Dkk3/REIC, an N-glycosylated Protein, Is a Physiological Endoplasmic Reticulum Stress Inducer in the Mouse Adrenal Gland

Dickkopf 3 (Dkk3) is a secreted protein belonging to the Dkk family and encoded by the orthologous gene of REIC. Dkk3/REIC is expressed by mouse and human adrenal glands, but the understanding of its roles in this organ is still limited. To determine the functions of Dkk3 in the mouse adrenal gland, we first identified that the mouse Dkk3 protein is N-glycosylated in the adrenal gland as well as in the brain. We performed proteome analysis on adrenal glands from Dkk3-null mice, in which exons 5 and 6 of the Dkk3 gene are deleted. Twodimensional polyacrylamide gel electrophoresis of adrenal proteins from wild-type and Dkk3-null mice revealed 5 protein spots whose intensities were altered between the 2 genotypes. Mass spectrometry analysis of these spots identified binding immunoglobulin protein (BiP), an endoplasmic reticulum (ER) chaperone. To determine whether mouse Dkk3 is involved in the unfolded protein response (UPR), we carried out a reporter assay using ER-stress responsive elements. Forced expression of Dkk3 resulted in the induction of distinct levels of reporter expression, showing the UPR initiated by the ER membrane proteins of activating transcription factor 6 (ATF6) and inositol-requring enzyme 1 (IRE1). Thus, it is possible that Dkk3 is a physiological ER stressor in the mouse adrenal gland

Prostaglandin E-2-EP2-NF-kappa B signaling in macrophages as a potential therapeutic target for intracranial aneurysms

Intracranial aneurysms are common but are generally untreated, and their rupture can lead to subarachnoid hemorrhage. Because of the poor prognosis associated with subarachnoid hemorrhage, preventing the progression of intracranial aneurysms is critically important. Intracranial aneurysms are caused by chronic inflammation of the arterial wall due to macrophage infiltration triggered by monocyte chemoattractant protein-1 (MCP-1), macrophage activation mediated by the transcription factor nuclear factor kappa B (NF-kappa B), and inflammatory signaling involving prostaglandin E-2 (PGE(2)) and prostaglandin E receptor subtype 2 (EP2). We correlated EP2 and cyclooxygenase-2 (COX-2) with macrophage infiltration in human intracranial aneurysm lesions. Monitoring the spatiotemporal pattern of NF-kappa B activation during intracranial aneurysm development in mice showed that NF-kappa B was first activated in macrophages in the adventitia and in endothelial cells and, subsequently, in the entire arterial wall. Mice with a macrophage-specific deletion of Ptger2 (which encodes EP2) or macrophage-specific expression of an I kappa B alpha mutant that restricts NF-kappa B activation had fewer intracranial aneurysms with reduced macrophage infiltration and NF-kappa B activation. In cultured cells, EP2 signaling cooperated with tumor necrosis factor-alpha (TNF-alpha) to activate NF-kappa B and synergistically induce the expression of proinflammatory genes, including Ptgs2 (encoding COX-2). EP2 signaling also stabilized Ccl2 (encoding MCP-1) by activating the RNA-stabilizing protein HuR. Rats administered an EP2 antagonist had reduced macrophage infiltration and intracranial aneurysm formation and progression. This signaling pathway in macrophages thus facilitates intracranial aneurysm development by amplifying inflammation in intracranial arteries. These results indicate that EP2 antagonists may therefore be a therapeutic alternative to surgery.Peer reviewe

Development of monitoring tool by pharmacists

Purpose: Drug side effects often lead to serious outcomes. Administration of second-generation antipsychotics has resulted in diabetic ketoacidosis and diabetic coma leading to death. Therefore, pharmacists are required to collect information on clinical test values, determine the appropriate test timing, and coordinate with doctors for further clinical laboratory orders, all of which are labor- and time-intensive tasks. In this study, we developed a side effect-monitoring tool and aimed to clarify the influence and efficiency of monitoring side effects by using the tool in patients taking atypical antipsychotics in whom it is necessary to check clinical test values such as blood sugar levels. Methods: We extracted clinical test values for patients treated with second-generation antipsychotics from electronic medical records. The test values are automatically displayed in the side effect grade classification specified by CTCAE ver. 4.0. A database was constructed using scripts to provide alerts for the timing of clinical testing. The pharmacist used this tool to confirm clinical test values for patients taking medication and requested the physician to inspect orders based on the appropriate test timings. Results: The management tool reduced the pharmacists’ effort in collecting information on patients’ prescription status and test values. It enabled patients to undergo tests at the appropriate time according to the progression of glucose metabolism and allowed for easy monitoring of side effects. Conclusion: The results suggested that regardless of pharmacists’ experience or skill, the introduction of this tool enables centralization of side-effect monitoring and can contribute to proper drug use

Association between periodontal condition and kidney dysfunction in Japanese adults : A cross‐sectional study

Recent studies have demonstrated that chronic kidney disease (CKD) may be associated with the progression of periodontal disease. Diabetes mellitus (DM) is a major risk factor for CKD. The objective of this study was to clarify the relationship between periodontal condition and kidney dysfunction in patients who had kidney failure with or without DM. One hundred sixty‐four patients with kidney dysfunction were enrolled (male: N = 105; female: N = 59), and the relationship between periodontal condition and kidney dysfunction was analyzed in a cross‐sectional study. The subjects were divided into three groups: (a) patients with DM, (b) dialysis patients with nephropathy due to various kidney diseases, and (c) dialysis patient with nephropathy due to DM (diabetic nephropathy). Then, the effect of DM on the periodontal condition was analyzed. The patients were also stratified by CKD stage (into G1–G5) using the estimated glomerular filtration rate (eGFR), and the G5 group was divided in patients with or without DM. Correlations between eGFR and parameters of periodontal condition were calculated in patients from G1 to G4. The number of missing teeth was significantly higher in dialysis patients with diabetic nephropathy than in patients with DM, whereas alveolar bone loss did not show a significant difference among the three groups. In addition, the G5 patients with DM had a significantly higher number of missing teeth than the other CKD groups, whereas alveolar bone loss did not show a significant difference. In G5 patients with DM, Community Periodontal Index and Oral Hygiene Index scores were significantly higher than in G1‐4 patients with DM. There was a significant negative correlation between eGFR and the number of missing teeth. Patients with diabetic nephropathy have a higher rate of periodontal problems such as missing teeth in Japanese adults

上部消化管出血における血液凝固第XIII因子活性の低下

We report on blood coagulation factor XⅢ（F１３）activity in upper gastrointestinal bleeding （UGIB）due to peptic ulcer（PU）. 【Methods】From January ２０１１ to December ２０１６, 42 patients who had UGIB with PU, performed endoscopic hemostasis（EH）, and measured F１３ activity （normal range：７０‐１４０％）, were retrospectively studied. The clinical signs, peripheral blood, biochemistry, coagulation, F１３ activity, and endoscopic findings were examined by logistic regression analysis（LRA）in３２patients with successful hemostasis and１０patients with rebleeding. 【Results】There were２５elderly patients aged７０ and over. The average F１３ activity was ６５．７±２２．５％, ６８．３±２２．１％ in the case of successful hemostasis, below the lower limit of normal, and further decreased to ５７．５±１８．１％ in the case of rebleeding. LRA showed association with rebleeding in Forrest classification and F１３activity. 【Conclusion】F１３activity decreased in many cases of UGIB due to PU, and associated with rebleeding after EH

Covalent functionalization:Towards soluble multiwalled boron nitride nanotubes

(Figure Presented) Playing with the band: Long alkyl chains are bound to boron nitride nanotubes (BNNTs) from the reaction of stearoyl chloride with amino groups on the BNNTs; the resulting functionalized BNNTs (see picture) are soluble in many organic solvents. Cathodoluminescence and UV/Vis absorption experiments indicate that the long alkyl chains may induce drastic changes in the band structure of BNNTs.</p

Boron nitride nanotube, nanocable and nanocone

Boron nitride nanotubes, nanocones and nanocables were prepared and their atomic structures were identified by using a 300 kV field emission transmission electron microscope equipped with an electron energy loss spectrometer and energy dispersion X-ray detector. Multiwalled BN nanotubes and nanocones were synthesized by reacting C nanotube templates and boron oxide under nitrogen atmosphere at 1723-2023 K. Additions of metal oxide promoters, e.g. MoO3, CuO, and PbO, significantly improved BN-rich nanotube yield at the expense of B-C-N nanotubes. It was shown that BN nanotubes had preferential "zigzag" chirality and exhibited either hexagonal or rhombohedral stacking between shells. An efficient synthetic route for bulk quantities of BN tube production was also developed, where a B-N-O precursor was used during a CVD process. Nanocones of BN were mostly found to have 240° disclinations which ensure the presence of B-N bonds only. One case was observed of a cone constituted of 300° disclination implying that structures may contain line defects of non B-N bonds. The first synthesis of insulating BN nanocables was carried out, where BN nanotubes were entirely filled with Invar Fe-Ni nanorods. The filled nanotube diameters ranged between 30 to 300 nm, whereas the length of filling reached several microns.</p

Characteristics of boron nitride nanotube-polyaniline composites

(Figure Presented) A self-organized film of boron nitride nanotube-polyaniline (BNNT-PANI) composite is fabricated by using a simple solution method. The BNNTs are fully coated with PANI as a result of strong interactions between these components (see picture). Mechanically tough, BNNTs may have potential as stabilizing additives to PANI or other polymers.</p