Differential regulation of interleukin-1 receptor associated kinase 1 (IRAK1) splice variants

IRAK family proteins play critical roles in regulating innate immunity. There are three differentially spliced variants of IRAK1, namely 1, 1b, and 1c. We and others have previously identified that the full length IRAK1 underwent covalent modifications such as phosphorylation and ubiquitination upon lipopolysaccharide challenge. In this report, we observed that IRAK1 could also undergo sumoylation which was responsible for its translocation into the nucleus. In contrast, IRAK1c remained stable and did not undergo modification upon various challenges. Furthermore, we showed that IRAK1c solely localized in the cytoplasm. IRAK1 was absent and IRAK1c was the primary form in human brains. The absence of full length IRAK1 and presence of IRAK1c may keep brain tissue in a resting non-inflammatory state. Intriguingly, the full length IRAK1 form was consistently detected in brain tissues obtained from aged humans, suggesting that differential splicing of IRAK1 may correlate with the aging process.     

HLA-associated genetic resistance and susceptibility to type I diabetes in French North Africans and French natives

The distribution of human leukocyte antigen (HLA)-DRB1-DQA1-DQB1 haplotypes was analyzed separately in two distinct French ethnic groups with type I diabetes (T1D), i.e. French North African migrants (n= 64, mean age at diagnosis = 8.25 years) and ancient French natives (n= 60, mean age at diagnosis = 7.42 years). HLA associations were determined by calculating odds ratios (ORs) between patients and two ethnic-matched control populations. Results show highly similar ORs for the conservative DRB1*0301-DQA1*0501-DQB1*0201 haplotype of susceptibility (OR: 3.22 and 3.93 in migrants and natives, respectively) and the DRB1*1501-DQA1*0102-DQB1*0602 haplotype of resistance (OR: 0.05 and 0.03, respectively). In contrast, among the more variable DRB1*04-DQB1*0302 haplotypes of susceptibility, the DRB1*0402 (OR: 3.10 and 32.84) and 0405 (OR: 5.90 and 16.25, respectively) were associated with T1D in migrants and natives, whereas an increase of DRB1*0401, a rare allele in migrants, was significant in natives only. Also, among the DRB1*11-DQA1*0505-DQB1*0301 haplotypes of resistance, the OR observed for DRB1*1104-DQA1*0505-DQB1*0301, common in migrants, was lower (OR: 0.08) than for DRB1*1101-DQA1*0505-DQB1*0301 (OR: 0.32), common in natives. How DRB1*11 subtypes might affect differently the risk conferred by DQA1*0505-DQB1*0301 will be discussed.     

Chronic high-inspired CO2 decreases excitability of mouse hippocampal neurons

To examine the effect of chronically elevated CO(2) on excitability and function of neurons, we exposed mice to 8 and 12% CO(2) for 4 wk (starting at 2 days of age), and examined the properties of freshly dissociated hippocampal neurons obtained from slices. Chronic CO(2)-treated neurons (CC) had a similar input resistance (R(m)) and resting membrane potential (V(m)) as control (CON). Although treatment with 8% CO(2) did not change the rheobase (64 +/- 11 pA, n = 9 vs. 47 +/- 12 pA, n = 8 for CC 8% vs. CON; means +/- SE), 12% CO(2) treatment increased it significantly (73 +/- 8 pA, n = 9, P = 0.05). Furthermore, the 12% CO(2) but not the 8% CO(2) treatment decreased the Na(+) channel current density (244 +/- 36 pA/pF, n = 17, vs. 436 +/- 56 pA/pF, n = 18, for CC vs. CON, P = 0.005). Recovery from inactivation was also lowered by 12% but not 8% CO(2). Other gating properties of Na(+) current, such as voltage-conductance curve, steady-state inactivation, and time constant for deactivation, were not modified by either treatment. Western blot analysis showed that the expression of Na(+) channel types I-III was not changed by 8% CO(2) treatment, but their expression was significantly decreased by 20-30% (P = 0.03) by the 12% treatment. We conclude from these data and others that neuronal excitability and Na(+) channel expression depend on the duration and level of CO(2) exposure and maturational changes occur in early life regarding neuronal responsiveness to CO(2).     

Quantification of in vivo gastric fluid volume in Bama miniature pigs in fasted state

Although the study of bioequivalence waivers in humans is already well‐established, their application and translation into animals, which are complicated by differences in physiology, have only recently become subjects of interest. The main purpose of this paper is to quantify the liquid volume affecting drug dissolution in pig stomachs. We used magnetic resonance imaging (MRI) to scan 18 Bama miniature pigs weighing 15, 30 or 50 kg. Amira 6.0.1 software was used for 3D image processing. We found that the gastric fluid volume had a linear relationship with the weight of pig (R² = 0.9935) over this weight range. The pig weight, therefore, could be used as a surrogate for the fasted gastric fluid volume. After combining data of gastric fluid secretion and drinking water volumes, our results could be used as a reference for the evaluation of oral drug absorption in pigs.     

Saroclazines A–C,thio-diketopiperazines from mangrove-derived fungi <Emphasis Type="Italic">Sarocladium kiliense</Emphasis> HDN11-84

Three new diketopiperazine derivatives (DKPs), saroclazines A–C (1–3) along with three known DKPs (4–6) were isolated from mangrove-derived fungi Sarocladium kiliense HDN11-84. Saroclazines A–B (1 and 2) possessed a free amide structure, which was first found in sulfur-containing aromatic DKPs. Their structures were elucidated by NMR, HRESIMS and X-ray. The cytotoxic activity of new compounds (1–3) was tested against HeLa cell lines, among which compound 2 showed an IC₅₀ value of 4.2 µM.     

Phenolic amides from <Emphasis Type="Italic">Tribulus terrestris</Emphasis> and their inhibitory effects on nitric oxide production in RAW 264.7 cells

A new phenolic amide, named cis-terrestriamide (7), together with ten known compounds (1–6, 8–11), were isolated from the methanolic extract of the fruits of Tribulus terrestris. The structure of 7 was elucidated on the basis of extensive analyses of 1D and 2D nuclear magnetic resonance spectroscopic and high resolution mass spectrometry data. Compounds 1, 2, 5, 6, 8, 9, and 11 exhibited inhibitory effects on the lipopolysaccharide-stimulated nitric oxide production in RAW 264.7 cells, with IC₅₀ values of 18.7–49.4 μM.     

Potential applications and human biosafety of nanomaterials used in nanomedicine

With the rapid development of nanotechnology, potential applications of nanomaterials in medicine have been widely researched in recent years. Nanomaterials themselves can be used as image agents or therapeutic drugs, and for drug and gene delivery, biological devices, nanoelectronic biosensors or molecular nanotechnology. As the composition, morphology, chemical properties, implant sites as well as potential applications become more and more complex, human biosafety of nanomaterials for clinical use has become a major concern. If nanoparticles accumulate in the human body or interact with the body molecules or chemical components, health risks may also occur. Accordingly, the unique chemical and physical properties, potential applications in medical fields, as well as human biosafety in clinical trials are reviewed in this study. Finally, this article tries to give some suggestions for future work in nanomedicine research. Copyright © 2017 John Wiley & Sons, Ltd.