Effects of hypoxia on the expression and function of P-gp in Caco-2 cells. / 低氧对Caco-2细胞P-gp表达及功能的影响.

OBJECTIVES: Hypoxia can alter the oral bioavailability of drugs, including various substrates (drugs) of P-glycoprotein (P-gp), suggesting that hypoxia may affect the function of P-gp in intestinal epithelial cells. Currently, Caco-2 monolayer model is the classic model for studying the function of intestinal epithelial P-gp. This study combines the Caco-2 monolayer model with hypoxia to investigate the effects of hypoxia on the expression and function of P-gp in Caco-2 cells, which helps to elucidate the mechanism of changes in drug transport on intestinal epithelial cells in high-altitude hypoxia environment. METHODS: Normally cultured Caco-2 cells were cultured in 1% oxygen concentration for 24, 48, and 72 h, respectively. After the extraction of the membrane proteins, the levels of P-gp were measured by Western blotting. The hypoxia time, with the most significant change of P-gp expression, was selected as the subsequent study condition. After culturing Caco-2 cells in transwell cells for 21 days and establishing a Caco-2 monolayer model, they were divided into a normoxic control group and a hypoxic group. The normoxic control group was continuously cultured in normal condition for 72 h, while the hypoxic group was incubated for 72 h in 1% oxygen concentration. The integrity and polarability of Caco-2 cells monolayer were evaluated by transepithelial electrical resistance (TEER), apparent permeability (Papp) of lucifer yellow, the activity of alkaline phosphatase (AKP), and microvilli morphology and tight junction structure under transmission electron microscope. Then, the Papp of rhodamine 123 (Rh123), a kind of P-gp specific substrate, was detected and the efflux rate was calculated. The Caco-2 cell monolayer, culturing at plastic flasks, was incubated for 72 h in 1% oxygen concentration, the expression level of P-gp was detected. RESULTS: P-gp was decreased in Caco-2 cells with 1% oxygen concentration, especially the duration of 72 h (P<0.01). In hypoxic group, the TEER of monolayer was more than 400 Ω·cm2, the Papp of lucifer yellow was less than 5×10-7 cm/s, and the ratio of AKP activity between apical side and basal side was greater than 3. The establishment of Caco-2 monolayer model was successful, and hypoxia treatment did not affect the integrity and polarization state of the model. Compared with the normoxic control group, the efflux rate of Rh123 was significantly reduced in Caco-2 cell monolayer of the hypoxic group (P<0.01). Hypoxia reduced the expression of P-gp in Caco-2 cell monolayer (P<0.01). CONCLUSIONS: Hypoxia inhibits P-gp function in Caco-2 cells, which may be related to the decreased P-gp level.

Ar plasma assists in enhanced oxygen evolution kinetics of MOG-derived multicomponent transition metal sulfides.

Transition metal sulfides are low-cost oxygen evolution reaction (OER) electrocatalysts that can potentially substitute noble metal catalysts. However, the adsorption process of their OER is impeded by their intrinsic poor catalytic activity. Constructing heterojunction and vacancy defects in transition metal sulfides is an efficient method to promote the process of oxygen evolution. Herein, a facile approach based on in situ sulfurization of metal-organic gels (MOGs) and a short-time plasma treatment was developed to fabricate vacancy-modified polymetallic sulfides heterojunction. The synergistic effect of the multi-component heterojunction and sulfur vacancy contributed greatly to improving the electron migration efficiency and OER ability of the electrocatalyst. As a result, the optimum oxygen evolution activity was achieved with appropriate surface vacancy concentrations by regulating the plasma radio frequency powers. The plasma-treated catalyst under 400 W showed the best OER performance (lower overpotential of 235 mV in 1 M KOH solution with the Tafel slope of 31 mV dec-1) and good durability over 11 h of chronopotentiometry testing. This work sheds new light on constructing multimetal-based heterojunction electrocatalysts with rich vacancy defects for oxygen evolution reactions.

[Research progress of ferroptosis in hypoxia-associated brain injury].

Cerebral hypoxia often brings irreversible damage to the central nervous system, which seriously endangers human health. It is of great significance to further explore the mechanism of hypoxia-associated brain injury. As a programmed cell death, ferroptosis mainly manifests as cell death caused by excessive accumulation of iron-dependent lipid peroxides. It is associated with abnormal glutathione metabolism, lipid peroxidation and iron metabolism, and is involved in the occurrence and development of various diseases. Studies have found that ferroptosis plays an important role in hypoxia-associated brain injury. This review summarizes the mechanism of ferroptosis, and describes its research progress in cerebral ischemia reperfusion injury, neonatal hypoxic-ischemic brain damage, obstructive sleep apnea-induced brain injury and high-altitude hypoxic brain injury.

Effects of plateau hypoxia on pharmacokinetic parameters and cerebral-blood distribution of levetiracetam in rats. / é«˜åŽŸä½Žæ°§å¯¹å¤§é¼ å·¦ä¹™æ‹‰è¥¿å¦è¯ä»£åŠ¨åŠ›å­¦ç‰¹å¾åŠè„‘è¡€åˆ†å¸ƒçš„å½±å“.

OBJECTIVES: Plateau hypoxia exposure causes changes in pharmacokinetic parameters and cerebral-blood distribution of drugs, including many substrates of P-glycoprotein (P-gp). Levetiracetam, a kind of antiepileptic drugs, is a substrate of P-gp. Whether plateau hypoxia exposure changes its pharmacokinetic characteristics and cerebral-blood distribution remains unclear. This study aims to investigate the effects of plateau hypoxia on the pharmacokinetics and cerebra-blood distribution of levetiracetam. METHODS: Wistar rats were divided into a low-altitude control group, a high-altitude group, a solvent group, and a P-gp induction group. After 24 h of exposure at altitude of 4 010 m, rats in the high-altitude group were given levetiracetam orally or intravenously. The plasma was respectively collected at 0.083, 0.25, 0.5, 0.83, 1.25, 2, 4, 6, 8, 10, 12, and 24 h after oral administration of the drug, while both plasma and brain were respectively collected at 5, 45, 60,120 and 240 min after intravenous injection. After 3 days administration of dexamethasone, plasma and brain of rats in the P-gp induction group were collected at 120 min after intravenously giving levetiracetam. Plasma and brain concentrations of the drug were determined by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The expression of P-gp in blood-brain barrier was detected by Western blotting. RESULTS: Compared with the low-altitude control group, the area under the curve (AUC) and mean residence time (MRT) of levetiracetam were respectively decreased by 14.69% (P<0.01) and 15.42% (P<0.01), while the clearance (CL) was increased by 16.67% (P<0.01) in the high-altitude group. The ratio of brain/blood plasma drug concentration was decreased by 22.82% (P<0.05), 12.42% (P<0.05), 17.40% (P<0.01), and 13.22% (P<0.01) at 5, 45, 120, and 240 min after injection, respectively. The expression of P-gp on the blood-brain barrier was increased by 86.3% (P<0.05). Compared with the solvent control group, the expression of P-gp on the blood-brain barrier in the P-gp induction group was increased by 56.3% (P<0.05), the ratio of brain/blood plasma drug concentration was decreased by 19.3% (P<0.05). CONCLUSIONS: After acute plateau hypoxia exposure, the pharmacokinetic of levetiracetam in rats are altered, and the cerebral-blood distribution of the drug in rats is decreased, which may be related to the up-regulation of P-gp expression on the blood-brain barrier.

Adsorption Effect and Adsorption Mechanism of High Content Zeolite Ceramsite on Asphalt VOCs.

In order to meet the requirements of industrial-scale fixed beds and develop an excellent adsorbent for asphalt VOCs. Zeolite ceramsite containing binder was prepared and successfully applied to the inhibition of asphalt VOCs. The results showed that prepared zeolite ceramsite possessed a high degree of crystallinity, and its main crystal phase is zeolite. The micropores with a pore size of 0.88 nm dominated the pore size distribution of the material. The adsorption experiment of asphalt VOCs showed a lower VOCs adsorption effect of 8.72% at a small dosage of 5%, while at a large dosage of 50%, the adsorption effect of VOCs exceeded 45%. This might be caused by the quite small external specific surface area, which occupied only 8.3% of the total specific surface area, and the low intraparticle diffusion coefficient due to the micropores. Meanwhile, the kinetics diameters of most aromatic hydrocarbons, which were comparable to the pore size of micropores, and the increase in the intraparticle diffusion resistance of aliphatic hydrocarbon molecules were the important factors in obtaining high adsorption of aromatic hydrocarbons in asphalt VOCs. Furthermore, the results indicated that the particulate adsorbent with a microporous structure should be mixed into the asphalt as a fine aggregate rather than an asphalt modifier for better asphalt VOCs adsorption effect.

Facile in Situ Transformation of NiOOH into MOF-74(Ni)/NiO OH Heterogeneous Composite for Enchancing Electrocatalytic Methanol Oxidation.

A new MOF-74(Ni)/NiOOH heterogeneous composite was synthesized via NiOOH microsphere precursor. The electrocatalytic methanol oxidation reactions' (MOR) performance was assessed. The as-prepared MOF-74(Ni)/NiOOH exhibited excellent activity with high peak current density (27.62 mA·cm-2) and high mass activity (243.8 mA·mg-1). The enhanced activity could be a result of the synergistic effect of the MOF-74(Ni)/NiOOH heterocomposite providing more exposed active sites, a beneficial diffusion path between the catalyst surface and electrolyte, and improved conductivity, favorable for improving MOR performance.

Four new prenylflavonol glycosides from the leaves of Cyclocarya paliurus.

Four new prenylflavonol glycosides (1-4) along with two known analogues (5-6) were isolated from the leaves of Cyclocarya paliurus for the first time. The structures of these compounds were characterized by comprehensive analysis of 1 D, 2 D NMR, HRESIMS, UV data and enzymatic hydrolysis. In bioassays, compounds 1-4 were evaluated for inhibitory effects on xanthine oxidase (XOD) and effects on the inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS) induced RAW264.7 cells. Moreover, compounds 1 and 2 showed outstanding XOD inhibitions with IC50 values of 18.16 ± 3.91 and 37.65 ± 5.67 µM, and exhibited inhibitions against LPS-induced NO production with IC50 values of 80.50 ± 3.09 and 82.28 ± 2.87 µM.

Two new triterpenoid glycosides from leaves of Cyclocarya paliurus.

Two dammarane glycosides (1-2) were isolated from the leaves of Cyclocarya paliurus. The structures of new compounds were established by application of spectroscopic methods, including one-dimensional and two-dimensional NMR, HRESIMS, and chemical hydrolysis. When evaluated against seven human cancer cell lines, the two compounds exhibited selective cytotoxicity to MCF-7 cells.[Formula: see text].

Research Hotspots and Development Trends on Recycled Construction Materials in Pavement Engineering: A Bibliometric Evaluation.

Road recycling technology is gradually becoming a research focus in road construction due to natural resource shortages. It is therefore necessary to carry out deep and extensive analysis of the huge amount of publications in the research area of recycling technology in road construction. Based on three databases (Web of Science, Compendex and Scopus) and VOSviewer visualization software, this study conducts a bibliometric analysis of the literature in the field of recycled construction materials in pavement engineering. The global research publications were reviewed to quantitatively identify the literature characteristics. A number of publications, document types, research areas and keywords were used to achieve the general statistics of this reviewed literature. H-index, publication number and citations per publication were used to evaluate the academic contributions by country, institution and journal. The results show that the most productive country and institution for publications are the USA and Chang'an University from China, respectively, followed by China and Wuhan University of Technology. In recent years, researchers have generally paid attention to two main approaches: the application of rubber modified asphalt and the performance enhancement of recycled pavement.

Cytotoxic triterpenoid glycosides from leaves of Cyclocarya paliurus.

Three previously undescribed dammarane triterpenoid glycosides (1-3) along with five known analogues (4-8) were isolated from the leaves of Cyclocarya paliurus. Their structures and configurations were determined on the basis of comprehensive spectroscopic analyses, chemical hydrolysis and DFT GIAO 13C NMR calculation. All the isolates were evaluated cytotoxic activities against seven human cancer cell lines (MCF-7, PC-3, Du145, NCI-H1975, PC-9, SKVO3 and HepG2). Moreover, compound 4 showed a wide spectrum of cytotoxicity against human cancer cells with IC50 values ranging from 11.31 to 29.51 µM.

New prenylflavonol glycosides with xanthine oxidase inhibitory activity from the leaves of Cyclocarya paliurus.

Eight new prenylflavonol glycosides (1-8), along with five known analogues (9-13) were isolated from the n-butanol extract of the dried leaves of Cyclocarya paliurus (family Juglandaceae) for the first time. The structures of these compounds were characterized by comprehensive analysis of 1D, 2D NMR, HRESIMS, UV data and acid hydrolysis. In bioassay, all these thirteen prenylflavonol glycosides exhibited inhibitory effects on xanthine oxidase (XOD) activity. Especially compounds 2 and 7, showed outstanding IC50 values of 31.81 ± 2.20 and 29.71 ± 3.69 µM, respectively.