Two cyano-bridged Gd(III)−Cr(III) complexes Gd(urea)4(H2O)22Cr(CN)62 (1) and {Gd(capro)2(H2O)4Cr(CN)6·H2O} n (2) (capro represents caprolactam) have been synthesized and characterized structurally ...and magnetically. Complex 1 has a tetranuclear Gd2Cr2 square structure, in which two cis-CN- ligands of each Cr(CN)6 link two Gd(urea)4(H2O)2 groups and in turn, two Gd(urea)4(H2O)2 link two Cr(CN)6 in a cis fashion. Complex 2 is composed of 1D chains with alternating Gd(capro)2(H2O)4 and Cr(CN)6 moieties connected by the trans-CN- ligands of Cr(CN)6. The dehydration of 2 at 120 °C generates a new complex, Gd(capro)2(H2O)2Cr(CN)6 (2‘). Magnetic studies show the existence of antiferromagnetic Gd(III)−Cr(III) interaction in these complexes. On the basis of the tetranuclear model, the magnetic susceptibilities of 1 have been analyzed giving the intermetallic magnetic coupling constant of −0.36 cm-1. Complex 2‘ exhibits a ferrimagnetic order below 2.1 K. Interestingly, 2‘ is quite soluble in water, and slow evaporation of the solution gives the hydrated complex 2. Therefore, 2‘ is a soluble molecular magnet, and this significant behavior implies potential applications. Isothermal magnetization measurements of 2‘ and other cyano-bridged Gd(III)−Cr(III) molecular magnets show unusual field-induced metamagnetic behavior from the ferrimagnetic ground state to the ferromagnetic state. Field dependence of magnetization of the cyano-bridged Gd(III)−Cr(III) complexes shows unusual field-induced metamagnetic behavior from the ferrimagnetic ground state to the ferromagnetic state.
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We have used patch-clamp recording from cultured neurones, immunohistochemistry and gene deletion techniques to characterize the P2X receptors present in mouse otic ganglion neurones, and ...demonstrated the presence of similar receptors in rat neurones. All neurones from wild-type (WT) mice responded to ATP (EC
50 109 μM), but only 38% also responded to αβ-meATP (EC
50 39 μM). The response to αβ-meATP was blocked by TNP-ATP with an IC
50 of 38.6 nM. Lowering extracellular pH and co-application of Zn
2+ potentiated responses to ATP and αβ-meATP. In P2X
3
−/− mouse otic ganglion, all neurones tested responded to 100 μM ATP with a sustained current, but none responded to αβ-meATP. In P2X
2
−/− mice, no sustained currents were observed, but 36% of neurones responded to both ATP and αβ-meATP with transient currents. In P2X
2/P2X
3
Dbl−/− mice, no responses to ATP or αβ-meATP were detected, suggesting that other P2X subunits were not involved. In rat otic ganglia, 96% of neurones responded to both ATP and αβ-meATP with sustained currents, suggesting a greater proportion of neurones expressing P2X
2/3 receptors. The maximum response to αβ-meATP was 40–60% of that evoked by ATP in the same cell. Immunohistochemistry revealed staining for P2X
2 and P2X
3 subunits in WT mouse otic ganglion neurones, which was absent in knockout animals. In conclusion, we have shown for the first time that at least two distinct P2X receptors are present in mouse and rat otic neurones, probably homomeric P2X
2 and heteromeric P2X
2/3 receptors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
The outer membrane proteins (OMPs) of the marine aquatic animal pathogen Vibrio alginolyticus play an important role in the virulence of the bacterium and are potential candidates for vaccine ...development. In this study, the major 35.6 kDa OMP of V. alginolyticus was isolated by gel excision from the crude OMP fraction from V. alginolyticus. The sequence of the first 27 amino acid residues from the N-terminal end of the protein is ATV YKD GGT ELL VGG RVE FRG DFI GSD, which has high homology with OmpU proteins from other Vibrio spp. (92%). Lutjanus erythropterus were vaccinated with OmpU, and immunogenicity was confirmed by subsequent western blotting. Enzyme-linked immunosorbent assay (ELISA) analysis demonstrated that OmpU produced an observable antibody response in all sera of the vaccinated fish. L. erythropterus vaccinated with OmpU produced specific antibodies, and were highly resistant to infection with virulent V. alginolyticus. These results indicate that OmpU is an effective vaccine candidate against V. alginolyticus for L. erythropterus.
Potentiation of Insulin Signaling in Tissues of Zucker Obese Rats After Acute and Long-Term Treatment With PPARγ Agonists
Guoqiang Jiang 1 ,
Qing Dallas-Yang 1 ,
Zhihua Li 1 ,
Deborah Szalkowski 1 ,
...Franklin Liu 1 ,
Xiaolan Shen 2 ,
Margaret Wu 1 ,
Gaochao Zhou 1 ,
Thomas Doebber 1 ,
Joel Berger 1 ,
David E. Moller 1 and
Bei B. Zhang 1
1 Department of Molecular Endocrinology-Diabetes, Merck Research Laboratories, Rahway, New Jersey
2 Department of Comparative Medicine, Merck Research Laboratories, Rahway, New Jersey
Abstract
Thiazolidinediones (TZDs), agonists of peroxisome proliferator-activated receptor-γ (PPARγ), improve insulin sensitivity in
vivo, and the mechanism remains largely unknown. In this study, we showed that, in Zucker obese ( fa/fa ) rats, acute (1-day) treatment with both rosiglitazone (a TZD) and a non-TZD PPARγ agonist (nTZD) reduced plasma free fatty
acid and insulin levels and, concomitantly, potentiated insulin-stimulated Akt phosphorylation at threonine 308 (Akt-pT308)
in adipose and muscle tissues. A similar effect on Akt was observed in liver after a 7-day treatment. The increase in Akt-pT308
was correlated with an increase in Akt phosphorylation at serine 473 (Akt-pS473), tyrosine phosphorylation of insulin receptor
β subunit and insulin receptor substrate-1, and serine phosphorylation of glycogen synthase kinase-3α/β. The agonists appeared
to potentiate Akt1 phosphorylation in muscle and liver and both Akt1 and Akt2 in adipose. Finally, potentiation of insulin
signaling was also observed in isolated adipose tissue ex vivo and differentiated 3T3 L1 adipocytes in vitro, but not in rat
primary hepatocytes in vitro. These results suggest that 1 ) PPARγ agonists acutely potentiate insulin signaling in adipose and muscle tissues and such regulation may be physiologically
relevant to insulin sensitization in vivo; 2 ) the agonists directly target adipose tissues; and 3 ) the metabolic and signaling effects of the agonists are mediated by structurally distinct PPARγ agonists.
Footnotes
Address correspondence and reprint requests to Guoqiang Jiang, Molecular Endocrinology-Diabetes, RY80N-C31, Merck Research
Laboratories, P.O. Box 2000, Rahway, NJ 07065. E-mail: guoqiang_jiang{at}merck.com .
Received for publication 22 January 2002 and accepted in revised form 20 May 2002/
GSK, glycogen synthase kinase; IRS-1, insulin receptor substrate-1; PI3K, phosphatidylinositol 3-kinase; PIP3, phosphatidylinositol
3,4,5-trisphosphate; PPARγ, peroxisome proliferator-activated receptor-γ; nTZD, non-TZD PPARγ agonist; TZD, thiazolidinedione.
DIABETES
Two cyano-bridged Ni(II)−Fe(III) complexes {(H3O)Ni(H2L)2Fe(CN)62·Fe(CN)6·6H2O} n (1 ) and K(18-C-6)(H2O)2Ni(H2L)2Fe(CN)63·4(18-C-6)·20H2O (2 ) (L = ...3,10-bis(2-aminoethyl)-1,3,6,8,10,12-hexaazacyclotetradecane, 18-C-6 = 18-crown-6-ether) have been synthesized and characterized structurally and magnetically. Complex 1 has a zigzag one-dimensional structure, in which two trans-CN- ligands of each Fe(CN)63- link two trans-Ni(H2L)4+ groups, and in turn, each trans-Ni(H2L)4+ links two Fe(CN)63- in a trans fashion. Complex 2 is composed of cyano-bridged pentanuclear molecules with moieties connected by the trans-CN- ligands of Fe(CN)63-. Magnetic studies show the existence of ferromagnetic Ni(II)−Fe(III) interactions in both complexes. The intermetallic magnetic coupling constant of both complexes was analyzed by using an approximate model on the basis of the structural features.
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A series of cyano-bridged Ni(II)−Cr(I/III) complexes have been synthesized by the reactions of hexaazacyclic NiII complexes with Cr(CN)63- or Cr(CN)5(NO)3-. Using the tetravalent NiII complex ...Ni(H2L2)4+ (L2 = 3,10-bis(2-aminoethyl)-1,3,6,8,10,12-hexaazacyclotetradecane), one-dimensional chainlike complexes were produced and subject to magnetic studies, affording the intermetallic magnetic exchange constants of J 1 = +0.23 cm-1 and J 2 = +8.4 cm-1 for the complex Ni(H2L2)Cr(CN)5(NO)ClO4·5H2O (1) and of J = +5.9 cm-1 for the complex Ni(H2L2)4Cr(CN)65OH·15H2O (2). X-ray diffraction analysis shows that complex 1 has a zigzag chain structure, whereas complex 2 consists of a branched chain structure. Complex 2 exhibits antiferromagnetic ordering at 8.0 K (T N). When an octahedral NiII complex cis-NiL3(en)2+ (en = 1,2-ethylenediamine, L3 = 3,10-bis(2-hydroxyethyl)-1,3,5,8,10,12-hexaazacyclotetradecane) was used for the synthesis, the common 2D honeycomb-layered complex NiL33Cr(CN)5(NO)2·8H2O (3) was obtained, which has a T N value of 3.3 K. Below T N, a metamagnetic behavior was observed in complexes 2 and 3.
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Peroxisome-proliferator-activated receptor gamma agonists such as rosiglitazone, a thiazolidinedione, improve insulin sensitivity in vivo, but the underlying mechanism(s) remains unclear. ...Phosphorylation of IRS1 (insulin receptor substrate protein 1) on certain serine residues, including S307 and S612 in rodent IRS1 (equivalent to S312 and S616 in human IRS1), has been shown to play a negative role in insulin signalling. In the present study, we investigated whether rosiglitazone improves insulin sensitivity by decreasing IRS1 inhibitory serine phosphorylation. In HEK-293 (human embryonic kidney 293) cells stably expressing recombinant IRS1 and in 3T3L1 adipocytes, rosiglitazone attenuated PMA-induced IRS1 S307/S612 phosphorylation and decreased insulin-stimulated Akt phosphorylation. We observed increased IRS1 S307 phosphorylation and concomitant decrease in insulin signalling as measured by insulin-stimulated IRS1 tyrosine phosphorylation, and Akt threonine phosphorylation in adipose tissues of Zucker obese rats compared with lean control rats. Treatment with rosiglitazone at 30 mg/kg body weight for 24 and 48 h increased insulin signalling and decreased IRS1 S307 phosphorylation concomitantly. Whereas the 48 h treatment reversed hyper-phosphorylation (and activation) of both c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, the 24 h treatments only decreased hyper-phosphorylation of p38 mitogen-activated protein kinase. The treatment of the Zucker obese rats with rosiglitazone also reversed the high circulating levels of non-esterified fatty acids, which have been shown to be correlated with increased IRS1 serine phosphorylation in other animal models. Taken together, these results suggest that IRS1 inhibitory serine phosphorylation is a key component of insulin resistance and its reversal contributes to the insulin sensitizing effects by rosiglitazone.
X-ray repair cross-complementing groups 1 and 3 (XRCC1 and XRCC3) and xeroderma pigmentosum group D (XPD) are mainly involved in base excision repair, homologous recombination repair, and nucleotide ...excision repair of DNA repair pathways, respectively. Previous studies have demonstrated that their gene polymorphisms were associated with some cancer susceptibility.
To investigate the effect of XPD Lys751Gln, XRCC1 Arg399Gln, Arg194Trp, Arg280His, and XRCC3 Thr241Met polymorphisms on the risk of nasopharyngeal carcinoma (NPC), a population-based case-control study of 153 NPC patients and 168 healthy controls among Sichuan population was conducted.
Our results showed that XRCC1 codon 194 Trp allele was associated with an increased risk of NPC (odds ratio OR = 1.828, 95% confidence interval CI: 1.286-2.598), and XPD codon 751Gln allele was associated with a borderline decrease of NPC (OR = 0.600, 95% CI: 0.361-1.000); combination analysis showed that individuals with both putative genotypes of XPD codon 751 Lys/Lys and XRCC1 codon 194 Arg/Trp or Trp/Trp have a significantly elevated risk of NPC (OR = 2.708, 95% CI: 1.338-5.478).
The results indicated that XRCC1 codon 194 Trp allele and XPD codon 751 Lys allele may be contributing factors in the risk of NPC.
A series of 3,6-diaryl-2,5-dihydroxybenzoquinones were synthesized and evaluated for their abilities to selectively activate human insulin receptor tyrosine kinase (IRTK). ...2,5-Dihydroxy-6-(1-methylindol-3-yl)-3-phenyl-1,4-benzoquinone (2h) was identified as a potent, highly selective, and orally active small-molecule insulin receptor activator. It activated IRTK with an EC50 of 300 nM and did not induce the activation of closely related receptors (IGFIR, EGFR, and PDGFR) at concentrations up to 30 000 nM. Oral administration of the compound to hyperglycemic db/db mice (0.1−10 mg/kg/day) elicited substantial to nearly complete correction of hyperglycemia in a dose-dependent manner. In ob/ob mice, the compound (10 mg/kg) caused significant reduction in hyperinsulinemia. A structurally related compound 2c, inactive in IRTK assay, failed to affect blood glucose level in db/db mice at equivalent exposure levels. Results from additional studies with compound 2h, aimed at evaluating classical quinone-related phenomena, provided sufficient grounds for optimism to allow more extensive toxicologic evaluation.
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