Glucose deprivation induces chemoresistance in colorectal cancer cells by increasing ATF4 expression

AIM: To investigate the role of activating transcription factor 4(ATF4) in glucose deprivation(GD) induced colorectal cancer(CRC) drug resistance and the mechanism involved.METHODS: Chemosensitivity and apoptosis were measured under the GD condition. Inhibition of ATF4 using short hairpin RNA in CRC cells under the GD condition and in ATF4-overexpressing CRC cells was performed to identify the role of ATF4 in the GD induced chemoresistance. Quantitative real-time RTPCR and Western blot were used to detect the mR NA and protein expression of drug resistance gene 1(MDR1), respectively.RESULTS: GD protected CRC cells from drug-induced apoptosis(oxaliplatin and 5-fluorouracil) and induced the expression of ATF4, a key gene of the unfolded protein response. Depletion of ATF4 in CRC cells under the GD condition can induce apoptosis and drug resensitization. Similarly, inhibition of ATF4 in the ATF4-overexpressing CRC cells reintroduced therapeutic sensitivity and apoptosis. In addition, increased MDR1 expression was observed in GD-treated CRC cells. CONCLUSION: These data indicate that GD promotes chemoresistance in CRC cells through up-regulating ATF4 expression.

Clinical implications of interleukins-31, 32, and 33 in gastric cancer

BACKGROUND Gastric cancer(GC) is one of the most common malignancies in China with a high morbidity and mortality.AIM To determine whether interleukin(IL)-31, IL-32, and IL-33 can be used as biomarkers for the detection of GC, via evaluating the correlations between their expression and clinicopathological parameters of GC patients.METHODS Tissue array(n = 180) gastric specimens were utilised. IL-31, IL-32, and IL-33 expression in GC and non-GC tissues was detected immunohistochemically. The correlations between IL-31, IL-32, and IL-33 expression in GC and severity of clinicopathological parameters were evaluated. Survival curves were plotted using the Kaplan-Meier method/Cox regression. Circulating IL-31, IL-32, and IL-33 were detected by ELISA.RESULTS We found that the expression levels of IL-31, IL-32, and IL-33 were all lower in GC than in adjacent non-GC gastric tissues(P < 0.05). IL-33 in peripheral blood of GC patients was significantly lower than that of healthy individuals(1.50 ± 1.11 vs 9.61 ± 8.00 ng/m L, P <0.05). Decreased IL-31, IL-32, and IL-33 in GC were observed in younger patients(< 60 years), and IL-32 and IL-33 were lower in female patients(P < 0.05). Higher IL-32 correlated with a longer survival in two GC subgroups: T4 invasion depth and TNM I-II stage. Univariate/multivariate analysis revealed that IL-32 was an independent prognostic factor for GC in the T4 stage subgroup. Circulating IL-33 was significantly lower in GC patients at TNM stage IV than in healthy people(P < 0.05).CONCLUSION Our findings may provide new insights into the roles of IL-31, IL-32, and IL-33 in the carcinogenesis of GC and demonstrate their relative usefulness as prognostic markers for GC. The underlying mechanism of IL-31, IL-32, and IL-33 actions in GC should be further explored.

Ultrahigh lithiation dynamics of Li_(4)Ti_(5)O_(12)as an anode material with open diffusion channels induced by chemical presodiation

Spinel lithium titanate(Li_(4)Ti_(5)O_(12),LTO),with the merits of safety operation voltage,stable crystal structure,and minor lattice volume changes,becomes an optimal anode material for high-power Li-ion batteries.However,the inherent wide bandgap and low lithiation reactivity of Li_(4)Ti_(5)O_(12)bring about poor conductivity and lithiation dynamics,limiting its further applications.Herein,we design and prepare unique Li_(4)Ti_(5)O_(12)anode materials with extremely low dopant content of Na^(+)utilizing the amorphous precursors.The resultant Li_(4)Na_(0.008-)Ti_(5)O_(12.004)sample(denoted as NLTO-0.008)presents superior rate performances and cycle ability,with a reversible capacity of 149.4 mAh·g^(-1)at the current rate of10.0C.NLTO-0.008 retains the charge capacity of151.3 mAh·g^(-1)with a capacity loss of 0.5%after 1000cycles at the current rate of 1.0C(charge)/10.0C(discharge).The kinetic studies furtherly demonstrate that the lithiation reaction energy and diffusion energy barrier decrease by 28.8%and 30%,respectively.Crystal structure analysis indicates that Na^(+)occupies the 16d Li site and forms distorted LiO_(4)tetrahedron and TiO_(6)octahedron.This lattice distortion forms open diffusion channels,thus enhancing the Li^(+)diffusion dynamics and decreasing the lithiation reaction energy barrier for Li_(4)Ti_(5)O_(12).Therefore,the pre-sodiation strategy may arouse great interest in understanding and developing intercalation-type transitionmetal-based electrode materials in high-power lithium-ion batteries.

Osa-miR1873 fine-tunes rice immunity against Magnaporthe oryzae and yield traits

MicroRNAs(miRNAs)are known to fine-tune growth,development,and stress-induced responses.Osa-miR1873 is a rice-specific miRNA targeting LOC_Os05g01790.Here,we show that Osa-miR1873 fine-tunes rice immunity against Magnaporthe oryzae and yield traits via LOC_Os05g01790.Osa-miR1873 was significantly upregulated in a susceptible accession but downregulated in a resistance accession at 24 h post-inoculation(hpi)of M.oryzae.Overexpressing Osa-miR1873 enhanced susceptibility to M.oryzae and compromised induction of defense responses.In contrast,blocking Osa-miR1873 through target mimicry compromised susceptibility to M.oryzae and enhanced induction of defense responses.Altered expression of Osa-miR1873 also resulted in some defects in yield traits,including grain numbers and seed setting rate.Moreover,overexpression of the target gene LOC_Os05g01790 increased rice blast disease resistance but severely penalized growth and yield.Taken together,we demonstrate that Osa-miR1873 fine-tunes the rice immunity-growth trade-off via LOC_Os05g01790,and blocking Osa-miR1873 could improve blast disease resistance without significant yield penalty.Thus,the Osa-miR1873-LOC_Os05g01790 regulatory module is valuable in balancing yield traits and blast resistance.

Overproduction of OsRACK1A,an effector-targeted scaffold protein promoting OsRBOHB-mediated ROS production,confers rice floral resistance to false smut disease without yield penalty

Grain formation is fundamental for crop yield but is vulnerable to abiotic and biotic stresses.Rice grain production is threatened by the false smut fungus Ustilaginoidea virens,which specifically infects rice floral organs,disrupting fertilization and seed formation.However,little is known about the molecular mechanisms of the U.virens-rice interaction and the genetic basis of floral resistance.Here,we report that U.virens secretes a cytoplasmic effector,UvCBP1,to facilitate infection of rice flowers.Mechanistically,UvCBP1 interacts with the rice scaffold protein OsRACK1A and competes its interaction with the reduced nicotinamide adenine dinucleotide phosphate oxidase OsRBOHB,leading to inhibition of reactive oxygen species(ROS)production.Although the analysis of natural variation revealed no OsRACK1A variants that could avoid being targeted by UvCBP1,expression levels of OsRACK1A are correlated with field resistance against U.virens in rice germplasm.Overproduction of OsRACK1A restores the OsRACK1A-OsRBOHB association and promotes OsRBOHB phosphorylation to enhance ROS production,conferring rice floral resistance to U.virens without yield penalty.Taken together,our findings reveal a new pathogenic mechanism mediated by an essential effector from a flower-specific pathogen and provide a valuable genetic resource for balancing disease resistance and crop yield.

Direct Construction of NOBINs via Domino Arylation and Sigmatropic Rearrangement Reactions

of main observation and conclusion Privileged 2-amino-2,-hydroxy-l/l,-binaphthyl(NOBIN)frameworks were constructed through a novel domino arylation of naphthylhydroxylamines with diarylhalonium salts and sigmatropic rearrangement in a transition metal-free fashion.This protocol bears broad substrate generality and proceeds under mild reaction conditions,affording diversified NOBINs in high efficiency with absolute regiocontrol during the rearrangement process.Optically active product was accessible by chiral A/-heterocyclic carbene-catalyzed kinetic resolution in one pot or diastereoselective[3,3]-rearrangement guided by a removable chiral auxiliary.Remarkably,diarylchloronium and diarylbrominium salts have been employed as arylation reagents for the first time in assembling such representative biaryl frameworks.

Network Pharmacology-Based Study of Chinese Herbal Qixiong Formula in Treating Oligoasthenospermia

Objective:The objective is to study the network pharmacology of Qixiong formula(QXF)and explore the mechanism of QXF in the treatment of oligoasthenospermia.Materials and Methods:Using Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),a Bioinformatics Analysis Tool for Molecular mech ANism of Traditional Chinese Medicine(BATMAN-traditional Chinese medicine),and an encyclopaedia of traditional Chinese medicine(ETCM)databases as well as data from relevant studies,the effective components and targets of QXF were obtained.Genes associated with oligospermia were screened using Gene Cards,OMIM,Dis Ge Net,Drug Bank,and GAD databases.The intersection target was obtained by mapping the target to the gene,and the protein interaction network was created using the STRING database to screen the core target of QXF in the treatment of oligospermia.The intersection target was enriched using gene ontology(GO)and the Kyoto Encyclopedia of genes and genomes(KEGG)pathway analysis with the DAVID database.The network of the disease drug target pathway was drawn using Cytoscape software.Results:Overall,536 active components of QXF and 40 core targets for the treatment of oligoasthenozoospermia were obtained.The analysis of GO and KEGG showed that QXF is mainly involved in oxidative stress,cell motility,nutritional response,and other biological processes.Through the regulation of FOXO,p53,PI3 K/Akt,MAPK,mammalian target of rapamycin,Foxo,Wnt,and other signaling pathways,QXF played a role in the treatment of oligoasthenospermia.Conclusion:QXF has multi-component,multi-target,and multi-channel characteristics,providing a new way to study the mechanism of QXF in the treatment of oligoasthenospermia.

Design and synthesis of chitin synthase inhibitors as potent fungicides

Chitin is a structural component of fungal cell walls but is absent in vertebrates,mammals,and humans.Chitin synthase is thus an attractive molecular target for developing fungicides.Based on the structure of its donor substrate,UDP-N-acetyl-glucosamine,as well as the modelled structure of the bacterial chitin synthase NodC,we designed a novel scaffold which was then further optimized into a series of chitin synthase inhibitors.The most potent inhibitor,compound 13,exhibited high chitin synthase inhibitory activity with an IC（50） value of 64.5 μmol/L All of the inhibitors exhibited antifungal activities against the growth of agriculturally-destructive fungi,Fusarium graminearum,Botrytis cinerea.and Colletotrichum lagenarium.This work presents a new scaffold which can be used for the development of novel fungicides.

Synthesis of structurally diversified BINOLs and NOBINs via palladium-catalyzed C-H arylation with diazoquinones

Privileged biaryl frameworks,BINOL and NOBIN,were efficiently constructed with sole 1-DNQs as arylation reagents under one set of reaction conditions.The judicious selection of palladium-catalytic system plays a pivotal role in the excellent selectivities.This transformation accommodated fairly broad substrate generality for both 2-naphthol and N-Boc-2-naphthylamine and afforded the structurally diversified BINOLs and NOBIN derivatives in high efficiency.Notably,the bromosubstituents which cannot survive in conventional palladium-catalyzed reactions were well-compatible with this set of conditions,providing an effective handle for further enriching the library of BINOLs and NOBINs.Preliminary attempts on the asymmetric variant of this reaction were also performed with up to 80:20 er for BINOLs synthesis.