Pretreatment of berbamine protects the heart from ischemia/reperfusion (I/R) injury. However it is unknown whether it has cardioprotection when given at the onset of reperfusion (postconditioning (PoC)), a protocol with more clinical impact. Autophagy is upregulated in I/R myocardium and exacerbates cardiomyocyte death during reperfusion. However, it is unknown whether the autophagy during reperfusion is regulated by berbamine. Here we investigated whether berbamine PoC (BMPoC) protects the heart through regulation of autophagy by analyzing the effects of BMPoC on infarct size and/or cell death, functional recovery and autophagy in perfused rat hearts and isolated cardiomyocytes subjected to I/R. Berbamine from 10 to 100 nM given during the first 5 min of reperfusion concentration-dependently improved post-ischemic myocardial function and attenuated cell death. Similar protections were observed in cardiomyocytes subjected to simulated I/R. Meanwhile, BMPoC prevented I/R-induced impairment of autophagosome processing in cardiomyocytes, characterized by increased LC3-II level and GFP-LC3 puncta, and decreased p62 degradation. Besides, lysosomal inhibitor chloroquine did not induce additional increase of LC3-II and P62 abundance after I/R but it reversed the effects of BMPoC in those parameters in cardiomyocytes, suggesting that I/R-impaired autophagic flux is restored by BMPoC. Moreover, I/R injury was accompanied by enhanced expression of Beclin 1, which was significantly inhibited by BMPoC. In vitro and in vivo adenovirus-mediated knockdown of Beclin 1 in myocardium and cardiomyocytes restored I/R-impaired autophagosome processing, associated with an improvement of post-ischemic recovery of myocardial contractile function and a reduction of cell death, but it did not have additive effects to BMPoC. Conversely, overexpression of Beclin 1 abolished the cardioprotection of BMPoC as did by overexpression of an essential autophagy gene Atg5. Furthermore, BMPoC-mediated cardioprotection was abolished by a specific Akt1/2 inhibitor A6730. Our results demonstrate that BMPoC confers cardioprotection by modulating autophagy during reperfusion through the activation of PI3K/Akt signaling pathway.

Rationale: Impaired autophagic flux contributes to ischemia/reperfusion (I/R)-induced cardiomyocyte death, but the underlying molecular mechanisms remain largely unexplored. Objective: To determine the role of lysosomal-associated transmembrane protein 4B (LAPTM4B) in the regulation of autophagic flux and myocardial I/R injury. Methods and Results: LAPTM4B was expressed in murine hearts but downregulated in hearts with I/R (30 minutes/2 hours) injury and neonatal rat cardiomyocytes (NRCMs) with hypoxia/reoxygenation (6 hours/2 hours) injury. During myocardial reperfusion, LAPTM4B knockout (LAPTM4B-/-) mice had a significantly increased infarct size and lactate dehydrogenase release, while adenovirus-mediated LAPTM4B-overexpression was cardioprotective. Concomitantly, LAPTM4B-/- mice showed higher accumulation of the autophagy markers LC3-II, but not P62, in the I/R heart, while they did not alter chloroquine-induced further increases of LC3-II and P62 in both Sham and I/R hearts. Conversely, LAPTM4B-overexpression had opposite effects. The hypoxia/reoxygenation-reduced viability of NRCMs, ratio of autolysosomes/autophagosomes, and function of lysosomes were further decreased by LAPTM4B-knockdown but reversed by LAPTM4B-overexpression. Moreover, the LAPTM4B-overexpression-mediated benefits were abolished by knockdown of lysosome-associated membrane protein-2 (an autophagosome-lysosome fusion protein) in vitro and by the autophagy inhibitor bafilomycin A1 in vivo. In contrast, rapamycin successfully restored the impaired autophagic flux in LAPTM4B-/- mice and the subsequent myocardial I/R injury. Mechanistically, LAPTM4B regulated the activity of mammalian target of rapamycin complex 1 (mTORC1) via interacting with mTOR through its EC3 domain. Thus, mTORC1 was overactivated in LAPTM4B-/- mice, leading to the repression of transcription factor EB (TFEB), a master regulator of lysosomal and autophagic genes, during myocardial I/R. The mTORC1 inhibition or TFEB-overexpression rescued the LAPTM4B-/--induced impairment in autophagic flux and I/R injury, whereas TFEB-knockdown abolished the LAPTM4B-overexpression-mediated recovery of autophagic flux and cardioprotection. Conclusions: The downregulation of LAPTM4B contributes to myocardial I/R-induced impairment of autophagic flux via modulation of the mTORC1/TFEB pathway.

With green development becoming a global movement, environmental tax has been adopted by many governments to promote green development. This study analyzes the impact of environmental tax on green development by using a four-dimension dynamical system. The establishment of the system is based on the complex and dynamic interactions among economic development, pollution emissions, resources consumption, and environmental tax, where roles of environmental tax are reflected by the linear parameters. A theoretic analysis shows the complexity of the behavior of the system. Mainly, the existence of chaos is inferred by Lyapunov exponent spectrum and bifurcation diagram, then verified by the presence of a chaotic attractor. An empirical study of the green development dynamical system in China demonstrates the particular evolution paths of economic growth, pollution intensity, and resource intensity under different environmental tax parameters. Results indicate a robust beneficial role of environmental tax on green development. Furthermore, when an environmental tax is imposed, a firm government control, an active consumer awareness, an advanced technology level can stimulate economic growth, decrease pollution intensity, and control the resource intensity. But the government control has a stronger effect. This study provides a viable and promising approach to analyze the role of imposing an environmental tax on green development and may have potential application in other areas and countries.

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Hyperglycemia in pregnancy (HIP) is a high-glycemic state that occurs during pregnancy, and gestational diabetes mellitus (GDM) is the major cause of it. Studies reveal that GDM has long-term adverse impacts on mothers and offspring, such as maternal type 2 diabetes, premature birth and stillbirth in newborns, cardiovascular disease, and metabolic disorders in adult offspring. In recent years, studies on the transcription level of GDM and metabonomics have provided new insights into the pathophysiological mechanism of GDM. This article reviews the transcriptional levels and metabolomics studies involving GDM and cardiovascular dysfunction in the offspring, which may provide insight to the long-term health of pregnant women and offspring.

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