RESUMEN
BACKGROUND: Myocardial insulin resistance is a hallmark of diabetic cardiac injury. However, the underlying molecular mechanisms remain unclear. Recent studies demonstrate that the diabetic heart is resistant to other cardioprotective interventions, including adiponectin and preconditioning. The "universal" resistance to multiple therapeutic interventions suggests impairment of the requisite molecule(s) involved in broad prosurvival signaling cascades. Cav (Caveolin) is a scaffolding protein coordinating transmembrane signaling transduction. However, the role of Cav3 in diabetic impairment of cardiac protective signaling and diabetic ischemic heart failure is unknown. METHODS: Wild-type and gene-manipulated mice were fed a normal diet or high-fat diet for 2 to 12 weeks and subjected to myocardial ischemia and reperfusion. Insulin cardioprotection was determined. RESULTS: Compared with the normal diet group, the cardioprotective effect of insulin was significantly blunted as early as 4 weeks of high-fat diet feeding (prediabetes), a time point where expression levels of insulin-signaling molecules remained unchanged. However, Cav3/insulin receptor-ß complex formation was significantly reduced. Among multiple posttranslational modifications altering protein/protein interaction, Cav3 (not insulin receptor-ß) tyrosine nitration is prominent in the prediabetic heart. Treatment of cardiomyocytes with 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride reduced the signalsome complex and blocked insulin transmembrane signaling. Mass spectrometry identified Tyr73 as the Cav3 nitration site. Phenylalanine substitution of Tyr73 (Cav3Y73F) abolished 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride-induced Cav3 nitration, restored Cav3/insulin receptor-ß complex, and rescued insulin transmembrane signaling. It is most important that adeno-associated virus 9-mediated cardiomyocyte-specific Cav3Y73F reexpression blocked high-fat diet-induced Cav3 nitration, preserved Cav3 signalsome integrity, restored transmembrane signaling, and rescued insulin-protective action against ischemic heart failure. Last, diabetic nitrative modification of Cav3 at Tyr73 also reduced Cav3/AdipoR1 complex formation and blocked adiponectin cardioprotective signaling. CONCLUSIONS: Nitration of Cav3 at Tyr73 and resultant signal complex dissociation results in cardiac insulin/adiponectin resistance in the prediabetic heart, contributing to ischemic heart failure progression. Early interventions preserving Cav3-centered signalsome integrity is an effective novel strategy against diabetic exacerbation of ischemic heart failure.
Asunto(s)
Insuficiencia Cardíaca , Resistencia a la Insulina , Daño por Reperfusión Miocárdica , Estado Prediabético , Ratones , Animales , Caveolina 3/genética , Caveolina 3/metabolismo , Adiponectina/metabolismo , Adiponectina/farmacología , Cloruros/metabolismo , Cloruros/farmacología , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismoRESUMEN
BACKGROUND: Despite significantly reduced acute myocardial infarction (MI) mortality in recent years, ischemic heart failure continues to escalate. Therapeutic interventions effectively reversing pathological remodeling are an urgent unmet medical need. We recently demonstrated that AdipoR1 (APN [adiponectin] receptor 1) phosphorylation by GRK2 (G-protein-coupled receptor kinase 2) contributes to maladaptive remodeling in the ischemic heart. The current study clarified the underlying mechanisms leading to AdipoR1 phosphorylative desensitization and investigated whether blocking AdipoR1 phosphorylation may restore its protective signaling, reversing post-MI remodeling. METHODS: Specific sites and underlying molecular mechanisms responsible for AdipoR1 phosphorylative desensitization were investigated in vitro (neonatal and adult cardiomyocytes). The effects of AdipoR1 phosphorylation inhibition upon APN post-MI remodeling and heart failure progression were investigated in vivo. RESULTS: Among 4 previously identified sites sensitive to GRK2 phosphorylation, alanine substitution of Ser205 (AdipoR1S205A), but not other 3 sites, rescued GRK2-suppressed AdipoR1 functions, restoring APN-induced cell salvage kinase activation and reducing oxidative cell death. The molecular investigation followed by functional determination demonstrated that AdipoR1 phosphorylation promoted clathrin-dependent (not caveolae) endocytosis and lysosomal-mediated (not proteasome) degradation, reducing AdipoR1 protein level and suppressing AdipoR1-mediated cytoprotective action. GRK2-induced AdipoR1 endocytosis and degradation were blocked by AdipoR1S205A overexpression. Moreover, AdipoR1S205E (pseudophosphorylation) phenocopied GRK2 effects, promoted AdipoR1 endocytosis and degradation, and inhibited AdipoR1 biological function. Most importantly, AdipoR1 function was preserved during heart failure development in AdipoR1-KO (AdipoR1 knockout) mice reexpressing hAdipoR1S205A. APN administration in the failing heart reversed post-MI remodeling and improved cardiac function. However, reexpressing hAdipoR1WT in AdipoR1-KO mice failed to restore APN cardioprotection. CONCLUSIONS: Ser205 is responsible for AdipoR1 phosphorylative desensitization in the failing heart. Blockade of AdipoR1 phosphorylation followed by pharmacological APN administration is a novel therapy effective in reversing post-MI remodeling and mitigating heart failure progression.
Asunto(s)
Insuficiencia Cardíaca , Infarto del Miocardio , Daño por Reperfusión Miocárdica , Adiponectina/metabolismo , Animales , Insuficiencia Cardíaca/metabolismo , Humanos , Isquemia/metabolismo , Ratones , Ratones Noqueados , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , Fosforilación , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismoRESUMEN
BACKGROUND: APN (adiponectin) and APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1) are potent vasculoprotective molecules, and their deficiency (eg, hypoadiponectinemia) contributes to diabetic vascular complications. However, the molecular mechanisms that govern their vasculoprotective genes as well as their alteration by diabetes remain unknown. METHODS: Diabetic medium-cultured rat aortic endothelial cells, mouse aortic endothelial cells from high-fat-diet animals, and diabetic human aortic endothelial cells were used for molecular/cellular investigations. The in vivo concept-prove demonstration was conducted using diabetic vascular injury and diabetic hindlimb ischemia models. RESULTS: In vivo animal experiments showed that APN replenishment caused APPL1 nuclear translocation, resulting in an interaction with HDAC (histone deacetylase) 2, which inhibited HDAC2 activity and increased H3Kac27 levels. Based on transcriptionome pathway-specific real-time polymerase chain reaction profiling and bioinformatics analysis, Angpt1 (angiopoietin 1), Ocln (occludin), and Cav1 (caveolin 1) were found to be the top 3 vasculoprotective genes suppressed by diabetes and rescued by APN in an APPL1-dependent manner. APN reverses diabetes-induced inhibition of Cav1 interaction with APPL1. APN-induced Cav1 expression was not affected by Angpt1 or Ocln deficiency, whereas APN-induced APPL1 nuclear translocation or upregulation of Angpt1/Ocln expression was abolished in the absence of Cav1 both in vivo and in vitro, suggesting Cav1 is upstream molecule of Angpt1/Ocln in response to APN administration. Chromatin immunoprecipitation-qPCR (quantitative polymerase chain reaction) demonstrated that APN caused significant enrichment of H3K27ac in Angpt1 and Ocln promoter region, an effect blocked by APPL1/Cav1 knockdown or HDAC2 overexpression. The protective effects of APN on the vascular system were attenuated by overexpression of HDAC2 and abolished by knocking out APPL1 or Cav1. The double knockdown of ANGPT1/OCLN blunted APN vascular protection both in vitro and in vivo. Furthermore, in diabetic human endothelial cells, HDAC2 activity is increased, H3 acetylation is decreased, and ANGPT1/OCLN expression is reduced, suggesting that the findings have important translational implications. CONCLUSIONS: Hypoadiponectinemia and dysregulation of APPL1-mediated epigenetic regulation are novel mechanisms leading to diabetes-induced suppression of vasculoprotective gene expression. Diabetes-induced pathological vascular remodeling may be prevented by interventions promoting APPL1 nuclear translocation and inhibiting HDAC2.
Asunto(s)
Diabetes Mellitus , Angiopatías Diabéticas , Lesiones del Sistema Vascular , Animales , Humanos , Ratones , Ratas , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adiponectina/metabolismo , Diabetes Mellitus/genética , Angiopatías Diabéticas/genética , Angiopatías Diabéticas/prevención & control , Angiopatías Diabéticas/metabolismo , Células Endoteliales/metabolismo , Epigénesis Genética , Lesiones del Sistema Vascular/genéticaRESUMEN
Diabetes enhances myocardial ischemic/reperfusion (MI/R) injury via an incompletely understood mechanism. Adiponectin (APN) is a cardioprotective adipokine suppressed by diabetes. However, how hypoadiponectinemia exacerbates cardiac injury remains incompletely understood. Dysregulation of miRNAs plays a significant role in disease development. However, whether hypoadiponectinemia alters cardiac miRNA profile, contributing to diabetic heart injury, remains unclear. Methods and Results: Wild-type (WT) and APN knockout (APN-KO) mice were subjected to MI/R. A cardiac microRNA profile was determined. Among 23 miRNAs increased in APN-KO mice following MI/R, miR-449b was most significantly upregulated (3.98-fold over WT mice). Administrating miR-449b mimic increased apoptosis, enlarged infarct size, and impaired cardiac function in WT mice. In contrast, anti-miR-449b decreased apoptosis, reduced infarct size, and improved cardiac function in APN-KO mice. Bioinformatic analysis predicted 73 miR-449b targeting genes, and GO analysis revealed oxidative stress as the top pathway regulated by these genes. Venn analysis followed by luciferase assay identified Nrf-1 and Ucp3 as the two most important miR-449b targets. In vivo administration of anti-miR-449b in APN-KO mice attenuated MI/R-stimulated superoxide overproduction. In vitro experiments demonstrated that high glucose/high lipid and simulated ischemia/reperfusion upregulated miR-449b and inhibited Nrf-1 and Ucp3 expression. These pathological effects were attenuated by anti-miR-449b or Nrf-1 overexpression. In a final attempt to validate our finding in a clinically relevant model, high-fat diet (HFD)-induced diabetic mice were subjected to MI/R and treated with anti-miR-449b or APN. Diabetes significantly increased miR-449b expression and downregulated Nrf-1 and Ucp3 expression. Administration of anti-miR-449b or APN preserved cardiac Nrf-1 expression, reduced cardiac oxidative stress, decreased apoptosis and infarct size, and improved cardiac function. Conclusion: We demonstrated for the first time that hypoadiponectinemia upregulates miR-449b and suppresses Nrf-1/Ucp3 expression, promoting oxidative stress and exacerbating MI/R injury in this population. Dysregulated APN/miR-449b/oxidative stress pathway is a potential therapeutic target against diabetic MI/R injury.
Asunto(s)
Diabetes Mellitus Experimental , MicroARNs , Daño por Reperfusión Miocárdica , Animales , Ratones , Adiponectina/genética , Adiponectina/metabolismo , Adiponectina/farmacología , Antagomirs , Apoptosis/genética , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Infarto/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , Regulación hacia Arriba/genéticaRESUMEN
The development of quantum radar technology presents a challenge to stealth targets, so it is necessary to study the quantum detection probability. In this study, an analytical expression of the quantum radar cross section (QRCS) for complex targets is presented. Based on this QRCS expression, a calculation method for the detection probability for quantum radar is creatively proposed. Moreover, a self-designed flying-wing stealth aircraft is adopted to obtain the detection probability distributions of the conventional radar and the quantum radar in different directions. As revealed by the result of this study, the detection probabilities of the quantum radar and the conventional radar are significantly different, and the detection probability of the quantum radar has obvious advantages in most regions with a certain distance.
RESUMEN
Radiation pressure refers to the momentum transfer of photons during light "particles" impacting a surface. The force is too small to drive microengines. Different from the classical radiation pressure, the indirect radiation pressure (Fm ) is introduced, coming from the momentum change of light-induced bubble expansion. Fm is shown to obey Fm â¼ (I·rb )2 , behaving faster growth of indirect radiation pressure versus light intensity I and bubble radius rb . An effective bubble size range is identified for Fm to suppress other forces for bubble in liquid. The top laser irradiation on nanofluid is used in this experiment. A well-defined bubble pulsating flow, being a new principle of bubble piston engine, is demonstrated. During pulse on (≈ns scale), Fm exceeding other forces generates an extremely large acceleration, which is three to four orders larger than the gravity acceleration, propelling the bubble traveling downward. During pulse off, the bubble is floating upward due to the nonexistence of Fm . In such a way, the piston engine sustains the oscillating ranges of 38-347 µm for bubble diameters and 2.7-457.9 µm for traveling distances of piston. This work is useful to manipulate bubble dynamics in solar energy systems, and can find various applications in optofluidics.
RESUMEN
Driven by nanoparticle plasmonic heating, sessile droplet evaporation presents challenges on the coupling mechanisms between time-spatial heat source distribution and flow/temperature fields in a droplet. Here, symmetric/asymmetric solar-driven droplet evaporation is investigated. An infrared camera captures droplet surface temperatures in the micrometer scale after correction. An optical three-dimensional profiler quantifies nanoparticle deposition in the nanoscale. We show that droplet surface temperatures do display a nonmonotonic variation trend. Based on measurements, we are able to decouple the droplet into a contact line region (CLR) and a bulk volume region (BVR). The CLR volume is two to three magnitudes smaller than the droplet volume. The temperature gradient is significant in CLR, but flat temperature exists in BVR. Radial flow in BVR transports nanoparticles from the droplet body to the contact line, while Marangoni flow in CLR stabilizes nanoparticles there. Light energy is also decoupled based on its wavelength band. It is found that CLR dominates the visible energy absorption, but BVR has a weak contribution. Top light heating causes symmetry temperatures and a coffee-ring profile along the circumference. However, side heating yields higher temperatures and more nanoparticles deposition on the sunny side than on the night side. The above findings are valid when the initial droplet volume and incident irradiation flux are changed on the hydrophilic wall. The hydrophilic wall and hydrophobic wall maintain the evaporation modes of constant contact diameter and "stick-slip", respectively. The present paper enhances the understanding of light-induced droplet evaporation from the multiscale point of view.
RESUMEN
Precise single-point positioning using carrier-phase measurements can be provided by the synchronized pseudolite system. The primary task of carrier phase positioning is ambiguity resolution (AR) with rapidity and reliability. As the pseudolite system is usually operated in the dense multipath environment, cycle slips may lead the conventional least-squares ambiguity decorrelation adjustment (LAMBDA) method to incorrect AR. A new AR method based on the idea of the modified ambiguity function approach (MAFA), which is insensitive to the cycle slips, is studied in this paper. To improve the model strength of the MAFA and to eliminate the influence of constant multipath biases on the time-average model in static mode, the kinematic multi-epoch MAFA (kinematic ME-MAFA) algorithm is proposed. A heuristic method for predicting the 'float position' corresponding to every Voronoi cell of the next epoch, making use of Doppler-based velocity information, is implemented to improve the computational efficiency. If the success rate is very close to 1, it is possible to guarantee reliable centimeter-level accuracy positioning without further ambiguity validation. Therefore, a computing method of the success rate for the kinematic ME-MAFA is proposed. Both the numerical simulations and the kinematic experiment demonstrate the feasibility of the new AR algorithm according to its accuracy and reliability. The accuracy of the horizontal positioning solution is better than 1.7 centimeters in our pseudolite system.
RESUMEN
Global Navigation Satellite System performance can be significantly enhanced by introducing inter-satellite links (ISLs) in navigation constellation. The improvement in position, velocity, and time accuracy as well as the realization of autonomous functions requires ISL distance measurement data as the original input. To build a high-performance ISL, the ranging consistency among navigation satellites is an urgent problem to be solved. In this study, we focus on the variation in the ranging delay caused by the sensitivity of the ISL payload equipment to the ambient temperature in space and propose a simple and low-power temperature-sensing ranging compensation sensor suitable for onboard equipment. The experimental results show that, after the temperature-sensing ranging compensation of the ISL payload equipment, the ranging consistency becomes less than 0.2 ns when the temperature change is 90 °C.
RESUMEN
Theperformanceoftheglobalnavigationsatellitesystem(GNSS)canbeenhancedsigniï¬cantly by introducing the inter-satellite links (ISL) of a navigation constellation. In particular, the improvement of the position, velocity, and time accuracy, and the realization of autonomous functions require the ISL distance measurement data as the original input. For building a high-performance ISL, the ranging consistency between navigation satellites becomes a crucial problem to be addressed. Considering the frequency aging drift and the relativistic effect of the navigation satellite, the frequency and phase adjustment (FPA) instructions for the 10.23 MHz must be injected from the ground station to ensure the time synchronization of the navigation constellation. Moreover, the uncertainty of the initial phase each time the onboard clock equipment boots also results in a pseudo-range offset. In this Ref., we focus on the inï¬uence of the frequency and phase characteristics of the onboard clock equipment on the ranging consistency of the ISL and propose a phase compensation sensor design method for the phase offset. The simulation and experimental results show that the proposed method not only realized a phase compensation for the pseudo-range jitter, but, when the 1 PPS (1 pulse per second) falls in the 10.23 MHz skip area, also overcomes the problem of compensating the ambiguous phase by directly tracking the 10.23 MHz to ensure consistency in the ranging.
RESUMEN
Background: Ventricular lead implantation is relatively difficult for patients with bradyarrhythmia after tricuspid valve replacement. Right atrial (RA) abnormalities often occurred in patients with tricuspid valve disease; conventional coronary sinus (CS) lead implantation is not easy to operate. Therefore, it is necessary to develop a safe method for implanting LV endocardial leads in patients after tricuspid valve replacement. Case presentation: A 76-year-old Asian woman who had been implanted with a metal tricuspid valve replacement 4 years ago was admitted to the Department of Cardiology for pacemaker implantation due to transient blackout related to persistent atrial fibrillation with long pauses. The patient's family rejected the surgical placement of an epicardial LV lead. Therefore, we first intended to operate LV lead implantation through the CS; however, the orifice of the CS was virtually difficult to seek. Ultimately, we utilized total 3-dimensional (T3D) transseptal puncture (TSP) under the guidance of the CARTO 3 system; thus, we implanted the LV endocardial lead, which contributed to the accurate puncture of the central fossa ovalis and ensured the safety of TSP in the case of RA enlargement. Meanwhile, the CARTO 3 system contributed to the localization of the LV lead to the LV free wall during implantation. All the intraoperative and postoperative pacemaker parameters were favorable; no intraoperative or postoperative complications occurred. Conclusions: This case report may provide a novel surgical approach for LV lead implantation in patients who underwent tricuspid valve replacement or patients who may benefit from cardiac resynchronization therapy but failed to implant CS lead.
RESUMEN
Introduction: To improve the mechanization level of rice planting, a new type of direct seeding device for rice was designed. The device's structural properties will be crucial in determining its seeding performance. Structure optimization in the current seed metering device design process focuses on a single or few indexes, resulting in improved individual performance but imbalanced overall performance. Therefore, a structure optimization method of the direct seeding device based on a multi-index orthogonal experiment was proposed in this study. Methods: First, the DEM-MBD coupling method observed the factors and levels that affected the performance overall. Second, a test platform based on the electric drive control model was constructed, and a multi-index orthogonal test was devised. Finally, the structural parameters of the seed metering devices were optimized based on matrix analysis. Results: From the results, the primary and secondary levels of significance of factors were just as follows: hole diameter > hole number > adjustment angle. The following are the optimal parameters found by optimization analysis: the diameter of the hole was 12 mm, the number of holes was 10, and the adjustment angle was 80°. Validation tests were carried out and analyzed based on the optimal structural parameter combination. The qualification rate of seeds per hole, empty hole rate, average seed number, coefficient of variation of seed number, average hole spacing, and the variance coefficient of hole spacing are 93.07%, 0%, 9.39,14.04%, 22.84 cm, and 9.14%, respectively. Discussion: In comparison to traditional design and structural parameter optimization methods for rice precision seed metering device, this study not just to provides an optimization scheme for improving the overall performance of rice precision seed metering device, but also serves as a technical reference for the development and design of new rice precision seed metering device.
RESUMEN
The rapid extraction of farmland boundaries is key to implementing autonomous operation of agricultural machinery. This study addresses the issue of incomplete farmland boundary segmentation in existing methods, proposing a method for obtaining farmland boundaries based on unmanned aerial vehicle (UAV) remote sensing images. The method is divided into two steps: boundary image acquisition and boundary line fitting. To acquire the boundary image, an improved semantic segmentation network, AttMobile-DeeplabV3+, is designed. Subsequently, a boundary tracing function is used to track the boundaries of the binary image. Lastly, the least squares method is used to obtain the fitted boundary line. The paper validates the method through experiments on both crop-covered and non-crop-covered farmland. Experimental results show that on crop-covered and non-crop-covered farmland, the network's intersection over union (IoU) is 93.25% and 93.14%, respectively; the pixel accuracy (PA) for crop-covered farmland is 96.62%. The average vertical error and average angular error of the extracted boundary line are 0.039 and 1.473°, respectively. This research provides substantial and accurate data support, offering technical assistance for the positioning and path planning of autonomous agricultural machinery.
RESUMEN
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV-2 variants, has become a global pandemic resulting in significant morbidity and mortality. Severe cases of COVID-19 are characterized by hypoxemia, hyper-inflammation, cytokine storm in lung. Clinical studies have reported an association between COVID-19 and cardiovascular disease (CVD). Patients with CVD tend to develop severe symptoms and mortality if contracted COVID-19 with further elevations of cardiac injury biomarkers. Furthermore, COVID-19 itself can induce and promoted CVD development, including myocarditis, arrhythmia, acute coronary syndrome, cardiogenic shock, and venous thromboembolism. Although the direct etiology of SARS-CoV-2 induced cardiac injury remains unknown and under-investigated, it is suspected that it is related to myocarditis, cytokine-mediated injury, microvascular injury, and stress-related cardiomyopathy. Despite vaccinations having provided the most effective approach to reducing mortality overall, an adapted treatment paradigm and regular monitoring of cardiac injury biomarkers is critical for improving outcomes in vulnerable populations at risk for severe COVID-19. In this review, we focus on the latest progress in clinic and research on the cardiovascular complications of COVID-19 and provide a perspective of treating cardiac complications deriving from COVID-19 in Emergency Medicine.
RESUMEN
The synergy between radiotherapy and immunotherapy in treating thoracic cancers presents a potent therapeutic advantage, yet it also carries potential risks. The extent and nature of cumulative cardiac toxicity remain uncertain, prompting the need to discern its mechanisms and devise effective mitigation strategies. Radiation alone or in combination with an anti- Programmed cell death protein1 (PD-1) antibody significantly reduced cardiac function in C57BL/6J mice, and this pathologic effect was aggravated by anti-PD-1 (anti-PD-1 + radiation). To examine the cellular mechanism that causes the detrimental effect of anti-PD-1 upon cardiac function after radiation, AC16 human cardiomyocytes were used to study cardiac apoptosis and cardiac autophagy. Radiation-induced cardiomyocyte apoptosis was significantly promoted by anti-PD-1 treatment, while anti-PD-1 combined radiation administration blocked the cardiac autophagic flux. Adenosine 5'-triphosphate (ATP) (a molecule that promotes lysosomal acidification) not only improved autophagic flux in AC16 human cardiomyocytes, but also attenuated apoptosis induced by radiation and anti-PD-1 treatment. Finally, ATP administration in vivo significantly reduced radiation-induced and anti-PD-1-exacerbated cardiac dysfunction. We demonstrated for the first time that anti-PD-1 can aggravate radiation-induced cardiac dysfunction via promoting cardiomyocyte apoptosis without affecting radiation-arrested autophagic flux. ATP enhanced cardiomyocyte autophagic flux and inhibited apoptosis, improving cardiac function in anti-PD-1/radiation combination-treated animals.
RESUMEN
Here, we have found for the first time that the catalytic activity of "naked" DNAzyme, a single-stranded G-quadruplex DNAzyme (S.DNAzyme), can be modulated by aflatoxin B1 (AFB1) and zearalenone (ZEN). In fact, S.DNAzyme can mimic the activity of horseradish peroxidase to perform oxidation of 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) to colored ABTSË+ (dark green). This catalytic activity can be inhibited upon addition of AFB1, leading to color fade of the solution. But with ZEN, the solution color will change to a yellowish-brown or yellow color. Thus, we have exploited this finding to achieve label-free, naked-eye detection of AFB1 or ZEN, and have explored the possible detection mechanisms. This approach is able to detect AFB1 and ZEN concentrations as low as 0.18 µM and 0.29 µM, respectively. Even in real samples, the limit of detection values of these two analytes are lower than 3 µM. Notably, S.DNAzyme cross-reacted with three other tested aflatoxins, including aflatoxin B2, aflatoxin G1 and aflatoxin M1, revealing the potential for a broadly applicable method to identify the family of aflatoxins. The AFB1- or ZEN-triggered new catalytic reaction between "naked" DNAzyme and ABTS may offer new opportunities for on-site visual detection of mycotoxins.
RESUMEN
Background The impairment of the inner blood-retinal barrier (iBRB) increases the pathological development of diabetic retinopathy (DR), a severe complication in diabetic patients. Identifying approaches to preserving iBRB integrity and function is a significant challenge in DR. C1q/tumor necrosis factor-related protein-3 (CTRP3) is a newly discovered adipokine and a vital biomarker, predicting DR severity. We sought to determine whether and how CTRP3 affects the pathological development of non-proliferative diabetic retinopathy (NPDR). Methods To clarify the pathophysiologic progress of the blood-retinal barrier in NPDR and explore its potential mechanism, a mouse Type 2 diabetic model of diabetic retinopathy was used. The capillary leakage was assessed by confocal microscope with fluorescent-labeled protein in vivo. Furthermore, the effect of CTRP3 on the inner blood-retinal barrier (iBRB) and its molecular mechanism was clarified. Results The results demonstrated that CTRP3 protects iBRB integrity and resists the vascular permeability induced by DR. Mechanistically, the administration of CTRP3 activates the AMPK signaling pathway and enhances the expression of Occludin and Claudin-5 (tight junction protein) in vivo and in vitro. Meanwhile, CTRP3 improves the injury of human retinal endothelial cells (HRMECs) induced by high glucose/high lipids (HG/HL), and its protective effects are AMPK-dependent. Conclusions In summary, we report, for the first time, that CTRP3 prevents diabetes-induced retinal vascular permeability via stabilizing the tight junctions of the iBRB and through the AMPK-dependent Occludin/Claudin-5 signaling pathway, thus critically affecting the development of NPDR.
Asunto(s)
Diabetes Mellitus , Retinopatía Diabética , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Barrera Hematorretinal , Claudina-5 , Complemento C1q/metabolismo , Diabetes Mellitus/metabolismo , Retinopatía Diabética/metabolismo , Células Endoteliales/metabolismo , Humanos , Ratones , Ocludina , Uniones Estrechas/metabolismoRESUMEN
Meng, Zhijun, Huan Gao, Tao Li, Peng Ge, Yixiao Xu, and Binghong Gao. Effects of eight weeks altitude training on the aerobic capacity and microcirculation function in trained rowers. High Alt Med Biol. 22:24-31, 2021. Background: The mechanism of aerobic improvement after altitude training (AT) has not been resolved yet. Few studies have looked at microcirculation changes after AT in athletes. Materials and Methods: Thirty-three male rowers were recruited and divided into either the AT (n = 18, altitude 2,280 m) or the sea level training (ST group, n = 15, altitude 50 m) for 8 weeks training. Microcirculation function was monitored using a laser Doppler flowmeter. VO2peak and ergometer 5 km time trial (Er5k) were conducted. Results: Within the AT group there was an 8.8% increment in VO2peak from pre- to post-training (4,708.9 ± 455.2 vs. 5,123.3 ± 391.2 ml/min, p < 0.01), whereas in ST group there was a 3.1% increase of VO2peak from pre- to post-training (4,975.4 ± 501.1 vs. 5,128.0 ± 499.3 m/min, p = 0.125). Er5k performance in AT group was significantly improved (1,040.3 ± 26.3 vs. 1,033.2 ± 27.5 seconds, p = 0.038), whereas in ST group Er5k performance was not improved (1,059.6 ± 30.9 vs. 1,060.4 ± 33.2 seconds, p = 0.819). Postocclusive reactive hyperemia reserve and heat reserve in the forearm of AT subjects increased significantly after 8 weeks. Meanwhile, the AT group's resting blood flow and cutaneous vascular conductance (CVC) of the thigh were higher after AT. For the ST group, resting blood flow and CVC in the thigh decreased significantly at third week post-training. There was a low correlation between the change of VO2peak and blood flow of the thigh (r = 0.45, p = 0.01). Conclusions: Trained rowers benefit more from 8 weeks of AT than from 8 weeks ST in terms of aerobic capacity. We have found that 8 weeks of AT increases thigh blood flow and improves endothelial function.
Asunto(s)
Altitud , Atletas , Tolerancia al Ejercicio , Humanos , Masculino , Microcirculación , Consumo de Oxígeno , Fenómenos Fisiológicos de la PielRESUMEN
OBJECTIVE: Atherosclerotic vascular disease remains the principal cause of death and disability among patients with type 2 diabetes. Unfortunately, the problem is not adequately resolved by therapeutic strategies with currently available drugs or approaches that solely focus on optimal glycemic control. To identify the key contributors and better understand the mechanism of diabetic atherosclerotic vascular disease, we aimed to elucidate the key genetic characteristics and pathological pathways in atherosclerotic vascular disease through nonbiased bioinformatics analysis and subsequent experimental demonstration and exploration in diabetic atherosclerotic vascular disease. METHODS AND RESULTS: Sixty-eight upregulated and 23 downregulated genes were identified from the analysis of gene expression profiles (GSE30169 and GSE6584). A comprehensive bioinformatic assay further identified that ferroptosis, a new type of programmed cell death and HMOX1 (a gene that encodes heme oxygenase), were vital factors in atherosclerotic vascular disease. We further demonstrated that diabetes significantly increased ferroptosis and HMOX1 levels compared to normal controls. Importantly, the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively attenuated diabetic atherosclerosis, suggesting the causative role of ferroptosis in diabetic atherosclerosis development. At the cellular level, Fer-1 ameliorated high glucose high lipid-induced lipid peroxidation and downregulated ROS production. More importantly, HMOX1 knockdown attenuated Fe2+ overload, reduced iron content and ROS, and alleviated lipid peroxidation, which led to a reduction in ferroptosis in diabetic human endothelial cells. CONCLUSIONS: We demonstrated that HMOX1 upregulation is responsible for the increased ferroptosis in diabetic atherosclerosis development, suggesting that HMOX1 may serve as a potential therapeutic or drug development target for diabetic atherosclerosis.
Asunto(s)
Aterosclerosis/enzimología , Aterosclerosis/genética , Diabetes Mellitus Experimental/enzimología , Diabetes Mellitus Experimental/genética , Ferroptosis , Hemo-Oxigenasa 1/genética , Regulación hacia Arriba , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/metabolismo , Aterosclerosis/complicaciones , Aterosclerosis/patología , Ciclohexilaminas/farmacología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patología , Dieta Alta en Grasa , Progresión de la Enfermedad , Conducta Alimentaria , Femenino , Ferroptosis/efectos de los fármacos , Perfilación de la Expresión Génica , Glutatión/metabolismo , Hemo-Oxigenasa 1/antagonistas & inhibidores , Hemo-Oxigenasa 1/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Sobrecarga de Hierro/complicaciones , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones Noqueados , NADP/metabolismo , Fenilendiaminas/farmacología , Mapas de Interacción de Proteínas/efectos de los fármacos , Mapas de Interacción de Proteínas/genética , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
There is limited and discordant evidence on the role of nicotine in diabetic vascular disease. Exacerbated endothelial cell dysregulation in smokers with diabetes is associated with the disrupted adipose function. Adipokines possess vascular protective, anti-inflammatory, and anti-diabetic properties. However, whether and how nicotine primes and aggravates diabetic vascular disorders remain uncertain. In this study, we evaluated the alteration of adiponectin (APN) level in high-fat diet (HFD) mice with nicotine (NIC) administration. The vascular pathophysiological response was evaluated with vascular ring assay. Confocal and co-immunoprecipitation analysis were applied to identify the signal interaction and transduction. These results indicated that the circulating APN level in nicotine-administrated diabetic Apolipoprotein E-deficient (ApoE-/-) mice was elevated in advance of 2 weeks of diabetic ApoE-/- mice. NIC and NIC addition in HFD groups (NIC + HFD) reduced the vascular relaxation and signaling response to APN at 6 weeks. Mechanistically, APN receptor 1 (AdipoR1) level was decreased in NIC and further significantly reduced in NIC + HFD group at 6 weeks, while elevated suppressor of cytokine signaling 3 (SOCS3) expression was induced by NIC and further augmented in NIC + HFD group. Additionally, nicotine provoked SOCS3, degraded AdipoR1, and attenuated APN-activated ERK1/2 in the presence of high glucose and high lipid (HG/HL) in human umbilical vein endothelial cells (HUVECs). MG132 (proteasome inhibitor) administration manifested that AdipoR1 was ubiquitinated, while inhibited SOCS3 rescued the reduced AdipoR1. In summary, this study demonstrated for the first time that nicotine primed vascular APN resistance via SOCS3-mediated degradation of ubiquitinated AdipoR1, accelerating diabetic endothelial dysfunction. This discovery provides a potential therapeutic target for preventing nicotine-accelerated diabetic vascular dysfunction.