The absorption of oral morroniside in rats: In vivo, in situ and in vitro studies

Morroniside is one of the most important iridoid glycosides from Cornus officinalis Sieb. et Zucc. In the present study, the pharmacokinetics and bioavailability studies of morroniside were conducted on Sprague-Dawley (SD) rats. A rat in situ intestinal perfusion model was used to characterize the absorption of morroniside. Caco-2 cells were used to examine the transport mechanisms of morroniside. The pharmacokinetic study of morroniside exhibited linear dose-proportional pharmacokinetic characteristics and low bioavailability (4.3 %) in SD rats. Its average Peff value for transport across the small intestinal segments changed from (3.09 ± 2.03) × 10–6 to (4.53 ± 0.94) × 10–6 cm s–1. In Caco-2 cells, the Papp values ranged from (1.61 ± 0.53) × 10–9 to (1.19 ± 0.22) × 10–7 cm s–1 for the apical to basolateral side and the Pratio values at three concentrations were all lower than 1.16. Morroniside showed poor absorption and it might not be a specific substrate of P-glycoprotein (P-gp)

Clinical efficacy of combination of oxaliplatin and vascular intervention in treatment of advanced cervical cancer and related prognostic factors

Purpose: To investigate the therapeutic effect of combination of oxaliplatin and vascular intervention in patients with advanced cervical cancer (ACC), and its influence on the prognosis of patients.Methods: One hundred ACC patients were selected and equally assigned to control (oxaliplatin) and combination or study (oxaliplatin plus vascular intervention) groups. The patients in control group received oxaliplatin, while those in study group were treated with oxaliplatin combined with vascular intervention. Clinical efficacy, levels of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR-2), fibroblast growth factor-2 (FGF-2), BFGF and platelet-derived growth factor (PDGF) before and after therapy, and survival rate at 3, 6, 12 and 18 months after therapy were determined compared between the two groups. The prognostic factors were analyzed with logistic factor analysis.Results: The clinical efficacy and survival rate at 3, 6, 12 and 18 months after therapy in the combination group were higher when compared with those of the control group (p < 0.05). After therapy, the levels of VEGF, VEGFR-2, FGF-2, BFGF and PDGF were lower in the combination group than in control group. Age, short-term efficacy and basic diseases were identified as the influencing factors for the prognosis of patients with advanced cervical cancer (p < 0.05).Conclusion: The combination of oxaliplatin and vascular intervention significantly improved clinical treatment efficacy and survival rate in ACC patients. Age, short-term efficacy and basic diseases affected the prognosis of patients

X-ray performance of a customized large-format scientifc CMOS detector

In recent years, the performance of Scientifc Complementary Metal Oxide Semiconductor (sCMOS) sensors has been improved signifcantly. Compared with CCD sensors, sCMOS sensors have various advantages, making them potentially better devices for optical and X-ray detection, especially in time-domain astronomy. After a series of tests of sCMOS sensors, we proposed a new dedicated high-speed, large-format X-ray detector in 2016 cooperating with Gpixel Inc. This new sCMOS sensor has a physical size of 6 cm by 6 cm, with an array of 4096 by 4096 pixels and a pixel size of 15 um. The frame rate is 20.1 fps under current condition and can be boosted to a maximum value around 100 fps. The epitaxial thickness is increased to 10 um compared to the previous sCMOS product. We show the results of its frst taped-out product in this work. The dark current of this sCMOS is lower than 10 e/pixel/s at 20C, and lower than 0.02 e/pixel/s at -30C. The Fixed Pattern Noise (FPN) and the readout noise are lower than 5 e in high-gain situation and show a small increase at low temperature. The energy resolution reaches 180.1 eV (3.1%) at 5.90 keV for single-pixel events and 212.3 eV (3.6%) for all split events. The continuous X-ray spectrum measurement shows that this sensor is able to response to X-ray photons from 500 eV to 37 keV. The excellent performance, as demonstrated from these test results, makes sCMOS sensor an ideal detector for X-ray imaging and spectroscopic application.Comment: 20 pages. published in PAS

Chloroquine reduces arylsulphatase B activity and increases chondroitin-4-sulphate: implications for mechanisms of action and resistance

<p>Abstract</p> <p>Background</p> <p>The receptors for adhesion of <it>Plasmodium falciparum</it>-infected red blood cells (RBC) in the placenta have been identified as chondroitin-4-sulphate (C4S) proteoglycans, and the more sulphate-rich chondroitin oligosaccharides have been reported to inhibit adhesion. Since the anti-malarial drug chloroquine accumulates in lysosomes and alters normal lysosomal processes, the effects of chloroquine on the lysosomal enzyme arylsulphatase B (ASB, N-acetylgalactosamine-4-sulphatase), which removes 4-sulphate groups from chondroitin-4-sulphate, were addressed. The underlying hypothesis derived from the recognized impairment of attachment of parasite-infected erythrocytes in the placenta, when chondroitin-4-sulphation was increased. If chloroquine reduced ASB activity, leading to increased chondroitin-4-sulphation, it was hypothesized that the anti-malarial mechanism of chloroquine might derive, at least in part, from suppression of ASB.</p> <p>Methods</p> <p>Experimental methods involved cell culture of human placental, bronchial epithelial, and cerebrovascular cells, and the <it>in vitro </it>exposure of the cells to chloroquine at increasing concentrations and durations. Measurements of arylsulphatase B enzymatic activity, total sulphated glycosaminoglycans (sGAG), and chondroitin-4-sulphate (C4S) were performed using <it>in vitro </it>assays, following exposure to chloroquine and in untreated cell preparations. Fluorescent immunostaining of ASB was performed to determine the effect of chloroquine on cellular ASB content and localization. Mass spectrometry and high performance liquid chromatography were performed to document and to quantify the changes in chondroitin disaccharides following chloroquine exposure.</p> <p>Results</p> <p>In the human placental, bronchial epithelial, and cerebrovascular cells, exposure to increasing concentrations of chloroquine was associated with reduced ASB activity and with increased concentrations of sGAG, largely attributable to increased C4S. The study data demonstrated: 1) decline in ASB activity following chloroquine exposure; 2) inverse correlation between ASB activity and C4S content; 3) increased content of chondroitin-4-sulphate disaccharides following chloroquine exposure; and 4) decline in extent of chloroquine-induced ASB reduction with lower baseline ASB activity. Confocal microscopy demonstrated the presence of ASB along the cell periphery, indicating extra-lysosomal localization.</p> <p>Conclusions</p> <p>The study data indicate that the therapeutic mechanism of chloroquine action may be attributable, at least in part, to reduction of ASB activity, leading to increased chondroitin-4-sulphation in human placental, bronchial epithelial, and cerebrovascular cells. In vivo, increased chondroitin-4-sulphation may reduce the attachment of <it>P. falciparum</it>-infected erythrocytes to human cells. Extra-lysosomal localization of ASB and reduced impact of chloroquine when baseline ASB activity is less suggest possible mechanisms of resistance to the effects of chloroquine.</p

Cytotoxic effects and the mechanism of three types of magnetic nanoparticles on human hepatoma BEL-7402 cells

The evaluation of the toxicity of magnetic nanoparticles (MNPs) has attracted much attention in recent years. The current study aimed to investigate the cytotoxic effects of Fe3O4, oleic acid-coated Fe3O4 (OA-Fe3O4), and carbon-coated Fe (C-Fe) nanoparticles on human hepatoma BEL-7402 cells and the mechanisms. WST-1 assay demonstrated that the cytotoxicity of three types of MNPs was in a dose-dependent manner. G1 (Fe3O4 and OA-Fe3O4) phase and G2 (C-Fe) phase cell arrests and apoptosis induced by MNPs were detected by flow cytometry analysis. The increase in apoptosis was accompanied with the Bax over-expression, mitochondrial membrane potential decrease, and the release of cytochrome C from mitochondria into cytosol. Moreover, apoptosis was further confirmed by morphological and biochemical hallmarks, such as swollen mitochondria with lysing cristae and caspase-3 activation. Our results revealed that certain concentrations of the three types of MNPs affect BEL-7402 cells viability via cell arrest and inducing apoptosis, and the MNPs-induced apoptosis is mediated through the mitochondrial-dependent pathway. The influence potency of MNPs observed in all experiments would be: C-Fe > Fe3O4 > OA-Fe3O4

Sequence Analysis of Alginate-Derived Oligosaccharides by Negative-Ion Electrospray Tandem Mass Spectrometry

Negative-ion electrospray tandem mass spectrometry (ES-MS/MS) with collision-induced dissociation (CID) is attempted for sequence determination of alginate oligosaccharides, derived from polyanionic alginic acid, polymannuronate, and polyguluronate by partial depolymerization using either alginate lyase or mild acid hydrolysis. Sixteen homo- and hetero-oligomeric fragments were obtained after fractionation by gel-filtration and strong anion exchange high performance liquid chromatography. The product-ion spectra of these alginate oligosaccharides were dominated by intense B-, C-, Y-, and Z-type ions together with 0,2A- and 2,5A-ions of lower intensities. Internal mannuronate residues (M) produce weak but specific decarboxylated Zint-ions (Zint − 44 Da; int: denotes internal), which can be used for distinction of M and a guluronate residue (G) at an internal position. A reducing terminal M or G, although neither gives rise to a specific ion, can be identified by differences in the intensity ratio of fragment ions of the reducing terminal residue [2,5Ared]/[0,4Ared] (red: denotes reducing terminal)

Tandem MS can distinguish hyaluronic acid from N-acetylheparosan

Isobaric oligosaccharides enzymatically prepared from hyaluronic acid (HA) and N-acetylheparosan (NAH), were distinguished using tandem mass spectrometry. The only difference between the two series of oligosaccharides was the linkage pattern (in HA 1→3 and in NAH 1→4) between glucuronic acid and N-acetylglucosamine residues. Tandem mass spectrometry afforded spectra, in which glycosidic cleavage fragment ions were observed for both HA and NAH oligosaccharides. Cross-ring cleavage ions 0,2An and 0,2An-h (n is even number) were observed only in GlcNAc residues of NAH oligosaccharides. One exception was an 0,2A2 ion fragment observed for the disaccharide from HA. These cross-ring cleavage fragment ions are useful to definitively distinguish HA and NAH oligosaccharides

BCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza virus infection

Neutrophils are vital for antimicrobial defense; however, their role during viral infection is less clear. Furthermore, the molecular regulation of neutrophil fate and function at the viral infected sites is largely elusive. Here we report that BCL6 deficiency in myeloid cells exhibited drastically enhanced host resistance to severe influenza A virus (IAV) infection. In contrast to the notion that BCL6 functions to suppress innate inflammation, we find that myeloid BCL6 deficiency diminished lung inflammation without affecting viral loads. Using a series of Cre-transgenic, reporter, and knockout mouse lines, we demonstrate that BCL6 deficiency in neutrophils, but not in monocytes or lung macrophages, attenuated host inflammation and morbidity following IAV infection. Mechanistically, BCL6 bound to the neutrophil gene loci involved in cellular apoptosis in cells specifically at the site of infection. As such, BCL6 disruption resulted in increased expression of apoptotic genes in neutrophils in the respiratory tract, but not in the circulation or bone marrow. Consequently, BCL6 deficiency promoted tissue neutrophil apoptosis. Partial neutrophil depletion led to diminished pulmonary inflammation and decreased host morbidity. Our results reveal a previously unappreciated role of BCL6 in modulating neutrophil apoptosis at the site of infection for the regulation of host disease development following viral infection. Furthermore, our studies indicate that tissue-specific regulation of neutrophil survival modulates host inflammation and tissue immunopathology during acute respiratory viral infection