[Regulation of P-glycoprotein gene expression by PKC/NF-κB-PXR signaling pathway].

P-glycoprotein (P-gp), an ATP binding cassette protein, plays a major role in efflux transport of drugs and xenobiotics due to its abundant expression on several barriers. This study aimed to investigate the potential role of PKC/NF-κB-PXR signaling pathway in modulation of P-gp gene expression in human colon adenocarcinoma LS174T. The effect of PMA on MDR1 luciferase activity was investigated by PXR-MDR1 dual luciferase reporter gene assay. Real-time qPCR assay and Western blot analysis were used to study the gene expression of P-gp and NF-κB, respectively. Compared to the vehicle-treated group, PMA statistically decreased P-gp luciferase activity, mRNA expression and protein expression. Moreover, PMA treatment yielded a significant and dose-dependent increase in RelA/p65 translocation to nucleus. Meanwhile, a remarkable increase of the pho-IκBα status was observed in LS174T cells after treatment with PMA (1-100 nmol·L(-1)). In addition, knockdown of PKCα, NF-κB or PXR can significantly attenuate PMA-induced P-gp suppression. These results suggested that PKC/NF-κB-PXR signaling pathway might play crucial roles in modulation of P-gp gene expression.

[OATP1B1 in drug-drug interactions between traditional Chinese medicine Danshensu and rosuvastatin].

The study was designed to explore the drug-drug interactions mechanisms mediated by OATP1B1 between traditional Chinese medicine Danshensu and rosuvastatin. First, the changes of rosuvastatin pharmacokinetics were investigated in presence of Danshensu in rats. Then, the primary rat hepatocytes model was established to explore the effects of Danshensu on the uptake of rosuvastatin by hepatocytes. Finally, HEK293T cells with overexpression of OATP1B1*a and OATP1B1*5 were established using a lentiviral delivery system to explore the effects of Danshensu on the uptake of rosuvastatin. Rosuvastatin pharmacokinetic parameters of C(max0, AUCO(0-t), AUC(0-∞) were increased about 123%, 194% and 195%, by Danshensu in rats, while the CL z/F value was decreased by 60%. Uptake of rosuvastatin in the primary rat hepatocytes was decreased by 3.13%, 41.15% and 74.62%, respectively in the presence of 20, 40 and 80 µmol x L(-1) Danshensu. The IC50 parameters was (53.04 ± 2.43) µmol x L(-1). The inhibitory effect of Danshensu on OATP1B1 mediated transport of rosuvastatin was related to the OATP1B1 gene type. In OATP1B1*5-HEK293T mutant cells, transport of rosuvastatin were reduced by (39.11 ± 4.94)% and (63.61 ± 3.94)%, respectively, by Danshensu at 1 and 10 µmol x L(-1). While transport of rosuvastatin was reduced by (8.22 ± 2.40)% and (11.56 ± 3.04)% and in OATP1B1*1a cells, respectively. Danshensu significantly altered the pharmacokinetics of rosuvastatin in rats, which was related to competitive inhibition of transport by OATPJBI. Danshensu exhibited a significant activity in the inhibition of rosuvastatin transport by OATP1B1*5-HEK293T, but not by OATP1B1*1a, suggesting a dependence on OATP1B1 sequence.

Effect of Ursolic Acid on Breast Cancer Resistance Protein-mediated Transport of Rosuvastatin In Vivo and Vitro.

OBJECTIVE: To evaluate whether ursolic acid can inhibit breast cancer resistance protein (BCRP)-mediated transport of rosuvastatin in vivo and in vitro. METHODS: Firstly, we explored the pharmacokinetics of 5-fluorouracil (5-FU, a substrate of BCRP) in rats in the presence or absence of ursolic acid. Secondly, we studied the pharmacokinetics of rosuvastatin in rats in the presence or absence of ursolic acid or Ko143 (inhibitor of BCRP). Finially, the concentration-dependent transport of rosuvastatin and the inhibitory effects of ursolic acid and Ko143 were examined in Madin-Darby Canine Kidney (MDCK) 2-BCRP421CC (wild type) cells and MDCK2-BCRP421AA (mutant type) cells. RESULTS: As a result, significant changes in pharmacokinetics parameters of 5-FU were observed in rats following pretreatment with ursolic acid. Both ursolic acid and Ko143 could significantly affect the pharmacokinetics of rosuvastatin. The rosuvastatin transport in the BCRP overexpressing system was increased in a concentration-dependent manner. However, there was no statistical difference in BCRP-mediated transport of rosuvastatin betweent the wild type cells and mutant cells. The same as Ko143, ursolic acid inhibited BCRP-mediated transport of rosuvastatin in vitro. CONCLUSION: Ursolic acid appears to be a potent modulator of BCRP that affects the pharmacokinetic of rosuvastatin in vivo and inhibits the transport of rosuvastatin in vitro.

[Study on action mechanism of Danhong injection based on computational system biology approach].

Danhong injection is a compound preparation of traditional Chinese medicine Salvia miltiorrhiza and Carthamus tinctorius, and has been widely applied in treating coronary heart diseases and ischemic encephalopathy in clinic. Despite the complexity of its chemical compounds and the diversity of targets, especially in system biology, there have not a report for its action mechanism as a whole regulatory biological network. In this study, protein data of S. miltiorrhiza and C. tinctorius were searched in TCMGeneDIT database and agilent literature search (ALS) system to establish the multi-component protein network of S. miltiorrhiza, C. tinctorius and Danhong injection. Besides, the protein interaction network was built based on the protein-protein interaction in Genecards, BIND, BioGRID, IntAct, MINT and other databases. According to the findings, 10 compounds of S. miltiorrhiza and 14 compounds of C. tinctorius were correlated with proteins. The 24 common compounds had interactions with 81 proteins, and formed a protein interaction network with 60 none-isolated nodes. The Cluster ONE module was applied to make an enrichment analysis on the protein interaction network and extract one sub-network with significant difference P <0.05. The sub-network contains 23 key proteins, which involved five signaling pathways, namely Nod-like receptor signaling pathway, epithelial cell signaling in helicobacter pylori infection, Toll-like receptor signaling pathway, RIG-I-like receptor signaling pathway and neurotrophin signaling pathway through KEGG signaling pathway mapping. In this study, the computational system biology approach was adopted to preliminarily explain the molecular mechanism of main compounds of Danhong injection in preventing and treating diseases and provide reference for systematic studies on traditional Chinese medicine compounds.

Chemical constituents of Caesalpinia decapetala (Roth) Alston.

The current study targets the chemical constituents of Caesalpinia decapetala (Roth) Alston and investigates the bioactivities of the isolated compounds. Fourteen known compounds were isolated using column chromatography, and structural identification was performed by physical and spectral analyses. The biological activities of the compounds were also evaluated by 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and 2,2-diphenlyl-1-picrylhydrazyl (DPPH) assays. Emodin (6), baicalein (9), and apigenin (12) displayed antitumor activities against the MGC-803 cell line, while quercetin (2), rutin (5), baicalein (9), and epicatechin (13) showed stronger DPPH scavenging activities compared with ascorbic acid. Andrographolide (1), quercetin (2), bergenin (4), rutin (5), emodin (6), betulin (7), baicalein (9), polydatin (10), salicin (11), and apigenin (12), were obtained from C. decapetala (Roth) Alston for the first time.

Pharmacotherapics Advice in Guidelines for COVID-19.

Since December 2019 to May 2020, coronavirus disease 2019 (COVID-19) has infected over 6 million people worldwide. Due to its sudden and rapid outbreak, effective treatment for COVID-19 is scarce. Based on national clinical trials of novel treatments, China, Italy, Germany, and other countries and organizations have published multiple guidelines for COVID-19 and advised many medicines, such as chloroquine and tocilizumab. In this paper, we summarize the pharmacotherapy for COVID-19 according to those guidelines, highlight updates of the pharmacotherapy guidelines, and review the efficacy and safety of the indicated anti-COVID-19 drugs.

[Functions and applications of Multi-Tower Platform of Qingyuan Forest Ecosystem Research Station of Chinese Academy of Sciences]. / ä¸­å›½ç§‘å­¦é™¢æ¸ åŽŸæ£®æž—ç”Ÿæ€ç³»ç»Ÿè§‚æµ‹ç ”ç©¶ç«™å¡”ç¾¤å¹³å°çš„åŠŸèƒ½å’Œåº”ç”¨.

The relationship between the structure and function of forest ecosystems is the main intere-sts in the research area of forest ecology and management. However, over complex terrains in particular, these studies had been challenged as uneasy tasks due to the limitations in the forest survey and measurement techniques and other supporting technologies. Chinese Academy of Sciences (CAS) funded "Multi-Tower LiDAR/ECFlux Platform for Monitoring the Structure and Function of Secondary Forest Ecosystems" (Multi-Tower Platform, MTP) as a field station network corner-stone research infrastructure project, which was completed by Qingyuan Forest CERN (Chinese Ecosystem Research Network). In a distinctively-bounded and monitored-outlet watershed, the MTP was integrated by light detection and ranging (LiDAR) scanners, eddy covariance (EC) flux instrument systems, whole- and sub-watershed hydrology station network, long-term forest plot arrays, and live data center. Using LiDAR scanning, the MTP can get cloud data for holographic information on canopy structure. The EC-flux instrument system and hydrology station network along with forest plot arrays could ensure the reliability of water and carbon observations over this complex terrain, which allows to verify the studies on flux measurement technologies and methods, as well as to understand the processes of ecohydrology and CO2 exchange between forest ecosystem and the atmosphere. Further, we can also assess the primary ecosystem services, including water conservation and carbon sequestration. All the data from "tower-station" were streamed through wireless network, which would facilitate data monitoring, management, and sharing. There are three tasks of MTP team: 1) defining innovative methods and descriptors to quantify three-dimensional forest structure; 2) developing theories and techniques to measure CO2/H2O fluxes and other trace gases over complex terrains; 3) understanding the relationship between structure and function of forest ecosystems, providing information and rationales for forest management practices to assure broad and sustainable benefits from forests.

Anti-inflammatory pentacyclic triterpenes from the stems of Euonymus carnosus.

Three new lupane-type triterpenoids (1-3), three new oleane-type triterpenoids (4-6), as well as two known compounds (7-8) were isolated from Euonymus carnosus. The structures of the compounds were elucidated on the basis of spectroscopic data analyses, including UV, IR, MS, and NMR experiments. The inhibitory on LPS-induced NO production in microglia BV2 cells of compounds 1-8 were also evaluated. Compounds 1 and 2 showed moderate abilities to inhibit NO production, with IC50 values of 5.99 and 8.47µM, respectively.

Meta-analysis of digoxin use and risk of mortality in patients with atrial fibrillation.

There is an ongoing debate on the safety of digoxin use in patients with atrial fibrillation (AF). To address this issue, the investigators assembled a synthesis of the available evidence on the relation between digoxin and all-cause mortality in patients with AF. PubMed and the Embase database were systematically searched to identify all eligible studies examining the association between digoxin use and the mortality risk in AF. Overall hazard ratios and 95% confidence intervals were calculated using the random-effects model. Eleven observational studies were identified that met the inclusion criteria, 5 of which additionally used propensity score matching for statistical adjustment. In total, 318,191 patients were followed up for a mean of 2.8 years. Overall, digoxin use was associated with a 21% increased risk for mortality (hazard ratio 1.21, 95% confidence interval 1.12 to 1.30). Sensitivity analyses found the results to be robust. In the propensity score-matched AF patients, digoxin use was associated with a 17% greater risk for mortality (hazard ratio 1.17, 95% confidence interval 1.13 to 1.22). When the AF cohort was grouped into patients with and without heart failure, the use of digoxin was associated with an increase in mortality in patients with and those without heart failure, and no significant heterogeneity was seen between the groups (p >0.10). In conclusion, the results suggest that digoxin use was associated with a greater risk for mortality in patients with AF, regardless of concomitant heart failure. A well-powered randomized trial is necessary to reveal the true effect of digoxin.

Lateral calcaneal artery perforator-based skin flaps for coverage of lower-posterior heel defects.

BACKGROUND: Perforator-based flaps have been explored across almost all of the lower leg except in the Achilles tendon area. This paper introduced a perforator flap sourced from this area with regard to its anatomic basis and clinical applications. METHODS: Twenty-four adult cadaver legs were dissected to investigate the perforators emerging along the lateral edge of the Achilles tendon in terms of number and location relative to the tip of the lateral malleolus, and distribution. Based on the anatomic findings, perforator flaps, based on the perforator(s) of the lateral calcaneal artery (LCA) alone or in concert with the perforator of the peroneal artery (PA), were used for reconstruction of lower-posterior heel defects in eight cases. Postoperatively, subjective assessment and Semmes-Weinstein filament test were performed to evaluate the sensibility of the sural nerve-innerved area. RESULTS: The PA ended into the anterior perforating branch and LCA at the level of 6.0 ± 1.4 cm (range 3.3-9.4 cm) above the tip of the lateral malleolus. Both PA and LCA, especially the LCA, gave rise to perforators to contribute to the integument overlying the Achilles tendon. Of eight flaps, six were based on perforator(s) of the LCA and two were on perforators of the PA and LCA. Follow-up lasted for 6-28 months (mean 13.8 months), during which total flap loss and nerve injury were not found. Functional and esthetic outcomes were good in all patients. CONCLUSION: The integument overlying the Achilles tendon gets its blood supply through the perforators of the LCA primarily and that of through the PA secondarily. The LCA perforator(s)-based and the LCA plus PA perforators-based stepladder flap is a reliable, sensate flap, and should be thought of as a valuable procedure of choice for coverage of lower-posterior heel defects in selected patients.

A series of rare earth complexes with novel non-interpenetrating 3D networks: synthesis, structures, magnetic and optical properties.

A series of metal-organic framework {Ln(BCPBA)(H2O)}n {Ln = Nd (1), Sm (2), Eu (3), Tb (4), Dy (5)}; {[Ln(BCPBA)(H2O)](H2O)}n {Ln = Pr (6), Gd (7)} have been synthesized through the hydrothermal synthesis method. These compounds possess non-interpenetrating 3D networks with 10.1438 Å× 17.9149 Å rhombic channels along the [001] direction. The results of temperature-dependent magnetic susceptibility measurements indicate that compounds 4 and 7 exhibit Ln(III)Ln(III) antiferromagnetic interactions, while compound 5 exhibits Ln(III)Ln(III) ferromagnetic interactions. Frequency dependent out-of-phase signals were observed in alternating current (ac) magnetic susceptibility measurements which indicate that they have slow magnetic relaxation characteristics. The luminescent properties of 1, 2, 3, 4, and 5 are also discussed. Due to the good match between the lowest triplet state of the ligand and the resonant energy level of the lanthanide ion, compound 4 has longer fluorescence lifetime (τ1 = 400.0000 ms, τ2 = 1143.469 ms) and higher quantum yield (Φ = 42%) compared with other compounds.

[Effects of reforestation on soil chemical properties and microbial communities in a severely degraded sub-tropical red soil region].

Taking the long-term reforestation experimental base established in a severely degraded sub-tropical hilly red soil region in Taihe County of Jiangxi Province in 1991 as the object, this paper studied the changes of soil nutrients and microbial communities after 19 years reforestation of Pinus elliottii forest, Liquidambarformosana forest, and P. elliotti-L. formosana forest, with the naturally restored grassland as the control. The soil organic carbon content in the L. formosana and P. elliottii-L. formosana forests (15.16+/-3.53 and 16.42+/-0.49 g kg-1, respectively) was significantly higher than that in the control (9.30+/-1.13 g kg-1), the soil total phosphorus content was in the order of the control (0.30+/-0.02 g kg-1) > P. elliottii-L. formosana forest (0.22+/-0.04 g kg-1 ) > L. formosana forest (0.14+/-0.01 g kg-1 ), while the soil available phosphorus content was 1.66+/-0.02 mg kg-1 in L. formosana forest, 2.47+/-0. 27 mg kg- in P. elliottii-L. formosana forest, and 1. 15+/-0.71 mg kg-1 in P. elliottii forest, being significantly higher than that in the control (0.01+/-0.00 mg kg-1). The total amounts of soil microbes, the amount and percentage of soil bacteria, and the amount of inorganic and organic phosphate-solubilizing microbes in L. formosana forest and P. elliottii-L. formosana forest were all significantly higher than those in P. elliottii forest and the control, while the amount and percentage of soil fungi and the percentage of soil actinomycetes in L. formosana forest and P. elliottii-L. formosana forest were significantly lower than those in the control. The soil organic carbon content was significantly positively correlated with the percentage of soil bactera, but negatively correlated with the percentage of soil fungi and actinomycetes, while the soil available phosphorus content was significantly positively correlated with the amount of organic phosphate-solubilizing microes, but not with the amount of inorganic phosphate-solubilizing microbes. It was suggested that L. formosana forest and P. elliottii-L. formosana forest could be the recommended reforestation models in sub-tropical degraded red soil region.

[Correlation analysis of thrombin-activatable fibrinolysis inhibitor single nucleotide polymorphism with venous thromboembolism].

This study was aimed to explore the change of single nucleotide polymorphism (SNP) of thrombin-activatable fibrinolysis inhibitor (TAFI) and its correlation of 2 sites (505a/g, 1040c/t) in its gene-coding region with venous thromboembolism (VTE). The genotype distribution of TAFI in 80 patients with VTE and 80 normal controls was detected by allele-specific PCR. The results showed that the distribution of each genotype of 505a/g polymorphism was not significantly different between the VTE and control groups (P > 0.05). However, t allele frequency of 1040c/t in VTE group decreased significantly as compared with the control group (40% vs 53.75%, P < 0.05), mainly due to the decrease of the proportion of tt homozygous in VTE group. It is concluded that obvious relationship is found between the polymorphism of 1040c/t in TAFI gene and VTE patients. t allele genotype may paly a protective role in VTE. The polymorphism of TAFI 505a/g may be not associated with VTE.