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An albumin-binding CsA analogue 4MCsA was achieved by attachment of a thiol-reactive maleimide group at the side-chain of P4 position of CsA derivative. 4MCsA was semi-synthesized from CsA, and the cell-impermeability of albumin-4MCsA was detected by mass spectrometry and a competitive flow cytometry. 4MCsA exhibits inhibition of chemotaxis activity and inflammation by targeting extracellular CypA without immunosuppressive effect and cellular toxicity. These combined results suggested that 4MCsA can be restricted extracellularly through covalently binding to Cys34 of albumin with its maleimide group, and regulate the functions of cyclophilin A extracellularly.

In recent years, the development of biophysical analysis methods has crossed with macromolecular condensates in cells. Researchers are interested in membrane-less organelles assembling into biomolecule ‘aggregates’ with similar liquid-like properties of phase separation. Cell biologists now think that many of the membrane-less organelles observed in cells are formed by phase separation caused by interactions between proteins and nucleic acids. Phase separation, thus, becomes a major player in the control of a variety of biological functions. Nevertheless, the biophysical regulation of these cells is still poorly understood. Here, we reviewed the current literature that collectively reveals the roles of epigenetic modification of N6-methyladenosine (m6A) in phase separation.

Purpose: To systematically analyze the overall m6A modification pattern in hyperplastic scars (HS).Methods: The m6A modification patterns in HS and normal skin (NS) tissues were described by m6A sequencing and RNA sequencing, and subsequently bioinformatics analysis was performed. The m6A-related RNA was immunoprecipitated and verified by real-time quantitative PCR.Results: The appearance of 14,791 new m6A peaks in the HS sample was accompanied by the disappearance of 7,835 peaks. The unique m6A-related genes in HS were thus associated with fibrosis-related pathways. We identified the differentially expressed mRNA transcripts in HS samples with hyper-methylated or hypo-methylated m6A peaks.Conclusion: This study is the first to map the m6A transcriptome of human HS, which may help clarify the possible mechanism of m6A-mediated gene expression regulation.

N6‐methyladenosine (m6A) is one of the most abundant messenger RNA (mRNA) modifications in eukaryotes and is involved in various key processes of RNA metabolism. In this issue of Nature, Ries et al (2019) described the fundamental features of m6A modification of mRNAs in regulating the composition of the phase‐separated transcriptome on the basis of number and distribution, and provide strong evidence that m6A plays a role in regulating phase separation in cells.

Supplemental Digital Content is available in the text, Objective: The current study aimed to understand epidemiological feature and critical factors associated with pathogenesis of circulating recombinant form (CRF) 01_AE strains in Northeast China. Design: Compared analysis was made between CRF01_AE and non-CRF01_AE samples to understand the pathogenicity features of CRF01_AE. Further analyses between CRF01_AE samples with high or low CD4+ cell counts and between samples with different coreceptor usages were done to explore the possible factors correlating to the pathogenesis of CRF01_AE viruses. Methods: The genotypes of newly identified strains were determined by phylogenetic analyses using Mega 6.06. Coreceptor usage was predicted by Geno2Pheno algorithm. Potential N-linked glycosylation site (PNGS) number was calculated using the online N-glycosite software. The properties of amino acid sequences were analyzed by the online ProtParam tool. Results: CRF01_AE become the main HIV-1 genotype since 2010. Compared with non-CRF01_AE group, the CRF01_AE group showed a higher proportion of samples with CD4+ cell count less than 200 cells/μl. Shorter amino acid length, fewer PNGSs and the presence of a basic motif R/KNXT or NR/KT in V4 correlated to a lower CD4+ cell count, and existence or coexistence of Thr12, Arg13, Val21 and Lys33, presence of more than 4 of net charges and lack of the PNGS within V3 favored to the X4/R5X4 coreceptor usage of CRF01_AE viruses. Conclusion: CRF01_AE has dominated HIV-1 genotype in Northeast China. Infection with CRF01_AE exhibited a fast disease progression, which may be associated with specific amino acid residues and PNGSs in V3 and V4 regions as well as amino acid length of V4 region.

The synthesis of antiaromatic NiII -norcorroles having primary, secondary, and tertiary alkyl groups at the reactive meso-positions was attempted. Reductive coupling of a NiII -dipyrrin precursor provided NiII -meso-dihexylnorcorrole, which underwent substantial degradation on silica gel. Introduction of tert-butyl groups was unsuccessful due to the difficult preparation of the corresponding dipyrrin precursor. Meanwhile, NiII -norcorroles with isopropyl and cyclohexyl groups were isolated as stable molecules under ambient conditions. Furthermore, we found that oxidation of NiII -meso-dialkylnorcorroles with hydrogen peroxide in the presence of sodium carbonate gave NiII -5-oxaporphyrins(2.0.1.0). In contrast, oxidation of NiII -meso-dimesitylnorcorrole under the same reaction conditions gave 10-oxaporphyrin(1.1.1.0). The contrasting reactivity can be attributed to the steric congestion around the meso-positions.

This paper proposed a novel method for the production of biodiesel from soy sauce residue under supercritical carbon dioxide for the first time. The effect of several parameters, such as the size of raw material, reaction pressure, temperature, time, and methanol/oil molar ratio were carefully optimized by single-factor experiments. The results showed that the optimized parameters were particle size 60 meshes, reaction pressure 16 MPa, temperature 100 °C, time 180min and methanol/oil molar ratio 35:1. Under this optimal conditions, biodiesel yield is as high as 96.21%. Furthermore, in order to better understand the advantages of this process, the mechanism and result of this process were compared with existing technology. The findings of this paper demonstrated that the soy sauce residue which was commonly considered as a waste can be efficiently converted to biodiesel by this method.

An efficient Cu(I)-catalyzed oxidative cyclization of alkynyl-tethered enynamides for the construction of fused bicyclic cyclopentadiene derivatives is disclosed. The cascade proceeds through alkyne oxidation, carbene/alkyne metathesis, and formal (3 + 2) cycloaddition. Employing aryl-tethered enynamides as starting materials, substituted 2-aminofurans can be exclusively formed.

The synthesis and properties of a 2-to-2′ 18-to-18′ doubly linked Ni(II) norcorrole dimer are described. It adopts a highly planar structure, resulting in effective electronic interactions between the constituent norcorrole units. Nevertheless, each norcorrole unit exhibits substantial antiaromaticity, which stands in sharp contrast to stacked norcorrole dimers.

Norcorrole is a ring-contracted porphyrinoid, exhibiting distinct antiaromaticity. Herein, we report the reactions of meso-dimesitylnorcorrole Ni(II) complex with two types of carbenes: dichlorocar...

A new hexadecahedron assembled by core-shell CoS2 particles@N-doped carbon (CoS2 @NCH) is prepared successfully through the self-templating method. The CoS2 @NCH hybrid electrode delivers a high lithium-storage capacity of 778 mA h g-1 after 1000 cycles at a high current density of 1 A g-1 , which is the longest cycle lifespan among the reported CoS2 anode materials in lithium-ion batteries. Furthermore, the CoS2 @NCH hybrid electrode shows excellent rate capability with a discharge capacity of 220 mA h g-1 at an extremely high current density of 20 A g-1 , and a charge capacity of 649 mA h g-1 is restored upon returning the current density back to 2 A g-1 . The superior performance is attributed to the unique construction of CoS2 @NCH. The N-doped interconnected porous carbon shells form highly conductive skeletons for quick electron transfer and prevent the electrode from collapsing. Moreover, the porous characteristic of the materials plays a key role: as some effective channels, the mesopores on the porous carbon shells provide greater access for lithium, and the mesopores derived from the particle interspace enables the complete immersion of the electrodes in electrolyte, which alleviates the volume expansion and ensures the integrity of the electrode. In addition, the nanosized CoS2 particles, which shorten the ion-transport path and provide extra electroactive sites, also improve the reaction kinetics.

Overproduction of inflammatory mediators contributes to uncontrolled inflammation during endotoxin shock. Cystathionine-γ-lyase (CSE), an enzyme involved in hydrogen sulfide (H2S) biosynthesis, has potential anti-inflammatory activity in a variety of inflammatory diseases. Jumonji domain-containing protein 3 (JMJD3), a histone 3 Lys27 (H3K27) demethylase, has been implicated in macrophage activation, but its function in CSE-mediated anti-inflammatory activities remains unknown. In the present study CSE was found to be upregulated in macrophages and mouse lipopolysaccharide (LPS) challenge models. LPS stimulation also enhanced the activation of JMJD3 and decreased H3K27me3 levels. JMJD3 knockdown upregulated H3K27me3 levels and attenuated the LPS-mediated inflammatory response. CSE knockout amplified the inflammatory cascade by increasing JMJD3 expression in septic mice. Similarly, enhanced production of inflammatory mediators by macrophages was mitigated by CSE overexpression via inhibition of JMJD3 expression. This is the first report indicating that inflammation enhanced CSE/H2S system biosynthesis, that in turn attenuated the LPS-triggered inflammatory response by regulating JMJD3 expression. Thus, the CSE/H2S system represents an epigenetic-based modification mechanism to prevent uncontrolled inflammation.

Background/Aims: Sepsis is a severe and complicated syndrome that is characterized by dysregulation of host inflammatory responses and organ failure. Cystathionine-γ-lyase (CSE)/ hydrogen sulfide (H2S) has potential anti-inflammatory activities in a variety of inflammatory diseases. NADPH oxidase 4 (Nox4), a member of the NADPH oxidases, is the major source of reactive oxygen species (ROS) and its expression is increased in sepsis, but its function in CSE-mediated anti-inflammatory activities remains unknown. Methods: Macrophages were either transfected with CSE, Nox4 siRNA or transduced with lentiviral vector encoding CSE or Nox4, and then stimulated with lipopolysaccharide (LPS). The expression of inflammatory mediators and signaling pathway activation were measured by quantitative PCR (qPCR), ELISA, and immunoblotting. LPS-induced shock severity in WT, Nox4 knockdown and CSE knockout (CSE-/-) mice was assessed. Results: Here we showed that CSE and Nox4 were upregulated in macrophage and mouse in response to LPS. After LPS stimulation, the inflammatory responses were significantly ameliorated by lentiviral Nox4 shRNA knockdown, but were exacerbated by lentiviral overexpressing Nox4. Furthermore, Nox4 mediated inflammation through PI3K/Akt and p-p38 mitogen-activated protein kinase signal pathway. Notably, CSE knockout served to amplify the inflammatory cascade by increasing Nox4-ROS signaling activation in septic mice and macrophage. Similarly, the enhanced production of inflammatory mediators by macrophages was reduced by CSE overexpression. Conclusion: Thus, we demonstrated that CSE/H2S attenuated LPS-induced sepsis against oxidative stress and inflammation damage probably largely through mediated Nox4 pathway.

Water loss is a key factor in pericarp browning during storage and transportation of litchi and longan fruit. However, whether this water loss is of biological significance is unclear. The loss of water in different tissues during browning of the two fruit, and the relationship between water loss and seed vigor were investigated. The pericarp of both fruit lost 60% of water after 4 days at 20 °C without packaging, in contrast, water loss in the aril and seed was insignificant. Water loss led to browning, a denser and thinner pericarp, correlating with a decrease in permeability to water of the pericarp. The seeds maintained 40% water content and 80% of them germinated when kept in the intact fruit after 12 days. In contrast, bare seeds stored without package retained 20% water content and germinated less than 10%. Germination was negatively correlated with fruit decay index. Phenols extracted from the pericarp after browning inhibited the growth of Peronophythora litchii more than those extracted before browning. Pericarp browning triggered by water loss of the tissue after harvest maintains seed vigor by preventing of dehydration and infection of the seeds.

A three-layered cathode structure was designed to minimize the shuttle effect of polysulfides and improve active material utilization. The three-layered configuration was fabricated by directly dropping pure sulfur composite slurry into multifunctional dual-barrier layers consisting of a self-standing TiO2/C interlayer and a very thin acetylene black layer (0.35 mg cm–2). In consequence, a decent discharge capacity of 963 mA h g–1 was acquired after 100 cycles at 0.1 C. With cycling at 0.1, 0.2, 0.5, 1, and 2 C, the cells displayed excellent reversible capacities of 1203, 1145, 1035, 934, and 820 mA h g–1, respectively. Furthermore, the cells still delivered a satisfactory discharge capacity of 799 mA h g–1 after 300 cycles at 0.5 C. The light mass of the three-layered configuration guarantees that the energy density is effectively improved, considering the overall mass of the cathode. The energy density (603 W h kg–1 after 100 cycles) was at a high level compared with those of the reported ones. Therefor...

Radioactive 85Kr is a major gaseous fission product emitted into the air by the nuclear fuel reprocessing industry. Measuring atmospheric 85Kr has applications in environmental monitoring, atmospheric transport model validation and dating of environmental water samples, including groundwater, sea water and glacier ice. We present an ultra-sensitive method for fast analysis of atmospheric 85Kr at 10−5 parts per trillion level. This method is based on laser cooling and trapping and is capable of counting individual 85Kr atoms. Measurements at the 3% precision level can be made on krypton extracted from 1L STP of air with a turnaround time of 1.5 h. Moreover, we have realized a system for continuous air sampling over days to weeks. Based on this atom-counting technology and a portable air sample integrator we have realized atmospheric 85Kr baseline monitoring in Hefei, China, for over 20 months. The technological advances presented in this work lay the ground for a global atmospheric 85Kr monitoring network.

In this work, oxygen-deficient anatase TiO2 nanosheets (A-TiO2-x NSs) are proposed as a substrate to improve the electrochemical properties of sulfur electrodes for lithium-sulfur (Li-S) batteries. The A-TiO2-x NSs are prepared by partly reducing pristine TiO2 nanosheets (A-TiO2 NSs) in NaBH4 solution. With some oxygen vacancies on the surface of the TiO2 nanosheets, A-TiO2-x NSs not only promote electronic transfer, but also act as more effective polysulfide reservoirs to minimize the dissolution of lithium polysulfides (LiPSs) than the A-TiO2 NSs control. Hence, upon utilization as modifiers for cathodes of Li-S batteries, the A-TiO2-x NSs-modified sulfur (A-TiO2-x NSs-S) cathode exhibits a higher reversible specific capacity and greater cycling performance and rate capability than the A-TiO2 NSs-modified one (A-TiO2 NSs-S). For example, A-TiO2-x NSs-S delivers an initial specific capacity of 1277.1 mAh g-1 at 0.1 C and maintains a stable Coulombic efficiency of approximately 99.2 % after the first five cycles; these values are higher than those of 997.3 mAh g-1 and around 96.7 %, respectively, for A-TiO2 NSs-S. The enhanced electrochemical properties of the A-TiO2-x NSs-S cathode can be ascribed mainly to the more effective adsorption of dissolvable and diffused LiPSs by the oxygen vacancies. Therefore, utilization of the structure of oxygen vacancies in Li-S batteries demonstrates great prospects for practical application.

Bimetallic transition-metal oxides, which exhibit superior electrochemical properties compared with pristine single-metal oxides, have recently become a topic of significant research interest for applications in lithium-ion batteries (LIBs). Herein, we report a simple and scalable electrospinning method to synthesize porous CoTiO3 nanofibers as the precursor for nanostructured bimetallic transition-metal oxides formed electrochemically in situ. This strategy ensures uniform mixing and perfect contact between two constituent transition-metal oxides during the lithiation/delithiation process. Furthermore, CoTiO3 nanofibers based on ultrafine CoTiO3 nanocrystals are interconnected to form a nano/microstructured 3D network, which ensures the high stability of the in situ formed structure composed of bimetallic transition-metal oxides, and also fast ion/electron transfer and electrolyte penetration into the electrode. Electrochemical measurements revealed the excellent lithium storage (647 mAh g-1 at 0.1 Ag-1 ) and retention properties (600 mAh g-1 at 1 Ag-1 after 1200 cycles) of the CoO/TiO2 electrode. Moreover, the electrochemical reaction mechanism was explored by using ex situ X-ray photoelectric spectroscopy and cyclic voltammetry tests, which confirmed the two-phase reaction processes in the electrodes. These results clearly validate the potential of CoTiO3 with a unique nano/microstructured morphology as the precursor for a bimetallic transition-metal oxide for use as the anode material for long-life LIBs.

Although the composite of metal oxide and porous carbon has been confirmed as an effective material to chemically adsorb polysulfides, the low conductivity of the metal oxide results in the need for extra pathways for the diffusion of polysulfides from adsorption sites to redox-active sites. This process results in sluggish reaction kinetics and escaped polysulfides. In this work, a Gerber tree-like interlayer with multiple components was designed to fully mediate the electrochemical conversion of Li–S batteries and shorten the diffusion distance of polysulfides in the composite. The branches of the interlayer contained TiO2 and Co3O4 nanocrystals embedded into N-doped porous carbon, while the fruit was catalytic metal cobalt. The two co-existing chemical adsorbents ensure the restriction of polysulfides through S–Ti–O bonding and Lewis acid–base interaction. Moreover, the metal Co catalyzes the transformation of adsorbed polysulfides into low-order ones, which largely shortens the diffusion pathway, improving the reaction kinetics and preventing the migration of polysulfides. The cell with the interlayer exhibited outstanding electrochemical performance. After 100 cycles, a reversible capacity of 968 mA h g−1 was maintained at 0.1C with a stable capacity retention of 85%. Even at the current rate of 1C, the cell delivered a capacity of 684.5 mA h g−1 after 300 cycles.

Background: Hypertrophic scar (HS) is characterized by the increased proliferation and decreased apoptosis of myofibroblasts. Myofibroblasts, the main effector cells for dermal fibrosis, develop from normal fibroblasts. Thus, the stimulation of myofibroblast apoptosis is a possible treatment for HS. We aimed to explore that whether over-activated myofibroblasts can be targeted for apoptosis by anticancer drug elesclomol. Methods: 4’,6-diamidino-2-phenylindole staining, flow cytometry, western blotting, collagen gel contraction and immunofluorescence assays were applied to demonstrate the proapoptotic effect of elesclomol in scar derived myofibroblasts and TGF-β1 induced myofibroblasts. The therapeutic potential of elesclomol was investigated by establishing rabbit ear hypertrophic scar models. Findings: Both 4′,6-diamidino-2-phenylindole staining and flow cytometry indicated that elesclomol targets myofibroblasts in vitro. Collagen gel contraction assay showed that elesclomol inhibited myofibroblast contractility. Flow cytometry and western blot analysis revealed that elesclomol resulted in excessive intracellular levels of reactive oxygen species(ROS), and caspase-3 and cytochrome c proteins. Moreover, compared with the control group, the elesclomol group had a significantly lower scar elevation index in vivo. Immunofluorescence assays for TUNEL and α-smooth muscle actin indicated that elesclomol treatment increased the number of apoptotic myofibroblasts. Interpretation: The above results indicate that elesclomol exerted a significant inhibitory effect on HS formation via targeted myofibroblast apoptosis associated with increased oxidative stress. Thus, elesclomol is a promising candidate drug for the treatment of myofibroblast-related diseases such as HS. Funding Statement: Funding for this study was provided by the Natural Science Foundation of China (81770876), Natural Science Foundation of Jiangsu Province (Grant BK20191141). Declaration of Interests: The authors declare no competing interests with relevance to this study. Ethics Approval Statement: The study protocols were approved by the ethics committee of the Affiliated Hospital of Jiangnan University. The study purpose and the procedures involved were explained to the patients, who all consented in writing to the use of their resected tissue specimens in this study. The animal experiments were approved by the Experimental Animal Committee of Jiangnan University.

Monitoring the consumption of pharmaceuticals and licit drugs is important for assessing the needs of public health owing to the impact on individuals as well as society. The present work applied wastewater-based epidemiology to profile the spatial patterns of metformin, nicotine, and caffeine use and their correlations. Influent wastewater samples were collected from 27 wastewater treatment plants in 22 typical Chinese cities that covered all geographic regions of the country. The consumption of metformin ranged from 0.02 g/d/1000 inh to 8.92 g/d/1000 inh, whereas caffeine and nicotine consumption ranged from 4.33 g/d/1000 inh to 394 g/d/1000 inh and 0.17 g/d/1000 inh to 1.88 g/d/1000 inh, respectively. There were significant regional differences in the consumption of caffeine, with the highest consumption in East China and the lowest consumption in Northeast China. The consumption and concentration of caffeine were related to the gross domestic product and per capita disposable income of urban residents, respectively. There was a correlation between the concentrations of caffeine and cotinine (a nicotine metabolite), thereby indicating that individuals that use one of these substances are likely to use the other substance. A significant relationship was found between the concentration of metformin and cotinine, thereby implying that the use of tobacco may be correlated with type 2 diabetes. Co-analysis of these substances in wastewater may provide a more accurate picture of substance use situations within different communities and provide more information on human health, human behavior, and the economy. This report describes the newest study related to the consumption of metformin among the general population in China.

The synergistic design of cathode region was conducted to minimize the shuttle effect of polysulfides and decrease the loading of inactive components in order to acquire high-energy-density lithium–sulfur (Li–S) batteries. The well-designed cathode region presented two special characteristics: one was the intertwined nanofibers interlayer based on ultrafine TiO2 nanocrystal uniformly embedded within N-doping porous carbon; the other was the lightweight and three-dimensional current collector of fibrous cellulose paper coated by reduced graphene oxide. In consequence, the decent reversible capacity of 874.8 mA h g–1 was acquired at 0.1 C with a capacity retention of 91.83% after 100 cycles. Besides, the satisfactory capacity of 670 mA h g–1 was delivered after 300 cycles at 1 C with the small decay rate of only 0.08%. Because of higher capacity and lower loading of inactive component in cathode region, the energy density of cell increased more than five times compared with unmodified cell. Moreover, to fur...

Background (7R, 8S)-9-Acetyl-dehydrodiconiferyl alcohol (ADDA), a novel lignan compound isolated from Clematis armandii Franch (Ranunculaceae) stems, has been found to exert potential anti-inflammatory activities in vitro. Purpose To investigate the pharmacological effects and molecular mechanisms of ADDA on lipopolysaccharide (LPS)-induced activation and migration of macrophages. Study design/methods Macrophages were stimulated with LPS in the presence or absence of ADDA. Expression of inflammatory mediators, including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and nitric oxide (NO) were measured by Western blot and commercial NO detection kit. Cellular viability and chemotactic properties of macrophages were investigated using MTT and transwell migration assays. The activation and expression of mitogen activated protein kinases, nuclear factor-κB (NF-κB), protein kinase B (Akt), Src, and focal adhesion kinase (FAK) were analyzed by Western blot. Results Non-toxic concentrations (12.5–50 µM) of ADDA concentration-dependently inhibited expression/release of inflammatory mediators (COX-2, iNOS, and NO), suppressed Akt and c-jun N-terminal kinase 1/2 (JNK) phosphorylation, and NF-κB activation in LPS-stimulated macrophages. In addition, ADDA blocked LPS-mediated macrophage migration and this was associated with inhibition of LPS-induced Src and FAK phosphorylation as well as Src expression in a concentration dependent manner. Notably, the inhibitory effects of ADDA on iNOS, NO, and Src could be mimicked by a Src inhibitor PP2 or an iNOS inhibitor l -NMMA. Conclusion Our results suggested that ADDA attenuated LPS-induced inflammatory responses in macrophages and cell migration, at least in part, through inhibition of NF-κB activation and modulation of iNOS/Src/FAK axis.

(7R,8S)-Dehydrodiconiferyl alcohol (DDA), a lignan isolated from the dried stems of Clematis armandii, has been found to exert potential anti-inflammatory activity in vitro. In the present study, we investigated the effects and possible mechanisms of DDA on lipopolysaccharide (LPS)-mediated inflammatory response in murine BV2 microglia. Our results revealed that non-toxic concentrations (6.25-25 μM) of DDA markedly suppressed LPS-induced production of nitric oxide, expression of inducible nitric oxide synthase and cyclooxygenase-2, and release of inflammatory factors, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in a concentration dependent manner. In addition, DDA time- and concentration-dependently attenuated LPS-induced phosphorylation of c-Jun N-terminal kinase 1/2 (JNK), but not protein kinase B, p38, or extracellular signal-regulated kinase 1/2. Moreover, DDA significantly suppress LPS-mediated nuclear factor-κB (NF-κB) activation by inhibiting phosphorylation and nuclear translocation of NF-κB p65. Collectively, our results demonstrated that DDA inhibited LPS-stimulated inflammatory response in BV2 cell, at least in part, through inhibition of NF-κB activation and modulation of JNK signaling.

Minimally modified low-density lipoprotein (mmLDL) is a well-known risk factor for cardiovascular diseases. The present study was designed to investigate the role of mmLDL in the endothelium-dependent relaxation of mouse mesenteric arteries. A sensitive myograph system was employed to examine the endothelial function of mesenteric arteries. mRNA and protein expression levels were determined using real-time PCR and Western blotting, respectively. The ultramicrostructure of mesenteric vascular beds was investigated using a transmission electron microscope. The results showed that mmLDL significantly impaired the acetylcholine-induced (3 × 10−10 to 1 × 10−4M) endothelium-dependent relaxation of mouse mesenteric arteries with markedly reduced pIC50 (p < 0.05) and Rmax values (p < 0.001). In addition, mmLDL increased the levels of superoxide production and nitrotyrosine concentration and impaired the endothelial microstructure with decreased KCa3.1 and KCa2.3 expression. In conclusion, mmLDL increases superoxide and nitrotyrosine levels, damages endothelial microstructure with decreased KCa3.1 and KCa2.3 expression, and ultimately attenuates relaxation mediated by nitric oxide- and endothelium-derived hyperpolarizing factor.

Recent rapid development in homogeneous gold catalysis affords an alternative and particularly thriving strategy for the generation of gold carbenes through gold-catalyzed oxidation/amination/cycloaddition of alkynes, while it avoids the employment of hazardous and potentially explosive diazo compounds as starting materials for carbene generation. In addition to facile and secure operation, gold carbenes generated in this strategy display good chemoselectivity distinct from other metal carbenes produced from the related diazo approach. N-heterocyclic carbene (NHC) gold is a special metal complex that can be used as ancillary ligands, which provides enhanced stability and can also act as an efficient chiral directing group. In this review, we will present an overview of these recent advances in alkyne oxidation/amination/cycloaddition by highlighting their specificity and applicability, aiming to facilitate progress in this very exciting area of research.

Human sirtuin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacylase, and is implicated in human diseases including cancer. Selective small-molecule inhibitors for SIRT2 are sought as chemical tools and potential therapeutics. Here we report the X-ray crystal structure guided structure-activity relationship studies of new N-(3-(phenoxymethyl)phenyl)acetamide derivatives with SIRT2, which led to the identification of potent, selective SIRT2 inhibitors. Crystallographic analyses reveal that the new inhibitors act via inducing the formation of an enlarged hydrophobic pocket and particularly mimicking the interactions made by myristoylated-lysine substrates. The most potent inhibitor 24a could dose-dependently elevate the acetylation level of α-tubulin in the non-small cell lung cancer H441 cells, which have a high expression level of SIRT2 as determinated by Western blotting analyses. Further cellular assays reveal that 24a restrains cell growth mainly through inhibiting cellular proliferation rather than inducing apoptosis. Moreover, 24a could suppress the migration and invasion of H441 cells. These results provide an excellent basis for further development of new potent, selective, and cell active SIRT2 inhibitors as chemical tools and potential therapeutics for SIRT2-driven non-small cell lung cancers.

Rheumatoid arthritis (RA) is an immune-mediated disease with the characteristics of progressive joint destruction, deformity, and disability. Epigenetic changes have been implicated in the development of some autoimmune disorders, resulting in an alteration of gene transcription. Here, we investigated how Jumonji C family of histone demethylases (JMJD3) regulated the proliferation and activation of fibroblast-like synoviocytes (FLSs), which are involved in RA joint destruction and pathologic process. The JMJD3 expression and proliferation markers in RA-FLS were higher than those in healthy-FLS and were upregulated in platelet-derived growth factor (PDGF)-induced FLS. Elevated JMJD3 promoted the proliferation and migration of FLS. Treatment with JMJD3 small interfering RNA or inhibitor glycogen synthase kinase (GSK) J4 led to decreased proliferation and migration of FLS. Interestingly, induction of proliferating cell nuclear antigen (PCNA), a major player of the cell-cycle regulation, was correlated with trimethylated lysine 27 in histone H3 loss around the gene promoters. The knockdown of JMJD3 abolished PCNA expression in PDGF-induced FLS and further inhibited cell proliferation and migration, suggesting that JMJD3/PCNA played a crucial role in aspects of FLS proliferation and migration. In vivo, the ability of GSK J4 to hinder collagen-induced arthritis (CIA) in DBA/1 mice was evaluated. We found that GSK J4 markedly attenuated the severity of arthritis in CIA mice. The therapeutic effects were associated with ameliorated joint swelling and reduced bone erosion and destruction. This study revealed how JMJD3 integrated with epigenetic processes to regulate RA-FLS proliferation and invasion. These data suggested that JMJD3 might contribute to rheumatoid synovial hyperplasia and have the potential as a novel therapeutic target for RA.-Jia, W., Wu, W., Yang, D., Xiao, C., Su, Z., Huang, Z., Li, Z., Qin, M., Huang, M., Liu, S., Long, F., Mao, J., Liu, X., Zhu, Y. Z. Histone demethylase JMJD3 regulates fibroblast-like synoviocyte-mediated proliferation and joint destruction in rheumatoid arthritis.

The risk of cardiovascular complications in diabetic patients is mainly associated with endothelial dysfunction. Reduced number of EPCs and impaired function of EPCs in diabetes result in imbalance of endothelial homeostasis and dysfunction of vessels. In patients with diabetes mellitus, plasma levels of asymmetric dimethylarginine (ADMA) were elevated, while the expression and activity of dimethylarginine dimethylaminohydrolase (DDAH) were reduced. In the present study, we investigated the role of the DDAH2/ADMA pathway in the senescence of EPCs in type 2 diabetic patients and cultured EPCs treated with high glucose. The results showed that the percentage of senescent EPCs increased while the expression of DDAH2 decreased concomitantly with an increase in the plasma levels of ADMA in patients with type 2 diabetes mellitus (T2DM). Similar results were seen in cultured EPCs treated with high glucose. Exogenous application of ADMA accelerated the senescence of EPCs in a dose-dependent manner, and overexpression of DDAH2 inhibited high glucose-induced EPCs senescence. In addition, it has also been reported that DDAH/ADMA pathway is regulated by silent information regulator 1 (SIRT1) in endothelial cell. In the present study, we found decreased expression of SIRT1 both in T2DM patients and EPCs pretreated with high glucose. And resveratrol (activating SIRT1) inhibited high glucose-induced EPCs senescence by upregulating the expression of DDAH2 and decreasing the levels of ADMA. Taken together, we concluded that DDAH2/ADMA is involved in the accelerated senescence of EPCs in diabetes, which is associated with the activation of SIRT1.

Under the acidic condition, 6-gingerol (C17H26O4) reacted with hydroxylamine to generate 6-gingerol oxime (C17H27NO4). Single-crystal X-ray diffraction with CuKα radiation (λ = 1.54184 Å) revealed the crystal belongs to the orthorhombic system, the space ground is P212121 with a = 5.24240(10), b = 25.7792(4), c = 25.9824(5) Å, V = 3511.39(11) Å3, Z = 8, Mr = 309.40, Dc = 1.171mg/mm3, μ = 0.669mm-1, S = 1.035, F(000) = 1344.0, the final wR2 was 0.1132 (all data) and R1 was 0.0412 [I>2σ (I)]. Two molecules compose one monomeric unit in the crystal. And the hydrogen bonds construct the dimer and the integral crystal spacial structure. The antioxidant activity of the 6-gingerol oxime was tested by the scavenging effect on DPPH radical and potassium ferricyanide reducing power test while Vitamin C was regarded as the comparison. The IC50 of the oxime for the scavenging effect on DPPH was 0.0471 g/L which was less strong than Vitamin C. The reducing power of Vitamin C was about three times powerful than the 6-gingerol oxime.

In this paper, a three-dimension model for the vanadium redox flow battery was established to simulate its mass transfer. The distribution of VO2+and VO2+ in positive electrode area, the distribution of V2+ and V3+ in the negative electrode area, and the influences of flow velocity, temperature and the electrolyte concentration on the mass transfer are analyzed. The results show that the mass fraction of VO2+ and V2+ decrease while those of VO2+and V3+increase along the channel direction; the species concentration under the ridge is lower than that under the flow channel. The flow velocity of electrolyte affects the mass distribution at the entrance of the cell, and hardly affects the electrochemical reaction rate; Increase of the temperature accelerates the electrochemical reaction rate; the electrolyte concentration affects both of the mass distribution and the number of ions. The study has great significance both on the optimization of vanadium redox flow battery and its application.

Chronic neuroinflammation is a pathological feature of neurodegenerative diseases. Inhibition of microglia-mediated neuroinflammation might be a potential strategy for neurodegeneration. Matairesinol, a dibenzylbutyrolactone plant lignan, presents in a wide variety of foodstuffs. It has been found to possess anti-angiogenic, anti-oxidative, anti-cancer and anti-fungal activities. In the present study, we investigated the anti-neuroinflammation effects of matairesinol on lipopolysaccharide (LPS)-induced BV2 microglia cells and the related molecular mechanisms. The results showed that matairesinol inhibited microglia activation by reducing the production of nitric oxide, the expression of inducible nitric oxide synthase and cyclooxygenase-2 in a concentration-dependent manner (6.25, 12.5, 25 μM). In the molecular signaling pathway, LPS-induced nuclear factor-kappa B (NF-κB) transcriptional activity and translocation into the nucleus were remarkably suppressed by matairesinol through the inhibition of the extracellular signal-regulated kinase (ERK)1/2 signal transduction pathways, but not p38 MAPK or c-jun N-terminal kinase (JNK). Meanwhile, matairesinol also blocked LPS-mediated microglia migration and this was associated with inhibition of LPS-induced Src phosphorylation as well as Src expression in a concentration-dependent manner. Taken together, these results suggest that matairesinol inhibited inflammatory response and migration in LPS-induced BV2 microglia, and the mechanisms may be associated with the NF-κB activation and modulation of Src pathway.

The objective of the current study was to evaluate the anti-inflammatory effects of shizukaol B, a lindenane-type dimeric sesquiterpene isolated from the whole plant of Chloranthus henryi, on lipopolysaccharide (LPS)-induced activation of BV2 microglial cells in vitro. Our data showed that shizukaol B concentration-dependently suppressed expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), production of nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) in LPS-stimulated BV2 microglia. Meanwhile, shizukaol B concentration- and time-dependently inhibited LPS-mediated c-Jun N-terminal kinase 1/2 (JNK) activation, but had little effect on extracellular signal-regulated kinase 1/2 or p38 phosphorylation. Furthermore, shizukaol B significantly blocked LPS-induced activator protein-1 (AP-1) activation, evidenced by reduced phosphorylation and nuclear translocation of c-Jun and DNA binding activity of AP-1. Taken together, our findings suggest that shizukaol B exerts anti-inflammatory effects in LPS-activated microglia partly by modulating JNK-AP-1 signaling pathway.

1. It has been reported that resveratrol exerts the inhibitory effects on aging through activation of sirtuin 1 (SIRT1) and dimethylarginine dimethylaminohydrolase (DDAH)/asymmetric dimethylarginine (ADMA) pathway involved in the high glucose-induced endothelial cell senescence. 2. The aims of this work were to explore whether BTM-0512, a novel derivative of resveratrol, was able to exert the beneficial effect on high glucose-induced cellular senescence through regulating the DDAH/ADMA pathway and to explore whether the regulatory effect of BTM-0512 on DDAH/ADMA pathway was related to the activation of SIRT1. 3. The senescence model of endothelial cells was induced by high glucose and the cells were collected for the determination of beta-galactosidase and DDAH activity, ADMA level, DDAH and SIRT1 mRNA expression. 4. The results showed that high glucose significantly increased the ratio of senescent cells concomitantly with the decreased DDAH activity, the downregulated DDAH2 and SIRT1 mRNA expressions and the increased ADMA levels, which were attenuated by pretreatment with BTM-0512. 5. The beneficial effects of BTM-0512 on high glucose-induced senescence were blocked by splimtomicin, the specific inhibitor of SIRT1, or by silencing DDAH2 expression. 6. The results suggest that BTM-0512 was able to exert the beneficial effects on high glucose-induced cellular senescence through regulating the DDAH/ADMA pathway, and its regulatory effect on DDAH/ADMA pathway was related to the activation of SIRT1.

Our previous studies showed that rutaecarpine (Rut) protected against myocardial ischemia/reperfusion (I/R) injury, which was associated with activation of transient receptor potential vanilloid subtype 1 (TRPV1). Recently, TRPV1 activation was also reported to exert neuroprotective effects. The present study was to investigate the effect of Rut on hypoxia/reoxygenation (H/R)-induced apoptosis in primary rat hippocampal neurons. Three-hour hypoxia (1% O2) and consequent 24-h reoxygenation significantly increased the apoptotic death of hippocampal neurons as evidenced by increases in both TUNEL-positive cell number and caspase-3 activity. However, pretreatment with Rut (1–10 mM) or caspase-3 specific inhibitor DEVD-CHO could markedly attenuate H/R-induced apoptosis in neurons. Rut markedly induced the phosphorylation of Akt and PI3K inhibitor LY294002 prevented the survival effect of Rut on neurons. Intracellular oxidative stress was significantly induced after H/R, which was inhibited by Rut and LY294002 as well as antioxidant PDTC. TRPV1 antagonist capsazepine or intracellular Ca 2þ chelator BAPTA/AM could abolish these effects of Rut mentioned above. In summary, the present data suggest that Rut inhibits H/R-induced apoptosis of hippocampal neurons via TRPV1-[Ca 2þ ]i-dependent and PI3K/Akt signaling pathway, which is related to inhibiting oxidative stress and caspase-3 activation.

Neuroinflammation underlies the pathogenesis and progression of neurodegenerative diseases. 2׳-hydroxy-4,3׳,4׳,6׳-tetramethoxychalcone (HTMC) is a known chalcone derivative isolated from Chloranthus henryi with anti-inflammatory activities in BV2 macrophages. However, its pharmacological effects on microglial cells have not been demonstrated. To this end, we examined the effects of HTMC on lipopolysaccharide (LPS)-induced inflammatory responses in BV2 microglial cells. HTMC concentration-dependently inhibited LPS-induced expression of inflammatory enzymes including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), nitric oxide (NO) production, and the secretion of inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. In addition, HTMC inhibited reactive oxygen species (ROS) production by reducing NADPH oxidase (Nox) 2 and Nox4 expression. In addition, HTMC interfered LPS-induced c-Jun N-terminal kinase 1/2 (JNK) phosphorylation in a time- and concentration-dependent manner. By inhibiting phosphorylation and nuclear translocation of Jun, HTMC suppressed LPS-induced activator protein-1 (AP-1) activation. Taken together, our data indicate that HTMC suppresses inflammatory responses in LPS-stimulated BV2 microglial cells by modulating JNK-AP-1 and NADPH oxidases-ROS pathways. HTMC represents a promising therapeutic agent for neurodegenerative and related aging-associated diseases.

Background Reactive oxygen species (ROS) is thought as a major reason of vascular injury in diabetes. Vascular peroxidase 1 (VPO1) is a newly found peroxidase playing an important role in inducing oxidative stress. In the present experiment, we tested the role of VPO1 in senescence of endothelial cells in streptozotocin (STZ)-induced diabetic rats and cultured endothelial cells. Methods Blood samples were collected from carotid arteries. Vasodilator responses to acetylcholine (Ach) in the isolated aortic rings were measured, serum concentration of glucose, tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) and the expression of VPO1 in the aorta were determined. Endothelial cells were treated with high glucose or H 2 O 2 , the concentrations of MCP-1, TNF-α and hypochlorous acid (HOCl) and the expression of VPO1 were determined. shRNA of VPO1 was used for mechanism research in cultured cells. Results Vasodilator responses to Ach were impaired markedly and the serum concentrations of glucose, TNF-α and MCP-1 were significantly increased in diabetic rats. The expression of VPO1 in the aorta was upregulated in diabetic rats. High glucose treatment significantly decreased cell viability and elevated the levels of MCP-1, TNF-α and HOCl and upregulated the expression of VPO1. H 2 O 2 treatment significantly induced cellular senescence, inhibited eNOS expression and NO production. The effects of high glucose and H 2 O 2 were attenuated by shRNA interference of VPO1. Conclusions VPO1 plays an important role in senescence of endothelial cells and endothelial dysfunction by induction of oxidative stress and inflammatory reaction in type 2 diabetic rats.

Endothelial progenitor cells (EPCs) are involved in the repair of vessels and angiogenesis and are useful in the treatment of ischemic diseases. The dimethylarginine dimethylaminohydrolase (DDAH)/asymmetric dimethylarginine (ADMA) pathway is regulated by silent information regulator 1 (SIRT1), leading to the senescence of endothelial cells (ECs). Here, we demonstrated that peripheral blood EPCs predominantly expressed DDAH2 that increased with EPC differentiation. EPC senescence and dysfunction were induced on interruption of DDAH2 expression, whereas the mRNA expression of vascular endothelial growth factor (VEGF) and kinase-domain insert containing receptor (KDR) were downregulated. Moreover, SIRT1 expression increased with EPC differentiation. Interruption of SIRT1 inhibited DDAH2, VEGF, and KDR expression, but had no effect on the level of ADMA. From our data, we concluded that DDAH2 is involved in the differentiation of EPCs and regulates the senescence and function of EPCs through the VEGF/KDR pathway by activation of SIRT1.

Tetrahydroacridine (THA), or Cognex, is currently awaiting FDA approval for the treatment of Alzheimer's disease. In addition to reports indicating that THA improves the symptoms of patients with Alzheimer's disease, we have found that THA possesses potent antiplatelet activity. THA produced dose-dependent inhibition of human platelet aggregation induced by collagen, ADP, A23187, and phorbol ester. THA, when added to activated platelets, dispersed the platelet aggregates. We have also examined the effects of THA on intracellular Ca++ mobilization, ATP release, and production of cyclic AMP.

Tetramethylpyrazine (TMPZ) is an active component that can be extracted from certain plants. In China, this herbal extract is used to treat ischemic vascular diseases. We have assessed the antithrombotic activity of TMPZ using arterial and venous thrombosis models in rats. Antithrombotic activity of TMPZ is at least partly due to its potent antiplatelet effect. We have shown that TMPZ inhibits platelet aggregation induced by ADP, collagen, thrombin, and A23187 but not by diacylglycerol (DAG). Platelets that were induced to produce maximal aggregation could be dispersed by the addition of TMPZ. Platelets could then be reaggregated by the addition of DAG. Studies monitoring intracellular ionized calcium suggest that TMPZ inhibits calcium mobilization from both the extracellular medium and from intracellular stores.

Tetramethylpyrazine (TMPZ) is an active ingredient of a Chinese herbal medicine. We have previously shown that TMPZ possesses antithrombotic activity in rat thrombotic models. Inhibition of platelet aggregation and promotion of disaggregation contributed to the antithrombotic activity of TMPZ. In this study, we evaluated the antiplatelet actions of TMPZ using human platelets and found that antiplatelet activity of TMPZ included the inhibition of intracellular Ca++ mobilization (mainly the release from internal stores), the enhancement of intracellular cAMP by inhibition of phosphodiesterase activity, and the reduction of GP IIb/IIIa exposure on the surface of activated platelets.