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Vascular endothelial cell senescence is a leading cause of age-associated diseases and cardiovascular diseases. Interventions and therapies targeting endothelial cell senescence and dysfunction would have important clinical implications. This study evaluated the effect of 10 resveratrol analogues, including pterostilbene (Pts) and its derivatives, against endothelial senescence and dysfunction. All the tested compounds at the concentrations from 10−9 M to 10−6 M did not show cytotoxicity in endothelial cells by MTT assay. Among the 10 resveratrol analogues, Pts and Pts nicotinate attenuated the expression of senescence-associated β-galactosidase, downregulated p21 and p53, and increased the production of nitric oxide (NO) in both angiotensin II – and hydrogen peroxide – induced endothelial senescence models. In addition, Pts and Pts nicotinate elicited endothelium-dependent relaxations, which were attenuated in the presence of endothelial NO synthase (eNOS) inhibitor L-NAME or sirtuin 1 (SIRT1) inhibitor sirtinol. Pts and Pts nicotinate did not alter SIRT1 expression but enhanced its activity. Both Pts and Pts nicotinate have high binding activities with SIRT1, according to surface plasmon resonance results and the molecular docking analysis. Inhibition of SIRT1 by sirtinol reversed the anti-senescent effects of Pts and Pts nicotinate. Moreover, Pts and Pts nicotinate shared similar ADME (absorption, distribution, metabolism, excretion) profiles and physiochemical properties. This study suggests that the Pts and Pts nicotinate ameliorate vascular endothelial senescence and elicit endothelium-dependent relaxations via activation of SIRT1. These two compounds may be potential drugs for the treatment of cardiovascular diseases related to endothelial senescence and dysfunction.

Heme oxygenase-1 (HO-1) has attracted accumulating attention for its antioxidant enzymatic activity. However, the exact regulatory role of its non-enzymatic activity in the cardiovascular system remains unaddressed. Here, we show that HO-1 was accumulated in the nuclei of stress-induced senescent endothelial cells, and conferred protection against endothelial senescence independent of its enzymatic activity. Overexpression of ΔHO-1, a truncated HO-1 without transmembrane segment (TMS), inhibited H2O2-induced endothelial senescence. Overexpression of ΔHO-1H25A, the catalytically inactive form of ΔHO-1, also exhibited anti-senescent effect. In addition, infection of recombinant adenovirus encoding ΔHO-1 with three nuclear localization sequences (NLS), alleviated endothelial senescence induced by knockdown of endogenous HO-1 by CRISPR/Cas9. Moreover, repression of HO-1 nuclear translocation by silencing of signal peptide peptidase (SPP), which is responsible for enzymatic cleavage of the TMS of HO-1, exacerbated endothelial senescence. Mechanistically, nuclear HO-1 interacted with NPM1 N-terminal portion, prevented NPM1 translocation from nucleolus to nucleoplasm, thus disrupted NPM1/p53/MDM2 interactions and inhibited p53 activation by NPM1, finally resisted endothelial senescence. This study provides a novel understanding of HO-1 as a promising therapeutic strategy for vascular senescence-related cardiovascular diseases.

Histone modification plays an important role in pathological cardiac hypertrophy and heart failure. However, the mechanisms underlying pathological cardiac hypertrophy still remain to be elucidated, especially involving histone arginine demethylation. Here, we investigated the roles of histone arginine demethylase jumonji domain-containing protein 6 (JMJD6) in isoproterenol (ISO)-induced pathological cardiac hypertrophy. JMJD6 level was upregulated in hypertrophic and ejection fraction preserved heart failure (EFpHF) rat cardiac tissues, while it was decreased in ejection fraction reduced heart failure (EFrHF) patients. JMJD6 overexpression attenuated ISO-induced cardiac hypertrophy as reflecting by the reduction of cardiomyocyte surface area and hypertrophic genes expression in cardiomyocytes. Meanwhile, cardiac-specific JMJD6 overexpression protected the hearts against ISO-induced cardiac hypertrophy, fibrosis, and rescued cardiac function. Conversely, depletion of JMJD6 by single-guide RNA (sgRNA) promoted ISO-induced hypertrophic responses in cardiomyocytes. We further demonstrated that JMJD6 interacts with nuclear factor kappa B (NF-κB) p65 in cytoplasm and reduces the nucleus level of p65 under hypertrophic stimulation in vivo and in vitro. Mechanistically, JMJD6 binds to p65 and demethylate p65 at arginine (R) 149 to inhibit the nuclear translocation of p65, and then inactivated NF-κB signaling, thereby protecting against pathological cardiac hypertrophy. We also found that JMJD6 demethylates histone H3R8, which may a new histone substrate of JMJD6. These findings indicate that JMJD6 may be a potential target for therapeutic interventions in cardiac hypertrophy and heart failure.

Silicone (Si) is one type of anode materials with intriguingly high theoretical capacity. However, the severe volume change associated with the repeated lithiation and delithiation processes hampers the mechanical/electrical integrity of Si anodes and hence reduces the battery's cycle‐life. To address this issue, sequence‐defined peptoids are designed and fabricated with two tailored functional groups, “—OH” and “—COOH”, as cross‐linkable polymeric binders for Si anodes of LIBs. Experimental results show that both the capacity and stability of such peptoids‐bound Si anodes can be significantly improved due to the decreased cracks of Si nanoparticles. Particularly, the 15‐mer peptoid binder in Si anode can result in a much higher reversible capacity (ca. 3110 mAh g−1) after 500 cycles at 1.0 A g−1 compared to other reported binders in literature. According to the density functional theory (DFT) calculations, it is the functional groups presented on the side chains of peptoids that facilitate the formation of Si−O binding efficiency and robustness, and then maintain the integrity of the Si anode. The sequence‐designed polymers can act as a new platform for understanding the interactions between binders and Si anode materials, and promote the realization of high‐performance batteries., The peptoids are programmed with the —COOH and —OH groups in precisely controlled numbers and distances acting as binders for Si anodes. These peptoids can not only facilitate the formation of Si—O binding efficiency and robustness, but also maintain the integrity of the Si anode, resulting in the increased active interaction between polymers and Si.

Utilization of lithium (Li) metal anode in solid‐state batteries (SSBs) with sulfide solid‐state electrolyte (SSE) is hindered by the instable Li/SSE interface. A general solution to solve this problem is to place an expensive indium (In) foil between the SSE and Li, while it decreases the output voltage and thus the energy density of the battery. In this work, an alternative strategy is demonstrated to boost the cycling performances of SSB by wrapping a graphene oxide (GO) layer on the anode. According to density functional theory results, initial deposition of a thin Li layer on the defective GO sheets leads to the formation of a dipole structure, due to the electron‐withdrawing ability of GO acting on Li. By incorporating GO sheets in a nanocomposite of copper‐cuprous oxide‐GO (Cu‐Cu2O‐GO, CCG), a composite Li anode enables a high coulombic efficiency above 99.5% over 120 cycles for an SSB using Li10GeP2S12 SSE and LiCoO2 cathode, and the sulfide SSE is not chemically decomposed after cycling. The highest occupied molecule orbital/lowest unoccupied molecular orbital energy gap of this Li/GO dipole structure likely stretches over those of Li and sulfide SSE, enabling stabilized Li/SSE interface that can replace the expensive In layer as Li protective structure in SSBs., A dipole‐structured Li‐GO interface can be achieved during initial Li plating on graphene oxide sheet to provide a favorable energy band change with lowered reactivity of Li metal. Uniform Li deposition with stabilized Li/electrolyte can be achieved for significantly improved cycling stability of all solid‐state batteries using sulfide electrolyte.

Background Vascular endothelial activation is pivotal for the pathological development of various infectious and inflammatory diseases. Therapeutic interventions to prevent endothelial activation are of great clinical significance to achieve anti-inflammatory strategy. Previous studies indicate that the total flavonoids from the endemic herbal medicine Nervilia fordii (Hance) Schltr exerts potent anti-inflammatory effect and protective effect against endotoxin lipopolysaccharide (LPS)-induced acute lung injury, and shows clinical benefit in severe acute respiratory syndromes (SARS). However, the exact effective component of Nervilia fordii and its potential mechanism remain unknown. Purpose The aim of this study was to investigate the effect and mechanism of rhamnocitrin (RH), a flavonoid extracted from Nervilia fordii, on LPS-induced endothelial activation. Methods The in vitro endothelial cell activation model was induced by LPS in human umbilical vein endothelial cells (HUVECs). Cell viability was measured to determine the cytotoxicity of RH. RT-PCR, Western blot, fluorescent probe and immunofluorescence were conducted to evaluate the effect and mechanism of RH against endothelial activation. Results RH was extracted and isolated from Nervilia fordii. RH at the concentration from 10−7 M-10−5 M inhibited the expressions of interlukin-6 (IL-6) and -8 (IL-8), monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell-adhesion molecule-1 (VCAM-1), and plasminogen activator inhibitor-1 (PAI-1) in response to LPS challenge. Mechanistically, RH repressed calcium store-operated Ca2+ entry (SOCE) induced by LPS, which is due to downregulation of stromal interaction molecule-1 (STIM-1) following upregulating microRNA-185 (miR-185). Ultimately, RH abrogated LPS-induced activation of SOCE-mediated calcineurin/NFATc3 (nuclear factor of activated T cells, cytoplasmic 3) signaling pathway. Conclusion The present study identifies RH as a potent inhibitor of endothelial activation. Since vascular endothelial activation is a pivotal cause of excessive cytokine production, leading to cytokine storm and severe pathology in infectious diseases such as SARS and the ongoing COVID-19 pneumonia disease, RH might suggest promising therapeutic potential in the management of cytokine storm in these diseases.

Aim By activating prostacyclin receptors (IP receptors), prostacyclin (PGI2 ) exerts cardiovascular protective effects such as vasodilation and inhibition of vascular smooth muscle cell (VSMC) proliferation. However, IP receptors are dysfunctional under pathological conditions, and PGI2 produces detrimental effects that are opposite to its physiological protective effects via thromboxane-prostanoid (TP) receptors. This attempted to investigate whether or not IP receptor dysfunction facilitates the shift of PGI2 action. Methods The effects of PGI2 and its stable analog iloprost on VSMC phenotypic transformation and proliferation were examined in A10 cells silencing IP receptors, in human aortic VSMCs (HAVSMCs) knocked down IP receptor by CRISPR-Cas9, or in HAVSMCs transfected with a dysfunctional mutation of IP receptor IPR212C . Results PGI2 /iloprost treatment stimulated cell proliferation, upregulated synthetic proteins and downregulated contractile proteins, suggesting that PGI2 /iloprost promotes VSMC phenotypic transformation in IP-deficient cells. The effect of PGI2 /iloprost was prevented by TP antagonist S18886 or TP knockdown, indicating that the VSMC detrimental effect of PGI2 is dependent on TP receptor. RNA sequencing and Western blotting results showed that RhoA/ROCKs, MEK1/2 and JNK signalling cascades were involved. Moreover, IP deficiency increased the distribution of TP receptors at the cell membrane. Conclusion PGI2 induces VSMC phenotypic transformation when IP receptors are impaired. This is attributed to the activation of TP receptor and its downstream signaling cascades, and to the increased membrane distribution of TP receptors. The VSMC detrimental effect of PGI2 medicated by IP dysfunction and TP activation might probably exacerbate vascular remodelling, accelerating cardiovascular diseases.

The superstructure of χ3 borophene on Ag (111) has recently been synthesized in experiment. In this work, we investigate its structural, electronic properties and the oxidation mechanism through first-principles calculations. We find the superstructure of χ3 borophene on Ag (111) maintain the planar characteristics, like its free-standing form, owing to the weakly interaction between adsorbate and substrate. Moreover, oxygen molecule can be spontaneously adsorbed on its superstructure in a manner of chemical adsorption. Importantly, the energy barrier of ∼0.35 eV for oxygen dissociation indicates its relative stability in ambient conditions compared with the active silicene. Furthermore, the mobility of O2-dissociation-induced O atom is poor at room temperature, implying the difficult migration of O atom on borophene surface. On the other hand, due to the strong B O bonding, desorption of O2-dissociation-induced O atoms on superstructure of χ3 borophene becomes impossible, ultimately leading to form the boron oxides.

The oxygen adsorption and dissociation on two types of free-standing borophene (β12 and χ3 phases) are studied through first-principles calculations. We find that oxygen molecule can be spontaneously and chemically adsorbed on free-standing borophene to lower the energy of the system. However, in contrast with the exceedingly unstable silicene in ambient conditions, β12 and χ3 borophene are relatively inactive due to an energy barrier for O2 dissociation of about 0.36 eV in β12 phase and 0.39 eV in χ3 phase, partly implying its chemical stability in oxygen. Moreover, the migration and desorption of O2-dissociation-induced O atoms at room temperature are very difficult due to the strong B O bonding in the O-adsorbed borophene, which is in favor of forming boron oxides ultimately. Our results reveal the interaction between borophene and O2 and suggest the enhanced stability of β12 and χ3 borophene in oxygen compared with silicene.

Understanding the mechanism of the interfacial reaction between the cathode material and the electrolyte is a significant work because the interfacial reaction is an important factor affecting the stability, capacity, and cycling performance of Li-ion batteries. In this work, spin-polarized density functional theory calculations with on-site Coulomb energy have been employed to study the adsorption of electrolyte components propylene carbonate (PC) on the LiMn2O4 (100) surface. The findings show that the PC molecule prefers to interact with the Mn atom on the LiMn2O4 (100) surface via the carbonyl oxygen (Oc), with the adsorption energy of −1.16 eV, which is an exothermic reaction. As the adsorption of organic molecule PC increases the Mn atoms coordination with O atoms on the (100) surface, the Mn3 + ions on the surface lose charge and the reactivity is substantially decreased, which improves the stability of the surface and benefits the cycling performance.

The Tin+1Cn multi-layers are promising anode material for Li-ion batteries due to their good electronic conductivity, fast Li diffusion, low operating voltage, and high theoretical storage capacity. Here, we use density functional theory calculations to investigate the structural and electronic properties of two-dimensional Tin+1Cn multi-layers in order to figure out the effect of thickness on the Li-ion adsorption behaviors. Results show that as n grows the Li adsorption energy slightly changes, indicating that the thickness of the Tin+1Cn does not have strong influence on the Li-adsorption strength. The number of Li-atoms that can be adsorbed on the Tin+1Cn is strongly dependent on the number of Ti-atoms at the surface, which act as the electron acceptor transferred from the adsorbed Li-atoms. As their surface structures are highly similar, the number of Li-adsorption on the Tin+1Cn is irrelevant to the layer number n, which takes effect only to increase the relative molecular mass of the host material rather than changing the electronic properties and the Li-adsorption behavior.

O-vacancy formation energies in the bulk and at the low index surfaces of typical cathode materials, including layered LiMO2 (M Co, Ni, Mn) and LiNi1/3Co1/3Mn1/3O2 (NCM-333), spinel LiMn2O4, and Li-rich Li2MnO3 for Li-ion batteries, are studied from density functional theory calculations. The thermodynamic stabilities of the oxygen vacancies in these materials are discussed. Except for the spinel type LiMn2O4, all considered materials are more likely to form oxygen vacancies after delithiation, as the vacancy formation energies are lower in their delithiated states. The delithiated Li2MnO3 is very unstable both in its bulk and at its surfaces, as the vacancy formation energies are negatively very large. For layered LiMO2, the (003) surfaces are more stable than the (104) surfaces for all M cases, but Mn is able to stabilize O atoms in the (104) surface of the NCM-333. Temperature can have a significant influence to O-vacancy formation, as formation energies may change from positive to negative when the temperature increases from 300 K to 800 K, for some cases. The oxygen partial pressure does not have obvious influence to the O-vacancy formation, but increasing pressure can also be practical treatment to suppress the formation of O-vacancies under high temperatures.

Background and purpose Activation of PKC-ζ is closely linked to the pathogenesis of cardiac hypertrophy. PKC-ζ can be activated by certain lipid metabolites such as phosphatidylinositol (3,4,5)-trisphosphate and ceramide. However, its endogenous negative regulators are not well defined. Here, the role of the sirtuin1-PKC-ζ signalling axis and the underlying molecular mechanisms were investigated in cardiac hypertrophy. Experimental approach Cellular hypertrophy in cultures of cardiac myocytes, from neonatal Sprague-Dawley rats, was monitored by measuring cell surface area and the mRNA levels of hypertrophic biomarkers. Interaction between sirtuin1 and PKC-ζ was investigated by co-immunoprecipitation and confocal immunofluorescence microscopy. Sirtuin1 activation was enhanced by resveratrol treatment or Ad-sirtuin1 transfection. A model of cardiac hypertrophy in Sprague-Dawley rats was established by abdominal aortic constriction surgery or induced by isoprenaline in vivo. Key results Overexpression of PKC-ζ led to cardiac hypertrophy and increased activity of NF-κB, ERK1/2 and ERK5, which was ameliorated by sirtuin1 overexpression. Enhancement of sirtuin1 activity suppressed acetylation of PKC-ζ, hindered its binding to phosphoinositide-dependent kinase 1 and inhibited PKC-ζ phosphorylation in cardiac hypertrophy. Consequently, the downstream pathways of PKC-ζ' were suppressed in cardiac hypertrophy. This regulation loop suggests a new role for sirtuin1 in mediation of cardiac hypertrophy. Conclusions and implications Sirtuin1 is an endogenous negative regulator for PKC-ζ and mediates its activity via regulating the acetylation and phosphorylation in the pathogenesis of cardiac hypertrophy. Targeting the sirtuin1-PKC-ζ signalling axis may suggest a novel therapeutic approach against cardiac hypertrophy.

Aim: Premature senescence of vascular endothelial cells is a leading cause of various cardiovascular diseases. Therapies targeting endothelial senescence would have important clinical implications. The present study was aimed to evaluate the potential of heme oxygenase-1 (HO-1) as a therapeutic target for endothelial senescence. Methods and Results: Upregulation of HO-1 by Hemin or adenovirus infection reversed H2O2-induced senescence in human umbilical vein endothelial cells (HUVECs); whereas depletion of HO-1 by siRNA or HO-1 inhibitor protoporphyrin IX zinc (II) (ZnPP) triggered HUVEC senescence. Mechanistically, overexpression of HO-1 enhanced the interaction between HO-1 and endothelial nitric oxide synthase (eNOS), and promoted the interaction between eNOS and its upstream kinase Akt, thus resulting in an enhancement of eNOS phosphorylation at Ser1177 and a subsequent increase of nitric oxide (NO) production. Moreover, HO-1 induction prevented the decrease of eNOS dimer/monomer ratio stimulated by H2O2 via its antioxidant properties. Contrarily, HO-1 silencing impaired eNOS phosphorylation and accelerated eNOS uncoupling. In vivo, Hemin treatment alleviated senescence of endothelial cells of the aorta from spontaneously hypertensive rats, through upregulating eNOS phosphorylation at Ser1177. Conclusions: HO-1 ameliorated endothelial senescence through enhancing eNOS activation and defending eNOS uncoupling, suggesting that HO-1 is a potential target for treating endothelial senescence.

Vascular endothelial cell senescence is a leading cause of age-associated and vascular diseases. Mammalian target of rapamycin complex 2 (mTORC2) is a conserved serine/threonine (Ser/Thr) protein kinase that plays an important regulatory role in various cellular processes. However, its impact on endothelial senescence remains controversial. In this study we investigated the role and molecular mechanisms of mTORC2 in endothelial senescence. A replicative senescence model and H(2)O(2)-induced premature senescence model were established in primary cultured human umbilical vein endothelial cells (HUVECs). In these senescence models, the formation and activation of mTORC2 were significantly increased, evidenced by the increases in binding of Rictor (the essential component of mTORC2) to mTOR, phosphorylation of mTOR at Ser2481 and phosphorylation of Akt (the effector of mTORC2) at Ser473. Knockdown of Rictor or treatment with the Akt inhibitor MK-2206 attenuated senescence-associated β-galactosidase (β-gal) staining and expression of p53 and p21 proteins in the senescent endothelial cells, suggesting that mTORC2/Akt facilitates endothelial senescence. The effect of mTORC2/Akt on endothelial senescence was due to suppression of nuclear factor erythroid 2-related factor 2 (Nrf2) at the transcriptional level, since knockdown of Rictor reversed the reduction of Nrf2 mRNA expression in endothelial senescence. Furthermore, mTORC2 suppressed the expression of Nrf2 via the Akt/GSK-3β/C/EBPα signaling pathway. These results suggest that the mTORC2/Akt/GSK-3β/C/EBPα/Nrf2 signaling pathway is involved in both replicative and inducible endothelial senescence. The deleterious role of mTORC2 in endothelial cell senescence suggests therapeutic strategies (targeting mTORC2) for aging-associated diseases and vascular diseases.

Developing carbon based anode materials for alkali and alkaline earth metal ion batteries is important for the development of non-Li metal ion batteries. From density functional theory calculations, we studied alkali metal (Li, Na, K, and Rb) and alkaline earth metal (Be, Mg, Ca, Sr, and Ba) ions adsorption on penta-graphene (PG), which is a novel two dimensional (2D) carbon isomer composed of both sp2 and sp3 hybridized C-atoms. Strong correlations are observed between the adsorption energy and the electronegativity of the M-atoms, namely, smaller electronegativity corresponds to lower adsorption energy. The suitable Ca-ion intercalation potential (~117 mV), metallic electronic structures of Ca-ion adsorbed PG, low Ca-ion diffusion energy barriers (0.36 eV to 0.51 eV), and high specific capacity (1487.6 mAh/g) suggest that PG can be applied as an excellent anode material for Ca-ion batteries.

Very recently, half-hydrogenated germanene has been achieved in an experiment. In this paper, we investigate the effects of tetracyanoquinodimethane (TCNQ) molecular adsorption and strain on the electronic properties of half-hydrogenated germanene through first-principles. As an electron-acceptor molecule, TCNQ is exploited to non-covalently functionalize the half-hydrogenated germanene. However, this physical adsorption induces a ferromagnetic semiconductor–metal transition in half-hydrogenated germanene due to charge transfer from the substrate to the TCNQ molecule. More importantly, the superstructure of half-hydrogenated germanene/TCNQ is extremely sensitive to biaxial tensile strain. Under the biaxial tensile strain of 0.25%, the ferromagnetic semiconductor–metal transition induced by molecular adsorption can surprisingly be overturned. Meanwhile, a strong p-type doping is exhibited. Remarkably, it would return from a ferromagnetic semiconductor to a metal again when the biaxial tensile strain increases to 1.5%. Our analysis based on the structural and electronic properties of half-hydrogenated germanene/TCNQ indicates that such metal–semiconductor–metal transition in half-hydrogenated germanene/TCNQ under biaxial tensile strain may originate from the strong local deformation, resulting in the energy of the valence band maximum decreasing below or increasing above the Fermi level.