Potential novel pharmacological therapies for myocardial remodelling

Left ventricular (LV) remodelling remains an important treatment target in patients after myocardial infarction (MI) and chronic heart failure (CHF). Accumulating evidence has supported the concept that beneficial effects of current pharmacological treatment strategies to improve the prognosis in these patients, such as angiotensin-converting enzyme (ACE) inhibition, angiotensin type 1 receptor blocker therapy, and beta-blocker therapy, are related, at least in part, to their effects on LV remodelling and dysfunction. However, despite modern reperfusion therapy after MI and optimized treatment of patients with CHF, LV remodelling is observed in a substantial proportion of patients and is associated with an adverse clinical outcome. These observations call for novel therapeutic strategies to prevent or even reverse cardiac remodelling. Recent insights from experimental studies have provided new targets for interventions to prevent or reverse LV remodelling, i.e. reduced endothelial nitric oxide (NO) synthase-derived NO availability, activation of cardiac and leukocyte-dependent oxidant stress pathways, inflammatory pathway activation, matrix-metalloproteinase activation, or stem cell transfer and delivery of novel paracrine factors. An important challenge in translating these observations from preclinical studies into clinical treatment strategies relates to the fact that clinical studies are designed on top of established pharmacological therapy, whereas most experimental studies have tested novel interventions without concomitant drug regimens such as ACE inhibitors or beta-blockers. Therefore, animal studies may overestimate the effect of potential novel treatment strategies on LV remodelling and dysfunction, since established pharmacological therapies may act, in part, via identical or similar signalling pathways. Nevertheless, preclinical studies provide essential information for identifying potential novel targets, and their potential drawbacks, and are required for developing novel clinical treatment strategies to prevent or reverse LV remodelling and dysfunctio

(+)-{1,2-Bis[(2R,5R)-2,5-diethyl-phospho-lan-1-yl]ethane- κ2 P,P′}(≠4-cyclo-octa-1,5-diene)rhodium(I) tetra-fluoridoborate

The title compound, [Rh(C8H12)(C18H 36P2)]BF4, exhibits a rhodium(I) complex cation with a bidentate bis-phosphine ligand and a bidentate 2, 2-coordinated cyclo-octa-1,5-diene ligand. The ligands form a slightly distorted square-planar coordination environment for the Rh(I) atom. An intra-molecular P-Rh-P bite angle of 83.91 (2)° is observed. The dihedral angle between the P - Rh - P and the X - Rh - X planes (X is the centroid of a double bond) is 14.0 (1)°. The BF4 anion is disordered over two positions in a 0.515 (7):0.485 (7) ratio

(+)-Chlorido[(1,2,3,4-η;P 2′)-2′- diphenylphosphanyl-2-diphenylphosphoryl-1,1′-binaphthyl]rhodium(I) methanol monosolvate

In the title complex, [RhCl(C 44H 32OP 2)]·CH 3OH, the Rh I ion is coordinated by a naphthyl group of a partially oxidized 2,2′-bis-(diphenylphosphanyl)-1, 1′-binaphthyl (BINAP) ligand in a 4 mode, one P atom of the diphenylphosphanyl group and one Cl atom. The P=O group does not interact with the Rh I ion but accepts an O - H⋯O hydrogen bond from the methanol solvent molecule

Characterization of the monocyte-specific esterase (MSE) gene

Carboxylic esterases are widely distributed in hematopoietic cells. Monocytes express the esterase isoenzyme (termed 'monocyte-specific esterase', MSE) that can be inhibited by NaF in the alpha-naphthyl acetate cytochemical staining. We examined the expression of MSE in normal cells and primary and cultured leukemia-lymphoma cells. The MSE protein was demonstrated by isoelectric focusing (IEF); MSE mRNA expression was investigated by Northern blotting and reverse transcriptase-polymerase chain reaction (RT-PCR). The following samples were positive for MSE protein and Northern mRNA expression: 20/24 monocytic, 4/32 myeloid, and 1/20 erythroid-megakaryocytic leukemia cell lines, but none of the 112 lymphoid leukemia or lymphoma cell lines; of the normal purified cell populations only the monocytes were positive whereas, T, B cells, and granulocytes were negative; of primary acute (myelo) monocytic leukemia cells (CD14-positive, FAB M4/M5 morphology) 14/20 were Northern mRNA and 11/14 IEF protein positive. RT-PCR revealed MSE expression in 29/49 Northern-negative lymphoid leukemia-lymphoma cell lines. The RT-PCR signals in monocytic cell lines were on average 50-fold stronger than the mostly weak trace expression in lymphoid specimens. On treatment with various biomodulators, only all-trans retinoic acid significantly upregulated MSE message and protein levels but could not induce new MSE expression in several leukemia cell lines; lipopolysaccharide and interferon-gamma increased MSE expression in normal monocytes. Analysis of DNA methylation with sensitive restriction enzymes showed no apparent regulation of gene expression by differential methylation; the MSE gene is evolutionarily conserved among mammalian species; the half-life of the human MSE transcripts was about 5-6 h. The extent of MSE expression varied greatly among different monocytic leukemia samples. However, the MSE overexpression in a significant number of specimens was not associated with gene amplification, gross structural rearrangements or point mutations within the cDNA region. Taken together, the results suggest that MSE expression is not absolutely specific for, but strongly associated with cells of the monocytic lineage; MSE is either not expressed at all or expressed at much lower levels in cells from other lineages. The biological significance, if any, of rare MSE messages in lymphoid cells detectable only by the hypersensitive RT-PCR remains unclear. Further studies on the regulation of this gene and on the physiological function of the enzyme will no doubt be informative with respect to its striking overexpression in some malignant cells and to a possible role in the pathobiology of monocytic leukemias

Crystal structure of (η4-norborna-2,5-dien)-(1,2-bis((R,R)-2,5-bis-(methoxymethyl)phospholanyl)benzene)rhodium(I) tetrafluoroborate, [Rh(C22H36O4P2)(C7H8)](BF4)

C29H44BF4O4P2Rh, monoclinic, P21 (no. 4), a= 10.119(2) Å, 6= 14.125(3) Å, c = 11.542(2) Å, β = 106.87(3)°, V = 1578.7 Å3, Z= 2, Rgt(F) = 0.034, wRref(F2) = 0.090, T = 200 K

Fluctuating-friction molecular motors

We show that the correlated stochastic fluctuation of the friction coefficient can give rise to long-range directional motion of a particle undergoing Brownian random walk in a constant periodic energy potential landscape. The occurrence of this motion requires the presence of two additional independent bodies interacting with the particle via friction and via the energy potential, respectively, which can move relative to each other. Such three-body system generalizes the classical Brownian ratchet mechanism, which requires only two interacting bodies. In particular, we describe a simple two-level model of fluctuating-friction molecular motor that can be solved analytically. In our previous work [M.K., L.M and D.P. 2000 J. Nonlinear Opt. Phys. Mater. vol. 9, 157] this model has been first applied to understanding the fundamental mechanism of the photoinduced reorientation of dye-doped liquid crystals. Applications of the same idea to other fields such as molecular biology and nanotechnology can however be envisioned. As an example, in this paper we work out a model of the actomyosin system based on the fluctuating-friction mechanism.Comment: to be published in J. Physics Condensed Matter (http://www.iop.org/Journals/JPhysCM

Resonant Photon-Assisted Tunneling Through a Double Quantum Dot: An Electron Pump From Spatial Rabi Oscillations

The time average of the fully nonlinear current through a double quantum dot, subject to an arbitrary combination of ac and dc voltages, is calculated exactly using the Keldysh nonequilibrium Green function technique. When driven on resonance, the system functions as an efficient electron pump due to Rabi oscillation between the dots. The pumping current is maximum when the coupling to the leads equals the Rabi frequency.Comment: 6 pages, REVTEX 3.0, 3 postscript figure

Molecular Motor of Double-Walled Carbon Nanotube Driven by Temperature Variation

An elegant formula for coordinates of carbon atoms in a unit cell of a single-walled nanotube (SWNT) is presented and a new molecular motor of double-walled carbon nanotube whose inner tube is a long (8,4) SWNT and outer tube a short (14,8) SWNT is constructed. The interaction between inner an outer tubes is analytically derived by summing the Lennard-Jones potentials between atoms in inner and outer tubes. It is proved that the molecular motor in a thermal bath exhibits a directional motion with the temperature variation of the bath.Comment: 9 pages, 4 figures, revtex