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1.
Artigo em Inglês | MEDLINE | ID: mdl-33400617

RESUMO

This study was to evaluate the effect of resveratrol on the pharmacokinetics of ticagrelor in rats and the metabolism of ticagrelor in human CYP3A4 and liver microsomes. Eighteen Sprague-Dawley rats were randomly divided into three groups: group A (control group), group B (50mg/kg resveratrol), and group C (150mg/kg resveratrol ). After 30 minutes administration of resveratrol, a single dose of ticagrelor (18mg/kg) was administered orally. The vitro experiment was performed to examine the influence of resveratrol on ticagrelor metabolism in CYP3A4*1, human, and rat liver microsomes. Serial biological samples were assayed by validated UHPLC-MS/MS methods. In vivo study, the AUC and Cmax of ticagrelor in group B and C appeared to be significantly higher than the control group, while Vz/F and CLz/F of ticagrelor in group B and C were significantly decreased. In vitro study, resveratrol exhibited an inhibitory effect on CYP3A4*1, human and rat liver microsomes. The IC50 values of resveratrol were 56.75µM,69.07µM and 14.22µM, respectively. Our results indicated that resveratrol had a inhibitory effect on the metabolism of ticagrelor in vitro and vivo. It should be paid more attention to the clinical combination of resveratrol with ticagrelor and ticagrelor plasma concentration should be monitored to avoid the occurrence of adverse reaction.

2.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 38(6): 642-646, 2020 Dec 01.
Artigo em Chinês | MEDLINE | ID: mdl-33377340

RESUMO

OBJECTIVE: To study the comprehensive impact of scar and maxillary expansion combined with protraction on the development of maxilla with cleft lip and palate after repair operation. METHODS: In the original finite element model of the maxilla with cleft palate, a finite element model of the maxilla with cleft lip and palate was established by using Boolean operation in ANSYS. Scar force after cleft lip and palate repair and maxillary expansion force combined with protraction were added simultaneously to process the stress analysis. RESULTS: Maxillary deformation occurred in the three-dimensional direction. The comparison of displacements was as follows: X-axis>Z-axis>Y-axis. CONCLUSIONS: Maxillary growth is significantly inhibited in the three-dimensional direction under the comprehensive impact of scar and maxillary expansion combined with protraction after repair operation, especially transverse and sagittal growth.


Assuntos
Fenda Labial , Fissura Palatina , Cicatriz/patologia , Fenda Labial/cirurgia , Fissura Palatina/patologia , Fissura Palatina/cirurgia , Análise de Elementos Finitos , Humanos , Maxila/patologia , Maxila/cirurgia , Técnica de Expansão Palatina
3.
Artigo em Inglês | MEDLINE | ID: mdl-33314677

RESUMO

During a long-duration manned spaceflight mission, such as flying to Mars and beyond, all crew members will spend a long period in an independent spacecraft with closed-loop bioregenerative life-support systems. Saving resources and reducing medical risks, particularly in mental heath, are key technology gaps hampering human expedition into deep space. In the 1960s, several scientists proposed that an induced state of suppressed metabolism in humans, which mimics 'hibernation', could be an ideal solution to cope with many issues during spaceflight. In recent years, with the introduction of specific methods, it is becoming more feasible to induce an artificial hibernation-like state (synthetic torpor) in non-hibernating species. Natural torpor is a fascinating, yet enigmatic, physiological process in which metabolic rate (MR), body core temperature (Tb ) and behavioural activity are reduced to save energy during harsh seasonal conditions. It employs a complex central neural network to orchestrate a homeostatic state of hypometabolism, hypothermia and hypoactivity in response to environmental challenges. The anatomical and functional connections within the central nervous system (CNS) lie at the heart of controlling synthetic torpor. Although progress has been made, the precise mechanisms underlying the active regulation of the torpor-arousal transition, and their profound influence on neural function and behaviour, which are critical concerns for safe and reversible human torpor, remain poorly understood. In this review, we place particular emphasis on elaborating the central nervous mechanism orchestrating the torpor-arousal transition in both non-flying hibernating mammals and non-hibernating species, and aim to provide translational insights into long-duration manned spaceflight. In addition, identifying difficulties and challenges ahead will underscore important concerns in engineering synthetic torpor in humans. We believe that synthetic torpor may not be the only option for manned long-duration spaceflight, but it is the most achievable solution in the foreseeable future. Translating the available knowledge from natural torpor research will not only benefit manned spaceflight, but also many clinical settings attempting to manipulate energy metabolism and neurobehavioural functions.

4.
J Pharm Pharmacol ; 72(10): 1405-1411, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32608074

RESUMO

OBJECTIVE: In this study, we aimed to investigate the potential interaction of apatinib and buspirone and underlying mechanism. METHODS: UPLC-MS/MS assay was applied to determine the concentrations of buspirone and its main metabolites (1-PP and 6-OH buspirone) after incubated with liver microsomes. Moreover, the connection of in vitro and in vivo was further determined. Sprague Dawley rats were randomly divided into two groups: group A (20 mg/kg buspirone) and group B (buspirone vs 40 mg/kg apatinib). Tail vein blood was collected and subjected to the UPLC-MS/MS detection. KEY FINDINGS: Apatinib inhibited the generations of 1-PP and 6-OH buspirone dose-dependently with IC50 of 1.76 and 2.23 µm in RLMs, and 1.51 and 1.48 µm in HLMs, respectively. There was a mixed mechanism underlying such an inhibition effect. In rat, AUC(0- t ) , AUC(0-∞) , Tmax and Cmax of buspirone and 6-OH buspirone increased significantly while co-administering with apatinib, but Vz/F and CLz/F decreased obviously while comparing group A with group B . CONCLUSIONS: Apatinib suppresses the CYP450 based metabolism of buspirone in a mixed mechanism and boosted the blood exposure of prototype drug and 6-OH buspirone dramatically. Therefore, extra caution should be taken when combining apatinib with buspirone in clinic.

5.
Mol Plant ; 13(5): 745-759, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32017998

RESUMO

Improved soybean cultivars have been adapted to grow at a wide range of latitudes, enabling expansion of cultivation worldwide. However, the genetic basis of this broad adaptation is still not clear. Here, we report the identification of GmPRR3b as a major flowering time regulatory gene that has been selected during domestication and genetic improvement for geographic expansion. Through a genome-wide association study of a diverse soybean landrace panel consisting of 279 accessions, we identified 16 candidate quantitative loci associated with flowering time and maturity time. The strongest signal resides in the known flowering gene E2, verifying the effectiveness of our approach. We detected strong signals associated with both flowering and maturity time in a genomic region containing GmPRR3b. Haplotype analysis revealed that GmPRR3bH6 is the major form of GmPRR3b that has been utilized during recent breeding of modern cultivars. mRNA profiling analysis showed that GmPRR3bH6 displays rhythmic and photoperiod-dependent expression and is preferentially induced under long-day conditions. Overexpression of GmPRR3bH6 increased main stem node number and yield, while knockout of GmPRR3bH6 using CRISPR/Cas9 technology delayed growth and the floral transition. GmPRR3bH6 appears to act as a transcriptional repressor of multiple predicted circadian clock genes, including GmCCA1a, which directly upregulates J/GmELF3a to modulate flowering time. The causal SNP (Chr12:5520945) likely endows GmPRR3bH6 a moderate but appropriate level of activity, leading to early flowering and vigorous growth traits preferentially selected during broad adaptation of landraces and improvement of cultivars.

6.
Plant Biotechnol J ; 18(2): 389-401, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31278885

RESUMO

Landraces often contain genetic diversity that has been lost in modern cultivars, including alleles that confer enhanced local adaptation. To comprehensively identify loci associated with adaptive traits in soya bean landraces, for example flowering time, a population of 1938 diverse landraces and 97 accessions of the wild progenitor of cultivated soya bean, Glycine soja was genotyped using tGBS® . Based on 99 085 high-quality SNPs, landraces were classified into three sub-populations which exhibit geographical genetic differentiation. Clustering was inferred from STRUCTURE, principal component analyses and neighbour-joining tree analyses. Using phenotypic data collected at two locations separated by 10 degrees of latitude, 17 trait-associated SNPs (TASs) for flowering time were identified, including a stable locus Chr12:5914898 and previously undetected candidate QTL/genes for flowering time in the vicinity of the previously cloned flowering genes, E1 and E2. Using passport data associated with the collection sites of the landraces, 27 SNPs associated with adaptation to three bioclimatic variables (temperature, daylength, and precipitation) were identified. A series of candidate flowering genes were detected within linkage disequilibrium (LD) blocks surrounding 12 bioclimatic TASs. Nine of these TASs exhibit significant differences in flowering time between alleles within one or more of the three individual sub-populations. Signals of selection during domestication and/or subsequent landrace diversification and adaptation were detected at 38 of the 44 flowering and bioclimatic TASs. Hence, this study lays the groundwork to begin breeding for novel environments predicted to arise following global climate change.


Assuntos
Adaptação Fisiológica , Genes de Plantas , Estudo de Associação Genômica Ampla , Soja , Adaptação Fisiológica/genética , Alelos , Genes de Plantas/genética , Genótipo , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Soja/genética
7.
Huan Jing Ke Xue ; 40(7): 3001-3007, 2019 Jul 08.
Artigo em Chinês | MEDLINE | ID: mdl-31854697

RESUMO

This study used Tenax TA absorption tubes to sample volatile aromatic compounds from different emission sources and functional zones in Taiyuan City, Shanxi Province, China. Thermal desorption-gas chromatography-isotope ratio mass spectrometry (TD-GC-IRMS) was subsequently employed to analyze the stable carbon isotope characteristics of the volatile aromatic compounds. The results revealed that the stable carbon isotope ratio (δ13C) of the volatile aromatic compounds emitted through diesel, gasoline, and solvent volatilization, vehicle exhaust, and domestic coal combustion ranged from (-30.79±0.98)‰ to (-29.10±0.14)‰, (-30.96±0.88)‰ to (-28.02±1.77)‰, (-32.13±0.59)‰ to (-27.67±0.49)‰, (-27.58±0.16)‰ to (-25.50±0.75)‰, and (-25.14±0.93)‰ to (-23.44±1.32)‰, respectively. The δ13C value of styrene was (-23.44±1.32)‰, which was only detected in the fumes emitted through domestic coal combustion. Additionally, the sample analysis based on data collected from four different functional zones of Taiyuan City revealed the following:① the δ13C values of the atmospheric volatile aromatic compounds in the mixed residential and traffic zone ranged from (-25.61±2.20)‰ to (-23.91±0.78)‰. Compared with other functional zones, the emissions in this zone were enriched with13C; and ② the δ13C values measured in the industrial zone ranged from (-29.15±1.06)‰ to (-24.53±1.07)‰; the emissions in this functional zone were relatively low in 13C compared with other zones. A comparison of the δ13C values of the atmospheric volatile aromatic compounds and emission sources indicated that the main sources of volatile aromatic compounds at the four sampling points in Taiyuan were vehicle exhausts and domestic coal combustion, while the air sampled in the industrial functional zone was heavily affected by the volatilization of solvents.

8.
Infect Drug Resist ; 12: 2809-2817, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571937

RESUMO

Background: Cytochrome P450 3A4 (CYP3A4) appears to be genetically polymorphic, which in turn contributes to interindividual variability in response to therapeutic drugs. Loperamide, identified as a CYP3A4 substrate, is prone to misuse and abuse and has high risks of life-threatening cardiotoxicity. Methods: Thus, this study is designed to evaluate the enzymatic characteristics of 29 CYP3A4 alleles toward loperamide in vitro, including the 7 novel CYP3A4 variants (*28-*34). The incubation system (containing CYP3A4 enzyme, cytochrome b5, 0.5-20 µM loperamide, potassium phosphate buffer and nicotinamide adenine dinucleotide phosphate) was subject to 40-mins incubation at 37°C and the concentrations of N-demethylated loperamide were quantified by UPLC-MS/MS. Results: As a result, CYP3A4.6, .17, .20 and .30 showed extremely low activity or no activity and the rest of CYP3A4 variants presented varying degrees of decrements in catalytical activities when compared with CYP3A4.1. Conclusion: As the first study to identify the properties of these CYP3A4 variants toward loperamide metabolism, our investigation may establish the genotype-phenotype relationship for loperamide, predict an individual's capability in response to loperamide, and provide some guidance of clinical medication and treatment for loperamide.

9.
J Pharm Pharmacol ; 71(11): 1677-1683, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31441067

RESUMO

OBJECTIVE: Macitentan is a new choice for pulmonary hypertension treatment which is converted to active metabolite ACT132577 by human cytochrome P450 3A4. Human cytochrome P450 3A4 often occurred gene mutations. Gene polymorphism might cause a variety of changes of protein expression and thus give rise to metabolic difference. The aim of this study was to investigate the catalytic characteristics of 27 CYP3A4 protein variants on the metabolism of macitentan in vitro. METHOD: The incubation mixtures (final volume of 200 µl in 1 m PBS) consisted of 1 pmol wild-type CYP3A4.1 or other CYP3A4 protein variants, 2.38 pmol CYP b5 and macitentan (10-600 µm) with 1 mm NADPH. All specimens were processed using same approach with acetonitrile precipitation. The metabolite of macitentan was analysed by ultra performance liquid chromatography-tandem mass spectrometry. KEY FINDING: Most CYP3A4 protein variants (CYP3A4.9, .11, .12, .13, .17, .20, .23, .24, .28, .29, .33, .34) exhibited a sharp decrease, meanwhile nearly one in five variants (CYP3A4.3, .4, .5, .10, .15, .16) showed a significant rise in intrinsic clearance. The relative clearance of CYP3A4 protein variants was ranged from 5.53 to 501.00%. CONCLUSION: Twenty-seven CYP3A4 protein variants displayed different catalytic characteristics towards macitentan in vitro, especially CYP3A4.5, .17, .20, .23. It is important to pay more attention to the dosage of macitentan in order to get better treatment for pulmonary arterial hypertension.


Assuntos
Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Polimorfismo Genético/genética , Pirimidinas/metabolismo , Sulfonamidas/metabolismo , Humanos
10.
Chem Biol Interact ; 310: 108744, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31299239

RESUMO

The epidemic of loperamide abuse and misuse in the patients for the alternative to opioids has become an increasing worldwide concern and has led to considerations about the potential for drug-drug interactions between loperamide and other combined drugs, especially inhibitors of cytochrome P450 (CYP450) enzymes, such as axitinib. This study assessed the effects of axitinib on the metabolism of loperamide and its main metabolite N-demethylated loperamide in rats and in rat liver microsomes (RLM), human liver microsomes (HLM) and recombinant human CYP3A4*1. The concentrations of both compounds were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The exposures (AUC(0-t), AUC(0-∞) and Cmax) of loperamide and N-demethylated loperamide showed a conspicuous increase when loperamide was co-administered with axitinib. The Tmax of loperamide increased while CLz/F decreased under the influence of axitinib. In vitro, axitinib inhibited loperamide metabolism with the IC50 of 18.34 µM for RLM, 1.705 µM for HLM and 1.604 µM for CYP3A4*1, and it was confirmed as a non-competitive inhibitor in all enzymes. Taken together, the results indicated that axitinib had an obvious inhibitory impact on loperamide metabolism both in vivo and in vitro. Thus, more attention should be paid to the concurrent use of loperamide and axitinib to reduce the risk of unexpected clinical outcomes.


Assuntos
Axitinibe/farmacologia , Loperamida/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP3A/metabolismo , Desmetilação , Interações Medicamentosas , Humanos , Loperamida/antagonistas & inibidores , Loperamida/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Espectrometria de Massas em Tandem
11.
Chem Res Toxicol ; 32(8): 1583-1590, 2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31293154

RESUMO

Cabozantinib is a multityrosine kinase inhibitor and has a wide range of applications in the clinic, whose metabolism is predominately dependent on CYP3A4. This study was performed to characterize the enzymatic properties of 29 CYP3A4 alleles toward cabozantinib and the functional changes of five selected alleles (the wild-type, CYP3A4.2.8.14 and .15) toward cabozantinib in the presence of ketoconazole. Cabozantinib, 1-100 µM, with/without the presence of ketoconazole and CYP3A4 enzymes in the incubation system went through 30 min incubation at 37 °C, and the concentrations of cabozantinib N-oxide were quantified by UPLC-MS/MS to calculate the corresponding kinetic parameters of each variant. Collectively, without the presence of ketoconazole, most variants displayed defective enzymatic activities in different degrees, and only CYP3A4.14 and .15 showed significantly augmented enzymatic activities. With the presence of ketoconazole, five tested CYP3A4 alleles, even CYP3A4.14 and .15, exhibited obvious reductions in intrinsic clearance. Besides, we compared cabozantinib with regorafenib in relative clearance to confirm that CYP3A4 has the property of substrate specificity. As the first study of CYP3A4 genetic polymorphisms toward cabozantinib, our observations can provide prediction of an individual's capability in response to cabozantinib and guidance for medication and treatment of cabozantinib.


Assuntos
Anilidas/metabolismo , Citocromo P-450 CYP3A/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Piridinas/metabolismo , Alelos , Citocromo P-450 CYP3A/genética , Variação Genética/genética , Humanos , Cetoconazol/metabolismo , Cinética , Fígado/enzimologia
12.
Sensors (Basel) ; 19(11)2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31174385

RESUMO

In this study, a new joint formation combined with a two-part underwater towed vehicle (towfish) with multiple autonomous underwater vehicles (AUVs) was investigated. A triangular structure formation was established based on graph theory, in which the main point is the secondary towed vehicle acting as the "leader," and the other two points are AUVs acting as "followers." The excellent real-time performance and high flexibility of the towfish is highlighted, and the communication delay and fixed routine of AUVs can be avoided simultaneously. As to the obstacle avoidance, the null-space-based behavioral approach is proposed. On the basis of this approach, the formation task moving to the target is decomposed into different subtasks, and the obstacle avoidance subtask is set as the highest priority. The vector of the low-level task is projected to the null space of the high-level task vector, and the integrated task output is used as the final output function. The low-level task is partially or completely accomplished while handling the higher task; therefore, the mutual conflict between different level targets can be avoided. Moreover, the corresponding task functions are designed in accordance with different subtask priorities. The comprehensive output function of formation motion is deduced and established to ensure that obstacles can be avoided effectively. Furthermore, simulation results demonstrate the effectiveness and feasibility of the proposed method in a complex underwater environment with obstacles.

13.
Basic Clin Pharmacol Toxicol ; 125(4): 337-344, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31058459

RESUMO

AIM: Regorafenib is a tyrosine kinase inhibitor that is mainly metabolized by CYP3A4. The genetic polymorphism of CYP3A4 would contribute to differences in metabolism of regorafenib. Previously, we had discovered several novel CYP3A4 variants. However, the catalytic characteristics of these 27 CYP3A4 variants on oxidizing regorafenib have not being determined. The purpose of this study was to investigate the catalytic characteristics of 27 CYP3A4 protein variants on the oxidative metabolism of regorafenib in vitro. METHOD: Wild-type CYP3A4.1 or other variants was incubated with 0.5-20 µmol/L regorafenib for 30 minutes. After sample processing, regorafenib-N-oxide, a primary metabolite, was detected by ultra-performance liquid chromatography-tandem mass spectrometry system. RESULT: CYP3A4.20 had no detectable enzyme activity compared with wild-type CYP3A4.1; five variants (CYP3A4.5, .16, .19, .24, .29) exhibited similar clearance value with CYP3A4.1; four variants (CYP3A4.14, .15, .28, .31) displayed increased enzymatic activities, while remaining variants showed markedly decreased intrinsic clearance values. CONCLUSION: This study is the first to investigate the function of 27 CYP3A4 protein variants on the metabolism of regorafenib in vitro, and it may provide some valuable information for further research in clinic.


Assuntos
Antineoplásicos/metabolismo , Citocromo P-450 CYP3A/genética , Compostos de Fenilureia/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Piridinas/metabolismo , Citocromo P-450 CYP3A/metabolismo , Humanos , Microssomos/metabolismo , Polimorfismo Genético , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
14.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(2): 585-593, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-30998175

RESUMO

OBJECTIVE: To screen the antioxidant small molecular compounds with optimal efficiency of expansing the human hematopoietic stem cells (hHSC) In vitro based on antioxidant small molecular compound database of LKT laboratory, and to verify the effects of these compounds on the biological functions of hHSC. METHODS: The umbilial cord blood CD34+ cells were enriched by using the MACS beads; the absolute number and percentage of CD34+ cells and CD34+ CD49f+ cells were detected by high throughput flow cytometry after culture of hHSC with compounds in vitro for 1 week, the SR1 (1 µmol/L) was used as positive control, the candidate compounds were screened out; then 4 compounds were selected for follow-up experiments by comprehensive evaluation of concentration, safety and expansion efficacy, the optimal used concentrations of selected compounds were determined through the concentration gradient analysis, and CFC short-term colony-forming cell test was performed by using the determined concentration so as to verify the effect of compounds on the self-renewal, multilineage differentiation. RESULTS: Out of 85 antioxidant small molecular compounds, 4 compounds (C2968, D3331, B1753 and B3358) with obvious expansion efficacy for CD34+ cells and CD34+ CD49f+ cells were screened out by high throughput flow cytometry; their optimal concentrations of 4 compounds were 0.5 µmol/L for C2968, 1.5 µmol/L for D3331 and 1.5 µmol/L for B1753 and 15 µmol/L for B3358. The CFC assay showed the colony formation number in compound-treated group significantly increased as compared with control group, moreover the self-renewal and multilineage differentiation were maintained. CONCLUSION: The antioxidant small molecular compounds C2968 (0.5 µmol/L), D3331 (1.5 µmol/L), B1753 (1.5 µmol/L) and B3358 (1.5 µmol/L) possess good expansion efficacy for hHSC, they can maintain hHSC self-renewal, at the same time ensure the multilineage differentiation potentiality of hHSC.


Assuntos
Células-Tronco Hematopoéticas , Antígenos CD34 , Antioxidantes , Células Cultivadas , Sangue Fetal , Citometria de Fluxo , Humanos
15.
Eur J Drug Metab Pharmacokinet ; 44(5): 611-618, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30825074

RESUMO

BACKGROUND AND OBJECTIVES: Myricetin is a flavonoid compound that is abundant in teas, red wine, berries, herbs and vegetables with a variety of pharmacological properties such as antioxidant, anti-inflammatory and anti-cancer effects. Although there are in vitro studies showing that myricetin inhibits human cytochrome P450 (CYP) 2D6 and CYP3A, the inhibitory mechanisms of myricetin on CYP enzymes are still unclear. The aim of this study was to evaluate the inhibitory effects of myricetin on human and rat CYPs, including CYP3A2/3A4, CYP2B1/2B6, CYP2C9/2C11 and CYP2D1/2D6. METHODS: This study was performed to investigate the inhibitory effects of myricetin on human CYP3A4, CYP2B6, CYP2C9, CYP2D6 and rat CYP3A2, CYP2B1, CYP2C11, CYP2D1 through the cocktail approach using ultra-performance liquid chromatography tandem mass spectrometry. Typical probe substrates were used as follows-midazolam for CYP3A2/3A4, dextromethorphan for CYP2D1/2D6, tolbutamide for CYP2C9/2C11, and bupropion for CYP2B1/2B6. RESULTS: The results of this study showed that myricetin might not be a time-dependent inhibitor. Moreover, myricetin inhibited CYP3A4 in an uncompetitive way with an inhibition constant (Ki) value of 143.1 µM. It was also a noncompetitive inhibitor of CYP2C9 and CYP2D6 with Ki values of 31.12 and 53.44 µM and a competitive inhibitor of CYP2B1 with a Ki value of 69.70 µM, as well as a mixed inhibitor of CYP3A2, CYP2C11 and CYP2D1with Ki values of 37.57, 14.88 and 17.39 µM, respectively. CONCLUSIONS: In conclusion, this study indicates that myricetin inhibited CYP3A4/3A2, CYP2C9/2C11, CYP2D6/2D1 and CYP2B1 by various mechanisms with different Ki values. Given that our experiments are established in vitro, further in vivo work is needed to confirm the interaction between myricetin and CYP enzymes, thus providing better guidance for the safe clinical use of myricetin.


Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Flavonoides/farmacologia , Fígado/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Animais , Cromatografia Líquida/métodos , Humanos , Ratos , Espectrometria de Massas em Tandem/métodos
16.
Eur J Gastroenterol Hepatol ; 31(7): 832-835, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30601336

RESUMO

BACKGROUND: Immune-tolerant chronic hepatitis B (CHB) patients awaiting assisted reproduction (AR) are required to initiate antiviral therapy because of laboratory safety concerns. The antiviral therapy in this group has not been well assessed. We sought to explore the efficacy and safety of the combination therapy (COM) of tenofovir (TDF) and telbivudine (LdT). PATIENTS AND METHODS: In this open-label, randomized, controlled study, we enrolled and randomized hepatitis B virus e-antigen (HBeAg)-positive CHB patients awaiting AR into the study COM group and the control (TDF) group. The COM group received combination therapy of TDF and LdT, and the TDF group received a single treatment of TDF. The patients were followed up for at least 48 weeks. The primary endpoint was the proportion of patients with undetectable HBV DNA level at week 12. RESULTS: A total of 121 patients were recruited into the COM group (n=60) and the TDF group (n=61). The percentages of patients with undetectable HBV DNA levels were 90.0% (54/60) in the COM group and 67.2% (41/61) (P=0.002) in the TDF group at week 12; the percentages were 96.6% (58/60) in the COM group and 85.2% (52/61) in the TDF group at week 48 (P=0.028), respectively. HBeAg seroconversion occurred in 5/60 (8.3%) patients in the COM group and 2/61 (3.3%) patients in the TDF group at week 48 (P=0.233). CONCLUSION: TDF and LdT combination therapy shows a rapid antivirological response in immune-tolerant CHB patients awaiting AR, which provide an alternative for this group at AR centers. However, the HBeAg seroconversion rate is unsatisfactory in the short term.


Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Telbivudina/uso terapêutico , Tenofovir/uso terapêutico , Carga Viral , Adulto , DNA Viral/sangue , Quimioterapia Combinada , Feminino , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/sangue , Humanos , Tolerância Imunológica , Masculino , Cuidado Pré-Concepcional/métodos , Técnicas de Reprodução Assistida , Soroconversão
17.
Plant Biotechnol J ; 17(2): 397-409, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29992702

RESUMO

Morella rubra, red bayberry, is an economically important fruit tree in south China. Here, we assembled the first high-quality genome for both a female and a male individual of red bayberry. The genome size was 313-Mb, and 90% sequences were assembled into eight pseudo chromosome molecules, with 32 493 predicted genes. By whole-genome comparison between the female and male and association analysis with sequences of bulked and individual DNA samples from female and male, a 59-Kb region determining female was identified and located on distal end of pseudochromosome 8, which contains abundant transposable element and seven putative genes, four of them are related to sex floral development. This 59-Kb female-specific region was likely to be derived from duplication and rearrangement of paralogous genes and retained non-recombinant in the female-specific region. Sex-specific molecular markers developed from candidate genes co-segregated with sex in a genetically diverse female and male germplasm. We propose sex determination follow the ZW model of female heterogamety. The genome sequence of red bayberry provides a valuable resource for plant sex chromosome evolution and also provides important insights for molecular biology, genetics and modern breeding in Myricaceae family.


Assuntos
Evolução Molecular , Genoma de Planta/genética , Myrica/genética , Mapeamento Cromossômico , Flores/genética , Flores/crescimento & desenvolvimento , Flores/fisiologia , Frutas/genética , Frutas/crescimento & desenvolvimento , Frutas/fisiologia , Marcadores Genéticos/genética , Anotação de Sequência Molecular , Myrica/crescimento & desenvolvimento , Myrica/fisiologia , Especificidade de Órgãos , Melhoramento Vegetal
18.
Huan Jing Ke Xue ; 39(9): 4042-4050, 2018 Sep 08.
Artigo em Chinês | MEDLINE | ID: mdl-30188044

RESUMO

Air samples were collected and analyzed by GC-MS to investigate the component characteristics of volatile organic compounds (VOCs) in winter in Jincheng. PMF, ratio analysis, and the backward trajectory model were used to investigate sources of VOCs. Ozone formation potential and secondary organic aerosol formation potential were calculated, in order to analyze the environmental implications of detected VOCs. Results showed that the average concentration of VOCs was 93.35 µg·m-3 in Jincheng, with the most abundant component being alkane (52.91 µg·m-3 and 56.68% of total VOCs). Based on PMF analysis, five sources of ambient VOCs in Jincheng were identified, namely industrial emission sources (33.71%), fuel combustion sources (30.27%), vehicle emissions (26.28%), solvent evaporation sources (9.00%), and plant emission sources (0.74%). Ratios of B/T and i-pentane/n-pentane were 1.58±0.68 and 2.07±0.43, indicating that VOCs were derived from the mixture of road and coal combustion sources. Clustered analysis of the air mass backward trajectory showed that three air masses cluster, which were accounting for 50%, 25% and 25% of the total back trajectories respectively, all came from the northwest, and industrial pollution from the northwest might therefore significantly influence VOCs in Jincheng. With low wind speed (<3 m·s-1), the air quality index, concentration of total VOCs, and contribution rate of vehicle emissions were 143, 162.48 µg·m-3, and 46.16%, respectively, higher than values at faster wind speeds (3-6.9 m·s-1). Ozone formation potential and secondary organic aerosol formation potential of aromatic hydrocarbons, which had the highest formation potential, were 98.89 µg·m-3 and 1.21 µg·m-3, respectively, accounting for 37.28% and 97.01% of total formation potential. To reduce the pollution of VOCs in Jincheng, it is important to control industrial emissions, vehicle emissions, and fuel combustion emissions.

19.
Basic Clin Pharmacol Toxicol ; 123(6): 721-726, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29964362

RESUMO

The objective of this study was to evaluate the effect of apatinib on the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine in SD rats and the inhibitory effects of apatinib on venlafaxine in rat and human liver microsomes. Twenty-one SD male rats were randomly divided into three groups (n = 7): group A (multiple dose of 40 mg/kg apatinib for 7 days), group B (single dose of 40 mg/kg apatinib) and group C (the control group). All samples were measured by UPLC-MS/MS. The results indicated that a single dose of apatinib increased the AUC(0-t) , AUC(0-∞) and Cmax of both venlafaxine and O-desmethylvenlafaxine significantly, while Vz/F and CLz/F were decreased. As for group A, only AUC(0-t) and CLz/F of venlafaxine were changed, while no parameters of O-desmethylvenlafaxine were altered. In addition, apatinib was determined to be a mixed inhibitor of venlafaxine.


Assuntos
Succinato de Desvenlafaxina/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Cloridrato de Venlafaxina/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão , Succinato de Desvenlafaxina/sangue , Interações Medicamentosas , Humanos , Concentração Inibidora 50 , Masculino , Espectrometria de Massas , Microssomos Hepáticos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Cloridrato de Venlafaxina/sangue
20.
Mol Plant ; 11(3): 485-495, 2018 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-29476915

RESUMO

Most plants are polyploid due to whole-genome duplications (WGD) and can thus have duplicated genes. Following a WGD, paralogs are often fractionated (lost) and few duplicate pairs remain. Little attention has been paid to the role of DNA methylation in the functional divergence of paralogous genes. Using high-resolution methylation maps of accessions of domesticated and wild soybean, we show that in soybean, a recent paleopolyploid with many paralogs, DNA methylation likely contributed to the elimination of genetic redundancy of polyploidy-derived gene paralogs. Transcriptionally silenced paralogs exhibit particular genomic features as they are often associated with proximal transposable elements (TEs) and are preferentially located in pericentromeres, likely due to gene movement during evolution. Additionally, we provide evidence that gene methylation associated with proximal TEs is implicated in the divergence of expression profiles between orthologous genes of wild and domesticated soybean, and within populations.


Assuntos
Metilação de DNA/genética , Elementos de DNA Transponíveis/genética , Soja/genética , Evolução Molecular , Regulação da Expressão Gênica de Plantas/genética , Genoma de Planta/genética , Poliploidia
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