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113.
Glucose Homeostatic Law: Insulin Clearance Predicts the Progression of Glucose Intolerance in Humans
Kaoru Ohashi Hisako Komada Shinsuke Uda Hiroyuki Kubota Toshinao Iwaki Hiroki Fukuzawa Yasunori Komori Masashi Fujii Yu Toyoshima Kazuhiko Sakaguchi Wataru Ogawa Shinya Kuroda 《PloS one》2015,10(12)
Homeostatic control of blood glucose is regulated by a complex feedback loop between glucose and insulin, of which failure leads to diabetes mellitus. However, physiological and pathological nature of the feedback loop is not fully understood. We made a mathematical model of the feedback loop between glucose and insulin using time course of blood glucose and insulin during consecutive hyperglycemic and hyperinsulinemic-euglycemic clamps in 113 subjects with variety of glucose tolerance including normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM). We analyzed the correlation of the parameters in the model with the progression of glucose intolerance and the conserved relationship between parameters. The model parameters of insulin sensitivity and insulin secretion significantly declined from NGT to IGT, and from IGT to T2DM, respectively, consistent with previous clinical observations. Importantly, insulin clearance, an insulin degradation rate, significantly declined from NGT, IGT to T2DM along the progression of glucose intolerance in the mathematical model. Insulin clearance was positively correlated with a product of insulin sensitivity and secretion assessed by the clamp analysis or determined with the mathematical model. Insulin clearance was correlated negatively with postprandial glucose at 2h after oral glucose tolerance test. We also inferred a square-law between the rate constant of insulin clearance and a product of rate constants of insulin sensitivity and secretion in the model, which is also conserved among NGT, IGT and T2DM subjects. Insulin clearance shows a conserved relationship with the capacity of glucose disposal among the NGT, IGT and T2DM subjects. The decrease of insulin clearance predicts the progression of glucose intolerance. 相似文献
114.
Emiko Matsunaga Yujiro Higuchi Kazuki Mori Nao Yairo Takuji Oka Saki Shinozuka Kosuke Tashiro Minoru Izumi Satoru Kuhara Kaoru Takegawa 《PloS one》2015,10(9)
β-D-galactofuranose (Galf) is a component of polysaccharides and glycoconjugates and its transferase has been well analyzed. However, no β-D-galactofuranosidase (Galf-ase) gene has been identified in any organism. To search for a Galf-ase gene we screened soil samples and discovered a strain, identified as a Streptomyces species by the 16S ribosomal RNA gene analysis, that exhibits Galf-ase activity for 4-nitrophenyl β-D-galactofuranoside (pNP-β-D-Galf) in culture supernatants. By draft genome sequencing of the strain, named JHA19, we found four candidate genes encoding Galf-ases. Using recombinant proteins expressed in Escherichia coli, we found that three out of four candidates displayed the activity of not only Galf-ase but also α-L-arabinofuranosidase (Araf-ase), whereas the other one showed only the Galf-ase activity. This novel Galf-specific hydrolase is encoded by ORF1110 and has an optimum pH of 5.5 and a Km of 4.4 mM for the substrate pNP-β-D-Galf. In addition, this enzyme was able to release galactose residue from galactomannan prepared from the filamentous fungus Aspergillus fumigatus, suggesting that natural polysaccharides could be also substrates. By the BLAST search using the amino acid sequence of ORF1110 Galf-ase, we found that there are homolog genes in both prokaryotes and eukaryotes, indicating that Galf-specific Galf-ases widely exist in microorganisms. 相似文献
115.
Agricultural landscapes generally include not only crop fields but also semi-natural habitats. In Japan, such a mixed rural landscape is called “satoyama.” Although ground beetles are potential predators of pests, the environmental factors that determine their distribution in Japanese rural landscapes have not been fully elucidated. To understand the effects of distance from woodland edges, soil moisture, and weed height on assemblages of carabid beetles, we examined the number of adult beetles in pitfall traps placed in a satoyama landscape in the lowlands of western Honshu, Japan. Our results show that the carabid species could be largely differentiated into woodland, intermediate, and open-land species. The “intermediate species” group includes species that depend on woodland or woodland edges for at least part of their life cycles. Paddy fields must have long provided semi-natural habitats that complement those in natural grasslands and wetlands for open-land beetles that prefer wet conditions. Weeds can also increase the abundance of some intermediate and woodland species; thus, the arrangement of such landscape elements as woodlands and paddies can determine the species richness and abundance of ground beetles in agricultural fields. 相似文献
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The Fanconi anemia (FA) pathway, of which the FANCD2 protein is a key component, plays crucial roles in the maintenance of hematopoietic stem cells and suppression of carcinogenesis. However, the function of FANCD2 remains unclear. Here, we report that FANCD2 is a novel and specific substrate of caspase 3. Cleavage of FANCD2 by caspase 3 did not require either the FA core complex or mono-ubiquitylation of FANCD2, and was stimulated by p53. In addition, we identified the cleavage sites and generated cell lines that stably express a caspase-resistant FANCD2 mutant. Our data suggest that FANCD2 is regulated by caspase-mediated degradation during apoptosis induced by DNA damage. 相似文献
118.
Yasuharu Otsubo Seizo Yashiro Kiyoteru Nozaki Kaoru Matsuura Kouhei Kiyonaga Ryotarou Mitsumata Yoshihiro Takahashi Mitsuaki Masuyama Atsunobu Muneoka Nobutoki Takamune Shozo Shoji Shogo Misumi 《Biochemical and biophysical research communications》2014
The presence of anti-CCR5 and anti-HIV-1 envelope glycoprotein (ENV) gp41 antibodies (Abs) at sites of HIV-1 exposure was effective in preventing its transmission to HIV-1-exposed seronegative (ESN) subjects. Here, we design an immunogen that can induce Abs against CCR5 and SIVmac239 ENV simultaneously and show that bovine alpha-2-HS-glycoprotein (bAHSG) functions as a booster antigen for efficiently stimulating humoral immune responses to CCR5 and ENV. Initially, we generated a rhesus CCR5-derived cyclopeptide (cDDR5) conjugated with a recombinant trimeric SIVmac239 Env. When inguinally administered to rhesus macaques, the immunogen simultaneously induced both anti-CCR5 and anti-ENV Abs in sera, and the purified serum IgG fraction exerted an inhibitory effect on SIVmac239 infection in vitro. When further boosted with bAHSG, the responses of both Abs were significantly enhanced. To examine the cross-reactivity of bAHSG, it was administered to naïve cynomolgus macaques. The results showed a statistically significant increase in IgG response against cynomolgus CCR5 and SIVmac239 ENV, and the induction of neutralizing activity against SIVmac239. These findings suggest that bAHSG is useful for immune strategies aimed at generating Abs against CCR5 and ENV simultaneously to confer HIV-protective immunity. 相似文献
119.
Hiroyuki Mukaiyama Hideki Tohda Kaoru Takegawa 《Applied microbiology and biotechnology》2010,86(4):1135-1143
Although the fission yeast Schizosaccharomyces pombe has been used for high-level heterologous protein production, the productivity of secreted human serum transferrin (hTF)
has been low, presumably, because the protein harbors twenty disulfide bonds and two N-glycosylation sites. In the present study, we found that overexpression of endogenous putative protein disulfide isomerase
(PDI) improved productivity. Whole genome sequence analysis of S. pombe revealed five putative PDI genes and overexpression of two of them, SPAC17H9.14c and SPBC3D6.13c (SpPdi2p or SpPdi3p, respectively),
significantly improved the productivity of secreted hTF. GFP-fused SpPdi2p and SpPdi3p were found to localize to the endoplasmic
reticulum. Co-overexpression of SpPdi2p or SpPdi3p with hTF coupled with modifications to the growth medium reported in our
previous study were able to increase the level of secreted hTF approximately 30-fold relative to conventional conditions. 相似文献
120.
Alimjan Idiris Hideki Tohda Mayumi Sasaki Katsunori Okada Hiromichi Kumagai Yuko Giga-Hama Kaoru Takegawa 《Applied microbiology and biotechnology》2010,85(3):667-677
Previously, we achieved approximately 30-fold enhanced secretion of the protease-sensitive model protein human growth hormone
(hGH) by multiple gene deletion of seven obstructive proteases in the fission yeast Schizosaccharomyces pombe. However, intracellular retention of secretory hGH was found in the resultant multiprotease-deficient strains. As a solution,
genetic modification of the intracellular trafficking pathway that is related to intracellular retention of hGH was attempted
on a protease octuple deletant strain. Vacuolar accumulation of the intracellularly retained hGH was identified by secretory
expression of hGH fused with EGFP, and three vacuolar protein sorting (vps)-deficient strains, vps10Δ, vps22Δ, and vps34Δ, were determined on account of their hGH secretion efficiency. The mutant vps10Δ was found to be effective for hGH secretion, which suggested a role for vps10 in the vacuolar accumulation of the intracellularly retained hGH. Finally, vps10 deletion was performed on the protease octuple deletant strain, which led to an approximately 2-fold increase in hGH secretion.
This indicated the possible application of secretory-pathway modification and multiple protease deletion for improving heterologous
protein secretion from the fission yeast S. pombe. 相似文献