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Efficient, phosphine-directed ortho C-H borylation of arylphosphine derivatives was achieved using Ru catalysts for the first time. The reaction is applicable to various tertiary arylphosphine and arylphosphinite derivatives to give (o-borylaryl)phosphorus compounds in high yields. This reaction enables easy access to a variety of functionalized phosphine ligands and ambiphilic phosphine boronate compounds, thus realizing a new late-stage modification of phosphorus compounds., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome. Osteocalcin (OC), a bone formation biomarker, acts directly on β-cells and increases insulin secretion. We determined the effects of Ca deficiency during pregnancy and/or lactation on insulin resistance in offspring. Female Wistar rats consumed either a Ca-deficient or control diet ad libitum from three weeks preconception to 21 days postparturition. Pups were allowed to nurse their original mothers until weaning. The offspring were fed a control diet beginning at weaning and were killed on day 180. Serum carboxylated OC (Gla-OC) and undercarboxylated OC (Glu-OC), insulin and adipokines in offspring were measured. In males, mean levels of insulin, glucose, and HOMA-IR were higher in the Ca-deficient group than in the control group. In addition, ionized Ca (iCa) was inversely associated with serum Glu-OC and adiponectin in males. In females, mean levels of Glu-OC and Gla-OC in the Ca-deficient group were higher than in the control group. In all offspring, serum leptin levels were correlated with serum insulin levels, and inversely correlated with iCa. In conclusion, maternal Ca restriction during pregnancy and/or lactation influences postnatal offspring Ca metabolism and insulin resistance in a sex-specific manner.

Background: We assessed the association between socioeconomic status at residential area-level in the 24 wards of Osaka City, differentiated by indices of mean income-related deprivation, and inequalities in childhood obesity and emaciation., Methods: Data from representative samples of 26 474 schoolchildren (first and fifth grades of elementary school, and third grade of junior high school [i.e. ninth grade of elementary school]) in Osaka City taken from a somatometric check in spring 2016 were analyzed. The cross-sectional association between socioeconomic factors, that is, the census-based annual income of each ward, and the prevalence of childhood overweight/obesity and emaciation, was examined., Results: The prevalence of overweight/obesity in boys and girls in the first and fifth grades of elementary school and the third grade of junior high school was 3.98% and 4.53%, 10.18% and 8.69%, and 7.02% and 5.55%, respectively. The prevalence of emaciation in boys and girls in the first and fifth grades of elementary school, and the third grade of junior high school was 0.14% and 0.10%, 0.46% and 1.06% and 3.95% and 3.05%, respectively. Mean physical value, expressed as % degree of overweight, had a negative correlation with mean annual income of each ward in girls in the first and fifth grades of elementary school, girls in the third grade of junior high school and boys in the first grade of elementary school., Conclusions: Overweight/obesity at school age is greatly affected by poverty. Efforts should be made to prevent emaciation not only in girls, but also in boys, in junior high school., (© 2018 Japan Pediatric Society.)

The transcription factor Hes family basic helix-loop-helix transcription factor 1 (Hes1) is a downstream effector of Notch signaling and plays a crucial role in orchestrating developmental processes during the embryonic stage. However, its aberrant signaling in adulthood is linked to the pathogenesis of cancer. In the present study, we report the discovery of small organic molecules (JI051 and JI130) that impair the ability of Hes1 to repress transcription. Hes1 interacts with the transcriptional corepressor transducing-like enhancer of split 1 (TLE1) via an interaction domain comprising two tryptophan residues, prompting us to search a chemical library of 1,800 small molecules enriched for indole-like π-electron-rich pharmacophores for a compound that blocks Hes1-mediated transcriptional repression. This screening identified a lead compound whose extensive chemical modification to improve potency yielded JI051, which inhibited HEK293 cell proliferation with an EC 50 of 0.3 μm Unexpectedly, using immunomagnetic isolation and nanoscale LC-MS/MS, we found that JI051 does not bind TLE1 but instead interacts with prohibitin 2 (PHB2), a cancer-associated protein chaperone. We also found that JI051 stabilizes PHB2's interaction with Hes1 outside the nucleus, inducing G 2 /M cell-cycle arrest. Of note, JI051 dose-dependently reduced cell growth of the human pancreatic cancer cell line MIA PaCa-2, and JI130 treatment significantly reduced tumor volume in a murine pancreatic tumor xenograft model. These results suggest a previously unrecognized role for PHB2 in the regulation of Hes1 and may inform potential strategies for managing pancreatic cancer., (© 2018 Perron et al.)

Efficient synthesis and catalysis of a series of palladium complexes having a group 13 metalloligand (Al, Ga, In) are reported utilizing 6,6″-bis(phosphino)terpyridine as a new scaffold for Pd-E bonds (E = Al, Ga, In). Systematic investigation revealed unique characteristics of the Al-metalloligand in both structure and reactivity, which exhibited the highest catalytic activity for hydrosilylation of CO 2 ever reported (TOF = 19 300 h -1 ). This study demonstrated fine-tuning of catalyst activity by the precisely designed metalloligand is a promising approach for new catalyst development in synthetic organometallic chemistry.

Asymmetric dimethylarginine (ADMA) is a nonselective nitric oxide (NO) synthase inhibitor associated with cardiovascular and metabolic disorders. NO regulates placental blood flow, which plays an important role in fetal growth. Many epidemiological studies have disclosed that restricted fetal growth is associated with an increased risk of insulin resistance in adult life. We studied the relationship between ADMA in cord blood and birth size. Nine small for gestational age (SGA) and 32 appropriate for gestational age (AGA) infants were studied. Their cord plasma ADMA, insulin, insulin-like growth factor-1 (IGF-1), and adipocytokine levels were determined using enzyme-linked immunosorbent assays. The relationship between birth weight and ADMA levels followed a U-shaped curve rather than inverse linear associations expected over a full range of birth weight distribution. ADMA positively correlated with birth weight in the AGA group (p<0.001, R=0.590), and inversely correlated with birth weight in the SGA group (p<0.05, R=-0.741). ADMA inversely correlated with adiponectin (p<0.05, R=-0.289) and quantitative insulin sensitivity check index (QUICKI) (p<0.05, R=-0.294) in all subjects, and did not correlate with nitrogen oxides (NO X ). Insulin, IGF-1, leptin, adiponectin and QUICKI were lower in the SGA than the AGA group. Plasma ADMA levels in cord blood may be a marker of fetal growth and insulin resistance.

A PGeP-pincer palladium-catalyzed hydrocarboxylation of styrenes to obtain pharmaceutically important α-arylpropionic acid derivatives was achieved using a formate salt as both a reductant and a CO 2 source. The reaction was also applicable to vinylsulfone and acrylates. Isotope labeling experiments demonstrated that a CO 2 -recycling mechanism is operative through generation and reaction of a benzylpalladium complex as a carbon nucleophile. This protocol has realized a mild and atom economical CO 2 -fixation reaction without the necessity of using strong metallic reductants.

A visible light driven catalytic cycle for hydrocarboxylation of alkenes with CO 2 was established using a combination of a Rh(i) complex as a carboxylation catalyst and [Ru(bpy) 3 ] 2+ (bpy = 2,2'- bipyridyl) as a photoredox catalyst. Two key steps, the generation of Rh(i) hydride species and nucleophilic addition of π-benzyl Rh(i) species to CO 2 , were found to be mediated by light.

A detailed mechanism of the Rh(i)-catalyzed carboxylation of simple aromatic compounds via C-H bond activation was investigated. Kinetic studies with model compounds of the postulated key intermediates revealed that 14-electron complexes, RhMe(dcype) and RhPh(dcype), participated in the C-H bond activation step and the carboxylation step, respectively. Interestingly, the undesired carboxylation of RhMe(dcype) to give acetic acid was found to be much faster than the desired C-H bond activation reaction under stoichiometric conditions, however, the C-H bond activation reaction could occur under catalytic conditions. Careful controlled experiments revealed that C-H bond activation using RhMe(dcype) became competitive with its direct carboxylation under the condition that the concentration of CO 2 in the liquid phase was rather low. This factor could be controlled to some extent by mechanical factors such as the stirring rate and the shape of the reaction vessel. The resting state of the rhodium species under catalytic conditions was found to be [RhCl(dcype)] 2 , and the proposed intermediates such as RhMe(dcype) and Rh(OBz)(dcype) were readily converted to the most stable state, [RhCl(dcype)] 2 , via transmetallation with [Al]-Cl species, thus preventing the decomposition of the active catalytic species.

Background: Osteocalcin (OC) is a bone-specific protein secreted by osteoblasts and often used as a bone formation biomarker. OC undergoes post-translational carboxylation to yield carboxylated osteocalcin (Gla-OC) and undercarboxylated osteocalcin (uc-OC) molecules. The aim of this study was to explore the association between bone and glucose metabolism by evaluating OC, ionized cations, and markers of glucose metabolism in children with obesity and type 2 diabetes mellitus (DM2)., Methods: The subjects were nine children with DM2 [six males, three females; age 15.7±4.1 years; duration of disease 3.2±1.2 years], 18 children with simple obesity [12 males, six females; age 12.6±4.1 years], and 12 controls [eight males, four females; age 12.3±3.2 years]. Serum Gla-OC and uc-OC levels were determined using an enzyme-linked immunosorbent assay (ELISA)., Results: Patients with DM2 (0.65±0.46 ng/mL), but not with obesity (1.11±0.55 ng/mL), had lower uc-OC levels than controls (1.25±0.49 ng/mL). Serum uc-OC was negatively correlated with mean serum glucose levels (r=-0.447, p=0.013) and hemoglobin A1c (HbA1c) (r=-0.455, p=0.012) in all subjects. Serum Gla-OC was correlated with serum alkaline phosphatase (r=0.601, p<0.001) and inorganic phosphorus (r=0.686, p<0.001), yet negatively correlated with age (r=-0.383, p=0.030). Mean serum ionized magnesium was lower in DM2 subjects than in controls. Mean serum ionized calcium was higher in obese subjects than in controls. In all subjects, mean serum ionized magnesium was negatively correlated with mean serum glucose levels., Conclusions: Osteoblast-derived protein OC, especially uc-OC, may have a role in the pathophysiology of diabetes by being associated with blood glucose homeostasis.

Background: Prenatal malnutrition can affect the phenotype of offspring by altering epigenetic regulation. Calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome., Aims: We hypothesized that a Ca-deficient diet during pregnancy would alter insulin resistance and secretion in more than 1 generation of offspring., Methods: Female Wistar rats consumed either a Ca-deficient or a control diet ad libitum from 3 weeks before conception to 21 days after parturition and were mated with control males. Randomly selected F1 and F2 females were mated with males of each generation on postnatal day 70. The F1 and F2 dams were fed a control diet ad libitum during pregnancy and lactation. All offspring were fed a control diet starting at the time of weaning and were sacrificed on day 180., Results: HOMA-β% decreased in F1 through F3, and levels in F2 and F3 males and females were significantly lower than in controls. The mean levels of insulin and HOMA-IR were higher in F1 males but lower in F3 males than in control males. The HOMA-IR did not differ between any of the female offspring and controls., Conclusions: Maternal Ca restriction during pregnancy and/or lactation influences insulin secretion in 3 generations of offspring., (© 2017 S. Karger AG, Basel.)

An efficient, regioselective synthesis of fluorine-substituted arylboronic esters was achieved through fluorine-controlled C-H borylation of arenes with diboron catalyzed by a PSiN-platinum complex. The promising utility of the PSiN-platinum catalyst and its unique regioselectivity were demonstrated for the first time, which would complement the well-developed Ir-catalyzed C-H borylation.

TRPA1 is a member of the transient receptor potential (TRP) cation channel family that is expressed primarily on sensory neurons. This chemosensor is activated through covalent modification of multiple cysteine residues with a wide range of reactive compounds including allyl isothiocyanate (AITC), a spicy component of wasabi. The present study reports on potent and selective agonists of TRPA1, discovered through screening 1657 electrophilic molecules. In an effort to validate the mode of action of hit molecules, we noted a new TRPA1-selective agonist, JT010 (molecule 1), which opens the TRPA1 channel by covalently and site-selectively binding to Cys621 (EC50 = 0.65 nM). The results suggest that a single modification of Cys621 is sufficient to open the TRPA1 channel. The TRPA1-selective probe described herein might be useful for further mechanistic studies of TRPA1 activation.

Magnesium deficiency during pregnancy as a result of insufficient or low intake of magnesium is common in developing and developed countries. Previous reports have shown that intracellular magnesium of cord blood platelets is lower among small for gestational age (SGA) groups than that of appropriate for gestational age (AGA) groups, suggesting that intrauterine magnesium deficiency may result in SGA. Additionally, the risk of adult-onset diseases such as insulin resistance syndrome is greater among children whose mothers were malnourished during pregnancy, and who consequently had a low birth weight. In a number of animal models, poor nutrition during pregnancy leads to offspring that exhibit pathophysiological changes similar to human diseases. The offspring of pregnant rats fed a magensium restricted diet have developed hypermethylation in the hepatic 11β-hydroxysteroid dehydrogenase-2 promoter. These findings indicate that maternal magnesium deficiencies during pregnancy influence regulation of non-imprinted genes by altering the epigenetic regulation of gene expression, thereby inducing different metabolic phenotypes. Magnesium deficiency during pregnancy may be responsible for not only maternal and fetal nutritional problems, but also lifelong consequences that affect the offspring throughout their life. Epidemiological, clinical, and basic research on the effects of magnesium deficiency now indicates underlying mechanisms, especially epigenetic processes., Competing Interests: Conflict of Interest: All authors declare no conflict of interest in this article.

GVHD is a crucial mortality factor in allogeneic bone marrow transplantation (ABMT). In this paper, we show that dehydroxymethylepoxyquinomicin (DHMEQ), a novel inhibitor of nuclear factor-κB, suppresses GVHD, resulting in an improved mortality rate in a mouse ABMT model. Bone marrow cells from C57BL/6 mice (B6 mice) were transplanted into lethally irradiated BALB/c mice. Two weeks later, spleen cells from B6 mice were transplanted into the irradiated BALB/c mice. From one week after the injection of spleen cells, when the mice started to show GVHD, the mice were also injected intraperitoneally daily with DHMEQ or vehicle only (DMSO) for 4 weeks. By 80 days after the ABMT, 6/14 of the vehicle-injected mice (43%) had died because of GVHD, whereas all DHMEQ-injected mice survived this observation period and developed milder GVHD than the vehicle-injected mice. When regulatory T cells were reduced by the injection of anti-folate receptor 4 (FR4) antibody, the effects of DHMEQ were reduced. These findings suggest that administration of DHMEQ could become a new strategy for preventing fatalities from GVHD., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Use of formate salts as a hydride as well as a CO2 source was achieved in a PGeP-palladium complex-catalyzed hydrocarboxylation of allenes through a highly efficient decarboxylation-carboxylation process. This reaction proceeds under mild conditions and provides an alternative strategy for utilizing formate salts as a C1 source.

Asymmetric dimethylarginine (ADMA) is a nonselective nitric oxide (NO) synthase inhibitor associated with cardiovascular and metabolic disorders. In several prospective and cross-sectional studies, ADMA has evolved as a marker of cardiovascular risk. However, there is limited information on this serum marker in young people, particularly in those with obesity, type 1 diabetes (DM1) and type 2 diabetes (DM2). We investigated ADMA concentrations in children and adolescents with hyperglycemia as compared with healthy age- and sex-matched individuals. The subjects were 21 simple obesity [male 13, female 8; aged 11.7±4.3 years], 18 with DM1 [male 4, female 14; aged 12.9±4.2 years, duration of disease 3.4±2.1 years], 10 with DM2 [male 5, female 5; aged 13.9±3.4 years, duration of disease 2.8±1.4 years] and 21 controls [male 12, female 9; aged 11.1±2.7 years]. ADMA levels were analyzed in a cross-sectional study. Concentrations of serum ADMA were determined using an enzyme-linked immunosorbent assay. Circulating levels of ADMA were significantly lower in subjects with DM1, DM2 or obesity. In all subjects, ADMA levels were inversely correlated with glycated hemoglobin A1c concentrations (r=-0.401, p=0.0003) and serum glucose levels (r=-0.341, p=0.0023). Low circulating ADMA levels are directly associated with glucose levels, suggesting that ADMA production is suppressed in childhood in order to compensate and protect vasculopathy due to hyperglycemia.

Direct carboxylation of simple arenes under atmospheric pressure of CO2 is achieved through a rhodium-catalyzed C-H bond activation without the assistance of a directing group. Various arenes such as benzene, toluene, xylene, electron-rich or electron-deficient benzene derivatives, and heteroaromatics are directly carboxylated with high TONs.

One of the major problems encountered in cell transplantation is the low level of survival of transplanted cells due to detachment-induced apoptosis, called anoikis. The present study reports on the chemical synthesis and biological evaluation of water-soluble molecules that protect suspended cells from anoikis. The synthetic molecules bind to and induce clusters of integrins and heparan-sulfate-bound syndecans, two classes of receptors that are important for extracellular matrix-mediated cell survival. Molecular biological analysis indicates that such molecules prolong the survival of suspended NIH3T3 cells, at least in part, by promoting clustering of syndecan-4 and integrin β1 on the cell surface, leading to the activation of small GTPase Rac-1 and Akt. In vivo experiments using animal disease models demonstrated the ability of the molecules to improve cell engraftment. The cluster-inducing molecules may provide a starting point for the design of new synthetic tools for cell-based therapy., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The mechanism and origin of the facile β-hydrogen elimination and hydrometalation of a palladium complex bearing a phenylene-bridged PSiP pincer ligand are clarified. Experimental and theoretical studies demonstrate a new mechanism for β-hydrogen elimination and hydrometalation mediated by a silyl ligand at palladium, which enables direct interconversion between an ethylpalladium(II) complex and an η(2) -(Si-H)palladium(0) complex without formation of a square-planar palladium(II) hydride intermediate. The flexibility of the PSiP pincer ligand enables it to act as an efficient scaffold to deliver the hydrogen atom as a hydride ligand., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Prenatal malnutrition can affect the phenotype of offspring by changing epigenetic regulation of specific genes. Several lines of evidence demonstrate that calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome. We hypothesized that pregnant female rats fed a Ca-deficient diet would have offspring with altered hepatic glucocorticoid-related gene expression and that lactation would modify these alterations., Methodology: We determined the effects of Ca deficiency during pregnancy and/or lactation on hepatic 11β-hydroxysteroid dehydrogenase-1 (Hsd11b1) expression in offspring. Female Wistar rats consumed either a Ca-deficient (D: 0.008% Ca) or control (C: 0.90% Ca) diet ad libitum from 3 weeks preconception to 21 days postparturition. On postnatal day 1, pups were cross-fostered to the same or opposite dams and divided into the following four groups: CC, DD, CD, and DC (first letter: original mother's diet; second letter: nursing mother's diet). All offspring were fed a control diet beginning at weaning (day 21) and were killed on day 200 ± 7. Serum insulin and adipokines in offspring were measured using ELISA kits., Principal Findings: In males, mean levels of insulin, glucose, and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) were higher in the DD and DC groups than in the CC group. We found no difference in HOMA-IR between the CC and CD groups in either males or females. Expression of Hsd11b1 was lower in male DD rats than in CC rats. Hsd11b1 expression in male offspring nursed by cross-fostered dams was higher than that in those nursed by dams fed the same diet; CC vs. CD and DD vs. DC. In females, Hsd11b1 expression in DC rats was higher than that in CC rats., Conclusions: These findings indicated that maternal Ca restriction during pregnancy and/or lactation alters postnatal growth, Hsd11b1 expression, and insulin resistance in a sex-specific manner.

Prenatal undernutrition affects offspring phenotype via changes in the epigenetic regulation of specific genes. We hypothesized that pregnant females that were fed a calcium (Ca)-deficient diet would have offspring with altered hepatic glucocorticoid-related gene expression and altered epigenetic gene regulation. Female Wistar rats ate either a Ca-deficient or control diet from 3 weeks before conception to 21 days after parturition. Pups were allowed to nurse from their original mothers and then euthanized on day 21. Methylation of individual cytosine-guanine dinucleotides in the phosphoenolpyruvate carboxykinase (Pck1), peroxisome proliferator-activated receptor α (Ppara), glucocorticoid receptor (Nr3c1), 11β-hydroxysteroid dehydrogenase-1 (Hsd11b1), and 11β-hydroxysteroid dehydrogenase-2 (Hsd11b2) promoters was measured in liver tissue using pyrosequencing. For each gene, quantitative real-time polymerase chain reaction was used to assess mRNA levels in liver tissue. Overall Hsd11b1 methylation was lower in the Ca-deficient group than in the control group; however, overall methylation of each other gene did not differ between groups. Serum corticosterone levels in male pups from Ca-deficient dams were higher than those in control pups. Expression of Pck1 and Nr3c1 was lower in the Ca-deficient group than in the control group. A Ca-deficient diet for a dam during gestation and early nursing may alter glucocorticoid metabolism and lead to higher intracellular glucocorticoid concentrations in the hepatic cells of her offspring; moreover, this abnormal glucocorticoid metabolism may induce the metabolic complications that are associated with Ca deficiency. These findings indicated that prenatal nutrition affected glucocorticoid metabolism in offspring in part by affecting the epigenome of offspring., (© 2013.)

Pd-catalyzed direct carboxylation of alkenyl C-H bonds with carbon dioxide was realized for the first time. Treatment of 2-hydroxystyrenes and a catalytic amount of Pd(OAc)2 with Cs2CO3 under atmospheric pressure of CO2 afforded corresponding coumarins in good yield. Furthermore, isolation of the key alkenylpalladium intermediate via C-H bond cleavage was achieved. The reaction was proposed to undergo reversible nucleophilic addition of the alkenylpalladium intermediate to CO2.

CDC45, which plays a role in eukaryotic DNA replication, is a member of the CMG (CDC45/MCM2-7/GINS) complex that is thought to function as a replicative DNA helicase. However, the biochemical properties of CDC45 are not fully understood. We systematically examined the interactions of human CDC45 with MCM2-7, GINS and other replication proteins by immunoprecipitation. We found that CDC45 can directly interact with all MCM2-7 proteins; with PSF2, PSF3 and SLD5 in GINS subunits; and with replication protein A2 (RPA2), AND-1 and topoisomerase 2-binding protein 1. These results are consistent with the notion that CDC45 plays a role in progression of DNA replication forks. Experiments using antibodies against CDC45 show that the level of CDC45 recovered from the Triton-insoluble chromatin-containing fraction is peaked at middle of S phase in synchronized HeLa cells. However, incubation of the Triton-insoluble fraction with nucleases resulted in recovery of less than half the amount of CDC45 in the nuclease-sensitive fraction; this result is in contrast with RPA1 and proliferating cell nuclear antigen distribution. These results indicate that a considerable portion of CDC45 localizes in a region other than the DNA replication forks in nuclei or it localizes on the replication forks but it is not fractionated with the fork proteins owing to its tight association with presumably nuclear scaffolds.

Two reversible σ-bond metathesis pathways for B-B bond activation to give borylpalladium complexes are demonstrated in the reaction of η(2)-(Si-H)Pd(0) complexes with B(2)pin(2). These two pathways are connected by fluxional behavior of the Si-H bond and can be efficiently controlled by the appropriate choice of phosphine ligand, enabling the selective synthesis of two types of five-coordinate borylpalladium complexes.

Background/aims: Minimal-change nephrotic syndrome (MCNS) is a kidney disease defined by selective proteinuria and hypoalbuminemia occurring in the absence of cellular glomerular infiltrates or immunoglobulin deposits. Recent observations suggest that nuclear factor κB (NF-κB) of podocyte is strongly associated with the development of proteinuria in MCNS. Dehydroxymethylepoxyquinomicin (DHMEQ) is a novel NF-κB inhibitor that potently inhibits DNA-binding activity of NF-κB, resulting in several therapeutic effects in various pathological conditions. We conducted this study to ask whether DHMEQ may ameliorate the nephrosis in mice induced by puromycin aminonucleoside (PAN), which is considered to be an animal model for MCNS., Methods/results: Pretreatment with DHMEQ alleviated the proteinuria and reversed the serum abnormalities in mice nephrosis induced by 450 mg/kg of PAN. Increased serum interleukin-6 level in PAN-induced nephrosis was also completely suppressed by DHMEQ. Electron microscopic analyses of glo-meruli indicated that DHMEQ can inhibit the podocyte foot process effacement via blocking the translocation of podocyte NF-κB from cytoplasm to nucleus., Conclusions: These results suggest that DHMEQ can be a potential therapeutic agent for MCNS., (Copyright © 2013 S. Karger AG, Basel.)

Background. Although angiotensin II (Ang II) has inflammatory effects, little is known about its role in polymorphonuclear leucocytes (PMLs). To elucidate the role of Ang II in PMLs ROS production, we examined hydrogen peroxide (H2O2), one of the ROS, and NO production in AT1a receptor knockout (AT1KO) mice. Methods and Results. PMLs were analyzed from Ang II type 1a receptor knockout mice (AT1KO) and C57BL/6 wild type mice. Using flow cytometry, we studied hydrogen peroxide (H2O2) production from PMLs after Staphylococcus aureus phagocytosis or phorbol myristate acetate (PMA) stimulation. Nitric oxide (NO) production in the AT1KO was low at basal and after phagocytosis. In the AT1KO, basal H2O2 production was low. After PMA or phagocytosis stimulation, however, H2O2 production was comparable to wild type mice. Next we studied the H2O2 production in C57BL/6 mice exposed to Ang II or saline. H2O2 production stimulated by PMA or phagocytosis did not differ between the two groups. Conclusions. AT1a pathway is not necessary for PMLs H2O2 production but for NO production. There was a compensatory pathway for H2O2 production other than the AT1a receptor.

An efficient protocol for the generation of acylcobalt species from alkyne-[Co(2)(CO)(6)] complexes is realized by treatment of the complexes with AcOH and pyridine. The generated acylcobalt species smoothly underwent addition reactions with various alkenes to give alkyl alkenyl ketones in good yield., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Many epidemiological studies have reported the link between magnesium deficiency and metabolic syndrome. We examined whether magnesium deficiency in rats induces changes in glucocorticoid metabolism. Twelve-week-old, female Wistar rats were weaned onto a very low-magnesium diet or a control diet for two weeks. Quantitative real-time PCR was used to assess mRNA for 11β hydroxysteroid dehydrogenase-1 (11β-HSD1), 11β-HSD2, phosphoenolpyruvate carboxykinase (PEPCK), peroxisome proliferator-activated receptor α (PPARα), and glucocorticoid receptor in the liver. Concentrations of adiponectin, leptin, corticosterone, insulin and asymmetric dimethylarginine (ADMA) in fasting serum were determined using a rat-specific enzyme-linked immunosorbent assay. After two weeks, no differences in serum glucose, leptin, corticosterone, or adiponectin levels were observed between the groups. Magnesium-deficient rats showed higher HOMA-IR, insulin, ionized calcium, ADMA levels and diastolic blood pressure. There were no significant differences in hepatic mRNA expression levels of GR, 11β-HSD1, 11β-HSD2, or PPARα between the groups. We observed lower expression of hepatic PEPCK mRNA, in the magnesium-deficient rats, thus suggesting a possible compensatory mechanism to diminish glycogenesis. A low-magnesium diet alters glucocorticoid metabolism, which leads to endothelial damage. Higher ADMA induces hypertension and insulin resistance. Hyperinsulinemia induces hepatic down-regulation of PEPCK, and is possibly a key mechanism inducing the metabolic complications of magnesium deficiency.

Dehydroxymethylepoxyquinomicin (DHMEQ), a new nuclear factor (NF)-κB inhibitor, has several beneficial effects, including the suppression of tumour growth and anti-inflammatory effects. DHMEQ can also suppress the production of tumour necrosis factor (TNF)-α induced by lipopolysaccharide (LPS) in vitro. In the present study, we examine the effects of DHMEQ on TNF-α production in vivo and on the survival of mice injected with LPS. When DHMEQ was injected into mice 2 h before LPS injection, the survival of the LPS-injected mice was prolonged. When DHMEQ was injected twice (2 h before LPS injection and the day after LPS injection), all the mice were rescued. The injection of DHMEQ 1 h after LPS injection and the day after LPS injection also resulted in the rescue of all mice. The serum levels of TNF-α in the mice that received both LPS and DHMEQ were suppressed compared to the mice that received only LPS. These results suggest that DHMEQ can be utilized for the prevention and treatment of endotoxin shock., (© 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.)

Reactions of bis(o-(diphenylphosphino)phenyl)methylsilane with M(PPh(3))(4) (M = Ni, Pd, Pt) were investigated. When M = Ni or Pd, synthesis and isolation of η(2)-(Si-H) complexes of mononuclear Ni(0) and Pd(0) were achieved for the first time as frozen intermediates for oxidative addition of the Si-H bond. Structural analysis by X-ray and NMR spectroscopy disclosed that their η(2)-(Si-H) structures were maintained in both solid and solution states and coordination of the Si-H bond to the metal center was relatively weak. On the other hand, reaction with a platinum(0) complex afforded two kinds of pentacoordinate silyl platinum(II) hydride complexes having a PSiP-pincer ligand, which underwent unique thermal isomerization from a square-pyramidal cis-H-Pt-Si to a trigonal-bipyramidal trans-H-Pt-Si isomer. Mechanistic investigations revealed that this isomerization proceeded via an intramolecular rearrangement process probably through a turnstile rotation., (This journal is © The Royal Society of Chemistry 2011)

The efficient synthesis of various diborylalkenes such as 1,1-, trans-1,2-, and cyclic 1,2-diborylalkenes from alkenes and diboron was achieved for the first time. Selective preparation of di- and monoborylalkenes was also realized by the appropriate choice of reaction conditions. The reaction was found to proceed via a new mechanism of dehydrogenative borylation through a monoborylpalladium complex bearing an anionic PSiP-pincer ligand as a key intermediate, which realized the efficient borylation without sacrificial hydroboration or hydrogenation of the alkene.

Prenatal under-nutrition involves changes in the epigenetic regulation of specific genes. Maternal magnesium (Mg) deficiency affects maternal glucocorticoid metabolism, but the mechanisms underlying changes in glucocorticoid homeostasis of offspring are not well understood. In this study, we investigated the effects of feeding pregnant rats a Mg-deficient diet (0.003% magnesium) on the methylation of cytosine-guanine (CpG) dinucleotides in hepatic glucocorticoid genes of neonatal offspring, compared with controls (0.082% magnesium). Methylation of CpG dinucleotides in the peroxisome proliferator-activated receptor α (Ppara), glucocorticoid receptor (Nr3c1) and 11β-hydroxysteroid dehydrogenase-2 (Hsd11b2) promoters in the liver were measured by pyrosequencing. Quantitative real-time PCR was used to assess hepatic mRNA expression of each gene. Mean methylation of the Hsd11b2 promoter in the Mg-deficient offspring (33.2%) was higher than in controls (10.4%). This was due to a specific increase at CpG dinucleotides 1 (20.0% vs. control 10.1%), 2 (58.8% vs. 17.0%), 3 (29.7% vs. 6.2%) and 4 (38.7% vs. 8.8%) (p < 0.05). Ppara and Nr3c1 methylation status and expression did not differ between the groups. No significant difference was noted between male and female pups, which were equally represented. Therefore, a Mg-deficient diet alters glucocorticoid metabolism, predicting higher hepatic intracellular glucocorticoid concentrations, and is possibly a key mechanism that induces the metabolic complications of Mg deficiency.

An efficient one-to-one coupling reaction of atmospheric pressure carbon dioxide with 1,3-dienes is realized for the first time through PSiP-pincer type palladium-catalyzed hydrocarboxylation. The reaction is applicable to various 1,3-dienes including easily available chemical feedstock such as 1,3-butadiene and isoprene. This protocol affords a highly useful method for the synthesis of β,γ-unsaturated carboxylic acid derivatives from CO(2).

Rh-catalyzed direct carboxylation of unactivated aryl C-H bond under atmospheric pressure of carbon dioxide was realized via chelation-assisted C-H activation for the first time. Variously substituted and functionalized 2-arylpyridines and 1-arylpyrazoles underwent the carboxylation in the presence of the rhodium catalyst and a stoichiometric methylating reagent, AlMe(2)(OMe), to give carboxylated products in good yields. The catalysis is proposed to consist of methylrhodium(I) species as the key intermediate, which undergoes C-H activation to afford rhodium(III), followed by reductive elimination of methane to give nucleophilic arylrhodium(I). This approach demonstrates promising application of C-H bond activation strategy in the field of carbon dioxide fixation.

Magnesium deficiency in pregnancy frequently occurs because of inadequate or low intake of magnesium. Magnesium deficiency during pregnancy can induce not only maternal and fetal nutritional problems, but also consequences that might last in offspring throughout life. Many epidemiological studies have disclosed that small for gestational age (SGA) is associated with an increased risk of insulin resistance in adult life. We reported that intracellular magnesium of cord blood platelets is lower in SGA groups than that in appropriate for gestational age groups, suggesting that intrauterine magnesium deficiency may result in SGA. Taken together, intrauterine magnesium deficiency in the fetus may lead to or at least program insulin resistance after birth. In this review, we propose that intrauterine magnesium deficiency may induce metabolic syndrome in later life. We discuss the potential contribution of aberrant magnesium regulation to SGA and to the pathogenesis of metabolic syndrome.

Background: Many epidemiologic studies have reported a link between calcium (Ca) deficiency and metabolic syndrome. In this study, we examine Ca deficiency in rats and whether changes in glucocorticoid metabolism are induced., Methods: Twelve-week-old female Wistar rats were weaned onto a very-low-Ca diet (low-Ca group) or a control diet (control group) for 2 weeks. Quantitative real-time PCR was used to assess mRNA for 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1), 11β-HSD2, phosphoenolpyruvate carboxykinase, peroxisome proliferator-activated receptor-α, and glucocorticoid receptor in the liver. Concentrations of adiponectin, leptin, corticosterone, intact parathyroid hormone, asymmetrical dimethylarginine and insulin in fasting serum were determined using a rat-specific enzyme-linked immunosorbent assay. Glucose concentrations were measured using a glucose oxidase system. Serum ionized Ca levels were measured with an automatic ion-selective electrode analyzer. Serum nitrite/nitrate levels were measured using a colorimetric assay kit., Results: After 2 weeks, no differences in serum glucose, corticosterone or insulin levels were observed. The low-Ca group rats showed higher homeostasis model assessment insulin resistance, lower adiponectin and higher intact parathyroid hormone levels. Serum nitrite/nitrate and asymmetrical dimethylarginine were significantly higher in the low-Ca group than in the control group. The expression of hepatic 11β-HSD1 mRNA was upregulated, while hepatic phosphoenolpyruvate carboxykinase expression was downregulated in the low-Ca group. Glucocorticoid receptor, peroxisome proliferator-activated receptor-α and 11β-HSD2 expression levels showed a similar tendency., Conclusion: A low-Ca diet alters glucocorticoid metabolism, which leads to hepatic upregulation of 11β-HSD1, and is possibly a key mechanism inducing the metabolic complications of Ca deficiency., (Copyright © 2011 S. Karger AG, Basel.)

RPA, which consisted of three subunits (RPA1, 2 and 3), plays essential roles in DNA transactions. At the DNA replication forks, RPA binds to single-stranded DNA region to stabilize the structure and to assemble other replication proteins. Interactions between RPA and several replication proteins have been reported but the analysis is not comprehensive. We systematically performed the qualitative analysis to identify RPA interaction partners to understand the protein-protein interaction at the replication forks. We expressed in insect cells the three subunits of human RPA, together with one replication protein, which is present at the forks under normal conditions and/or under the replication stress conditions, to examine the interaction. Among 30 proteins examined in total, it was found that at least 14 proteins interacted with RPA. RPA interacted with MCM3-7, MCM-BP and CDC45 proteins among the proteins that play roles in the initiation and the elongation of the DNA replication. RPA bound with TIPIN, CLASPIN and RAD17, which are involved in the DNA replication checkpoint functions. RPA also bound with cyclin-dependent kinases and an amino-terminal fragment of Rb protein that negatively regulates DNA replication. These results suggest that RPA interacts with the specific proteins among those that play roles in the regulation of the replication fork progression.

Introduction: Magnesium is a critical cofactor in numerous enzymatic reactions. Diabetic patients and obese subjects are often reported to have intracellular magnesium ([Mg(2+)](i)) deficiency. We studied the change of [Mg(2+)](i) in obese children and children with type 2 diabetes mellitus (DM2) after educational intervention or treatment., Methods: A total of 25 subjects were included: 13 with simple obesity (10 male, 3 female; mean age 16±8 years, intervention period 1.0±0.6 years), 12 with DM2 (8 male, 4 female; mean age 15±3 years, medication period 1.1±0.7 years), and 16 controls (8 male, 8 female; mean age 17±7 years). By using a fluorescent probe, mag-fura-2, we examined the basal and insulin-stimulated [Mg(2+)](i) of platelets in the blood. Plasma leptin, ghrelin, adiponectin, and resistin levels were determined with the use of enzyme-linked immunosorbent assay (ELISA)., Results: Mean basal [Mg(2+)](i) was lower in the obesity (160±65 μmol/L) and DM2 groups (140±30 μmol/L) compared with the control group (330±28 μmol/L). The elevated [Mg(2+)](i) after insulin stimulation was also lower in these two groups (420±140 μmol/L, and 330±70 μmol/L, respectively) compared with the control group (690±270 μmol/L). In the DM2 group, the basal [Mg(2+)](i) was significantly increased after treatment, while in the obesity group, stimulated [Mg(2+)](i) was increased after intervention., Conclusion: Platelet [Mg(2+)](i) increased after intervention in children with obesity or DM2.

Purpose: The aim of our study was to determine the safety and usefulness of capsule endoscopy (CE) in pediatric patients., Methods: We prospectively examined children (aged 10-18 years) with suspected small bowel disease and recorded capsule transit times, findings, and complications., Results: We performed 19 CE examinations in 12 patients (median age 11.8 years; range 10-18 years). One of the two patients with obscure gastrointestinal bleeding (OGIB), a 14-year-old girl whose OGIB occurred after cord-blood transplantation due to leukemia, was diagnosed with thrombotic microangiopathy. Repeated CE allowed visualization of real-time mucosal changes, such as the improvement of ulcers and bleeding, and newly emerged lymphangiectasia, without causing the patient physical and mental stress. This information facilitated both subsequent evaluation of the clinical course and determination of the appropriate treatment strategy. In the second patient with chronic OGIB, a 10-year-old girl, the detection of severe ileal stenoses by capsule retention led to the diagnosis of non-specific multiple ulcers of the small intestine. After ileal resection, repeated CE detected the recurrence of multiple ulcers and enabled the optimal treatment strategy to be applied. CE confirmed small bowel involvement in a patient with unresponsive Crohn's disease (CD) and excluded CD in all five patients with suspected CD. Similarly, CE confirmed the absence of small bowel involvement in three of the four patients with recurrent abdominal pain, although one patient had nodular lymphoid hyperplasia., Conclusions: Based on our results, CE is a valuable tool in the differential diagnoses of small bowel diseases, and repeated examination can provide real-time information that will enable evaluation of the clinical course in pediatric patients.

The WHIM syndrome is a rare immunological disorder characterized by warts, hypogammaglobulinemia, infections, and myelokathexis. We hypothesized that immunological or genetic mechanisms may link WHIM syndrome and type 1 diabetes. We report that the young girl with WHIM syndrome developed diabetes and transient hypothyroidism. A nonsense mutation (C-->T) truncating the CXC chemokine receptor 4 (CXCR4) C-terminal cytoplasmic tail domain occurred at nucleotide position 1000(R334X) of the CXCR4 gene in one allele of the patient was identified, and the person was diagnosed as having WHIM syndrome. Recent observation suggested that the CXCR4, a G-protein-coupled receptor with a unique ligand, CXCL12, might be involved in the pathogenesis for type 1 diabetes. Taken into consideration the concurrent prevalence of the two disorders and the speculated common pathogenesis associated with the CXCR4, our patient may enable us to understand the genetic damage related to accelerated apoptosis.

Although calcium is an essential mineral for bones, little is known about its effect on inflammatory or oxidative regulation. We hypothesize that calcium plays the role in the production of reactive oxygen species (ROS) and nitric oxide (NO) from polymorphonuclear leukocytes (PMNs). Our purpose was to determine the relationship of NO and ROS produced from PMNs, taking into account the role of calcium and magnesium in diet. Using flow cytometry, we compared ROS and NO production from PMNs after the stimulation by S. aureus or phorbol myristate acetate (PMA). PMNs taken from three murine groups were analyzed: C57BL/6 wild-type mice, low-calcium diet (Low Ca Group), or low-magnesium diet fed for 2 weeks. ROS production at baseline in the Low Ca Group was highest among the groups. PMA- and S. aureus-stimulated ROS production was also highest in the Low Ca Group. On the contrary, NO production at baseline in the Low Ca Group was lowest among the groups, while there was no significant difference among the groups in S. aureus-stimulated PMNs. A low-calcium diet increases ROS production from stimulated PMNs and decreases NO production at baseline. This finding suggests that calcium regulates ROS production from PMNs.

Background: Neutrophils of patients with Down syndrome (DS) are known to have numerous abnormalities associated with diminished resistance to infection. The intracellular calcium (Ca(2+)i) acts as a second messenger and regulates diverse functions in many cell types. The purpose of the present study was to compare the intracellular calcium concentration ([Ca(2+)]i) at baseline and stimulated conditions in DS patients and in normal subjects to investigate [Ca(2+)]i regulation in neutrophils., Methods: The study group consisted of 27 subjects with DS (age, 8.6 +/- 4.6 years) and 14 healthy subjects (age, 12.0 +/- 3.9 years). Using a fluorescent probe, fura-2, the baseline levels and changes in [Ca(2+)]i were examined after stimulation of neutrophils with N-formyl-methionyl-leucyl-phenylalanine (fMLP)., Results: At baseline, the [Ca(2+)]i of neutrophils from DS subjects was significantly higher than that of the controls (70.6 +/- 28.0 nmol/L vs 44.4 +/- 16.0 nmol/L, P < 0.01). The absolute [Ca(2+)]i after addition of fMLP in the DS subjects was also significantly higher than that of the control group (250 +/- 91 nmol/L vs 167 +/- 60 nmol/L, respectively: P < 0.01). The neutrophils from the DS subjects had a consistently and significantly prolonged response to fMLP as compared to the neutrophils of control subjects., Conclusions: The higher [Ca(2+)]i and the prolonged response of [Ca(2+)]i to fMLP appear to be phenotypic traits of neutrophils in subjects with DS. This suggests intrinsic cellular defects in DS.

Tridentate PSiP pincer-type palladium complex-catalyzed hydrocarboxylation of allenes under carbon dioxide to give synthetically useful beta,gamma-unsaturated carboxylic acids was developed. This novel CO2-fixation reaction is thought to proceed through the catalytic generation of sigma-allyl palladium species via hydropalladation of allenes, followed by its regioselective nucleophilic addition to CO2 in the presence of an appropriate reducing agent. The reaction is successfully applied to various allenes bearing functional groups such as ester, carbamate, ketone, and alkene, showing high synthetic utility of this protocol.