Mesenchymal stem cells (MSCs) are one of a number of cell types undergoing extensive investigation for cardiac regeneration therapy. It has not yet been determined whether this cell therapy also ...substantially contributes to vascular remodeling of diseased vessels.
Human MSCs and a variety of progenitor and vascular cells were used for in vitro and in vivo experiments. Wire-induced vascular injury mobilized MSCs into the circulation. Compared with human aortic smooth muscle cells, MSCs exhibited a 2.8-fold increase in the adhesion capacity in vitro (P<0.001) and a 6.3-fold increase in vivo (P<0.001). In all animal models, a significant amount of MSCs contributed to intimal hyperplasia after vascular injury. MSCs were able to differentiate into cells of endothelial or smooth muscle lineage. Coculture experiments demonstrated that late-outgrowth endothelial cells (OECs) guided MSCs to differentiate toward an endothelial lineage through a paracrine effects. In vivo, cell therapy with OECs significantly attenuated the thickness of the neointima contributed by MSCs (intima/media ratio, from 3.2+/-0.4 to 0.4+/-0.1, P<0.001).
Tissue regeneration therapy with MSCs or cell populations containing MSCs requires a strategy to attenuate the high potential of MSCs to develop intimal hyperplasia on diseased vessels.
•Exenatide reverses high-fat diet-induced cortical neuroinflammation and related behavior changes.•Exenatide increased M2-type microglia marker expression in mice.•Exenatide inhibited scavenger ...receptor-A4 expression in mice.•Scavenger receptor-A4 knockout reduced diet-induced neuroinflammation.•GLP-1 receptor agonist can potentially be used for the inhibition of neuroinflammation-related neurodegeneration.
Obesity is associated with multiple comorbidities, such as metabolic abnormalities and cognitive dysfunction. Moreover, accumulating evidence indicates that neurodegenerative disorders are associated with chronic neuroinflammation. GLP-1 receptor agonists (RAs) have been extensively studied as a treatment for type 2 diabetes. Emerging evidence has demonstrated a protective effect of GLP-1 RAs on neurodegenerative disease, which is independent of its glucose-lowering effects. In this study, we aimed to examine the effects of a long-acting GLP-1 RA, exenatide, on high-fat diet (HFD)-induced neuroinflammation and related brain function impairment. First, mice treated with exenatide exhibited significantly reduced HFD-increased body weight and blood glucose. In an open field test, exenatide treatment ameliorated the reduction in local motor activity and anxiety in HFD-fed mice. Moreover, HFD induced astrogliosis, microgliosis, and upregulation of IL-1β, IL-6 and TNF-α in hippocampus and cortex. Exenatide treatment reduced HFD-induced astrogliosis and IL-1β and TNF-α expressions. Moreover, exenatide increased phosphor-ERK and M2-type microglia marker arginase-1 expression in the hippocampus and cortex. In addition, we found that scavenger receptor-A4 protein expression was induced by HFD and was subsequently inhibited by exenatide. SR-A4 knockout reversed the locomotor activity impairment but not the anxiety behavior caused by HFD consumption. SR-A4 knockout also reduced HFD-induced neuroinflammation, as shown by the reduced expression of GFAP and IBA-1 compared with that in wild-type control mice. These results demonstrate that exenatide decreases HFD-increased neuroinflammation and promotes anti-inflammatory M2 differentiation. The inhibition of SR-A4 by exenatide exerts anti-inflammatory activity.
Abstract Background Abnormal ventilatory/hemodynamic responses to exercise contribute to functional impairment in patients with heart failure (HF). This study investigates how interval and continuous ...exercise regimens influence functional capacity by modulating ventilatory efficiency and hemodynamic function in HF patients. Methods Forty-five HF patients were randomized to perform either aerobic interval training (AIT; 3-minute intervals at 40% and 80% VO2peak ) or moderate continuous training (MCT; sustained 60% VO2peak ) for 30 min/day, 3 days/week for 12 weeks, or to a control group that received general healthcare (GHC). A noninvasive bio-reactance device was adopted to measure cardiac hemodynamics, whereas a near-infrared spectroscopy was employed to assess perfusion/O2 extraction in frontal cerebral lobe (∆THbFC / ∆HHbFC ) and vastus lateralis (∆THbVL / ∆HHbVL ), respectively. Results Following the 12-week intervention, the AIT group exhibited higher oxygen uptake efficiency slope (OUES) and lower VE -VCO2 slope than the MCT and GHC groups. Furthermore, AIT, but not MCT, boosted cardiac output (CO) and increased ∆THbFC , ∆THbVL , and ∆HHbVL during exercise. In multivariate analyses, CO was the dominant predictor of VO2peak . ∆THbFC and ∆THbVL , which modulated the correlation between CO and OUES, were significantly correlated with OUES. Simultaneously, ∆THbVL was the only factor significantly associated with VE -VCO2 slope. Additionally, AIT reduced plasma brain natriuretic peptide, myeloperoxidase, and interleukin-6 levels and increased the Short Form-36 physical/mental component scores and decreased the Minnesota Living with Heart Failure questionnaire score. Conclusions AIT effectively improves oxygen uptake efficiency by enhancing cerebral/muscular hemodynamics and suppresses oxidative stress/inflammation associated with cardiac dysfunction, and also promotes generic/disease-specific qualities of life in patients with HF.
Mitochondrial dysfunction is a major contributor to myocyte loss and the development of heart failure. Myocytes have quality control mechanisms to retain functional mitochondria by removing damaged ...mitochondria via specialized autophagy, i.e., mitophagy. The underlying mechanisms of fission affect the survival of cardiomyocytes, and left ventricular function in the heart is poorly understood. Here, we demonstrated the direct effect and potential mechanisms of mitochondrial functional defects associated with abnormal mitochondrial dynamics in heart failure. We observed that IGF-IIR signaling produced significant changes in mitochondrial morphology and function; such changes were associated with the altered expression and distribution of dynamin-related protein (Drp1) and mitofusin (Mfn2). IGF-IIR signaled extracellular signal-regulated kinase (ERK) activation to promote Drp1 phosphorylation and translocation to mitochondria for mitochondrial fission and mitochondrial dysfunction. Moreover, IGF-IIR signaling triggered Rab9-dependent autophagosome formation by the JNK-mediated phosphorylation of Bcl-2 at serine 87 and promoted ULK1/Beclin 1-dependent autophagic membrane formation. Excessive mitochondrial fission by Drp1 enhanced the Rab9-dependent autophagosome recognition and engulfing of damaged mitochondria and eventually decreased cardiomyocyte viability. Therefore, these results demonstrated the connection between Rab9-dependent autophagosomes and mitochondrial fission in cardiac myocytes, which provides a potential therapeutic strategy for treating heart disease.
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•IGF-IIR activates JNK-mediated Bcl-2 phosphorylation to promote ULK1/Beclin 1-dependent autophagosome formation.•IGF-IIR signals ERK activation to promote Drp1 phosphorylation and result in mitochondrial fission for mitophagy.•These excessive mitochondria fission enhanced Rab9-dependent autophagosome recognition and engulfing damaged mitochondria.
Human epidermal growth factor receptor-2 (HER-2)-positive breast cancer tends to be aggressive, highly metastatic, and drug resistant and spreads rapidly. Studies have indicated that emodin inhibits ...HER-2 expression. This study compared the HER-2-inhibitory effects of two compounds extracted from rhubarb roots: aloe-emodin (AE) and rhein. Our results indicated that AE exerted the most potent inhibitory effect on HER-2 expression. Treatment of HER-2-overexpressing breast cancer cells with AE reduced tumor initiation, cell migration, and cell invasion. AE was able to suppress YB-1 expression, further suppressing downstream HER-2 expression. AE suppressed YB-1 expression through the inhibition of Twist in HER-2-overexpressing breast cancer cells. Our data also found that AE inhibited cancer metastasis and cancer stem cells through the inhibition of EMT. Interestingly, AE suppressed YB-1 expression through the downregulation of the intracellular integrin-linked kinase (ILK)/protein kinase B (Akt)/mTOR signaling pathway in HER-2-overexpressing breast cancer cells. In vivo study showed the positive result of antitumor activity of AE in nude mice injected with human HER-2-overexpressing breast cancer cells. These findings suggest the possible application of AE in the treatment of HER-2-positive breast cancer.
Mobilization of retrotransposons to new genomic locations is a significant driver of mammalian genome evolution, but these mutagenic events can also cause genetic disorders. In humans, ...retrotransposon mobilization is mediated primarily by proteins encoded by LINE-1 (L1) retrotransposons, which mobilize in pluripotent cells early in development. Here we show that TEX19.1, which is induced by developmentally programmed DNA hypomethylation, can directly interact with the L1-encoded protein L1-ORF1p, stimulate its polyubiquitylation and degradation, and restrict L1 mobilization. We also show that TEX19.1 likely acts, at least in part, through promoting the activity of the E3 ubiquitin ligase UBR2 towards L1-ORF1p. Moreover, loss of
increases L1-ORF1p levels and L1 mobilization in pluripotent mouse embryonic stem cells, implying that
prevents
retrotransposition in the pluripotent phase of the germline cycle. These data show that post-translational regulation of L1 retrotransposons plays a key role in maintaining trans-generational genome stability in mammals.
Functional capacity is a crucial parameter correlated with outcomes. The currently used New York Heart Association functional classification (NYHA Fc) system has substantial limitations, leading to ...inaccurate classification. This study investigated whether amino acid-based assessment on metabolic status provides an objective way to assess functional capacity and prognosis in heart failure (HF) outpatients. Plasma concentrations of histidine, ornithine, and phenylalanine (HOP) were measured on 890 HF outpatients to assess metabolic status by calculating the HOP score. Cardiopulmonary exercise testing (CPET) was performed in 387 patients to measure metabolic equivalents (MET) in order to define the functional class based on MET (MET Fc). Patients were followed for composite events (death/HF-related rehospitalization) up to one year. We found only 47% concordance between the MET Fc and NYHA Fc. HOP scores worked better than NYHA Fc for discriminating patients with MET Fc II and III from those with MET Fc I, with the optimal cutoff value set at 8.8. HOP scores≥8.8 were associated with risk factors for composite events in different kinds of HF populations and were a powerful predictor of composite events in univariate analysis. In multivariable analysis, HOP scores≥8.8 remained a powerful event predictor, independent of other risk factors. Kaplan-Meier curves revealed that HOP scores of ≥8.8 stratified patients at higher risk of composite events in a variety of HF populations. In conclusion, amino acid-based assessment of metabolic status correlates with functional capacity in HF outpatients and provides prognostic value for a variety of HF populations.
Advances in cancer treatments have led to an increasing number of cancer survivors, but also high rates of short-and long-term cardiovascular (CV) toxicities. The number of new cancer drugs is ...constantly increasing, and the uncertain CV toxicities of these drugs make long-term care and monitoring difficult. Moreover, traditional type I and type II cardiotoxicities may not be applicable to all of these agents. Multidisciplinary care with expertise in oncology, cardiology and other related specialties is required to mitigate cancer therapeutics-related cardiovascular dysfunction (CTRCD). The aim of this review is to provide an overview of the main CTRCD, risk assessment, early diagnosis, and strategies for the prevention and management of patients receiving cancer therapies. There are still unmet needs for cardio-oncology researchers with regards to early detection measures, better treatment strategies, better follow-up protocols, and better management of CTRCD. Experts in cardiology, oncology, hematology, and radio-oncology should thus work closely in an attempt to foster patient awareness and research in this field, as well as call for support from public and industrial sources to initiate pivotal clinical trials to solve these unmet needs.
The 2019 International Symposium on Remote Sensing (ISRS-2019) took place in Taipei, Taiwan from 17 to 19 April 2019. ISRS is one of the distinguished conferences on the photogrammetry, remote ...sensing and spatial information sciences, especially in East Asia. More than 220 papers were presented in 37 technical sessions organized at the conference. This Special Issue publishes a limited number of featured peer-reviewed papers extended from their original contributions at ISRS-2019. The selected papers highlight a variety of topics pertaining to innovative concepts, algorithms and applications with geospatial sensors, systems, and data, in conjunction with emerging technologies such as artificial intelligence, machine leaning and advanced spatial analysis algorithms. The topics of the selected papers include the following: the on-orbit radiometric calibration of satellite optical sensors, environmental characteristics assessment with remote sensing, machine learning-based photogrammetry and image analysis, and the integration of remote sensing and spatial analysis. The selected contributions also demonstrate and discuss various sophisticated applications in utilizing remote sensing, geospatial data, and technologies to address different environmental and societal issues. Readers should find the Special Issue enlightening and insightful for understanding state-of-the-art remote sensing and spatial information science research, development and applications.
Purpose:
To report the patency rates after implantation of an interwoven nitinol stent to salvage failing arteriovenous grafts (AVGs) caused by intragraft stenoses.
Methods:
Between May 2018 and May ...2020, 21 Supera stents were placed in 20 patients (18 women; mean age: 79.9 years) who had a failing AVG due to repeat intragraft stenoses. Recurrent AVG dysfunction with same intragraft stenosis within 3 months after first time angioplasty was a criterion for stenting. Those with concurrent treatment for other lesions were excluded.
Results:
The technical success rate was 100%. Intragraft stenoses were treated at a median of 19.7 (interquartile range: 6–36) months after graft creation. Access circuit primary patency rates after stent placement were 84% and 35% at 6 and 12 months, respectively. Access circuit secondary patency rates were 100% at 6 and 12 months and 89% at 18 months. Only one patient presented with graft failure due to proximal drainage vein occlusion. The target lesion patency rates were 100% at 6 months and 75% at 12 months. The rate of reintervention for intragraft lesion was 0.15 procedures per year. Stent distortion did not occur under regular cannulation.
Conclusion:
The interwoven nitinol stent is a promising treatment for failing AVGs with recurrent intragraft stenoses. The 1-year access circuit primary, secondary, and target lesion patency rates were acceptable, with a low reintervention rate. Stent fracture does not occur in areas of needle puncture.
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