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The Yongdeng Qishan sheep (QS) is a sheep population found locally in China. To gain in-depth knowledge of its population characteristics, three control groups were chosen, comprising the Lanzhou fat-tailed sheep (LFT), TAN sheep (TAN), and Minxian black fur sheep (MBF), inhabiting the nearby environments. This study genotyped a total of 120 individuals from four sheep populations: QS, LFT, TAN, and MBF. Using Specific-Locus Amplified Fragment Sequencing, we conducted genetic diversity, population structure, and selective sweep analysis, and constructed the fingerprint of each population. In total, there were 782 535 single nucleotide polymorphism (SNP) variations identified, with most being situated within regions that are intergenic or intronic. The genetic diversity analysis revealed that the QS population exhibited lower genetic diversity compared to the other three populations. Consistent results were obtained from the principal component, phylogenetic tree, and population structure analysis, indicating significant genetic differences between QS and the other three populations. However, a certain degree of differentiation was observed within the QS population. The linkage disequilibrium (LD) patterns among the four populations showed clear distinctions, with the QS group demonstrating the most rapid LD decline. Kinship analysis supported the findings of population structure, dividing the 90 QS individuals into two subgroups consisting of 23 and 67 individuals. Selective sweep analysis identified a range of genes associated with reproduction, immunity, and adaptation to high-altitude hypoxia. These genes hold potential as candidate genes for marker-assisted selection breeding. Additionally, a total of 86 523 runs of homozygosity (ROHs) were detected, showing non-uniform distribution across chromosomes, with chromosome 1 having the highest coverage percentage and chromosome 26 the lowest. In the high-frequency ROH islands, 79 candidate genes were associated with biological processes such as reproduction and fat digestion and absorption. Furthermore, a DNA fingerprint was constructed for the four populations using 349 highly polymorphic SNPs. In summary, our research delves into the genetic diversity and population structure of QS population. The construction of DNA fingerprint profiles for each population can provide valuable references for the identification of sheep breeds both domestically and internationally.
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Dermatoglifia del ADN , Genoma , Humanos , Ovinos/genética , Animales , Filogenia , Dermatoglifia del ADN/veterinaria , Genotipo , Genómica , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Gastric cancer is one of the most common malignant tumors in the digestive system, ranking sixth in incidence and fourth in mortality worldwide. Since 42.5% of metastatic lymph nodes in gastric cancer belong to nodule type and peripheral type, the application of imaging diagnosis is restricted. AIM: To establish models for predicting the risk of lymph node metastasis in gastric cancer patients using machine learning (ML) algorithms and to evaluate their predictive performance in clinical practice. METHODS: Data of a total of 369 patients who underwent radical gastrectomy at the Department of General Surgery of Affiliated Hospital of Xuzhou Medical University (Xuzhou, China) from March 2016 to November 2019 were collected and retrospectively analyzed as the training group. In addition, data of 123 patients who underwent radical gastrectomy at the Department of General Surgery of Jining First People's Hospital (Jining, China) were collected and analyzed as the verification group. Seven ML models, including decision tree, random forest, support vector machine (SVM), gradient boosting machine, naive Bayes, neural network, and logistic regression, were developed to evaluate the occurrence of lymph node metastasis in patients with gastric cancer. The ML models were established following ten cross-validation iterations using the training dataset, and subsequently, each model was assessed using the test dataset. The models' performance was evaluated by comparing the area under the receiver operating characteristic curve of each model. RESULTS: Among the seven ML models, except for SVM, the other ones exhibited higher accuracy and reliability, and the influences of various risk factors on the models are intuitive. CONCLUSION: The ML models developed exhibit strong predictive capabilities for lymph node metastasis in gastric cancer, which can aid in personalized clinical diagnosis and treatment.
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The present study evaluated the effect of fermentation with Lactiplantibacillus plantarum B7 and Bacillus subtilis natto on phenolic compound levels and enzyme activity, as well as antioxidant capacity of the rose residue. Results showed that the polyphenol content of rose residue was significantly increased from 16.37 ± 1.51 mg/100 mL to 41.02 ± 1.68 mg/100 mL by fermentation at 37 °C and 2.0% (v/v) inoculum size for 40 h. The flavone, soluble dietary, and protein contents were also enhanced by almost 1-fold, 3-fold, and 1-fold, respectively. Fifteen phenolic compounds were quantified in the fermented broth, among which the concentration of gallic acid, quercetin, and p-coumaric acid increased by 5-fold, 4-fold, and almost 8-fold, respectively. Chlorogenic acid was a new phenolic compound produced during fermentation. Moreover, the fermented rose residue presented higher superoxide dismutase, α-amylase, and protease activity. ABTSâ¢+, hydroxylradical, and DPPH⢠scavenging activity increased by 60.93%, 57.70%, and 37.00%, respectively. This provides an effective means of transforming rose residue into a highly bioactive value-added substance.
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Bacillus subtilis , Rosa , PolifenolesRESUMEN
Interferon-gamma (IFN-γ) is a cytokine involved in the pathogenesis of Takayasu's arteritis (TAK). However, the source of IFN-γ in TAK patients is not fully clear. We aimed to investigate the source of IFN-γ in TAK. 60 TAK patients and 35 health controls were enrolled. The lymphocyte subsets of peripheral blood were detected by flow cytometry, cytokines were detected by Bio-plex. The correlation among lymphocyte subsets, cytokines and disease activity indexes was analyzed by person correlation. The level of serum IFN-γ in TAK patients was significantly increased (P < 0.05). The percentage of CD3+IFN-γ+ cells in peripheral blood CD3+ cells was significantly higher in TAK patients than that of healthy control group (P = 0.002). A higher proportion of CD3+CD8+IFN-γ+ cells/CD3+IFN-γ+ cells (40.23 ± 11.98% vs 35.12 ± 11.51%, P = 0.049), and a significantly lower CD3+CD4+IFN-γ+/ CD3+CD8+IFN-γ+ ratio (1.34 ± 0.62% vs 1.80 ± 1.33%, P = 0.027) were showed in the TAK group than that of control group. The CD3+CD8+IFN-γ+/CD3+IFN-γ+ ratio was positively correlated with CD3+IFN-γ+cells/ CD3+cells ratio (r = 0.430, P = 0.001), serum IFN-γ level (r = 0.318, P = 0.040) and IL-17 level (r = 0.326, P = 0.031). It was negatively correlated with CD3+CD4+IFN-γ+/CD3+IFN-γ+ ratio (r = - 0.845, P < 0.001). IFN-γ secreted by CD3+CD8 + T cells is an important source of serum IFN-γ in TAK patients.
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Linfocitos T CD8-positivos/inmunología , Interferón gamma/metabolismo , Arteritis de Takayasu/inmunología , Adulto , Células Cultivadas , Femenino , Humanos , Interferón gamma/genética , Masculino , Persona de Mediana Edad , Arteritis de Takayasu/sangreRESUMEN
OBJECTIVES: Takayasu's arteritis (TAK) involves inflammatory vasculitis of large vessels and mainly affects the aorta and its major branches. Abnormal immunity may play a vital role in TAK pathogenesis. Regulatory T cells (Treg cells) are important for peripheral tolerance, but under certain conditions Treg cells can differentiate into Th-like cells that have lost immune suppressive function and promote the development of autoimmune diseases. The role of Th-like Treg cells in TAK is unclear and this study aims to investigate the function of Th-like Treg cell subsets and associated cytokines in TAK. METHODS: A total of 51 patients with TAK and 32 healthy controls were enrolled. The percentage of Th1, Th2, Th17, Tregs and Th-like Treg cells in blood samples was analyzed by flow cytometry. Serum cytokine levels were detected using a cytometric bead array for cytokines. RESULTS: TAK patients had decreased numbers of Th2-like Treg cells in the peripheral blood (p=0.002) relative to healthy controls. The percentage of Treg cells in samples from TAK patients also decreased (p=0.002), but the Th2 cell percentage (p=0.04) increased compared to healthy controls. TAK patients had higher serum levels of IL-4 (p<0.001) and IL-13 (p<0.001) than healthy controls, and levels of both cytokines correlated to IL-6 levels. CONCLUSIONS: We studied changes in T helper-like Treg cell subsets in TAK for the first time and discovered that the number of Th2-like Treg cells in peripheral blood decreased. Results of this study suggested that Th2-like Treg cells could contribute to TAK pathogenesis.
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Linfocitos T Reguladores/inmunología , Arteritis de Takayasu/patología , Estudios de Casos y Controles , Citocinas/sangre , Humanos , Arteritis de Takayasu/inmunología , Células TH1 , Células Th17 , Células Th2RESUMEN
Background: Survival of very-low-birth-weight infants is improving in neonatology and family-centered-care might contribute to premature infants' clinical outcomes. Aim: To evaluate a family-centered care intervention on clinical outcomes of very-low-birth-weight infants. Methods: A quasi-experimental study was conducted in a Chinese NICU between June 2016 and June 2017. The intervention included parental education of basic care knowledge and skills followed by active participation in care for at least 4 h a day. A total of 319 very-low-birth-weight infants were recruited by convenience sampling; intervention group n = 156 and control group n = 163. Primary outcome measures were weight at discharge, length-of-stay, breastfeeding, nasal feeding, total parental nutrition, re-admission, hospital expenses. Secondary outcome measures were infant complications. Results: Infants' weight at discharge was higher in the interventions group (2,654 g vs. 2,325 g, p < 0.001). Nutritional outcomes improved significantly: breastfeeding rate 139 vs. 91, p < 0.001; days of total parental nutrition 25 d vs. 32 d, p < 0.001; gastric feeding days 23 d vs. 35 d, p < 0.001. Length-of-stay and hospital expenses did not differ between both groups. Improved infants' complications were bronchopulmonary dysplasia (32 vs. 51, p = 0.031), retinopathy of prematurity (between groups no/mild and moderate/severe, p = 0.003), necrotizing enterocolitis (6 vs. 18, p = 0.019), and re-admission rate (21 vs. 38, p = 0.023). No differences were observed in intraventricular hemorrhage and nosocomial infections. Conclusion: Very-low-birth-weight premature infants might experience improved clinical health outcomes when parents are present and caring from them. Family-centered care is as a beneficial care model for premature infants and should be recognized and implemented by NICUs where parents have currently limited access.
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The first highly efficient and practical chiral Brønsted acid catalyzed dynamic kinetic asymmetric hydroamination (DyKAH) of racemic allenes and asymmetric hydroamination of unactivated dienes with both high E/Z selectivity and enantioselectivity are described herein. The transformation proceeds through a new catalytic asymmetric model involving a highly reactive π-allylic carbocationic intermediate, generated from racemic allenes or dienes through a proton transfer mediated by an activating/directing thiourea group. This method affords expedient access to structurally diverse enantioenriched, potentially bioactive alkenyl-containing aza-heterocycles and bicyclic aza-heterocycles.
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An asymmetric intermolecular, three-component radical-initiated dicarbofunctionalization of 1,1-diarylalkenes with diverse carbon-centered radical precursors and electron-rich heteroaromatics by a copper(I) and chiral phosphoric acid cooperative catalysis strategy has been developed, providing straightforward access to chiral triarylmethanes bearing quaternary all-carbon stereocenters with high efficiency as well as excellent chemo- and enantioselectivity. The key to success is not only the introduction of a sterically demanding chiral phosphoric acid to favor radical difunctionalization over the otherwise remarkable side reactions but also the in situ generation of carbocation intermediates from benzylic radical to realize asymmetric induction with the aid of a removable hydroxy directing group via cooperative interactions with chiral phosphate. Density functional theory calculations elucidated the critical chiral environment created by the hydrogen-bonding and ion-pair interactions between the chiral phosphoric acid catalyst and substrates, which leads to the enantioselective C-C bond formation.
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This study evaluated transepithelial transport mechanisms of Ile-Gln-Pro (IQP) and Val-Glu-Pro (VEP), two ACE-inhibitory peptides derived from Spirulina platensis, using human intestinal Caco-2 cell monolayers. IQP and VEP were absorbed intact through Caco-2 cell monolayers with Papp values of 7.48 ± 0.58 × 10-6 and 5.05 ± 0.74 × 10-6 cm/s, respectively. The transport of IQP and VEP were affected neither by Gly-Pro nor by wortmannin, indicating that they were not PepT1-mediated and did not involve endocytosis. However, transport of IQP and VEP were increased significantly by sodium deoxycholate, suggesting that the major transport mechanism was paracellular. In addition, the increased transport of VEP and IQP were followed with the addition of sodium azide, suggesting influence of energy to the process. The transport of VEP was also increased by verapamil, indicating an apical-to-basolateral flux mediated by P-gp. PRACTICAL APPLICATION: Bioactive peptides derived from food proteins have been considered as potentially ideal products to reduce hypertension because of their safety and positive impacts on health. IQP and VEP are the 2 ACE inhibitory peptides derived from Spirulina platensis, a kind of edible cyanobacteria with rich nutrition and multiple physiological functions, and were demonstrated to inhibit ACE and lower blood pressure in spontaneously hypertensive rats. However, it is prerequisite that such bioactive peptides must be absorbed intact across the intestinal epithelium, so as to exert antihypertensive effects in vivo. This study evaluated transepithelial transport mechanisms of IQP and VEP. It contributes to the study of Spirulina in lowering blood pressure and supports the development of bioactive peptide products.
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Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Péptidos/metabolismo , Spirulina/metabolismo , Antihipertensivos/metabolismo , Transporte Biológico , Células CACO-2 , Dipéptidos/metabolismo , Humanos , Hipertensión/fisiopatología , Mucosa Intestinal/metabolismoRESUMEN
Inflammatory cells such as macrophages can play a pro-tumorigenic role in the tumor stroma. Tumor-associated macrophages (TAMs) generally display an M2 phenotype with tumor-promoting activity; however, the mechanisms regulating the TAM phenotype remain unclear. Complement 5a (C5a) is a cytokine-like polypeptide that is generated during complement system activation and is known to promote tumor growth. Herein, we investigated the role of C5a on macrophage polarization in colon cancer metastasis in mice. We found that deficiency of the C5a receptor (C5aR) severely impairs the metastatic ability of implanted colon cancer cells. C5aR was expressed on TAMs, which exhibited an M2-like functional profile in colon cancer liver metastatic lesions. Furthermore, C5a mediated macrophage polarization and this process relied substantially on activation of the nuclear factor-kappa B (NF-κB) pathway. Finally, analysis of human colon carcinoma indicated that C5aR expression is negatively associated with tumor differentiation grade. Our results demonstrate that C5aR has a central role in regulating the M2 phenotype of TAMs, which in turn, contributes to hepatic metastasis of colon cancer through NF-κB signaling. C5a is a potential novel marker for cancer prognosis and drugs targeting complement system activation, specifically the C5aR pathway, may offer new therapeutic opportunities for colon cancer management.
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Neoplasias del Colon/patología , Complemento C5a/metabolismo , Neoplasias Hepáticas/secundario , Macrófagos/patología , Receptor de Anafilatoxina C5a/metabolismo , Receptor de Anafilatoxina C5a/fisiología , Animales , Carcinogénesis , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Complemento C5a/genética , Citocinas/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Activación de Macrófagos , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor de Anafilatoxina C5a/genética , Transducción de Señal , Células Tumorales Cultivadas , Microambiente TumoralRESUMEN
The degeneration of vascular smooth muscle cell(s) (SMC) is one of the key features of thoracic aortic aneurysm and dissection (TAAD). We and others have shown that elevated endoplasmic reticulum (ER) stress causes SMC loss and TAAD formation, however, the mechanism of how SMC dysfunction contributes to intimal damage, leading to TAAD, remains to be explored. In the present study, in vitro assay demonstrated that elevated mechanical stretch (18% elongation, 3600 cycles/h) stimulated the ER stress response and microparticle(s) (MP) production from both SMC and endothelial cell(s) (EC) in a time-dependent manner. Treatment of EC with isolated MP led to anoikis, which was determined by measuring the fluorescence of the ethidium homodimer (EthD-1) and Calcein AM cultured in hydrogel-coated plates and control plates. MP stimulation of EC also up-regulated the mRNA levels of inflammatory molecules (i.e. Vascular cellular adhesion molecular-1 (VCAM-1)), intercellular adhesion molecular-1 (ICAM-1), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6)). Use of an ER stress inhibitor or knockout of CHOP decreased mechanical stretch-induced MP production in SMC. In vivo, administration of an ER stress inhibitor or knockout of CHOP suppressed both apoptosis of EC and the infiltration of inflammatory cells. Moreover, TAAD formation was also suppressed by the administration of an ER stress inhibitor. In conclusion, our study demonstrates that elevated mechanical stretch induces MP formation in SMC leading to endothelial dysfunction, which is ER stress dependent. The inhibition of ER stress suppressed EC apoptosis, inflammation in the aorta, and TAAD development.
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Aneurisma de la Aorta Torácica/metabolismo , Disección Aórtica/metabolismo , Micropartículas Derivadas de Células/metabolismo , Estrés del Retículo Endoplásmico , Retículo Endoplásmico/metabolismo , Células Endoteliales/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Aminopropionitrilo , Disección Aórtica/inducido químicamente , Disección Aórtica/genética , Disección Aórtica/patología , Animales , Anoicis , Aorta Torácica/metabolismo , Aorta Torácica/patología , Aneurisma de la Aorta Torácica/inducido químicamente , Aneurisma de la Aorta Torácica/genética , Aneurisma de la Aorta Torácica/patología , Micropartículas Derivadas de Células/patología , Células Cultivadas , Modelos Animales de Enfermedad , Retículo Endoplásmico/patología , Células Endoteliales/patología , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Mediadores de Inflamación/metabolismo , Masculino , Mecanotransducción Celular , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/patología , Comunicación Paracrina , Fenotipo , ARN Mensajero/genética , Estrés Mecánico , Factores de Tiempo , Factor de Transcripción CHOP/genética , Factor de Transcripción CHOP/metabolismoRESUMEN
The effects of moderate salinity on the responses of woody plants to UV-B radiation were investigated using two Populus species (Populus alba and Populus russkii). Under UV-B radiation, moderate salinity reduced the oxidation pressure in both species, as indicated by lower levels of cellular H2O2 and membrane peroxidation, and weakened the inhibition of photochemical efficiency expressed by O-J-I-P changes. UV-B-induced DNA lesions in chloroplast and nucleus were alleviated by salinity, which could be explained by the higher expression levels of DNA repair system genes under UV-B&salt condition, such as the PHR, DDB2, and MutSα genes. The salt-induced increase in organic osmolytes proline and glycine betaine, afforded more efficient protection against UV-B radiation. Therefore moderate salinity induced cross-tolerance to UV-B stress in poplar plants. It is thus suggested that woody plants growing in moderate salted condition would be less affected by enhanced UV-B radiation than plants growing in the absence of salt. Our results also showed that UV-B signal genes in poplar plants PaCOP1, PaSTO and PaSTH2 were quickly responding to UV-B radiation, but not to salt. The transcripts of PaHY5 and its downstream pathway genes (PaCHS1, PaCHS4, PaFLS1 and PaFLS2) were differently up-regulated by these treatments, but the flavonoid compounds were not involved in the cross-tolerance since their concentration increased to the same extent in both UV-B and combined stresses.
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Hojas de la Planta/crecimiento & desarrollo , Populus/crecimiento & desarrollo , Tolerancia a la Sal/efectos de la radiación , Cloruro de Sodio/farmacología , Estrés Fisiológico/efectos de los fármacos , Rayos Ultravioleta/efectos adversos , Adaptación Fisiológica , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Regulación de la Expresión Génica de las Plantas/efectos de la radiación , Hojas de la Planta/efectos de los fármacos , Hojas de la Planta/efectos de la radiación , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Populus/efectos de los fármacos , Populus/efectos de la radiación , Estrés Fisiológico/efectos de la radiaciónRESUMEN
Thoracic aortic aneurysm/dissection (TAAD) is characterized by excessive smooth muscle cell (SMC) loss, extracellular matrix (ECM) degradation and inflammation. However, the mechanism whereby signaling leads to SMC loss is unclear. We used senescence-associated (SA)-ß-gal staining and analysis of expression of senescence-related proteins (p53, p21, p19) to show that excessive mechanical stretch (20% elongation, 3600cycles/h, 48h) induced SMC senescence. SMC senescence was also detected in TAAD specimens from both mice and humans. High-performance liquid chromatography and luciferin-luciferase-based assay revealed that excessive mechanical stretch increased adenosine diphosphate (ADP) release from SMCs both in vivo and in vitro. Elevated ADP induced SMC senescence while genetic knockout of the ADP receptor, P2Y G protein-coupled receptor 12 (P2ry12), in mice protected against SMC senescence and inflammation. Both TAAD formation and rupture were significantly reduced in P2ry12-/- mice. SMCs from P2ry12-/- mice were resistant to senescence induced by excessive mechanical stretch or ADP treatment. Mechanistically, ADP treatment sustained Ras activation, whereas pharmacological inhibition of Ras protected against SMC senescence and reduced TAAD formation. Taken together, excessive mechanical stress may induce a sustained release of ADP and promote SMC senescence via P2ry12-dependent sustained Ras activation, thereby contributing to excessive inflammation and degeneration, which provides insights into TAAD formation and progression.
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Adenosina Difosfato/metabolismo , Aneurisma de la Aorta Torácica/metabolismo , Disección Aórtica/metabolismo , Miocitos del Músculo Liso/metabolismo , Receptores Purinérgicos P2Y12/metabolismo , Transducción de Señal , Disección Aórtica/diagnóstico por imagen , Disección Aórtica/etiología , Disección Aórtica/patología , Animales , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Aneurisma de la Aorta Torácica/etiología , Aneurisma de la Aorta Torácica/patología , Biopsia , Senescencia Celular , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Masculino , Metaloproteinasas de la Matriz/metabolismo , Ratones , Ratones Noqueados , Receptores Purinérgicos P2Y12/deficiencia , Receptores Purinérgicos P2Y12/genética , Estrés Mecánico , UltrasonografíaRESUMEN
A novel asymmetric radical aminotrifluoromethylation of alkenes has been developed for the first time, providing straightforward access to densely functionalized CF3-containing azaheterocycles bearing an α-tertiary stereocenter with excellent enantioselectivity. The key to success is not only the introduction of a Cu(I)/chiral phosphoric acid dual-catalytic system but also the use of urea with two acidic N-H as both the nucleophile and directing group. The utility of this method is illustrated by facile transformations of the products into other important compounds useful in organic synthesis and medicinal chemistry.
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BACKGROUND/AIMS: Hypertension plays a critical role in the cardiac inflammation and injury. However, the mechanism of how hypertension causes the cardiac injury at a molecular level remains to be elucidated. METHODS: RNA-Seq has been demonstrated to be an effective approach for transcriptome analysis, which is essential to reveal the molecular constituents of cells and tissues. In this study, we investigated the global molecular events associated with the mechanism of hypertension induced cardiac injury using RNA-Seq analysis. RESULTS: Our results showed that totally 1,801 genes with different expression variations were identified after Ang II infusion at 1, 3 and 7 days. Go analysis showed that the top 5 high enrichment Go terms were response to stress, response to wounding, cellular component organization, cell activation and defense response. KEGG pathway analysis revealed the top 5 significantly overrepresented pathways were associated with ECM-receptor interaction, focal adhesion, protein digestion and absorption, phagosome and asthma. Moreover, protein-protein interaction network analysis indicated that ubiquitin C may play a key role in the processes of hypertension-induced cardiac injury. CONCLUSION: Our study provides a comprehensive understanding of the transcriptome events in hypertension-induced cardiac pathology.
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Perfilación de la Expresión Génica , Lesiones Cardíacas/genética , Hipertensión/genética , Miocardio/patología , Transcriptoma , Animales , Fibrosis , Regulación de la Expresión Génica , Ontología de Genes , Lesiones Cardíacas/complicaciones , Lesiones Cardíacas/metabolismo , Lesiones Cardíacas/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Hipertensión/complicaciones , Hipertensión/metabolismo , Hipertensión/patología , Inflamación/complicaciones , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Ratones , Miocardio/metabolismo , Mapas de Interacción de ProteínasRESUMEN
Thoracic aortic aneurysm/dissection (TAAD) is characterized by excessive smooth muscle cell (SMC) loss, extracellular matrix (ECM) degradation and inflammation. In response to certain stimuli, endoplasmic reticulum (ER) stress is activated and regulates apoptosis and inflammation. Excessive apoptosis promotes aortic inflammation and degeneration, leading to TAAD. Therefore, we studied the role of ER stress in TAAD formation. A lysyl oxidase inhibitor, 3-aminopropionitrile fumarate (BAPN), was administrated to induce TAAD formation in mice, which showed significant SMC loss (α-SMA level). Excessive apoptosis (TUNEL staining) and ER stress (ATF4 and CHOP), along with inflammation, were present in TAAD samples from both mouse and human. Transcriptional profiling of SMCs after mechanical stress demonstrated the expression of genes for ER stress and inflammation. To explore the causal role of ER stress in initiating degenerative signalling events and TAAD, we treated wild-type (CHOP(+/+)) or CHOP(-/-) mice with BAPN and found that CHOP deficiency protected against TAAD formation and rupture, as well as reduction in α-SMA level. Both SMC apoptosis and inflammation were significantly reduced in CHOP(-/-) mice. Moreover, SMCs isolated from CHOP(-/-) mice were resistant to mechanical stress-induced apoptosis. Taken together, our results demonstrated that mechanical stress-induced ER stress promotes SMCs apoptosis, inflammation and degeneration, providing insight into TAAD formation and progression.
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Aneurisma de la Aorta Torácica/patología , Apoptosis , Estrés del Retículo Endoplásmico , Transducción de Señal , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , Aminopropionitrilo/farmacología , Animales , Aorta/metabolismo , Aneurisma de la Aorta Torácica/inducido químicamente , Aneurisma de la Aorta Torácica/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Inflamación , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Miocitos del Músculo Liso/metabolismo , Factor de Transcripción CHOP/genética , Factor de Transcripción CHOP/metabolismoRESUMEN
PURPOSE: Platelets are essential for primary hemostasis; however, platelet activation also plays an important proinflammatory role. Inflammation promotes the development of cardiac fibrosis and heart failure induced by hypertension. In this study, we aimed to determine whether inhibiting platelet activation using clopidogrel could inhibit hypertension-induced cardiac inflammation and fibrosis. METHODS: Using a mouse model of angiotensin II (Ang II) infusion (1,500 ng/[kg·min] for 7 days), we determined the role of platelet activation in Ang II infusion-induced cardiac inflammation and fibrosis using a P2Y12 receptor inhibitor, clopidogrel (50 mg/[kg·day]). RESULTS: CD41 staining showed that platelets accumulated in Ang II-infused hearts. Clopidogrel treatment inhibited Ang II infusion-induced accumulation of α-SMA(+) myofibroblasts and cardiac fibrosis (4.17 ± 1.26 vs. 1.46 ± 0.81, p < 0.05). Infiltration of inflammatory cells, including Mac-2(+) macrophages and CD45(+)Ly6G(+) neutrophils (30.38 ± 4.12 vs. 18.7 ± 2.38, p < 0.05), into Ang II-infused hearts was also suppressed by platelet inhibition. Real-time PCR and immunohistochemical staining showed that platelet inhibition significantly decreased the expression of interleukin-1ß and transforming growth factor-ß. Acute injection of Ang II or PE stimulated platelet activation and platelet-leukocyte conjugation, which were abolished by clopidogrel treatment. CONCLUSION: Thus, inhibition of platelet activation by clopidogrel prevents cardiac inflammation and fibrosis in response to Ang II. Taken together, our results indicate Ang II infusion-induced hypertension stimulated platelet activation and platelet-leukocyte conjugation, which initiated inflammatory responses that contributed to cardiac fibrosis.
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Fibrosis/prevención & control , Hipertensión/complicaciones , Miocarditis/prevención & control , Inhibidores de Agregación Plaquetaria/uso terapéutico , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Ticlopidina/análogos & derivados , Angiotensina II , Animales , Clopidogrel , Fibrosis/patología , Hipertensión/inducido químicamente , Hipertensión/patología , Hipertensión/fisiopatología , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Miocarditis/patología , Miocardio/patología , Activación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Antagonistas del Receptor Purinérgico P2Y/farmacología , Ticlopidina/farmacología , Ticlopidina/uso terapéutico , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
To study the implementation of the epidemic prevention by the authorities of the concession and late Qing dynasty through investigation of the prevention and treatment of pestilence in Shanghai from 1872 to 1911, this paper analyzes the issues concerning municipal administration, inspection and disinfection, food sanitation, vaccination, regulatory legislation and health promotion, etc. The experiences are summarized in the study. The lessons drawn from what the concession authority did to prevent pestilence imply that the implementation of health promotion should be carried out according to the variation of the time, location and population, and that traditional Chinese medicine should be involved in the prevention and treatment of pestilence.