[Clinical application of the modified pediatric nutritional risk screening tool].

OBJECTIVE: To study the clinical application of the modified nutritional risk screening tool and nutrition assessment in pediatric patients in China, and to provide a theoretical basis for establishing a standardized nutritional management process for pediatric patients. METHODS: A retrospective analysis was performed for the nutritional risk screening and nutrition assessment data of 16 249 hospitalized children. According to the degree of nutritional risk, the children were divided into a high nutritional risk group with 588 children, a moderate nutritional risk group with 4 330 children, and a non-nutritional risk group with 11 331 children. Nutrition assessment results were compared between groups. The composition of nutritional risk screening scores and the impact of nutritional risk screening on the rate of nutrition support therapy were analyzed. RESULTS: The incidence rate of nutritional risk was 30.27% (4 918/16 249), and the incidence rates of malnutrition and overnutrition were 27.37% (4 448/16 249) and 11.29% (1 834/16 249), respectively. Nutrition assessment results were significantly correlated with nutritional risk (≥ 5 years old:rs=0.313, P < 0.05; < 5 years old:rs=-0.304, P < 0.05). There was a significant difference in the composition of scoring items between the groups with different nutritional risks (P < 0.05). With the implementation of nutritional risk screening, there was a gradual increase in the rate of nutrition support therapy year by year (P < 0.05). CONCLUSIONS: There is a high incidence rate of nutritional risk in hospitalized children. The use of the modified pediatric nutritional risk screening tool can promote the implementation of standardized nutritional management.

Inhibitor of CBP Histone Acetyltransferase Downregulates p53 Activation and Facilitates Methylation at Lysine 27 on Histone H3.

Tumor suppressor p53-directed apoptosis triggers loss of normal cells, which contributes to the side-effects from anticancer therapies. Thus, small molecules with potential to downregulate the activation of p53 could minimize pathology emerging from anticancer therapies. Acetylation of p53 by the histone acetyltransferase (HAT) domain is the hallmark of coactivator CREB-binding protein (CBP) epigenetic function. During genotoxic stress, CBP HAT-mediated acetylation is essential for the activation of p53 to transcriptionally govern target genes, which control cellular responses. Here, we present a small molecule, NiCur, which blocks CBP HAT activity and downregulates p53 activation upon genotoxic stress. Computational modeling reveals that NiCur docks into the active site of CBP HAT. On CDKN1A promoter, the recruitment of p53 as well as RNA Polymerase II and levels of acetylation on histone H3 were diminished by NiCur. Specifically, NiCur reduces the levels of acetylation at lysine 27 on histone H3, which concomitantly increases the levels of trimethylation at lysine 27. Finally, NiCur attenuates p53-directed apoptosis by inhibiting the Caspase 3 activity and cleavage of Poly (ADP-ribose) polymerase (PARP) in normal gastrointestinal epithelial cells. Collectively, NiCur demonstrates the potential to reprogram the chromatin landscape and modulate biological outcomes of CBP-mediated acetylation under normal and disease conditions.

Spatially constrained tandem bromodomain inhibition bolsters sustained repression of BRD4 transcriptional activity for TNBC cell growth.

The importance of BET protein BRD4 in gene transcription is well recognized through the study of chemical modulation of its characteristic tandem bromodomain (BrD) binding to lysine-acetylated histones and transcription factors. However, while monovalent inhibition of BRD4 by BET BrD inhibitors such as JQ1 blocks growth of hematopoietic cancers, it is much less effective generally in solid tumors. Here, we report a thienodiazepine-based bivalent BrD inhibitor, MS645, that affords spatially constrained tandem BrD inhibition and consequently sustained repression of BRD4 transcriptional activity in blocking proliferation of solid-tumor cells including a panel of triple-negative breast cancer (TNBC) cells. MS645 blocks BRD4 binding to transcription enhancer/mediator proteins MED1 and YY1 with potency superior to monovalent BET inhibitors, resulting in down-regulation of proinflammatory cytokines and genes for cell-cycle control and DNA damage repair that are largely unaffected by monovalent BrD inhibition. Our study suggests a therapeutic strategy to maximally control BRD4 activity for rapid growth of solid-tumor TNBC cells.

[Characteristics of soil microbial community under different vegetation types in Wuyishan National Nature Reserve, East China].

By using Biolog Ecoplate system, this paper studied the structure and functional diversity of soil microbial community under different vegetation types in Wuyishan National Nature Reserve, aimed to probe into the effects of vegetation type on the diversity of soil microbial community. The results showed that the soil chemical properties, soil enzyme activities, and average well color development (AWCD) were higher in natural forest than in planted forest, and were the lowest in abandoned field. The AWCD reflecting soil microbial activity and functional diversity was increased with increasing incubation time, but there existed significant differences among different vegetation types. The carbon sources mostly used by soil microbes were carbohydrates and carboxylic acids, followed by amino acids, phenolic acids and polymers, and amines had the lowest utilization rate. The Simpson index, Shannon index, Richness index and McIntosh index in natural forest were holistically higher than those in planted forest. Principal component analysis (PCA) identified 2 principal component factors in relation to carbon sources, explaining 56.3% and 30.2% of the variation, respectively. The carbon sources used by soil microbial community differed with vegetation types. Amino acids and amides were the two main carbon sources separating the 2 principal component factors. The results of this study could provide basis for further approaching the relationships between vegetation diversity and soil microbial community diversity.

γ-H2AX kinetics as a novel approach to high content screening for small molecule radiosensitizers.

BACKGROUND: Persistence of γ-H2AX after ionizing radiation (IR) or drug therapy is a robust reporter of unrepaired DNA double strand breaks in treated cells. METHODS: DU-145 prostate cancer cells were treated with a chemical library ±IR and assayed for persistence of γ-H2AX using an automated 96-well immunocytochemistry assay at 4 hours after treatment. Hits that resulted in persistence of γ-H2AX foci were tested for effects on cell survival. The molecular targets of hits were validated by molecular, genetic and biochemical assays and in vivo activity was tested in a validated Drosophila cancer model. RESULTS: We identified 2 compounds, MS0019266 and MS0017509, which markedly increased persistence of γ-H2AX, apoptosis and radiosensitization in DU-145 cells. Chemical evaluation demonstrated that both compounds exhibited structurally similar and biochemical assays confirmed that these compounds inhibit ribonucleotide reductase. DNA microarray analysis and immunoblotting demonstrates that MS0019266 significantly decreased polo-like kinase 1 gene and protein expression. MS0019266 demonstrated in vivo antitumor activity without significant whole organism toxicity. CONCLUSIONS: MS0019266 and MS0017509 are promising compounds that may be candidates for further development as radiosensitizing compounds as inhibitors of ribonucleotide reductase.

Optimization of ultrasonic-assisted enzymatic hydrolysis for the extraction of luteolin and apigenin from celery.

The extraction of flavonoids is of increasing interest because of their various pharmacological effects. This study is the first attempt for the ultrasonic-assisted enzymatic hydrolysis (USAEH) applied in the extraction of 2 bioactive flavonoid compounds in celery--luteolin and apigenin. The quantitative yields of luteolin and apigenin were determined by high-performance liquid chromatography (HPLC). To achieve high yields of extracted compounds, the procedure was optimized with regard to the relative parameters involved. The optimal conditions for enzymatic hydrolysis using pectinase treatment were a reaction time of 30 min and a concentration of 0.4 mg/mL at pH 3 for luteolin and pH 5.5 for apigenin. The optimal ultrasonic parameters were an exposure period of 30 min at a temperature of 25 °C using a power source of 80 W. Under these optimal conditions, the yields of luteolin and apigenin were increased to 42.5 and 25.3 mg/g, respectively, which represented a 26.1-fold and a 32.2-fold increase in the yields of these 2 compounds, respectively, compared with the control model of aqueous extraction without enzyme or ultrasonic treatment.

Integration of small-molecule discovery in academic biomedical research.

Rapid advances in biomedical sciences in recent years have drastically accelerated the discovery of the molecular basis of human diseases. The great challenge is how to translate the newly acquired knowledge into new medicine for disease prevention and treatment. Drug discovery is a long and expensive process, and the pharmaceutical industry has not been very successful at it, despite its enormous resources and spending on the process. It is increasingly realized that academic biomedical research institutions ought to be engaged in early-stage drug discovery, especially when it can be coupled to their basic research. To leverage the productivity of new-drug development, a substantial acceleration in validation of new therapeutic targets is required, which would require small molecules that can precisely control target functions in complex biological systems in a temporal and dose-dependent manner. In this review, we describe a process of integration of small-molecule discovery and chemistry in academic biomedical research that will ideally bring together the elements of innovative approaches to new molecular targets, existing basic and clinical research, screening infrastructure, and synthetic and medicinal chemistry to follow up on small-molecule hits. Such integration of multidisciplinary resources and expertise will enable academic investigators to discover novel small molecules that are expected to facilitate their efforts in both mechanistic research and new-drug target validation. More broadly academic drug discovery should contribute new entities to therapy for intractable human diseases, especially for orphan diseases, and hopefully stimulate and synergize with the commercial sector.

Target structure-based discovery of small molecules that block human p53 and CREB binding protein association.

Lysine acetylation of human tumor suppressor p53 in response to cellular stress signals is required for its function as a transcription factor that regulates cell cycle arrest, senescence, or apoptosis. Here, we report small molecules that block lysine 382-acetylated p53 association with the bromodomain of the coactivator CBP, an interaction essential for p53-induced transcription of the cell cycle inhibitor p21 in response to DNA damage. These chemicals were discovered in target structure-guided nuclear magnetic resonance spectroscopy screening of a focused chemical library constructed based on the structural knowledge of CBP bromodomain/p53-AcK382 binding. Structural characterization shows that these chemicals inhibit CBP/p53 association by binding to the acetyl-lysine binding site of the bromodomain. Cell-based functional assays demonstrate that the lead chemicals can modulate p53 stability and function in response to DNA damage.

Structure-based rational design of chemical ligands for AMPA-subtype glutamate receptors.

Ionotropic glutamate receptors (GluRs) function as an excitatory transmitter system in human brain, particularly in learning and memory. Development of small-molecule chemical ligands that selectively potentiate the ion channel activity of AMPA-subtype GluRs would hold promise for treating an exceptionally wide range of disorders including neurodegenerative diseases such as Alzheimer's. Toward this goal, we have obtained nearly complete main-chain NMR resonance assignments of the extracellular ligand-binding domain of GluR2, which enables us to investigate receptor-ligand interactions in physiological conditions at atomic detail. With our NMR structure-based methods, we have discovered several chemical compounds that bind specifically to the GluR2 protein. Notably, our initial lead compounds interact with GluR2 at sites near the interface of receptor dimerization, which plays a pivotal role in controlling receptor gating and desensitization. Our NMR structural analysis further reveals that the regions of GluR2 at the dimer interface exhibit distinct conformational dynamics as compared to the rest of the protein, which we hypothesize to be linked to the mechanisms by which the protein interacts with its ligand, either an agonist or antagonist. This newly discovered relationship of possibly coupling of ligand binding to receptor dimerization, gating and desensitization, which is being further validated, could serve as an excellent in vitro biophysical parameter to evaluate the potential biological effects of the chemical ligands being developed and optimized in our study.