Efficacy and safety of luseogliflozin added to various oral antidiabetic drugs in Japanese patients with type 2 diabetes mellitus

Introduction: Two studies were carried out to investigate the efficacy and safety of luseogliflozin added to existing oral antidiabetic drugs (OADs) in Japanese type 2 diabetic patients inadequately controlled with OAD monotherapy. Materials and Methods: In the trial involving add‐on to sulfonylureas (study 03‐1), patients were randomly assigned to receive luseogliflozin 2.5 mg or a placebo for a 24‐week double‐blind period, followed by a 28‐week open‐label period. In the open‐label trial involving add‐on to other OADs; that is, biguanides, dipeptidyl peptidase‐4 inhibitors, thiazolidinediones, glinides and α‐glucosidase inhibitors (study 03‐2), patients received luseogliflozin for 52 weeks. Results: In study 03‐1, luseogliflozin significantly decreased glycated hemoglobin at the end of the 24‐week double‐blind period compared with the placebo (–0.88%, P < 0.001), and glycated hemoglobin reduction from baseline at week 52 was –0.63%. In study 03‐2, luseogliflozin added to other OADs significantly decreased glycated hemoglobin from baseline at week 52 (–0.52 to –0.68%, P < 0.001 for all OADs). Bodyweight reduction was observed in all add‐on therapies, even with agents associated with weight gain, such as sulfonylureas and thiazolidinediones. Most adverse events were mild in severity. When added to a sulfonylurea, incidences of hypoglycemia during the double‐blind period were 8.7% and 4.2% for luseogliflozin and placebo, respectively, but no major hypoglycemic episodes occurred. The frequency and incidences of adverse events of special interest for sodium glucose cotransporter 2 inhibitors and adverse events associated with combined OADs were acceptable. Conclusions: Add‐on therapies of luseogliflozin to existing OADs improved glycemic control, reduced bodyweight and were well tolerated in Japanese type 2 diabetic patients. These trials were registered with the Japan Pharmaceutical Information Center (add on to sulfonylurea: JapicCTI‐111507; add on to other OADs: JapicCTI‐111508)

Enhanced Si and B diffusion in semiconductor-grade SiO 2 and the effect of strain on diffusion

Abstract We present experimental and simulation results of Si self-diffusion and B diffusion in SiO 2 formed directly on Si substrates by thermal oxidation. We show that both Si and B diffusion in SiO 2 are enhanced by SiO generated at the Si/SiO 2 interface and diffusing into SiO 2 . We also show that the existence of high-concentration B in SiO 2 enhances SiO diffusion, which enhances both Si self-diffusion and B diffusion. This correlated diffusion of Si and B in SiO 2 is consistent with the first-principles calculation results, which show that B diffuses via a complex of BSiO with frequent bond exchanges in the SiO 2 network. Furthermore, based on the results, the enhancement of Si self-diffusion and B diffusion in SiO 2 by compressive strain and their retardation by tensile strain are suggested.

Türkçeden garp dillerine tercümeler

Taha Toros Arşivi, Dosya Adı: Namık Kemalİstanbul Kalkınma Ajansı (TR10/14/YEN/0033) İstanbul Development Agency (TR10/14/YEN/0033

Smad1の条件付き遺伝子削除は進行性糸球体腎炎による糸球体傷害を改善する

Matrix expansion and cell proliferation are concomitantly observed in various glomerular injuries. However, the molecular mechanisms responsible for these changes have not been fully elucidated. We have reported that Smad1 is a key signalling molecule that regulates the transcription of type IV collagen (Col4) in mesangial matrix expansion and is thereby involved in glomerular injury in an acute model of glomerulonephritis. In this study, we addressed the role of Smad1 signalling in accelerated nephrotoxic nephritis (NTN), a model of progressive glomerulonephritis, using conditional deletion of Smad1 in Rosa26CreERT2 mice (Smad1-CKO). Mesangial matrix expansion in the Smad1-CKO mice with NTN was significantly inhibited compared with that in wild type mice with NTN, which was consistent with the decrease in Col4 expression level. On the other hand, STAT3 activation and cell proliferation were not influenced by Smad1 deletion in the NTN model. Therefore, we investigated another factor that activates cell proliferation in the absence of Smad1. Id2 induced VEGF secretion and subsequent STAT3 activation, independently of Smad1 expression in mouse mesangial cells. Here we show that Smad1 plays an important role in the development of glomerular injury without affecting cell proliferation, in progressive glomerulonephritis

Conditional Deletion of Smad1 Ameliorates Glomerular Injury in Progressive Glomerulonephritis

Matrix expansion and cell proliferation are concomitantly observed in various glomerular injuries. However, the molecular mechanisms responsible for these changes have not been fully elucidated. We have reported that Smad1 is a key signalling molecule that regulates the transcription of type IV collagen (Col4) in mesangial matrix expansion and is thereby involved in glomerular injury in an acute model of glomerulonephritis. In this study, we addressed the role of Smad1 signalling in accelerated nephrotoxic nephritis (NTN), a model of progressive glomerulonephritis, using conditional deletion of Smad1 in Rosa26CreERT2 mice (Smad1-CKO). Mesangial matrix expansion in the Smad1-CKO mice with NTN was significantly inhibited compared with that in wild type mice with NTN, which was consistent with the decrease in Col4 expression level. On the other hand, STAT3 activation and cell proliferation were not influenced by Smad1 deletion in the NTN model. Therefore, we investigated another factor that activates cell proliferation in the absence of Smad1. Id2 induced VEGF secretion and subsequent STAT3 activation, independently of Smad1 expression in mouse mesangial cells. Here we show that Smad1 plays an important role in the development of glomerular injury without affecting cell proliferation, in progressive glomerulonephritis

Potential of Genome-Wide Studies in Unrelated Plus Trees of a Coniferous Species, Cryptomeria japonica (Japanese Cedar)

A genome-wide association study (GWAS) was conducted on more than 30,000 single nucleotide polymorphisms (SNPs) in unrelated first-generation plus tree genotypes from three populations of Japanese cedar Cryptomeria japonica D. Don with genomic prediction for traits of growth, wood properties and male fecundity. Among the assessed populations, genetic characteristics including the extent of linkage disequilibrium (LD) and genetic structure differed and these differences are considered to be due to differences in genetic background. Through population-independent GWAS, several significant SNPs found close to the regions associated with each of these traits and shared in common across the populations were identified. The accuracies of genomic predictions were dependent on the traits and populations and reflected the genetic architecture of traits and genetic characteristics. Prediction accuracies using SNPs selected based on GWAS results were similar to those using all SNPs for several combinations of traits and populations. We discussed the application of genome-wide studies for C. japonica improvement

Aphids acquired symbiotic genes via lateral gene transfer

<p>Abstract</p> <p>Background</p> <p>Aphids possess bacteriocytes, which are cells specifically differentiated to harbour the obligate mutualist <it>Buchnera aphidicola </it>(γ-Proteobacteria). <it>Buchnera </it>has lost many of the genes that appear to be essential for bacterial life. From the bacteriocyte of the pea aphid <it>Acyrthosiphon pisum</it>, we previously identified two clusters of expressed sequence tags that display similarity only to bacterial genes. Southern blot analysis demonstrated that they are encoded in the aphid genome. In this study, in order to assess the possibility of lateral gene transfer, we determined the full-length sequences of these transcripts, and performed detailed structural and phylogenetic analyses. We further examined their expression levels in the bacteriocyte using real-time quantitative RT-PCR.</p> <p>Results</p> <p>Sequence similarity searches demonstrated that these fully sequenced transcripts are significantly similar to the bacterial genes <it>ldcA </it>(product, LD-carboxypeptidase) and <it>rlpA </it>(product, rare lipoprotein A), respectively. <it>Buchnera </it>lacks these genes, whereas many other bacteria, including <it>Escherichia coli</it>, a close relative of <it>Buchnera</it>, possess both <it>ldcA </it>and <it>rlpA</it>. Molecular phylogenetic analysis clearly demonstrated that the aphid <it>ldcA </it>was derived from a rickettsial bacterium closely related to the extant <it>Wolbachia </it>spp. (α-Proteobacteria, Rickettsiales), which are intracellular symbionts of various lineages of arthropods. The evolutionary origin of <it>rlpA </it>was not fully resolved, but it was clearly demonstrated that its double-ψ β-barrel domain is of bacterial origin. Real-time quantitative RT-PCR demonstrated that <it>ldcA </it>and <it>rlpA </it>are expressed 11.6 and 154-fold higher in the bacteriocyte than in the whole body, respectively. LdcA is an enzyme required for recycling murein (peptidoglycan), which is a component of the bacterial cell wall. As <it>Buchnera </it>possesses a cell wall composed of murein but lacks <it>ldcA</it>, a high level of expression of the aphid <it>ldcA </it>in the bacteriocyte may be essential to maintain <it>Buchnera</it>. Although the function of RlpA is not well known, conspicuous up-regulation of the aphid <it>rlpA </it>in the bacteriocyte implies that this gene is also essential for <it>Buchnera</it>.</p> <p>Conclusion</p> <p>In this study, we obtained several lines of evidence indicating that aphids acquired genes from bacteria via lateral gene transfer and that these genes are used to maintain the obligately mutualistic bacterium, <it>Buchnera</it>.</p

Activation of Src Mediates PDGF-Induced Smad1 Phosphorylation and Contributes to the Progression of Glomerulosclerosis in Glomerulonephritis

Platelet-derived growth factor (PDGF) plays critical roles in mesangial cell (MC) proliferation in mesangial proliferative glomerulonephritis. We showed previously that Smad1 contributes to PDGF-dependent proliferation of MCs, but the mechanism by which Smad1 is activated by PDGF is not precisely known. Here we examined the role of c-Src tyrosine kinase in the proliferative change of MCs. Experimental mesangial proliferative glomerulonephritis (Thy1 GN) was induced by a single intravenous injection of anti-rat Thy-1.1 monoclonal antibody. In Thy1 GN, MC proliferation and type IV collagen (Col4) expression peaked on day 6. Immunohistochemical staining for the expression of phospho-Src (pSrc), phospho-Smad1 (pSmad1), Col4, and smooth muscle α-actin (SMA) revealed that the activation of c-Src and Smad1 signals in glomeruli peaked on day 6, consistent with the peak of mesangial proliferation. When treated with PP2, a Src inhibitor, both mesangial proliferation and sclerosis were significantly reduced. PP2 administration also significantly reduced pSmad1, Col4, and SMA expression. PDGF induced Col4 synthesis in association with increased expression of pSrc and pSmad1 in cultured MCs. In addition, PP2 reduced Col4 synthesis along with decreased pSrc and pSmad1 protein expression in vitro. Moreover, the addition of siRNA against c-Src significantly reduced the phosphorylation of Smad1 and the overproduction of Col4. These results provide new evidence that the activation of Src/Smad1 signaling pathway plays a key role in the development of glomerulosclerosis in experimental glomerulonephritis