Reversal of Pulmonary Hypertension in a Human-Like Model: Therapeutic Targeting of Endothelial DHFR.

Background: Pulmonary hypertension (PH) is a progressive disorder characterized by remodeling of the pulmonary vasculature and elevated mean pulmonary arterial pressure, resulting in right heart failure.

Methods: Here, we show that direct targeting of the endothelium to uncouple eNOS (endothelial nitric oxide synthase) with DAHP (2,4-diamino 6-hydroxypyrimidine; an inhibitor of GTP cyclohydrolase 1, the rate-limiting synthetic enzyme for the critical eNOS cofactor tetrahydrobiopterin) induces human-like, time-dependent progression of PH phenotypes in mice.

Results: Critical phenotypic features include progressive elevation in mean pulmonary arterial pressure, right ventricular systolic blood pressure, and right ventricle (RV)/left ventricle plus septum (LV+S) weight ratio; extensive vascular remodeling of pulmonary arterioles with increased medial thickness/perivascular collagen deposition and increased expression of PCNA (proliferative cell nuclear antigen) and alpha-actin; markedly increased total and mitochondrial superoxide production, substantially reduced tetrahydrobiopterin and nitric oxide bioavailabilities; and formation of an array of human-like vascular lesions.

NADPH Oxidase Isoforms in COPD Patients and Acute Cigarette Smoke-Exposed Mice: Induction of Oxidative Stress and Lung Inflammation.

Cigarette smoke (CS) is a major risk factor for chronic obstructive pulmonary disease (COPD), which represents the third leading cause of death worldwide. CS induces reactive oxygen species (ROS) production, leading to pulmonary inflammation and remodeling. NADPH oxidases (NOXs) represent essential sources of ROS production in the cardiovascular system.

Novel and robust treatment of pulmonary hypertension with netrin-1 and netrin-1-derived small peptides.

Limited medical therapies have been implemented for the treatment of the devastating cardiorespiratory disease of pulmonary hypertension (PH) while none of which is sufficiently effective to stop or regress development of PH. We have previously shown that netrin-1, an axon-guiding protein during development, protects against ischemia reperfusion injury induced myocardial infarction via modest and stable production of nitric oxide (NO) and attenuation of oxidative stress. Since NO deficiency and oxidative stress-mediated vascular remodeling play important roles in the pathogenesis of PH, our present study investigated therapeutic effects on PH of netrin-1 and its derived small peptides.

Reversal of pulmonary arterial hypertension and neointimal formation by kinin B1 receptor blockade.

Background: This study examined whether BI113823, a novel selective kinin B1 receptor antagonist can reverse established pulmonary arterial hypertension (PAH), prevent right heart failure and death, which is critical for clinical translation.

Methods: Left pneumonectomized male Wistar rats were injected with monocrotaline to induce PAH. Three weeks later, when PAH was well established, the rats received daily treatment of BI113823 or vehicle for 3 weeks.

Targeting MicroRNA-192-5p, a Downstream Effector of NOXs (NADPH Oxidases), Reverses Endothelial DHFR (Dihydrofolate Reductase) Deficiency to Attenuate Abdominal Aortic Aneurysm Formation.

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NADPH oxidases and oxidase crosstalk in cardiovascular diseases: novel therapeutic targets.

Reactive oxygen species (ROS)-dependent production of ROS underlies sustained oxidative stress, which has been implicated in the pathogenesis of cardiovascular diseases such as hypertension, aortic aneurysm, hypercholesterolaemia, atherosclerosis, diabetic vascular complications, cardiac ischaemia-reperfusion injury, myocardial infarction, heart failure and cardiac arrhythmias. Interactions between different oxidases or oxidase systems have been intensively investigated for their roles in inducing sustained oxidative stress. In this Review, we discuss the latest data on the pathobiology of each oxidase component, the complex crosstalk between different oxidase components and the consequences of this crosstalk in mediating cardiovascular disease processes, focusing on the central role of particular NADPH oxidase (NOX) isoforms that are activated in specific cardiovascular diseases.

Photoluminescence studies on nanocomposite graphene decorated with tantalum oxide.

Graphene-tantalum oxide (TaO) hybrid material is synthesized using a simple hydrothermal method to elucidate its optical properties. The prepared sample is characterized by X-ray diffraction, scanning electron microscope (SEM), high-resolution-transmission electron microscope (HR-TEM), thermo-gravimetric and differential thermal analysis (TG-DTA), Fourier transform-Raman spectra, and photoluminescence (PL) studies. SEM and HR-TEM analysis revealed that the TaO particles are embedded on the surface of thin sheets of well-defined graphene structure.

Knockout of dihydrofolate reductase in mice induces hypertension and abdominal aortic aneurysm via mitochondrial dysfunction.

Hypertension and abdominal aortic aneurysm (AAA) are severe cardiovascular diseases with incompletely defined molecular mechanisms. In the current study we generated dihydrofolate reductase (DHFR) knockout mice for the first time to examine its potential contribution to the development of hypertension and AAA, as well as the underlying molecular mechanisms. Whereas the homozygote knockout mice were embryonically lethal, the heterozygote knockout mice had global reduction in DHFR protein expression and activity.

Kinin B1 Receptor Inhibition With BI113823 Reduces Inflammatory Response, Mitigates Organ Injury, and Improves Survival Among Rats With Severe Sepsis.

Background: This study examined the therapeutic effects of an orally active nonpeptide kinin B1 receptor antagonist, BI113823, in a clinically relevant experimental model of polymicrobial sepsis in rats.

Methods: Sepsis was induced by cecal ligation and puncture (CLP). Animals received treatment with either vehicle or BI113823.

Inhibition of kinin B1 receptors attenuates pulmonary hypertension and vascular remodeling.

This study examined whether the kinin B1 receptor is involved in the pathogenesis of pulmonary hypertension, and whether its inhibition could reduce inflammation, pulmonary hypertension, vascular remodeling, and right heart dysfunction. Male Wistar rats underwent left pneumonectomy. Seven days later, the rats were injected subcutaneously with monocrotaline (60 mg/kg).

Mussel-Inspired Electrospun Nanofibers Functionalized with Size-Controlled Silver Nanoparticles for Wound Dressing Application.

Electrospun nanofibers that contain silver nanoparticles (AgNPs) have a strong antibacterial activity that is beneficial to wound healing. However, most of the literature available on the bactericidal effects of this material is based on the use of AgNPs with uncontrolled size, shape, surface properties, and degree of aggregation. In this study, we report the first versatile synthesis of novel catechol moieties presenting electrospun nanofibers functionalized with AgNPs through catechol redox chemistry.

Electrospun polyurethane-dextran nanofiber mats loaded with Estradiol for post-menopausal wound dressing.

Post-menopausal wound care management is a substantial burden on health services, since there are an increased number of elderly populations linked with age-related delayed wound healing. The controlled estrogen replacement can accelerate healing of acute cutaneous wounds, linked to its potent anti-inflammatory activity. The electrospinning technique can be used to introduce the desired therapeutic agents to the nanofiber matrix.