Search

Aims: Cardiac lipotoxicity is the common consequence of lipid metabolism disorders in cardiomyocytes during development of heart failure (HF). Adenosine 5′monophosphate-activated protein kinase (AMPK) acts as an energy sensor and has a beneficial effect in reducing lipotoxicity. Notoginsenoside R1 (NGR1) is extracted from the traditional Chinese medicine Panax notoginseng (Burkill) F.H.Chen (P. notoginseng) and has definite cardioprotective effects. However, whether NGR1 can attenuate HF by mitigating lipotoxicity has not been elucidated yet. This study aimed to explore whether NGR1 plays a protective role against HF by ameliorating cardiac lipotoxicity via the AMPK pathway.Methods: In this study, HF mice model was established by left anterior descending (LAD) ligation. palmitic acid (PA) stimulated H9C2 cell model was applied to clarify the effects and potential mechanism of NGR1 on lipotoxicity. In vivo, NGR1 (7.14 mg/kg/days) and positive drug (simvastatin: 2.9 mg/kg/days) were orally administered for 14 days. Echocardiography was applied to assess heart functions. Lipid levels were measured by Enzyme-linked immunosorbent assay (ELISA) and key proteins in the AMPK pathway were detected by western blots. In vitro, NGR1 (40 μmol/L) or Compound C (an inhibitor of AMPK, 10 μmol/L) was co-cultured with PA stimulation for 24 h in H9C2 cells. CCK-8 assay was used to detect cell viability. Key lipotoxicity-related proteins were detected by western blots and the LipidTOX™ neutral lipid stains were used to assess lipid accumulation. In addition, Apoptosis was assessed by Hoechst/PI staining.Results: NGR1 could significantly improve the cardiac function and myocardial injury in mice with HF and up-regulate the expression of p-AMPK. Impressively, NGR1 inhibited the synthesis of diacylglycerol (DAG) and ceramide and promoted fatty acid oxidation (FAO) in vivo. Moreover, NGR1 significantly promoted expression of CPT-1A, the key enzyme in FAO pathway, and down-regulated the expression of GPAT and SPT, which were the key enzymes catalyzing production of DAG and ceramide. In vitro experiments showed that NGR1 could significantly attenuate lipid accumulation in PA-induced H9C2 cells and the Hoechst/PI staining results showed that NGR1 ameliorated lipotoxicity-induced apoptosis in PA-stimulated H9C2 cell model. Furthermore, co-treatment with inhibitor of AMPK abrogated the protective effects of NGR1. The regulative effects of NGR1 on lipid metabolism were also reversed by AMPK inhibitor.Conclusion: NGR1 could significantly improve the heart function of mice with HF and reduce cardiac lipotoxicity. The cardio-protective effects of NGR1 are mediated by the activation of AMPK pathway.

Super-large span twin tunnels, which can relieve traffic burden and improve the efficiency of roads, have been rapidly popularized in urban construction. Hence, it is very important to master the share rate of support structure in this sort of tunnel correctly. In this paper, some field monitoring and numerical simulation work has been carried out in such a tunnel in Daling, China. The content of field monitoring consisted of the vault settlement, stress of the concrete, and the sum pressure. Firstly, the calculation formula of rock pressure in this kind of tunnel had been deduced, which was based on the theoretical sliding failure mode. Then, the calculated rock pressure was applied to the load structure model step by step with 10% intervals (10%, 20%, …). By comparing the monitoring and the simulation results on vault settlement, the share rate of the primary support was ensured to be 40%. Similarly, by comparing the result on safety factors, the share rate of the secondary lining was obtained (40%). The remained load was born mainly by the surrounding rock itself and the advanced support. Finally, the reliability of the results were verified by the sum pressure. This paper can provide reference for the effective design of support structure in super-large span twin tunnels.

In order to ensure the safety of the Daling tunnel with extralarge section and small space, the three-dimensional model of blasting dynamic simulation had been established and verified. Then, the model was used to analyze the influence of the surrounding rock characteristics and blasting design parameters on the blasting vibration of the first hole, and the analysis of the sensitivity of each factor was carried out. The results showed that blasting of the second hole had a serious impact on the safety of the first hole lining structure. Based on the safety threshold and analysis of sensitivity, the explosive velocity, charge density, and digging length were selected as the key parameters affecting the safety of the tunnel structure. Meanwhile, the corresponding engineering measure was taken based on the results of sensitivity and the actual situation on site, and, after that, the maximum PPV of the right wall of the first hole had been reduced to 9.3 cm/s, which effectively guaranteed the safe construction of the tunnel.