CSN6 promotes tumorigenesis of gastric cancer by ubiquitin-independent proteasomal degradation of p16INK4a

Objective: CSN6 is a vital subunit of the constitutive photomorphogenesis 9(COP9) signalosome(CSN), which is responsible for development disorders and promotes ubiquitin-26 S proteasome-dependent degradation in vitro and vivo.Its role in the tumor development of gastric cancer remains unclear.In this study, we investigated the role of CSN6 in gastric cancer progression.Methods: Human gastric cancer samples were collected and immunohistochemistry was performed to identify the role of CSN6 in gastric cancer.The cell proliferation was measured by CCK-8 and the EdU incorporation method.Immunofluorescence localization and a co-immunoprecipitation study were used to show the interaction between the protein CSN6 and p16.Ubiquitination assay was performed to validate whether ubiquitination is involved in CSN6-mediated p16 degradation.BALB/c nude mice were used to produce a tumor model in order to test the effect of CSN6 on cancer growth in vivo.Results: CSN6 expression was dramatically increased in gastric cancer tissues compared with paired adjacent non-tumor tissues and CSN6 was correlated with worse overall and disease-specific survival.Additionally, we also found that CSN6 downregulated p16 protein expression, thereby promoting gastric cancer cell growth and proliferation.Moreover, CSN6 interacted with p16 and a proteasome activator REGγ(PA28γ), thereby facilitating ubiquitin-independent degradation of p16.Conclusions: CSN6 promoted the loss of p16-mediated tumor progression and played an important role in regulating ubiquitin-independent proteasomal degradation of p16.

Cardioprotective effect of Yiqi Huoxue granule through regulation of mitophagy after myocardial infarction in rats

Objective:To investigate the cardioprotective effect of Yiqi Huoxue granule(YQHXG)in the regulation of autophagy in rats induced with myocardial infarction(MI).Methods:An acute MI animal model was established by ligation of the left anterior descending branch of the coronary artery in Sprague-Dawley rats.Besides,20 rats received sham operation were classified into a control group.The remaining 59 rats were randomly divided into MI model group(n=19),YQHXG group(n=20),and perindopril group(n=20).Relevant indicators on days 7 and 28 were observed in each group.Left ventricular function was determined by echocardiography.The structure and morphology of mitochondria,and the number of autophagic vesicles,were observed by transmission electron microscopy.The mRNA and protein expression levels of LC3,FUNDC1,Beclin-1,and BNIP3 were examined in the tissue of the MI marginal area.Results:Compared with the MI model group,YQHXG showed obvious improvements in cardiac functions.Observing the microscopic morphology of the heart tissue,myocardial tissue damage attenuated,autophagic signs of autophagosomes and autolysosomes reduced,vacuolization in mitochondria mitigated,and mitochondria arranged in order.YQHXG could reduce the degree of tissue lesion after MI and regulate the expression of autophagy-related molecules at different stages.On Day 7,YQHXG significantly downregulated the expression of Fundc1,Becn1,Bnip3 mRNA and reduced the levels of FUNDC1,Beclin-1,BNIP3,and LC3 B proteins expression(all P<.001).On Day 28,YQHXG could upregulate the expression of Becn1,Fundc1 and Bnip3 mRNA and increased the levels of the corresponding proteins expression(all P<.001).Besides,it also increased LC3 B protein expression level(P=.0344).Conclusion:YQHXG regulated the expression of mitochondrial autophagy-related factors in myocardial tissue and mitochondrial autophagic activity at different stages to protect the heart following MI.

同质园环境和遗传分化影响锦鸡儿属植物根际土壤固氮菌多样性和群落结构

环境和遗传分化共同影响植物的功能性状,进而能够通过根系分泌物影响根际微生物。本研究利用同质园试验,通过高通量测序技术,基于固氮酶基因nifH的同源性,分析同质园栽培的不同种源小叶锦鸡儿(Caragana microphylla)、中间锦鸡儿(C.liouana)和荒漠锦鸡儿(C.roborovskyi)根际土壤固氮菌多样性,并探究其与种源地气候及同质园土壤属性的关系。结果表明,3种锦鸡儿植物根际土壤固氮菌隶属6门9纲18目21科33属72种,其中变形菌门、疣微菌门和蓝细菌门为优势门,优势属为中慢生根瘤菌属(Mesorhizobium)、固氮氢自养单胞菌属(Azohydromonas)和慢生根瘤菌属(Bradyrhizobium)。3种锦鸡儿根际土壤固氮菌α多样性种间差异不显著,但中间锦鸡儿和荒漠锦鸡儿根际土壤固氮菌的α多样性存在显著的种内差异(P<0.05),小叶锦鸡儿和荒漠锦鸡儿根际土壤固氮菌群落结构存在显著的种内差异(P<0.05)。冗余分析表明同质园土壤pH和种源地年均温分别是影响3种锦鸡儿根际土壤固氮菌多样性和群落结构变化的主要因子,说明3种锦鸡儿属植物根际土壤固氮菌群落多样性受同质园环境与遗传分化的共同调控。本研究结果为锦鸡儿属植物的生态适应机制和引种栽培提供理论依据和数据支持。

BnlR:A multi-omics database with various tools for Brassica napus research and breeding

In the post-genome-wide association study era,multi-omics techniques have shown great power and poten-tial for candidate gene mining and functional genomics research.However,due to the lack of effective data integration and multi-omics analysis platforms,such techniques have not still been applied widely in rape-seed,an important oil crop worldwide.Here,we report a rapeseed multi-omics database(BnlR;http:/l yanglab.hzau.edu.cn/BnlR),which provides datasets of six omics including genomics,transcriptomics,variomics,epigenetics,phenomics,and metabolomics,as well as numerous"variation-gene expression-phenotype"associations by using multiple statistical methods.In addition,a series of multi-omics search and analysis tools are integrated to facilitate the browsing and application of these datasets.BnlR is the most comprehensive multi-omics database for rapeseed so far,and two case studies demonstrated its power to mine candidate genes associated with specific traits and analyze their potential regulatory mechanisms.

α/Sulfono-γ-AA peptide hybrids agonist of GLP-1R with prolonged action both in vitro and in vivo

Peptides are increasingly important resources for biological and therapeutic development,however,their intrinsic susceptibility to proteolytic degradation represents a big hurdle.As a natural agonist for GLP-1R,glucagon-like peptide 1(GLP-1)is of significant clinical interest for the treatment of type-2 diabetes mellitus,but its in vivo instability and short half-life have largely prevented its therapeutic application.Here,we describe the rational design of a series of a/sulfono-γ-AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists.Certain GLP-1 hybrid analogues exhibited enhanced stability(t_(1/2)>14 days)compared to t_(1/2)(<1 day)of GLP-1 in the blood plasma and in vivo.These newly developed peptide hybrids may be viable alternative of semaglutide for type-2 diabetes treatment.Additionally,our findings suggest that sulfono-γ-AA residues could be adopted to substitute canonical amino acids residues to improve the pharmacological activity of peptide-based drugs.

BnVIR:bridging the genotype-phenotype gap to accelerate mining of candidate variations underlying agronomic traits in Brassica napus

Dear Editor,Genetic variations,which range from single nucleotide polymor-phisms(SNPs)and short insertion/deletions(InDels)to large-scale structural variations(SVs),are the basis of phenotypic diversity.Understanding the effect of genetic variations on traits is critical for uncovering the genetic architecture of various phe-notypes.

Peptidomimetic-based antibody surrogate for HER2

Inhibition of human epidermal growth factor receptor 2 mediated cell signaling pathway is an important therapeutic strategy for HER2-positive cancers.Although monoclonal antibodies are currently used as marketed drugs,their large molecular weight,high cost of production and susceptibility to proteolysis could be a hurdle for long-term application.In this study,we reported a strategy for the development of artificial antibody based on y-AApeptides to target HER2 extracellular domain(ECD).To achieve this,we synthesized a one-bead-two-compound(OBTC)library containing 320,000 cyclic y-AApeptides,from which we identified a y-AApeptide,M-3-6,that tightly binds to HER2 selectively.Subsequently,we designed an antibody-like dimer of M-3-6,named M-3-6-D,which showed excellent binding affinity toward HER2 comparable to monoclonal antibodies.Intriguingly,M-3-6-D was completely resistant toward enzymatic degradation.In addition,it could effectively inhibit the phosphorylation of HER2,as well as the downstream signaling pathways of AKT and ERK.Furthermore,M-3-6-D also efficiently inhibited cell proliferation in vitro,and suppressed tumor growth in SKBR3 xenograft model in vivo,implying its therapeutic potential for the treatment of cancers.Its small molecular weight,antibody-like property,resistance to proteolysis,may enable it a new generation of artificial antibody surrogate.Furthermore,our strategy of artificial antibody surrogate based on dimers of cyclicγ-AApeptides could be applied to a myriad of disease-related receptor targets in future.

One-step synthesis and self-assembly behavior of thermo-responsive star-shaped β-cyclodextrin-（P（M EO2MA-co-PEGMA））21 copolymers

A novel β-cyclodextrin-poly（2-（2-methoxyethoxy）ethyl methacrylate）-co- poly（ethylene glycol） methacrylate （abbreviated as： β-CD-（P（MEO2MA-co-PEGMA））21） was prepared by using the one-step strategy, and then the star-shaped copolymers were used in the atom transfer radical polymerization （ATRP）. The structure of star-shaped β- CD-（P（MEO2MA-co-PEGMA））21 copolymers were studied by FTIR, 1H NMR and gel permeation chromatography （GPC）. The star-shaped copolymers could self-assembled into micelles in aqueous solution owing to the outer amphiphilic β-CD as a core and the hydrophilic P（MEO2MA-co-PEGMA） segments as a shell. These thermo-responsive starshaped copolymers micelles exhibited lower critical solution temperature （LCST） in water, which could be finely tuned by changing the feed ratio of MEO2MA to PEGMA. The LCST of star-shaped β-CD-（P（MEO2MA-co-PEGMA））21 copolymer micelles were increased from 35℃ to 58℃ with the increasing content of PEGMA. The results were investigated by DLS and TEM. When the temperature was higher than corresponding LCSTs, the micelles started to associate and form spherical nanoparticles. Therefore, β- CD-（P（MEO2MA-co-PEGMA））21 star-shaped copolymer micelles could be potentially applied in nano-carrier, nano-reactor, smart materials and biomedical fields.

Folate-conjugated pH-responsive nanocarrier designed for active tumor targeting and controlled release of doxorubicin

A novel type of amphiphilic pH-responsive folate-poly（ε-caprolactone）- block-poly（ 2-hydroxyethylmethacrylate ）-co-poly（ 2-（ dimethylamino ）-ethylmethacrylate ） （FA-PCL-b-P（HEMA-co-DMAEMA）） （MFP） block copolymers were designed and synthe- sized via atom transfer radical polymerization （ATRP） and ring opening polymerization （ROP） techniques. The molecular structures of the copolymers were confirmed with IH NMR, FTIR and GPC measurements. The critical micelle concentration （CMC） of MFP in aqueous solution was extremely low （about 6.54 mglL）. The in vitro release behavior of DOX-Ioaded micelles was significantly accelerated when the pH value of solution decreased from 7.4 to 5.0. In vitro antitumor efficiency was evaluated by incubating DOX- loaded micelles with Hela cells. The results demonstrated that this copolymer possessed excellent biocompatibility, and FA-decorated micelles MFP showed higher cellular uptake than those micelles without the FA moiety, indicating their unique targetability. These folate-conjugated biodegradable micelles are highly promising for targeted cancer chemothe-rapy.

Combination of ultrasonication/mechanical refining with alkali treatment to improve the accessibility and porosity of bamboo cellulose fibers for the preparation of magnetic bionanocomposite cellulose beads

Ultrasonication and mechanical refining pretreatments were carried out to enhance alkali swelling of bamboo fibers to improve accessibility and porosity.Cellulose-based magnetic beads were synthesized with the alkali swollen bamboo fibers and Fe3O4 nanoparticles.Compared to the fibers treated with alkali alone,the water retention value(WRV)increased by 33.87%for the fibers treated by sonication and alkali,and by 94.58%for those treated by mechanical refining and alkali.The increased WRV was attributed to disruption of the crystalline region of fibers in the combined treatments which resulted in decreased crystallinity and degree of polymerization of cellulose.Furthermore,compared with the control sample which was treated by alkali alone,the specific surface area and pore volume of the samples treated by the combined processes increased markedly,which favored the adsorption of Fe3O4 nanoparticles in the synthesis of functional magnetic cellulose beads for the applications of protein immobilization,drug carrier and wastewater treatment.

An aqueous ZnCl2/Fe(bpy)3Cl2 flow battery with mild electrolyte

The kinetics of electrode reaction was investigated by cyclic voltammetry,and cyclic voltammograms show that the reversibility of the Fe(bpy)3^2+/Fe(bpy)^3+electrode reaction is better than that of the Zn/Zn^2+electrode reaction on the graphite disc.However,the Fe(bpy)3^2+ion diffusion in electrolyte is subject to greater resistance than that of the Zn^2+ion one.The stability of the Fe(bpy)3Cl2 solution was investigated by UV-vis spectroscopy,and the performance of a mild redox flow battery employing ZnCl2 and Fe(bpy)3Cl2 in the NaCl aqueous solution with various membranes as the separator was also investigated.It was found that the Celgard 3501 membrane cannot effectively prevent Fe(bpy)3^2+ions from leaking into anolyte,leading to the rapid failure of the flow battery.Although the Nafion 115 membrane can be polluted by Fe(bpy)32+ions,it is not invalidated.The Nafion 115 membrane shows good selectivity,which can avoid Fe(bpy)32 ions from leakage into anolyte.The ZnCl2/Fe(bpy)3Cl2 flow battery with the Nafion 115 membrane exhibits the capacity retention of 80%after 200 cycles.

Editorial of Special Column“Novel Peptides and Peptidomimetics in Drug Discovery”

Since insulin,a natural peptide composed of 51 amino acids,was first isolated and commercialized in the 1920s,peptide drugs have greatly reshaped our modern drug discovery area^(1).To date,the total number of approved peptide drugs for human use worldwide has exceeded 60^(2).Popular peptide drugs such as liraglutide(Victoza)^(2) and glucagon-like peptide 1(GLP-1)^(3) are the topselling drugs for type 2 diabetes.However,significant hurdles associated with natural peptide sequences as therapeutics,such as metabolic instability and,consequently,have low oral bioavailability and shorter half-life^(4),are still remaining.To overcome the limitations of natural peptides and further optimize their advantages,peptidomimetics emerged as an alternative strategy.

Purification and anti-inflammatory effect of selenium-containing protein fraction from selenium-enriched Spirulina platensis

Spirulina platensis is an excellent carrier of Se,and thus widely used in medical fields and as well as in the food industry.However,there is little information about the characteristics and bioactivity of selenium-containing S.platensis proteins(Se-SP).In this study,Se-SP with different molecular weights were isolated from selenium-enriched S.platensis,and the bioactivities(such as antioxidant and anti-inflammatory activities)of Se-SP were investigated.Se-SP3(with a molecular weight range of 20-48 kDa)showed better free radical scavenging ability(ABTS)than the other Se-SPs.In addition,Se-SP3 suppressed inflammatory cytokines,in which decreased by 74% interleukin 6(IL-6),42.28% tumor necrosis factor-α(TNF-α),69.07% content of malondialdehyde(MDA),40.45% interleukin-1β(IL-1β)relative to the LPS group.Moreover,Se-SP3 decreased the nitric oxide(NO)production by 64.84% compared with the LPS group and increased the activities of superoxide dismutase(SOD)and glutathione peroxidase(GSH-Px),indicating that Se-SP3 has excellent antioxidant and anti-inflammatory activities,and could be used as a functional food ingredient or natural medicine.