Advances of Apetala2/Ethylene Response Factors in Regulating Development and Stress Response in Maize.

Apetala2/ethylene response factor (AP2/ERF) is one of the largest families of transcription factors, regulating growth, development, and stress response in plants. Several studies have been conducted to clarify their roles in Arabidopsis and rice. However, less research has been carried out on maize. In this review, we systematically identified the AP2/ERFs in the maize genome and summarized the research progress related to AP2/ERF genes. The potential roles were predicted from rice homologs based on phylogenetic and collinear analysis. The putative regulatory interactions mediated by maize AP2/ERFs were discovered according to integrated data sources, implying that they involved complex networks in biological activities. This will facilitate the functional assignment of AP2/ERFs and their applications in breeding strategy.

The Synthesis, Structure, and Dielectric Properties of a One-Dimensional Hydrogen-Bonded DL-α-Phenylglycine Supramolecular Crown-Ether-Based Inclusion Compound.

A novel hydrogen-bonded supramolecular crown-ether-based inclusion compound, [(DL-α-Phenylglycine)(18-crown-6)]+[(CoCl4)0.5]-(1), was obtained via evaporation in a methanolic solution at room temperature using DL-α-phenylglycine, 18-crown-6, cobalt chloride (CoCl2), and hydrochloric acid. Its structure, thermal properties, and electrical properties were characterized via elemental analysis, single-crystal X-ray diffraction, variable-temperature infrared spectroscopy, thermogravimetric analysis, differential scanning calorimetry, and variable temperature-variable frequency dielectric constant testing. The compound was a monoclinic crystal system in the C2 space group at low temperature (100 K) and room temperature (293 K). Analysis of the single crystal structure showed that [(CoCl4)0.5]- presented an edge-sharing ditetrahedral structure in the disordered state, while the protonated DL-α-phenylglycine molecule in the disordered state and intramolecular hydroxyl group (-OH) underwent dynamic rocking, causing a significant stretching motion of the O-H···Cl-type one-dimensional hydrogen bond chain. This resulted in dielectric anomalies in the three axes of the crystal, thus showing significant dielectric anisotropy.

Studies on Lotus Genomics and the Contribution to Its Breeding.

Lotus (Nelumbo nucifera), under the Nelumbonaceae family, is one of the relict plants possessing important scientific research and economic values. Because of this, much attention has been paid to this species on both its biology and breeding among the scientific community. In the last decade, the genome of lotus has been sequenced, and several high-quality genome assemblies are available, which have significantly facilitated functional genomics studies in lotus. Meanwhile, re-sequencing of the natural and genetic populations along with different levels of omics studies have not only helped to classify the germplasm resources but also to identify the domestication of selected regions and genes controlling different horticultural traits. This review summarizes the latest progress of all these studies on lotus and discusses their potential application in lotus breeding.

Metabolomics Analyses of Cotyledon and Plumule Showing the Potential Domestic Selection in Lotus Breeding.

Lotus (Nelumbo nucifera) seeds are widely consumed as functional food or herbal medicine, of which cotyledon (CL) is the main edible part, and lotus plumule (LP) is commonly utilized in traditional Chinese medicine. However, few studies have been conducted to investigate the chemical components of CL and LP in dry lotus seeds, not to mention the comparison between wild and domesticated varieties. In this study, a widely targeted metabolomics approach based on Ultra Performance Liquid Chromatography-electrospray ionization-Tandem mass spectrometry (UPLC-ESI-MS/MS) was utilized to analyze the metabolites in CL and LP of China Antique ("CA", a wild variety) and Jianxuan-17 ("JX", a popular cultivar). A total of 402 metabolites were identified, which included flavonoids (23.08% to 27.84%), amino acids and derivatives (14.18-16.57%), phenolic acids (11.49-12.63%), and lipids (9.14-10.95%). These metabolites were classified into ten clusters based on their organ or cultivar-specific characters. Most of these metabolites were more abundant in LP than in CL for both varieties, except for metabolites belonging to organic acids and lipids. The analysis of differentially accumulated metabolites (DAMs) demonstrated that more than 25% of metabolites detected in our study were DAMs in CL and LP comparing "JX" with "CA", most of which were less abundant in "JX", including 35 flavonoids in LP, 23 amino acids and derivatives in CL, 7 alkaloids in CL, and 10 nucleotides and derivatives in LP, whereas all of 11 differentially accumulated lipids in LP were more abundant in "JX". Together with the fact that the seed yield of "JX" is much higher than that of "CA", these results indicated that abundant metabolites, especially the functional secondary metabolites (mainly flavonoids and alkaloids), were lost during the process of breeding selection.

Pharmacokinetics and Tissue Distribution of a Novel Bis-Chelated Gold(I) Diphosphine Compound, Bis(2,3-bis(tert-butylmethylphosphino)Quinoxaline)Aurate(I), in Rats.

GC20, a novel soluble bis-chelated gold(I)-diphosphine compound, has been reported as a promising anticancer candidate. Assessing the pharmacokinetic properties of GC20 is critical for its medicinal evaluation. First, a sensitive and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed and well validated to determine GC20 in rat plasma and rat tissue homogenate after one step protein precipitation. Chromatographic separation was achieved on an Angilent ZORBAX-C18 column (3.5 µm, 2.1 × 50 mm) with gradient elution and mass spectrometry was performed on a triple quadrupole in positive ion mode using an electrospray ionization source. This method was then applied to investigate the pharmacokinetics and tissue distribution of GC20 in rats after intravenous administration. The results showed that the plasma exposure of GC20 in vivo increased with increasing doses after a single dose. However, after multiple doses, a significant accumulation and a saturation at elimination were observed for GC20 in rats. Moreover, after intravenous administration, GC20 was widely distributed in various tissues, with the highest levels in the lung, spleen, liver, and pancreas, followed by the kidney and heart, while the lowest level was found in the brain. This is the first report on the pharmacokinetic properties of GC20.

Wnt/ß-catenin signaling plays an important role in the protective effects of FDP-Sr against oxidative stress induced apoptosis in MC3T3-E1 cell.

Strontium fructose 1,6-diphosphate (FDP-Sr) is a new strontium-containing compound. The primary aim of this study was to clarify whether the structure component of FDP-Sr, FDP could benefit the protective effect of Sr (II) against oxidative stress induced apoptosis, and meanwhile to further explore the important role of Wnt/ß-catenin signaling in the anti-apoptosis effect of FDP-Sr in response to oxidative stress induced by H2O2 in an osteoblastic MC3T3-E1 cell line. Results showed that FDP-Sr could improve the osteoblastic differentiation under oxidative stress with induced cell proliferation and improved mineralization. The inhibition effect of FDP-Sr on cell apoptosis induced by H2O2 was proved by reduced reactive oxygen species production and activated caspase3. Under oxidative stress, mRNA and protein levels of phospho-ß-catenin reduced, while ß-catenin increased in the FDP-Sr treatment cell, leaded to the up-regulations of Runx2 and OPG at both mRNA and protein levels, finally improved the differentiation of osteoblasts. By the engagement of Wnt/ß-catenin pathway's inhibitor (XAV-939), the protective effects of FDP-Sr on osteoblastic differentiation against oxidative stress were repressed along with inhibited wnt/ß-catenin signaling and reduced mRNA and protein levels of Runx2 and OPG. In conclusion, FDP-Sr was demonstrated to protect osteoblast differentiation from oxidative damage induced by H2O2 through up-regulation of Wnt/ß-catenin signaling, and FDP in FDP-Sr was able to directly improve the oxidative stress injury through its ROS scavenging ability.

Guanfu base A, an antiarrhythmic alkaloid of Aconitum coreanum, Is a CYP2D6 inhibitor of human, monkey, and dog isoforms.

Guanfu base A (GFA) is a novel heterocyclic antiarrhythmic drug isolated from Aconitum coreanum (Lèvl.) rapaics and is currently in a phase IV clinical trial in China. However, no study has investigated the influence of GFA on cytochrome P450 (P450) drug metabolism. We characterized the potency and specificity of GFA CYP2D inhibition based on dextromethorphan O-demethylation, a CYP2D6 probe substrate of activity in human, mouse, rat, dog, and monkey liver microsomes. In addition, (+)-bufuralol 1'-hydroxylation was used as a CYP2D6 probe for the recombinant form (rCYP2D6), 2D1 (rCYP2D1), and 2D2 (rCYP2D2) activities. Results show that GFA is a potent noncompetitive inhibitor of CYP2D6, with inhibition constant Ki = 1.20 ± 0.33 µM in human liver microsomes (HLMs) and Ki = 0.37 ± 0.16 µM for the human recombinant form (rCYP2D6). GFA is also a potent competitive inhibitor of CYP2D in monkey (Ki = 0.38 ± 0.12 µM) and dog (Ki = 2.4 ± 1.3 µM) microsomes. However, GFA has no inhibitory activity on mouse or rat CYP2Ds. GFA did not exhibit any inhibition activity on human recombinant CYP1A2, 2A6, 2C8, 2C19, 3A4, or 3A5, but showed slight inhibition of 2B6 and 2E1. Preincubation of HLMs and rCYP2D6 resulted in the inactivation of the enzyme, which was attenuated by GFA or quinidine. Beagle dogs treated intravenously with dextromethorphan (2 mg/ml) after pretreatment with GFA injection showed reduced CYP2D metabolic activity, with the Cmax of dextrorphan being one-third that of the saline-treated group and area under the plasma concentration-time curve half that of the saline-treated group. This study suggests that GFA is a specific CYP2D6 inhibitor that might play a role in CYP2D6 medicated drug-drug interaction.

A comprehensive assay for nine major cytochrome P450 enzymes activities with 16 probe reactions on human liver microsomes by a single LC/MS/MS run to support reliable in vitro inhibitory drug-drug interaction evaluation.

1. A comprehensive method for the simultaneous characterization of xenobiotic compound inhibition of nine major CYP enzymes in human liver microsomes was established by using 16 CYP-catalyzed reactions of 14 probe substrates with three cocktail incubation sets and a single LC/MS/MS analysis. 2. The three cocktail subgroups were developed to minimize the effects of organic solvents, polyunsaturated fatty acids and mutual substrate interactions: Group I was composed of tolbutamide (CYP2C9), S-mephenytoin (CYP2C19), testosterone (CYP3A4), dextromethorphan (CYP2D6); Group II was composed of nifedipine (CYP3A4), midazolam (CYP3A4), coumarin (CYP2A6), bupropion (CYP2B6), diclofenac (CYP2C9); Group III was composed of phenacetin (CYP1A2), chlorzoxazone (CYP2E1), omeprazole (CYP2C19 and CYP3A4), paclitaxel (CYP2C8), (+)-bufuralol (CYP2D6). In the case of CYP2C9, CYP2C19, CYP2D6 and CYP3A4, multiple probe substrates were used due to the phenomenon of multiple substrate-binding pockets and substrate-dependent inhibition. All probe metabolites were simultaneously analyzed with a polarity switching mode in a single LC/MS/MS run. 3. This method was validated against the single probe substrate assay using 12 well-characterized CYP inhibitors and two new entities (GT0918, MDV3100). The IC50 values of each inhibitor in the cocktail agreed well with that of the individual probe drug as well as with values reported in previous literatures.

General combining ability of most yield-related traits had a genetic basis different from their corresponding traits per se in a set of maize introgression lines.

Evaluation of combining ability is a crucial process in hybrid breeding, and dissection of the genetic basis of combining ability will facilitate hybrid breeding. In this study, molecular markers significantly associated with general combining ability (GCA) of seven yield-related traits and the traits per se were detected in a set of maize introgression lines (ILs) under three environments. Totally 25 and 31 significant loci for GCA and the traits per se were commonly detected under multiple environments, respectively. Correlation analysis and comparison among these significant loci revealed that the genetic basis of GCA of these yield-related traits was generally different from that of the traits per se except for the trait of ear row number. In addition, GCA of the ILs was positively and significantly correlated to the total relative effects of significant GCA loci in the ILs in general, implying that the GCA loci identified in this study would be useful in molecular breeding. Correlation analysis also showed that the GCA of yield per plant was strongly correlated to the GCA of kernel number per row, ear length and 100-kernel-weight, thus these traits were more important in genetic improvement for GCA. Results in this study would provide useful information for hybrid breeding in maize.

Identification of combining ability loci for five yield-related traits in maize using a set of testcrosses with introgression lines.

Combining ability is essential for hybrid breeding in crops. However, the genetic basis of combining ability remains unclear and has been seldom investigated. Identifying molecular markers associated with this complex trait would help to understand its genetic basis and provide useful information for hybrid breeding in maize. In this study, we identified genetic loci of general combining ability (GCA) and specific combining ability (SCA) for five yield-related traits under three environments using a set of testcrosses with introgression lines (ILs). GCA or SCA of the five yield-related traits of the ILs was estimated by the performance of testcrosses with four testers from different heterotic groups. Genetic correlations between GCA of the traits and the corresponding traits per se were not significant or not strong, suggesting that the genetic basis between them is different. A total of 56 significant loci for GCA and 21 loci for SCA were commonly identified in at least two environments, and only 5 loci were simultaneously controlling GCA and SCA, indicating that the genetic basis of GCA and SCA is different. For all of the traits investigated, positive and significant correlations between the number of GCA loci in the ILs and the performance of the corresponding GCA of the ILs were detected, implying that pyramiding GCA loci would have positive effect on the performance of GCA. Results in this study would be useful for maize hybrid breeding.

Metacognitive prompts and numerical ordinality in solving word problems: An eye-tracking study.

BACKGROUND: The ability to translate concrete manipulatives into abstract mathematical formulas can aid in the solving of mathematical word problems among students, and metacognitive prompts play a significant role in enhancing this process. AIMS: Based on the concept of semantic congruence, we explored the effects of metacognitive prompts and numerical ordinality on information searching and cognitive processing, throughout the process of solving mathematical word problems among primary school students in China. SAMPLE: Participants included 73 primary school students (38 boys and 35 girls) with normal or corrected visual acuity. METHODS: This study was based on a 2 (prompt information: no-prompt, metacognitive-prompt) × 2 (number attribute: cardinal number, ordinal number) mixed experimental design. We analysed multiple eye-movement indices, such as fixation duration, saccadic amplitude, and pupil size, since they pertained to the areas of interest. RESULTS: When solving both types of problems, pupil sizes were significantly smaller under the metacognitive-prompt condition compared with the no-prompt condition, and shorter dwell time for specific sentences, conditional on metacognitive prompts, indicated the optimization of the presented algorithm. Additionally, the levels of fixation durations and saccadic amplitudes were significantly higher when solving ordinal number word problems compared with solving ordinal number problems, indicating that primary school students were less efficient in reading and faced increased levels of difficulty when solving ordinal number problems. CONCLUSIONS: The results indicate that for Chinese upper-grade primary school students, cognitive load was lower in the metacognitive prompting condition and when solving cardinal problems, and higher when solving ordinal problems.

Effects of health qigong exercise on sleep and life quality in patients with drug abuse.

Objective: The aim of this study was to investigate the effect of Health Qigong (HQ) exercise on the subjective and objective sleep quality and the quality of life in male patients with drug abuse who received treatment at a mandatory drug rehabilitation residential institution. Methods: Ninety male patients (mean age, 36.85 ± 8.72 y) were included and randomly divided into the Health Qigong (HQ) group, aerobic exercise (AE) group, or control group. The participants in the HQ and AE groups exercised four times a week for 1 hour per session for 12 weeks, while the control group maintained their original lifestyle. The following parameters were recorded before and after exercise: Pittsburgh Sleep Quality Index (PSQI); SF-36; and total sleep time, sleep efficiency, sleep latency, deep sleep time, deep sleep rate, light sleep time, and light sleep rate using actigraphy. Results: Health Qigong improved the subjective sleep quality, objective sleep quality, and quality of life after a 12-week intervention. Considering the subjective sleep quality, Health Qigong helped improve several aspects of the PSQI, including the overall sleep quality (p < 0.01), sleep latency (p < 0.01), sleep duration (p < 0.01), sleep latency (p < 0.01), sleep disturbance (p < 0.01), and day dysfunction (p < 0.01). In relation to the objective sleep quality, Health Qigong improved the total sleep time (p < 0.01), sleep efficiency (p < 0.01), sleep latency (p < 0.01), deep and light sleep rate (p < 0.01). Considering the quality of life, Health Qigong helped improve the role-physical (p < 0.01), general health (p < 0.01), bodily pain (p < 0.01), and mental health (p < 0.01) aspects of SF-36. Conclusion: Health Qigong may be an effective approach to improve the subjective and objective quality of sleep and life quality of patients with drug abuse.

Exploring domestication pattern in lotus: insights from dispensable genome assembly.

Lotus (Nelumbo nucifera Gaertn.), an important aquatic plant in horticulture and ecosystems, has been cultivated for more than 7000 years and domesticated into three different subgroups: flower lotus, rhizome lotus, and seed lotus. To explore the domesticated regions of each subgroup, re-sequencing data of 371 lotus accessions collected from the public database were aligned to the genome of 'China-Antique (CA)'. Unmapped reads were used to build the dispensable genome of each subgroup using a metagenome-like assembly strategy. More than 27 Mb of the dispensable genome in these three subgroups and the wild group was assembled, of which 11,761 genes were annotated. Some of the contigs in the dispensable genome were similar to the genomic segments of other lotus accessions other than 'CA'. The annotated genes in each subgroup played essential roles in specific developmental processes. Dissection of selective signals in three cultivated subgroups also demonstrated that subgroup-specific metabolic pathways, such as the brassinosteroids metabolism enrichment in FL, associated with these selected genes in each subgroup and the contigs in dispensable genome nearly located in the domesticated regions of each subgroup, respectively. Our data presented a valuable resource for facilitating lotus genomic studies, complemented the helpful information to the reference genome, and shed light on the selective signals of domesticated subgroups.

Identifying RNA Modifications by Direct RNA Sequencing Reveals Complexity of Epitranscriptomic Dynamics in Rice.

Transcriptome analysis based on high-throughput sequencing of a cDNA library has been widely applied to functional genomic studies. However, the cDNA dependence of most RNA sequencing techniques constrains their ability to detect base modifications on RNA, which is an important element for the post-transcriptional regulation of gene expression. To comprehensively profile the N6-methyladenosine (m6A) and N5-methylcytosine (m5C) modifications on RNA, direct RNA sequencing (DRS) using the latest Oxford Nanopore Technology was applied to analyze the transcriptome of six tissues in rice. Approximately 94 million reads were generated, with an average length ranging from 619 nt to 1013 nt, and a total of 45,707 transcripts across 34,763 genes were detected. Expression profiles of transcripts at the isoform level were quantified among tissues. Transcriptome-wide mapping of m6A and m5C demonstrated that both modifications exhibited tissue-specific characteristics. The transcripts with m6A modifications tended to be modified by m5C, and the transcripts with modifications presented higher expression levels along with shorter poly(A) tails than transcripts without modifications, suggesting the complexity of gene expression regulation. Gene Ontology analysis demonstrated that m6A- and m5C-modified transcripts were involved in central metabolic pathways related to the life cycle, with modifications on the target genes selected in a tissue-specific manner. Furthermore, most modified sites were located within quantitative trait loci that control important agronomic traits, highlighting the value of cloning functional loci. The results provide new insights into the expression regulation complexity and data resource of the transcriptome and epitranscriptome, improving our understanding of the rice genome.

Liquid chromatography/tandem mass spectrometry method for quantification of trans-stilbene glycoside in rat plasma and its pharmacokinetic application.

A rapid and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of trans-stilbene glycoside (SG) in rat plasma. As trans-SG can be rapidly isomerized under light exposure, trans-SG plasma samples were prepared in the dark and assayed immediately. Trans-SG and internal standard were extracted by protein precipitation. Chromatographic separation was achieved on a C(18) column with a gradient elution program. The detection of analytes was performed by negative ion via multiple reaction monitoring mode. The precursor-to-product ions of m/z 405.1 → 242.9 for trans-SG and m/z 389.1 → 226.9 for polydatin (internal standard) were monitored. No interference of endogenous components was observed for any plasma samples that we studied.The method was linear over the concentration range of 1.0-1000.0 ng/mL with a good correlation coefficient. The lower limit of quantification was 1.0 ng/mL for trans-SG. The intra and inter-batch accuracy for trans-SG in stable rat plasma samples ranged from 93.3 to 102.7% and the variation was less than 8.1%. The extraction recoveries of trans-SG in rat plasma were from 102.8 to 112.4% and the matrix effects were also acceptable. This method was successfully applied to pharmacokinetic study of trans-SG in rats after intravenous administration.

Sleep disorders as a prospective intervention target to prevent drug relapse.

Objective: The high rate of relapse has become the primary obstacle of drug rehabilitation. In this study, we explored the relationship between sleep disorders and relapse inclination in substance users, as well as the potential mediating mechanisms and corresponding interventions. Methods: A total of 392 male substance users were recruited to complete the questionnaires on sleep disorders, quality of life and relapse inclination. On account of this, 60 participants with sleep disorders were randomly screened and allocated to the intervention and control groups. The former received 12 weeks of Health Qigong aimed at treating sleep disorders, whereas the latter performed their regular production work. Results: Sleep disorders had a positive effect on relapse inclination, quality of life was a potential mediator of this relationship, and 12-week Health Qigong designed to treat sleep disorders improved not only their sleep quality but also their overall quality of life, which in turn reduce the tendency to relapse. Conclusion: Current research not only explores the high-risk factors influencing relapse, but also develops customized intervention strategies, which have theoretical and practical implications for decreasing relapse and increasing abstinence.

Genome-Wide Identification and Characterization of Heat Shock Protein 20 Genes in Maize.

Maize is an important cereal crop worldwide and is sensitive to abiotic stresses in fluctuant environments that seriously affect its growth, yield, and quality. The small heat shock protein (HSP20) plays a crucial role in protecting plants from abiotic stress. However, little is known about HSP20 in maize (ZmHSP20). In this study, 44 ZmHSP20s were identified, which were unequally distributed over 10 chromosomes, and 6 pairs of ZmHSP20s were tandemly presented. The gene structure of ZmHSP20s was highly conserved, with 95% (42) of the genes having no more than one intron. The analysis of the cis-element in ZmHSP20s promoter demonstrated large amounts of elements related to hormonal and abiotic stress responses, including abscisic acid (ABA), high temperature, and hypoxia. The ZmHSP20s protein had more than two conserved motifs that were predictably localized in the cytoplasm, nucleus, endoplasmic reticulum, peroxisome, mitochondria, and plasma. Phylogenetic analysis using HSP20s in Arabidopsis, rice, maize, and Solanum tuberosum indicated that ZmHSP20s were classified into 11 categories, of which each category had unique subcellular localization. Approximately 80% (35) of ZmHSP20 were upregulated under heat stress at the maize seedling stage, whereas the opposite expression profiling of 10 genes under 37 and 48 °C was detected. A total of 20 genes were randomly selected to investigate their expression under treatments of ABA, gibberellin (GA), ethylene, low temperature, drought, and waterlogging, and the results displayed that more than half of these genes were downregulated while ZmHSP20-3, ZmHSP20-7, ZmHSP20-24, and ZmHSP20-44 were upregulated under 1 h treatment of ethylene. A yeast-one-hybrid experiment was conducted to analyze the binding of four heat stress transcription factors (ZmHSFs) with eight of the ZmHSP20s promoter sequences, in which ZmHSF3, ZmHSF13, and ZmHSF17 can bind to most of these selected ZmHSP20s promoters. Our results provided a valuable resource for studying HSP20s function and offering candidates for genetic improvement under abiotic stress.

Comparative pharmacokinetics of amphotericin B after single- and multiple-dose administration of G-ABCD and conventional amphotericin B deoxycholate to rats.

OBJECTIVE: G-ABCD is a biosimilar product of amphotericin B colloidal dispersion (ABCD). This study was designed to systematically examine the plasma pharmacokinetics (PK) and tissue distribution of G-ABCD in rats, using amphotericin B deoxycholate (DAmB) as a positive control. METHODS: Male Sprague-Dawley rats received single dose or 14 doses of G-ABCD (1.0, 2.0 or 5.0 mg/kg) or the conventional micellar formulation DAmB) (1.0 mg/kg) via intravenous injection. Plasma and tissue samples were obtained for analysis of amphotericin B concentration by liquid chromatography-tandem mass spectrometry. RESULTS: After a single-dose administration of 1 mg/kg, G-ABCD resulted in a significantly lower plasma peak drug concentration (Cmax) (1536 vs. 5256 ng/mL) and area under the curve from time 0 to ∞ (AUC0-∞) (3972 vs. 7006 h ng/mL) of non-complexed amphotericin B than DAmB. G-ABCD was associated with quicker distribution but slower elimination of amphotericin B than DAmB. Amphotericin B concentration reached a steady state after seven doses of G-ABCD. After multiple doses of 1 mg/kg, G-ABCD showed a lower peak level and longer half-life of amphotericin B in plasma than DAmB. G-ABCD treatment in rats was associated with relatively higher distribution to liver and spleen, but reduced amphotericin B delivery to kidneys, the major target organ of toxicity. CONCLUSION: These results suggest that G-ABCD provides a flatter but more lasting plasma level of amphotericin B and lower kidney burden in rats than DAmB.

Pharmacokinetic and pharmacodynamic profiling of generic amphotericin B colloidal dispersion in a rat model of invasive candidiasis.

OBJECTIVES: We reported the pharmacokinetic/pharmacodynamic (PK/PD) targets of a biosimilar generic product of amphotericin B colloidal dispersion (G-ABCD) againstCandida albicans (MIC 1-2 µg/mL) in a rat model of invasive candidiasis (IC) to facilitate its precision administration. METHODS: Single-dose plasma PKs of G-ABCD was studied in a rat IC model following intravenous administration at doses of 0.0625-10 mg/kg. Amphotericin B concentrations were determined and PK parameters were calculated based on the concentrations in plasma. The efficacy of G-ABCD was evaluated after single administration by the log reduction of CFU counts in kidney, liver, spleen and lung. The relationship between G-ABCD PK/PD index and log CFU reduction in kidney was calculated. RESULTS: Following intravenous administration of G-ABCD at doses of 0.0625-10 mg/kg to rats, the maximum plasma concentration (Cmax) was 0.05-0.82 mg/L and the area under the concentration-time curve from 0 to 24 h (AUC0-24) was 0.50-5.29 mg h/L. G-ABCD showed potent antifungal activity against C. albicans C-13 with a maximum log CFU reduction of 2.1 in kidney. The mean AUC0-24/MIC target of G-ABCD against C. albicans was 0.97 for stasis, 1.40 for 1-log kill and 3.34 for 2-log kill, and the mean Cmax/MIC target was 0.063 for stasis, 0.097 for 1-log kill and 0.348 for 2-log kill. CONCLUSIONS: The antifungal effect of G-ABCD was potent and correlated with AUC0-24/MIC and Cmax/MIC in this rat model of IC. The results of this study provide data for optimising G-ABCD dosing regimens and breakpoints for antifungals.

Association between metabolic profiles in urine and bone mineral density of pre- and postmenopausal Chinese women.

OBJECTIVE: In the present study, we aimed to characterize the pathological development of menopausal osteoporosis, as well as to explore potential biomarkers and metabolic pathways involved in osteoporosis. METHODS: Urine samples from 322 female participants categorized by menopause status and different bone conditions were collected and analyzed based on a gas chromatography-mass spectrometry (GC-MS) approach. Multivariate and univariate statistical analyses were carried out for urinary metabolomic profile characterization and comparison. RESULTS: Seventeen metabolites in the low bone mineral density (BMD) groups were clearly differentiated from those in normal BMD groups. Among these 17 differentiating metabolites, taurine, ß-alanine, and 5-hydroxycaproic acid were found to be potential biomarkers of osteoporosis. The taurine metabolic pathway and the ß-alanine metabolic pathway were found to be related to menopause and bone loss. CONCLUSIONS: Based on the GC-MS metabolomic platform, four typical pathological phases during the progression of postmenopausal osteoporosis were described. Several differentiating metabolites and metabolic pathways were found to be closely related to the pathology of postmenopausal osteoporosis. Our results provided a solid foundation for further studies on early diagnosis and pathomechanistic evaluation.