Understanding transporter-mediated drug–drug interactions (DDIs) for investigational agents is important during drug development to assess DDI liability, its clinical relevance, and to determine ...appropriate DDI management strategies. P-glycoprotein (P-gp) is an efflux transporter that influences the pharmacokinetics (PK) of various compounds. Assessing transporter induction in vitro is challenging and is not always predictive of in vivo effects, and hence there is a need to consider clinical DDI studies; however, there is no clear guidance on when clinical evaluation of transporter induction is required. Furthermore, there is no proposed list of index transporter inducers to be used in clinical studies. This review evaluated DDI studies with known P-gp inducers to better understand the mechanism and site of P-gp induction, as well as the magnitude of induction effect on the exposure of P-gp substrates. Our review indicates that P-gp and cytochrome P450 (CYP450) enzymes are co-regulated via the pregnane xenobiotic receptor (PXR) and the constitutive androstane receptor (CAR). The magnitude of the decrease in substrate drug exposure by P-gp induction is generally less than that of CYP3A. Most P-gp inducers reduced total bioavailability with a minor impact on renal clearance, despite known expression of P-gp at the apical membrane of the kidney proximal tubules. Rifampin is the most potent P-gp inducer, resulting in an average reduction in substrate exposure ranging between 20 and 67%. For other inducers, the reduction in P-gp substrate exposure ranged from 12 to 42%. A lower reduction in exposure of the P-gp substrate was observed with a lower dose of the inducer and/or if the administration of the inducer and substrate was simultaneous, i.e. not staggered. These findings suggest that clinical evaluation of the impact of P-gp inducers on the PK of investigational agents that are substrates for P-gp might be warranted only for compounds with a relatively steep exposure–efficacy relationship.
The water footprint theory was used to analyze the agricultural water footprint (AWF) and its spatiotemporal characteristics in the Hexi corridor, Northwest of China from 2002 to 2017. The AWF ...increased during 2002–2017. Meanwhile, the water footprint of cash crops rapidly increased from 10.08 billion m3 to 100.94 billion m3; however, the water footprint of grain production increased slowly and remained relatively stable. There were great differences in the water footprint of various agricultural products in twenty counties in the Hexi corridor. Furthermore, this study explored the equilibrium relationship between the gross domestic product (GDP), population, grain yield, fertilization, urbanization rate, and AWF using the Panel Pool Mean Group and autoregressive distributive lag (PMG/ARDL) model. Our findings demonstrated that economic growth, grain yield, and fertilization had a significant positive relationship with AWF, and population and the urbanization rate had a negative long-run but non-significant relationship with AWF. The panel causality analysis showed a one-way causal relationship between the AWF with population and urbanization rate. The grain yield, the rate of urbanization, and fertilization in the Hexi corridor need further improvements to ensure the sustainable development of water resources.
•Significant spatial-temporal variation of the AWF in the Hexi Corridor, China.•The ARDL model was creatively introduced to explore the driving factors of AWF.•The structure of the AWF has changed significantly.•Economic and social factors as key drivers of AWF change.
The advances accelerated by next‐generation sequencing and long‐read sequencing technologies continue to provide an impetus for plant phylogenetic study. In the past decade, a large number of ...phylogenetic studies adopting hundreds to thousands of genes across a wealth of clades have emerged and ushered plant phylogenetics and evolution into a new era. In the meantime, a roadmap for researchers when making decisions across different approaches for their phylogenomic research design is imminent. This review focuses on the utility of genomic data (from organelle genomes, to both reduced representation sequencing and whole‐genome sequencing) in phylogenetic and evolutionary investigations, describes the baseline methodology of experimental and analytical procedures, and summarizes recent progress in flowering plant phylogenomics at the ordinal, familial, tribal, and lower levels. We also discuss the challenges, such as the adverse impact on orthology inference and phylogenetic reconstruction raised from systematic errors, and underlying biological factors, such as whole‐genome duplication, hybridization/introgression, and incomplete lineage sorting, together suggesting that a bifurcating tree may not be the best model for the tree of life. Finally, we discuss promising avenues for future plant phylogenomic studies.
This review highlights the major challenges faced by phylogenomic studies, including genomic conflict and orthology inference, and makes practical recommendations for the transformation from a few loci‐based analyses to large‐scale phylogenomics.
Background:
Cerebral small vessel disease (CSVD) is a group of clinical syndromes covering all pathological processes of small vessels in the brain, which can cause stroke and serious dementia. ...However, as the pathogenesis of CSVD is not clear, so the treatment is limited. Endothelial cell dysfunction is earlier than clinical symptoms, such as hypertension and leukosis. Therefore, the treatment of endothelial cells is expected to be a new breakthrough. Quercetin, a flavonoid present in a variety of plants, has the function of anti-inflammation and anti-oxidation. This study aimed to investigate the protective effect of quercetin on endothelial cell injury and provide a basic theory for subsequent application in the clinic.
Methods:
Human brain microvascular endothelial cells (HBMECs) were cultured
in vitro
, and the injury model of endothelial cells was established by hypoxia and reoxygenation (H/R). The protective effects of quercetin on HBMECs were studied from the perspectives of cell viability, cell migration, angiogenesis and apoptosis. In order to further study the mechanism of quercetin, oxidative stress and endoplasmic reticulum stress were analyzed. What’s more, blood-brain barrier (BBB) integrity was also studied.
Results:
Quercetin can promote the viability, migration and angiogenesis of HBMECs, and inhibit the apoptosis. In addition, quercetin can also activate Keap1/Nrf2 signaling pathway, reduce ATF6/GRP78 protein expression. Further study showed that quercetin could increase the expression of Claudin-5 and Zonula occludens-1.
Conclusions:
Our experiments show that quercetin can protect HBMECs from H/R, which contains promoting cell proliferation, cell migration and angiogenesis, reducing mitochondrial membrane potential damage and inhibiting cell apoptosis. This may be related to its antioxidation and inhibition of endoplasmic reticulum stress. At the same time, quercetin can increase the level of BBB connexin, suggesting that quercetin can maintain BBB integrity.
Gait disturbance is a manifestation of cerebral small vessel disease (CSVD). The posterolateral thalamus (PL), whose blood is mainly supplied by the P2 segment of posterior cerebral artery (P2-PCA), ...plays pivotal roles in gait regulation. We investigated the influence of the distance between P2-PCA and PL on gait with varying CSVD burden. 71 participants were divided into low and high CSVD burden groups. The distance from P2-PCA to PL was measured using 7 T TOF-MRA and categorized into an immediate or distant PCA-to-thalamus pattern. Functional connectivity (FC) and voxel-based morphometry were assessed to evaluate functional and structural alterations. In the low CSVD burden group, immediate PCA-to-thalamus supply strongly correlates with longer step length and higher wave phase time percent, and exhibited enhanced FCs in left supplementary motor area, right precentral cortex (PreCG.R). While in the high CSVD burden group, no association between PCA-to-thalamus pattern and gait was found, and we observed reduced FC in PreCG.R with immediate PCA-to-thalamus pattern. Higher CSVD burden was associated with decreased gray matter density in bilateral thalamus. However, no significant structural thalamic change was observed between the two types of PCA-to-thalamus patterns in all patients. Our study demonstrated patients with immediate PCA-to-thalamus supply exhibited better gait performance in low CSVD burden populations, which also correlated with enhanced FCs in motor-related cortex, indicating the beneficial effects of the immediate PCA-to-thalamus supply pattern. In the higher burden CSVD populations, the effects of PCA-to-thalamus pattern on gait are void, attributable to the CSVD-related thalamic destruction and impairment of thalamus-related FC.
The rapid expansion of next-generation sequencing (NGS) has generated a powerful array of approaches to address fundamental questions in biology. Several genome-partitioning strategies to sequence ...selected subsets of the genome have emerged in the fields of phylogenomics and evolutionary genomics. In this review, we summarize the applications, advantages and limitations of four NGS-based genome-partitioning approaches in plant phylogenomics: genome skimming, transcriptome sequencing (RNA-seq), restriction site associated DNA sequencing (RAD-Seq), and targeted capture (Hyb-seq). Of these four genome-partitioning approaches, targeted capture (especially Hyb-seq) shows the greatest promise for plant phylogenetics over the next few years. This review will aid researchers in their selection of appropriate genome-partitioning approaches to address questions of evolutionary scale, where we anticipate continued development and expansion of whole-genome sequencing strategies in the fields of plant phylogenomics and evolutionary biology research.
The double digest restriction-site associated DNA sequencing technology (ddRAD-seq) is a reduced representation sequencing technology by sampling genome-wide enzyme loci developed on the basis of ...next-generation sequencing. ddRAD-seq has been widely applied to SNP marker development and genotyping on animals, especially on marine animals as the original ddRAD protocol is mainly built and trained based on animal data. However, wide application of ddRAD-seq technology in plant species has not been achieved so far. Here, we aim to develop an optimized ddRAD library preparation protocol be accessible to most angiosperm plant species without much startup pre-experiment and costs.
We first tested several combinations of enzymes by in silico analysis of 23 plant species covering 17 families of angiosperm and 1 family of bryophyta and found AvaII + MspI enzyme pair produced consistently higher number of fragments in a broad range of plant species. Then we removed two purifying and one quantifying steps of the original protocol, replaced expensive consumables and apparatuses by conventional experimental apparatuses. Besides, we shortened P1 adapter from 37 to 25 bp and designed a new barcode-adapter system containing 20 pairs of barcodes of varying length. This is an optimized ddRAD strategy for angiosperm plants that is economical, time-saving and requires little technical expertise or investment in laboratory equipment. We refer to this simplified protocol as MiddRAD and we demonstrated the utility and flexibility of our approach by resolving phylogenetic relationships of two genera of woody bamboos (Dendrocalamus and Phyllostachys). Overall our results provide empirical evidence for using this method on different model and non-model plants to produce consistent data.
As MiddRAD adopts an enzyme pair that works for a broad range of angiosperm plants, simplifies library constructing procedure and requires less DNA input, it will greatly facilitate designing a ddRAD project. Our optimization of this method may make ddRAD be widely used in fields of plant population genetics, phylogenetics, phylogeography and molecular breeding.
Diabetes exacerbates brain damage in cerebral ischemic stroke. Our previous study has demonstrated that after cerebral ischemia, type 2 diabetes rats displayed worse neurological outcomes, larger ...cerebral infarction and severer blood-brain barrier disruption. However, our knowledge of the mechanisms of how diabetes impacts the cerebrovascular repair process is limited. This study was aimed to characterize structural alterations and potential mechanisms in brain microvessels before and after ischemic stroke in type 2 diabetic rats treated with high-fat diet and streptozotocin (HFD/STZ). Furtherly, we tested our hypothesis that dysregulated intercellular Jagged1-Notch1 signaling was involved in the dysfunctional cerebral neovascularization both before and after ischemic stroke in HFD/STZ rats. In our study, we found increased yet dysfunctional neovascularization with activated Jagged1-Notch1 signaling in the cerebrovasculature before cerebral ischemia in HFD/STZ rats compared with non-diabetic rats. Furthermore, we observed delayed angiogenesis as well as suppressed Jagged1-Notch1 signaling after ischemic stroke. Our results elucidate the potential mechanisms underlying diabetes-related cerebral microvasculature dysfunction after ischemic stroke.
To meet the requirements of high performance, low cost, and easy operation of the robot, a brushless motor drive and control system for the robot joint is designed, including CAN bus, WPF upper host ...computer development, and magnetic encoders, and other sensors, in which the STM32F103 chip is used as the main control chip, and the DRV8323 is a brushless motor drive chip. The principle of field-oriented control (FOC) brushless motor drive is elaborated. Meanwhile, the drive and control system design is completed from both hardware and software aspects. Finally, the PID algorithm is used for the closed-loop speed test of the robot joint. The experimental result shows that the designed robot joints and control system run smoothly and reliably, have the characteristics of modularization and miniaturization, and are suitable for the control of micro-service robots and manipulators.
Sandwich-cultured hepatocytes (SCH) are metabolically competent and have proper localization of basolateral and canalicular transporters with functional bile networks. Therefore, this cellular model ...is a unique tool that can be used to estimate biliary excretion of compounds. SCH have been used widely to assess hepatobiliary disposition of endogenous and exogenous compounds and metabolites. Mechanistic modeling based on SCH data enables estimation of metabolic and transporter-mediated clearances, which can be used to construct physiologically based pharmacokinetic models for prediction of drug disposition and drug-drug interactions in humans. In addition to pharmacokinetic studies, SCH also have been used to study cytotoxicity and perturbation of biological processes by drugs and hepatically generated metabolites. Human SCH can provide mechanistic insights underlying clinical drug-induced liver injury (DILI). In addition, data generated in SCH can be integrated into systems pharmacology models to predict potential DILI in humans. In this review, applications of SCH in studying hepatobiliary drug disposition and bile acid-mediated DILI are discussed. An example is presented to show how data generated in the SCH model were used to establish a quantitative relationship between intracellular bile acids and cytotoxicity, and how this information was incorporated into a systems pharmacology model for DILI prediction.
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