Aldehyde dehydrogenase 2 protects against sympathetic excitation-induced cardiac fibrosis.

Sympathetic stimulated-cardiac fibrosis imposes great significance on both disease progression and survival in the pathogenesis of many cardiovascular diseases. However, there are few effective therapies targeting it clinically. The cardioprotective effect of aldehyde dehydrogenase 2 (ALDH2) has been explored in many pathological conditions, whether it can exert benefit effects on chronic sympathetic stimulus-induced cardiac fibrosis remains unclear. In this study, we determined to explore the role of ALDH2 on isoproterenol (ISO)-induced cardiac fibroblasts (CF) proliferation and cardiac fibrosis. It was found that ALDH2 enzymatic activity was impaired in ISO-induced HCF proliferation and Aldh2 deficiency promoted mouse CF proliferation. Alda-1, an ALDH2 activator, exerted obvious suppressive effect on ISO-induced HCF proliferation, together with the induction of cell cycle arrest at G0/G1 phase and decreased expression of cyclin E1 and cyclin-dependent kinase 2 (CDK2). Mechanistically, the inhibitory role of Alda-1 on HCF proliferation was achieved by decreasing mitochondrial reactive oxygen species (ROS) production, which was partially reversed by rotenone, an inducer of ROS. In addition, wild-type mice treated with Alda-1 manifested with reduced fibrosis and better cardiac function after ISO pump. In summary, Alda-1 alleviates sympathetic excitation-induced cardiac fibrosis via decreasing mitochondrial ROS accumulation, highlighting ALDH2 activity as a promising drug target of cardiac fibrosis.

Appropriate dose of ethanol exerts anti-senescence and anti-atherosclerosis protective effects by activating ALDH2.

Moderate alcohol consumption has been shown to reduce atherosclerosis-associated diseases. As shown in our earlier works, ethanol has a dose-dependent protective effects against endothelial cellular senescence by activating aldehyde dehydrogenase 2 (ALDH2) in vitro. However, whether ethanol administration possesses anti-atherosclerosis properties and whether ALDH2 is involved in the underlying mechanisms are unknown. In the present study, we revealed that the appropriate dose of ethanol reduced atherosclerotic plaque formation, and upregulated ALDH2 expression and activity in ApoE-/- mice. ALDH2 deficiency blocked the protection of ethanol against atherosclerotic plaque formation by inhibiting endothelium senescence. In contrast, Alda-1, which is a specific enzymatic agonist of ALDH2, enhanced the anti-senescence and anti-atherosclerosis effects of the appropriate dose of ethanol. Furthermore, following ALDH2 knockdown, resveratrol (an anti-aging compound) recovered the beneficial effects of ethanol against endothelial senescence in vitro. Thus, these results suggest that the appropriate dose of ethanol has protective effects against endothelial senescence and atherosclerosis by activating ALDH2.

ALDH2 Activation Inhibited Cardiac Fibroblast-to-Myofibroblast Transformation Via the TGF-ß1/Smad Signaling Pathway.

Pathological stimulus-triggered differentiation of cardiac fibroblasts plays a major role in the development of myocardial fibrosis. Aldehyde dehydrogenase 2 (ALDH2) was reported to exert a protective role in cardiovascular disease, and whether ALDH2 is involved in cardiac fibroblast differentiation remains unclear. In this study, we used transforming growth factor-ß1 (TGF-ß1) to induce the differentiation of human cardiac fibroblasts (HCFs) and adopted ALDH2 activator Alda-1 to verify the influence of ALDH2 on HCF differentiation. Results showed that ALDH2 activity was obviously impaired when treating HCFs with TGF-ß1. Activation of ALDH2 with Alda-1 inhibited the transformation of HCFs into myofibroblasts, demonstrated by the decreased smooth muscle actin (α-actin) and periostin expression, reduced HCF-derived myofibroblast proliferation, collagen production, and contractility. Moreover, application of Smad2/3 inhibitor alleviated TGF-ß1-induced HCF differentiation and improved ALDH2 activity, which was reversed by the application of ALDH2 inhibitor daidzin. Finally, Alda-1-induced HCF alterations alleviated neonatal rat cardiomyocyte hypertrophy, supported by the immunostaining of α-actin. To summarize, activation of ALDH2 enzymatic activity inhibited the differentiation of cardiac fibroblasts via the TGF-ß1/Smad signaling pathway, which might be a promising strategy to relieve myocardial fibrosis of various causes.

ALDH2 mediates the dose-response protection of chronic ethanol against endothelial senescence through SIRT1/p53 pathway.

Aldehyde dehydrogenase 2 (ALDH2) plays essential roles in drinking-associated diseases or effects. As we have previously reported, ALDH2 mediates acute ethanol-induced eNOS activation in vitro. However, whether chronic ethanol treatment has a dose-response endothelial protection, as well as the possible mediating role of ALDH2 involved, is unclear. Here, we show that appropriate dose of ethanol preserved the expression and activity of ALDH2 and eNOS, and alleviated senescence-associated phenotypes in human aortic endothelial cells. Furthermore, ALDH2 deficiency impairs the dose-response protection of ethanol against endothelial senescence by promoting the accumulation of 4-HNE, the formation of 4-HNE-SIRT1 protein adducts and the subsequent decrease in SIRT1-dependent p53 deacetylation. Collectively, our data indicate that ALDH2 mediates the protection of appropriate ethanol by modulating SIRT1/p53-dependent endothelial senescence.

Vaspin alleviates myocardial ischaemia/reperfusion injury via activating autophagic flux and restoring lysosomal function.

Visceral adipose tissue-derived serine protease inhibitor (vaspin), as a secretory adipokine, was reported to exert a protective role on insulin resistance. Recent studies showed that serum vaspin level was downregulated in patients with coronary artery disease. However, whether vaspin exerted specific effects on myocardial injury remains unknown. In this study, we determined to explore the role of vaspin overexpression in myocardial ischaemia/reperfusion (I/R) injury and the underlying mechanisms. Our results showed that the systemic delivery of adeno-associated virus-vaspin to mice reduced myocardial infarct size and apoptosis, and improved cardiac function after reperfusion, accompanied with upregulated autophagic flux and restored lysosomal function in the ischaemic heart. Blockage of the autophagic flux with choroquine mitigated the protection of vaspin on myocardial I/R injury. Moreover, we testified that administration of exogenous recombinant human vaspin on cultured cardiomyocytes suppressed hypoxia/reoxygenation-induced apoptosis, through the AMPK-mTOR-upregulated autophagic flux. Overall, we verified that vaspin functions as an adipokine which can alleviate I/R injury in the heart by suppressing myocardial apoptosis through AMPK-mTOR-dependent activation of autophagic flux, and then provided a potential breakthrough in the treatment of myocardial I/R injury and other ischaemic diseases.

LiFePO4/C twin microspheres as cathode materials with enhanced electrochemical performance.

Self-assembled lithium iron phosphate (LiFePO4) with tunable microstructure is an effective way to improve the electrochemical performance of cathode materials for lithium ion batteries. Herein, self-assembled LiFePO4/C twin microspheres are synthesized by a hydrothermal method using a mixed solution of phosphoric acid and phytic acid as the phosphorus source. The twin microspheres are hierarchical structures composed of primary nano-sized capsule-like particles (about 100 nm in diameter and 200 nm in length). The uniform thin carbon layer on the surface of the particles improves the charge transport capacity. The channel between the particles facilitates the electrolyte infiltration, and the high electrolyte accessibility enables the electrode material to obtain excellent ion transport. The optimal LiFePO4/C-60 exhibits excellent rate performance with discharge capacity of 156.3 mA h g-1 and 118.5 mA h g-1 respectively at 0.2C and 10C, and low temperature performances with discharge capacity of 90.67 mA h g-1 and 66.7 mA h g-1 at -15 °C and -25 °C, respectively. This research may provide a new pathway to improve the performance of LiFePO4 by tuning the micro-structures by adjusting the relative content of phosphoric acid and phytic acid.

Carbon microspheres built of La2O3 quantum dots-implanted nanorods: Superb hosts with ultra-long Li2Sn-catalysis durability.

Practical utilization of Li-sulfur batteries (LSBs) is still hindered by the sulfur cathode side due to its inferior electrical conductivity, huge volume expansion and adverse polysulfide shuttling effects. Though using polar catalysts coupled with mesoporous carbons may well surmount these barriers, such unsheltered catalysts rarely survive due to oversaturated polysulfide adsorption and extra sulfuration side reactions. To overcome above constrains, we herein propose to implant highly reactive nanocatalysts into carbon matrix with few nanometers insertion depth for mechanical protection. As a paradigm study, we have embedded La2O3-quantum dots (QDs) into carbon nanorods, which are then assembled into carbon microspheres (CMs). As evaluated, La2O3 QDs-CMs can help elevate the cathode redox reaction kinetics and sulfur utilization ratios, delivering a large capacity of 1392 mAh g-1 at 0.25C and high-capacity retention of 76% after total cycling. The thin carbon layers on La2O3 QDs exert a key role in impeding excess polysulfide accumulation on catalysts and thus prevent their deactivation/failure. Our strategy may guide a smart way to make catalysts-involved sulfur cathode systems with ultra-long working durability for LSBs applications.

Continuous Amorphous Metal-Organic Frameworks Layer Boosts the Performance of Metal Anodes.

Employing metal anodes can greatly increase the volumetric/gravimetric energy density versus a conventional ion-insertion anode. However, metal anodes are plagued by dendrites, corrosion, and interfacial side reaction issues. Herein, a continuous and flexible amorphous MOF layer was successfully synthesized and used as a protective layer on metal anodes. Compared with the crystalline MOF layer, the continuous amorphous MOF layer can inhibit dendrite growth at the grain boundary and eliminate ion migration near the grain boundary, showing high interfacial adhesion and a large ion migration number (tZn2+ = 0.75). In addition, the continuous amorphous MOF layer can effectively solve several key challenges, e.g., corrosion of the zinc anode, hydrogen evolution reaction, and dendrite growth on the zinc surface. The prepared Zn anode with the continuous amorphous MOF (A-MOF) layer exhibited an ultralong cycling life (around one year, more than 7900 h) and a low overpotential (<40 mV), which is 12 times higher than that of the crystalline MOF protective layer. Even at 10 mA cm-2, it still showed high stability for more than 5500 cycles (1200 h). The enhanced performance is realized for full cells paired with a MnO2 cathode. In addition, a flexible symmetrical battery with the Zn@A-ZIF-8 anode exhibited good cyclability under different bending angles (0°, 90°, and 180°). More importantly, various metal substrates were successfully coated with compact A-ZIF-8. The A-ZIF-8 layer can obviously improve the stability of other metal anodes, including those of Mg and Al. These results not only demonstrate the high potential of amorphous MOF-decorated Zn anodes for AZIBs but also propose a type of protective layer for metal anodes.

Rationally tuning ratio of micro- to meso-pores of biomass-derived ultrathin carbon sheets toward supercapacitors with high energy and high power density.

The carbon pore structure could have a significant effect on supercapacitor performance; however, this effect has not yet been systematically studied. A facile approach for synthesizing porous, ultrathin carbon sheets while rationally tuning the ratio of micro-to meso-pores via partial corrosion has been developed for the fabrication of high-performance devices. The prepared carbon from biomass with an optimal ratio of micro- to meso-pores has a large specific surface area of 1785 m2 g -1, a high specific capacitance of 447F g -1 at 0.5 A g-1, a high energy density of 15.5-9.7 Wh kg-1, and an excellent power density of 0.062-6.24 kW kg-1. After 10,000 charge-discharge cycles, the capacitance retention was maintained at 95%, which exceeded most of the biomass-carbon-based capacitors. Volcano relationships were found to exist through plots of both specific surface area and specific capacitance versus the micro-to meso-pore ratio. An enhancement mechanism with a rational pore structure is proposed, which not only networks micropores to remove died-end micropores to achieve the largest specific active surface area and high specific capacitance but also realizes fast mass-transport channels, resulting in high power density. This work provides an effective approach based on waste re-use by tuning a rational pore structure for achieving high energy/power density toward green energy applications with universal significance.

YAP1 silencing attenuated lung injury/fibrosis but worsened diaphragmatic function by regulating oxidative stress and inflammation response in mice.

Oxidative stress is a crucial mechanism in the pathophysiology of lung injury/fibrosis and diaphragmatic dysfunction. Yes-associated protein 1 (YAP1) is a key oxidative stress response regulator. However, how lung injury/fibrosis and the subsequent YAP1 silencing treatment affect diaphragmatic function remains largely uncharacterized. In this study, mice models of acute lipopolysaccharide (LPS) and paraquat exposure were used to establish acute lung injury and chronic pulmonary fibrosis. AT2 and C2C12 cells were co-cultured under LPS and paraquat challenge. YAP1 was interfered with shRNA given in vivo and verteporfin administration in vitro. Pulmonary histology, contractile properties, and cross-sectional areas (CSAs) of the diaphragm and gastrocnemius were evaluated. Histological and biochemical analyses were performed for targeted biomarker determination. We found that LPS and paraquat caused significant lung injury/fibrosis and significantly reduced the diaphragmatic-specific force and CSAs compared with the control. YAP1 silencing alleviated inflammatory cell infiltration or collagen deposition in the lungs yet worsened the already impaired diaphragmatic function by increasing inflammatory cytokines (IL-6 and TNF-α), mitochondrial reactive oxidative species (ROS) emission, protein degradation (Murf-1, atrogin-1, and calpain), and decreasing antioxidant capabilities (superoxide dismutase 2 and glutathione peroxidase). No significant improvements were observed in diaphragmatic function by transient YAP1 knockdown in the gastrocnemius. In vitro, LPS- or paraquat-caused cytotoxicity in AT2 cells was mostly alleviated by verteporfin in a concentration that was 20-fold higher than that in C2C12 cells (20 and 1 µg/mL, respectively). Finally, 0.5 µg/mL of verteporfin significantly ameliorated hydrogen peroxide-induced proteolytic activity and antioxidant enzyme suppression in C2C12 cells, whereas 2 µg/mL of verteporfin deteriorated the same. Collectively, lung injury/fibrosis adversely affects the diaphragm. YAP1 inhibition alleviates lung injury/fibrosis but worsens diaphragmatic function potentially by enhancing inflammatory cytokines and ROS-mediated protein degradation. This disparity might be attributed to differences in susceptibility to YAP1 inhibition between muscles and the lungs.

Efficacy evaluation of acupotomy combined with platelet-rich plasma in the treatment of early and middle osteoarthritis.

OBJECTIVE: To investigate the efficacy of traditional Chinese medicine acupotomy combined with platelet-rich plasma (PRP) in the treatment of early and middle osteoarthritis. METHODS: Eighty cases of early and middle knee joint pain patients admitted in our hospital were selected in this retrospective study. They were divided into the control group and observation group according to treatment methods, with 40 cases in each group. The control group was treated with PRP, and the observation group was treated with acupotomy + PRP. Clinical response rate, visual analogue scale (VAS) pain score, Lequesne score, Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and SF-36 quality of life score were compared between the two groups. RESULTS: The total clinical response rate in the observation group was higher than that in control group (P<0.01). VAS pain score, knee joint WOMAC index and Lequesne score in the two groups after treatment were lower than those before treatment, and those in the observation group were lower than those in the control group (all P<0.05). SF-36 quality of life score was significantly higher in the observation group than in the control group (all P<0.001). CONCLUSION: Acupotomy combined with PRP in the treatment of early and middle osteoarthritis can relieve pain and improve joint function, which is worthy of clinical promotion.

Effect evaluation of acupuncture combined with nerve block treatment on patients with lumbar spondylolisthesis.

OBJECTIVE: To explore the clinical effect of acupuncture combined with nerve block treatment on Grade I lumbar spondylolisthesis. METHODS: Seventy patients with Grade I lumbar spondylolisthesis were randomly divided into a control group (n=70) treated with merely nerve block and an observation group (n=70) treated with acupuncture based on the nerve block treatment in the control group. The clinical efficacy rate, pain severity evaluated by VAS (on the 3rd day and in one week after treatment), recovery of spinal functions evaluated by Oswestry Dysfunction Index (ODI) and the quality of life reflected by the 36-Item Short Form Health Survey (SF-36) were compared between the two groups. RESULTS: The overall efficacy rate (94.29% vs 77.14%, P=0.036) and SF-36 score of the observation group were higher than those of the control group (both P<0.05). The VAS and ODI scores of the two groups after treatment were decreased and the observation group had lower scores (all P<0.05). CONCLUSION: Acupuncture combined with nerve block can improve the efficacy rate of treatment of Grade I lumbar spondylolisthesis, relieve the pain of patients, restore their spinal functions and improve their quality of life, which is worthy of clinical promotion.

Isorhynchophylline enhances Nrf2 and inhibits MAPK pathway in cardiac hypertrophy.

Isorhynchophylline (IRN) is one of the major tetracyclic oxindole alkaloids found in Uncaria rhynchophylla. Studies have found that IRN has diverse biological activities including antioxidant, anti-apoptosis, and neuroprotection. However, little is known about the effect of IRN on the development of cardiac hypertrophy. In this study, we investigated the change of the cell surface area and nascent protein synthesis of cultured H9c2 cardiomyocytes on exposure to phenylephrine (PE) plus IRN, and thus confirmed that IRN ameliorated cardiomyocyte hypertrophy induced by PE in vitro. Meanwhile, it turns out that IRN is also effective in neonatal rat ventricular myocytes (NRVMs) stimulated with angiotensin II (AngII). We also showed that IRN prevented cardiac dysfunction in mice with pressure overload due to transverse aortic constriction (TAC) and attenuated cardiac hypertrophy and fibrosis. IRN treatment improved the cardiac function assessed by echocardiographic parameters fractional shortening (FS) as well as suppressed the cardiac hypertrophy phenotypes, such as the increasing of ventricular mass/body weight and myocyte cross-sectional area. RT-PCR analysis showed that IRN treatment also alleviated the expression of fetal genes of ANP, BNP, Myh7, and the correlated fibrosis genes including TGF-ß1, collagen I, collagen III, and CTGF in vivo. Meanwhile, IRN had anti-oxidative effects on cardiac remodeling with suppressed 4-HNE and MDA. Western blot analysis showed that the Nrf2 nuclear translocation and MAPK pathway were involved in the potential mechanisms of IRN on cardiac hypertrophy inhibition. The results of our study provide further evidence that IRN is a promising drug for the treatment of cardiac hypertrophy.

Postinfarction Hearts Are Protected by Premature Senescent Cardiomyocytes Via GATA 4-Dependent CCN 1 Secretion.

Background Stress-induced cell premature senescence participates in a variety of tissue and organ remodeling by secreting such proteins as proinflammatory cytokines, chemokines, and growth factors. However, the role of cardiomyocyte senescence in heart remodeling after acute myocardial infarction has not been thoroughly elucidated to date. Therefore, we sought to clarify the impact of premature myocardial senescence on postinfarction heart function. Methods and Results Senescence markers, including p16 INK4a, p21 CIP1/WAF1, and SA -ß-gal staining, were analyzed in several heart disease models by immunostaining. Both postinfarction mouse hearts and ischemic human myocardium demonstrated increased senescence markers. Additionally, senescence-related secretory phenotype was activated after acute myocardial infarction, which upregulated senescence-related secretory phenotype factors, including CCN family member 1 ( CCN 1), interleukin-1α, tumor necrosis factor α, and monocyte chemoattractant protein-1. In vivo, a tail vein injection of AAV 9- Gata4-sh RNA significantly attenuated senescence-related secretory phenotype secretion and aggravated postinfarction heart dysfunction. Furthermore, among activated senescence-related secretory phenotype factors, CCN 1 administration reduced myofibroblast viability in vitro and rescued the deleterious effect of AAV 9- Gata4-sh RNA in vivo. Conclusions Myocardial premature senescence was observed in the ischemic hearts and improved postinfarction heart function, partly through the GATA-binding factor 4- CCN 1 pathway.

Enhanced power factor via the control of structural phase transition in SnSe.

Tin selenide has attracted much research interest due to its unprecedentedly high thermoelectric figure of merit (ZT). For real applications, it is desirable to increase the ZT value in the lower-temperature range, as the peak ZT value currently exists near the melting point. It is shown in this paper that the structural phase transition plays an important role in boosting the ZT value of SnSe in the lower-temperature range, as the Cmcm phase is found to have a much higher power factor than the Pnma phase. Furthermore, hydrostatic pressure is predicted to be extremely effective in tuning the phase transition temperature based on ab-initio molecular dynamic simulations; a remarkable decrease in the phase transition temperature is found when a hydrostatic pressure is applied. Dynamical stabilities are investigated based on phonon calculations, providing deeper insight into the pressure effects. Accurate band structures are obtained using the modified Becke-Johnson correction, allowing reliable prediction of the electrical transport properties. The effects of hydrostatic pressure on the thermal transport properties are also discussed. Hydrostatic pressure is shown to be efficient in manipulating the transport properties via the control of phase transition temperature in SnSe, paving a new path for enhancing its thermoelectric efficiency.