Masayuki Sugimoto

Inhibition of CCR2 Ameliorates Insulin Resistance and Hepatic Steatosis in db/db Mice

Objective—Recently, adipose tissue inflammation induced by macrophage infiltration through MCP-1/C-C chemokine receptor-2 (CCR2) pathway is considered to play a role in the development of visceral obesity and insulin resistance. In the present study, to further examine the role of CCR2 in the development of obesity and type 2 diabetes, we studied the effect of pharmacological inhibition of CCR2 from the early stage of obesity in db/db mice. Methods and Results—Db/+m (lean control) and db/db mice were fed with a standard diet with or without 0.005% propagermanium, as a CCR2 inhibitor for 12 weeks from 6 weeks of age. Propagermanium treatment decreased body weight gain, visceral fat accumulation, and the size of adipocytes only in db/db mice. Further, propagermanium suppressed macrophage accumulation and inflammation in adipose tissue. Propagermanium treatment also ameliorated glucose tolerance and insulin sensitivity, and decreased hepatic triglyceride contents in db/db mice. Conclusions—Propagermanium improved obesity and related metabolic disorders, such as insulin resistance and hepatic steatosis by suppressing inflammation in adipose tissue. Our data indicate that inhibition of CCR2 could improve obesity and type 2 diabetes by interfering adipose tissue inflammation, and that propagermanium may be a beneficial drug for the treatment of the metabolic syndrome.

Changes in bone after high-dose irradiation. Biomechanics and histomorphology

We studied the effects of high-dose irradiation on the mechanical properties and morphology of cortical bone in rabbits for 52 weeks after a single dose of 50 Gy of electron-beam to the tibia. After four weeks, the bending strength of the irradiated bone was unchanged, but at 12 weeks, the strength had decreased significantly. At 24 weeks after irradiation mean strength was less than half of controls but by 52 weeks there was a tendency toward recovery. Similar, synchronous changes of damage and recovery were seen in cortical porosity, haematopoietic cells in the bone marrow and endosteal new bone formation.

Dense Coordination Network Capable of Selective CO2 Capture from C1 and C2 Hydrocarbons

We elucidated the specific adsorption property of CO(2) for a densely interpenetrated coordination polymer which was a nonporous structure and observed gas separation properties of CO(2) over CH(4), C(2)H(4), and C(2)H(6), studied under both equilibrium and kinetic conditions of gases at ambient temperature and pressure.

Long-term changes in the haversian systems following high-dose irradiation. An ultrastructural and quantitative histomorphological study.

The effects of high-dose irradiation on the morphology of haversian bone were studied, over a fifty-two-week period, in seventy-seven adult rabbits, after the administration of a single dose of radiation (therapeutic x-ray; twenty-five, fifty, or 100 gray) to one knee joint. The specimens of bone were examined with microangiography, light and transmission electron microscopy, and histomorphometry. Analysis was performed on the haversian bone in the subchondral bone plate of weight-bearing portions of the femoral condyles. Microangiography demonstrated dilatation of the microvasculature four weeks after irradiation. Beginning at twelve weeks, there was a marked decrease in vascularity; no obvious recovery of the subchondral bone had occurred by fifty-two weeks. At four weeks, morphological analysis revealed two changes in the haversian canals: simple occlusion of the haversian vessels with loss of cells in the canal, and dilatation of the capillaries with abnormal resorption of the perivascular bone matrix by osteoclasts. The abnormal bone resorption was not coupled with subsequent new-bone formation, resulting in increased porosity. Beginning at four weeks, a progressive decrease in the number of haversian vessels and in cellularity became prominent. The decrease in cellularity involved all types of cells, including endothelial cells, pericytes, perivascular mesenchymal cells, osteoblasts, osteocytes, and osteoclasts. The loss of perivascular cells was often but not always associated with occlusion of the haversian vessels. Histomorphometry revealed both time-dependent and dose-dependent decreases in capillary density (the number of intraosseous capillaries per unit area) and in the number of osteocytes in the subchondral bone plate. The porosity of the same areas showed a significant increase by four weeks (p < 0.001 after administration of twenty-five gray and p < 0.01 after administration of both fifty and 100 gray), but between twelve and fifty-two weeks, there was only a slight additional increase. Statistical analysis revealed significant correlations between capillary density and osteocyte survival (p < 0.001) and between capillary density and porosity (p < 0.001). The portion of the subchondral bone plate that was located farthest from the non-irradiated normal bone showed progressive damage and no sign of recovery at fifty-two weeks.

Relationship between channel and sorption properties in coordination polymers with interdigitated structures.

Porous coordination polymers constructed from Zn(2+) and isophthalate with linear bipyridyl-type ligands were synthesized. [Zn(ip)(bpb)](n) (CID-21; ip=isophthalate, bpb=1,4-bis(4-pyridyl)benzene), [Zn(ip)(bpt)](n) (CID-22; bpt=3,6-bis(4-pyridyl)-1,2,4,5-tetrazine), and [Zn(ip)(bpa)](n) (CID-23; bpa=1,4-bis(4-pyridyl)acetylene) all have interdigitated structures of layers and similar void volumes (≈27%). In these compounds, 1D bottleneck-type channels run along the perpendicular direction of the layer stacking and their properties are strongly dominated by the dipyridyl linker ligands. Because of the difference in packing of 2D layers, CID-21 and CID-22 have relatively rigid porous structures, whereas CID-23 has greater flexibility, as indicated by the results of powder X-ray diffraction studies. The micropores of CID-22 surrounded by tetrazine moieties adsorb polar molecules, such as methanol and water. The higher affinity of CID-22 for water than CID-21 is supported by a theoretical study. The 1D channel of CID-23 is wider than that of the other two compounds, which enables the incorporation of aromatic molecules. This is because the shape of the bpa linker ligand generates a wider pore diameter (8.6 Å). Only CID-23 can adsorb a benzene molecule and the isotherm of benzene has a gate-opening-type profile. This offers proof of the guest accommodation process through large structural transformation from a nonporous to a porous structure. The flexibility and restricted pore space of CID-23, at 298 K, allows only benzene, but not cyclohexane, to enter the channels. The porous structure exhibits clear selectivity for these similar guests. The incorporation of an elongated dipyridyl linker ligand in the 2D coordination layers provides a strategy for the design of microporous compounds with different flexibilities, microporous environments, and separation abilities.

Mulberry leaf ameliorates the expression profile of adipocytokines by inhibiting oxidative stress in white adipose tissue in db/db mice

Previous study showed that mulberry (Morus Alba L.) leaf (ML) ameliorates atherosclerosis in apoE(-/-) mice. Although the adipocytokine dysregulation is an important risk factor for atherosclerotic cardiovascular disease, the effect of ML on metabolic disorders related to adipocytokine dysregulation and inflammation has not been studied. Therefore, we studied the effects of ML in metabolic disorders and examined the mechanisms by which ML ameliorates metabolic disorders in db/db mice. We treated db/db mice with ML, pioglitazone, or both for 12 weeks and found that ML decreased blood glucose and plasma triglyceride. Co-treatment with ML and pioglitazone showed additive effects compared with pioglitazone. Moreover, their co-treatment attenuated the body weight increase observed under the pioglitazone treatment. ML treatment also increased the expression of adiponectin, and decreased the expression of TNF-alpha, MCP-1, and macrophage markers in white adipose tissue (WAT). Furthermore, ML decreased lipid peroxides and the expression of NADPH oxidase subunits in WAT and liver. Their co-treatment enhanced these effects. Thus, ML ameliorates adipocytokine dysregulation at least in part through inhibiting oxidative stress in WAT of db/db mice, and that ML may be a basis for a pharmaceutical for the treatment of the metabolic syndrome as well as reducing adverse effects of pioglitazone.

Incorporation of cortical bone autografts following intraoperative extracorporeal irradiation in rabbits

In an experimental study using 60 rabbits, a cortical bone segment of the unilateral tibial diaphysis was resected, irradiated extracorporeally, and reimplanted immediately as an autograft. The subsequent process of graft incorporation was examined over a 26-week period by roentgenography, histology, and histomorphometry. The irradiation doses were 0 (control), 50, 100, and 200 Gy. Roentgenographic and histologic examinations revealed that cortical bone autografts irradiated at 50 to 200 Gy were incorporated in the same manner as non-irradiated controls. By histomorphometry, the mean unresorbed fraction of the grafts at 6 weeks post-implantation was estimated to be 88.4% for the control group and 89.4% for the 200 Gy group. That of 26 weeks postimplantation was 17.5% for the control and 28.5%, 26.1%, and 27.8% for the 50, 100, and 200 Gy groups, respectively. Cumulative new bone formation showed a similar but inverse pattern of difference between the control and irradiated groups at 26 weeks. However, these differences were not statistically significant and were considered to be slight when compared with the overall similarity of the process. The total cross-sectional area of cortical bone at 26 weeks was similar to that of the contralateral side in all groups. In none of the adopted evaluation methods was any difference detected among the three irradiated groups with different doses. The results of this study suggest that extracorporeal irradiation of autografts at the specified doses impairs possible cellular contribution of the grafted marrow to the incorporation process, but does not interfere with the contribution of the matrices. The results provide useful information concerning the method of limb salvage surgery using intraoperatively-irradiated autografts.

Surgical treatment for symptomatic spinal adhesive arachnoiditis

This report concerns the outcome of 36 operations for spinal adhesive arachnoiditis (SAA) performed at Kyoto University Hospital since 1956; the follow-up period ranged from 1 to 25 years (average, 4 years 8 months). The original procedure Involved intradural neurolysis after extradural decompression, but more recently microlysis was performed. The percentage of cases in which good results were obtained by nonmicroscoplc lysis and microlysis was only 54.8%, however, when microlysis was followed by spondylodesis, the ratio increased to 80%, clearly showing the benefits of this new procedure. The authors therefore emphasize the value of spondylodesis following microlysis for symptomatic SAA.

Synthesis and Porous Properties of Chromium Azolate Porous Coordination Polymers

We developed a new route for synthesis of Cr-based porous coordination polymers (PCPs) with azole ligands and characterized the unique open structures by single-crystal X-ray studies and other spectroscopy techniques. Chromium-based PCPs have been prepared from azolate ligands 3,5-dimethyl-1H-pyrazole-4-carboxylic acid (H2dmcpz) and 1,4-di(1H-tetrazole-5yl)benzene (H2BDT) by solvothermal reactions under an Ar atmosphere. [Cr3O(Hdmcpz)6(DMF)3]⊃DMF (1⊃DMF) is a coordination compound that forms a hydrogen-bonded porous network. [Cr3O(HBDT)2(BDT)Cl3)]⊃DMF (2⊃DMF) possesses a new type of trinuclear chromium μ3-O unit cluster and the novel topology of a Cr-based PCP with 700 m(2) g(-1) of Brunauer-Emmett-Teller surface area. [Cr(BDT)(DEF)]⊃DEF (3⊃DEF) is structurally flexible and reactive to O2 molecules because of the unsaturated Cr(2+) centers. This is the first report of a Cr-based PCP/metal-organic framework with noncarboxylate ligands and characterization by single-crystal X-ray diffraction.

Fe2+-based layered porous coordination polymers and soft encapsulation of guests via redox activity

2-D layer type porous coordination polymers containing redox active Fe2+ centers were synthesized. One of the compounds [Fe(isophthalate)(4,4′-bipyridyl)] showed structural flexibility via guest adsorption, and we observed reversible Fe2+ and Fe3+ switching by iodine insertion. The composite showed electric conductivity.