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Purpose Endothelial dysfunction and the subsequent decrease in endothelium-dependent vascular relaxation of small arteries are major features of hypertension. Artemisinin, a well-known antimalarial drug, has been shown to exert protecting roles against endothelial cell injury in cardiac and pulmonary vascular diseases. The current study aimed to investigate the effects of artemisinin on endothelium-dependent vascular relaxation and arterial blood pressure, as well as the potential signalling pathways in spontaneously hypertensive rats (SHRs). Methods In this study, acetylcholine (ACh)-induced dose-dependent relaxation assays were performed to evaluate vascular endothelial function after treatment with artemisinin. Artemisinin was administered to the rats by intravenous injection or to arteries by incubation for the acute exposure experiments, and it was administered to rats by intraperitoneal injection for 28 days for the chronic experiments. Results Both acute and chronic administration of artemisinin decreased the heart rate and improved ACh-induced endothelium-dependent relaxation but negligibly affected the arterial blood pressure in SHRs. Incubation with artemisinin decreased basal vascular tension, NAD(P)H oxidase activity and reactive oxygen species (ROS) levels, but it also increased endothelial nitric oxide (NO) synthase (eNOS) activity and NO levels in the mesenteric artery, coronary artery, and pulmonary artery of SHRs. Artemisinin chronic administration to SHRs increased the protein expression of eNOS and decreased the protein expression of the NAD(P)H oxidase subunits NOX-2 and NOX-4 in the mesenteric artery. Conclusion These results indicate that treatment with artemisinin has beneficial effects on reducing the heart rate and basal vascular tension and improving endothelium-dependent vascular relaxation in hypertension, which might occur by increasing eNOS activation and NO release and inhibiting NAD(P)H oxidase derived ROS production., Graphical Abstract

Abnormal and rapid proliferation of colon cancer cells is a severe problem that can be regulated by non-coding RNAs. Thus, our study focused on effects of lncRNA CASC2 and miR-19a on colon cancer cells. Expressions of lncRNA CASC2, miR-19a, Bcl-2, Bax and NF-κB/p65 were examined by RT-qPCR. Cell viabilities were detected by CCK-8. A luciferase report assay was used for measuring binding conditions between lncRNA CASC2 and miR-19a. Western blotting was used to evaluate expression of LC3-I, LC3-II and p62 related to autophagy. Expression of lncRNA CASC2 lower in cancer cell lines and the overexpression reduced the cell viability of HT29 and SW480. Furthermore, Bcl-2 was suppressed by overexpressed lncRNA CASC2, while Bax was upregulated. LC3-Ⅰ and p62 were both inhibited, but LC3-Ⅱ was promoted. MiR-19a was predicted to bind lncRNA CASC2 and expressed higher in cancer cell lines. Overexpressed miR-19a reduced expression of lncRNA CASC2 and increased cell viability. This was repressed by upregulated lncRNA CASC2. Bcl-2 and Bax expression and proteins implicated in autophagy that are regulated by lncRNA CASC2 upregulation were reversed by miR-19a overexpression. NF-κB was upregulated in colon cancer cell lines, while inhibition of NF-κB reversed functions of lncRNA CASC2 and magnified roles of miR-19a. Our findings showed that lncRNA CASC2 inhibited cell viability in colon cancer cell lines and miR-19a reversed its functions through the NF-κB signalling pathway, suggesting that these could be factors in treating colon cancer in the future.

[Image: see text] We report herein the discovery of quinazolindiones as potent and selective tankyrase inhibitors. Elucidation of the structure–activity relationship of the lead compound 1g led to truncated analogues that have good potency in cells, pharmacokinetic (PK) properties, and excellent selectivity. Compound 21 exhibited excellent potencies in cells and proliferation studies, good selectivity, in vitro activities, and an excellent PK profile. Compound 21 also inhibited H292 xenograft tumor growth in nude mice. The synthesis, biological, pharmacokinetic, in vivo efficacy studies, and safety profiles of compounds are presented.

Delphinidin is an anthocyanin that belongs to the group of flavonoids that exert numerous biological activities. However, the molecular mechanisms underlying the anticancer effects of delphinidin remain poorly understood. In our study we analyzed delphinidin modulate STAT-3 and MAPKinase signaling thereby inhbits cell proliferation and promote apoptosis. Our study demonstrated that delphinidin treatment significantly reduced the viability of human colon cancer HCT116 in a concentration-dependent manner. We noticed that delphinidin effectively induced oxidative stress-mediated apoptosis by generating intracellular ROS, decreasing antioxidant levels, inducing lipid peroxidation, and single-strand break on colon cancer cells. In this study, we observed that delphinidin treatment alters the mitochondrial membrane potential, thereby induces apoptosis was closely associated with the induction of pro-apoptotic Bax, Caspase- 3,8 & 9, cytochrome C, and inhibition of anti-apoptotic protein expression. Studies on STAT-3 and MAPKinase signaling showed delphinidin inhibited the phosphorylation of these transcription factors' activity. Inhibition of STAT-3, p38, and ERK1/2 phosphorylation and modulation pro-apoptotic protein expression might be responsible for the anticancer activity of delphinidin in colon cancer cells.

Fe-based amorphous magnetic powder cores (AMPCs) with excellent comprehensive properties were successfully fabricated via using the uniform double insulating layer core-shell structured FeSiBPC/Fe3O4@Epoxy resin (EP). The effects of the in-situ hydrothermal oxidized time on the magnetic properties of the AMPCs have been systematically investigated on the basis of the growth mechanism of the insulating layer of spherical amorphous powder in alkaline environment. The hydrothermal oxidation process could well ensure the uniformity of the oxide layer composed of Fe3O4 nanoparticle. The evolution of the insulating layer is a process of homogeneous nucleation and growth at different hydrothermal oxidation time. After 10 h of hydrothermal oxidation, a thin and dense layer composed of Fe3O4 nanoparticle was formed on the surface of the amorphous powder. As a consequent, the FeSiBPC AMPCs exhibit excellent performance such as stable effective permeability of 49.5 at 2 MHz, a very low core loss of 187 mW/cm3 at 100 kHz@0.05 T and high-quality factor of 160 at 600 kHz. The results indicate that the thickness of the Fe3O4 insulating layer can be completely controlled via the reaction parameters, and can effectively suppress the eddy current loss, which is promising for high-frequency electromagnetic systems.

A novel quality evaluation method of Corydalis yanhusuo was established by researching the high-performance liquid chromatography behavior of alkaloids under different buffer solutions and exploring the correlation between alkaloids in C. yanhusuo. The retention times of tetrahydropalmatine and corydaline were significantly influenced by pH, while the peak shape was affected by buffer types and ionic strength. The resolution of compounds in fingerprint was satisfactory under acetonitrile-0.2% phosphoric acid buffer (adjusted pH to 5.0 with triethylamine). Twelve common peaks were found by comparing 20 batches of C. yanhusuo fingerprints, and three tertiary alkaloids and four quaternary alkaloids were identified. The fingerprints were analyzed by similarity analysis, hierarchical cluster analysis, principal component analysis, and partial least squares discriminant analysis. All samples were divided into three groups, and the contents of dehydrocorydaline and coptisine from Zhejiang province were relatively higher than other origins. There were six components performing more contributions to the quality of C. yanhusuo. The correlations between alkaloids were conducted by Pearson correlation analysis and mathematical model analysis. The content correlation between palmatine and berberine was y = 0.28x2 + 0.03x + 0.03, and the dehydrocorydaline and coptisine was y = -7.54/(1 + (x/0.14)0.5 ) + 2.61. The established mathematical model of alkaloids provided a guiding significance for the quality control of C. yanhusuo.

Due to its good properties and low cost, melamine formaldehyde foam has been widely used in cars, furniture and construction. However, how to recycle the spent foam still remains challenging for scientists. In this work, a new method was designed to prepare N-doped carbon dot (NCD) materials by calcining sodium lignin sulfonate/melamine formaldehyde foam (LSMF) via one step. TEM, IR and XPS were used to characterize the structure and morphology of newly-synthesized NCDs. It is shown that carbon powder is obtainable by calcination. Since it derives from the collapse of the foam structure of LSMF, the carbon powder can almost completely dissolve in deionized water. The particle size ranges from 5 to 20 nm. The fluorescence properties of NCDs were studied by fluorescence spectroscopy. A strong emission has been detected at 580 nm with the quantum yield of 2.94%. When applying NCDs to detect various metal ions, there is a significant fluorescence quenching effect and good selectivity for Fe3+. The mechanism has been hypothesised. Our study provides a method for productive preparation of NCDs from spent foam.

The infection induced by implantation of biomedical materials may result from the biofilm formation after bacteria attachment. Hence, the antibiofilm surface coating represents a novel technique to improve the antibacterial activity of biomedical materials. The traditional antibiofilm surface coatings exhibited some disadvantages and provided a limited service life. In this work, we used polyethyleneimine grafted 3-maleimidopropionic acid (PEIM) and poly(acrylic acid) grafted 2-furfurylamine (PAAF) to achieve robust and self-healable crosslinked multilayer coatings, employing Layer-by-Layer (LbL) self-assembly technique and Diels-Alder reaction. Then, thiol-terminated poly((3-acrylamidopropyl) trimethylammonium chloride) (PAMPTMA-SH) was grafted onto the crosslinked multilayer coating by thiol-ene click reaction to form a novel multilayer coating (PEIM/PAAF)10-PAMPTMA. We found that this coating showed robust and self-healable activity, and significantly inhibited the bacterial growth and biofilm formation after infection with Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) by in vitro and in vivo assays for 120 h. In addition, the multilayer coating did not induce significant hemolysis or affect the cell viability of red blood cells. In vivo studies also showed that (PEIM/PAAF)10-PAMPTMA coating efficiently blocked the infiltration of inflammatory cells and gene expression in the mouse skin challenged with E. coli or S. aureus. Taken together, these results showed that the prepared multilayer coating exhibited strong antibiofilm activity and provided a new strategy for the application of highly efficient antibiofilm surface coating of biomedical materials.

Anisotropic conductive films (ACFs) composed of polymer adhesive resin and conductive particles have been used as interconnection materials for ultrafine pitch chip-on-flex (COF) packages due to their flexibility, stable electrical properties, and bending reliability. To realize an efficient ultrafine pitch COF package, a new anchoring polymer layer (APL) was recently introduced. However, the chip flexibility in terms of ACFs materials after APL layer integration needs lot of improvement. Herein, we study the order to obtain more flexible and reliable COF packages using ACFs interconnection materials, and the effect of the ACFs material properties on the COF bending reliability was investigated. It was found that when the APL ACFs were used for the COF packages, 100% electric insulation rates were obtained due to the suppression of conductive particle movement by the APL structure compared with the conventional ACFs. Furthermore, the polyacrylonitrile (PAN) APL ACFs showed better ACFs joint properties and dynamic bending properties compared with the polyvinylidene fluoride (PVDF) APL ACFs due to its higher adhesion property caused by the chemical reaction between the PAN and the curing agent inside the epoxy polymer adhesive resin confirmed by the Fourier transform-infrared spectroscopy (FT-IR) analysis. In addition, the strain applied to the PAN APL ACFs joints during the bending test was 1.35% which was quite smaller than that of the PVDF APL ACFs joints, 2.01% resulting in better bending reliability too. For the bending reliability, there was no failure at the PAN APL ACFs joints up to 150 000 cycles, not only because of the excellent mechanical properties of PAN APL ACFs but also because of the lower strain applied to the APL ACFs joints during the dynamic bending test in COF packages.

Core-shell structured FeSiBCCr@SiO2 amorphous soft magnetic composites (ASMCs) with tunable insulating layer thicknesses have been designed and fabricated by the powder metallurgy method. The growth process of the coatings obtained via the sol-gel method has been systematically studied based on the analysis of the growth mechanism and the insulating layer thicknesses calculated by a modified method. In the powder-coating process using small quantities of tetraethyl orthosilicate (TEOS) (0.025–0.1 mL/g), a relatively uniform insulating layer is formed on the surface of the powders. Increasing the TEOS concentration further (0.25–1 mL/g) greatly enhances the reaction kinetics of the hydrolysis and condensation reactions. Consequently, the SiO2 shells of the amorphous powder rapidly grow in thickness and also generate aggregates. The evolution of the thickness of the coatings under different growth conditions also corresponds to the variation of the magnetic performance of the ASMCs. The ASMCs with an appropriate SiO2 insulating layer exhibit stability at high frequencies and significantly lower the contribution of eddy current to the total loss. Conversely, a thick insulation layer results in a high fraction of the non-magnetic phase and consequently enhances the hysteresis loss. Thus, an enhanced magnetic performance of the FeSiBCCr ASMCs can be achieved by adjusting the TEOS concentration (0.025–0.1 mL/g) or the thickness of the SiO2 insulating layer.

The extraction condition of curcumin from Curcuma longa L was optimized through four factors and three levels orthogonal experiment based on the results of single factor tests. Under the optimal conditions: the concentration of ethanol 80%, extraction temperature 70°C, the ratio of liquid to material 20, and extraction time 3 h, a crude extract with the yield of curcumin 56.8 mg/g could be obtained. The isolation and purification of curcuminoids from the crude extract was performed on high performance counter current chromatography employing an optimized solvent system n-hexane/ethyl acetate/methanol/water (2/3/3/1, v/v/v/v). From 97 mg crude sample (in which the purity of curmumin was 68.56%), 67 mg curmumin, 18 mg demethoxycurcumin, and 9.7 mg bisdemethoxycurcumin with a high-performance liquid chromatography purity of 98.26, 97.39, and 98.67%, respectively, were obtained within 70 min. The antioxidant activities and cytotoxicity of purified curcumin was comparable to that of the commercial product, indicating that the biological activity of curcumin could be maintained by this method.

C26H18N6ZnS4, triclinic, P 1 ‾ $P‾{1}$ (no. 2), a = 9.4677(13) Å, b = 12.0147(17) Å, c = 13.571(3) Å, α = 102.907(3)°, β = 102.302(3)°, γ = 110.419(2)°, V = 1336.7(4) Å3, Z = 2, R gt (F) = 0.0441, wR ref (F 2) = 0.1202, T = 296(2) K.

The Chinese natural product, berberine, has biological properties that support its potential efficacy as a colon cancer prevention agent. Its longstanding use in China to treat gastrointestinal tract and rheumatologic disorders is generally regarded as safe, supporting initial investigations in an at-risk population, such as individuals with ulcerative colitis. However, the safety of berberine in this population is not established. Individuals living in China with biopsy-proven ulcerative colitis, ≤grade 2 dysplasia, and with a ulcerative colitis disease activity index (UCDAI) score ≤1 on mesalamine, were randomized 3:1 in a double-blind phase I trial to berberine 900 mg/day or placebo for 3 months, with the primary objective of assessing safety. Blood samples and biopsies of the colorectum, from prespecified locations, were collected prior to and following therapy. Secondary endpoints included changes in UCDAI score, and in tissue and plasma markers of inflammation. Of toxicities at least possibly related, one episode of grade 3 elevation in transaminases and one episode of grade 1 nausea were observed among 12 individuals on berberine, and none were observed among 4 on placebo. The mean plasma berberine concentration was 3.5 nmol/L after berberine treatment, significantly higher than 0.5 nmol/L with placebo. Berberine significantly decreased the Geboes grade in colonic tissue, but had a nonsignificant effect on other tissue or blood biomarkers related to cell growth and inflammation. The combination of berberine and mesalamine is well tolerated in Chinese with ulcerative colitis and may enhance mesalamine's anti-inflammatory effects in colonic tissue.

A novel strategy for synthesizing the high-performance thin and compact sodalite zeolite membrane over rough α-Al2O3 support was developed. The synthesis involved the deposition of a layer of flaky...

Background The tumor-targeting ability and pH-sensitive properties of intelligent drug delivery systems are crucial for effective drug delivery and anti-tumor therapy. Methods In this study, sHA-DOX/HA-GA mixed micelles were designed with the following properties: sulfated hyaluronic acid (sHA) was synthesized to block cell migration by inhibiting HAase; sHA-DOX conjugates were synthesized via pH-sensitive hydrazone bond to realize DOX-sensitive release. The introduction of HA-GA conjugate could improve active-targeting ability and cellular uptake. Results The results showed that the mixed micelles possessed a nearly spherical shape, nanoscale particle size (217.70±0.89 nm), narrow size distribution (PDI=0.07±0.04), negative zeta potential (-31.87±0.61 mV) and pH-dependent DOX release. In addition, the sHA-DOX/HA-GA micelles exhibited concentration-dependent cytotoxicities against liver carcinoma cells (HepG2) and HeLa cells, and were shown to be effectively taken up by HepG2 cells by confocal microscopy analysis. Furthermore, the in vivo anti-tumor study showed that mixed micelles had a superior anti-tumor effect compared to that of free DOX. Further evidence obtained from the hematoxylin-eosin staining and immunohistochemistry analysis also demonstrated that sHA-DOX/HA-GA exhibited stronger tumor inhibition and lower systemic toxicity than free DOX. Conclusion The sHA-DOX/HA-GA mixed micelles could be a potential drug delivery system for anti-hepatoma therapy.

Background: To investigate the effects of recombinant human thrombopoietin (rhTPO) and interleukin-2 (IL-2) on a basic gemcitabine (GEM) plus carboplatin (GC) treatment regimen in a murine lung carcinoma model. Methods: Fifty nude mice with subcutaneous tumors derived from human lung cancer cells were divided into 5 groups, each comprised of 10 mice: A blank group (intraperitoneal injection of saline), a control group (GC) (intraperitoneal injections of GC), a rhTPO group (same as the control group plus subcutaneous injection of rhTPO), an IL-2 group (same as the control group plus subcutaneous injection of IL-2) and a rhTPO + IL-2 group (same as the rhTPO group plus subcutaneous injection of IL-2). Tumor development and histology as well as CD4+, phosphorylated-adenosine monophosphate-activated protein kinase (p-AMPK), phosphorylated-protein kinase B (p-AKT), phosphorylated-extracellular signal-regulated kinase (p-ERK), phosphorylated-phosphoinositide 3-kinase (p-pI3K) and GTPase RAS1 expression in tumor tissues were measured and blood analyses performed. Results: Tumor sizes from all treated mice were significant smaller than the controls, as were the tumors of IL-2 plus GC treated mice compared to other treated groups. CD4+ expressing cells were increased in tumors after IL-2 and rhTPO treatment and the application of rhTPO significantly restored the blood platelet count. The expression of p-AMPK, p-AKT, p-ERK, p-pI3K and RAS1 in tumor cells were all significantly diminished after the addition of rhTPO and IL-2 to the GC regimen. Conclusions: The supplementation of rhTPO and IL-2 to a GC regime effectively reduced tumor sizes and restored the platelet count in a human lung cancer mouse model.

Dysregulated hepatic gluconeogenesis is a hallmark of insulin resistance and type 2 diabetes mellitus (T2DM). Although existing drugs have been proven to improve gluconeogenesis, achieving this objective with functional food is of interest, especially using conjugated linoleic acid (CLA) found in dairy products. Both cis-9, trans-11 (c9,t11) and trans-10, cis-12 (t10,c12) isomers of CLA were tested in human (HepG2) and rat (H4IIE) hepatocytes for their potential effects on gluconeogenesis. The hepatocytes exposed for 24 h with 20 μM of c9,t11-CLA had attenuated the gluconeogenesis in both HepG2 and H4IIE by 62.5% and 80.1%, respectively. In contrast, t10,c12-CLA had no effect. Of note, in HepG2 cells, the exposure of c9,t11-CLA decreased the transcription of gluconeogenic enzymes, cytosolic phosphoenolpyruvate carboxykinase (PCK1) by 87.7%, and glucose-6-phosphatase catalytic subunit (G6PC) by 38.0%, while t10,c12-CLA increased the expression of G6PC, suggesting the isomer-specific effects of CLA on hepatic glucose production. In HepG2, the peroxisome proliferator-activated receptor (PPAR) agonist, rosiglitazone, reduced the glucose production by 72.9%. However, co-administration of c9,t11-CLA and rosiglitazone neither exacerbated nor attenuated the efficacy of rosiglitazone to inhibit glucose production; meanwhile, t10,c12-CLA abrogated the efficacy of rosiglitazone. Paradoxically, PPARγ antagonist GW 9662 also led to 70.2% reduction of glucose production and near undetectable PCK1 expression by abrogating CLA actions. Together, while the precise mechanisms by which CLA isomers modulate hepatic gluconeogenesis directly or via PPAR warrant further investigation, our findings establish that c9,t11-CLA suppresses gluconeogenesis by decreasing PEPCK on hepatocytes.

Lanosterol is a potential drug for cataracts treatment, which can reverse the aggregation of intracrystalline proteins. The low concentration in lanolin calls for high-performance separation methods. In this study, a counter-current chromatography dual-mode elution method was developed for the first time to separate and purify lanosterol from hexane extract of lanolin after saponification, in which the column was first eluted with the lower phase as mobile phase in head-to-tail mode, followed by the upper phase in the tail-to-head mode. High purity of lanosterol, dihydrolanosterol, and cholesterol can be obtained simultaneously. A solvent system composed of n-heptane/acetonitrile/ethyl acetate (5:5:1, v/v/v) was selected and optimized via partition coefficient determination. Compounds such as 111 mg lanosterol, 84 mg dihydrolanosterol, and 183 mg cholesterol with high purity of 99.77, 95.71, and 91.43%, respectively, analyzed by high-performance liquid chromatography were obtained within 80 min from 700 mg crude extract from 1.78 g lanolin. The method was also used to improve the purity of commercial lanosterol product from 66.97 to above 99%. Counter-current chromatography could serve as a potential and powerful technique for commercial production of highly pure lanosterol.

Background Recent efforts have been focused on combining two or more therapeutic approaches with different mechanisms to enhance antitumor therapy. Moreover, nanosize drug-delivery systems for codelivering two drugs with proapoptotic and antiangiogenic activities have exhibited great potential in efficient treatment of cancers. Methods Glycyrrhetinic acid (GA)-modified liposomes (GA LPs) for liver-targeted codelivery of curcumin (Cur) and combretastatin A4 phosphate (CA4P) were prepared and characterized. In vitro cellular uptake, cytotoxicity, cell migration, in vivo biodistribution, antitumor activity, and histopathological studies were performed. Results Compared with unmodified LPs (Cur-CA4P LPs), Cur-CA4P/GA LPs were taken up effectively by human hepatocellular carcinoma cells (BEL-7402) and showed higher cytotoxicity than free drugs. In vivo real-time near-infrared fluorescence-imaging results indicated that GA-targeted LPs increased accumulation in the tumor region. Moreover, Cur-CA4P/GA LPs showed stronger inhibition of tumor proliferation than Cur, Cur + CA4P, and Cur-CA4P LPs in vivo antitumor studies, which was also verified by H&E staining. Conclusion GA-modified LPs can serve as a promising nanocarrier for liver-targeted co-delivery of antitumor drugs against hepatocellular carcinoma.

Ethylene metabolism is very important for climacteric fruit, and apricots are typical climacteric fruit. The activity of pectinase is closely related to fruit firmness, which further affects fruit quality. To better understand ethylene metabolism, pectinase activity and their molecular regulation mechanisms during the development and ripening of apricot fruit, ethylene metabolism, pectinase activity and the “Luntaibaixing” apricot fruit transcriptome were analyzed at different developmental stages. Ethylene metabolic precursors, enzyme activities and ethylene release increased during fruit development and ripening, with significant differences between the ripening stage and other stages (P

RNA editing (DNA/RNA differences) as a post-transcriptional modification approach to enrich genetic information, plays the crucial role in regulating diverse biological processes in eukaryotes. Although it has been extensively studied in plant chloroplast and mitochondria genome, RNA editing in plant nuclear genome, especially those associated with Fusarium head blight (FHB), is not well studied at present. Here, we investigated the DNA/RNA differences associated with FHB through a novel method by comparing the RNA-seq data from Fusarium-infected and control samples from 4 wheat genotypes. A total of 187 DNA/RNA differences were identified in 36 wheat genes, representing the first landscape of the FHB-responsive RNA editome in wheat. Furthermore, all of these 36 edited genes were located in the FHB related co-expression gene modules, which may involve in regulating FHB response. Finally, the effects of DNA/RNA differences were systematically investigated to show that they could cause the change of RNA structure and protein structure in edited genes. In particular, the G to C editing (chr3A_487854715) in TraesCS3A02G263900, which is the orthology of OsRACK1, resulted that it was targeted by tae-miR9664-3p to control its expression in different genotype through different editing efficiency, suggesting RNA editing could mediate miRNA to participate in the regulation network of FHB tolerance. This study reported the first wheat DNA/RNA differences associated with FHB, which not only contribute to better understand the molecular basis underlying FHB tolerance, but also shed light on improving FHB tolerance through epigenetic method in wheat and beyond.

Objectives Glucosamine, chondroitin and diacerein are natural compounds commonly used in treating osteoarthritis. Their concomitant intake may trigger drug–natural product interactions. Cytochrome P450 (CYP) has been implicated in such interactions. Cytochrome P450 2D6 (CYP2D6) is a major hepatic CYP involved in metabolism of 25% of the clinical drugs. This study aimed to investigate the inhibitory effect of these antiarthritic compounds on CYP2D6. Methods CYP2D6 was heterologously expressed in Escherichia coli. CYP2D6–antiarthritic compound interactions were studied using in vitro enzyme kinetics assay and molecular docking. Results The high-performance liquid chromatography (HPLC)-based dextromethorphan O-demethylase assay was established as CYP2D6 marker. All glucosamines and chondroitins weakly inhibited CYP2D6 (IC50 values >300 µM). Diacerein exhibited moderate inhibition with IC50 and K i values of 34.99 and 38.27 µM, respectively. Its major metabolite, rhein displayed stronger inhibition potencies (IC50=26.22 μM and K i =32.27 μM). Both compounds exhibited mixed-mode of inhibition. In silico molecular dockings further supported data from the in vitro study. From in vitro–in vivo extrapolation, rhein presented an area under the plasma concentration-time curve (AUC) ratio of 1.5, indicating low potential to cause in vivo inhibition. Conclusions Glucosamine, chondroitin and diacerein unlikely cause clinical interaction with the drug substrates of CYP2D6. Rhein, exhibits only low potential to cause in vivo inhibition.

Context Although metabolic profiles appear to play an important role in menopausal bone loss, the functional mechanisms by which metabolites influence bone mineral density (BMD) during menopause are largely unknown. Objective We aimed to systematically identify metabolites associated with BMD variation and their potential functional mechanisms in peri- and postmenopausal women. Design and Methods We performed serum metabolomic profiling and whole-genome sequencing for 517 perimenopausal (16%) and early postmenopausal (84%) women aged 41 to 64 years in this cross-sectional study. Partial least squares regression and general linear regression analysis were applied to identify BMD-associated metabolites, and weighted gene co-expression network analysis was performed to construct co-functional metabolite modules. Furthermore, we performed Mendelian randomization analysis to identify causal relationships between BMD-associated metabolites and BMD variation. Finally, we explored the effects of a novel prominent BMD-associated metabolite on bone metabolism through both in vivo/in vitro experiments. Results Twenty metabolites and a co-functional metabolite module (consisting of fatty acids) were significantly associated with BMD variation. We found dodecanoic acid (DA), within the identified module causally decreased total hip BMD. Subsequently, the in vivo experiments might support that dietary supplementation with DA could promote bone loss, as well as increase the osteoblast and osteoclast numbers in normal/ovariectomized mice. Dodecanoic acid treatment differentially promoted osteoblast and osteoclast differentiation, especially for osteoclast differentiation at higher concentrations in vitro (eg,10, 100 μM). Conclusions This study sheds light on metabolomic profiles associated with postmenopausal osteoporosis risk, highlighting the potential importance of fatty acids, as exemplified by DA, in regulating BMD.

Salusin-β is a biologically active peptide with 20 amino acids that exerts several cardiovascular activity-regulating effects, such as regulating vascular endothelial function and the proliferation of vascular smooth muscle cells. However, the regulatory effects of salusin-β in myocardial infarction-induced chronic heart failure (CHF) are still unknown. The current study is aimed at investigating the effects of silencing salusin-β on endothelial function, cardiac function, vascular and myocardial remodeling, and its underlying signaling pathways in CHF rats induced by coronary artery ligation. CHF and sham-operated (Sham) rats were subjected to tail vein injection of adenoviral vectors encoding salusin-β shRNA or a control-shRNA. The coronary artery (CA), pulmonary artery (PA), and mesenteric artery (MA) were isolated from rats, and isometric tension measurements of arteries were performed. Compared with Sham rats, the plasma salusin-β, leptin and visfatin levels and the salusin-β protein expression levels of CA, PA, and MA were increased, while the acetylcholine- (ACh-) induced endothelium-dependent vascular relaxation of CA, PA, and MA was attenuated significantly in CHF rats and was improved significantly by salusin-β gene knockdown. Salusin-β knockdown also improved cardiac function and vascular and myocardial remodeling, increased endothelial nitric oxide synthase (eNOS) activity and nitric oxide (NO) levels, and decreased NAD(P)H oxidase activity, NOX-2 and NOX-4 expression, and reactive oxygen species (ROS) levels in arteries in CHF rats. The effects of salusin-β knockdown in CHF rats were attenuated significantly by pretreatment with the NOS inhibitor L-NAME. These results indicate that silencing salusin-β contributes to the improvement of endothelial function, cardiac function, and cardiovascular remodeling in CHF by inhibiting NAD(P)H oxidase-ROS generation and activating eNOS-NO production.

PurposeSalusin-β, a multifunctional vasoactive peptide, has a potentially important function in the pathological development of hypertension. However, the exact functional role of salusin-β and the underlying mechanism in this process are still not fully understood. The current study aimed to investigate the effects of silencing salusin-β on vascular function and vascular remodeling, as well as its signaling pathways in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY).MethodsSilencing salusin-β was performed by caudal vein injection of adenovirus expressing salusin-β short hairpin RNA (shRNA). Acetylcholine (ACh)-induced endothelium-dependent relaxation was used to evaluate vasodilator function, and high K+ solution-induced constriction was used to evaluate vasoconstriction function.ResultsSalusin-β levels in plasma and its protein expression in mesenteric artery (MA), coronary artery (CA), and pulmonary artery (PA) of SHR were higher than those in WKY. The salusin-β level and expression were decreased effectively by salusin-β shRNA. Knockdown of salusin-β decreased arterial blood pressure (ABP) and high K+ solution-induced vascular constrictions, and improved the endothelium-dependent relaxation and vascular remodeling in SHR. The improved effect of silencing salusin-β on ACh-induced relaxation in SHR was almost blocked by the nitric oxide synthase (NOS) inhibitor L-NAME. Compared to WKY, the endothelial NOS (eNOS) activity and level, and nitric oxide (NO) level were decreased, while NAD(P)H oxidase activity and reactive oxygen species (ROS) levels in MA, CA, and PA of SHR were increased, which were all redressed by salusin-β knockdown.ConclusionThese results indicate that knockdown of salusin-β improves endothelium-dependent vascular relaxation and vascular remodeling and decreases ABP and vasoconstriction in SHR, which might be accomplished by increasing eNOS activation and NO release while inhibiting NAD(P)H oxidase derived-ROS generation. Scavenging salusin-β improves vascular function and then prevents the development and progression of vasculopathy of hypertension.

Macrophages show two main phenotypes, the M1-type (pro-inflammatory) and the M2-type (anti-inflammatory). The purpose of this research was to investigate the regulatory effect of carbon monoxide releasing molecule-3 (CORM-3) on LPS-induced macrophage polarization. LPS-induced RAW264.7 cells were exposed to CORM-3 for 24 h. Polarization of cells was checked by flow cytometry; expression of M1 or M2 macrophage-related factors and NF-κB signaling factors was examined by RT-PCR, ELISA, and Western blot. Male C57 mice were divided into three groups: normal group; periodontitis group, where experimental periodontitis was established in mice; LPS+CORM-3 group, where mice with experimental periodontitis were treated with CORM-3. Polarization of macrophages and the expression of M1 or M2 macrophage-related factors were detected by immunofluorescence, ELISA, and RT-PCR. CORM-3 significantly reduced M1 macrophage proportion, but increased M2 proportion in LPS-stimulated cells. Accordingly, CORM-3 significantly suppressed the expression of M1 macrophage-related TNF-α, iNOS, IL-1β, and IL-6, but promoted M2-related IL-10 and Arg-1. The expression of p-p65, p-p50, and p-IκB induced with LPS was inhibited by CORM-3. In vivo experiments indicated that CORM-3 induced more M2 macrophages in periodontal tissues in mice with experimental periodontitis. The expression of M1 macrophage-related factor in periodontitis was inhibited, but the expression of M2-related factors was increased by CORM-3. CORM-3 inhibits macrophage polarization to pro-inflammatory M1-type and promotes to anti-inflammatory M2-type, which provides scientific basis for the application of CORM-3 in the treatment of periodontitis.

Background Bitter tastants can activate bitter taste receptors (TAS2Rs) and thus initiate relaxation of airway smooth muscle cells (ASMCs), which have great potential in the development of novel bronchodilator drugs for asthma therapy. However, the canonical bitter substance, denatonium is known to induce apoptosis of airway epithelial cells (AECs), indicating that other bitter tastants may also impair the epithelial integrity to prevent hazardous particulate matters such as coronaviruses. Therefore, any bitter tastants intended for treating airway disease should be carefully evaluated for potential toxicity to AECs. Hypothesis/Purpose Considering the vast diversity of bitter tastants in nature and different types of TAS2Rs expressed in airway cells, we hypothesized that there must be some natural bitter tastants to be not only potent in inducing relaxation of ASMCs but also unharmful to AECs. Study design and methods Here we evaluated a group of bitter flavonoids that are derived from fruits and commonly used in traditional herbal medicine, including apigenin, hesperetin, kaempferol, naringenin, quercetin, and naringin, for their effects on the proliferation of human airway epithelial-like (16HBE14o-, BEAS-2B, and A549) cells cultured in vitro. Cell proliferation and associated signaling pathways were assessed by cell counting, ATP assay, cell cycling assay, quantitative RT-PCR, Fluo-4 labeling, and fluorescence resonance energy transfer, respectively. Results The results show that five of the six tested bitter tastants inhibited, but only naringin promoted the proliferation of the 16HBE14o-, BEAS-2B, and A549 cells at the dose of a few hundred micromoles. Furthermore, the naringin-promoted proliferation of the 16HBE14o- cells was associated with enhanced cell cycle progression, mRNA expression of cyclin E, and evoked calcium signaling/ERK signaling, which were all attenuated by inhibition of the TAS2R signaling pathways with specific blockers. Conclusion These findings indicate that although the majority of the bitter flavonoids may inhibit the proliferation of AECs, naringin emerged as one to promote the proliferation of AECs via cell cycle progression and TAS2R-activated intracellular signaling. It suggests that naringin and not a few other bitter tastants can be proven with nontoxicity to the airway epithelial structure and function, which provides further confidence in the development of safe and effective TAS2R-based bronchodilators for asthma therapy.

Attenuated vasodilatation of small arteries is a hallmark feature of hypertension. Salusin-β, which is a TOR2A gene product and an important vasoactive peptide, has a close relationship with cardiovascular disease. This study aimed to determinate the roles of salusin-β in vasodilatation, and its signal pathways in Wistar–Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Isometric tension experiments were performed. Vasodilatation was induced by acetylcholine (ACh) or sodium nitroprusside (SNP). Plasma salusin-β levels and their protein expressions in coronary artery (CA), mesenteric artery (MA), and pulmonary artery (PA) of SHR were much higher than that of WKY. Intravenous injection of salusin-β increased arterial blood pressure in SHR, while anti-salusin-β IgG decreased it. Salusin-β further deteriorated, while anti-salusin-β IgG improved, the attenuated ACh-induced relaxation, the decreased nitric oxide (NO) level, and endothelial nitric oxide synthase (eNOS) activity in arteries of SHR, and salusin-β had no significant effect on SNP-induced relaxation. The NAD(P)H oxidase activity and reactive oxygen species (ROS) level in arteries of SHR were much higher than that of WKY, which was further increased by salusin-β but reduced by anti-salusin-β IgG. ROS scavenger NAC or antioxidant apocynin significantly inhibited, while SOD inhibitor DETC aggravated, the effects of salusin-β, and the eNOS inhibitor L-NAME inhibited the effects of anti-salusin-β IgG. These results indicated that enhanced salusin-β activity is involved in attenuated endothelium-dependent vasodilatation pathogenesis in SHR by activating NAD(P)H oxidase derived ROS generation and inhibiting eNOS activation and NO release.

Excessive contraction of airway smooth muscle cells (ASMCs) is a hallmark feature of asthma. Intriguing, the activation of bitter taste receptor (TAS2R) in ASMCs can relax ASMCs. However, there is a lack of potent TAS2R agonists that can be used in asthma therapies since those tested agonists cannot relax ASMCs at the dose below a few hundred micromolar. Considering that sanguinarine (SA) is a bitter substance often used in small doses for the treatment of asthma in folk medicine, the present study was to determine the rapid relaxation effect of SA on ASMCs and to reveal the underlying mechanisms associated with TAS2R signaling. Here, cell stiffness, traction force, calcium signaling, cAMP levels, and the mRNA expression were evaluated by using optical magnetic twisting cytometry, traction force microscopy, Fluo-4/AM labeling, enzyme-linked immunosorbent assay (ELISA), and quantitative (q)RT-PCR, respectively. We found that 0.5 µM SA immediately decreased cell stiffness and traction force, which is comparable with the effect of 5 µM isoproterenol. In addition, 0.5 µM SA immediately increased intracellular free calcium concentration ([Ca2+]i) and decreased the mRNA expression of contractile proteins such as calponin and α-smooth muscle actin after the treatment for 24 h. Furthermore, SA-mediated decrease in cell stiffness/traction force and increase in [Ca2+]i were significantly blunted by inhibiting the TAS2Rs signaling. These findings establish the rapid relaxation effect of SA at low concentration (

Two polysaccharides, MDP-1 and MDP-2, were obtained from the fermentation liquid of M. dendrobii by anion exchange chromatography and gel filtration. Their chemical structures were measured by FT-IR, GC, 1H and 13C NMR spectra, indicating the mainly compositions of mannose, xylose, and galactose for MDP-1; galacturonic acid, galactose and rhamnose for MDP-2. Furthermore, the antioxidant activities of MDPs were investigated, showing different antioxidant activities, in which MDP-2 performed noticeable, with excellent superoxide radical activity better than BHT, high DPPH radical activity (IC50 at 227 μg/mL) comparable with BHT, moderate reducing power activity and hydroxyl radical scavenging activity. The results indicated that the fermentation liquid of M. dendrobii could be used as a potential natural source of antioxidant.

Although gut microbiota influences osteoporosis risk, the individual species involved, and underlying mechanisms, are unknown. We performed integrative analyses in a Chinese cohort with metagenomics/targeted metabolomics/whole-genome sequencing. Bacteroides vulgatus was found negatively associated with bone mineral density (BMD), this association was validated in US Caucasians. Serum valeric acid was positively associated with BMD, and B.vulgatus causally downregulated it. Ovariectomized mice fed B.vulgatus had decreased bone formation and increased bone resorption, lower BMD and poorer bone micro-structure. Valeric acid suppressed NF-κB p65 protein production (pro-inflammatory), and enhanced IL-10 mRNA expression (anti-inflammatory), leading to suppressed maturation of osteoclast-like cells, and enhanced maturation of osteoblasts in vitro. B.vulgatus and valeric acid represent promising targets for osteoporosis prevention/treatment.

Highly sensitive and flexible pressure sensors were developed based on dielectric membranes composed of insulating microbeads contained within polyvinylidene fluoride (PVDF) nanofibers. The membrane is fabricated using a simple electrospinning process. The presence of the microbeads enhances porosity, which in turn enhances the sensitivity (1.12 kPa

Purpose This paper aims to clarify the effects of metallic nanoparticles (NPs) additives and room temperature ionic liquids (ILs) on the tribological performance of electric contacts. Design/methodology/approach Tribological properties of copper (Cu) and silver (Ag) NPs as lubricant additives in different lubricants of ILs or polyalphaolefin (PAO) oils under applied electric currents were investigated. After tribological tests, morphologies of worn surfaces were observed; meanwhile, lubrication and anti-wear properties were analyzed. Findings The mixture solution of the IL and Cu NPs showed desirable lubrication and anti-wear properties due to the reduction of electrocorrosion and the enhancement of rolling effects of particles in the contact region. The anti-wear performance of Cu NPs is better than that of Ag NPs due to the difference in the particle size. The PAO oil with the Cu NPs additives showed poor lubrication properties due to the low solubility of the particles in the oil. When the direction of applied current was changed, the friction of the lubricant with better conductivity was more stable in the variation trend. Originality/value This paper begins with a study of tribological properties of Cu and Ag NPs as lubricant additives in different lubricants of IL or PAO oils under applied electric currents. The authors then propose several methods and possible solutions which could be implemented to improve the tribological performance of electric contacts.

Many dietary supplements are promoted to patients with osteoarthritis (OA) including the three naturally derived compounds, glucosamine, chondroitin and diacerein. Despite their wide spread use, research on interaction of these antiarthritic compounds with human hepatic cytochrome P450 (CYP) enzymes is limited. This study aimed to examine the modulatory effects of these compounds on CYP2C9, a major CYP isoform, using in vitro biochemical assay and in silico models. Utilizing valsartan hydroxylase assay as probe, all forms of glucosamine and chondroitin exhibited IC50 values beyond 1000 μM, indicating very weak potential in inhibiting CYP2C9. In silico docking postulated no interaction with CYP2C9 for chondroitin and weak bonding for glucosamine. On the other hand, diacerein exhibited mixed-type inhibition with IC50 value of 32.23 μM and Ki value of 30.80 μM, indicating moderately weak inhibition. Diacerein's main metabolite, rhein, demonstrated the same mode of inhibition as diacerein but stronger potency, with IC50 of 6.08 μM and Ki of 1.16 μM. The docking of both compounds acquired lower CDOCKER interaction energy values, with interactions dominated by hydrogen and hydrophobic bondings. The ranking with respect to inhibition potency for the investigated compounds was generally the same in both in vitro enzyme assay and in silico modeling with order of potency being diacerein/rhein > various glucosamine/chondroitin forms. In vitro-in vivo extrapolation of inhibition kinetics (using 1 + [I]/Ki ratio) demonstrated negligible potential of diacerein to cause interaction in vivo, whereas rhein was predicted to cause in vivo interaction, suggesting potential interaction risk with the CYP2C9 drug substrates.

Aim Schisandra chinensis is a well-known traditional Chinese medicine used mainly as a recipe for hepatoprotection. Modern researches have revealed that the hepatoprotection is related to its lignans and crude polysaccharide. In this study, we examined the effect and mechanism of Schisandra chinensis acidic polysaccharide (SCAP) on the liver injury induced by ethanol. Main methods SCAP was extracted with water extraction and ethanol precipitation. Liver injury models of both mice and HepG2 cells were produced by ethanol. The liver index, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in serum of the mice and cell culture supernatant were examined; HE staining was performed for observing pathological changes of liver. The malondialdehyde (MDA) level and superoxide dismutase (SOD) activities in serum, liver tissue and HepG2 cells, and triglyceride (TG) content in liver tissue were tested. Western blot was conducted to determine cytochrome P450 2E1 (CYP2E1) expression in liver tissue of mice and HepG2 cells. Key findings SCAP significantly reduced serial AST and ALT levels in the injuried liver and HepG2 cells induced by ethanol and also decreased TG level in the liver tissue. SCAP also obviously improved the hepatopathological changes and decreased MDA level as well as increased SOD activities in the serum, liver tissue and HepG2 cells induced by ethanol. Furthermore, Western blot analysis indicated that SCAP significantly inhibited the upregulation of CYP2E1 protein. Significance SCAP has a protective effect on ethanol-induced liver injury in mice and cells, and the mechanism underlying may be via inhibiting the expression of CYP2E1 protein and then alleviating oxidative stress injury induced by ethanol.

Treatment choices for acute myelogenous leukemia (AML) patients resistant to conventional chemotherapies are limited and novel therapeutic agents are needed. IL3 receptor alpha (IL3Rα, or CD123) is expressed on the majority of AML blasts, and there is evidence that its expression is increased on leukemic relative to normal hematopoietic stem cells, which makes it an attractive target for antibody-based therapy. Here, we report the generation and preclinical characterization of SGN-CD123A, an antibody–drug conjugate using the pyrrolobenzodiazepine dimer (PBD) linker and a humanized CD123 antibody with engineered cysteines for site-specific conjugation. Mechanistically, SGN-CD123A induces activation of DNA damage response pathways, cell-cycle changes, and apoptosis in AML cells. In vitro, SGN-CD123A–mediated potent cytotoxicity of 11/12 CD123+ AML cell lines and 20/23 primary samples from AML patients, including those with unfavorable cytogenetic profiles or FLT3 mutations. In vivo, SGN-CD123A treatment led to AML eradication in a disseminated disease model, remission in a subcutaneous xenograft model, and significant growth delay in a multidrug resistance xenograft model. Moreover, SGN-CD123A also resulted in durable complete remission of a patient-derived xenograft AML model. When combined with a FLT3 inhibitor quizartinib, SGN-CD123A enhanced the activity of quizartinib against two FLT3-mutated xenograft models. Overall, these data demonstrate that SGN-CD123A is a potent antileukemic agent, supporting an ongoing trial to evaluate its safety and efficacy in AML patients (NCT02848248). Mol Cancer Ther; 17(2); 554–64. ©2017 AACR.

Although the mining area has been restored, the environmental problems caused by years of large-scale oil shale mining are still continuing, coupled with the intensive distribution of the surrounding petrochemical industry, posing a serious threat to the local ecological environment. In this study, we investigated eight heavy metals (Cu, Ni, Pb, Cd, As, Cr, Mn and Zn) contamination and distribution around mining area, evaluated the potential risks of environment, identified the main sources of metal pollution and performed source apportionment. The results showed that the original north and south dumps were seriously polluted, and the CF values were significantly higher than other sampling sites. Ni, Zn and Mn have high coefficients of variation, which may be greatly affected by human factors and especially the waste slag piled up. The concentration of heavy metals in the water was lower than in the soil; soil particles, pH, Eh and acid mine drainage influence the variation of heavy metal concentrations. As and Cd have very high RAC values, and accordingly they were mainly present in the exchangeable and reduced fractions. Mn was exposed to higher ecological risks, followed by Pb, although there were high loads on carbonate bound and oxidizable fractions. APCS-MLL receptor model was used to identify and apportionment three main sources of contamination. The mean contribution rates of industrial activity, atmospheric deposition and mixed sources accounted for 39.77%, 22.24% and 37.99%, respectively. Cluster analysis further classified the metal pollution sources according to the spatial distance of sampling points.

Acid mine drainage (AMD) poses a potential threat to human health worldwide, due to its high content of inorganic contaminants including heavy metals. Nevertheless, AMD is commonly used for irrigation of paddy soils. To determine the extent to which AMD affects contaminant levels in such practices, the effect of continuous AMD flooding on pH, redox potential Eh and the migration of Cu and Cd in contaminated paddy soil was studied in column experiments. By means of simulated AMD, dynamic changes of Cu and Cd concentrations in pore water were measured and the controlling factors pH, Eh and presence of Fe, dissolved organic carbon and sulfate were determined over a period of 60 days. Minerals in the soil were assessed by means of an Eh-pH diagram and solid-phase mineral detection. During continuous flooding with AMD-simulated water the soil pH increased, while Eh decreased over time. After 60 days the soil pH stabilized. Cu and Cd concentrations in the pore water negatively correlated with pH and with sulfate concentrations. Five-step sequential extraction illustrated that the fraction of exchangeable Cu increased significantly during AMD flooding. The overall content of Cu increased from initially 0.29 mg/g to 0.41 mg/g, while the content of Cd decreased from 9.2 mg/g to approximately 7.2 mg/g. Mobility factors were calculated and these conformed that Cd mobility significantly increased in contaminated soils during continuous AMD flooding. Our findings indicate that the release of Cu and Cd under AMD flooding can increase potential environmental risks, even though they lead to formation of metal sulfide deposits under anaerobic conditions. The presented data improves our understanding of the impact of overlying water conditions on the mobility of toxic metals in contaminated paddy soils.

Polypyrrole-sepiolite (PPy/SPL) nanofibers were prepared by in situ chemical oxidation polymerization in the presence of sepiolite. A PPy/SPL composite modified glassy carbon electrode (PPy/SPL/GCE) was prepared and characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, and electrochemical methods. Differential pulse anodic stripping voltammetry for the simultaneous determination of trace Pb(II) and Cd(II) was carried out at the PPy/SPL/GCE. Operational parameters such as the deposition potential and time, the amount of modified suspension, and the pH values were optimized for the purpose of determination of trace metal ions in 0.10 M acetate buffer solution. Under the optimal conditions, the stripping peak currents showed good linear relationships with Pb(II) and Cd(II) at concentration ranges of 5.0 × 10–9‒1.2 × 10–6 M and 5.0 × 10–9‒1.2 × 10–7 M, and the detection limits were 1.2 and 1.5 nM, respectively. The proposed method is applicable to the simultaneous determination of trace Pb(II) and Cd(II) in real water samples with the relative standard deviations of less than 4.4% and the recovery rates of 97.9‒102.2%.

Bupleurum chinense DC. is one of the most important traditional Chinese medicines. Among its primary pharmacologically active components, saikosaponins play a vital role. We investigated the ecophysiological characteristics, accumulation of secondary metabolites, and antioxidant system of wild plants at low light intensity in the forest understory at shady and sunny sites. Compared with plants at sunny sites, plants at the shady site were more abundant, had higher specific leaf area (SLA), a lower maximum electron transport rate ( J max ), higher triose phosphate utilization (TPU), and higher chlorophyll b content (Chlb), but lower net photosynthesis ( P n ), root and aboveground biomass, dark respiration rate ( R d ), light compensation point (LCP), chlorophyll a to b ratio, carotenoid content, and nonphotochemical quenching (NPQ). These features suggest that under low light conditions, the species developed larger leaves to catch more light energy through light-harvesting complex II to increase its photosynthetic efficiency (its ability to use weak light) and photosynthetic electron transport, thereby improving carbon metabolism and survival. The maximum quantum efficiency of photosystem II was about 0.8 at both sites; thus, photoinhibition was not a major problem. Contents of saikosaponins a and d and the total saikosaponin content (SSa, SSd, and SS total ) were much higher at the shady site, accompanied by increased superoxide dismutase (SOD), catalase(CAT), and peroxidases (POD) activity and decreased malondialdehyde (MDA). This suggested that low light activates antioxidant stress-response pathways, leading to increased SSa, SSd, and SS total . Our results suggest that B. chinense has strong shade tolerance and would be suitable for cultivation in an agroforestry system.

The four polymers with different contents of alkyl chain (C12–C18), styrene, and vinyl acetate were synthesized and employed as the viscosity reducers for super heavy oils A and B. Compared with the apparent viscosity of heavy oil in a wide share rate range (0–200 s−1) at 50°C, it can be seen that the optimal efficiency could be achieved to reduce viscosity when the polymers have suitable length of alkyl chain in the permeation of small molecules (vinyl acetate). Furthermore, the adaptation of the polymers to different oil samples and application temperature of polymers were also studied.

C26H18N6NiS4, triclinic, P 1 ¯ $\overline{1}$ (no. 2), a = 8.2947(4) Å, b = 8.9964(5) Å, c = 9.4210(5) Å, α = 70.988(1)°, β = 79.971(1)°, γ = 82.567(1)°, V = 652.52(6) Å3, Z = 1, R gt (F) = 0.0340, wR ref (F 2) = 0.0643, T = 296(2) K.

Background The goal was to study the role of serum IgA in patients with IgA nephropathy (IgAN) found during physical examination, and to explore its value in diagnosis, assessment of pathological injury, and clinical prediction of IgAN. Methods The study included 457 patients who were hospitalized between January 2010 and June 2018 due to physical abnormalities and diagnosed with kidney disease via renal biopsy. Renal histopathology was quantified according to Katafuchi semi-quantitative standards, while the IgAN patients were also scored according to Lee's grading system. Results The average age of the 457 patients was 39.62 ± 13.52 years when abnormalities were found during physical examination. IgAN (202 cases, 46.12%) was the most common type of primary glomerulonephritis in the 457 patients. Of the IgAN patients, 75.25% (152 cases) were under 45 years old at the time of abnormal physical examination and IgAN patients were significantly younger than non-IgAN patients. There was a significant difference in the gender ratio between IgAN patients and non-IgAN patients (χ2 = 4.24, p = 0.039). In IgAN patients, the proportion of male patients, serum creatinine (SCr), the glomerular lesion and tubulointerstitial scores, and serum IgA were statistically higher than in non-IgAN patients with other types of primary glomerulonephritis; however, MDRD-GFR was lower. The ROC curve of serum IgA in the diagnosis of IgAN showed the AUC was 0.602. One hundred forty-seven cases (72.77%) were Lee's III - V grade. The proportion of patients who were at Lee's III - V grades in the normal serum IgA group (184 cases) was higher than that of the elevated serum IgA group (18 cases). There were no significant differences in gross hematuria, proteinuria, MDRD-GFR, SCr, and hypertension between the two groups. Conclusions Serum IgA may be of little value in the diagnosis of patients with IgA nephropathy detected via physical examination. The level of serum IgA may have predictive value in evaluating Lee's pathological damage in IgAN patients.

In this study, levels of dechlorane plus (DP) in breast milk and matched adipose tissue samples were measured from 54 women living in Wenling, China. Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) were measured simultaneously for comparison. The levels of ∑DPs/∑PBDEs varied from less than one to several dozens of ng g−1 lipid weight (lw) in matrices and the levels of ∑PCBs varied between several to hundreds of ng g−1 lw. In the same matrix, ∑DPs and ∑PCBs/∑PBDEs showed a significant relationship (p

[Retraction]AIM: To explore the topographic distribution features of choroidal thickness (CT) and retinal nerve fiber layer thickness (RNFLT), and determine the relationship between CT and ocular parameters in school-aged children. METHODS: The healthy school-aged children with low myopia or emmetropia in Wenzhou were recruited for this cross-sectional study. With high-density optical coherence tomography (HD-OCT) combined with MATLAB software, the CT and RNFLT values in the macular area were measured at different locations and compared. Statistical analyses were performed to evaluate the correlation between CT and ophthalmic parameters, such as spherical equivalent (SE) and the axial length (AL). RESULTS: A total of 279 school-aged children with 8.00±1.35 years of mean age (range, 6-10y) were included. The mean AL was 23.66±0.86 mm. The mean CT in CT-C (264.31±48.93 µm) was thicker than that in CT-N1 (249.54±50.52 µm), and the average CT in the parafoveal region was also thicker than that in CT-N2 (235.65±50.63 µm). The subfoveal CT also varied substantially across refractive errors (P

Importance: Retinopathy of prematurity (ROP) is an important risk factor for blindness in children due to neovascularization (NV). Hypoxia stimulates the formation of NV, as retinal hypoxia affects the stability and function of hypoxia-inducible factor (HIF) transcription factors. The purpose of this study is to study the mechanism of ROP and provide theoretical basis for clinical treatment of ROP. Objective: In the present study, we used a mouse model of oxygen-induced retinopathy (OIR) to demonstrate the effects of the HIF-1α inhibitor PX-478 on OIR, and to determine its mechanism of action, to provide a theoretical basis for the clinical treatment of ROP. Materials and Methods: The OIR mouse model was induced by exposing neonatal mouse pups and their mothers to 75 ± 5% oxygen from postnatal day 7 (P7) to P12, before being returned to room air from P12 to P17. Flat mount analyses were performed at P12 and P17. Hif1a, Hif2a, Hif3a, and Vegfa mRNA were detected by reverse transcription-polymerase chain reaction in OIR mice at P12 and P17. Hif1a and Vegfa mRNA were detected in OIR mice at P12 and P17 treatment with PX-478. Western blot analyses were used to assess the levels of HIF-1α, VEGF-A, and EPO before and after treatment with PX-478 at P12 and P17. Results: Hif1a mRNA was increased in OIR mice at P12 and P17, while Vegfa mRNA was increased at P12 and P17. HIF-1α, VEGF-A, and EPO protein levels were increased in OIR mice at P12 and P17, as compared to control mice at the same age (all p < 0.05). Inhibition of HIF-1α by injection of PX-478 in OIR mice (P9–P16) caused a decrease in the retinal avascular area at P12 and P17 (both p < 0.05), NV areas at P17 (p < 0.05), Vegfa mRNA decreased at P12 and P17, as compared to control mice (p < 0.05), and VEGF-A and EPO protein levels at P12 and P17, as compared to control mice. Our study found that there were PX-478 both retina and vitreous body of OIR. Inhibition of HIF-1α by injection of PX-478 in OIR mice caused a decrease in the retinal avascular area at P12 and P17, NV areas decreased at P17, VEGF-A and EPO protein levels at P12 and P17. Endothelial cell migration assays and cell tube formation indication PX-478 attenuate cell migration and significantly weakened the cell cavity formation under the condition of hypoxia. Conclusion: HIF-1α plays a main role in OIR and can be considered a therapeutic target in OIR by suppressing downstream angiogenic factors, PX-478 decreasing the retinal avascular area and NV.

Acid mine drainage (AMD) poses a potential environmental risk due to the low pH combined with high concentrations of toxic metals and sulfate. The Hengshi River in China is continually contaminated by the AMD from upstream mining areas and this river was selected as a study site to investigate the spatial distribution of Cu, Cd, Pb, Zn and the microbial communities in the paddy soil in vicinity of the river. Various geochemical parameters were determined for five sites, where river water was sampled together with paddy soil (at three depths) and soil pore water. The distribution of toxic metals at these sites was ranked as soil > river water > pore water. The metals in the soil samples were divided into five extractable fractions. With the increase of soil depth, F1 Zn, F2 Pb, F3 Zn, F4 Zn, F5 Cu basically produced a decreasing trend. The sum of the F1 and the F2 fractions of the toxic metals followed the order of Cd > Pb > Cu > Zn. Among the predominant bacteria detected were Fe- and S- metabolizing genera, including Anaeromyxobacter, Thiobacillus, and Geobacter. Based upon canonical correspondence analysis, sand content, Cu and pH correlated most strongly with the composition of the microbial communities. Significant correlations were found between toxic metal fraction and environmental parameters such as organic matter and total S content, while Fe only had a minor effect. The toxic metal fractions were the dominant drivers in changing the soil microbial community. The potential ecological risk of the toxic metals was assessed as Cd > Cu > Pb > Zn. Collectively, these results suggest that the geochemical gradients caused by AMD altered the toxic metals speciation and enriched relevant soil microbiota which adapted to the different conditions.

// Xin Li 1 , Shengjun Fan 1 , Xueyang Pan 1, 2 , Yilixiati Xiaokaiti 1 , Jianhui Duan 1 , Yundi Shi 1 , Yan Pan 1 , Lu Tie 1 , Xin Wang 2 , Yuhua Li 1 , Xuejun Li 1 1 State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China 2 Current address: University of Minnesota, Twin cities, MN 55455, USA Correspondence to: Xuejun Li, email: xjli@bjmu.edu.cn Keywords: nordihydroguaiaretic acid, neuropilin 1, cancer cell migration and metastasis, proteomics, prostate cancer Received: July 18, 2016 Accepted: November 07, 2016 Published: November 15, 2016 ABSTRACT Tumor metastasis is a major cause leading to the deaths of cancer patients. Nordihydroguaiaretic acid (NDGA) is a natural product that has been demonstrated to show therapeutic values in multiple diseases. In this study, we report that NDGA can inhibit cell migration and tumor metastasis via a novel mechanism. NDGA suppresses NRP1 function by downregulating its expression, which leads to attenuated cell motility, cell adhesion to ECM and FAK signaling in cancer cells. Moreover, due to its cross-cell type activity on NRP1 suppression, NDGA also impairs angiogenesis function of endothelial cells and fibronectin assembly by fibroblasts, both of which are critical to promote metastasis. Based on these comprehensive effects, NDGA effectively suppresses tumor metastasis in nude mice model. Our findings reveal a novel mechanism underlying the anti-metastasis function of NDGA and indicate the potential value of NDGA in NRP1 targeting therapy for selected subtypes of cancer.

Asthma has become a common chronic respiratory disease worldwide and its prevalence is predicted to continue increasing in the next decade, particularly in developing countries. A key component in asthma therapy is to alleviate the excessive bronchial airway narrowing ultimately due to airway smooth muscle contraction, which is often facilitated by a smooth muscle relaxant, such as the β2-adrenergic agonists. Recently, bitter taste receptor (TAS2R) agonists, including saccharin and chloroquine, have been found to potently relax the airway smooth muscle cells (ASMCs) via intracellular Ca2+ signaling. This inspires a great interest in screening the vast resource of natural bitter substances for potential bronchodilatory drugs. In the present study, the relaxation effect of naringin, a compound extracted from common grapefruit, on ASMCs cultured in vitro or bronchial airways of Balb/c mice in vivo was evaluated. The results demonstrated that, when exposed to increasing doses of naringin (0.125, 0.25, 0.5 and 1.0 mM), the traction force generated by the cultured ASMCs decreased progressively, while the intracellular calcium flux signaling in the ASMCs increased. When inhaled at increasing doses (15, 30 and 60 µg), naringin also dose-dependently reduced the bronchial airway resistance of the normal and ovalbumin-induced asthma Balb/c mice in response to challenge with methacholine. In conclusion, these findings indicate that naringin was able to effectively relax murine ASMCs in vitro and in vivo, thus suggesting that it is a promising drug agent to be further investigated in the development of novel bronchodilators for the treatment of asthma.