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Diabetes is a significant global public health issue with implications for vascular endothelial cells (ECs) dysfunction and the subsequent development and advancement of diabetes complications. This study aims to compare the cellular and molecular properties of the aorta in normal and streptozotocin (STZ)-induced diabetic mice, with a focus on elucidating potential mechanism underlying EC dysfunction. Here, we performed a single-cell RNA sequencing survey of 32,573 cells from the aorta of normal and STZ-induced diabetic mice. We found a compendium of 10 distinct cell types, mainly ECs, smooth muscle cells, fibroblast, pericyte, immune cells, and stromal cells. As the diabetes condition progressed, we observed a subpopulation of aortic ECs that exhibited significantly elevated expression of complement (C) molecule C1qa compared with their healthy counterparts. This increased expression of C1qa was found to induce reactive oxygen species (ROS) production, facilitate EC migration and increased permeability, and impair the vasodilation within the aortic segment of mice. Furthermore, AAV-Tie2-shRNA-C1qa was administered into diabetic mice by tail vein injection, showing that inhibition of C1qa in the endothelium led to a reduction in ROS production, decreased vascular permeability, and improved vasodilation. Collectively, these findings highlight the crucial involvement of C1qa in endothelial dysfunction associated with diabetes.
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Complemento C1q , Diabetes Mellitus Experimental , Endotelio Vascular , Animales , Diabetes Mellitus Experimental/metabolismo , Complemento C1q/metabolismo , Complemento C1q/genética , Ratones , Endotelio Vascular/metabolismo , Masculino , Especies Reactivas de Oxígeno/metabolismo , Células Endoteliales/metabolismo , Aorta/metabolismo , Ratones Endogámicos C57BL , Vasodilatación/efectos de los fármacos , Permeabilidad Capilar , Movimiento CelularRESUMEN
The prevalence of chirality, or, handedness in biological world is a fundamental phenomenon and a characteristic hallmark of life. Thus, understanding the origin of enantio-selection, i.e., the sense and magnitude of asymmetric induction, has been a long-pursued goal in asymmetric catalysis. Herein, we demonstrated a polarizability-derived electronic effect that was shown to be capable of rationalizing a broad range of stereochemical observations made in the field of asymmetric catalysis. This effect provided a consistent enantio-control model for the prediction of major enantiomers formed in a ruthenium-catalyzed asymmetric transfer hydrogenations of ketones. Direct and quantitative linear free energy relationships between substrates' local polarizabilities and observed enantio-selectivity were also revealed in three widely known asymmetric catalytic systems covering both reductions and oxidations. This broadly applicable polarizability-based electronic effect, in conjunction with conventional wisdom mainly leveraging on steric effect considerations, should aid rational design of enantio-selective processes for better production of chiral substances.
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BACKGROUND: Single-cell RNA-Seq analysis can determine the heterogeneity of cells between different tissues at a single-cell level. Coronary artery endothelial cells (ECs) are important to coronary blood flow. However, little is known about the heterogeneity of coronary artery ECs, and cellular identity responses to flow. Identifying endothelial subpopulations will contribute to the precise localization of vascular endothelial subpopulations, thus enabling the precision of vascular injury treatment. METHODS: Here, we performed a single-cell RNA sequencing of 31â 962 cells and functional assays of 3 branches of the coronary arteries (right coronary artery/circumflex left coronary artery/anterior descending left coronary artery) in wild-type mice. RESULTS: We found a compendium of 7 distinct cell types in mouse coronary arteries, mainly ECs, granulocytes, cardiac myocytes, smooth muscle cells, lymphocytes, myeloid cells, and fibroblast cells, and showed spatial heterogeneity between arterial branches. Furthermore, we revealed a subpopulation of coronary artery ECs, CD133+TRPV4high ECs. TRPV4 (transient receptor potential vanilloid 4) in CD133+TRPV4high ECs is important for regulating vasodilation and coronary blood flow. CONCLUSIONS: Our study elucidates the nature and range of coronary arterial cell diversity and highlights the importance of coronary CD133+TRPV4high ECs in regulating coronary vascular tone.
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Células Endoteliales , Canales Catiónicos TRPV , Ratones , Animales , Células Endoteliales/metabolismo , Canales Catiónicos TRPV/genética , Análisis de Expresión Génica de una Sola Célula , Vasodilatación/fisiología , Endotelio Vascular/metabolismoRESUMEN
The facile oxidation of Sn2+ to Sn4+ poses an inherent challenge that limits the efficiency and stability of tin-lead mixed (Sn-Pb) perovskite solar cells (PSCs) and all-perovskite tandem devices. In this work, we discover the sustainable redox reactions enabling self-healing Sn-Pb perovskites, where their intractable oxidation degradation can be recovered to their original state under light soaking. Quantitative and operando spectroscopies are used to investigate the redox chemistry, revealing that metallic Pb0 from the photolysis of perovskite reacts with Sn4+ to regenerate Pb2+ and Sn2+ spontaneously. Given the sluggish redox reaction kinetics, V3+ /V2+ ionic pair is designed as an effective redox shuttle to accelerate the recovery of Sn-Pb perovskites from oxidation. The target Sn-Pb PSCs enabled by V3+ /V2+ ionic pair deliver an improved power conversion efficiency (PCE) of 21.22 % and excellent device lifespan, retaining nearly 90 % of its initial PCE after maximum power point tracking under light for 1,000â hours.
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With a stacking-layered architecture, the bilayer two-dimensional-three-dimensional (2D-3D) perovskite heterostructure (PHS) not only eliminates surface defects but also protects the 3D perovskite matrix from external stimuli. However, these bilayer 2D-3D PHSs suffer from impaired interfacial charge carrier transport due to the relatively insulating 2D perovskite fragments with a random phase distribution. Over the past decade, substantial efforts have been devoted to pioneering molecular and structural designs of the 2D perovskite interlayers for improving their charge carrier mobility, which enables state-of-the-art perovskite solar cells with high power conversion efficiency and exceptional operational stability. Herein, this review offers a comprehensive and up-to-date overview on the recent progress of bilayer 2D-3D PHSs, encompassing advancements on spacer cation engineering, interfacial charge carrier modification, advanced deposition protocols, and characterization techniques. Then, the evolutionary trajectory of bilayer 2D-3D PHSs is outlined by summarizing its mainstream development trends, followed by a perspective discussion about its future research opportunities toward efficient and durable perovskite solar cells.
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A highly efficient kinetic resolution of allylic alcohols with Z/E mixtures was achieved via Ru-catalyzed selective dehydrogenation. Not only allylic alcohols were obtained with pure Z-geometry, but the corresponding selectivity factors rank among the few highest for kinetic resolution reported in the literature.
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BACKGROUND AND PURPOSE: High-fat diet (HFD) induces dysregulated pathways in coronary artery endothelial cells (CAECs), which leads to altered regulation of vascular tone, tissue perfusion and increases the risk of coronary artery diseases. Ca2+ -activated K+ (KCa ) channels are known to be associated with transient receptor potential (TRP) channels, which are important for regulating endothelial function. But how TRPV4 channels interacts with KCa channels in regulating coronary vascular tone in HFD mice requires further exploration. EXPERIMENTAL APPROACH: TRPV4 channel activity was assessed by fluorescent Ca2+ imaging. Interactions between TRPV4 and KCa 3.1 channels were verified by co-immunoprecipitation and immunofluorescence resonance energy transfer (FRET), and their binding site was found by site-directed mutagenesis. Endothelium-specific TRPV4 knockout (TRPV4EC -/- ) mice were used to study the effect of the interactions between TRPV4-KCa 3.1 channels on coronary vascular tone. Coronary blood flow was measured by Doppler ultrasound device. KEY RESULTS: TRPV4 channels were involved in regulating coronary vascular tone, through coupling with a Ca2+ -sensitive K+ channel (KCa 3.1) in CAECs, affecting vasodilation and coronary blood flow. In mice fed a HFD diet, the coupling was damaged by a high concentration of plasma 1-heptadecanoyl-2-hydroxy-sn-glycero-3-phosphocholine. Using a bridging approach, we then identified folic acid as an effective drug to repair the uncoupled TRPV4-KCa 3.1 channels and to improve coronary arterial function. CONCLUSION AND IMPLICATIONS: Our data highlight the importance of coupling between TRPV4 and KCa 3.1 channels in the regulation of coronary vascular tone and provide a novel strategy for developing new drugs to reduce the incidence of cardiovascular events.
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Vasos Coronarios , Canales de Potencial de Receptor Transitorio , Ratones , Animales , Vasos Coronarios/metabolismo , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo , Células Endoteliales/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismo , Vasodilatación , Endotelio/metabolismo , Endotelio VascularRESUMEN
[This corrects the article DOI: 10.7150/ijbs.36429.].
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Asymmetric transfer hydrogenation (ATH) of acyclic imines has been rarely reported by using Ru-based catalysts. In this manuscript, employing Ru-catalysts with minimal stereogenicity in combination with formic acid/triethylamine as the hydrogen donor enables a highly efficient ATH of N-diphenylphosphinyl acyclic imines. These substrates that include various aryl alkyl and heteroaryl alkyl substituted imines were all compatible with this catalytic system, and the corresponding reduced amines were obtained with excellent enantiomeric excess (ee's) and yields.
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Quantum dots (QDs) of formamidinium lead triiodide (FAPbI3 ) perovskite hold great potential, outperforming their inorganic counterparts in terms of phase stability and carrier lifetime, for high-performance solar cells. However, the highly dynamic nature of FAPbI3 QDs, which mainly originates from the proton exchange between oleic acid and oleylamine (OAm) surface ligands, is a key hurdle that impedes the fabrication of high-efficiency solar cells. To tackle such an issue, here, protonated-OAm in situ to strengthen the ligand binding at the surface of FAPbI3 QDs, which can effectively suppress the defect formation during QD synthesis and purification processes is selectively introduced. In addition, by forming a halide-rich surface environment, the ligand density in a broader range for FAPbI3 QDs without compromising their structural integrity, which significantly improves their optoelectronic properties can be modulated. As a result, the power conversion efficiency of FAPbI3 QD solar cells (QDSCs) is enhanced from 7.4% to 13.8%, a record for FAPbI3 QDSCs. Furthermore, the suppressed proton exchange and reduced surface defects in FAPbI3 QDs also enhance the stability of QDSCs, which retain 80% of the initial efficiency upon exposure to ambient air for 3000 hours.
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BACKGROUND AND PURPOSE: Reduced NO levels and activity are signs of endothelial dysfunction, which is important in mediating BP changes. Previously, we demonstrated that transient receptor potential channel V4 (TRPV4) could form a functional complex with other proteins to mediate vasodilation in endothelial cells (ECs). But how TRPV4 interacts with the NO pathway in larger arteries requires further exploration. EXPERIMENTAL APPROACH: We used single-cell RNA-sequencing to find the CD106+ TRPV4high NOS3high ECs. The TRPV4-eNOS interaction was verified by co-immunoprecipitation and immuno-FRET, and their binding site was found by site-directed mutagenesis. Endothelium-specific TRPV4 knockout (TRPV4EC-/- ) mice were used to study the effect of the TRPV4-eNOS interaction on BP. A small molecule, JNc-463, was designed through molecular docking technology. KEY RESULTS: We uncovered CD106+ TRPV4high NOS3high ECs in the mouse aorta, which could regulate vasodilation via a TRPV4-eNOS interaction, and were essential to regulate BP. The TRPV4-eNOS interaction markedly decreased during the process of hypertension. We further attempted to identify molecules involved in the TRPV4-eNOS interaction and developed a small-molecule drug, JNc-463, which could increase the TRPV4-eNOS interaction to enhance vasodilation and exert antihypertensive effects in mice. CONCLUSION AND IMPLICATIONS: This is the first study integrating single-cell RNA-Seq, single-cell functional study and drug screening in aorta. We identified a subpopulation of CD106+ TRPV4high NOS3high ECs, in which an impaired TRPV4-eNOS interaction was important in the progress of hypertension, and we designed a small molecule, JNc-463, to improve the impaired TRPV4-eNOS interaction in hypertension.
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Hipertensión , Óxido Nítrico Sintasa de Tipo III/metabolismo , Canales de Potencial de Receptor Transitorio , Animales , Antihipertensivos/farmacología , Células Endoteliales , Endotelio Vascular , Hipertensión/metabolismo , Arterias Mesentéricas , Ratones , Simulación del Acoplamiento Molecular , Canales Catiónicos TRPV/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismo , VasodilataciónRESUMEN
[This corrects the article DOI: 10.1155/2020/2346369.].
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A highly enantioselective asymmetric transfer hydrogenation (ATH) of densely functionalized diheteroaryl and diaryl ketones was developed using Ru-catalysts of minimal stereogenicity. Various ketone substrates with structurally and electronically similar groups attached to the prochiral centers were reduced successfully in good to excellent enantioselectivities and yields. This protocol provides practical and efficient access to chiral diheteroarylmethanols and benzhydrols, which are key intermediates in pharmaceuticals and biologically active compounds.
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The borrowing-hydrogen (or hydrogen autotransfer) process, where the catalyst dehydrogenates a substrate and formally transfers the H atom to an unsaturated intermediate, is an atom-efficient and environmentally benign transformation. Described here is an example of an asymmetric borrowing-hydrogen cascade for the formal anti-Markovnikov hydroamination of allyl alcohols to synthesize optically enriched γ-secondary amino alcohols. By exploiting the Ru-(S)-iPrPyme catalyst with minimal stereogenicity, a cascade process including dehydrogenation, conjugate addition, and asymmetric reduction was developed. The mild conditions, functional group tolerance, and broad substrate scope (54 examples) demonstrate the synthetic practicality of the catalytic system.
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Circular RNAs (circRNAs) play important roles in cellular physiology. The association between circRNAs and myocardial ischemia/reperfusion (I/R) injury remains largely unknown. The aim of this study was to test the effects of myocardial I/R circRNA expression and explore the potential roles of these circRNAs. CircRNAs were screened by high-throughput sequencing, and the expression of dysregulated circRNAs was further validated using quantitative real-time polymerase chain reaction. Nineteen upregulated and 20 downregulated circRNAs were identified. Gene Ontology analysis indicated that the dysregulated transcripts were associated with fundamental pathophysiologic processes. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed significant changes in adherens junction, the HIF-1 signaling pathway, the cell cycle, and the FoxO signaling pathway which have a close relationship with myocardial I/R injury. The circRNA-miRNA analysis demonstrated the broad potential of the differentially expressed circRNAs to regulate target genes by acting on the miRNAs. This study provides a foundation for understanding the roles and mechanisms of circRNAs in myocardial I/R injury.
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Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , Transcriptoma/genética , Animales , Análisis por Conglomerados , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/genética , Ontología de Genes , Masculino , Ratones , Ratones Endogámicos C57BL , ARN Circular/análisis , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
BACKGROUND: Depression is common in patients with myocardial infarction and has been independently associated with adverse outcomes. However, the association between depression and myocardial injury on cardiac magnetic resonance (CMR) in patients with ST-segment elevation myocardial infarction (STEMI) has still not been assessed. AIM: To assess the association between depression and myocardial injury on CMR in patients with STEMI. METHODS: A total of 107 STEMI patients undergoing primary percutaneous coronary intervention (P-PCI) were analyzed in this prospectivecohort study. Each subject completed the Patient Health Questionnaire-9 (PHQ-9) to assess the presence and severity of depressive symptoms. CMR was performed at a median of 3 d after P-PCI for quantifying post-MI myocardial injury. Correlations between depression identified by the PHQ-9 and myocardial injury measured on CMR were assessed. RESULTS: In this study, 19 patients (17.8%) were diagnosed with major depression identified by the PHQ-9 ≥ 10. PHQ-9 was analyzed both as a continuous variable and dichotomous variable. After multivariable adjustment, the proportion of patients with large infarction size was significantly higher in the major depression group (PHQ-9 ≥ 10) (OR: 4.840, 95%CI: 1.122-20.868, P =0.034). When the PHQ-9 was evaluated as a continuous variable, after multivariable adjustment, an increased PHQ-9 score was associated with an increased risk of large infarction size (OR: 1.226, 95%CI: 1.073-1.401, P =0.003). CONCLUSION: In patients with STEMI undergoing PCI, depression was independently associated with a large infarction size.
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Mammalian transient receptor potential (TRP) channels are major components of Ca2+ signaling pathways and control a diversity of physiological functions. Here, we report a specific role for TRPC1 in the entry of herpes simplex virus type 1 (HSV-1) into cells. HSV-1-induced Ca2+ release and entry were dependent on Orai1, STIM1, and TRPC1. Inhibition of Ca2+ entry or knockdown of these proteins attenuated viral entry and infection. HSV-1 glycoprotein D interacted with the third ectodomain of TRPC1, and this interaction facilitated viral entry. Knockout of TRPC1 attenuated HSV-1-induced ocular abnormality and morbidity in vivo in TRPC1-/- mice. There was a strong correlation between HSV-1 infection and plasma membrane localization of TRPC1 in epithelial cells within oral lesions in buccal biopsies from HSV-1-infected patients. Together, our findings demonstrate a critical role for TRPC1 in HSV-1 infection and suggest the channel as a potential target for anti-HSV therapy.
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Herpes Simple/metabolismo , Herpes Simple/virología , Herpesvirus Humano 1/fisiología , Interacciones Huésped-Patógeno , Canales Catiónicos TRPC/metabolismo , Internalización del Virus , Animales , Calcio/metabolismo , Línea Celular Tumoral , Chlorocebus aethiops , Humanos , Activación del Canal Iónico , Ratones , Modelos Biológicos , Mutación , Unión Proteica , Canales Catiónicos TRPC/genética , Células VeroRESUMEN
Transient receptor potential cation channel subfamily V member 1 (TRPV1) plays an important role in pain and inflammatory responses. Previous studies have shown that the expression of TRPV1 increases in the sensory neurons of the esophagus during the development of gastroesophageal reflux disease and esophagitis, but the response of TRPV1 in esophageal epithelial cells (EECs), which directly confront the refluxed acid, is still unknown. Here, we found that acid reflux triggered esophageal damage, which was accompanied by increased expression of TRPV1 in EECs and TRPV1 channel activity in these cells. Furthermore, menthol inhibited the Ca2+ influx induced by acid stimulation in EECs. After menthol treatment, the expression of TRPV1 in EECs was significantly reduced, and their hyperplasia was significantly reduced; finally, the inflammation pathway elicited in EECs was diminished in mice with acid reflux. These results suggest that menthol improves the clinical symptoms caused by gastroesophageal acid reflux by interfering with TRPV1 in EECs.
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Great quantity of intergenic noncoding RNAs (lncRNAs) have been identified in the mammalian genome and involved in various biological processes, especially in the development and metastasis of cancer. In this study, we identified one lncRNA, lncRNA NONHSAT028712 (Lnc712), was highly expressed in breast cancer cell lines and tissues based on microarray screening. Knockdown of Lnc712 largely inhibited breast cancer cell proliferation. Mechanistically, Lnc712 bound specifically to heat-shock protein 90 (HSP90). Interaction between Lnc712 and HSP90 is required for HSP90 binding to cell division cycle 37 (Cdc37). The Lnc712/HSP90/Cdc37 complex regulated cyclin-dependent kinase 2 (CDK2) activation and then triggered breast cancer cell proliferation. In summary, our results identified a new lncRNA regulate breast cancer proliferation though interaction with HSP90.
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Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , ARN Largo no Codificante/metabolismo , Animales , Neoplasias de la Mama/genética , Línea Celular Tumoral , Proliferación Celular/genética , Proliferación Celular/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Proteínas HSP90 de Choque Térmico/genética , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Células MCF-7 , Unión Proteica , ARN Largo no Codificante/genéticaRESUMEN
OBJECTIVE: An elevated fibrinogen level has been demonstrated to be a predictor of adverse coronary heart disease outcome. This study aimed to assess whether fibrinogen is a useful marker to predict the prognosis of patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) undergoing percutaneous coronary intervention (PCI). Additionally, the prognostic accuracy of fibrinogen level was compared with that of the Global Registry of Acute Coronary Events (GRACE) score. METHODS: A total of 1211 patients with NSTE-ACS undergoing PCI were analyzed in a prospective cohort study. The enrolled patients were divided into a low fibrinogen group (n = 826, fibrinogen ≤ 3.49 mg/dl) and a high fibrinogen group (n = 385, fibrinogen > 3.49 mg/dl) based on a receiver operating characteristic (ROC) curve. The clinical endpoints were death and death/nonfatal reinfarction. An ROC curve analysis was performed and the area under the curve with a 95% confidence interval (CI) was derived and compared with those for the GRACE score to determine the diagnostic value of the serum fibrinogen level. RESULTS: Multivariate analysis showed that an elevated baseline fibrinogen level was an independent predictor of death/nonfatal reinfarction (hazard ratio = 1.498, 95% CI: 1.030-2.181, P = 0.035). The prognostic performance of fibrinogen was equivalent to that of the GRACE system in predicting clinical endpoints (C-statistic: z = 1.486, P = 0.14). CONCLUSION: Fibrinogen is an independent predictor of death/nonfatal reinfarction in patients with NSTE-ACS undergoing PCI, and its accuracy is similar to that of the GRACE system.