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The C═N double bond of 2H-imidazole has been employed as a C-electrophile for the ruthenium(II)-catalyzed [3 + 2] spiroannulation reaction of 4-phenyl-2H-imidazoles and 2-alkynoates to synthesize spiroimidazole-4,1'-indenes. This strategy features high regioselectivity, broad functional group tolerance, and use of ruthenium as a catalyst, providing a new method to synthesize spirocycles with potential applications in pharmaceuticals.

Serpins are evolutionarily conserved serine protease inhibitors that are widely distributed in animals, plants and microbes. In this study, we reported the cloning and functional characterizations of two novel serpin genes, HlSerpin-a and HlSerpin-b, from the hard tick Haemaphysalis longicornis of China. Recombinant HlSerpin-a and HlSerpin-b displayed protease inhibitory activities against multiple mammalian proteases. Similar to other tick serpins, HlSerpin-a and HlSerpin-b suppressed the expression of inflammatory cytokines such as TNF-α, interleukin (IL)-6 and IL-1β from lipopolysaccharide-stimulated mouse bone-marrow-derived macrophages (BMDMs) or mouse bone-marrow-derived dendritic cells (BMDCs). The minimum active region (reaction centre loop) of HlSerpin-a, named SA-RCL, showed similar biological activities as HlSerpin-a in the protease inhibition and immune suppression assays. The immunosuppressive activities of full-length HlSerpin-a and SA-RCL are impaired in Cathepsin G or Cathepsin B knockout mouse macrophages, suggesting that the immunomodulation functions of SA and SA-RCL are dependent on their protease inhibitory activity. Finally, we showed that both full-length HlSerpins and SA-RCL can relieve the joint swelling and inflammatory response in collagen-induced mouse arthritis models. These results suggested that HlSerpin-a and HlSerpin-b are two functional arthropod serpins, and the minimal reactive peptide SA-RCL is a potential candidate for drug development against inflammatory diseases.

The char-O 2 /H 2 O combustion under high-temperature entrained flow conditions was investigated experimentally and numerically to study the effect of H 2 O on the char-nitrogen (char-N) conversion. A numerical model was established based on the unsteady convection–diffusion equations for mass and heat transfer. Local Random Pore Model (RPM) was adopted to consider the change of specific surface area during char combustion. The Langmuir-Hinshelwood mechanism was used in the rate equations of main heterogeneous reactions to consider the competitions on surface active sites. The numerical results of char conversion and fractional conversion of char-N to NO reproduce the experimental results well. Both of the numerical and experimental results shows that the added H 2 O promotes the fractional conversion of char-N to NO and the promotion effect becomes weaker with the increase of O 2 concentration. Based on numerical results, four crucial factors that affect char-N conversion were decoupled and discussed quantitatively with addition of H 2 O. The added H 2 O promotes nitrogen release rate at lower oxygen concentration but inhibits nitrogen release rate at higher oxygen concentration. The added H 2 O lowers the heterogeneous char-NO reduction rate constant greatly but enlarges the pore surface area slightly, resulting in a lower overall heterogeneous char-NO reduction rate. Char-NO reaction is the main NO reduction pathway, and most of HCN formed in char-N–H 2 O reaction is more likely to release out of char particle and converts to NO through HCN→NH 3 →NO pathway in the ambient flow.

Pathogenic inflammation mediated by overactive type 1 helper T cell (Th1) responses could exacerbate and perpetuate Crohn's disease. Programmed death (PD)-1 and its ligand PD-L1 pathway could be upregulated to suppress inflammation. We wondered why this pathway is ineffective at suppressing pathogenic Th1 inflammation in Crohn's disease patients. Here, we found that overexpression of T-bet via transfection significantly reduced the expression of PD-1. PD-L1 was capable of suppression proinflammatory CD4+ T cells, but T-bet transfection significantly reduced the susceptibility of CD4+ T cells toward PD-L1-mediated suppression, evidenced by the observations that at low PD-L1 concentration T-bet transfected and mock transfected CD4+ T cells presented comparable IL-2 production, but at high PD-L1 concentration, T-bet transfected CD4+ T cells presented significantly higher IL-2 than mock transfected CD4+ T cells. PD-L1 could significantly reduce the survival of CD4+ T cells from Crohn's disease patients, but interestingly, in the absence of PD-L1, the survival was better in mock transfected CD4+ T cells, while in the presence of PD-L1, the survival was better in T-bet transfected CD4+ T cells. Crohn's disease patients with greater severity presented higher T-bet expression and lower PD-1 expression in CD4+ T cells, demonstrating an association between T-bet expression and disease progression. We also discovered that stimulation with bacterial antigens could upregulate the expression of T-bet. Together, this study demonstrated that T-bet overexpression could interfere with PD-1/PD-L1-mediated suppression of CD4+ T cell inflammation and survival, and potentially contributed to the development and persistence of Crohn's disease.

Aims The acquired drug resistance has been regarded as a main barrier for the effective treatment of temozolomide (TMZ) in glioblastoma (GBM). MiR-126-3p is commonly down-regulated and exerts tumor-suppressive roles in kinds of human cancers, including GBM. This study was designed to investigate the functions and mechanisms of miR-126-3p in regulating TMZ resistance in GBM. Materials and methods qRT-PCR analysis was used to measure the expressions of miR-126-3p and SOX2 mRNA in GBM tissues and cells. Cell viability, colony forming ability and apoptosis were detected to evaluate the effect of miR-126-3p or SOX2 on TMZ resistance. Luciferase reporter experiments were applied to identify the target genes of miR-126-3p. Western blot analysis was performed to determine the protein levels associated with Wnt/β-catenin signaling. TOP/FOP Flash assays were conducted to determine the effects of miR-126-3p or SOX2 on Wnt/β-catenin signaling. Key findings miR-126-3p expression was decreased in TMZ-resistant GBM tissues and cells. High levels of miR-126-3p enhanced TMZ sensitivity by inhibiting cell viability, reducing colony forming potential and inducing apoptosis. Additionally, SOX2 was identified as a downstream target of miR-126-3p. On the contrary, SOX2 overexpression conferred TMZ resistance of GBM cells. Moreover, miR-126-3p-mediated TMZ sensitivity was reversed following increased expression of SOX2. Furthermore, miR-126-3p-induced inactivation of Wnt/β-catenin signaling was greatly abrogated by SOX2 up-regulation. Significance MiR-126-3p sensitizes GBM cells to TMZ possibly by repressing SOX2 expression and blocking Wnt/β-catenin signaling. This study provides novel targets to overcome TMZ resistance in GBM chemotherapy.

Hepatocellular carcinoma (HCC) is the most common primary liver carcinoma and has one of the highest mortality rates of all cancers. The γδ T cells could infiltrate HCC and have demonstrated potent tumor-killing capacity. Here, we found that in peripheral blood, the vast majority of γδ T cells were Vδ2 T cells. In HCC patients, the frequency of Vδ2 T cells was significantly lower than in controls. γδ T cells that were harvested directly ex vivo possessed very limited capacity to eliminate Zol-loaded HCC cell lines, even at a high effector to target ratio. In vitro expansion with Zol could significantly increase the capacity of γδ T cells to eliminate HCC cell lines. But even with in vitro expansion, the γδ T cells from HCC patients presented significantly lower cytotoxic capacity than the γδ T cells from healthy individuals. The expression of IL-2 and IL-21 by γδ T cells was significantly lower in HCC patients than in control volunteers. Supplementing recombinant human IL-2 and IL-21 in the in vitro expansion culture increased the cytotoxic capacity of γδ T cells. In addition, the frequency of PD-1+ γδ T cells was significantly higher in HCC patients than in controls ex vivo, and was significantly elevated after in vitro expansion. Hep3B and HepG2 did not express PD-L1, while a small fraction of SNU-398 expressed PD-L1. Interestingly, co-incubation with γδ T cell elevated PD-L1 expression in HCC cell lines. Blocking PD-1 during in vitro expansion stage significantly elevated cytotoxicity toward all the HCC cell lines, while blocking PD-1 during the cytotoxicity assay significantly elevated cytotoxicity toward HepG2 and SNU-398, but not toward Hep3B. Overall, these results demonstrated that the circulating γδ T cells in HCC patients were reduced in cytotoxic capacity, possibly associated with the lack of IL-2 and IL-21 production and PD-1 upregulation.

Cadmium (Cd) is a highly carcinogenic metal that plays an important role in the risk management of soil pollution. In this study, 153 soil samples were collected from a coal chemical plant in northwest China, and the human health risks associated with Cd were assessed through multiple exposure pathways. Meanwhile, by the Kriging interpolation method, the spatial distribution and health risks of Cd were explored. The results showed that the average concentration of Cd in the soil was 0.540 mg/kg, which was 4.821 and 5.567 times that of the soil background value in Ningxia and China, respectively. In comparison, the concentration of Cd in the soil was below the national soil environmental quality three-level standard (1.0 mg/kg). In addition, health risk assessment results showed that the total carcinogenic risk of Cd was 1.269 × 10−6–2.189 × 10−6, both above the acceptable criteria (1 × 10−6), while the hazard quotient was within the acceptable level. Oral intake and ingestion of soil particles were the main routes of exposure, and the carcinogenic risk control value of oral intake was the lowest (0.392 mg/kg), which could be selected as the strict reference of the safety threshold for Cd in the coal chemical soil. From Kriging, a prediction map can be centrally predicted on heavy metal pollution in the area surrounding the coal entrance corridor and pedestrian entrance. This study can provide a theoretical basis for the determination of the heavy metal safety threshold of the coal chemical industry in China.

A facile synthesis of various pyrazolo[1,2-a] indazoles from pyrazolidinones and propiolates via iridium(iii)-catalysed C-H bond activation/subsequent [4+1] cyclization has been developed. The reaction proceeds smoothly under mild reaction conditions and propiolates act as a novel C1 synthon. This transformation represents a redox-neutral process, exhibits a highly regioselectivity, and tolerates various functional groups.

Nitrophenols in wastewater have posed a serious threat to ecosystem and human health, hence it is very important to remove them from wastewater using an environmental-friendly and effective method. In this study, Fe3O4@SiO2@ZnO magnetic nanoparticles (ZnO MNPs) were synthesized via a moderate and rapid route using microwave irradiation and diethylene glycol (DEG) as solvent. The facile synthesis conditions of ZnO nanoparticles coating on Fe3O4@SiO2 were confirmed owing to lower reaction temperature (160 °C) and quick reaction time (15 min microwave irradiation). In addition, the synthesized ZnO MNPs demonstrated the comparable or even better photocatalytic activity for 4-nitrophenol (4-NP) as compared with TiO2 with respect to small catalyst dosage, quick degradation rate and broad pH range. Moreover, ZnO MNPs exhibited good stability and reusability after eight times successive degradation experiments of 4-NP. The mechanism of the enhanced photocatalytic activity of ZnO MNPs was mainly related to the stronger adsorption ability for 4-NP, the improved light absorption ability and the retarding recombination of hole–electron pairs. In summary, ZnO MNPs is a promising candidate for 4-NP photocatalytic degradation from wastewater.

Collagen Triple Helix Repeat Containing 1 (CTHRC1) has been picked out as a cancer-related, secreted glycoprotein that possesses multifaceted functions such as wound repair, the formation of adipose tissue, hepatocytes fibrosis, and bone remodeling. This study aims to explore the biological function and the profound regulative mechanism of CTHRC1 in human prostate cancer (PCa). We found that CTHRC1 was upregulated in patients with PCa. The knockdown of CTHRC1 suppressed PCa cell proliferation, invasion, migration, and colony formation significantly. The expression of CTHRC1 was down-regulated and up-regulated by miR-30e-5p mimics and inhibitors, respectively, in PCa cells. The dual-luciferase reporter assay validated the binding of miR-30e-5p with CTHRC1 mRNA, indicating the regulation of CTHC1 by miR-30e-5p. In consequence, this study demonstrated that CTHRC1 acts as an oncogenic gene and targeting the miR-30e-5p-CTHRC1 axis may provide novel therapeutic treatment for PCa.

International audience; The generation of 2,3-dihydro-benzo[c][1,2]diazepine derivatives via rhodium(III)-catalyzed [4+3] annulation of pyrazolidinones and propargylic acetates is disclosed. The reaction proceeds smoothly under relatively mild conditions from propargylic acetates as novel C3 synthons. A range of dinitrogen-fused heterocyclic compounds are readily accessed by this approach.

Bladder neck contracture (BNC) after GreenLight laser photoselective vaporization (PVP) of benign prostatic hyperplasia is a common complication. In the present study, data of patients received 80 or 180 W PVP were collected. Perioperative parameters, including applied energy, irradiation time, catheter removal time, and hospital stay, were recorded. Postoperative parameters, including maximum urinary flow rate, International Prostate Symptom Score, post-void residual volume, and incidences of BNC, were recorded at 3 and 12 months after operations. Bladder neck tissues were taken at 3 months after operations for immunohistochemical staining and western blot analysis to examine the expressions of collagen I, matrix metalloproteinase-3 (MMP-3), and transforming growth factor-β (TGF-β). Sample size of patients was calculated with a power of 80 %. Chi-square test and one-way analysis of variance were performed as statistical methods. Three hundred twenty-six patients who received potassium titanyl phosphate (KTP) laser and 256 who received X-ray photoelectron spectroscopy (XPS) laser entered into the study. Perioperative parameters were comparable, except for shorter irradiation time in 180 W group (P = 0.032). Postoperative parameters were also similar, except for higher incidence of BNC in 80 W group at 3 months after operations (P = 0.022). Immunohistochemical staining and western blot analysis showed higher expressions of collagen I, MMP-3, and TGF-β in 80 W group than in 180 W group. In conclusion, 80 W GreenLight laser showed a comparable efficacy with 180-W laser in PVP but showed a higher incidence of BNC in short term, which might be the result of up-regulated fibrotic factors in bladder neck triggered by lasers.

Aims Accumulating evidence elucidates the biological significance of long non-coding RNA (lncRNAs) in tumorigenesis and development. FGD5 antisense RNA 1 (FGD5-AS1) was previously revealed as an oncogene in several types of malignancies. However, the roles of FGD5-AS1 in glioblastoma (GBM) and its potential molecular mechanisms remain unclear. Materials and methods The expression of FGD5-AS1, miR-129-5p, and heterogeneous nuclear ribonucleoprotein K (HNRNPK) mRNA were measured by qRT-PCR. Cell proliferation, invasion and apoptosis were determined by MTT, colony formation, transwell and flow cytometry assays. The protein levels of Ki-67, HNRNPK and Wnt signaling-associated genes were examined by western blot assay. The possible action mechanism of FGD5-AS1 was detected by bioinformatic tools, luciferase reporter, RIP and TOP/FOP Flash reporter assays. A nude mouse xenograft model was built to analyze the function of FGD5-AS1 in vivo. Key findings FGD5-AS1 expression was increased in GBM tumor tissues and cells. Knockdown of FGD5-AS1 inhibited cell proliferation and invasion in vitro, and slowed tumor growth in vivo. Mechanistically, FGD5-AS1 served as a sponge of miR-129-5p to relieve its suppression on HNRNPK. Moreover, down-regulation of HNRNPK repressed cell proliferation and invasion, while enhanced apoptosis. Additionally, si-FGD5-AS1-mediated suppression of cell proliferation and invasion was obviously reversed by the decrease of miR-129-5p or restoration of HNRNPK. Furthermore, FGD5-AS1 promoted cell growth and invasion by stimulating Wnt/β-catenin signaling via regulation of miR-129-5p/HNRNPK. Significance FGD5-AS1 promoted GBM progression at least partly by regulating miR-129-5p/HNRNPK to activate Wnt/β-catenin signaling, suggesting the potential of FGD5-AS1 as a candidate target to improve GBM therapy.

Patients with non-muscle invasive bladder cancer (NMIBC) frequently relapse following surgery due to incomplete resection and chemoresistance, highlighting the importance of developing novel therapeutic strategies that mechanistically assist in eradicating the residual tumor. The aim of the present study was to evaluate the anticancer effect of chlorophyllin e6-mediated photodynamic therapy (e6-PDT) and its potential mechanisms by using monolayer cells or multicellular tumor spheroid models of human bladder cancer cells (T24 and 5637). The results revealed that e6-PDT exhibited significant cytotoxicity in the T24 and 5637 cells of these two models as detected by the Water-Soluble Tetrazolium Salts-1 and CellTiter-Glo Luminescent Cell Viability assays, respectively. Cell migration and invasion capacities decreased markedly following e6-PDT. In addition, the cells following e6-PDT exhibited typical morphological changes of apoptosis as detected by fluorescence microscopy with 4′,6-diamidino-2-phenylindole staining and transmission electron microscopy. A greater number of apoptotic cells were observed post-e6-PDT by flow cytometry. The expression levels of poly(adenosine diphosphate-ribose) polymerase (PARP) and B-cell lymphoma 2 protein were decreased, while cleaved PARP was increased, significantly following e6-PDT as determined by western blotting. The level of intracellular reactive oxygen species (ROS) was increased, while the activity of superoxide dismutase (SOD) was decreased, significantly in e6-PDT-treated cells. Thus, the novel e6-PDT exhibits prominent photo-cytotoxicity effect and the induction of apoptosis was probably due to the inhibition of SOD activity and the generation of ROS. These results indicate that chlorophyllin e6 is an effective photosensitizer and that e6-PDT may have a therapeutic application for the treatment of bladder cancer.

Our study is to explore the expression profiles and potential functions of circRNAs in prostate cancer (PCa). A total of 95 circRNAs and 830 mRNAs were screened to be significantly differentially expressed in PCa tissues by microarrays. Co-expression and competitive endogenous RNA (ceRNA) network were constructed to reveal the potential regulatory mechanisms of circRNAs. Three circRNAs, hsa_circ_0001206, hsa_circ_0001633, and hsa_circ_0009061 were validated to be down-regulated in PCa by quantitative real-time PCR (qRT-PCR) and hsa_circ_0001206 as well as hsa_circ_0009061 was significantly associated with clinical features of PCa patients. Meanwhile, Receiver Operating Characteristic (ROC) curves showed their good diagnostic value as biomarkers for PCa. The down-regulation of hsa_circ_001206 was partly because of the regulation of DExH-Box Helicase 9 (DHX9). Moreover, overexpression of hsa_circ_0001206 inhibited PCa cell proliferation, migration, and invasion in vitro and prevented tumor growth in vivo. Dual-luciferase reporter assays showed hsa_circ_0001206 could directly bind to miR-1285-5p. The expression of Smad4, a well-known suppressive gene in PCa, can be increased by overexpression of hsa_circ_0001206 and this effect could be partly reversed by co-transfection of miR-1285-5p mimic. The study revealed expression profiles and potential functions of circRNAs and demonstrated hsa_circ_0001206 played a suppressive role in the pathogenesis of PCa.

The aim of the present study was to explore the effect of bergamottin, a natural furanocoumarin obtained from grapefruit juice, on the invasiveness of human glioma cells. The results revealed that treatment with bergamottin for 48 h significantly inhibited wound-healing migration and Matrigel invasion of human glioma cells, compared with untreated cells (P

Models of benzalkonium chloride (BAC)-induced ocular disruption have been created and are widely used in various animals. This study aimed to compare the effects of BAC on the ocular surfaces of C57BL/6 and BALB/c mice. C57BL/6 and BALB/c mice were treated separately with BAC eye-drops at different concentrations. Eyes were evaluated by scoring epithelial disruption, corneal opacity and neovascularization in vivo, and by histological assays with hematoxylin/eosin (H/E) and periodic acid-Schiff stainings and by determining the expression of inflammatory factors in vitro on Days 7 and 14. The in vivo corneal epithelial disruption, corneal edema/opacity and neovascularization, which were in accordance with the results of the H/E staining and peaked at Day 7, were observed in a dose-dependent manner in the BAC-treated mice, with more severe signs in the C57BL/6 mice than the BALB/c mice. The loss of conjunctival goblet cells in the conjunctivas and the increasing expression of monocyte chemoattractant protein 1 (MCP-1), growth-regulated protein alpha (GROa) and macrophage inflammatory protein-1 alpha (MIP-1a) in the corneas were found in a dose-dependent manner in both strains of mice. Topical application of BAC can dramatically disrupt the ocular surfaces of C57BL/6 and BALB/c mice, and the disruptions were much more severe in the C57BL/6 mice that received high doses of BAC.

A new type of light-collecting structure that can greatly improve signal-to-noise ratio for gas test was designed on the basis of mid-infrared absorption spectrum principle. A rotational symmetric ellipsoid reflector was employed to collect the mid-infrared radiation with the light source and detector on two focuses, and Beer–Lambert law was applied to construct related math models. Theoretical analysis showed that this structure could perfectly enhance the gains of signals by 648 times. Experimental analysis of methane gas was carried out by using principle of differential absorption, 3.31 μm mid-infrared absorption wavelength and double PbSe detectors. The detection limit of this system was 50 ppm and the test precision was as high as 3%. Due to the attenuation and imprecise ellipsoid reflector, the experimental gain of differential signal was 220 times.

The authors report the design and characteristics of a mid-infrared quantum cascade laser-based CO detection system using the absorption in the P (14) line, at 2086.32 cm −1 . Measurements are performed through line scanning and signal processing to give sensitivities down to 2 ppm with the response time of 7 s.

Titanium doped indium oxide (TIO) thin films were deposited on glass substrate by DC sputtering with different O2/Ar gas ratios at 330 °C. The effects of sputtering on the structural, morphologic, optical and electrical characteristics of TIO thin films were investigated by XRD, Hall measurement and optical transmission spectroscopy. The deposited films exhibited polycrystalline in the preferred (222) orientation, with higher mean grain size and lower resistivity 3.37 ×10-4Ω·cm at O2/Ar ratio of 1/10. The average optical transmittance of the films is over 90%, and the transmittance has no evident change with changing O2/Ar ratio.