Pharmacokinetic and Pharmacogenetic Factors Contributing to Platelet Function Recovery After Single Dose of Ticagrelor in Healthy Subjects

Objectives: This study aimed to elucidate the contribution of candidate single nucleotide polymorphisms (SNPs) related to pharmacokinetics on the recovery of platelet function after single dose of ticagrelor was orally administered to healthy Chinese subjects.Methods: The pharmacokinetic profiles of ticagrelor and its metabolite AR-C124910XX (M8), and the platelet aggregation (PA), were assessed after 180 mg of single-dose ticagrelor was orally administered to 51 healthy Chinese subjects. Effects of CYP2C19*2, CYP2C19*3, CYP3A5*3, UGT1A1*6, UGT1A1*28, UGT2B7*2, UGT2B7*3, SLCO1B1 388A>G, and SLCO1B1 521T>C, on the pharmacokinetics of ticagrelor and M8, and platelet function recovery were investigated.Results: The time to recover 50% of the maximum drug effect (RT50) ranging from 36 to 126 h with 46.9% CV had a remarkable individual difference and was positively associated with the half-life (t1/2) of M8 (r = 0.3901, P = 0.0067). The time of peak concentration (Tmax) of ticagrelor for CYP2C19*3 GG homozygotes was significantly higher than that of GA heterozygotes (P = 0.0027, FDR = 0.0243). Decreased peak concentration (Cmax) of M8 was significantly associated with SLCO1B1 388A>G A allele (P = 0.0152, FDR = 0.1368). CYP2C19*2 A was significantly related to decreased Cmax of M8 (P = 0.0455, FDR = 0.2048). While, the influence of these nine SNPs on the recovery of platelet function was not significant.Conclusion: Our study suggests that the elimination of M8 is an important factor in determining the recovery of platelet function. Although CYP2C19 and SLCO1B1 genetic variants were related to the pharmacokinetics of ticagrelor or M8, they did not show a significant effect on the platelet function recovery in this study.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT03092076, identifier: NCT0309207

Meta-analysis of the effect of expression of MYB transcription factor genes on abiotic stress

Background MYB proteins are a large group of transcription factors. The overexpression of MYB genes has been reported to improve abiotic stress tolerance in plant. However, due to the variety of plant species studied and the types of gene donors/recipients, along with different experimental conditions, it is difficult to interpret the roles of MYB in abiotic stress tolerance from published data. Methods Using meta-analysis approach, we investigated the plant characteristics involved in cold, drought, and salt stress in MYB-overexpressing plants and analyzed the degrees of influence on plant performance by experimental variables. Results The results show that two of the four measured plant parameters in cold-stressed plants, two of the six in drought-stressed, and four of the 13 in salt-stressed were significantly impacted by MYB overexpression by 22% or more, and the treatment medium, donor/recipient species, and donor type significantly influence the effects of MYB-overexpression on drought stress tolerance. Also, the donor/recipient species, donor type, and stress duration all significantly affected the extent of MYB-mediated salt stress tolerance. In summary, this study compiles and analyzes the data across studies to help us understand the complex interactions that dictate the efficacy of heterologous MYB expression designed for improved abiotic stress tolerance in plants

Simultaneous Isolation of Lactoferrin and Lactoperoxidase from Bovine Colostrum by SPEC 70 SLS Cation Exchange Resin

In this work, simultaneous isolation of lactoferrin (Lf) and lactoperoxidase (Lp) from defatted bovine colostrum by one-step cation exchange chromatography with SPEC 70 SLS ion-exchange resin was investigated. A RP-HPLC method for Lf and Lp determination was developed and optimized as the following conditions: detection wavelength of 220 nm, flow rate of 1 mL/min and acetonitrile concentration from 25% to 75% within 20 min. The adsorption process of Lf on SPEC 70 SLS resin was optimized using Lf standard as substrate. The maximum static binding capacity of SPEC 70 SLS resin was of 22.0 mg/g resin at 15 °C, pH 7.0 and adsorption time 3 h. The Lf adsorption process could be well described by the Langmuir adsorption isotherm model, with a maximum adsorption capacity of 21.73 mg/g resin at 15 °C. In batch fractionation of defatted colostrum, the binding capacities of SPEC 70 SLS resin for adsorbing Lf and Lp simultaneously under the abovementioned conditions were 7.60 and 6.89 mg/g resin, respectively, both of which were superior to those of CM Sepharose F.F. or SP Sepharose F.F. resins under the same conditions. As a result, SPEC 70 SLS resin was considered as a successful candidate for direct and economic purification of Lf and Lp from defatted colostrum

Propagation of Computer Virus under Human Intervention: A Dynamical Model

This paper examines the propagation behavior of computer virus under human intervention. A dynamical model describing the spread of computer virus, under which a susceptible computer can become recovered directly and an infected computer can become susceptible directly, is proposed. Through a qualitative analysis of this model, it is found that the virus-free equilibrium is globally asymptotically stable when the basic reproduction number R0≤1, whereas the viral equilibrium is globally asymptotically stable if R0>1. Based on these results and a parameter analysis, some appropriate measures for eradicating the spread of computer virus across the Internet are recommended

CsICE1 Functions in Cold Tolerance by Regulating Polyamine levels May through Interacting with Arginine Decarboxylase in the Tea Tree

Background: The identification of C-repeat binding factor (CBF), and the characterization as an inducer of CBF Expression 1 (ICE1), and a major activator for C-repeat binding factor, were important breakthroughs in the cold signaling network. Methods: In the present study, the full length cDNA of ICE1 was isolated from the tea tree (Camellia sinensis). CsICE1 protein was located in the cell nucleus as revealed by subcellular localization analysis. To investigate the biological functions of CsICE1, a transgenic line fused with the CsICE1 gene in Arabidopsis thaliana (arabidopsis) was generated by the floral dip method. Results: The CsICE1 was expressed differentially in various tea tree tissues, mostly in buds and leaves, and the transcript level of CsICE1 was increased after 1 h and peaked at 2 h under cold treatment. Transcription activity assay indicated that the spermine synthase (SPMS) and arginine decarboxylase (ADC) genes were possible targets of CsICE1. In addition, the values of net photosynthetic rate, transpiration rate, stomatal conductance in transgenic lines declined by less extent than wild-type plants under low temperatures. Furthermore, transcript levels of ADC genes in the transgenic lines had no apparent alteration under normal growth conditions but substantially increased under cold conditions, consistent of changes in free polyamine levels. Taken together, these results demonstrated that CsICE1 plays a positive role in cold tolerance, which may be due to the modulation of polyamine levels through interacting with CsADC

Gene expression analysis in leaf of Camellia sinensis reveals the response to fluoride

Tea plants (Camellia sinensis (L.) Kuntze) can hyperaccumulate fluoride (F-) without any toxic symptom, especially in mature leaves. However, the molecular mechanism of absorption and hyperaccumulation of F- was poorly understood in C. sinensis. Here, a transcriptomic analysis was performed to compare the responses to fluoride stress of tea leaves to understand F- accumulation and its influence on gene expression in C. sinensis leaves. The results indicated that numerous differentially expressed genes involved in ion absorption and transport exist in the process of F- absorption in C. sinensis leaves. The up-regulated expression of genes associated with uptake and transport of Ca2+ and K+ (CNGC, TPC1, CAX, and VHA) increased the intracellular and vacuole cation concentration during F- accumulation in C. sinensis leaves. We also found that some of AQP (PIPs and TIPs) genes may promote F- into the intracellular spaces and vacuoles in C. sinensis leaves, respectively. In addition, F- induced the expression of differential genes related to plant hormone metabolism and signaling pathways (ABA, auxin, and GA). Subsequently, a lot of transcription factors (WRKY, MYB, NAC, bHLH and AP2/ERF) were activated to respond to F- stress in tea leaves by regulating plant hormone signal transduction and other pathways. And ubiquitin systems were involved in the regulation of proteins homeostasis under F- stress indicating that they are responsible for the response of C. sinensis leaves to F-. Overall, these findings provide a comprehensive understanding of the F- absorption mechanism and its influence on gene expression in tea leaves

Metabolic analyses reveal different mechanisms of leaf color change in two purple-leaf tea plant (Camellia sinensis L.) cultivars

Plant breeding: Coloring tea leaves Researchers in China have uncovered how the leaves of purple-leaf tea varieties acquire their color. Wanping Fang and Xujun Zhu of Nanjing Agricultural University analyzed the biochemical profile and gene expression patterns in the young purple leaves and older green leaves of two purple tea varieties, one new and one previously studied. The purple leaves of both varieties had higher levels of red/purple pigments known as flavonoids, as well as increased expression of genes related to their synthesis. However, only the new variety also had increased chlorophyll levels in green leaves. Both varieties are purple because flavonoids mask the color of chlorophyll, but the process is driven by different mechanisms in each. These findings clarify how tea varieties develop different levels of flavonoids, which affect tea quality due to their antioxidant and antimicrobial activity

Transcriptome Analysis Reveals the Mechanism of Fluoride Treatment Affecting Biochemical Components in Camellia sinensis

Tea (Camellia sinensis (L.) O. Kuntze), one of the main crops in China, is high in various bioactive compounds including flavonoids, catechins, caffeine, theanine, and other amino acids. C. sinensis is also known as an accumulator of fluoride (F), and the bioactive compounds are affected by F, however, the mechanism remains unclear. Here, the effects of F treatment on the accumulation of F and major bioactive compounds and gene expression were investigated, revealing the molecular mechanisms affecting the accumulation of bioactive compounds by F treatment. The results showed that F accumulation in tea leaves gradually increased under exogenous F treatments. Similarly, the flavonoid content also increased in the F treatment. In contrast, the polyphenol content, free amino acids, and the total catechins decreased significantly. Special amino acids, such as sulfur-containing amino acids and proline, had the opposite trend of free amino acids. Caffeine was obviously induced by exogenous F, while the theanine content peaked after two day-treatment. These results suggest that the F accumulation and content of bioactive compounds were dramatically affected by F treatment. Furthermore, differentially expressed genes (DEGs) related to the metabolism of main bioactive compounds and amino acids, especially the pivotal regulatory genes of catechins, caffeine, and theanine biosynthesis pathways, were identified and analyzed using high-throughput Illumina RNA-Seq technology and qRT-PCR. The expression of pivotal regulatory genes is consistent with the changes of the main bioactive compounds in C. sinensis leaves, indicating a complicated molecular mechanism for the above findings. Overall, these data provide a reference for exploring the possible molecular mechanism of the accumulation of major bioactive components such as flavonoid, catechins, caffeine, theanine and other amino acids in tea leaves in response to fluoride treatment

Lifestyle Characteristics and Gene Expression Analysis of Colletotrichum camelliae Isolated from Tea Plant [Camellia sinensis (L.) O. Kuntze] Based on Transcriptome

Colletotrichum camelliae is one of the most serious pathogens causing anthracnose in tea plants, but the interactive relationship between C. camelliae and tea plants has not been fully elucidated. This study investigated the gene expression changes in five different growth stages of C. camelliae based on transcriptome analysis to explain the lifestyle characteristics during the infection. On the basis of gene ontology (GO) enrichment analyses of differentially expressed genes (DEGs) in comparisons of germ tube (GT)/conidium (Con), appressoria (App)/Con, and cellophane infectious hyphae (CIH)/Con groups, the cellular process in the biological process category and intracellular, intracellular part, cell, and cell part in the cellular component category were significantly enriched. Hydrolase activity, catalytic activity, and molecular_function in the molecular function category were particularly enriched in the infection leaves (IL)/Con group. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that the DEGs were enriched in the genetic information processing pathway (ribosome) at the GT stage and the metabolism pathway (metabolic pathways and biosynthesis of secondary metabolism) in the rest of the stages. Interestingly, the genes associated with melanin biosynthesis and carbohydrate-active enzymes (CAZys), which are vital for penetration and cell wall degradation, were significantly upregulated at the App, CIH and IL stages. Subcellular localization results further showed that the selected non-annotated secreted proteins based on transcriptome data were majorly located in the cytoplasm and nucleus, predicted as new candidate effectors. The results of this study may establish a foundation and provide innovative ideas for subsequent research on C. camelliae