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Cardiac remodeling (CR), characterized by cardiac hypertrophy and fibrosis, leads to the development and progression of heart failure (HF). Nowadays, emerging evidence implicated that inflammation plays a vital role in the pathogenesis of CR and HF. Astragaloside IV (AS-IV), an effective component of Astragalus membranaceus, exerts cardio-protective and anti-inflammatory effects, but the underlying mechanism remains not fully elucidated. This present study aimed to investigate the effects of AS-IV on cardiac hypertrophy and fibrosis in cultured H9C2 cells stimulated with LPS, as well as explore its underlying mechanisms. As a result, we found AS-IV could reduce the cell surface size, ameliorate cardiac hypertrophy and fibrosis in LPS-induced H9C2 cells. To specify which molecules or signaling pathways play key roles in the process, RNA-seq analysis was performed. After analyzing the transcriptome data, CCL2 has captured our attention, of which expression was sharply increased in model group and reversed by AS-IV treatment. The results also indicated that AS-IV could ameliorate the inflammatory response by down-regulating NF-κB signaling pathway. Additionally, a classical inhibitor of CCL2 (bindarit) were used to further explore whether the anti-inflammatory effect of AS-IV was dependent on this chemokine. Our results indicated that AS-IV could exert a potent inhibitory effect on CCL2 expression and down-regulated NF-κB signaling pathway in a CCL2-dependent manner. These findings provided a scientific basis for promoting the treatment of HF with AS-IV.
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Lipopolisacáridos , FN-kappa B , Humanos , FN-kappa B/metabolismo , Lipopolisacáridos/farmacología , Miocitos Cardíacos/metabolismo , Transducción de Señal , Cardiomegalia/inducido químicamente , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/metabolismo , Antiinflamatorios/farmacología , Colágeno/metabolismo , Fibrosis , Quimiocina CCL2/metabolismoRESUMEN
Proinflammatory cytokines, reactive oxygen species and imbalance of neurotransmitters are involved in the pathophysiology of angiotensin II-induced hypertension. The hypothalamic paraventricular nucleus (PVN) plays a vital role in hypertension. Evidences show that microglia are activated and release proinflammatory cytokines in angiocardiopathy. We hypothesized that angiotensin II induces PVN microglial activation, and the activated PVN microglia release proinflammatory cytokines and cause oxidative stress through nuclear factor-kappa B (NF-κB) pathway, which contributes to sympathetic overactivity and hypertension. Male Sprague-Dawley rats (weight 275-300 g) were infused with angiotensin II to induce hypertension. Then, rats were treated with bilateral PVN infusion of microglial activation inhibitor minocycline, NF-κB activation inhibitor pyrrolidine dithiocarbamate or vehicle for 4 weeks. When compared to control groups, angiotensin II-induced hypertensive rats had higher mean arterial pressure, PVN proinflammatory cytokines, and imbalance of neurotransmitters, accompanied with PVN activated microglia. These rats also had more PVN gp91phox (source of reactive oxygen species production), and NF-κB p65. Bilateral PVN infusion of minocycline or pyrrolidine dithiocarbamate partly or completely ameliorated these changes. This study indicates that angiotensin II-induced hypertensive rats have more activated microglia in PVN, and activated PVN microglia release proinflammatory cytokines and result in oxidative stress, which contributes to sympathoexcitation and hypertensive response. Suppression of activated PVN microglia by minocycline or pyrrolidine dithiocarbamate attenuates inflammation and oxidative stress, and improves angiotensin II-induced hypertension, which indicates that activated microglia promote hypertension through activated NF-κB. The findings may offer hypertension new strategies.
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Hipertensión , Minociclina , Ratas , Masculino , Animales , Minociclina/efectos adversos , Microglía/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Especies Reactivas de Oxígeno/efectos adversos , Especies Reactivas de Oxígeno/metabolismo , FN-kappa B/metabolismo , Angiotensina II/efectos adversos , Angiotensina II/metabolismo , Ratas Sprague-Dawley , Hipertensión/tratamiento farmacológico , Citocinas/metabolismo , Neurotransmisores/efectos adversos , Neurotransmisores/metabolismoRESUMEN
Background: Pulmonary hemorrhage (PH) in neonates is a life-threatening respiratory complication. We aimed to analyze the perinatal risk factors and morbidity with PH among very preterm infants in a large multicenter study. Methods: This was a multicenter case-control study based on a prospective cohort. Participants included 3,680 in-born infants with a gestational age at 24-32 weeks (birth weight <1,500 g) who were admitted between January 1, 2019, and October 31, 2021. All infants were divided into two groups, namely, the PH and no-PH groups, at a ratio of 1:2 according to the following factors: gestational age (GA), birth weight (BW), and the Score for Neonatal Acute Physiology with Perinatal extension II (SNAPPE II). Perinatal factors and outcomes were compared between the two groups by logistic regression analyses. Results: A total of 3,680 infants were included in the study, and the number of identified cases of PH was 262 (7.1%). The incidence was 16.9% (136/806) for neonates with extremely low BW (BW < 1,000 g) infants. The multivariate analysis showed that CPAP failure (OR 2.83, 95% CI 1.57, 5.08) was significantly associated with PH. PH was associated with a high likelihood of death (OR 3.81, 95% CI 2.67, 5.43) and bronchopulmonary dysplasia (BPD) (≥grade II) (OR 1.58, 95% CI 1.00, 2.48). Conclusions: In this multicenter case-control study based on a prospective cohort, PH to be common among VLBW infants. PH is associated with significant morbidity and mortality, and perinatal management, especially CPAP failure. Respiratory management strategies to decrease the risk of PH should be optimized.
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BACKGROUND: Immune checkpoints are a set of costimulatory and inhibitory molecules that maintain self-tolerance and regulate immune homeostasis. The expression of immune checkpoints on T cells in malignancy, chronic inflammation, and neurodegenerative diseases has gained increasing attention. RESULTS: To characterize immune checkpoints in neurodegenerative diseases, we aimed to examine the expression of the immune checkpoint PD-1/PD-L1 in peripheral T cells in different Alzheimer's disease (AD) patients. To achieve this aim, sixteen AD patients and sixteen age-matched healthy volunteers were enrolled to analyze their CD3+ T cells, CD3+CD56+ (neural cell adhesion molecule, NCAM) T cells, CD4+/CD8+ T cells, and CD4+/CD8+CD25+ (interleukin-2 receptor alpha, IL-2RA) T cells in this study. The expression of PD-1 on T cells was similar between the AD patients and healthy volunteers, but increased expression of PD-L1 on CD3+CD56+ T cells (natural killer T cells, NKT-like), CD4+ T cells (helper T cells, Th), CD4+CD25+ T cells, and CD8+ T cells (cytotoxic T lymphocytes, CTL) was detected in the AD patients. In addition, we found negative correlations between the AD patients' cognitive performance and both CD8+ T cells and CD8+CD25+ T cells. To identify CD8+ T-cell phenotypic and functional characteristic differences between the healthy volunteers and AD patients in different stages, a machine learning algorithm, t-distributed stochastic neighbor embedding (t-SNE), was implemented. Using t-SNE enabled the above high-dimensional data to be visualized and better analyzed. The t-SNE analysis demonstrated that the cellular sizes and densities of PD-1/PD-L1 on CD8+ T cells differed among the healthy, mild AD, and moderate AD subjects. CONCLUSIONS: Our results suggest that changes in PD-1/PD-L1-expressing T cells in AD patients' peripheral blood could be a potential biomarker for monitoring disease and shed light on the AD disease mechanism. Moreover, these findings indicate that PD-1/PD-L1 blockade treatment could be a novel choice to slow AD disease deterioration.
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In the era of bathing in big data, it is common to see enormous amounts of data generated daily. As for the medical industry, not only could we collect a large amount of data, but also see each data set with a great number of features. When the number of features is ramping up, a common dilemma is adding computational cost during inferring. To address this concern, the data rotational method by PCA in tree-based methods shows a path. This work tries to enhance this path by proposing an ensemble classification method with an AdaBoost mechanism in random, automatically generating rotation subsets termed Random RotBoost. The random rotation process has replaced the manual pre-defined number of subset features (free pre-defined process). Therefore, with the ensemble of the multiple AdaBoost-based classifier, overfitting problems can be avoided, thus reinforcing the robustness. In our experiments with real-world medical data sets, Random RotBoost reaches better classification performance when compared with existing methods. Thus, with the help from our proposed method, the quality of clinical decisions can potentially be enhanced and supported in medical tasks.
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The rapid Cretaceous diversification of flowering plants remains Darwin's 'abominable mystery' despite numerous fossil flowers discovered in recent years. Wildfires were frequent in the Cretaceous and many such early flower fossils are represented by charcoalified fragments, lacking complete delicate structures and surface textures, making their similarity to living forms difficult to discern. Furthermore, scarcity of information about the ecology of early angiosperms makes it difficult to test hypotheses about the drivers of their diversification, including the role of fire in shaping flowering plant evolution. We report the discovery of two exquisitely preserved fossil flower species, one identical to the inflorescences of the extant crown-eudicot genus Phylica and the other recovered as a sister group to Phylica, both preserved as inclusions together with burned plant remains in Cretaceous amber from northern Myanmar (~99 million years ago). These specialized flower species, named Phylica piloburmensis sp. nov. and Eophylica priscastellata gen. et sp. nov., exhibit traits identical to those of modern taxa in fire-prone ecosystems such as the fynbos of South Africa, and provide evidence of fire adaptation in angiosperms.
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Ámbar , Rhamnaceae , Ecosistema , Fósiles , MianmarRESUMEN
AIM: Due to high invasion and metastasis, hepatocellular carcinoma (HCC) is known as one of the most fatal carcinomas. We aim to further investigate regulatory mechanisms of invasion and metastasis to elucidate HCC pathogenesis and develop novel medications. METHODS: Patient specimens were collected for assessing gene expression and correlation between gene expressions. The expression of Ki67 and E-cadherin in subcutaneous xenograft tumor were examined by immunohistochemistry staining. The expression of activating transcription factor 2 (ATF2), miR-548p and TUFT1 were determined using Real-time quantitative reverse transcription polymerase chain reaction. Epithelial-mesenchymal transition and PI3K/AKT signaling-associated markers were examined with western blot. The proliferation, migration and invasion were assessed by 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide, colony formation and transwell assays, respectively. Cell apoptosis was assessed via Annexin V and propidium iodide staining. Gene interaction was confirmed using chromatin immunoprecipitation and luciferase activity assays. Subcutaneous and intravenous xenograft mouse models were established for analyzing HCC growth and metastasis in vivo. RESULTS: ATF2 was up-regulated in HCC patients and cells. ATF2 promoted HCC cell proliferation, migration and invasion and inhibited cell apoptosis through directly targeting miR-548p and controlling its expression. miR-548p suppressed HCC cell proliferation, migration and invasion and enhanced cell apoptosis. miR-548p directly bound to the 3'UTR of TUFT1 to restrain its expression and subsequently suppress the PI3K/AKT signaling. ATF2 knock-down significantly suppressed the growth and metastasis of HCC. CONCLUSION: ATF2 accelerates HCC progression by promoting cell proliferation, migration, invasion and metastasis, which is dependent on regulating the miR-548p/TUFT1 axis.
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Enteroscopia de Balón/instrumentación , Infecciones Relacionadas con Catéteres/prevención & control , Cirugía Endoscópica por Orificios Naturales/instrumentación , Complicaciones Posoperatorias/prevención & control , Recto/cirugía , Adulto , Infecciones Relacionadas con Catéteres/etiología , Femenino , Enfermedades de la Vesícula Biliar/cirugía , Cálculos Biliares/cirugía , Humanos , Masculino , Persona de Mediana Edad , Pólipos/cirugía , Complicaciones Posoperatorias/etiologíaRESUMEN
Tumor-initiating cells (TICs) or cancer stem cells are believed to be responsible for gastrointestinal tumor initiation, progression, metastasis, and drug resistance. It is hypothesized that gastrointestinal TICs (giTICs) might originate from cell-cell fusion. Here, we systemically evaluate the evidence that supports or opposes the hypothesis of giTIC generation from cell-cell fusion both in vitro and in vivo. We review giTICs that are capable of initiating tumors in vivo with 5000 or fewer in vivo fused cells. Under this restriction, there is currently little evidence demonstrating that giTICs originate from cell-cell fusion in vivo. However, there are many reports showing that tumor generation in vitro occurs with more than 5000 fused cells. In addition, the mechanisms of giTIC generation via cell-cell fusion are poorly understood, and thus, we propose its potential mechanisms of action. We suggest that future research should focus on giTIC origination from cell-cell fusion in vivo, isolation or enrichment of giTICs that have tumor-initiating capabilities with 5000 or less in vivo fused cells, and further clarification of the underlying mechanisms. Our review of the current advances in our understanding of giTIC origination from cell-cell fusion may have significant implications for the understanding of carcinogenesis and future cancer therapeutic strategies targeting giTICs.
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INTRODUCTION: Appendectomy remains the gold standard for treating uncomplicated and complicated appendicitis. However, the vermiform appendix may play a significant role in the immune system (secondary immune function) and maintain a reservoir of the normal microbiome for the human body. The aim of this study was to summarize the long-term effects after appendectomy and discuss whether appendectomy is suitable for all appendicitis patients. AREAS COVERED: A comprehensive and unbiased literature search was performed in PubMed. The terms 'appendix,' 'appendicitis,' 'appendectomy,' and 'endoscopic retrograde appendicitis therapy' were searched in the title and/or abstract. This review summarizes the long-term effects of appendectomy on some diseases in humans and describes three methods including appendectomy, medical treatment, and an 'organ-sparing' technique, named endoscopic retrograde appendicitis therapy (ERAT) to treat appendicitis. EXPERT OPINION: Appendectomy remains the first-line therapy for appendicitis. The patient's problem is appendix, not appendicitis. If we treat appendicitis, the problem should be resolved. During COVID-19, an initial antibiotic treatment of mild appendicitis represents a promising strategy. For patients who are worried about the long-term adverse effect after appendectomy and have a strong desire to preserve the appendix and are aware of the risk of appendicitis recurrence, medical treatment, or ERAT could be proposed.
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Apendicectomía/efectos adversos , Apendicitis/cirugía , COVID-19/prevención & control , Complicaciones Posoperatorias/epidemiología , Antibacterianos/uso terapéutico , Apendicitis/tratamiento farmacológico , Apendicitis/etiología , COVID-19/epidemiología , COVID-19/transmisión , Endoscopía , Humanos , Selección de PacienteRESUMEN
Chinese components of the genus Hexarhopalus Fairmaire, 1891 are revised. Four new species, Hexarhopalus (Hexarhopalus) liuyixiaoi Jiang, Bai, Ren Wang sp. nov. from Hunan and Hubei, Hexarhopalus (Leprocaulus) qiujianyueae Jiang, Bai, Ren Wang sp. nov. and Hexarhopalus (Leprocaulus) qiului Jiang, Bai, Ren Wang sp. nov. from Yunnan and Hexarhopalus (Leprocaulus) xuhaoi Jiang, Bai, Ren Wang sp. nov. from Xizang are described, figured and compared with their congeners. Hexarhopalus (Leprocaulus) difformis (Pic, 1922) is recorded from Yunnan, China for the first time. New distributional records are provided for Hexarhopalus (Leprocaulus) bisinuatus Ren Xu, 2011 from Hunan, Sichuan and Fujian, China. Supplementary description is presented for Hexarhopalus (Hexarhopalus) sculpticollis Fairmaire, 1891, Hexarhopalus (Hexarhopalus) sculptilis Kaszab 1960 and Hexarhopalus (Leprocaulus) difformis (Pic, 1922) to include the genital characters. A checklist, key and the distribution map of all known Chinese Hexarhopalus species are also provided.
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Escarabajos , Distribución Animal , Animales , ChinaRESUMEN
Orchestrated control of multiple overlapping and sequential processes is required for the maintenance of epidermal homeostasis and the response to and recovery from a variety of skin insults. Previous studies indicate that membrane-associated serine protease matriptase and prostasin play essential roles in epidermal development, differentiation, and barrier formation. The control of proteolysis is a highly regulated process, which depends not only on gene expression but also on zymogen activation and the balance between protease and protease inhibitor. Subcellular localization can affect the accessibility of protease inhibitors to proteases and, thus, also represents an integral component of the control of proteolysis. To understand how membrane-associated proteolysis is regulated in human skin, these key aspects of matriptase and prostasin were determined in normal and injured human skin by immunohistochemistry. This staining shows that matriptase is expressed predominantly in the zymogen form at the periphery of basal and spinous keratinocytes, and prostasin appears to be constitutively activated at high levels in polarized organelle-like structures of the granular keratinocytes in the adjacent quiescent skin. The membrane-associated proteolysis appears to be elevated via an increase in matriptase zymogen activation and prostasin protein expression in areas of skin recovering from epidermal insults. There was no noticeable change observed in other regulatory aspects, including the expression and tissue distribution of their cognate inhibitors HAI-1 and HAI-2. This study reveals that the membrane-associated proteolysis may be a critical epidermal mechanism involved in responding to, and recovering from, damage to human skin.
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Regulación del Desarrollo de la Expresión Génica , Expresión Génica , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Fenómenos Fisiológicos de la Piel/genética , Piel/lesiones , Cicatrización de Heridas/genética , Cicatrización de Heridas/fisiología , Heridas y Lesiones/genética , Heridas y Lesiones/metabolismo , Células Cultivadas , Precursores Enzimáticos/genética , Precursores Enzimáticos/metabolismo , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas Inhibidoras de Proteinasas Secretoras/genética , Proteínas Inhibidoras de Proteinasas Secretoras/metabolismo , Proteolisis , Serina Endopeptidasas/fisiología , Piel/metabolismoRESUMEN
BACKGROUND: Herpes simplex virus (HSV) can cause encephalitis. Its infected cell polypeptide 47 (ICP47), encoded by immediate-early gene US12, promotes immune escape. ICP47 was modified in the clinically approved oncolytic HSV (oHSV) T-Vec. However, transcription regulatory sequence (TRS) and transcription regulatory factor (TRF) of HSV US12 are seldom reported. METHODS: Previously, our laboratory isolated a new HSV strain named HSV-1-LXMW from a male patient with oral herpes in Beijing, China. Firstly, the genetic tree was used to analyze its genetic relationship. The US12 TRS and TRF in HSV-1-LXMW were found by using predictive software. Secondly, the further verification by the multi-sequence comparative analysis shown that the upstream DNA sequence of HSV US12 gene contained the conserved region. Finally, the results of literature search shown that the expression of transcription factors was related to the tissue affinity of HSV-1 and HSV-2, so as to increase the new understanding of the transcriptional regulation of HSV biology and oncolytic virus (OVs) therapy. RESULTS: Here we reported the transcriptional regulation region sequence of our new HSV-1-LXMW, and its close relationship with HSV-1-CR38 and HSV-1-17. Importantly we identified eight different kinds of novel TRSs and TRFs of HSV US12 for the first time, and found they are conserved among HSV-1 (c-Rel, Elk-1, Pax-4), HSV-2 (Oct-1, CF2-II, E74A, StuAp) or both HSVs (HNF-4). The TRFs c-Rel and Oct-1 are biologically functional respectively in immune escape and viral replication during HSV infection. CONCLUSIONS: Our findings have important implication to HSV biology, infection, immunity and oHSVs.
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Regulación Viral de la Expresión Génica , Herpesvirus Humano 1/genética , Proteínas Inmediatas-Precoces/genética , Evasión Inmune , Transcripción Genética , China , Herpes Simple/virología , Herpesvirus Humano 1/clasificación , Humanos , Masculino , Filogenia , Replicación ViralRESUMEN
Metformin (MET), an antidiabetic agent, also has antioxidative effects in metabolic-related hypertension. This study was designed to determine whether MET has anti-hypertensive effects in salt-sensitive hypertensive rats by inhibiting oxidative stress in the hypothalamic paraventricular nucleus (PVN). Salt-sensitive rats received a high-salt (HS) diet to induce hypertension, or a normal-salt (NS) diet as control. At the same time, they received intracerebroventricular (ICV) infusion of MET or vehicle for 6 weeks. We found that HS rats had higher oxidative stress levels and mean arterial pressure (MAP) than NS rats. ICV infusion of MET attenuated MAP and reduced plasma norepinephrine levels in HS rats. It also decreased reactive oxygen species and the expression of subunits of NAD(P)H oxidase, improved the superoxide dismutase activity, reduced components of the renin-angiotensin system, and altered neurotransmitters in the PVN. Our findings suggest that central MET administration lowers MAP in salt-sensitive hypertension via attenuating oxidative stress, inhibiting the renin-angiotensin system, and restoring the balance between excitatory and inhibitory neurotransmitters in the PVN.
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Hipertensión/tratamiento farmacológico , Metformina/farmacología , Estrés Oxidativo/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Cloruro de Sodio Dietético/farmacología , Animales , Antioxidantes/uso terapéutico , Presión Arterial/efectos de los fármacos , Hipertensión/inducido químicamente , Infusiones Intraventriculares , Masculino , Metformina/administración & dosificación , Neurotransmisores/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Angiotensin-(1-7) [Ang-(1-7)] is a multifunctional bioactive angiotensin peptide which exerts a cardiovascular protective function mainly by opposing the effects of angiotensin II. We aimed to determine whether brain Ang-(1-7) regulates nitric oxide (NO) and neurotransmitter levels in the hypothalamic paraventricular nucleus (PVN), and influences sympathetic activity, blood pressure and cardiac hypertrophy in salt-sensitive hypertension. Dahl salt-sensitive rats receiving a high-salt (HS, 8% NaCl) or a normal-salt (NS, 0.3% NaCl) diet were treated with an intracerebroventricular (ICV) infusion of Ang-(1-7) for 6 weeks. Seven rats were measured in each group. In comparison with NS rats, HS rats exhibited significantly increased mean arterial pressure, plasma norepinephrine (NE) and cardiac hypertrophy. In addition, HS rats (compared to NS rats) had increased glutamate, NE and tyrosine hydroxylase (TH) expression, and reduced NO levels as well as reduced expression of γ-aminobutyric acid (GABA) and the 67 kDa isoform of glutamate decarboxylase (GAD67) in the PVN. Treatment with ICV infusion of Ang-(1-7) reversed these changes in the salt-sensitive hypertensive rats. The results suggest that the beneficial effects of brain Ang-(1-7) on salt-sensitive hypertension and cardiac hypertrophy are partly due to an elevation in the NO level and restoration of neurotransmitter balance in the PVN.
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Induction of oxidative stress has a causal role in atherosclerosis. The aim of the present study was to examine the role of lectinlike oxidized lowdensity lipoprotein receptor1 (LOX1) in oxidized lowdensity lipoprotein (OxLDL)induced oxidative stress in atherosclerosis. Small interfering RNA (siRNA) technology was employed to decrease the expression of LOX1 in mouse RAW264.7 macrophages and the effects of LOX1 silencing on OxLDLinduced reactive oxygen species (ROS) generation and NADPH oxidase (NOX) expression were investigated. The in vivo effects of reducing LOX1 were also examined in a mouse model (ApoE/) of highfat dietinduced atherosclerosis. Compared with the control cells, OxLDL exposure led to a significant (P<0.05) increase in the intracellular levels of malondialdehyde and ROS and a significant decrease in the activity of superoxide dismutase. Delivery of LOX1targeting siRNA significantly (P<0.05) reversed the alterations in oxidative stress parameters induced by OxLDL. LOX1 silencing downregulated the expression of NOX2, Rac1, p47phox and p22phox and impaired the activation of mitogenactivated protein kinases in OxLDLtreated cells. Adenoviral delivery of LOX1 siRNA caused a significant increase in the size of the fibrous cap and a decrease in the macrophage content in lesions, compared with the control mice. Western blot analysis demonstrated that the protein expression levels of NOX1, Rac1, p47phox and p22phox in aortic lesions were significantly lower in the LOX1 siRNA group than in the control group. LOX1 is implicated in OxLDLinduced oxidative stress of macrophages in atherosclerosis, which in part, involves the regulation of NADPH oxidases.
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Aterosclerosis/metabolismo , Aterosclerosis/patología , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Estrés Oxidativo , Receptores Depuradores de Clase E/metabolismo , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/genética , Línea Celular , Grupo Citocromo b/genética , Grupo Citocromo b/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Silenciador del Gen , Lípidos/sangre , Lipoproteínas LDL/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Macrófagos/efectos de los fármacos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Noqueados , NADPH Oxidasa 2 , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Placa Aterosclerótica/genética , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología , ARN Interferente Pequeño/genética , Receptores Depuradores de Clase E/genética , Proteína de Unión al GTP rac1/genética , Proteína de Unión al GTP rac1/metabolismoRESUMEN
Angiotensin II (Ang II) and Ang-(1-7) are key effector peptides of the renin-angiotensin system. The present study aimed to investigate the effects of Ang-(1-7) on Ang II-stimulated cholesterol efflux and the associated molecular mechanisms. Differentiated THP-1 macrophages were treated with Ang II (1 µM) and/or Ang-(1-7) (10 and 100 nM) for 24 h and the cholesterol efflux and gene expression levels were assessed. Pharmacological inhibition of peroxisome proliferator-activated receptor (PPAR)γ and mitogen-activated protein kinases (MAPKs) were performed to identify the signaling pathways involved. The results demonstrated that Ang II significantly inhibited the cholesterol efflux from cholesterol-loaded THP-1 macrophages. Treatment with Ang-(1-7) led to a dose-dependent restoration of cholesterol efflux in the Ang II-treated cells. The co-treatment with Ang-(1-7) and Ang II significantly increased the expression levels of adenosine triphosphate (ATP)-binding cassette (ABC)A1 and ABCG1 compared with treatment with Ang II alone. This was coupled with increased expression levels of PPARγ and liver X receptor (LXR)α. The pharmacological inhibition of PPARγ significantly (P<0.05) eliminated the Ang-(1-7)-mediated induction of ABCA1 and ABCG1 mRNA expression. Treatment with Ang-(1-7) caused the inactivation of c-Jun N-terminal kinases (JNK) and p38 MAPK signaling in the Ang II-treated THP-1 macrophages. In addition, the inhibition of JNK or p38 MAPK signaling using specific pharmacological inhibitors mimicked the Ang-(1-7)-induced expression of PPARγ and LXRα. In conclusion, the data demonstrated that treatment with Ang-(1-7) promoted cholesterol efflux in Ang II-treated THP-1 macrophages, partly through inactivation of p38 and JNK signaling and by inducing the expression of PPARγ and LXRα. Ang (1-7) may, therefore, have therapeutic benefits for the treatment of atherosclerosis.
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Aterosclerosis/genética , Colesterol/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/biosíntesis , Receptores Nucleares Huérfanos/biosíntesis , Proteínas Quinasas p38 Activadas por Mitógenos/biosíntesis , Transportador 1 de Casete de Unión a ATP/biosíntesis , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1 , Transportadoras de Casetes de Unión a ATP/biosíntesis , Angiotensina I/administración & dosificación , Angiotensina II/administración & dosificación , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/patología , Regulación Enzimológica de la Expresión Génica , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Receptores X del Hígado , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Receptores Nucleares Huérfanos/genética , PPAR gamma/antagonistas & inhibidores , Fragmentos de Péptidos/administración & dosificación , ARN Mensajero/biosíntesis , Sistema Renina-Angiotensina , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
BACKGROUND: Fine particulate matter (PM) air pollution is associated with numerous adverse health effects, including increased blood pressure (BP) and vascular dysfunction. Coarse PM substantially contributes to global air pollution, yet differs in characteristics from fine particles and is currently not regulated. However, the cardiovascular (CV) impacts of coarse PM exposure remain largely unknown. OBJECTIVES: Our goal was to elucidate whether coarse PM, like fine PM, is itself capable of eliciting adverse CV responses. METHODS: We performed a randomized double-blind crossover study in which 32 healthy adults (25.9 ± 6.6 years of age) were exposed to concentrated ambient coarse particles (CAP; 76.2 ± 51.5 µg/m(3)) in a rural location and filtered air (FA) for 2 hr. We measured CV outcomes during, immediately after, and 2 hr postexposures. RESULTS: Both systolic (mean difference = 0.32 mmHg; 95% CI: 0.05, 0.58; p = 0.021) and diastolic BP (0.27 mmHg; 95% CI: 0.003, 0.53; p = 0.05) linearly increased per 10 min of exposure during the inhalation of coarse CAP when compared with changes during FA exposure. Heart rate was on average higher (4.1 bpm; 95% CI: 3.06, 5.12; p < 0.0001) and the ratio of low-to-high frequency heart rate variability increased (0.24; 95% CI: 0.07, 0.41; p = 0.007) during coarse particle versus FA exposure. Other outcomes (brachial flow-mediated dilatation, microvascular reactive hyperemia index, aortic hemodynamics, pulse wave velocity) were not differentially altered by the exposures. CONCLUSIONS: Inhalation of coarse PM from a rural location is associated with a rapid elevation in BP and heart rate during exposure, likely due to the triggering of autonomic imbalance. These findings add mechanistic evidence supporting the biological plausibility that coarse particles could contribute to the triggering of acute CV events.
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Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/estadística & datos numéricos , Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Material Particulado/toxicidad , Adolescente , Adulto , Presión Sanguínea/efectos de los fármacos , Estudios Cruzados , Método Doble Ciego , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Exposición por Inhalación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Tamaño de la Partícula , Población Rural , Adulto JovenRESUMEN
To cope with environmental high osmolarity, the budding yeast Saccharomyces cerevisiae activates the mitogen-activated protein kinase (MAPK) Hog1, which controls an array of osmoadaptive responses. Two independent, but functionally redundant, osmosensing systems involving the transmembrane sensor histidine kinase Sln1 or the tetraspanning membrane protein Sho1 stimulate the Hog1 MAPK cascade. Furthermore, the Sho1 signaling branch itself also involves the two functionally redundant osmosensors Hkr1 and Msb2. However, any single osmosensor (Sln1, Hkr1, or Msb2) is sufficient for osmoadaptation. We found that the signaling mechanism by which Hkr1 or Msb2 stimulated the Hog1 cascade was specific to each osmosensor. Specifically, activation of Hog1 by Msb2 required the scaffold protein Bem1 and the actin cytoskeleton. Bem1 bound to the cytoplasmic domain of Msb2 and thus recruited the kinases Ste20 and Cla4 to the membrane, where either of them can activate the kinase Ste11. The cytoplasmic domain of Hkr1 also contributed to the activation of Ste11 by Ste20, but through a mechanism that involved neither Bem1 nor the actin cytoskeleton. Furthermore, we found a PXXP motif in Ste20 that specifically bound to the Sho1 SH3 (Src homology 3) domain. This interaction between Ste20 and Sho1 contributed to the activation of Hog1 by Hkr1, but not by Msb2. These differences between Hkr1 and Msb2 may enable differential regulation of these two proteins and provide a mechanism through Msb2 to connect regulation of the cytoskeleton with the response to osmotic stress.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas de la Membrana/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Presión Osmótica/fisiología , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Citoesqueleto/genética , Citoesqueleto/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Proteínas de la Membrana/genética , Proteínas Quinasas Activadas por Mitógenos/genética , Unión Proteica/fisiología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genéticaRESUMEN
CONTEXT: High-density lipoprotein (HDL) particles perform numerous vascular-protective functions. Animal studies demonstrate that exposure to fine or ultrafine particulate matter (PM) can promote HDL dysfunction. However, the impact of PM on humans remains unknown. OBJECTIVE: We aimed to determine the effect of exposure to coarse concentrated ambient particles (CAP) on several metrics of HDL function in healthy humans. METHODS: Thirty-two adults (25.9 ± 6.6 years) were exposed to coarse CAP [76.2 ± 51.5 µg·m(-3)] in a rural location and filtered air (FA) for 2 h in a randomized double-blind crossover study. Venous blood collected 2- and 20-h post-exposures was measured for HDL-mediated efflux of [(3)H]-cholesterol from cells and 20-h exposures for HDL anti-oxidant capacity by a fluorescent assay and paraoxonase activity. The changes [median (first, third quartiles)] between exposures among 29 subjects with available results were compared by matched Wilcoxon tests. RESULTS: HDL-mediated cholesterol efflux capacity did not differ between exposures at either time point [16.60% (15.17, 19.19) 2-h post-CAP versus 17.56% (13.43, 20.98) post-FA, p = 0.768 and 14.90% (12.47, 19.15) 20-h post-CAP versus 17.75% (13.22, 23.95) post-FA, p = 0.216]. HOI [0.26 (0.24, 0.35) versus 0.28 (0.25, 0.40), p = 0.198] and paraoxonase activity [0.54 (0.39, 0.82) versus 0.60 µmol·min(-1 )ml plasma(-1) (0.40, 0.85), p = 0.137] did not differ 20-h post-CAP versus FA, respectively. CONCLUSIONS: Brief inhalation of coarse PM from a rural location did not acutely impair several facets of HDL functionality. Whether coarse PM derived from urban sites, fine particles or longer term PM exposures can promote HDL dysfunction warrant future investigations.