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51.
Miyamoto Y Banno Y Yamashita T Fujimoto T Oi S Moritoh Y Asakawa T Kataoka O Takeuchi K Suzuki N Ikedo K Kosaka T Tsubotani S Tani A Funami M Amano M Yamamoto Y Aertgeerts K Yano J Maezaki H 《Bioorganic & medicinal chemistry》2011,19(1):172-185
We have previously discovered nicotinic acid derivative 1 as a structurally novel dipeptidyl peptidase IV (DPP-4) inhibitor. In this study, we obtained the X-ray co-crystal structure between nicotinic acid derivative 1 and DPP-4. From these X-ray co-crystallography results, to achieve more potent inhibitory activity, we targeted Arg125 as a potential amino acid residue because it was located near the pyridine core, and some known DPP-4 inhibitors were reported to interact with this residue. We hypothesized that the guanidino group of Arg125 could interact with two hydrogen-bond acceptors in a bidentate manner. Therefore, we designed a series of 3-pyridylacetamide derivatives possessing an additional hydrogen-bond acceptor that could have the desired bidentate interaction with Arg125. We discovered the dihydrochloride of 1-{[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-(2-methylpropyl)pyridin-3-yl]acetyl}-l-prolinamide (13j) to be a potent and selective DPP-4 inhibitor that could interact with the guanidino group of Arg125 in a unique bidentate manner. 相似文献
52.
Matsuo O Takahashi Y Abe C Tanaka K Nakashima A Morita H 《Advances in physiology education》2011,35(2):237-240
In most laboratory practices for students in medical schools, a laboratory guidebook is given to the students, in which the procedures are precisely described. The students merely follow the guidebook without thinking deeply, which spoils the students and does not entice them to think creatively. Problem-based learning (PBL) could be one means for the students themselves to actively learn, find problems, and resolve them. Such a learning attitude nurtures medical students with lifelong learning as healthcare professionals. We merged PBL and laboratory practices to promote deep thinking habits and developed an integrated laboratory practice. We gave a case sheet to groups of students from several schools. The students raised hypotheses after vivid discussion, designed experimental protocols, and performed the experiments. If the results did not support or disproved the hypothesis, the students set up another hypothesis followed by experiments, lasting for 4 or 5 consecutive days. These procedures are quite similar to those of professional researchers. The main impact achieved was the fact that the students developed the experimental design by themselves, for the first time in their college lives. All students enjoyed the laboratory practice, which they had never experienced before. This is an antidote to the guidebook-navigated traditional laboratory practice, which disappoints many students. As educators in basic medical sciences stand on the edge in terms of educating the next generation, there is a need to provide a strong foundation for medical students to design and perform scientific experiments. The integrated laboratory practice may provide the solution. 相似文献
53.
54.
Calorimetric measurements were carried out using a differential scanning calorimeter in the temperature range from 10 to 120 degrees C for characterizing the thermal response of beta2-microglobulin amyloid fibrils. The thermograms of amyloid fibril solution showed a remarkably large decrease in heat capacity that was essentially released upon the thermal unfolding of the fibrils, in which the magnitude of negative heat capacity change was not explicable in terms of the current accessible surface area model of protein structural thermodynamics. The heat capacity-temperature curve of amyloid fibrils prior to the fibril unfolding exhibited an unusual dependence on the fibril concentration and the heating rate. Particularly, the heat needed to induce the thermal response was found to be linearly dependent on the heating rate, indicating that its thermal response is under a kinetic control and precluding the interpretation in terms of equilibrium thermodynamics. Furthermore, amyloid fibrils of amyloid beta peptides also exhibited a heating rate-dependent exothermic process before the fibril unfolding, indicating that the kinetically controlled thermal response may be a common phenomenon to amyloid fibrils. We suggest that the heating rate-dependent negative change in heat capacity is coupled to the association of amyloid fibrils with characteristic hydration pattern. 相似文献
55.
Involvement of the Toll-like receptor 9 signaling pathway in the induction of innate immunity by baculovirus
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Abe T Hemmi H Miyamoto H Moriishi K Tamura S Takaku H Akira S Matsuura Y 《Journal of virology》2005,79(5):2847-2858
We have previously shown that mice inoculated intranasally with a wild-type baculovirus (Autographa californica nuclear polyhedrosis virus [AcNPV]) are protected from a lethal challenge by influenza virus. However, the precise mechanism of induction of this protective immune response by the AcNPV treatment remained unclear. Here we show that AcNPV activates immune cells via the Toll-like receptor 9 (TLR9)/MyD88-dependent signaling pathway. The production of inflammatory cytokines was severely reduced in peritoneal macrophages (PECs) and splenic CD11c(+) dendritic cells (DCs) derived from mice deficient in MyD88 or TLR9 after cultivation with AcNPV. In contrast, a significant amount of alpha interferon (IFN-alpha) was still detectable in the PECs and DCs of these mice after stimulation with AcNPV, suggesting that a TLR9/MyD88-independent signaling pathway might also participate in the production of IFN-alpha by AcNPV. Since previous work showed that TLR9 ligands include bacterial DNA and certain oligonucleotides containing unmethylated CpG dinucleotides, we also examined the effect of baculoviral DNA on the induction of innate immunity. Transfection of the murine macrophage cell line RAW264.7 with baculoviral DNA resulted in the production of the inflammatory cytokine, while the removal of envelope glycoproteins from viral particles, UV irradiation of the virus, and pretreatment with purified baculovirus envelope proteins or endosomal maturation inhibitors diminished the induction of the immune response by AcNPV. Together, these results indicate that the internalization of viral DNA via membrane fusion mediated by the viral envelope glycoprotein, as well as endosomal maturation, which releases the viral genome into TLR9-expressing cellular compartments, is necessary for the induction of the innate immune response by AcNPV. 相似文献
56.
Kawase T Okuda K Saito Y Amizuka N Suzuki H Yoshie H 《In vitro cellular & developmental biology. Animal》2005,41(5-6):171-176
Summary Platelet-rich plasma (PRP) has been used to promote periodontal regeneration following the premise that constituent transforming
growth factor-β1 (TGF-β1) and platelet-derived growth factor-AB will stimulate cell proliferation at the site of application.
In previous studies, we demonstrated that PRP mimics TGF-β1 to modulate proliferation in a cell type-specific manner, that
fibrin clot formation by PRP upregulates type I collagen, and that an unidentified factor(s) in PRP increases alkaline phosphatase
(ALP) activity in human periodontal ligament (PDL) cell cultures. We have now examined the effects of PRP on in vitro mineralization.
Platelet-rich plasma and PDL cells were prepared from human adult volunteers or rats. After 20 d of continuous treatment with
PRP in dexamethazone (Dex)-containing osteogenic medium, PRP time dependently promoted mineralization by rat PDL cells but
failed to fully induce the osteoblastic phenotype. Furthermore, when human PDL cells were induced to increase ALP activity
in osteogenic medium that lacked Dex, a condition that should delay (or suppress) osteoblastic differentiation, transmission
electron microscopy revealed that mineralized spicules were initially deposited onto PRP-derived platelet aggregates. Taken
together with our previous data, these findings suggest that PRP provides platelet aggregates as nuclei to initiate mineralization
while stimulating PDL cell proliferation, differentiation, and collagen production. The combination of these effects may effectively
mediate PRP's ability to promote regeneration of periodontal tissue, including skeletal tissue, at the site of injury. 相似文献
57.
Chiba S Itateyama E Oka K Masaki T Sakata T Yoshimatsu H 《Experimental biology and medicine (Maywood, N.J.)》2005,230(5):334-342
This study examined the contribution of hypothalamic neuronal histamine (HA) to the anorectic and febrile responses induced by lipopolysaccharide (LPS), an exogenous pyrogen, and the endogenous pyrogens interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). Intraperitoneal (ip) injection of LPS, IL-1beta, or TNF-alpha suppressed 24-hr cumulative food intake and increased rectal temperature in rats.To analyze the histaminergic contribution, rats were pretreated with intracerebroventricular (icv) injection of 2.44 mmol/kg or ip injection of 244 mmol/kg of alpha-fluoromethylhistidine (FMH), a suicide inhibitor of histidine decarboxylase (HDC), to deplete neural HA. The depletion of neural HA augmented the febrile response to ip injection of LPS and IL-1beta and alleviated the anorectic response to ip injection of IL-1beta. However, the depletion of neural HA did not modify the LPS-induced anorectic response or TNF-alpha-induced febrile and anorectic responses. Consistent with these results, the rate of hypothalamic HA turnover, assessed by the accumulation of tele-methylhistamine (t-MH), was elevated with ip injections of LPS and IL-1beta, but unaffected by TNF-alpha at equivalent doses. This suggests that (i) LPS and IL-1beta activate hypothalamic neural HA turnover; (ii) hypothalamic neural HA suppresses the LPS- and IL-1beta-induced febrile responses and accelerates the IL-1beta-induced anorectic response; and (iii) TNF-alpha modulates the febrile and anorectic responses via a neural HA-independent pathway. Therefore, hypothalamic neural HA is involved in the IL-1beta-dominant pathway, rather than the TNF-alpha-dominant pathway, preceding the systemic inflammatory response induced by exogenous pyrogens, such as LPS. Further research on this is needed. 相似文献
58.
Acute central infusion of leptin modulates fatty acid mobilization by affecting lipolysis and mRNA expression for uncoupling proteins 总被引:5,自引:0,他引:5
Tajima D Masaki T Hidaka S Kakuma T Sakata T Yoshimatsu H 《Experimental biology and medicine (Maywood, N.J.)》2005,230(3):200-206
Chronic administration of leptin has been shown to reduce adiposity through energy intake and expenditure. The present study aims to examine how acute central infusion of leptin regulates peripheral lipid metabolism, as assessed by markers indicative of their mobilization and utilization. A bolus infusion of 1 microg/rat leptin into the third cerebroventricle increased the expression of mRNA for hormone-sensitive lipase (HSL), an indicator of lipolysis, in white adipose tissue (WAT). This was accompanied by elevation of plasma levels of glycerol, but not of free fatty acids, as compared to the saline control (P < 0.03). The same treatment with leptin decreased plasma insulin levels but did not affect the plasma glucose level (P < 0.05 for insulin). Among the major regulators of the transportation or utilization of energy substrates, leptin treatment increased expression of mRNA for uncoupling protein 1 (UCP1) in brown adipose tissue (BAT), UCP2 in WAT, and UCP3 in quadriceps skeletal muscle, but not those for fatty acid-binding protein in WAT, carnitine phosphate transferase-1, a marker for beta oxidation of fatty acids in muscle, nor glucose transporter 4 in WAT and muscle (P < 0.01 for HSL, P < 0.05 for UCP1, and P < 0.005 for UCP2 and UCP3). These results indicate that, even in a single bolus, leptin may regulate the mobilization and/or utilization of energy substrates such as fatty acids by affecting lipolytic activity in WAT and by increasing the expression of UCPs in BAT, WAT, and muscle. 相似文献
59.
To obtain insight into the mechanism of fibril formation, we examined the effects of ultrasonication, a strong agitator, on beta2-microglobulin (beta2-m), a protein responsible for dialysis-related amyloidosis. Upon sonication of an acid-unfolded beta2-m solution at pH 2.5, thioflavin T fluorescence increased markedly after a lag time of 1-2 h with a simultaneous increase of light scattering. Atomic force microscopy images showed the formation of a large number of short fibrils 3 nm in diameter. When the sonication-induced fibrils were used as seeds in the next seeding experiment at pH 2.5, a rapid and intense formation of long fibrils 3 nm in diameter was observed demonstrating seed-dependent fibril growth. We then examined the effects of sonication on the native beta2-m at neutral pH, conditions under which amyloid deposits occur in patients. In the presence of 0.5 mm sodium dodecyl sulfate, a model compound of potential trigger and stabilizer of amyloid fibrils in patients, a marked increase of thioflavin T fluorescence was observed after 1 day of sonication at pH 7.0. The products of sonication caused the accelerated fibril formation at pH 7.0. Atomic force microscopy images showed that the fibrils formed at pH 7.0 have a diameter of more than 7 nm, thicker than those prepared at pH 2.5. These results indicate that ultrasonication is one form of agitation triggering the formation of amyloid fibrils of beta2-m, producing fibrils adapted to the respective pH. 相似文献
60.
Raman B Chatani E Kihara M Ban T Sakai M Hasegawa K Naiki H Rao ChM Goto Y 《Biochemistry》2005,44(4):1288-1299
Investigation of factors that modulate amyloid formation of proteins is important to understand and mitigate amyloid-related diseases. To understand the role of electrostatic interactions and the effect of ionic cosolutes, especially anions, on amyloid formation, we have investigated the effect of salts such as NaCl, NaI, NaClO(4), and Na(2)SO(4) on the amyloid fibril growth of beta(2)-microglobulin, the protein involved in dialysis-related amyloidosis. Under acidic conditions, these salts exhibit characteristic optimal concentrations where the fibril growth is favored. The presence of salts leads to an increase in hydrophobicity of the protein as reported by 8-anilinonaphthalene-1-sulfonic acid, indicating that the anion interaction leads to the necessary electrostatic and hydrophobic balance critical for amyloid formation. However, high concentrations of salts tilt the balance to high hydrophobicity, leading to partitioning of the protein to amorphous aggregates. Such amorphous aggregates are not competent for fibril growth. The order of anions based on the lowest concentration at which fibril formation is favored is SO(4)(2)(-) > ClO(4)(-) > I(-) > Cl(-), consistent with the order of their electroselectivity series, suggesting that preferential anion binding, rather than general ionic strength effect, plays an important role in the amyloid fibril growth. Anion binding is also found to stabilize the amyloid fibrils under acidic condition. Interestingly, sulfate promotes amyloid growth of beta(2)-microglobulin at pH between 5 and 6, closer to its isoelectric point. Considering the earlier studies on the role of glycosaminoglycans and proteoglycans (i.e., sulfated polyanions) on amyloid formation, our study suggests that preferential interaction of sulfate ions with amyloidogenic proteins may have biological significance. 相似文献