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N6-methyladenosine (m6A) methylation regulates gene expression/protein by influencing numerous aspects of mRNA metabolism and contributes to neuropsychiatric diseases. Here, we integrated multi-omics data and genome-wide association study summary data of schizophrenia (SCZ), bipolar disorder (BP), attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), major depressive disorder (MDD), Alzheimer's disease (AD), and Parkinson's disease (PD) to reveal the role of m6A in neuropsychiatric disorders by using transcriptome-wide association study (TWAS) tool and Summary-data-based Mendelian randomization (SMR). Our investigation identified 86 m6A sites associated with seven neuropsychiatric diseases and then revealed 7881 associations between m6A sites and gene expressions. Based on these results, we discovered 916 significant m6A-gene associations involving 82 disease-related m6A sites and 606 genes. Further integrating the 58 disease-related genes from TWAS and SMR analysis, we obtained 61, 8, 7, 3, and 2 associations linking m6A-disease, m6A-gene, and gene-disease for SCZ, BP, AD, MDD, and PD separately. Functional analysis showed the m6A mapped genes were enriched in "response to stimulus" pathway. In addition, we also analyzed the effect of gene expression on m6A and the post-transcription effect of m6A on protein. Our study provided new insights into the genetic component of m6A in neuropsychiatric disorders and unveiled potential pathogenic mechanisms where m6A exerts influences on disease through gene expression/protein regulation.
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BACKGROUND: Integrating quantitative trait loci (QTL) data related to molecular phenotypes with genome-wide association study (GWAS) data is an important post-GWAS strategic approach employed to identify disease-associated molecular features. Various types of molecular phenotypes have been investigated in neuropsychiatric disorders. However, these findings pertaining to distinct molecular features are often independent of each other, posing challenges for having an overview of the mapped genes. METHODS: In this study, we comprehensively summarized published analyses focusing on four types of risk-related molecular features (gene expression, splicing transcriptome, protein abundance, and DNA methylation) across five common neuropsychiatric disorders. Subsequently, we conducted supplementary analyses with the latest GWAS dataset and corresponding deficient molecular phenotypes using Functional Summary-based Imputation (FUSION) and summary data-based Mendelian randomization (SMR). Based on the curated and supplemented results, novel reliable genes and their functions were explored. RESULTS: Our findings revealed that eQTL exhibited superior ability in prioritizing risk genes compared to the other QTL, followed by sQTL. Approximately half of the genes associated with splicing transcriptome, protein abundance, and DNA methylation were successfully replicated by eQTL-associated genes across all five disorders. Furthermore, we identified 436 novel reliable genes, which enriched in pathways related with neurotransmitter transportation such as synaptic, dendrite, vesicles, axon along with correlations with other neuropsychiatric disorders. Finally, we identified ten multiple molecular involved regulation patterns (MMRP), which may provide valuable insights into understanding the contribution of molecular regulation network targeting these disease-associated genes. CONCLUSIONS: The analyses prioritized novel and reliable gene sets related with five molecular features based on published and supplementary results for five common neuropsychiatric disorders, which were missed in the original GWAS analysis. Besides, the involved MMRP behind these genes could be given priority for further investigation to elucidate the pathogenic molecular mechanisms underlying neuropsychiatric disorders in future studies.
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Metilación de ADN , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Trastornos Mentales , Fenotipo , Sitios de Carácter Cuantitativo , Humanos , Sitios de Carácter Cuantitativo/genética , Trastornos Mentales/genética , Metilación de ADN/genética , Análisis de la Aleatorización Mendeliana , Transcriptoma/genéticaRESUMEN
Off-axis integrated cavity output spectroscopy (OA-ICOS) has attracted much interest because it potentially allows highly sensitive field measurements with robust optical alignment. In this paper, a novel instrument that employs a high-finesse optical cavity as an absorption cell has been developed for sensitive measurements of multi-component gases N2O, H2O and CO in the atmosphere based on a mid-infrared quantum cascade laser (QCL) and OA-ICOS. In order to improve the energy utilization and increase the signal-to-noise ratio (SNR) of the signal, a new type of optical path structure of the laser re-injection method is adopted. Furthermore, the system performance can be effectively improved by using a new intervention method of injecting radio frequency (RF) white noise into a laser driver to suppress cavity mode noise and combining the wavelength modulation method (WMS). We compared the sensitivity of the second harmonic signal demodulation between the re-injection method and the standard OA-ICOS, and the SNR increased by 2.68 times compared to the latter. Analysis of the spectral measurements with Allan variance indicates that within an integration time of 1 s, the measurement accuracy of N2O, H2O, and CO is 6.71 ppb, 13.945 ppm, and 1.81 ppb, respectively, and within an integration time of 820 s, the measurement accuracy of N2O, H2O, and CO can be further improved to 1.26 ppb, 2.089 ppm, and 172 ppt, respectively. Our approach represents an underlying analytical method that provides guidelines for monitoring of representative gases in the atmosphere, industrial processes, emergency safety, etc.
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The thermodynamically stable 2H-phase MoS2 is a brilliant material toward hydrogen evolution reaction (HER) owing to its excellent Gibbs free energy of hydrogen adsorption. Nevertheless, the poor intrinsic properties of 2H-MoS2 limit its electrocatalytic performances toward HER. In this work, graphitic carbon nitride covalently bridging 2H-MoS2 (MoS2/GCN) is proposed to construct robust HER electrocatalysts. The strong π-p electron coupling between the delocalized π electrons of GCN and the localized p electrons of S atoms sufficiently expose active sites and accelerate the reaction kinetics. To be specific, MoS2/GCN exhibits remarkable HER activity (160 mV at 10 mA·cm-2) and long-term durability. Importantly, MoS2/GCN also provides great potential for industrial application. Density functional theory (DFT) calculations disclose that the π-p electron coupling at the MoS2/GCN interface regulates the electronic structure of S atoms, consequently providing enhanced HER performance. This work presents a feasible pathway to develop advanced electrocatalysts for energy conversions.
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The "cyan gap" is the bottleneck problem in violet-driven full-spectrum white-light-emitting diodes (wLEDs) in healthy lighting. Accordingly, we develop a novel broadband-blue-cyan emission Na3KMg7(PO4)6-x(BO3)x:Eu2+ (NKMPB:Eu2+) phosphor via crystal-site engineering. This phosphor is derived from the Na3KMg7(PO4)6:Eu2+ phosphor, which shows desired abundant cyan emissive components. A comparative study is conducted to reveal the microstructure-property relationship and the key influential factors to its spectrum distribution. It can be found that the introduced (BO3)3- units can manipulate the site-selective occupation of Eu2+ activators, asymmetrically broadening the emission spectrum in NKMPB:Eu2+. Considering detailed luminescence performance analysis and the density functional theory calculations, a new substitution pathway of Eu2+ is created by substituting (PO4)3- with (BO3)3- units, making partial Eu2+ ions enter the Mg2+ (CN = 5, CN = 6) crystallographic sites, and yielding an extra emission band at 600 nm (16667 cm-1) and especially 501 nm (19960 cm-1). Meanwhile, a high-color-quality full-spectrum-emitting wLEDs was fabricated, upon 100 mA forward-bias current driven. Due to the achieved extra cyan emissive components of NKMPB:Eu2+, the constructed NKMPB:Eu2+-based wLEDs show better color rendering ability (â¼90.9) than that of Na3KMg7(PO4)6:Eu2+-based wLEDs (â¼86.3), and also demonstrate its great potential in full-spectrum healthy lighting.
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Pyroptosis is a key inflammatory form of cell death participating in the progression of many inflammatory diseases, such as experimental autoimmune encephalomyelitis (EAE) and sepsis. Identification of small molecules to inhibit pyroptosis is emerging as an attractive strategy. In this study, we performed a screening based on in silico docking of compounds on the reported Gasdermin D (GSDMD) three-dimensional structure and found C202-2729 demonstrated strong anti-inflammatory effects in both endotoxin shock and EAE mouse models. Oral administration of C202-2729 was capable of attenuating EAE disease severity significantly and has the comparable effects to teriflunomide, the first-line clinical drug of multiple sclerosis. We found C202-2729 remarkably suppressed macrophage and T cell-associated immune inflammation. Mechanistically, C202-2729 neither impact GSDMD cleavage nor the upstream inflammasome activation in mouse immortalized bone marrow-derived macrophages. However, C202-2729 exposure significantly repressed the IL-1ß secretion and cell pyroptosis. We found C202-2729 directly bonds to the N terminus of GSDMD and blocks the migration of the N-terminal GSDMD fragment to cell membrane, restraining the pore-forming and mature IL-1ß release. Collectively, our findings provide a new molecule with the potential for translational application in GSDMD-associated inflammatory diseases.
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Encefalomielitis Autoinmune Experimental , Sepsis , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Inflamasomas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Proteínas de Unión a Fosfato/metabolismo , Piroptosis , Sepsis/tratamiento farmacológicoRESUMEN
In this work, the eco-friendly N-doped carbon dots KF-CDs and A-CDs were derived from kiwifruit by a simple one-step hydrothermal strategy at 180 °C for 6 h. KF-CDs have a high fluorescence quantum yield (27.85%), it is obviously rapid quenched by Fe3+, and have a good linear relationship from 1 to 8.26 µM (the detection limit was 0.077 µM). Basic red 9 is extensively used in biological, environmental and industry. Although it makes a great contribution to the economy, its toxicity should be taken seriously, especially with harmful metal ions. Within 2 h, A-CDs could degrade basic red 9 with degradation efficiency 89.6%, even though there was a stable compound formed with Fe3+ that the degradation efficiency was up to 88.3%. The results complement the research blank of carbon dots in catalytic degradation of basic red 9.
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Shengxian decoction, a traditional Chinese medicinal prescription, has been shown to alleviate doxorubicin-induced chronic heart failure. This study established an ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry method to separate and characterize the complex chemical compositions of Shengxian decoction, and the absorbed compounds in the bio-samples of the cardiotoxicity rats with chronic heart failure after its oral delivery. Note that 116 chemical compounds were identified from Shengxian decoction in vitro, 81 more than previously detected. Based on the three-dimensional data of these compounds, 28 absorbed compounds were confirmed in vivo. Network pharmacology and molecular docking experiments indicated that timosaponin B-II, timosaponin A-III, gitogenin, and 7,8-didehydrocimigenol were recognized as the key effective compounds to exert effects against doxorubicin cardiotoxicity by acting on targets such as caspase 3, cyclin-dependent kinase 1, cyclin-dependent kinase 4, receptor tyrosine-protein kinase erbB-2, and mitogen-activated protein kinase 1 in p53 and phosphatidylinositol 3-kinase-Akt signaling pathways. This study developed the understanding of the composition of Shengxian decoction for the treatment of doxorubicin cardiotoxicity, as well as a feasible strategy to elucidate the effective constituents in traditional Chinese medicines.
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Doxorrubicina , Medicamentos Herbarios Chinos , Farmacología en Red , Ratas Sprague-Dawley , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/análisis , Animales , Ratas , Cromatografía Líquida de Alta Presión , Masculino , Espectrometría de Masas , Cardiotoxicidad , Simulación del Acoplamiento Molecular , Combinación de MedicamentosRESUMEN
The demand for precise indoor localization services is steadily increasing. Among various methods, fingerprint-based indoor localization has become a popular choice due to its exceptional accuracy, cost-effectiveness, and ease of implementation. However, its performance degrades significantly as a result of multipath signal attenuation and environmental changes. In this paper, we propose an indoor localization method based on fingerprints using self-attention and long short-term memory (LSTM). By integrating a self-attention mechanism and LSTM network, the proposed method exhibits outstanding positioning accuracy and robustness in diverse experimental environments. The performance of the proposed method is evaluated under two different experimental scenarios, which involve 2D and 3D moving trajectories, respectively. The experimental results demonstrate that our approach achieves an average localization error of 1.76 m and 2.83 m in the respective scenarios, outperforming the existing state-of-the-art methods by 42.67% and 31.64%.
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There are three main classes of actin nucleation factors: Arp2/3 complexes, Spire and Formin. Spire assembles microfilaments by nucleating stable longitudinal tetramers and binding actin to the growing end of the microfilament. As early as 1999, Wellington et al. identified Spire as an actin nucleating agent, however, over the years, most studies have focused on Arp2/3 and Formin proteins; there has been relatively less research on Spire as a member of the actin nucleating factors. Recent studies have shown that Spire is involved in the vesicular transport through the synthesis of actin and plays an important role in neural development. In this paper, we reviewed the structure, expression and function of Spire, and its association with disease in order to identify meaningful potential directions for studies on Spire.
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Actinas , Proteínas de Microfilamentos , Proteínas Nucleares , Proteínas de Microfilamentos/metabolismo , Proteínas de Microfilamentos/fisiología , Humanos , Animales , Actinas/metabolismo , Actinas/fisiología , Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/fisiologíaRESUMEN
For wide dynamic range gas concentration detection based on tunable diode laser absorption spectroscopy (TDLAS), direct absorption spectroscopy (DAS) and wavelength modulation spectroscopy (WMS) are usually used in combination. However, in some application scenarios such as high-speed flow field detection, natural gas leakage, or industrial production, the requirements of wide-range, fast response and calibration-free must be met. Taking applicability and cost of TDALS-based sensor into consideration, a method of optimized direct absorption spectroscopy (ODAS) based on signal correlation and spectral reconstruction is developed in this paper. This method can achieve adaptive selection of the optimal benchmark spectrum for spectral reconstruction. Moreover, methane (CH4) is taken as an example to carry out the experimental verification. Experimental results proved that the method satisfies wide dynamic range detection of more than 4 orders of magnitude. It is worth noting that when measuring large absorbance with concentration of 75 × 104â ppm with DAS and ODAS method, respectively, the maximum value of residual is reduced from 3.43 to 0.07. Furthermore, whether measuring gas of small or large absorbance with different concentrations, which vary from 100â ppm to 75 × 104â ppm, the correlation coefficient between standard concentrations and inverted concentrations is 0.997, showing the linear consistency of the method in wide dynamic range. In addition, the absolute error is 1.81 × 104â ppm when measuring large absorbance of 75 × 104â ppm. It greatly improves the accuracy and reliability with the new method. In summary, the ODAS method can not only fulfill the measurement of gas concentration in wide range, but also further expand the application prospects of TDLAS.
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Vascular dementia (VD) is characterized with vascular cognitive impairment (VCI), which currently has few effective therapies in clinic. Neuronal damage and white matter injury are involved in the pathogenesis of VCI. Citicoline has been demonstrated to exhibit neuroprotection and neurorepair to improve cognition in cerebrovascular diseases. Nicotinamide adenine dinucleotide (NAD+)-dependent sirtuin (SIRT) signaling pathway constitutes a strong intrinsic defense system against various stresses including neuroinflammation in VCI. Our hypothesis is that the combined use of citicoline and the precursor of NAD+, nicotinamide mononucleotide (NMN), could enhance action on cognitive function in VCI. We investigated the synergistic effect of these two drugs in the rat model of VCI by bilateral common carotid artery occlusion (BCCAO). Citicoline significantly enhanced neurite outgrowth in Neuro-2a cells, and the combination of citicoline and NMN remarkably induced neurite outgrowth in Neuro-2a cells and primary cortical neuronal cells with an optimal proportion of 4:1. In the rat model of BCCAO, when two drugs in combination of 160 mg/kg citicoline and 40 mg/kg NMN, this combination administrated at 7 days post-BCCAO significantly improved the cognitive impairment in BCCAO rats compared with vehicle group by the analysis of the Morris water maze and the novel object recognition test. This combination also decreased microglial activation and neuroinflammation, and protected white matter integrity indicated by the increased myelin basic protein (MBP) expression through activation of SIRT1/TORC1/CREB signaling pathway. Our results suggest that the combination of citicoline and NMN has a synergistic effect for the treatment of VD associated with VCI.
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Disfunción Cognitiva , Demencia Vascular , Ratas , Animales , Citidina Difosfato Colina/farmacología , Citidina Difosfato Colina/uso terapéutico , NAD/metabolismo , NAD/uso terapéutico , Mononucleótido de Nicotinamida/farmacología , Mononucleótido de Nicotinamida/uso terapéutico , Sirtuina 1 , Enfermedades Neuroinflamatorias , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Demencia Vascular/tratamiento farmacológico , Proyección NeuronalRESUMEN
BACKGROUND: Sepsis is a life-threatening disease with a limited effectiveness and the potential mechanism remains unclear. LncRNA NEAT-2 is reported to be involved in the regulation of cardiovascular disease. This study aimed to investigate the function of NEAT-2 in sepsis. METHODS: We built sepsis animal model with Male Balb/C mice induced by cecal ligation and puncture (CLP). A total of 54 mice were randomly assigned into eight groups: sham operation group (n = 18), CLP group (n = 18), CLP plus si-control group (n = 3), CLP plus si-NEAT2 group (n = 3), CLP plus mimic control group (n = 3), CLP plus miR-320 group (n = 3), CLP plus normal saline group (n = 3), and normal control group (n = 3). The number of peripheral endothelial progenitor cells (EPCs), the expression level of NEAT-2 and miR-320 were detected during progression of sepsis, as well as the number of peripheral EPCs and level of TNF-α, IL-6, VEGF, ALT, AST and Cr. In addition, the function of EPCs was evaluated after NEAT-2 knockdown and miR-320 overexpression in vitro. RESULTS: The number of circulating EPCs increased significantly in sepsis. NEAT-2 expression was significantly increased in the progress of sepsis, accompanied with miR-320 downregulated. NEAT-2 knockdown and miR-320 overexpression attenuated hepatorenal function and increased cytokines in sepsis. Moreover, NEAT-2 knockdown and miR-320 overexpression decreased the proliferation, migration and angiogenesis of endothelial progenitor cells in vitro. CONCLUSIONS: LncRNA-NEAT2 regulated the number and function of endothelial progenitor cells via miR-320 in sepsis, which may contribute to the development of novel potential clinical therapy for sepsis.
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Células Progenitoras Endoteliales , MicroARNs , ARN Largo no Codificante , Sepsis , Ratones , Masculino , Animales , ARN Largo no Codificante/genética , Hígado/metabolismo , Sepsis/genética , Sepsis/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Modelos Animales de EnfermedadRESUMEN
Adenocarcinoma of the gastroesophageal junction (AEG) has become increasingly common in Western and Asian populations. Surgical resection is the mainstay of treatment for AEG; however, determining the distance from the upper edge of the tumor to the esophageal margin (PM) is essential for accurate prognosis. Despite the relevance of these studies, most have been retrospective and vary widely in their conclusions. The PM is now widely accepted to have an impact on patient outcomes but can be masked by TNM at later stages. Extended PM is associated with improved outcomes, but the optimal PM is uncertain. Academics continue to debate the surgical route, extent of lymphadenectomy, preoperative tumor size assessment, intraoperative cryosection, neoadjuvant therapy, and other aspects to further ensure a negative margin in patients with gastroesophageal adenocarcinoma. This review summarizes and evaluates the findings from these studies and suggests that the choice of approach for patients with adenocarcinoma of the esophagogastric junction should take into account the extent of esophagectomy and lymphadenectomy. Although several guidelines and reviews recommend the routine use of intraoperative cryosections to evaluate surgical margins, its generalizability is limited. Furthermore, neoadjuvant chemotherapy and radiotherapy are more likely to increase the R0 resection rate. In particular, intraoperative cryosections and neoadjuvant chemoradiotherapy were found to be more effective for achieving negative resection margins in signet ring cell carcinoma.
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Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Estudios Retrospectivos , Neoplasias Gástricas/patología , Pronóstico , Adenocarcinoma/patología , Neoplasias Esofágicas/patología , Unión Esofagogástrica/cirugía , Unión Esofagogástrica/patología , Esofagectomía , Estadificación de NeoplasiasRESUMEN
When measuring the concentrations of individual gases in gas mixtures via laser absorption spectroscopy, the widening of adjacent absorption spectral lines can cause them to overlap, which hinders the calculation of the gas concentrations. In this study, the causes of this hindrance are analyzed. By using the Partial Least Squares (PLS) algorithm, the relative error in the measured CO concentration for a mixture of CO and CH4 gases was less than 10% even when the volume ratio VCH4/CO (The ratio of CH4 gas concentration to CO gas concentration) reached 100. These results show that the PLS algorithm is able to determine accurate concentrations even with significant broadening and interference of spectral lines in mixed gases.
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Long non-coding RNAs (lncRNAs) can not only regulate gene transcription and translation, but also participate in the development of central nervous system diseases as epigenetic modification factors. However, their functional significance in atherosclerosis-induced ischemic stroke (AIIS) is unclear. The study aimed to screen out differentially expressed lncRNAs (delncRNAs), and to elucidate their potential regulatory mechanisms in the pathophysiology of AIIS. Based on the clinicopathological features and clinical images, we screened out 10 patients with AIIS and recruited 10 healthy volunteers. Then we used microarray to detect the whole blood RNA of subjects, and explored the biological functions of delncRNAs by GO and KEGG analysis. After further analyzing the delncRNAs of THP-1 stimulated with ox-LDL, selective lncRNAs were screened and a corresponding lncRNA-mRNA interaction network was constructed through co-expression analysis. We yielded 180 delncRNAs (44 up-regulated and 136 down-regulated) and 218 demRNAs (45 up-regulated and 173 down-regulated). Lnc-SCARNA8 and lnc-SNRPN-2 are the most significant elevated and decreased lncRNA in AIIS, respectively. The delncRNAs may play a significant role in ubiquitination-mediated protein degradation signaling pathways. According to lncRNA-mRNA network, the expression of vacuolar protein sorting 13 homolog B (VPS13B) and biliverdin reductase B (BLVRB) were significantly regulated. Our findings suggest that the ubiquitinated proteasome pathway, VPS13B and BLVRB may play a fundamental role in the pathological process of AIIS.
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Aterosclerosis , Accidente Cerebrovascular Isquémico , ARN Largo no Codificante , Aterosclerosis/complicaciones , Aterosclerosis/genética , Redes Reguladoras de Genes , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Transcriptoma/genéticaRESUMEN
Phidianidines A and B are novel marine indole alkaloids with various biological activities. Based on their potential anti-inflammatory properties, a series of phidianidine derivatives were designed, synthesized, and tested for their effects on IL-17A production in PMA/ionomycin-stimulated T-cell-lymphoma EL-4 cells. Compounds 9a and 22c exhibited excellent anti-inflammatory activity and low toxicity, with IC50 values of 7.7 µM and 5.3 µM for IL-17A production in PMA/ionomycin-stimulated EL-4 cells, respectively. Further mechanistic study showed that 9a could decrease the STAT3 phosphorylation at Y705 to inhibit IL-17A production in EL-4 cells, indicating its ability of preventing the differentiation of Th17 cells and their possible function. This research may give an insight for the discovery of marine indole alkaloid derived anti-inflammatory drug leads for the treatment of T cell-mediated diseases.
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Alcaloides Indólicos , Interleucina-17 , Antiinflamatorios/farmacología , Ionomicina , Relación Estructura-ActividadRESUMEN
AIM: Brain microvascular endothelial cells (BMVECs), as the important structure of blood-brain barrier (BBB), play a vital role in ischemic stroke. Pyroptosis of different cells in the brain may aggravate cerebral ischemic injury, and PGC-1α plays a major role in pyroptosis. However, it is not known whether BMVECs undergo pyroptosis after ischemic stroke and whether PGC-1α activator Medioresinol (MDN) we discovered may be useful against pyroptosis of endothelial cells and ischemic brain injury. METHODS: For in vitro experiments, the bEnd.3 cells and BMVECs under oxygen and glucose-deprivation (OGD) were treated with or without MDN, and the LDH release, tight junction protein degradation, GSDMD-NT membrane location and pyroptosis-associated proteins were evaluated. For in vivo experiments, mice underwent transient middle cerebral artery occlusion (tMCAO) for ischemia model, and the neuroprotective effects of MDN were measured by infarct volume, the permeability of BBB and pyroptosis of BMVECs. For mechanistic study, effects of MDN on the accumulation of phenylalanine, mitochondrial reactive oxygen species (mtROS) were tested by untargeted metabolomics and MitoSOX Red probe, respectively. RESULTS: BMVECs underwent pyroptosis after ischemia. MDN dose-dependently activated PGC-1α, significantly reduced pyroptosis, mtROS and the expressions of pyroptosis-associated proteins (NLRP3, ASC, cleaved caspase-1, IL-1ß, GSDMD-NT), and increased ZO-1 and Occludin protein expressions in BMVECs. In tMCAO mice, MDN remarkably reduced brain infarct volume and the permeability of BBB, inhibited pyroptosis of BMVECs, and promoted long-term neurobehavioral functional recovery. Mechanistically, MDN promoted the interaction of PGC-1α with PPARα to increase PPARα nuclear translocation and transcription activity, further increased the expression of GOT1 and PAH, resulting in enhanced phenylalanine metabolism to reduce the ischemia-caused phenylalanine accumulation and mtROS and further ameliorate pyroptosis of BMVECs. CONCLUSION: In this study, we for the first time discovered that pyroptosis of BMVECs was involved in the pathogenesis of ischemic stroke and MDN as a novel PGC-1α activator could ameliorate the pyroptosis of endothelial cells and ischemic brain injury, which might attribute to reduction of mtROS through PPARα/GOT1 axis in BMVECs. Taken together, targeting endothelial pyroptosis by MDN may provide alternative therapeutics for brain ischemic stroke.
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Aspartato Aminotransferasa Citoplasmática/metabolismo , Endotelio Vascular/efectos de los fármacos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Lignanos/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , PPAR alfa/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/agonistas , Piroptosis/efectos de los fármacos , Animales , Inmunoprecipitación de Cromatina , Modelos Animales de Enfermedad , Endotelio Vascular/metabolismo , Técnica del Anticuerpo Fluorescente , Cromatografía de Gases y Espectrometría de Masas , Células HEK293/efectos de los fármacos , Humanos , Lignanos/farmacología , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos ICR , Fármacos Neuroprotectores/farmacología , Ratas Sprague-DawleyRESUMEN
Neuroinflammation plays a pivotal part in the pathogenesis of stroke. Orphan nuclear receptor NR4A1 is involved in the inflammatory response of microglia and macrophages. In this study, we discovered an old drug, 9-aminoacridine (9-AA), as a novel NR4A1 activator from our in-house FDA-approved drug library, which exhibited anti-inflammatory activities through an NR4A1/IL-10/SOCS3 signaling pathway and modulated the microglia activation. To improve the druggability of 9-AA, different liposomal formulations were screened and investigated. 9-AA-loaded liposome (9-AA/L) was prepared to reduce the adverse effect of 9-AA. Furthermore, 9-AA-loaded PEG/cRGD dual-modified liposome (9-AA/L-PEG-cRGD) was obtained, which displayed prolonged circulation, improved biodistribution, and increased brain accumulation. In the transient middle cerebral artery occlusion (tMCAO) rat model, 9-AA/L-PEG-cRGD significantly reduced brain infarct area, ameliorated ischemic brain injury, and promoted long-term neurological function recovery. This "from drug discovery to drug delivery" methodology provides a potential therapeutic strategy using the liposomal 9-AA, the NR4A1 activator to suppress neuroinflammation for treatment of ischemic stroke.
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Aminacrina , Descubrimiento de Drogas , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Aminacrina/química , Aminacrina/farmacocinética , Aminacrina/farmacología , Animales , Células HEK293 , Humanos , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Liposomas , Masculino , Ratones , Microglía/metabolismo , Microglía/patología , Proteínas del Tejido Nervioso/metabolismo , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacocinética , Péptidos Cíclicos/farmacología , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Polietilenglicoles/farmacología , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
Sigma-1 (σ-1) receptor agonists are considered as potential treatment for stroke. TS-157 is an alkoxyisoxazole-based σ-1 receptor agonist previously discovered in our group. The present study describes TS-157 profile in a battery of tests for cerebral ischemia. Initial evaluation demonstrated the compound's safety profile and blood-brain barrier permeability, as well as its ability to induce neurite outgrowth in vitro. The neurite outgrowth was shown to be mediated via σ-1 receptor agonism and involves upregulation of ERK phosphorylation (pERK). In particular, TS-157 also significantly accelerated the recovery of motor function in rats with transient middle cerebral artery occlusion (tMCAO). Overall, the results herein support the notion that σ-1 receptor agonists are potential therapeutics for stroke and further animal efficacy studies are warranted.