities. Pilocarpine as a miotic treatment is safe and effective for such patients.