219 research outputs found
Dexamethasone induces apoptosis in pulmonary arterial smooth muscle cells
BACKGROUND: Dexamethasone suppressed inflammation and haemodynamic changes in an animal model of pulmonary arterial hypertension (PAH). A major target for dexamethasone actions is NF-κB, which is activated in pulmonary vascular cells and perivascular inflammatory cells in PAH. Reverse remodelling is an important concept in PAH disease therapy, and further to its anti-proliferative effects, we sought to explore whether dexamethasone augments pulmonary arterial smooth muscle cell (PASMC) apoptosis. METHODS: Analysis of apoptosis markers (caspase 3, in-situ DNA fragmentation) and NF-κB (p65 and phospho-IKK-α/β) activation was performed on lung tissue from rats with monocrotaline (MCT)-induced pulmonary hypertension (PH), before and after day 14–28 treatment with dexamethasone (5 mg/kg/day). PASMC were cultured from this rat PH model and from normal human lung following lung cancer surgery. Following stimulation with TNF-α (10 ng/ml), the effects of dexamethasone (10(−8)–10(−6) M) and IKK2 (NF-κB) inhibition (AS602868, 0–3 μM (0-3×10(−6) M) on IL-6 and CXCL8 release and apoptosis was determined by ELISA and by Hoechst staining. NF-κB activation was measured by TransAm assay. RESULTS: Dexamethasone treatment of rats with MCT-induced PH in vivo led to PASMC apoptosis as displayed by increased caspase 3 expression and DNA fragmentation. A similar effect was seen in vitro using TNF-α-simulated human and rat PASMC following both dexamethasone and IKK2 inhibition. Increased apoptosis was associated with a reduction in NF-κB activation and in IL-6 and CXCL8 release from PASMC. CONCLUSIONS: Dexamethasone exerted reverse-remodelling effects by augmenting apoptosis and reversing inflammation in PASMC possibly via inhibition of NF-κB. Future PAH therapies may involve targeting these important inflammatory pathways
The Effect of 2,4-Dichlorophenoxyacetic Acid on Phosphorylase, Phosphatase, Amylase, Catalase, and Peroxidase Activity in Wheat
BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production.
BACKGROUND: Bone morphogenetic proteins (BMPs) and their receptors, such as bone morphogenetic protein receptor (BMPR) II, have been implicated in a wide variety of disorders including pulmonary arterial hypertension (PAH). Similarly, endothelin-1 (ET-1), a mitogen and vasoconstrictor, is upregulated in PAH and endothelin receptor antagonists are used in its treatment. We sought to determine whether there is crosstalk between BMP signalling and the ET-1 axis in human pulmonary artery endothelial cells (HPAECs), possible mechanisms involved in such crosstalk and functional consequences thereof. METHODOLOGY/PRINCIPAL FINDING: Using western blot, real time RT-PCR, ELISA and small RNA interference methods we provide evidence that in HPAECs BMP-9, but not BMP-2, -4 and -6 significantly stimulated ET-1 release under physiological concentrations. This release is mediated by both Smad1 and p38 MAPK and is independent of the canonical Smad4 pathway. Moreover, knocking down the ALK1 receptor or BMPR II attenuates BMP-9 stimulated ET-1 release, whilst causing a significant increase in prepro ET-1 mRNA transcription and mature peptide release. Finally, BMP-9 induced ET-1 release is involved in both inhibition of endothelial cell migration and promotion of tubule formation. CONCLUSIONS/SIGNIFICANCE: Although our data does not support an important role for BMP-9 as a source of increased endothelial ET-1 production seen in human PAH, BMP-9 stimulated ET-1 production is likely to be important in angiogenesis and vascular stability. However, increased ET-1 production by endothelial cells as a consequence of BMPR II dysfunction may be clinically relevant in the pathogenesis of PAH
X-ray induced photocurrent characteristics of CVD diamond detectors with different carbon electrodes
Mesons in the massive Schwinger model on the light-cone
We investigate mesons in the bosonized massive Schwinger model in the
light-front Tamm-Dancoff approximation in the strong coupling region. We
confirm that the three-meson bound state has a few percent fermion six-body
component in the strong coupling region when expressed in terms of fermion
variables, consistent with our previous calculations. We also discuss some
qualitative features of the three-meson bound state based on the information
about the wave function.Comment: 19 pages, RevTex, included 6 figures which are compressed and
uuencode
Nonperturbative Light-Front QCD
In this work the determination of low-energy bound states in Quantum
Chromodynamics is recast so that it is linked to a weak-coupling problem. This
allows one to approach the solution with the same techniques which solve
Quantum Electrodynamics: namely, a combination of weak-coupling diagrams and
many-body quantum mechanics. The key to eliminating necessarily nonperturbative
effects is the use of a bare Hamiltonian in which quarks and gluons have
nonzero constituent masses rather than the zero masses of the current picture.
The use of constituent masses cuts off the growth of the running coupling
constant and makes it possible that the running coupling never leaves the
perturbative domain. For stabilization purposes an artificial potential is
added to the Hamiltonian, but with a coefficient that vanishes at the physical
value of the coupling constant. The weak-coupling approach potentially
reconciles the simplicity of the Constituent Quark Model with the complexities
of Quantum Chromodynamics. The penalty for achieving this perturbative picture
is the necessity of formulating the dynamics of QCD in light-front coordinates
and of dealing with the complexities of renormalization which such a
formulation entails. We describe the renormalization process first using a
qualitative phase space cell analysis, and we then set up a precise similarity
renormalization scheme with cutoffs on constituent momenta and exhibit
calculations to second order. We outline further computations that remain to be
carried out. There is an initial nonperturbative but nonrelativistic
calculation of the hadronic masses that determines the artificial potential,
with binding energies required to be fourth order in the coupling as in QED.
Next there is a calculation of the leading radiative corrections to these
masses, which requires our renormalization program. Then the real struggle of
finding the right extensions to perturbation theory to study the
strong-coupling behavior of bound states can begin.Comment: 56 pages (REVTEX), Report OSU-NT-94-28. (figures not included,
available via anaonymous ftp from pacific.mps.ohio-state.edu in subdirectory
pub/infolight/qcd
Pulmonary Hypertension: Intensification and Personalization of Combination Rx (PHoenix): A phase IV randomized trial for the evaluation of dose-response and clinical efficacy of riociguat and selexipag using implanted technologies
\ua9 2024 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.Approved therapies for the treatment of patients with pulmonary arterial hypertension (PAH) mediate pulmonary vascular vasodilatation by targeting distinct biological pathways. International guidelines recommend that patients with an inadequate response to dual therapy with a phosphodiesterase type-5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), are recommended to either intensify oral therapy by adding a selective prostacyclin receptor (IP) agonist (selexipag), or switching from PDE5i to a soluble guanylate-cyclase stimulator (sGCS; riociguat). The clinical equipoise between these therapeutic choices provides the opportunity for evaluation of individualized therapeutic effects. Traditionally, invasive/hospital-based investigations are required to comprehensively assess disease severity and demonstrate treatment benefits. Regulatory-approved, minimally invasive monitors enable equivalent measurements to be obtained while patients are at home. In this 2
7 2 randomized crossover trial, patients with PAH established on guideline-recommended dual therapy and implanted with CardioMEMSâ„¢ (a wireless pulmonary artery sensor) and ConfirmRxâ„¢ (an insertable cardiac rhythm monitor), will receive ERA + sGCS, or PDEi + ERA + IP agonist. The study will evaluate clinical efficacy via established clinical investigations and remote monitoring technologies, with remote data relayed through regulatory-approved online clinical portals. The primary aim will be the change in right ventricular systolic volume measured by magnetic resonance imaging (MRI) from baseline to maximal tolerated dose with each therapy. Using data from MRI and other outcomes, including hemodynamics, physical activity, physiological measurements, quality of life, and side effect reporting, we will determine whether remote technology facilitates early evaluation of clinical efficacy, and investigate intra-patient efficacy of the two treatment approaches
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