Alternate-day fasting ameliorated anxiety-like behavior in high-fat diet-induced obese mice.

Alternate-day fasting (ADF) has been reported to reduce body weight, neuroinflammation, and oxidative stress damage. However, it is not known whether ADF affects obesity-induced anxiety-like behavior. Here, male C57BL/6 mice were given an alternate fasting and high-fat diet (HFD) or standard chow diet (SD) every other day for 16 or 5 weeks. After the intervention, the degree of anxiety of the mice was evaluated by the open field test (OFT) and the elevated plus maze (EPM) test. Pathological changes in the hippocampus, the expression of Sirt1 and its downstream protein monoamine oxidase A (MAO-A) in the hippocampus, and the expression of 5-hydroxytryptamine (5-HT) were detected. Compared with HFD-fed mice, HFD-fed mice subjected to ADF for 16 weeks had a lower body weight but more brown adipose tissue (BAT), less anxiety behavior, and less pathological damage in the hippocampus, and lower expression of Sirt1 and MAO-A protein and higher 5-HT levels in the hippocampus could be observed. In addition, we noted that long-term ADF intervention could cause anxiety-like behavior in SD mice. Next, we changed the intervention time to 5 weeks. The results showed that short-term ADF intervention could reduce the body weight and increase the BAT mass of SD mice, but it did not affect anxiety. These results indicated that long-term ADF ameliorated obesity-induced anxiety-like behavior and hippocampal damage, but caused anxiety in normal-weight mice. Short-term ADF did not produce adverse emotional reactions in normal-weight mice. Here, we might provide new ideas for the treatment of obesity-induced anxiety.

Upregulation of TRIM16 mitigates doxorubicin-induced cardiotoxicity by modulating TAK1 and YAP/Nrf2 pathways in mice.

The clinic application of doxorubicin (DOX) is severely limited by its severe cardiotoxicity. Tripartite motif-containing protein 16 (TRIM16) has E3 ubiquitin ligase activity and is upregulated in cardiomyocytes under pathological stress, yet its role in DOX-induced cardiotoxicity remains elusive. This study aims to investigate the role and mechanism of TRIM16 in DOX cardiotoxicity. Following TRIM16 overexpression in hearts with AAV9-TRIM16, mice were intravenously administered DOX at a dose of 4 mg/kg/week for 4 weeks to assess the impact of TRIM16 on doxorubicin-induced cardiotoxicity. Transfection of OE-TRIM16 plasmids and siRNA-TRIM16 was performed in neonatal rat cardiomyocytes (NRCMs). Our results revealed that DOX challenge elicited a significant upregulation of TRIM16 proteins in cardiomyocytes. TRIM16 overexpression efficiently ameliorated cardiac function while suppressing inflammation, ROS generation, apoptosis and fibrosis provoked by DOX in the myocardium. TRIM16 knockdown exacerbated these alterations caused by DOX in NRCMs. Mechanistically, OE-TRIM16 augmented the ubiquitination and degradation of p-TAK1, thereby arresting JNK and p38MAPK activation evoked by DOX in cardiomyocytes. Furthermore, DOX enhanced the interaction between p-TAK1 and YAP1 proteins, resulting in a reduction in YAP and Nrf2 proteins in cardiomyocytes. OE-TRIM16 elevated YAP levels and facilitated its nuclear translocation, thereby promoting Nrf2 expression and mitigating oxidative stress and inflammation. This effect was nullified by siTRIM16 or TAK1 inhibitor Takinib. Collectively, the current study elaborates that upregulating TRIM16 mitigates DOX-induced cardiotoxicity through anti-inflammation and anti-oxidative stress by modulating TAK1-mediated p38 and JNK as well as YAP/Nrf2 pathways, and targeting TRIM16 may provide a novel strategy to treat DOX-induced cardiotoxicity.

Flt3 Activation Mitigates Mitochondrial Fragmentation and Heart Dysfunction through Rebalanced L-OPA1 Processing by Hindering the Interaction between Acetylated p53 and PHB2 in Cardiac Remodeling.

Recent studies have shown that FMS-like receptor tyrosine kinase 3 (Flt3) has a beneficial effect on cardiac maladaptive remodeling. However, the role and mechanism of Flt3 in mitochondrial dynamic imbalance under cardiac stress remains poorly understood. This study aims to investigate how Flt3 regulates p53-mediated optic atrophy 1 (OPA1) processing and mitochondrial fragmentation to improve cardiac remodeling. Mitochondrial fragmentation in cardiomyocytes was induced by isoprenaline (ISO) and H2O2 challenge, respectively, in vitro. Cardiac remodeling in mice was established by ligating the left anterior descending coronary artery or by chronic ISO challenge, respectively, in vivo. Our results demonstrated that the protein expression of acetylated-p53 (ac-p53) in mitochondria was significantly increased under cell stress conditions, facilitating the dissociation of PHB2-OPA1 complex by binding to prohibitin 2 (PHB2), a molecular chaperone that stabilizes OPA1 in mitochondria. This led to the degradation of the long isoform of OPA1 (L-OPA1) that facilitates mitochondrial fusion and resultant mitochondrial network fragmentation. This effect was abolished by a p53 K371R mutant that failed to bind to PHB2 and impeded the formation of the ac-p53-PHB2 complex. The activation of Flt3 significantly reduced ac-p53 expression in mitochondria via SIRT1, thereby hindering the formation of the ac-p53-PHB2 complex and potentiating the stability of the PHB2-OPA1 complex. This ultimately inhibits L-OPA1 processing and leads to the balancing of mitochondrial dynamics. These findings highlight a novel mechanism by which Flt3 activation mitigates mitochondrial fragmentation and dysfunction through the reduction of L-OPA1 processing by dampening the interaction between ac-p53 and PHB2 in cardiac maladaptive remodeling.

Activation of FMS-like tyrosine kinase 3 protects against isoprenaline-induced cardiac hypertrophy by improving autophagy and mitochondrial dynamics.

FMS-like receptor tyrosine kinase 3 (Flt3) expression was reported to increase in the heart in response to pathological stress, but the role of Flt3 activation and its underlying mechanisms remain poorly elucidated. This study was designed to investigate the role of Flt3 activation in sympathetic hyperactivity-induced cardiac hypertrophy and its mechanisms through autophagy and mitochondrial dynamics. In vivo, cardiac hypertrophy was established by subcutaneous injection of isoprenaline (6 mg/kg·day) in C57BL/6 mice for 7 consecutive days. The Flt3-ligand intervention was launched 2 h prior to isoprenaline each day. In vitro, experiments of cardiomyocyte hypertrophy, autophagy, and mitochondrial dynamics were performed in neonatal rat cardiomyocytes (NRCMs). Our results revealed that the expression level of Flt3 protein was significantly increased in the hypertrophic myocardium provoked by isoprenaline administration. Flt3-ligand intervention alleviated isoprenaline-induced cardiac oxidative stress, hypertrophy, fibrosis, and contractile dysfunction. Isoprenaline stimulation impaired autophagic flux in hypertrophic mouse hearts, supported by the accumulation of LC3II and P62 proteins, while Flt3-ligand restored the impairment of autophagic flux. Flt3 activation normalized the imbalance of mitochondrial fission and fusion in the hearts of mice evoked by isoprenaline as evidenced by the neutralization of elevated mitochondrial fission markers and reduced mitochondrial fusion markers. In NRCMs, Flt3-ligand treatment attenuated isoprenaline-stimulated hypertrophy, which was abolished by a Flt3-specific blocker AC220. Activating Flt3 reversed isoprenaline-induced autophagosome accumulation and impairment of autophagic flux probably by enhancing SIRT1 expression and consequently TFEB nuclear translocation. Flt3 activation improved the imbalance of mitochondrial dynamics induced by isoprenaline in NRCMs through the SIRT1/P53 pathway. Activation of Flt3 mitigated ISO-stimulated hypertrophy probably involves the restoration of autophagic flux and balance of mitochondrial dynamics. Therefore, activation of Flt3 attenuates isoprenaline-induced cardiac hypertrophy in vivo and in vitro, the potential mechanism probably attributes to SIRT1/TFEB-mediated autophagy promotion and SIRT1/P53-mediated mitochondrial dynamics balance. These findings suggest that activation of Flt3 may be a novel target for protection against cardiac remodeling and heart failure during sympathetic hyperactivity.

Impaired autophagy and mitochondrial dynamics are involved in Sorafenib-induced cardiomyocyte apoptosis.

Sorafenib (Sor), a novel multi-target anticancer drug also induces severe toxicity in heart, while the mechanism of its cardiotoxicity remains to be fully elucidated. Dysregulation of autophagy and mitochondrial dynamics imbalance have been implicated in cardiomyocyte death. The aim of this study is to test the hypothesis that Sor disrupts autophagy and mitochondrial dynamics, thereby aggravating Sor-induced oxidative stress damage to cardiomyocytes. Our results revealed that Sor (≥ 5 µM) concentration- and time-dependently reduced cell viability and induced apoptosis in H9c2 myoblasts. Sor treatment promoted intracellular reactive oxygen species (ROS) generation, and subsequent Ca2+ overload as well as apoptosis, which were abolished by the ROS scavenger MPG. Sor inhibited the basal autophagy activity of cells, as supported by the fact that ERK1/2 inhibition-dependent decreases of autophagosomes and autolysosomes, and p62 accumulation in a concentration- and time-dependent manner. Improving autophagy with rapamycin abrogated Sor-induced ROS and Ca2+ overloads, and cell apoptosis. Furthermore, Sor compromised mitochondrial morphology and caused excessive mitochondrial fragmentation in cells. The imbalance of mitochondrial dynamics was attributed to ROS-mediated CaMKII overactivity, and increased phosphorylation of dynamin-related protein 1 (phosph-Drp1). Suppression of CaMKII with KN-93 or mitochondrial fission with mitochondrial division inhibitor-1 (Mdivi-1) attenuated Sor-induced ROS and Ca2+ overloads as well as apoptosis. In conclusion, these results provide the first evidence that impairments in autophagy and mitochondrial dynamics are involved in Sor-induced cardiomyocyte apoptosis. The present study may provide a potential strategy for preventing or reducing cardiotoxicity of Sor.

Nanoscale Control of Polar Surface Phases in Layered van der Waals CuInP2S6.

Antiferroelectric (AFE) materials, in which alternating dipole moments cancel out to a zero net macroscopic polarization, can be used for high-density energy storage and memory applications. The AFE phase can exist in bulk CuInP2Se6, CuBiP2S6, and a few other transition-metal thiophosphates below 200 K. The required low temperature poses challenges for practical applications. In this work, we report the coexistence of ferrielectric (FE) states and a stable surface phase that does not show piezoelectric response ("zero-response phase") in bulk CuInP2S6 at room temperature. Using piezoresponse force microscopy (PFM) tomographic imaging together with density functional theory, we find that direct and alternating voltages can locally and stably convert FE to zero-response phases and vice versa. While PFM loops show pinched hystereses reminiscent of antiferroelectricity, PFM tomography reveals that the zero-response areas form only on top of the FE phase in which the polarization vector is pointing up. Theoretical calculations suggest that the zero-response phase may correspond to AFE ordering where stacked CuInP2S6 layers have alternating polarization orientations thereby leading to a net-zero polarization. Consistent with experimental findings, theory predicts that the FE polarization pointing down is robust up to the top surface, whereas FE polarization pointing up energetically favors the formation of an AFE surface layer, whose thickness is likely to be sensitive to local strains. AFE order is likely to be more robust against detrimental size effects than polar order, therefore providing additional opportunities to create multifunctional heterostructures with 2D electronic materials.

Downregulation of miR-128 Ameliorates Ang II-Induced Cardiac Remodeling via SIRT1/PIK3R1 Multiple Targets.

Recent studies reported that miR-128 was differentially expressed in cardiomyocytes in response to pathologic stress. However, its function and mechanism remain to be fully elucidated. The aim of the present study was to investigate the role of miR-128 in chronic angiotensin II (Ang II) infusion-induced cardiac remodeling and its underlying mechanism. The cardiac remodeling and heart failure in vivo were established in C57BL/6 mice by chronic subcutaneous Ang II delivery. Knocking down miR-128 was conducted in the hearts of the mice by intravenous injection of HBAAV2/9-miR-128-GFP sponge (miR-128 inhibitor). In vitro experiments of cardiac hypertrophy, apoptosis, and aberrant autophagy were performed in cultured cells after Ang II treatment or transfection of miR-128 antagomir. Our results showed that chronic Ang II delivery for 28 days induced cardiac dysfunction, hypertrophy, fibrosis, apoptosis, and oxidative stress in the mice, while the miR-128 expression was notably enhanced in the left ventricle. Silencing miR-128 in the hearts of mice ameliorated Ang II-induced cardiac dysfunction, hypertrophy, fibrosis apoptosis, and oxidative stress injury. Moreover, Ang II induced excessive autophagy in the mouse hearts, which was suppressed by miR-128 knockdown. In cultured cells, Ang II treatment induced a marked elevation in the miR-128 expression. Downregulation of miR-128 in the cells by transfection with miR-128 antagomir attenuated Ang II-induced apoptosis and oxidative injury probably via directly targeting on the SIRT1/p53 pathway. Intriguingly, we found that miR-128 inhibition activated PIK3R1/Akt/mTOR pathway and thereby significantly damped Ang II-stimulated pathological autophagy in cardiomyocytes, which consequently mitigated cell oxidative stress and apoptosis. In conclusion, downregulation of miR-128 ameliorates Ang II-provoked cardiac oxidative stress, hypertrophy, fibrosis, apoptosis, and dysfunction in mice, likely through targeting on PIK3R1/Akt/mTORC1 and/or SIRT1/p53 pathways. These results indicate that miR-128 inhibition might be a potent therapeutic strategy for maladaptive cardiac remodeling and heart failure.

Inhibition of the Ras/ERK1/2 pathway contributes to the protective effect of ginsenoside Re against intimal hyperplasia.

Neointimal hyperplasia is the major cause of carotid stenosis after vascular injury, which restricts the long-term efficacy of endovascular treatment and endarterectomy in preventing stenosis. Ginsenoside Re (Re) is a major active ingredient of ginseng having multifaceted pharmacological effects on the cardiovascular system, and is a potential treatment for restenosis. In this study, we demonstrated that Re treatment significantly inhibited vascular injury-induced neointimal thickening, reduced the intimal area and intima/media (I/M) ratio, increased the lumen area, and inhibited pro-inflammatory cytokines. In cultured A7R5 cells, Re inhibited LPS-induced proliferation and migration as evidenced by suppressed colony formation and shortened migration distance, accompanied by the downregulated expression of pro-inflammatory cytokines. Re promoted VSMC apoptosis induced by balloon injury in vivo and LPS challenge in vitro. Moreover, Re inhibited autophagy in VSMCs evoked by balloon injury and LPS as supported by reduced LC3II and increased p62 expressions. Suppression of autophagy with the specific autophagy inhibitor spautin-1 efficiently inhibited LPS-induced cell proliferation and inflammation and promoted caspase-3/7 activities. Mechanistically, we found that Re attenuated Ras/ERK1/2 expression in VSMCs in vivo and in vitro. The MEK1/2 inhibitor PD98059 showed similar effects to Re on cell proliferation, migration, apoptosis, and the levels of autophagy and cytokines. In conclusion, we provided significant evidence that Re inhibited vascular injury-induced neointimal thickening probably by promoting VSMC apoptosis and inhibiting autophagy via suppression of the Ras/MEK/ERK1/2 signaling pathway.

Cardiac adaptation and cardioprotection against arrhythmias and ischemia-reperfusion injury in mammalian hibernators.

Hibernation allows animals to enter an energy conserving state to survive severe drops in external temperatures and a shortage of food. It has been observed that the hearts of mammalian hibernators exhibit intrinsic protection against ischemia-reperfusion (I/R) injury and cardiac arrhythmias in the winter whether they are hibernating or not. However, the molecular and ionic mechanisms for cardioprotection in mammalian hibernators remain elusive. Recent studies in woodchucks (Marmota monax) have suggested that cardiac adaptation occurs at different levels and mediates an intrinsic cardioprotection prior to/in the winter. The molecular/cellular remodeling in the winter (with or without hibernation) includes (1) an upregulation of transcriptional factor, anti-apoptotic factor, nitric oxide synthase, protein kinase C-ε, and phosphatidylinositol-4,5-bisphosphate 3-kinase; (2) an upregulation of antioxidant enzymes (e.g. superoxide dismutase and catalase); (3) a reduction in the oxidation level of Ca2+/calmodulin-dependent protein kinase II (CaMKII); and (4) alterations in the expression and activity of multiple ion channels/transporters. Therefore, the cardioprotection against I/R injury in the winter is most likely mediated by enhancement in signaling pathways that are shared by preconditioning, reduced cell apoptosis, and increased detoxification of reactive oxygen species (ROS). The resistance to cardiac arrhythmias and sudden cardiac death in the winter is closely associated with an upregulation of the antioxidant catalase and a downregulation of CaMKII activation. This remodeling of the heart is associated with a reduction in the incidence of afterdepolarizations and triggered activities. In this short review article, we will discuss the seasonal changes in gene and protein expression profiles as well as alterations in the function of key proteins that are associated with the occurrence of cardioprotection against myocardial damage from ischemic events and fatal arrhythmias in a mammalian hibernator. Understanding the intrinsic cardiac adaptive mechanisms that confer cardioprotection in hibernators may offer new strategies to protect non-hibernating animals, especially humans, from I/R injury and ischemia-induced fatal cardiac arrhythmias.

Low-dose alcohol ameliorated high fat diet-induced anxiety-related behavior via enhancing adiponectin expression and activating the Nrf2 pathway.

Long-term high-fat-diet (HFD)-induced obesity is associated with many comorbidities, such as cognitive impairment and anxiety, which are increasing public health burdens that have gained prevalence in adolescents. Although low-dose alcohol could attenuate the risk of cardiovascular disease, its mechanism on HFD-induced anxiety-related behavior remains not clear. The mice were divided into 4 groups, Control (Con), Alcohol (Alc), HFD and HFD + Alc groups. To verify the effects of low-dose alcohol on HFD-induced anxiety-related behavior, the mice were fed with HFD for 16 weeks. At the beginning of week 13, the HFD-fed mice were administered intragastrically with low-dose alcohol (0.8 g kg-1) for 4 weeks. After 4 weeks of oral administration, low-dose alcohol decreased body weight and Lee's index in HFD-induced obese mice. Moreover, low-dose alcohol alleviated the anxiety-related behaviors of obese mice in the open field test and the elevated plus maze test. The HFD-induced damage to the hippocampus was improved in hematoxylin-eosin staining assay in mice. In addition, low-dose alcohol also suppressed HFD-induced oxidative stress and increased HFD-suppressed adiponectin (APN) expression and nuclear factor erythroid 2-related factor 2 (Nrf2) activation in the hippocampus. Taken together, low-dose alcohol significantly ameliorates HFD-induced obesity, oxidative stress and anxiety-related behavior in mice, which might be related to APN upregulation, Nrf2 activation and related antioxidase expression including SOD1, HO-1, and catalase.

Antidepressant Activity of Euparin: Involvement of Monoaminergic Neurotransmitters and SAT1/NMDAR2B/BDNF Signal Pathway.

Depression is the most significant risk factor for suicide, yet the causes are complex and disease mechanism remains unclear. The incidence and disability rate of depression are very high and the efficacy of some traditional antidepressants is not completely satisfactory. Recently, some studies have found that benzofurans have anti-oxidation and anti-monoamine oxidase properties, which are related to depression. Euparin is a monomer compound of benzofuran, previous work by our team found that it improves the behavior of depressed mice. However, additional antidepressant effects and mechanisms of Euparin have not been reported. In this study, the Chronic Unpredictable Mild Stress (CUMS) model of mice was used to further investigate the effect and mechanism of Euparin on depression. Results showed that Euparin (8, 16 and 32 mg/kg) reduced depression-like behavior in mice compared with the model group. Meanwhile, all doses of Euparin were found to increase the contents of monoamine neurotransmitter and decrease monoamine oxidase and reactive oxygen species (ROS) levels in brain of depression mice. Additionally, Euparin restored CUMS-induced decrease of Spermidine/Spermine N1-Acetyltransferase 1 (SAT1), N-methyl-D-aspartate receptor subtype 2B (NMDAR2B) and brain derived neurotrophic factor (BDNF) expression. These findings demonstrate that Euparin has antidepressant properties, and its mechanism involves the SAT1/NMDAR2B/BDNF signaling pathway.

Activated FMS-like tyrosine kinase 3 ameliorates angiotensin II-induced cardiac remodelling.

AIM: FMS-like receptor tyrosine kinase 3 (Flt3) has been reported to be increased in cardiomyocytes responding to ischaemic stress. This study was to determine whether Flt3 activation could ameliorate pressure overload-induced heart hypertrophy and fibrosis, and to elucidate the mechanisms of action. METHODS: In vivo cardiac hypertrophy and remodelling experiments were conducted by infusing angiotensin II (Ang II) chronically in male C57BL/6 mice. Flt3-specific ligand (FL) was administered intraperitoneally every two days (5 µg/mouse). In vitro experiments on hypertrophy, apoptosis and autophagy mechanism were performed in neonatal rat cardiomyocytes (NRCMs) and H9c2 cells with adenovirus vector-mediated overexpression of Flt3. RESULTS: Our results demonstrated that following chronic Ang II infusion for 4 weeks, the mice exhibited heart hypertrophy, fibrosis, apoptosis and contractile dysfunction. Meanwhile, Ang II induced autophagic responses in mouse hearts, as evidenced by increased LC3 II and decreased P62 expression. These pathological alterations in Ang II-treated mice were significantly ameliorated by Flt3 activation with FL administration. In NRCMs and Flt3-overexpressed H9c2 cells, FL attenuated Ang II-induced pathological autophagy and inactivated AMPK/mTORC1/FoxO3a signalling, thereby efficiently mitigating cell hypertrophy and apoptosis. Conversely, the AMPK activator metformin or the mTORC1 inhibitor rapamycin reversed the effects of FL on the alterations of autophagy, hypertrophy and apoptosis in cardiomyocytes induced by Ang II. CONCLUSION: Flt3 activation ameliorates cardiac hypertrophy, fibrosis and contractile dysfunction in the mouse model of chronic pressure overload, most likely via suppressing AMPK/mTORC1/FoxO3a-mediated autophagy. These results provide new evidence supporting Flt3 as a novel therapeutic target in maladaptive cardiac remodelling.

In Situ Phosphatizing of Triphenylphosphine Encapsulated within Metal-Organic Frameworks to Design Atomic Co1-P1N3 Interfacial Structure for Promoting Catalytic Performance.

The engineering coordination environment offers great opportunity in performance tunability of isolated metal single-atom catalysts. For the most popular metal-Nx (MNx) structure, the replacement of N atoms by some other atoms with relatively weak electronegativity has been regarded as a promising strategy for optimizing the coordination environment of an active metal center and promoting its catalytic performance, which is still a challenge. Herein, we proposed a new synthetic strategy of an in situ phosphatizing of triphenylphosphine encapsulated within metal-organic frameworks for designing atomic Co1-P1N3 interfacial structure, where a cobalt single atom is costabilized by one P atom and three N atoms (denoted as Co-SA/P-in situ). In the acidic media, the Co-SA/P-in situ catalyst with Co1-P1N3 interfacial structure exhibits excellent activity and durability for the hydrogen evolution reaction (HER) with a low overpotential of 98 mV at 10 mA cm-2 and a small Tafel slope of 47 mV dec-1, which are greatly superior to those of catalyst with Co1-N4 interfacial structure. We discover that the bond-length-extended high-valence Co1-P1N3 atomic interface structure plays a crucial role in boosting the HER performance, which is supported by in situ X-ray absorption fine structure (XAFS) measurements and density functional theory (DFT) calculation. We hope this work will promote the development of high performance metal single-atom catalysts.

Cardiotoxicity of sorafenib is mediated through elevation of ROS level and CaMKII activity and dysregulation of calcium homoeostasis.

Sorafenib, a multi-kinase inhibitor, is recommended as a new standard therapy for advanced hepatocellular carcinoma (HCC); however, it also exhibits severe cardiotoxicity and the toxicity mechanisms are not completely elucidated. Recent studies suggested that sorafenib-enhanced ROS may partially contribute to its anti-HCC effect, which implies that redox mechanism might also be involved in sorafenib's cardiotoxicity. In this study, we aimed to investigate if sorafenib is able to induce oxidative stress and how this may impair cellular functions in cardiomyocyte, ultimately accounting for its cardiotoxicity. Our results showed that in isolated rat hearts, sorafenib caused ventricular arrhythmias and left ventricular dysfunction, which were alleviated by the antioxidant N-(2-mercaptopropionyl)-glycine (MPG). In isolated ventricular myocytes, sorafenib increased diastolic intracellular Ca2+ levels, decreased Ca transients and the occurrence of Ca2+ waves. These changes were eliminated by MPG, CaMKII inhibitor KN-93 and the mitochondrial permeability transition pore (mPTP)inhibitor cyclosporin A (CsA). Moreover, the levels of oxidized and phosphorylated CaMKII were significantly increased. Sorafenib elevated ROS levels, which was reversed by CsA and MPG; additionally, sorafenib reduced the activity of mitochondrial complex III and augmented mitochondrial ROS production. In vivo rats treated with sorafenib exhibited a reduction of antioxidant defence and abnormal histological alterations including hypertrophy, increased fibrosis, disordered myofibrils and damaged mitochondria, which were protected by MPG. We conclude that sorafenib induces the disruption of Ca2+ homoeostasis and cardiac injury via enhanced ROS potentially through inhibiting mitochondrial complex III, the opening of mPTP and overactivating CaMKII. These results provide a potential strategy for preventing or reducing cardiotoxicity of sorafenib.

Low-dose alcohol ameliorated homocysteine-induced anxiety-related behavior via attenuating oxidative stress in mice.

Recent studies showed that homocysteine (Hcy) levels were obviously elevated in patients with anxiety, furthermore, oxidative stress and inflammation were closely linked with Hcy-related damage. Despite alcohol exposure has differential effects on different forms of anxiety, the role of alcohol on anxiety-related behavior induced by high Hcy levels is still not entirely clear. The present study investigated the protective potential of low-dose alcohol against homocysteine-induced anxiety-related behavior and explored the possible underlying mechanisms. Mice were administered intragastrically with methionine (2.0 g/kg/day) or alcohol (0.6 g/kg/day). After 21 days of administration, the anxiety-related behavior was evaluated through open field (OF) and elevated plus maze (EPM) tests, and the variations of oxidative stress and inflammation levels were measured. The results of OF and EPM tests showed that the anxiety-related behavior in mice was prevented by alcohol treatment. Alcohol lowered the elevated serum Hcy levels and alleviated the damage of hippocampal tissues in hyperhomocysteinemia (HHcy) mice. Meanwhile, the superoxide dismutase (SOD) activity of the hippocampal tissues enhanced, and the malondialdehyde (MDA) concentration of the hippocampal tissues and the serum interleukin-1ß (IL-1ß) level decreased. In addition, after administering alcohol, the increase of superoxide dismutase 1 (SOD1), heme oxygenase 1 (HO-1) protein expression and the decrease of IL-1ß protein expression were also detected in HHcy mice hippocampal tissues. Taken together, low-dose alcohol significantly ameliorated the Hcy-induced anxiety-related behavior in mice, which might be related to SOD1 and HO-1 upregulation and IL-1ß downregulation.

Guiding Principles for Designing Highly Efficient Metal-Free Carbon Catalysts.

Carbon nanomaterials are promising metal-free catalysts for energy conversion and storage, but the catalysts are usually developed via traditional trial-and-error methods. To rationally design and accelerate the search for the highly efficient catalysts, it is necessary to establish design principles for the carbon-based catalysts. Here, theoretical analysis and material design of metal-free carbon nanomaterials as efficient photo-/electrocatalysts to facilitate the critical chemical reactions in clean and sustainable energy technologies are reviewed. These reactions include the oxygen reduction reaction in fuel cells, the oxygen evolution reaction in metal-air batteries, the iodine reduction reaction in dye-sensitized solar cells, the hydrogen evolution reaction in water splitting, and the carbon dioxide reduction in artificial photosynthesis. Basic catalytic principles, computationally guided design approaches and intrinsic descriptors, catalytic material design strategies, and future directions are discussed for the rational design and synthesis of highly efficient carbon-based catalysts for clean energy technologies.

Prediction of Stable and Active (Oxy-Hydro) Oxide Nanoislands on Noble-Metal Supports for Electrochemical Oxygen Reduction Reaction.

Developing cost-effective oxygen electrocatalysts with high activity and stability is key to their commercialization. However, economical earth-abundant catalysts based on first-row transition-metal oxides suffer from low electrochemical stability, which is difficult to improve without compromising their activity. Here, using density functional theory calculations, we demonstrate that noble-metal supports lead to bifunctional enhancement of both the stability and the oxygen reduction reaction (ORR) activity of metal (oxy-hydro) oxide nanoislands. We observe a significant stabilization of supported nanoislands beyond the intrinsic stability limits of bulk phases, which originates from a favorable lattice mismatch and reductive charge transfer from oxophilic supports. We discover that interfacial active sites (located between the nanoisland and the support) reinforce the binding strength of reaction intermediates, hence boosting ORR activity. Considering that both stability and activity lead to discovery of CoOOH|Pt, NiOOH|Ag, and FeO2|Ag as viable systems for alkaline ORR, we then use a multivariant linear regression method to identify elementary descriptors for efficient screening of promising cost-effective nanoisland|support catalysts.

Antioxidant defense and protection against cardiac arrhythmias: lessons from a mammalian hibernator (the woodchuck).

Hibernating animals show resistance to hypothermia-induced cardiac arrhythmias. However, it is not clear whether and how mammalian hibernators are resistant to ischemia-induced arrhythmias. The goal of this investigation was to determine the susceptibility of woodchucks ( Marmota monax) to arrhythmias and their mechanisms after coronary artery occlusion at the same room temperature in both winter, the time for hibernation, and summer, when they do not hibernate. By monitoring telemetric electrocardiograms, we found significantly higher arrhythmia scores, calculated as the severity of arrhythmias, with incidence of ventricular tachycardia, ventricular fibrillation, and thus sudden cardiac death (SCD) in woodchucks in summer than they had in winter. The level of catalase expression in woodchuck hearts was significantly higher, whereas the level of oxidized Ca2+/calmodulin-dependent protein kinase II (CaMKII) was lower in winter than it was in summer. Ventricular myocytes isolated from woodchucks in winter were more resistant to H2O2-induced early afterdepolarizations (EADs) compared with myocytes isolated from woodchucks in summer. The EADs were eliminated by inhibiting CaMKII (with KN-93), l-type Ca current (with nifedipine), or late Na+ current (with ranolazine). In woodchucks, in the summer, the arrhythmia score was significantly reduced by overexpression of catalase ( via adenoviral vectors) or the inhibition of CaMKII (with KN-93) in the heart. This study suggests that the heart of the mammalian hibernator is more resistant to ischemia-induced arrhythmias and SCD in winter. Increased antioxidative capacity and reduced CaMKII activity may confer resistance in woodchuck hearts against EADs and arrhythmias during winter. The profound protection conferred by catalase overexpression or CaMKII inhibition in this novel natural animal model may provide insights into clinical directions for therapy of arrhythmias.-Zhao, Z., Kudej, R. K., Wen, H., Fefelova, N., Yan, L., Vatner, D. E., Vatner, S. F., Xie, L.-H. Antioxidant defense and protection against cardiac arrhythmias: lessons from a mammalian hibernator (the woodchuck).

Rational design of efficient transition metal core-shell electrocatalysts for oxygen reduction and evolution reactions.

Ag can form core-shell structures with other non-precious transition metals, which is a promising candidate as an efficient and cost-effective electrocatalyst to replace Pt and RuO2 for oxygen reduction and evolution reactions (ORR and OER) in fuel cells and metal-air batteries. In this paper, polyicosahedral (plh) Ag32X6 (X = 3d transition metals) core-shell structures are calculated systematically by the density functional theory (DFT) method to predict their electrocatalytic activities for ORR and OER. It is found that the strain on the outer shell of the core-shell structures can be an intrinsic descriptor that describes the bifunctional catalytic activities of the catalysts. A higher compressive strain leads to more positive charge on the surface of the shell and consequently higher catalytic activities. The results provide a theoretical base for the rational design and screening of the Ag-based core-shell catalysts for clean energy conversion and storage.

Potential Arrhythmogenic Role of TRPC Channels and Store-Operated Calcium Entry Mechanism in Mouse Ventricular Myocytes.

Background and Purpose: Store-operated calcium entry (SOCE) is an important physiological phenomenon that extensively mediates intracellular calcium ion (Ca2+) load. It has been previously found in myocytes isolated from neonatal or diseased hearts. We aimed to determine its existence, molecular nature in undiseased hearts and its potential arrhythmogenic implications under hyperactive conditions. Experimental Approach: Ventricular myocytes isolated from adult FVB mice were studied by using Ca2+ imaging and whole-cell perforated patch-clamp recording. In addition, lead II ECGs were recorded in isolated Langendorff-perfused mice hearts. Functional TRPC channel antibodies and inhibitors, and TRPC6 activator hyperforin were used. Key Results: In this study, we demonstrate the existence and contribution of SOCE in normal adult mouse cardiac myocytes. For an apparent SOCE activation, complete depletion of sarcoplasmic reticulum (SR) Ca2+ by employing both caffeine (10 mM) and thapsigargin (1 µM) or cyclopiazonic acid (10 µM) was required. Consistent with the notion that SOCE may be mediated by heteromultimeric TRPC channels, SOCEs observed from those myocytes were significantly reduced by the pretreatment with anti-TRPC1, 3, and 6 antibodies as well as by gadolinium, a non-selective TRPC channel blocker. In addition, we showed that SOCE may regulate spontaneous SR Ca2+ release, Ca2+ waves, and triggered activities which may manifest cardiac arrhythmias. Since the spontaneous depolarization in membrane potential preceded the elevation of intracellular Ca2+, an inward membrane current presumably via TRPC channels was considered as the predominant cause of cellular arrhythmias. The selective TRPC6 activator hyperforin (0.1-10 µM) significantly facilitated the SOCE, SOCE-mediated inward current, and calcium load in the ventricular myocytes. ECG recording further demonstrated the proarrhythmic effects of hyperforin in ex vivo mouse hearts. Conclusion and Implications: We suggest that SOCE, which is at least partially mediated by TRPC channels, exists in adult mouse ventricular myocytes. TRPC channels and SOCE mechanism may be involved in cardiac arrhythmogenesis via promotion of spontaneous Ca2+ waves and triggered activities under hyperactivated conditions.