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Heart failure (HF) has emerged as the most pressing health concerns globally, and extant clinical therapies are accompanied by side effects and patients have a high burden of financial. The protein products of nuclear factor erythroid 2-related factor 2 (Nrf2) target genes have a variety of cardioprotective effects, including antioxidant, metabolic functions and anti-inflammatory. By evaluating established preclinical and clinical research in HF to date, we explored the potential of Nrf2 to exert unique cardioprotective functions as a novel therapeutic receptor for HF. In this review, we generalize the progression, structure, and function of Nrf2 research in the cardiovascular system. The mechanism of action of Nrf2 involved in HF as well as agonists of Nrf2 in natural compounds are summarized. Additionally, we discuss the challenges and implications for future clinical translation and application of pharmacology targeting Nrf2. It's critical to developing new drugs for HF.
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Insuficiencia Cardíaca , Factor 2 Relacionado con NF-E2 , Transducción de Señal , Factor 2 Relacionado con NF-E2/metabolismo , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Humanos , Animales , Transducción de Señal/efectos de los fármacosRESUMEN
Circadian rhythm (24-hour period of physiological and behavioral changes) is the basis of the overall health, including mood and health. This study aimed to explore the influence of circadian rhythm and sleep schedules on depressive symptoms in Chinese adolescents. In this cross-sectional study, 841 middle school students were recruited and divided into two groups (depressive group, DG, n = 210, and control group, n = 631) depending on the total score of The Center for Epidemiological Studies Depression Scale for Children (CES-DC). The circadian rhythm and sleep quality among adolescents were evaluated by using the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) and Self-rating scale of Sleep (SRSS) scales. Furthermore, correlation analysis and logistic regression analysis were used to determine the effects of demographic factors, sleeping arrangement, sleep quality, and circadian rhythm on depressive symptoms. The DG group's CES-DC, BRIAN and SRSS scores were significantly higher than the control group's. Higher scores of BRIAN and SRSS were risk factors for depressive symptoms in Chinese adolescents. Attending a day school and waking up later on weekends may be weak protective factors. Our results suggest that circadian rhythm disturbance, sleep quality, and sleeping arrangement have a significant influence on depressive symptoms among adolescents in China.
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BACKGROUND: The alveolar epithelial type II cell (AT2) and its senescence play a pivotal role in alveolar damage and pulmonary fibrosis. Cell circadian rhythm is strongly associated with cell senescence. Differentiated embryonic chondrocyte expressed gene 1 (DEC1) is a very important circadian clock gene. However, the role of DEC1 in AT2 senescence and pulmonary fibrosis was still unclear. RESULTS: In this study, a circadian disruption model of light intervention was used. It was found that circadian disruption exacerbated pulmonary fibrosis in mice. To understand the underlying mechanism, DEC1 levels were investigated. Results showed that DEC1 levels increased in lung tissues of IPF patients and in bleomycin-induced mouse fibrotic lungs. In vitro study revealed that bleomycin and TGF-ß1 increased the expressions of DEC1, collagen-I, and fibronectin in AT2 cells. Inhibition of DEC1 mitigated bleomycin-induced fibrotic changes in vitro and in vivo. After that, cell senescence was observed in bleomycin-treated AT2 cells and mouse models, but these were prevented by DEC1 inhibition. At last, p21 was confirmed having circadian rhythm followed DEC1 in normal conditions. But bleomycin disrupted the circadian rhythm and increased DEC1 which promoted p21 expression, increased p21 mediated AT2 senescence and pulmonary fibrosis. CONCLUSIONS: Taken together, circadian clock protein DEC1 mediated pulmonary fibrosis via p21 and cell senescence in alveolar epithelial type II cells.
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Bleomicina , Senescencia Celular , Ritmo Circadiano , Fibrosis Pulmonar , Animales , Humanos , Masculino , Ratones , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/patología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Ritmo Circadiano/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Ratones Endogámicos C57BL , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Fine particulate matter (PM2.5) has been linked to increased severity and incidence of airway diseases, especially chronic obstructive pulmonary disease (COPD) and asthma. Airway remodeling is an important event in both COPD and asthma, and airway smooth muscle cells (ASMCs) are key cells which directly involved in airway remodeling. However, it was unclear how PM2.5 affected ASMCs. This study investigates the effects of PM2.5 on airway smooth muscle and its mechanism. We first showed that inhaled particulate matter was distributed in the airway smooth muscle bundle, combined with increased airway smooth muscle bundle and collagen deposition in vivo. Then, we demonstrated that PM2.5 induced up-regulation of collagen-I and alpha-smooth muscle actin (α-SMA) expression in rat and human ASMCs in vitro. Next, we found PM2.5 led to rat and human ASMCs senescence and exhibited senescence-associated secretory phenotype (SASP) by autophagy-induced GATA4/TRAF6/NF-κB signaling, which contributed to collagen-I and α-SMA synthesis as well as airway smooth muscle remodeling. Together, our results provided evidence that SASP induced by PM2.5 in airway smooth muscle cells prompted airway remodeling.
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Asma , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Ratas , Animales , Remodelación de las Vías Aéreas (Respiratorias) , Fenotipo Secretor Asociado a la Senescencia , Miocitos del Músculo Liso , Asma/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/inducido químicamente , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Colágeno Tipo I , Proliferación Celular , Material Particulado/metabolismo , Células CultivadasRESUMEN
BACKGROUND: The terminal stage of all cardiovascular diseases typically culminates in heart failure (HF), with no effective intervention available to halt its progression. LuQi formula (LQF) has been employed in clinical for numerous years to significantly ameliorate cardiac function in HF patients. Nevertheless, the underlying mechanism of LQF's efficacy remains inadequately comprehended. Cardiomyocyte ferroptosis has served as a pathogenic mechanism in HF. The goal of the current experiment was to ascertain whether LQF ameliorates HF by preventing cardiomyocyte ferroptosis and to elucidate the intrinsic mechanism involved. PURPOSE: This research objective is to investigate the impact and underlying mechanism of LQF attenuating cardiomyocyte ferroptosis in heart failure. METHODS: Transverse aortic constriction (TAC) was performed to construct the HF mouse model. Neonatal rat cardiomyocytes (NRCMs) were subjected to in vitro experiments. High-performance liquid chromatography (HPLC) identified the bioactive compounds in LQF. Transcriptomic and quantitative proteomic analyses revealed the potential targets of LQF anti-HF. Specifically, histological staining evaluated cardiac hypertrophy and fibrosis. Transmission electron microscopy (TEM) observed mitochondrial morphology. The content of Fe2+, ROS, MDA, GSH, and GSSH was detected using kits. Molecular docking evaluated the binding activities between essential active ingredients of LQF and critical proteins of cardiomyocyte ferroptosis. Mechanistically, the expression levels of Nrf2, Keap1, HO-1, SLC7A11, and GPX4 were evaluated using qPCR, Western blot (WB), or immunohistochemical staining. RESULTS: The primary nine active ingredients in LQF were detected. Transcriptomic and proteomic analyses demonstrated that LQF may ameliorate HF by preventing cardiomyocyte ferroptosis. Histomorphometric analyses revealed that LQF attenuates myocardial hypertrophy and fibrosis. TEM revealed that LQF diminished mitochondrial shrinkage and increased membrane density in myocardial tissue. Additionally, LQF diminished reactive oxygen species (ROS) generation in cardiomyocytes and suppressed cardiomyocyte ferroptosis. Furthermore, the molecular docking technique revealed that the primary active ingredients of LQF had suitable binding activities with Nrf2, GPX4, and SLC7A11. Western analysis further verified that LQF activated the Nrf2/GPX4 signaling axis. decreased SLC7A11 and HO-1 expression. CONCLUSIONS: These results demonstrated that LQF prevents cardiomyocyte ferroptosis via activating Nrf2/GPX4 signaling axis and suppressing SLC7A11 and HO-1 expression. Concurrently, it contributed to elucidating the intrinsic mechanism of LQF and provided a scientific rationale for its development as a novel cardiovascular therapeutic drug.
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Fármacos Cardiovasculares , Ferroptosis , Insuficiencia Cardíaca , Ratones , Humanos , Animales , Ratas , Miocitos Cardíacos , Proteína 1 Asociada A ECH Tipo Kelch , Factor 2 Relacionado con NF-E2 , Simulación del Acoplamiento Molecular , Proteómica , Especies Reactivas de Oxígeno , Insuficiencia Cardíaca/tratamiento farmacológico , FibrosisRESUMEN
BACKGROUND: Myocardial infarction (MI) dramatically changes the mechanical stress, which is intensified by the fibrotic remodeling. Integrins, especially the αV subunit, mediate mechanical signal and mechanoparacrine of transforming growth factor ß1 (TGF-ß1) in various organ fibrosis by activating CFs into myofibroblasts (MFBs). We investigated a possible role of integrin αV mediated mechanoparacrine of TGF-ß1 in MFBs activation for fibrous reparation in mice with MI. METHODS: Heart samples from MI, sham, or MI plus cilengitide (14 mg/kg, specific integrin αV inhibitor) treated mice, underwent functional and morphological assessments by echocardiography, and histochemistry on 7, 14 and 28 days post-surgery. The mechanical and ultrastructural changes of the fibrous scar were further evaluated by atomic mechanics microscope (AFM), immunofluorescence, second harmonic generation (SHG) imaging, polarized light and scanning electron microscope, respectively. Hydroxyproline assay was used for total collagen content, and western blot for protein expression profile examination. Fibroblast bioactivities, including cell shape, number, Smad2/3 signal and expression of extracellular matrix (ECM) related proteins, were further evaluated by microscopic observation and immunofluorescence in polyacrylamide (PA) hydrogel with adjustable stiffness, which was re-explored in fibroblast cultured on stiff matrix after silencing of integrin αV. The content of total and free TGF-ß1 was tested by enzyme-linked immunosorbent assay (ELISA) in both infarcted tissue and cell samples. RESULT: Increased stiffness with heterogeneity synchronized with integrin αV and alpha smooth muscle actin (α-SMA) positive MFBs accumulation in those less mature fibrous areas. Cilengitide abruptly reduced collagen content and disrupted collagen alignment, which also decreased TGF-ß1 bioavailability, Smad2/3 phosphorylation, and α-SMA expression in the fibrous area. Accordingly, fibroblast on stiff but not soft matrix exhibited obvious MFB phenotype, as evidenced by enlarged cell, hyperproliferation, well-developed α-SMA fibers, and elevated ECM related proteins, while silencing of integrin αV almost abolished this switch via attenuating paracrine of TGF-ß1 and nuclear translocation of Smad2/3. CONCLUSION: This study illustrated that increased tissue stiffness activates CFs into MFBs by integrin αV mediated mechanoparacrine of TGF-ß1, especially in immature scar area, which ultimately promotes fibrous scar maturation.
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Infarto del Miocardio , Miofibroblastos , Animales , Ratones , Actinas/metabolismo , Cicatriz/metabolismo , Colágeno/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Fibrosis , Integrina alfaV/metabolismo , Infarto del Miocardio/patología , Miofibroblastos/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Mitochondrial transplantation is a promising solution for the heart following ischemia-reperfusion injury due to its capacity to replace damaged mitochondria and restore cardiac function. However, many barriers (such as inadequate mitochondrial internalization, poor survival of transplanted mitochondria, few mitochondria colocalized with cardiac cells) compromise the replacement of injured mitochondria with transplanted mitochondria. Therefore, it is necessary to optimize mitochondrial transplantation therapy to improve clinical effectiveness. By analogy, myocardial ischemia-reperfusion injury is like a withered flower, it needs to absorb enough nutrients to recover and bloom. In this review, we present a comprehensive overview of "nutrients" (source of exogenous mitochondria and different techniques for mitochondrial isolation), "absorption" (mitochondrial transplantation approaches, mitochondrial transplantation dose and internalization mechanism), and "flowering" (the mechanism of mitochondrial transplantation in cardioprotection) for myocardial ischemia-reperfusion injury.
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Daño por Reperfusión Miocárdica , Humanos , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Mitocondrias Cardíacas , CorazónRESUMEN
Cardiovascular diseases (CVDs) are the leading cause of death and disability worldwide. The CVDs are accompanied by inflammatory progression, resulting in innate and adaptive immune responses. Regulatory T cells (Tregs) have an immunosuppressive function and are one of the subsets of CD4+T cells that play a crucial role in inflammatory diseases. Whether using Tregs as a biomarker for CVDs or targeting Tregs to exert cardioprotective functions by regulating immune balance, suppressing inflammation, suppressing cardiac and vascular remodeling, mediating immune tolerance, and promoting cardiac regeneration in the treatment of CVDs has become an emerging research focus. However, Tregs have plasticity, and this plastic Tregs lose immunosuppressive function and produce toxic effects on target organs in some diseases. This review aims to provide an overview of Tregs' role and related mechanisms in CVDs, and reports on the research of plasticity Tregs in CVDs, to lay a foundation for further studies targeting Tregs in the prevention and treatment of CVDs.
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Enfermedades Cardiovasculares , Linfocitos T Reguladores , Humanos , Tolerancia Inmunológica , Inmunosupresores , BiomarcadoresRESUMEN
Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors. Although hundreds of ASD risk genes, implicated in synaptic formation and transcriptional regulation, have been identified through human genetic studies, the East Asian ASD cohorts are still under-represented in genome-wide genetic studies. Here, we applied whole-exome sequencing to 369 ASD trios including probands and unaffected parents of Chinese origin. Using a joint-calling analytical pipeline based on GATK toolkits, we identified numerous de novo mutations including 55 high-impact variants and 165 moderate-impact variants, as well as de novo copy number variations containing known ASD-related genes. Importantly, combined with single-cell sequencing data from the developing human brain, we found that the expression of genes with de novo mutations was specifically enriched in the pre-, post-central gyrus (PRC, PC) and banks of the superior temporal (BST) regions in the human brain. By further analyzing the brain imaging data with ASD and healthy controls, we found that the gray volume of the right BST in ASD patients was significantly decreased compared to healthy controls, suggesting the potential structural deficits associated with ASD. Finally, we found a decrease in the seed-based functional connectivity between BST/PC/PRC and sensory areas, the insula, as well as the frontal lobes in ASD patients. This work indicated that combinatorial analysis with genome-wide screening, single-cell sequencing, and brain imaging data reveal the brain regions contributing to the etiology of ASD.
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Trastorno del Espectro Autista , Trastorno Autístico , Humanos , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Secuenciación del Exoma , Variaciones en el Número de Copia de ADN , Pueblos del Este de Asia , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Mutación/genética , Predisposición Genética a la Enfermedad/genéticaRESUMEN
Acute myocardial infarction (AMI) is a severe ischemic disease with high morbidity and mortality worldwide. Maladaptive cardiac remodeling is a series of abnormalities in cardiac structure and function that occurs following myocardial infarction (MI). The pathophysiology of this process can be separated into two distinct phases: the initial inflammatory response, and the subsequent longer-term scar revision that includes the regression of inflammation, neovascularization, and fibrotic scar formation. Extracellular vesicles are nano-sized lipid bilayer vesicles released into the extracellular environment by eukaryotic cells, containing bioinformatic transmitters which are essential mediators of intercellular communication. EVs of different cellular origins play an essential role in cardiac remodeling after myocardial infarction. In this review, we first introduce the pathophysiology of post-infarction cardiac remodeling, as well as the biogenesis, classification, delivery, and functions of EVs. Then, we explore the dual role of these small molecule transmitters delivered by EVs in post-infarction cardiac remodeling, including the double-edged sword of pro-and anti-inflammation, and pro-and anti-fibrosis, which is significant for post-infarction cardiac repair. Finally, we discuss the pharmacological and engineered targeting of EVs for promoting heart repair after MI, thus revealing the potential value of targeted modulation of EVs and its use as a drug delivery vehicle in the therapeutic process of post-infarction cardiac remodeling.
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BACKGROUND: Fine particulate matter (PM2.5) is associated with increased incidence and severity of asthma. PM2.5 exposure disrupts airway epithelial cells, which elicits and sustains PM2.5-induced airway inflammation and remodeling. However, the mechanisms underlying development and exacerbation of PM2.5-induced asthma were still poorly understood. The aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1) is a major circadian clock transcriptional activator that is also extensively expressed in peripheral tissues and plays a crucial role in organ and tissue metabolism. RESULTS: In this study, we found PM2.5 aggravated airway remodeling in mouse chronic asthma, and exacerbated asthma manifestation in mouse acute asthma. Next, low BMAL1 expression was found to be crucial for airway remodeling in PM2.5-challenged asthmatic mice. Subsequently, we confirmed that BMAL1 could bind and promote ubiquitination of p53, which can regulate p53 degradation and block its increase under normal conditions. However, PM2.5-induced BMAL1 inhibition resulted in up-regulation of p53 protein in bronchial epithelial cells, then increased-p53 promoted autophagy. Autophagy in bronchial epithelial cells mediated collagen-I synthesis as well as airway remodeling in asthma. CONCLUSIONS: Taken together, our results suggest that BMAL1/p53-mediated bronchial epithelial cell autophagy contributes to PM2.5-aggravated asthma. This study highlights the functional importance of BMAL1-dependent p53 regulation during asthma, and provides a novel mechanistic insight into the therapeutic mechanisms of BMAL1. Video Abstract.
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Factores de Transcripción ARNTL , Asma , Animales , Ratones , Remodelación de las Vías Aéreas (Respiratorias) , Factores de Transcripción ARNTL/metabolismo , Asma/metabolismo , Autofagia , Células Epiteliales/metabolismo , Material Particulado/toxicidad , Material Particulado/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Lymph node metastasis of gastric cancer is more common, metastatic lymph nodes are often around the stomach, and metastasis is carried out in a certain order, but gastric cancer metastasis to axillary lymph nodes is very rare. Due to the small number of patients with this kind of metastasis, its clinical features and treatment are not very clear. We initially thought that the enlarged axillary lymph nodes were inflammatory lesions. Axillary lymph node biopsy was later diagnosed as gastric cancer metastases to axillary lymph nodes. The patient refused further treatment and died 11 months after the second operation because of multiple systemic metastases. We believe that metastasis of gastric cancer to axillary lymph nodes is rare and the prognosis is poor. In clinical work, the possibility of metastatic lymph nodes should be considered in patients with a history of gastric cancer with enlarged axillary lymph nodes.
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Chicken coccidiosis is one of the most common and economically important diseases in the global poultry industry, and it is caused by at least one of the seven Eimeria species. A simple and reliable way to distinguish Eimeria species in infected chicken is critical for the surveillance, control, and eradication of chicken coccidiosis. In this study, a recombinase polymerase amplification (RPA) assay coupled with the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas12a system (RPA-CRISPR/Cas12a) was developed for the detection of Eimeria species in chicken fecal samples. This assay is highly specific to the seven Eimeria species and it does not cross react between species. Assessment of analytical sensitivity revealed that a single copy of plasmid DNA could be detected. Comparative analysis revealed strong agreement between RPA-CRISPR/Cas12a assays and real-time qPCR to reliably detect all seven Eimeria species in fecal chicken samples. Importantly, the cleavage products could be visualized under a blue light instrument, making it possible for the rapid detection of Eimeria species for on-site testing. Collectively, our study demonstrated that RPA-CRISPR/Cas12a assays offer a simple and reliable diagnostic method for Eimeria species.
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Coccidiosis , Eimeria , Animales , Pollos/parasitología , Coccidiosis/diagnóstico , Coccidiosis/veterinaria , Coccidiosis/genética , Sistemas CRISPR-Cas , ADN , Eimeria/genética , Técnicas de Amplificación de Ácido Nucleico/métodos , Técnicas de Amplificación de Ácido Nucleico/veterinaria , Recombinasas/genéticaRESUMEN
BACKGROUND: Avian coccidiosis is an important parasitic disease that has serious adverse effects on the global poultry industry. The extensive use of anticoccidial drugs has resulted in an increase in drug resistance. Ethanamizuril (EZL) is a novel triazine with high anticoccidial activity. METHODS: We compared oocyst production and sporulation between EZL-sensitive (S) and EZL-resistant Eimeria tenella strains (R10 and R200) and used label-free quantitative proteomics to identify differentially expressed proteins (DEPs) between these strains. RESULTS: We generated two EZL-resistant E. tenella strains: strain R10, which was induced using a constant dose of 10 mg EZL/kg poultry feed, and strain R200, which was generated by gradually increasing the EZL dosage to 200 mg EZL/kg poultry feed. With an increase in resistance, the total oocyst output decreased, but the percentage of sporulation did not change significantly. We identified a total of 7511 peptides and 1282 proteins, and found 152 DEPs in the R10 strain versus the S strain, 426 DEPs in the R200 strain versus the S strain and 494 DEPs in the R200 strain versus the R10 strain. When compared with the S strain, 86 DEPs were found to have consistent trends in both resistant strains. The DEPs were primarily involved in ATP and GTP binding, invasion, and membrane components. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses of the DEPs suggested that they are involved in transcription and translation processes. Protein-protein interaction network analysis of the 86 DEPs showed that 10 proteins were hubs in the functional interaction network (≥ 8 edges) and five of them were ribosomal proteins. CONCLUSIONS: The results of the present study indicate that the resistance mechanisms of E. tenella against EZL might be related to the transcriptional and translational processes, especially in the factors that inhibit the growth of parasites. The DEPs found in this study provide new insights into the resistance mechanisms of E. tenella against EZL. Further research on these potential targets holds promise for new chemotherapeutic approaches for controlling E. tenella infections.
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Coccidiosis , Eimeria tenella , Enfermedades de las Aves de Corral , Animales , Pollos/parasitología , Coccidiosis/tratamiento farmacológico , Coccidiosis/parasitología , Coccidiosis/veterinaria , Oocistos , Enfermedades de las Aves de Corral/tratamiento farmacológico , Enfermedades de las Aves de Corral/parasitología , Proteómica , Triazinas/farmacología , Triazinas/uso terapéuticoRESUMEN
Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrotic disease with high mortality. Currently, pirfenidone and nintedanib are the only approved drugs for IPF by the U.S. Food and Drug Administration (FDA), but their efficacy is limited. The activation of multiple phosphotyrosine (pY) mediated signaling pathways underlying the pathological mechanism of IPF has been explored. A Src homology-2 (SH2) superbinder, which contains mutations of three amino acids (AAs) of natural SH2 domain has been shown to be able to block phosphotyrosine (pY) pathway. Therefore, we aimed to introduce SH2 superbinder into the treatment of IPF. Methods: We analyzed the database of IPF patients and examined pY levels in lung tissues from IPF patients. In primary lung fibroblasts obtained from IPF patient as well as bleomycin (BLM) treated mice, the cell proliferation, migration and differentiation associated with pY were investigated and the anti-fibrotic effect of SH2 superbinder was also tested. In vivo, we further verified the safety and effectiveness of SH2 superbinder in multiple BLM mice models. We also compared the anti-fibrotic effect and side-effect of SH2 superbinder and nintedanib in vivo. Results: The data showed that the cytokines and growth factors pathways which directly correlated to pY levels were significantly enriched in IPF. High pY levels were found to induce abnormal proliferation, migration and differentiation of lung fibroblasts. SH2 superbinder blocked pY-mediated signaling pathways and suppress pulmonary fibrosis by targeting high pY levels in fibroblasts. SH2 superbinder had better therapeutic effect and less side-effect compare to nintedanib in vivo. Conclusions: SH2 superbinder had significant anti-fibrotic effects both in vitro and in vivo, which could be used as a promising therapy for IPF.
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Fibrosis Pulmonar Idiopática , Animales , Bleomicina/farmacología , Proliferación Celular , Fibroblastos/metabolismo , Fibrosis , Fibrosis Pulmonar Idiopática/metabolismo , Ratones , Fosfotirosina/química , Fosfotirosina/metabolismo , Fosfotirosina/farmacologíaRESUMEN
BACKGROUND AND PURPOSE: Previous studies have revealed abnormal regional homogeneity (ReHo) in individuals with autism spectrum disorder (ASD); however, there is little consistency across the findings within these studies, partly due to small sample size and great heterogeneity among participants between studies. Additionally, few studies have explored the association between ReHo aberrance and clinical symptoms in individuals with ASD. METHODS: Forty-eight adolescents with high-functioning ASD and 63 group-matched typically developing (TD) controls received functional magnetic resonance imaging at rest. Group-level analysis was performed to detect differences in ReHo between ASD and TD. Evaluation of symptom severity in individuals with ASD was based on the Autism Behavior Checklist (ABC). Voxel-wise correlation analysis was undergone to examine the correlations between the symptom severity and ReHo map in individuals with ASD within brain areas with ReHo abnormalities. RESULTS: Compared with the TD controls, individuals with ASD exhibited increased ReHo in the bilateral anterior cingulate cortex, left caudate, right posterior cerebellum (cerebellar tonsil), and bilateral brainstem and decreased ReHo in the left precentral gyrus, left inferior parietal lobule, bilateral postcentral gyrus, and right anterior cerebellum (culmen). The correlation analysis indicated that the ReHo value in the brainstem was negatively associated with the ABC total scores and the scores of Relating factor, respectively. CONCLUSIONS: Our findings indicated that widespread ReHo abnormalities occurred in ASD, shedding light on the underlying neurobiology of pathogenesis and symptomatology of ASD.
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Trastorno del Espectro Autista , Trastorno Autístico , Adolescente , Trastorno del Espectro Autista/diagnóstico por imagen , Encéfalo , Mapeo Encefálico/métodos , Humanos , Imagen por Resonancia Magnética/métodosRESUMEN
Objectives: To explore the clinical effect and prognostic factors of mechanical thrombectomy in the treatment of acute ischemic stroke. Methods: The records of patients with acute ischemic stroke treated in our hospital from April 2020 to April 2021 were retrospectively selected. A total of 65 patients were treated with mechanical thrombectomy. After treatment, they were scored with modified Rankin Scale (MRS). The treatment effect and prognostic factors were analyzed. Results: The occluded vessels were successfully opened in 65 patients. The recanalization rate was 96.92%. There were no serious complications of thrombectomy. The time from femoral artery puncture to vascular recanalization was (84.06±16.64) minutes and the number of thrombectomies was (2.52±0.71). There were 42 patients with good prognosis and 23 patients with poor prognosis. Analysis of the prognostic factors showed that the time from onset to admission in the good prognosis group was shorter, the NIHSS score before thrombectomy was higher, and the Alberta stroke program early CT Score (ASPECT) score was lower as compared to the patients in the poor prognosis group. The grade of vascular recanalization in the good prognosis group was better than that in the poor prognosis group, and the level of PCT was lower (P<0.05). Logistic regression analysis showed that the time from onset to admission, NIHSS and ASPECT scores before thrombectomy were the prognostic factors of mechanical thrombectomy in the treatment of acute ischemic stroke. Conclusion: Mechanical thrombectomy is effective in the treatment of acute ischemic stroke and can effectively promote the recanalization of occluded vessels, but the NIHSS and ASPECT scores from the onset to the time of admission before thrombectomy can directly affect the prognosis of patients.
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Background: Previous studies have indicated abnormal gray matter volume (GMV) in individuals with autism spectrum disorder (ASD); however, there is little consistency across the findings within these studies, partly due to small sample size and great heterogeneity among participants between studies. Additionally, few studies have explored the correlation between clinical symptoms and GMV abnormalities in individuals with ASD. Here, the current study examined GMV alterations in whole brain and their correlations with clinical symptoms in a relatively large and homogeneous sample of participants with ASD matched typically developing (TD) controls. Methods: Forty-eight adolescents with high-functioning ASD and 29 group-matched TD controls underwent structural magnetic resonance images. Voxel-based morphometry was applied to investigate regional GMV alterations. The participants with ASD were examined for the severity of clinical symptoms with Autism Behavior Checklist (ABC). The relationship between GMV abnormalities and clinical symptoms was explored in ASD group using voxel-wise correlation analysis within brain regions that showed significant GMV alterations in individuals with ASD compared with TD controls. Results: We found increased GMV in multiple brain regions, including the inferior frontal gyrus, medial frontal gyrus, superior frontal gyrus, superior temporal gyrus, occipital pole, anterior cingulate, cerebellum anterior lobe, cerebellum posterior lobe, and midbrain, as well as decreased GMV in cerebellum posterior lobe in individuals with ASD. The correlation analysis showed the GMV in the left fusiform was negatively associated with the scores of sensory factor, and the GMV in the right cerebellum anterior lobe was positively associated with the scores of social self-help factor. Conclusion: Our results indicated that widespread GMV abnormalities of brain regions occurred in individuals with ASD, suggesting a potential neural basis for the pathogenesis and symptomatology of ASD.
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Schizophrenia is a complex, severe psychiatric disorder with a high heritability that affects approximately 1% of the world's population. Numerous schizophrenia-related risk genes have been reported in large-scale studies, but the role of most genetic abnormalities in the pathogenesis of the disease is still obscure. In this study, using whole-exome sequencing, we identified a novel nonsense mutation c.1324C > T in the Interleukin 1 receptor accessory protein (IL1RAP) gene in four affected individuals with schizophrenia of a Chinese family. IL1RAP was found involved in initiating the immune responses and regulating synaptic formation. Considering that schizophrenia has been hypothesized to be neurodevelopment disorder for decades, we further explored the influence of altered expression of IL1RAP gene on neuronal growth, and assessed whether this mutation affects the function of IL1RAP protein in IL-1 signaling pathway. We used lentivirus-mediated shRNA to knockdown the IL1RAP gene expression, which suppressed the axon and dendrites growth of cultured mouse cortical neurons. These defects can be recovered by human IL1RAP wild type construct, but not the R442* mutant construct. Furthermore, this mutant even inhibited neuronal growth and IL-1ß-induced JNK phosphorylation when overexpressed in cortical neurons. Although overexpression of this mutant in HePG2 cells did not change IL1RAP protein expression, it partially prohibited the IL-1ß-induced nuclear translocation of transcript factor NF-κB, indicating that IL1RAP c.1324C > T is a loss-of-function mutation. Our findings show that IL1RAP plays an important role in early stages of neurodevelopment, and the mutation c.1324C > T may contribute to the pathogenesis of schizophrenia.
Asunto(s)
FN-kappa B , Esquizofrenia , Animales , Humanos , Proteína Accesoria del Receptor de Interleucina-1/genética , Proteína Accesoria del Receptor de Interleucina-1/metabolismo , Ratones , Mutación , FN-kappa B/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo , Transducción de SeñalRESUMEN
Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia. It is unknown why fibrosis in IPF distributes in the peripheral or named sub-pleural area. Migration of pleural mesothelial cells (PMC) should contribute to sub-pleural fibrosis. Calpain is known to be involved in cell migration, but the role of calpain in PMC migration has not been investigated. In this study, we found that PMCs migrated into lung parenchyma in patients with IPF. Then using Wt1tm1(EGFP/Cre)Wtp /J knock-in mice, we observed PMC migration into lung parenchyma in bleomycin-induced pleural fibrosis models, and calpain inhibitor attenuated pulmonary fibrosis with prevention of PMC migration. In vitro studies revealed that bleomycin and transforming growth factor-ß1 increased calpain activity in PMCs, and activated calpain-mediated focal adhesion (FA) turnover as well as cell migration, cell proliferation, and collagen-I synthesis. Furthermore, we determined that calpain cleaved FA kinase in both C-terminal and N-terminal regions, which mediated FA turnover. Lastly, the data revealed that activated calpain was also involved in phosphorylation of cofilin-1, and p-cofilin-1 induced PMC migration. Taken together, this study provides evidence that calpain mediates PMC migration into lung parenchyma to promote sub-pleural fibrosis in IPF.