Roxadustat alleviates nitroglycerin-induced migraine in mice by regulating HIF-1α/NF-κB/inflammation pathway.

Sensitization of central pain and inflammatory pathways play essential roles in migraine, a primary neurobiological headache disorder. Since hypoxia-inducible factor-1α (HIF-1α) is implicated in neuroprotection and inflammation inhibition, herein we investigated the role of HIF-1α in migraine. A chronic migraine model was established in mice by repeated injection of nitroglycerin (10 mg/kg, i.p.) every other day for 5 total injections. In the prevention and acute experiments, roxadustat, a HIF-1α stabilizer, was orally administered starting before or after nitroglycerin injection, respectively. Pressure application measurement, and tail flick and light-aversive behaviour tests were performed to determine the pressure pain threshold, thermal nociceptive sensitivity and migraine-related light sensitivity. At the end of experiments, mouse serum samples and brain tissues were collected for analyses. We showed that roxadustat administration significantly attenuated nitroglycerin-induced basal hypersensitivity and acute hyperalgesia by improving central sensitization. Roxadustat administration also decreased inflammatory cytokine levels in serum and trigeminal nucleus caudalis (TNC) through NF-κB pathway. Consistent with the in vivo results showing that roxadustat inhibited microglia activation, roxadustat (2, 10, and 20 µM) dose-dependently reduced ROS generation and inflammation in LPS-stimulated BV-2 cells, a mouse microglia cell line, by inhibiting HIF-1α/NF-κB pathway. Taken together, this study demonstrates that roxadustat administration ameliorates migraine-like behaviours and inhibits central pain sensitization in nitroglycerin-injected mice, which is mainly mediated by HIF-1α/NF-κB/inflammation pathway, suggesting the potential of HIF-1α activators as therapeutics for migraine.

Simultaneous quantitative analysis of multi-compounds by a single marker in Radix Astragali by using serum HPLC-MS feature.

Using the serum pharmacochemistry method for Chinese Medicine, the material basis of Radix Astragali (RA) for "regulating and enriching blood" was studied. By compared with blank blood sample as a positive control in adult Wistar rats, four original saponinsas the material basis for "regulating and enriching blood" were absorbed into the blood after oral administration of RA. They were identified as astragaloside, astragaloside, astragaloside and astragaloside by HPLC-MS. According to the constituents absorbed into blood, the extracts of RA were prepared. In addition, the present patterns of quality control are limited to industrial application because most of the natural standard ingredients are very expensive and unavailable. Therefore, a quantitative analysis method of multi-components with a single marker (QAMS) was established and used to simultaneously measure four saponins from RA absorbed into the blood (Astragaloside, astragaloside, astragaloside and astragaloside). We used astragaloside I as the reference, the relative correction factors (f) of the other three saponins were measured by HPLC-MS. Within the linear ranges, the values of f of astragaloside I to astragaloside IV, astragaloside III and astragaloside II were 0.533, 0.779 and 0.934, respectively. According to the f values, we simultaneously determined four saponins using only one marker. The results of QAMS method were validated compared to that of external standard method, and no significant difference was observed.

Ultrasound-driven secondary self-assembly of amphiphilic ß-cyclodextrin dimers.

The controlled secondary self-assembly of amphiphilic molecules in solution is theoretically and practically significant in amphiphilic molecular applications. An amphiphilic ß-cyclodextrin (ß-CD) dimer, namely LA-(CD)2 , has been synthesized, wherein one lithocholic acid (LA) unit is hydrophobic and two ß-CD units are hydrophilic. In an aqueous solution at room temperature, LA-(CD)2 self-assembles into spherical micelles without ultrasonication. The primary micelles dissociates and then secondarily form self-assemblies with branched structures under ultrasonication. The branched aggregates revert to primary micelles at high temperature. The ultrasound-driven secondary self-assembly is confirmed by transmission electron microscopy, dynamic light scattering, (1) H NMR spectroscopy, and Cu(2+) -responsive experiments. Furthermore, 2D NOESY NMR and UV/Vis spectroscopy results indicate that the formation of the primary micelles is driven by hydrophilic-hydrophobic interactions, whereas host-guest interactions promote the formation of the secondary assemblies. Additionally, ultrasonication is shown to be able to effectively destroy the primary hydrophilic-hydrophobic balances while enhancing the host-guest interaction between the LA and ß-CD moieties at room temperature.

Cross-resistance and biochemical resistance mechanisms of avermectin resistant population of Dendrolimus punctatus.

To identify the resistance risk and the resistance mechanism of avermectin against Dendrolimus punctatus, we examined the cross-resistance of avermectin resistance population (AV) to multiple tested insecticides and the synergism of piperonyl butoxide (PBO), triphenyl phosphate (TPP) and diethyl maleate (DEM) to AV, Qin-ling Jieguanting (JGT) and susceptible (S) popultions, by leaf dipping method. The activities of carboxylesterase (CarE), glutathione S-transferases (GST) and mixed-functional oxidases (MFOs) in AV, JGT and S populations of D. punctatus was measured with spectrophotometry. The results showed that the AV population of D. punctatus had medium level of cross-resistance to emamectin benzoate (resistance ratio, RR50=25.0), chlorpyrifos (RR50=19.0), and cyhalothrin (RR50=15.4), and low level of cross-resistance to chlorfenapyr (RR50=8.1), but no cross-resistance to spinetoram, spinosad and chlorantraniliprole. Both PBO and TPP had significant synergism of avermectin to AV, JGT, and S populations, while DEM had no synergism to all the three populations. Compared with the S population, the AV population had higher content of MFOs cytochromes P450(3.5-fold) and b5(3.1-fold) and the activities of O-demethylase (4.1-fold) and CarE (2.2-fold). There was no significant difference in the activities of GST between AV and S populations. The increasing mixed-functional oxidases and CarE played an important role in the resistance of D. punctatus to avermectin. Spinetoram, spinosad, chlorantraniliprole, and avermectin were recommended to control D. punctatus.

PKCδ promotes the invasion and migration of colorectal cancer through c-myc/NDRG1 pathway.

Objective: Colorectal cancer (CRC) is the third cause of expected cancer deaths both in men and women in the U.S. and the third most commonly diagnosed cancer in China Targeted therapy has been proven to improve overall survival for unresectable metastatic CRC. But the location of the primary tumor or the presence of various core driver gene mutations that confer resistance may limit the utility of targeted therapy. Therefore, it is of great significance to further elucidate novel mechanisms of invasion and metastasis of CRC and find potential novel therapeutic targets. Protein Kinase C Delta (PKCδ) plays an important role in various diseases, including tumors. In CRC, the function of PKCδ on proliferation and differentiation is mostly studied but various research results were reported. Therefore, the role of PKCδ in CRC needs to be further studied, especially in tumor invasion and metastasis in CRC which few studies have looked into. Methods: The expression of PRKCD was analyzed by the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases and Immunohistochemical (IHC). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) enrichment analysis were used to explore the biological functions and pathways related to PRKCD. Lentivirus transfection was used to construct CRC cell lines with overexpression and knock-down of PKCδ or N-myc Downstream Regulated Gene 1 (NDRG1). Cell invasion and migration assay, wound healing assay were used to detect the function of PKCδ and NDRG1 in the invasion and migration of cells. Flow cytometry analysis was used to detect the influence of PKCδ on the CRC cell cycles .Immunofluorescence histochemistry ,Immunoprecipitation Assay and qPCR were used to detect the relationship of PKCδ and NDRG1. Xenograft model was used to verify the role of PKCδ in vivo. Results: PKCδ is overexpressed in CRC and could promote Epithelial-Mesenchymal Transition (EMT) and the invasion and migration of CRC in vitro. We confirmed that PKCδ and the tumor suppressor factor NDRG1 had a co-localization relationship in CRC. PKCδ inhibited NDRG1 transcription and protein expression. Overexpressing NDRG1 could inhibit the function of PKCδ in promoting tumor invasion and migration. PKCδ could regulate c-Myc, one transcription factor of NDRG1, to down-regulate NDRG1. In vivo, overexpressing PKCδ could promote xenograft growth and volume. Thus, our results showed that PKCδ reduced the expression of NDRG1 through c-Myc, promoting the invasion and migration of CRC through promoting EMT. Conclusion: The increased expression of PKCδ in CRC tumor tissue could promote the invasion and migration of tumor cells, and one of the mechanisms may be regulating c-Myc to inhibit the expression of NDRG1 and promote EMT.

[Therapeutic effect of metformin for clomiphene-resistant infertility patients with polycystic ovary syndrome: a systematic analysis].

OBJECTIVE: To evaluate the efficacy of metformin (MTF) in treatment of clomiphene (CC)-resistant patients with polycystic ovary syndrome (PCOS). METHODS: The published articles of randomized controlled trial (RCT) of comparison of MTF combined with CC and CC alone in treatment of CC-resistant PCOS were searched in PubMed, EMBASE, OVID, EBSCO databases and Cochrane Library, and these studies were screened under inclusion and exclusion criteria. The quality of included studies and extract data of comparison of ovulation rates and pregnancy rates were evaluated. And the Meta-analysis using statistic software RevMan 5.0 was completed. RESULT: Total of 333 patients in total 8 trials were included. Meta analysis showed that MTF plus CC led to a significantly higher clinical ovulation rate (OR = 7.31, 95%CI: 2.57 - 20.76, P < 0.05) and pregnancy rate (OR = 7.93, 95%CI: 2.45 - 25.63, P < 0.05) than that of CC alone. CONCLUSION: MTF can increase ovulation and pregnancy rates of CC-resistant PCOS women.

[A meta-analysis of tubeless versus standard percutaneous nephrostolithotomy].

OBJECTIVE: To systematically review the advantages of tubeless percutaneous nephrolithotomy. METHODS: The randomized controlled trials (RCTs) of tubeless and standard percutaneous nephrolithotomy were retrieved and their included references investigated. Data analyses of literatures fulfilling the inclusion criteria were performed with the Cochrane ColLaboration's RevMan 5.0 software. RESULTS: Seven literatures were finally retrieved after screening. A total of 1365 patients were included for a meta-analysis. The results showed that, as compared with the control group (standard percutaneous nephrolithotomy), the patients in the trial group (tubeless percutaneous nephrolithotomy) had the following features. (1) There was no significant difference in mean operative duration and change of hemoglobin (95%CI -15.16 to 0.13, P = 0.05; 95%CI -0.16 to 0.19, P = 0.90 respectively). (2) The hospitalization stay was shortened an average of 23.86 hours (95%CI -32.35 to -15.36, P = 0.000). (3) The postoperative analgesic dose was lowered by 69.02 mg (95%CI -107.67 to -30.36, P = 0.000). (4) There was a remarkable improvement of the stone-free rate (95%CI 1.25 to 2.95, P = 0.003). CONCLUSION: Tubeless percutaneous nephrolithotomy may shorten the hospitalization stay, lower the postoperative analgesic dose and improve the stone-free rate. It is significantly superior to standard percutaneous nephrolithotomy.

[Effect of recombinant hIFN-alpha-2b-BCG on mouse bladder tumor MB49 cells in vitro].

OBJECTIVE: To investigate the antitumor effect of recombinant IFN-alpha-2b-BCG on mouse bladder cancer MB49 cells in vitro, and to explore its antitumor mechanisms. METHODS: MB49 cells were co-cultured with recombinant BCG or wild BCG, and than were examined by light and transmission electron microscopy. The cell growth was assessed by MTT assay, and apoptosis rate and MHC-I of the MB49 cells was detected by flow cytometry using AO and Hoechst33258 fluorescence immunostaining. RESULTS: The hIFN-alpha-2b-BCG-treated tumor cells showed slow growth, detachment of some cells, and various degree of degeneration. Light microscopy revealed organelle disorganization, chromatin aggregation, nuclear pyknosis, and cytolysis in some cells. Cellular membrane bulged and some bubbles were seen under fluorescence microscope using AO staining. Hoechst33258 assay also depicted frequent apoptosis in the tumor cells. The MTT assay showed that rBCG more actively than the wild BCG inhibited the proliferation of MB49 cells. The apoptosis rate of the recombinant BCG group was 19.7% and 46.6% at the time point of 24 h and 48 h, respectively, significantly higher than 10.8% and 20.9%, respectively, in the wild BCG group. The results of flow cytometry indicated that both types of BCG enhanced the expression of MHC-I in the MB49 cells, but more effective in the recombinant BCG group. CONCLUSION: The recombinant hIFN-alpha-2b-BCG has more strong immuno-modulatory properties, anti-tumor effect on MB49 cells and induces apparent cytotoxicity in the bladder cancer cells in vitro.

Synthesis and characterization of core-shell acrylate based latex and study of its reactive blends.

Techniques in resin blending are simple and efficient method for improving the properties of polymers, and have been used widely in polymer modification field. However, polymer latex blends such as the combination of latexes, especially the latexes with water-soluble polymers, were rarely reported. Here, we report a core-shell composite latex synthesized using methyl methacrylate (MMA), butyl acrylate (BA), 2-ethylhexyl acrylate (EHA) and glycidyl methacrylate (GMA) as monomers and ammonium persulfate and sodium bisulfite redox system as the initiator. Two stages seeded semi-continuous emulsion polymerization were employed for constructing a core-shell structure with P(MMA-co-BA) component as the core and P(EHA-co-GMA) component as the shell. Results of Transmission Electron Microscopy (TEM) and Dynamics Light Scattering (DLS) tests confirmed that the particles obtained are indeed possessing a desired core-shell structural character. Stable reactive latex blends were prepared by adding the latex with waterborne melamine-formaldehyde resin (MF) or urea-formaldehyde resin (UF). It was found that the glass transition temperature, the mechanical strength and the hygroscopic property of films cast from the latex blends present marked enhancements under higher thermal treatment temperature. It was revealed that the physical properties of chemically reactive latexes with core-shell structure could be altered via the change of crosslinking density both from the addition of crosslinkers and the thermal treatment.

[A systematic review of anti-interleukin-17 antibody in the treatment of plaque psoriasis].

OBJECTIVE: To evaluate the efficacy and safety of anti-interleukin-17 antibody in the treatment of plaque psoriasis. METHDOS: Randomized controlled trials (RCT) of anti-interleukin-17 antibody (Secukinumab, Brodalumab, and Ixekizumab) in the treatment of plaque psoriasis published between January, 2000 and March, 2017 were searched from PubMed, Cochrane Library, EBSCO, EMbase, CBM, CNKI, VIPdetabase, and Wangfang database. The quality of the retrieved trials was evaluated and the results of studies were analyzed using RevMan 5.0 software. RESULTS: Thirteen RCTs were included involving a total of 11 203 patients. Meta-analysis showed a significant differences between anti-interleukin-17 antibody and placebo (or positive drug) in terms of PASI75 and sPGA (P<0.05). The total incidence of adverse events differed significantly between anti- interleukin-17 antibody and placebo, but no significant differences were found between them in the incidence of serious adverse events and discontinuation rate due to adverse events (P>0.05). CONCLUSION: Anti-interleukin-17 antibody is safe and effective for treatment of plaque psoriasis.