Repeated exposure to recombinant profilin from
(rAc-PF) induces allergic airway responses in vitro and in vivo. Based on the role of toll-like receptors (TLRs) in allergic airway diseases, TLRs play ...a central role in innate immune responses and the adaptive immune system and regulate responses against antigens through antigen-specific receptors. In this study, we attempted to determine the molecular mechanisms underlying rAc-PF-induced allergic inflammatory responses.
We determined the correlation between rAc-PF and TLRs and analyzed changes in allergic immune responses after blocking multiple TLR signaling under rAc-PF treatment conditions in vitro. We also compared allergic inflammatory responses in TLR2 knockout (KO) and wild-type (WT) mice. To investigate the effect of TLR2 on antigen prototyping and T cell activation in the inflammatory response induced by rAc-PF, we assessed maturation of BMDCs and polarization of naïve T cells by rAc-PF stimulation. Additionally, we compared changes in inflammation-related gene expression by rAc-PF treatment in primary lung epithelial cells isolated from TLR2 KO and WT mice.
The rAc-PF treatment was increased the expression level of TLR2 and 9 in vitro. But, there were not significantly differ the others TLRs expression by rAc-PF treated group. And then, the mRNA expression levels of inflammation-related genes were reduced in the TLR2 or TLR9 antagonist-treated groups compared to those in the rAc-PF alone, were no difference the treated with the other TLRs (TLR4, 6, and 7/8) antagonist. The difference was higher in the TLR2 antagonist group. Additionally, the levels of airway inflammatory disease indicators were lower in the TLR2 KO group than in the WT group after rAc-PF treatment. Furthermore, the expression of bone marrow-derived dendritic cell (BMDC) surface molecular markers following rAc-PF stimulation was lower in TLR2 KO mice than in WT mice, and TLR2 KO in BMDCs resulted in a remarkable decline in Th2/17-related cytokine production and Th2/17 subset differentiation. In addition, the expression levels of rAc-PF-induced inflammatory genes were reduced inTLR2 KO primary lung cells compared to those in normal primary lung cells.
These results suggest that the rAc-PF-induced airway inflammatory response is regulated by TLR2 signaling.
This study investigated the potential adverse effects of zinc oxide nanoparticles (ZnO(SM20(+)) NPs zinc oxide nanoparticles, positively charged, 20 nm) on pregnant dams and embryo-fetal development ...after maternal exposure over the period of gestational days 5-19 with Sprague-Dawley rats. ZnO(SM20(+)) NPs were administered to pregnant rats by gavage at 0, 100, 200, and 400 mg/kg/day. All dams were subjected to a cesarean section on gestational day 20, and all of the fetuses were examined for external, visceral, and skeletal alterations. Toxicity in the dams manifested as significantly decreased body weight after administration of 400 mg/kg/day NPs; reduced food consumption after administration of 200 and 400 mg/kg/day NPs; and decreased liver weight and increased adrenal glands weight after administration of 400 mg/kg/day NPs. However, no treatment-related difference in: number of corpora lutea; number of implantation sites; implantation rate (%); resorption; dead fetuses; litter size; fetal deaths and placental weights; and sex ratio were observed between the groups. On the other hand, significant decreases between treatment groups and controls were seen for fetal weights after administration of 400 mg/kg/day NPs. Morphological examinations of the fetuses demonstrated significant differences in incidences of abnormalities in the group administered 400mg/kg/day. Meanwhile, no significant difference was found in the Zn content of fetal tissue between the control and high-dose groups. These results showed that oral doses for the study with 15-days repeated of ZnO(SM20(+)) NPs were maternotoxic in the 200 mg/kg/day group, and embryotoxic in the 400 mg/kg/day group.
pH-Sensitive bipolar ion-permselective films of polyelectrolyte multilayers were prepared by layer-by-layer (LbL) assembly and photo-cross-linking of benzophenone-modified poly(acrylic acid) (PAA-BP) ...and poly(allylamine hydrochloride) (PAH-BP). The multilayer structure and ionizable group composition was finely tuned by changing the pH of the dipping solution. This structure and composition was in turn “preserved” by photo-cross-linking, forming highly stable membrane films. Since PAA-BP and PAH-BP are weak polyelectrolytes, it is possible to control the number of unbound, un-ionized -COOH or -NH2 groups in the multilayer by changing the pH. Moreover, the pH of the deposited film also plays an important role in determining selective latter permselectivity. For example, PAA-BP/PAH-BP multilayers deposited from two pH conditions, pH = 3 (PAA-BP) and pH = 6 (PAH-BP), showed pH-switchable permselectivity for both cationic (pH = 10) and anionic (pH = 3) probe molecules in a single film. The system offers advantages in film stability and introducing reversible selective ion permeability over previous multilayer film and cross-linking methods.
Cold induces expression of a number of genes that encode proteins that enhance tolerance to freezing temperatures in plants. A cis-acting element responsive to cold and drought, the ...C-repeat/dehydration-responsive element (C/DRE), was identified in the Arabidopsis thaliana stress-inducible genes RD29A and COR15a and found in other cold-inducible genes in various plants. C/DRE-binding factor/DRE-binding protein (CBF/DREB) is an essential component of the cold-acclimation response, but the signaling pathways and networks are mostly unknown. Here we used targeted genetic approach to isolate A. thaliana mutants with altered cold-responsive gene expression (acg) and identify ACG1 as a negative regulator of the CBF/DREB pathway. acg1 flowered late and had elevated expression of FLOWERING LOCUS C (FLC), a repressor of flowering encoding a MADS-box protein. We showed that acg1 is a null allele of the autonomous pathway gene FVE. FVE encodes a homolog of the mammalian retinoblastoma-associated protein, a component of a histone deacetylase (HDAC) complex involved in transcriptional repression. We also showed that plants sense intermittent cold stress through FVE and delay flowering with increasing expression of FLC. Dual roles of FVE in regulating the flowering time and the cold response may have an evolutionary advantage for plants by increasing their survival rates.
To characterize meal patterns across ten European countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) calibration study.
Cross-sectional study utilizing ...dietary data collected through a standardized 24 h diet recall during 1995-2000. Eleven predefined intake occasions across a 24 h period were assessed during the interview. In the present descriptive report, meal patterns were analysed in terms of daily number of intake occasions, the proportion reporting each intake occasion and the energy contributions from each intake occasion.
Twenty-seven centres across ten European countries.
Women (64 %) and men (36 %) aged 35-74 years (n 36 020).
Pronounced differences in meal patterns emerged both across centres within the same country and across different countries, with a trend for fewer intake occasions per day in Mediterranean countries compared with central and northern Europe. Differences were also found for daily energy intake provided by lunch, with 38-43 % for women and 41-45 % for men within Mediterranean countries compared with 16-27 % for women and 20-26 % for men in central and northern European countries. Likewise, a south-north gradient was found for daily energy intake from snacks, with 13-20 % (women) and 10-17 % (men) in Mediterranean countries compared with 24-34 % (women) and 23-35 % (men) in central/northern Europe.
We found distinct differences in meal patterns with marked diversity for intake frequency and lunch and snack consumption between Mediterranean and central/northern European countries. Monitoring of meal patterns across various cultures and populations could provide critical context to the research efforts to characterize relationships between dietary intake and health.
Combination therapy with insulin-independent sodium-glucose cotransporter 2 inhibitors and thiazolidinedione drugs, such as lobeglitazone, has been reported to elicit potential additive efficacy in ...glycemic control in type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetic (PK) drug-drug interactions between empagliflozin and lobeglitazone in healthy subjects.
A randomized, open-label, multiple-dose study was conducted in 30 healthy subjects using a three-treatment, six-sequence, three-way crossover design. Subjects received one of the following treatments once daily for 5 days in each period: 25 mg empagliflozin, 0.5 mg lobeglitazone sulfate, or a combination. Serial blood sampling before every dose and up to 24 h after the last dose was performed during each treatment period. The PK parameters were estimated using noncompartmental methods with the plasma empagliflozin and lobeglitazone concentrations. The absence of a PK interaction was construed as the 90% confidence interval (90% CI) of maximum concentration at steady state (C
) and area under the concentration-time curve over the dosing interval (AUC
) for combination therapy-to-monotherapy ratios within the limits of 0.80-1.25.
The steady-state plasma empagliflozin and lobeglitazone concentration-time profiles of combination therapy and monotherapy were comparable in the 25 subjects who completed the study. Coadministration of empagliflozin with lobeglitazone did not affect empagliflozin PK (with 90% CIs of 0.956-1.150 and 0.945-1.133 for C
and AUC
, respectively). Likewise, empagliflozin did not affect lobeglitazone C
or AUC
(with 90% CIs of 0.869-0.995 and 0.851-1.018, respectively). All treatment groups tolerated mild adverse events well.
The lack of PK interactions between lobeglitazone and empagliflozin in combination therapy, along with their good tolerability, indicates that the two drugs can be coadministered without dose adjustment.
NCT02854748, Registered on August 7, 2016.
Prostaglandin E
(PGE
) synthesis is modulated by COX2. Changes in PGE
could be used to quantify the COX2 inhibition after ibuprofen administration. This study investigated the pharmacokinetic and ...pharmacodynamic relationships for COX2 inhibition according to three formulations of ibuprofen in healthy male subjects.
A randomized, open-label, single-dose, three-treatment, six-sequence crossover study was performed in 36 healthy South Korean male volunteers. Enrolled subjects received the following three 200 mg ibuprofen formulations: ibuprofen arginine, solubilized ibuprofen capsule, and standard ibuprofen. Pharmacokinetic and pharmacodynamic blood samples were collected for 16 hours following treatment. For pharmacodynamic evaluations, lipopolysaccharide (LPS)-induced PGE
inhibition at each time point compared to predose was measured. Noncompartmental analysis was used for pharmacokinetic assessment, and time-weighted average inhibition (WAI) of PGE
was applied to the pharmacodynamic evaluation.
After a single oral dose of the ibuprofen formulations, the median times to maximum concentration were 0.42, 0.5, and 1.25 hours in ibuprofen arginine, solubilized ibuprofen capsule, and ibuprofen, respectively. The maximum observed plasma concentration was lower in ibuprofen, and the area under the plasma concentration-time curve was comparable among the three formulations. A significant difference was observed between fast-acting formulations and standard ibuprofen tablets for both maximum concentration and time taken to reach it. Individual formulations had an effect on PGE
WAI during the 8 hours following treatment, resulting in significantly lower WAI in standard ibuprofen: ibuprofen arginine 18.4%, solubilized ibuprofen capsule 18.4%, and standard ibuprofen 11.6%.
Rapid absorption and higher peak concentration were observed in ibuprofen arginine and the solubilized ibuprofen capsule. Additionally, fast-acting formulations had more predominant inhibitory activity on the COX2 enzyme.
Recent studies of the pathogenesis of rheumatoid arthritis (RA) have revealed that both synovial fibroblasts and T cells participate in the perpetuation of joint inflammation as dynamic partners in a ...mutual activation feedback, via secretion of cytokines and chemokines that stimulate each other. In this study, we investigated the role of IL-17, a major Th1 cytokine produced by activated T cells, in the activation of RA synovial fibroblasts. Transcripts of IL-17R (IL-17 receptor) and IL-17RB (IL-17 receptor B) were present in fibroblast-like synoviocytes (FLS) of RA patients. IL-17R responded with increased expression upon in vitro stimulation with IL-17, while the level of IL-17RB did not change. IL-17 enhanced the production of IL-6 and IL-8 in FLS, as previously shown, but did not affect the synthesis of IL-15. IL-17 appears to be a stronger inducer of IL-6 and IL-8 than IL-15, and even exerted activation comparable to that of IL-1 beta in RA FLS. IL-17-mediated induction of IL-6 and IL-8 was transduced via activation of phosphatidylinositol 3-kinase/Akt and NF- Kappa B, while CD40 ligation and p38 MAPK (mitogen-activated protein kinase) are not likely to partake in the process. Together these results suggest that IL-17 is capable of more than accessory roles in the activation of RA FLS and provide grounds for targeting IL-17-associated pathways in therapeutic modulation of arthritis inflammation.
Conductive core-shell particles were prepared by the deposition of polyaniline (PANI) and poly(sodium 4-styrenesulfonate) (PSS) multilayers onto polystyrene (PS) colloidal particles via the alternate ...electrostatic layer-by-layer (LbL) assembly technique. PSS was used as a polymeric counterion for multilayer formation as well as a stabilizer and codopant for PANI. Electrophoresis, FT-IR spectroscopy, and transmission electron microscopy (TEM) confirmed the regular growth of PSS/PANI multilayers on PS colloidal particles. It was found that the PSS/PANI-coated particle is oxidatively more stable due to stabilization of the partially oxidized emeraldine salt by PSS. The conductivity of (PSS/PANI)5-coated PS particles was 0.003 S/cm and increased to 0.1 S/cm after additional dopant exposure with HCl vapor. Furthermore, hollow shells made up of PSS/PANI layers were produced by dissolution of the PS core from PSS/PANI-coated particles. Cyclic voltammetry (CV) showed that PSS/PANI multilayers maintained their oxidative stability and electrochemical properties after removal of the core.
TiO2 nanoparticles were prepared by hydrothermal reaction of titanium alkoxide stabilized in acidic ethanol/water solution. The sizes of particles have been controlled to the range of 7−25 nm by ...adjusting the concentration of Ti precursor and the composition of the solvent system. The TiO2 samples synthesized under this acidic ethanol/water environment were mainly primary particles in anatase phase without secondary structure. The suspension of as-prepared 7-nm-sized TiO2 nanoparticles demonstrates long-term stability, and has been applied successfully for the fabrication of ultra-transparent particulate TiO2 films. The photocatalytic efficiency of TiO2 films prepared from the 7-nm-sized nanoparticles was 1.6 times of that of films derived from Degussa P25 in decomposing gaseous 2-propanol.
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