Effects of vascular endothelial growth factor-C and -D on osteoclast differentiation and function in human peripheral blood mononuclear cells

ObjectiveThe purpose of this study was to clarify the interaction of vascular endothelial growth factors (VEGFs)-C and -D with cell surface foetal liver kinase-1 (Flk-1) and fms-like tyrosine kinase-4 (Flt-4) receptors in the induction and activity of osteoclasts in cultured human peripheral blood mononuclear cells (PBMCs).DesignPBMCs were cultured on chamber slides or on ivory discs for 2 or 3 weeks in the presence of macrophage-colony stimulating factor (M-CSF), VEGF-A, -C or -D, or placental growth factor (PlGF) with or without receptor activator of nuclear factor kappa-B ligand (RANKL). The number of osteoclasts in each group was counted and the area of ivory resorption was measured. In addition, osteoclast differentiation was further analysed under the same conditions, but with the addition of specific neutralizing antibodies against Flk-1 and Flt-4.ResultsRANKL was essential for the induction of osteoclasts in PBMCs. However, significant differences were found in the number of osteoclasts induced by VEGF-A, -C, -D or M-CSF with RANKL compared with control groups lacking or containing RANKL. Blocking of either Flk-1 or Flt-4 resulted in a reduction in the enhancement of osteoclast differentiation in PBMCs by VEGF-C or -D with RANKL. The osteoclasts induced by VEGF-A, -C, -D or M-CSF with RANKL formed significantly larger resorption lacunae than those formed by osteoclasts induced by RANKL alone.ConclusionsThis study showed that VEGF-C and -D play a role in the induction of osteoclast differentiation through both Flk-1 and Flt-4 receptors and influence the area of the ivory resorption in PBMCs.     

Benidipine reduces ischemia reperfusion-induced systemic oxidative stress through suppression of aldosterone production in mice

Aldosterone is implicated in the pathogenesis of several cardiovascular diseases, including ischemia reperfusion (I/R) and myocardial infarction, and also causes oxidative stress and inflammation in cardiovascular systems. Benidipine, a long-acting T- and L-type calcium channel blocker, reduces infarct size following myocardial I/R in rabbits. Benidipine also inhibits the production of aldosterone in vitro. However, the precise mechanism of this phenomenon in vivo remains unknown. We therefore evaluated whether benedipine has a beneficial role through the regulation of oxidative stress in myocardial I/R. C57BL/6J mice were subjected to 30?min of left ascending coronary I/R. Benidipine was administered orally at 3?mg?kg(-1) daily for 3 weeks without any changes in hemodynamic variables. Benidipine significantly reduced infarction size (13.4±2.5%) compared with controls (25.5±3.6%). Urinary 8-hydroxy-2' deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, increased significantly after I/R. I/R induced increases in 8-OHdG were significantly lower with benidipine. Local myocardial 8-OHdG was also elevated in I/R, but this augmentation was significantly suppressed with benidipine. The plasma aldosterone concentration (PAC) significantly increased 2 days after I/R and remained elevated at least 7 days after I/R. Treatment with benidipine significantly decreased I/R-induced elevation of the PAC. I/R-induced markers of fibrosis in hearts also reduced in benidipine. These results suggest that the administration of benidipine reduces myocardial infarct size as well as systemic oxidative stress after I/R. These phenomena are partially linked to reduced plasma aldosterone levels.     

Elucidation of the electron energy structure of TiO2(B) and anatase photocatalysts through analysis of electron trap density

A clear understanding of the electron energy structure of TiO₂(B)/anatase is needed to study the related catalytic reactions and design new composite photocatalysts. In this study, the electron energy structures of TiO₂(B) and anatase were estimated by analyzing the energy-resolved distribution of electron traps measured by reversed double-beam photoacoustic spectroscopy. In the mixture of TiO₂(B) and anatase, interfacial charge-transfer excitation from anatase to electron traps of TiO₂(B) was suggested. By analyzing this for TiO₂(B), the electron level with a relatively high density of states was found to be located ∼0.07 eV deeper than that for anatase. Furthermore, a similar electron energy structure was suggested for a composite photocatalyst having a mixed phase of TiO₂(B) and anatase.

The electron energy structures of TiO₂(B) and anatase were estimated by analyzing the energy-resolved distribution of electron traps.     

Age-related production of osteoclasts and the changes of serum levels of vascular endothelial growth factor (VEGF) and receptor activator for nuclear factor (NF)-κB ligand (RANKL) in osteopetrotic (op/op) mice

ObjectiveExpression of osteoclasts in osteopetrotic (op/op) mice is substantially reduced by the absence of functional macrophage colony-stimulating factor (M-CSF). However, it has been reported that osteoclasts do gradually appear in the bones of op/op mice and spontaneously correct the osteopetrosis.DesignAge-related production of osteoclasts and the changes of serum levels of vascular endothelial growth factor (VEGF) and receptor activator for nuclear factor (NF)-κB ligand (RANKL) in op/op mice were examined.ResultsThe number of femoral osteoclasts, and the serum levels of VEGF, both gradually increased in op/op mice after birth and reached a peak in 120- and 60-day-old mice, respectively. However, the serum levels of RANKL showed an inverse relationship to osteoclast number.ConclusionsThese findings suggest that the appearance of osteoclasts may be influenced by the serum levels of VEGF and that the serum levels of RANKL may be influenced by the appearance of osteoclasts.     

Toll‐like receptor 2‐mediated modulation of growth and functions of regulatory T cells by oral streptococci

This study was designed to determine whether oral streptococci modulate the growth and functions of regulatory T cells. Heat‐killed cells of wild‐type strains of Streptococcus gordonii and Streptococcus mutans induced the Toll‐like receptor 2 (TLR2) ‐mediated nuclear factor‐κB (NF‐κB) activation, but their lipoprotein‐deficient strains did not. Stimulation with these streptococci resulted in a significant increase in the frequency of CD4⁺ CD25⁺ Foxp3⁺ regulatory T cells in splenocytes derived from both TLR2^+/+ and TLR2^?/? mice, but the level of increase in TLR2^+/+ splenocytes was stronger than that in TLR2^?/? splenocytes. Both strains of S. gordonii enhanced the proliferation of CD4⁺ CD25⁺ Foxp3⁺ regulatory T cells isolated from TLR2^+/+ mice at the same level as those from TLR2^?/? mice in an interleukin‐2‐independent manner. However, wild‐type and lipoprotein‐deficient strains of both streptococci did not enhance the suppressive activity of the isolated regulatory T cells in vitro, but rather inhibited it. TLR ligands also inhibited the suppressive activity of the regulatory T cells. Inhibition of the suppressive activity was recovered by the addition of anti‐IL‐6 antibody. Pretreatment of antigen‐presenting cells with the NF‐κB inhibitor BAY11‐7082 enhanced the suppressive activity of the regulatory T cells. These results suggested that interleukin‐6 produced by antigen‐presenting cells inhibits the suppressive activity of the regulatory T cells. Wild‐type strain, but not lipoprotein‐deficient strain, of S. gordonii reduced the frequency of CD4⁺ CD25⁺ Foxp3⁺ regulatory T cells in the acute infection model, whereas both strains of S. gordonii increased it in the chronic infection model mice. Hence, this study suggests that oral streptococci are capable of modulating the growth and functions of regulatory T cells in vitro and in vivo.     

Evaluation of a newly proposed renal risk score for Japanese patients with ANCA-associated glomerulonephritis

Clinical and Experimental Nephrology - We determined the usefulness and prognostic ability of the renal risk score (RRS), proposed in Europe, for Japanese patients with antineutrophil cytoplasmic...     

Disruption of blood flow in the outflow graft is a valuable marker for detecting suction events in patients with continuous-flow left ventricular assist devices

Journal of Echocardiography -     

Progressive renal decline as the major feature of diabetic nephropathy in type 1 diabetes

Despite almost universal implementation of renoprotective therapies over the past 25 years, the risk of end-stage renal disease (ESRD) in type 1 diabetes (T1D) is not decreasing, and ESRD remains the major cause of excess morbidity and premature mortality [1]. Such a state of affairs prompts a call to action. In this review we re-evaluated the proteinuria-centric model of diabetic nephropathy and showed its deficiencies. On the basis of extensive studies that we have been conducting on the patients attending the Joslin Clinic, we propose that progressive renal decline, not abnormalities in urinary albumin excretion, should be considered as the major feature of disease processes leading to ESRD in T1D. The etiology of diabetic nephropathy should be reconsidered in light of our new findings so our perspective can be broadened regarding new therapeutic targets available for interrupting the progressive renal decline in T1D. Reduction in the loss of glomerular filtration rate, not reduction of albumin excretion rate, should become the measure for evaluating the effectiveness of new therapeutic interventions. We need new accurate methods for early diagnosis of patients at risk of progressive renal decline or, better still, for detecting in advance which patients will have rapid, moderate or minimal rate of progression to ESRD.