The Ruthenium Nitrosyl Moiety in Clusters: Trinuclear Linear μ-Hydroxido Magnesium(II)-Diruthenium(II), μ3-Oxido Trinuclear Diiron(III)–Ruthenium(II), and Tetranuclear μ4-Oxido Trigallium(III)-Ruthenium(II) Complexes

The ruthenium nitrosyl moiety, {RuNO}6, is important as a potential releasing agent of nitric oxide and is of inherent interest in coordination chemistry. Typically, {RuNO}6 is found in mononuclear complexes. Herein we describe the synthesis and characterization of several multimetal cluster complexes that contain this unit. Specifically, the heterotrinuclear μ3-oxido clusters [Fe2RuCl4(μ3-O)(μ-OMe)(μ-pz)2(NO)(Hpz)2] (6) and [Fe2RuCl3(μ3-O)(μ-OMe)(μ-pz)3(MeOH)(NO)(Hpz)][Fe2RuCl3(μ3-O)(μ-OMe)(μ-pz)3(DMF)(NO)(Hpz)] (7·MeOH·2H2O) and the heterotetranuclear μ4-oxido complex [Ga3RuCl3(μ4-O)(μ-OMe)3(μ-pz)4(NO)] (8) were prepared from trans-[Ru(OH)(NO)(Hpz)4]Cl2 (5), which itself was prepared via acidic hydrolysis of the linear heterotrinuclear complex {[Ru(μ-OH)(μ-pz)2(pz)(NO)(Hpz)]2Mg} (4). Complex 4 was synthesized from the mononuclear Ru complexes (H2pz)[trans-RuCl4(Hpz)2] (1), trans-[RuCl2(Hpz)4]Cl (2), and trans-[RuCl2(Hpz)4] (3). The new compounds 4-8 were all characterized by elemental analysis, ESI mass spectrometry, IR, UV-vis, and 1H NMR spectroscopy, and single-crystal X-ray diffraction, with complexes 6 and 7 being characterized also by temperature-dependent magnetic susceptibility measurements and Mössbauer spectroscopy. Magnetometry indicated a strong antiferromagnetic interaction between paramagnetic centers in 6 and 7. The ability of 4 and 6-8 to form linkage isomers and release NO upon irradiation in the solid state was investigated by IR spectroscopy. A theoretical investigation of the electronic structure of 6 by DFT and ab initio CASSCF/NEVPT2 calculations indicated a redox-noninnocent behavior of the NO ancillary ligand in 6, which was also manifested in TD-DFT calculations of its electronic absorption spectrum. The electronic structure of 6 was also studied by an X-ray charge density analysis

Impaired dynamin 2 function leads to increased AP-1 transcriptional activity through the JNK/c-Jun pathway

Activation of AP-1 transcription factors, composed of the Jun and Fos proteins, regulates cellular fates, such as proliferation, differentiation or apoptosis. Among other stimuli, the AP-1 pathway can be initiated by extracellular ligands, such as growth factors or cytokines, which undergo internalization in complex with their receptors. Endocytosis has been implicated in the regulation of several signaling pathways; however its possible impact on AP-1 signaling remains unknown. Here we show that inhibition of dynamin 2 (Dyn2), a major regulator of endocytic internalization, strongly stimulates the AP-1 pathway. Specifically, expression of a dominant-negative Dyn2 K44A mutant increases the total levels of c-Jun, its phosphorylation on Ser63/73 and transcription of AP-1 target genes. Interestingly, DNM2 mutations implicated in human neurological disorders exhibit similar effects on AP-1 signaling. Mechanistically, Dyn2 K44A induces AP-1 by increasing phosphorylation of several receptor tyrosine kinases. Their activation is required to initiate a Src- and JNK-dependent signaling cascade converging on c-Jun and stimulating expression of AP-1 target genes. Cumulatively, our data uncover a link between the Dyn2 function and JNK signaling which leads to AP-1 induction

The ruthenium nitrosyl moiety in clusters: Trinuclear linear μ-hydroxido magnesium(II)-diruthenium(II), μ3μ_3-oxido trinuclear diiron(III)–ruthenium(II), and tetranuclear μ4μ_4-oxido trigallium(III)-ruthenium(II) complexes

International audienceThe ruthenium nitrosyl moiety, {RuNO}$^6$, is important as a potential releasing agent of nitric oxide and is of inherent interest in coordination chemistry. Typically, {RuNO}$^6$ is found in mononuclear complexes. Herein we describe the synthesis and characterization of several multimetal cluster complexes that contain this unit. Specifically, the heterotrinuclear $\mu_3$-oxido clusters [Fe$_2$RuCl$_4$($\mu_3$-O)($\mu$-OMe)($\mu$-pz)$_2$(NO)(Hpz)$_2$] and [Fe$_2$RuCl$_3$($\mu_3$-O)($\mu$-OMe)($\mu$-pz)$_3$(MeOH)(NO)(Hpz)][ Fe$_2$RuCl$_3$($\mu_3$)-O)($\mu$-OMe)($\mu$-pz)(3)(DMF)(NO)(Hpz)] ((7·MeOH·2H$_2$O) and the heterotetranuclear $\mu_4$)-oxido complex [Ga$_3$RuCl$_3$($\mu_4$-O)($\mu$-OMe)(3)($\mu$-pz)$_4$(NO)] were prepared from trans-[Ru(OH)(NO)(Hpz)$_4$]Cl-$_2$, which itself was prepared via acidic hydrolysis of the linear heterotrinuclear complex {[Ru($\mu$-OH)($\mu$-pz)$_2$(pz)(NO)(Hpz)]$_2$Mg}. Complex 4 was synthesized from the mononuclear Ru complexes (H$_2$pz)[trans-RuCl$_4$(Hpz)$_2$], $trans$-[RuCl$_2$(Hpz)$_4$]Cl, and trans-[RuCl$_2$(Hpz)$_4$]. The new compounds 4-8 were all characterized by elemental analysis, ESI mass spectrometry, IR, UV-vis, and $^1$H NMR spectroscopy, and single-crystal X-ray diffraction, with complexes 6 and 7 being characterized also by temperature-dependent magnetic susceptibility measurements and Mossbauer spectroscopy. Magnetometry indicated a strong antiferromagnetic interaction between paramagnetic centers in 6 and 7. The ability of 4 and 6-8 to form linkage isomers and release NO upon irradiation in the solid state was investigated by IR spectroscopy. A theoretical investigation of the electronic structure of 6 by DFT and ab initio CASSCF/NEVPT2 calculations indicated a redox-noninnocent behavior of the NO ancillary ligand in 6, which was also manifested in TD-DFT calculations of its electronic absorption spectr$um. The electronic structure of 6 was also studied by an X-ray charge density analysis

ESCRT proteins restrict constitutive NF-kappa B signaling by trafficking cytokine receptors

Because signaling mediated by the transcription factor nuclear factor kappa B (NF-kappa B) is initiated by ligands and receptors that can undergo internalization, we investigated how endocytic trafficking regulated this key physiological pathway. We depleted all of the ESCRT (endosomal sorting complexes required for transport) subunits, which mediate receptor trafficking and degradation, and found that the components Tsg101, Vps28, UBAP1, and CHMP4B were essential to restrict constitutiveNF-kappa B signaling in human embryonic kidney 293 cells. In the absence of exogenous cytokines, depletion of these proteins led to the activation of both canonical and noncanonical NF-kappa B signaling, as well as the induction of NF-kappa B-dependent transcriptional responses in cultured human cells, zebrafish embryos, and fat bodies in flies. These effects depended on cytokine receptors, such as the lymphotoxin beta receptor (LT beta R) and tumor necrosis factor receptor 1 (TNFR1). Upon depletion of ESCRT subunits, both receptors became concentrated on and signaled from endosomes. Endosomal accumulation of LT beta R induced its ligand-independent oligomerization and signaling through the adaptors TNFR-associated factor 2 (TRAF2) and TRAF3. These data suggest that ESCRTs constitutively control the distribution of cytokine receptors in their ligand-free state to restrict their signaling, which may represent a general mechanism to prevent spurious activation of NF-kappa B

Functional polymorphism of the renalase gene is associated with cardiac hypertrophy in female patients with aortic stenosis

<div><p>Renalase decreases circulating catecholamines concentration and is important in maintaining primary cellular metabolism. Renalase acts through the plasma membrane calcium ATPase 4b in the heart, which affects pressure overload but not exercise induced heart hypertrophy. The aim of this study was to test the association between a functional polymorphism Glu37Asp (rs2296545) of the renalase gene and left ventricular hypertrophy in a large cohort of patients with aortic stenosis. The study group consisted of 657 patients with aortic stenosis referred for aortic valve replacement. Preoperative echocardiographic assessment was performed to obtain cardiac phenotypes. Generalized-linear models were implemented to analyze data using crude or full model adjusted for selected clinical factors. In females, the Asp37 variant of the Glu37Asp polymorphism was associated with higher left ventricular mass (p = 0.0021 and p = 0.055 crude and full model respectively), intraventricular septal thickness (p = 0.0003 and p = 0.0143) and posterior wall thickness (p = 0.0005 and p = 0.0219) all indexed to body surface area, as well as relative wall thickness (p = 0.001 and p = 0.0097). No significant associations were found among the male patients. In conclusion, we have found the association of the renalase Glu37Asp polymorphism with left ventricle hypertrophy in large group of females with aortic stenosis. The Glu37Asp polymorphism causes not only amino-acid substitution in FAD binding domain but may also change binding affinity of the hypoxia- and hypertrophy-related transcription factors and influence renalase gene expression. Our data suggest that renalase might play a role in hypertrophic response to pressure overload, but the exact mechanism requires further investigation.</p></div

Echocardiographic parameters of left ventricular hypertrophy classified by genotype at rs2296545 and gender.

<p>BSA, body surface area; IVST, intraventricular septal thickness in diastole; LVEDD, left ventricular end-diastolic diameter; LVM, left ventricular mass; PWT, posterior wall thickness in diastole; RWT, relative wall thickness; *P < 0.05, **P < 0.005, ***P < 0.0005; crude model; generalized linear models. (A) Association between rs2296545 and natural logarithm of LVM/BSA in the additive genetic model. (B) Association between rs2296545 and natural logarithm of RWT in the dominant genetic model. (C) Natural logarithm of LVEDD/BSA based on rs2296545 in the additive genetic model. (D) Association between rs2296545 and natural logarithm of (IVST+PWT)/BSA in the additive genetic model.</p

Association between functional SNP in the RNLS gene and natural logarithm of LVM/BSA.

<p>Association between functional SNP in the RNLS gene and natural logarithm of LVM/BSA.</p