High-fat diet induces protein kinase A and G-protein receptor kinase phosphorylation of β2 -adrenergic receptor and impairs cardiac adrenergic reserve in animal hearts.

Key pointsPatients with diabetes show a blunted cardiac inotropic response to β-adrenergic stimulation despite normal cardiac contractile reserve. Acute insulin stimulation impairs β-adrenergically induced contractile function in isolated cardiomyocytes and Langendorff-perfused hearts. In this study, we aimed to examine the potential effects of hyperinsulinaemia associated with high-fat diet (HFD) feeding on the cardiac β2 -adrenergic receptor signalling and the impacts on cardiac contractile function. We showed that 8 weeks of HFD feeding leads to reductions in cardiac functional reserve in response to β-adrenergic stimulation without significant alteration of cardiac structure and function, which is associated with significant changes in β2 -adrenergic receptor phosphorylation at protein kinase A and G-protein receptor kinase sites in the myocardium. The results suggest that clinical intervention might be applied to subjects in early diabetes without cardiac symptoms to prevent further cardiac complications.AbstractPatients with diabetes display reduced exercise capability and impaired cardiac contractile reserve in response to adrenergic stimulation. We have recently uncovered an insulin receptor and adrenergic receptor signal network in the heart. The aim of this study was to understand the impacts of high-fat diet (HFD) on the insulin-adrenergic receptor signal network in hearts. After 8 weeks of HFD feeding, mice exhibited diabetes, with elevated insulin and glucose concentrations associated with body weight gain. Mice fed an HFD had normal cardiac structure and function. However, the HFD-fed mice displayed a significant elevation of phosphorylation of the β2 -adrenergic receptor (β2 AR) at both the protein kinase A site serine 261/262 and the G-protein-coupled receptor kinase site serine 355/356 and impaired adrenergic reserve when compared with mice fed on normal chow. Isolated myocytes from HFD-fed mice also displayed a reduced contractile response to adrenergic stimulation when compared with those of control mice fed normal chow. Genetic deletion of the β2 AR led to a normalized adrenergic response and preserved cardiac contractile reserve in HFD-fed mice. Together, these data indicate that HFD promotes phosphorylation of the β2 AR, contributing to impairment of cardiac contractile reserve before cardiac structural and functional remodelling, suggesting that early intervention in the insulin-adrenergic signalling network might be effective in prevention of cardiac complications in diabetes

3D-printed polycaprolactone-chitosan based drug delivery implants for personalized administration

Fused deposition molding (FDM) can complete most complex preparation of drug delivery implants to meet the personalized needs of patients. However, the drug activity has strict requirements on processing temperature and preparation method of filaments, the implant also has strict biocompatibility requirements for the materials. In this study, a drug delivery implant was prepared with good biocompatibility, controlled and efficient drug release using FDM printing for personalized administration. Drug-loaded filaments were developed for FDM process by hot-melt extrusion (HME). Polycaprolactone was used as a drug delivery carrier, and ibuprofen as the model drug. Notably, chitosan was dissolved to form controlled and efficient release channels. The printability, changes in physical and chemical properties during HME and FDM processes of the filament, and drug release behavior, mechanism and biocompatibility of the implants were investigated. The results showed that the filament tensile strength decreased with the increase of drug and chitosan content. No obvious degradation and chemical change occurred during the whole process. The drug release efficiency could reach\u3e99% and lasted for 120 h mainly via the diffusion - erosion mechanism. The viability of cells cultured for 24 h in 72 h, 100% implant extract was 75.3%

Transdisciplinary, co-designed and adaptive management for the sustainable development of rongcheng, a coastal city in China in the context of human activities and climate change

Half the population of China live in coastal zones where 70% of large cities are also located. Intensive human activities pose significant environmental and ecological hazards to these cities that are already vulnerable to natural hazards and climate change. The sustainable development of coastal cities is thus both a national and international issue. Rongcheng is a typical coastal city in east China. It is a national marine ranch demonstration area that is subjected to multi-stressors from human activities and climate change. The dominant economic sectors include aquaculture and fisheries, agriculture, shipping and tourism. A multitude of resulting pressures come mainly from intensified human activities, such as intensive aquaculture, overfishing, industrial pollutants, agricultural runoff, land reclamation and port expansion. In addition, Rongcheng is also facing exogenic pressures from extreme climate events such as intensified storms, storm surges, droughts and sea ice. A growing awareness of these problems brought together a trans-disciplinary group from local government, research institutions, local practitioners and coastal representatives to jointly explore and co-design adaptive coastal management options. In this transdisciplinary study, a social-ecological analysis based on a combination of the Systems Approach Framework and the Drivers-Pressures-States-Impacts-Responses framework was used to analyze and formulate an adaptive management plan for the sustainability of Rongcheng. More than 40 stakeholders including government, companies, civil society and institutions participated in the study through questionnaires and on-site meetings. A statistical analysis of the results identified urgent issues impeding the sustainable development of Rongcheng. The issues identified were poorly regulated aquaculture, loss of shoreline, and the decline of seagrass and cultural heritage.The study identified management options and measures, some of which were adopted by the local government in a co-designed management plan. The measures included upgrading of aquaculture industry, habitat conservation and restoration, and the development of cultural tourism. Another outcome was the increased knowledge exchange between stakeholders to inform management, policy, and decision making, as well as raised awareness of vulnerability to natural hazards and climate change. The success of this case study provides a reference for the adaptive management of other coastal cities and their sustainable development in a changing climate.info:eu-repo/semantics/publishedVersio

Insulin inhibits cardiac contractility by inducing a Gi-biased β2-adrenergic signaling in hearts.

Insulin and adrenergic stimulation are two divergent regulatory systems that may interact under certain pathophysiological circumstances. Here, we characterized a complex consisting of insulin receptor (IR) and β2-adrenergic receptor (β2AR) in the heart. The IR/β2AR complex undergoes dynamic dissociation under diverse conditions such as Langendorff perfusions of hearts with insulin or after euglycemic-hyperinsulinemic clamps in vivo. Activation of IR with insulin induces protein kinase A (PKA) and G-protein receptor kinase 2 (GRK2) phosphorylation of the β2AR, which promotes β2AR coupling to the inhibitory G-protein, Gi. The insulin-induced phosphorylation of β2AR is dependent on IRS1 and IRS2. After insulin pretreatment, the activated β2AR-Gi signaling effectively attenuates cAMP/PKA activity after β-adrenergic stimulation in cardiomyocytes and consequently inhibits PKA phosphorylation of phospholamban and contractile responses in myocytes in vitro and in Langendorff perfused hearts. These data indicate that increased IR signaling, as occurs in hyperinsulinemic states, may directly impair βAR-regulated cardiac contractility. This β2AR-dependent IR and βAR signaling cross-talk offers a molecular basis for the broad interaction between these signaling cascades in the heart and other tissues or organs that may contribute to the pathophysiology of metabolic and cardiovascular dysfunction in insulin-resistant states

hSef potentiates EGF-mediated MAPK signaling through affecting EGFR trafficking and degradation

Sef (similar expression to fgf genes) was identified as an effective antagonist of fibroblast growth factor (FGF) in vertebrates. Previous reports have demonstrated that Sef interacts with FGF receptors (FGFRs) and inhibits FGF signaling, however, its role in regulating epidermal growth factor receptor (EGFR) signaling remains unclear. In this report, we found that hSef localizes to the plasma membrane (PM) and is subjected to rapid internalization and well localizes in early/recycling endosomes while poorly in late endosomes/lysosomes. We observed that hSef interacts and functionally colocalizes with EGFR in early endosomes in response to EGF stimulation. Importantly, we demonstrated that overexpression of hSef attenuates EGFR degradation and potentiates EGF-mediated mitogen-activated protein kinase (MAPK) signaling by interfering EGFR trafficking. Finally, our data showed that, with overexpression of hSef, elevated levels of Erk phosphorylation and differentiation of rat pheochromocytoma (PC12) cells occur in response to EGF stimulation. Taken together, these data suggest that hSef plays a positive role in the EGFR-mediated MAPK signaling pathway. This report, for the first time, reveals opposite roles for Sef in EGF and FGF signalings

Association between Physical Activity and Neighborhood Environment among Middle-Aged Adults in Shanghai

Objective. To determine the perceived neighborhood environment (NE) variables that are associated with physical activity (PA) in urban areas in China. Methods. Parents of students at two junior high schools in Shanghai, one downtown and the other in the suburbs, were recruited to participate in the study. They completed an International Physical Activity Questionnaire (IPAQ) and Neighborhood Environment Walkability Scale-Abbreviated (NEWS-A) survey. Participant physical activity was also objectively measured using accelerometers. Results. Participants from downtown areas were more positively associated with transportation PA and leisure-time PA than respondents living in the suburbs. Residential density was found to be a significant positive predictor of recreational or leisure-based PA. Street connectivity was negatively associated with leisure time PA for respondents. Moderate-vigorous PA was found to be negatively associated with traffic safety. There were no significant associations between environmental factors and transportation PA. Women had higher levels of moderate-vigorous PA than men. Conclusions. The results of this study demonstrate that residential density, street connectivity, and traffic safety have a significant impact on Chinese middle-aged adults' PA, suggesting urban planning strategies for promoting positive public health outcomes