Efficacy of Flaxseed Compared to ACE Inhibition in Treating Anthracycline- and Trastuzumab-Induced Cardiotoxicity.

Background: Although the current combination of surgery, radiation, and chemotherapy is used in the breast-cancer setting, the administration of the anticancer drugs doxorubicin and trastuzumab is associated with an increased risk of developing heart failure. The aim of this study is to determine whether dietary flaxseed is comparable and/or synergistic with the angiotensin-converting enzyme inhibitor perindopril in the treatment of doxorubicin- and trastuzumab-mediated cardiotoxicity.

Methods: In a chronic murine model (n = 110), doxorubicin and trastuzumab (8 mg/kg and 3 mg/kg, respectively) were administered weekly for 3 weeks.

Nitric oxide augments signaling for contraction in hypoxic pulmonary arterial smooth muscle-Implications for hypoxic pulmonary hypertension.

Hypoxic persistent pulmonary hypertension in the newborn (PPHN) is usually treated with oxygen and inhaled nitric oxide (NO), both pulmonary arterial relaxants. But treatment failure with NO occurs in 25% of cases. We previously demonstrated that 72 h exposure to hypoxia, modeling PPHN, sensitized pulmonary artery smooth muscle cells (PASMC) to the contractile agonist thromboxane and inhibited relaxant adenylyl cyclase (AC) activity.

Mitochondrial autophagy and cell survival is regulated by the circadian gene in cardiac myocytes during ischemic stress.

Cardiac function is highly reliant on mitochondrial oxidative metabolism and quality control. The circadian gene is critically linked to vital physiological processes including mitochondrial fission, fusion and bioenergetics; however, little is known of how the gene regulates these vital processes in the heart. Herein, we identified a putative circadian CLOCK-mitochondrial interactome that gates an adaptive survival response during myocardial ischemia.

Impact of Wnt/β-catenin signaling on ethanol-induced changes in brain endothelial cell permeability.

Chronic exposure to ethanol is associated with enhanced leakiness in the brain microvessel endothelial cells that form the blood-brain barrier (BBB). As previous studies suggested Wnt/β-catenin signaling could improve the BBB phenotype of brain endothelial cells, we examined the extent to which Wnt signaling is altered following ethanol exposure, using both a cell culture model of the BBB and mice exposed to ethanol, and the ability of Wnt activation to reverse the permeability effects of ethanol. The human brain endothelial cells, hCMEC/D3, were exposed to ethanol (17-200 mM) for various periods of time (0-96 hr) and Wnt signaling, as well as expression of downstream genes influencing BBB integrity in the cell monolayers were monitored.

Doxorubicin-loaded iron oxide nanoparticles for glioblastoma therapy: a combinational approach for enhanced delivery of nanoparticles.

Although doxorubicin (DOX) is an effective anti-cancer drug with cytotoxicity in a variety of different tumors, its effectiveness in treating glioblastoma multiforme (GBM) is constrained by insufficient penetration across the blood-brain barrier (BBB). In this study, biocompatible magnetic iron oxide nanoparticles (IONPs) stabilized with trimethoxysilylpropyl-ethylenediamine triacetic acid (EDT) were developed as a carrier of DOX for GBM chemotherapy. The DOX-loaded EDT-IONPs (DOX-EDT-IONPs) released DOX within 4 days with the capability of an accelerated release in acidic microenvironments.

Salinomycin-Loaded Iron Oxide Nanoparticles for Glioblastoma Therapy.

Salinomycin is an antibiotic introduced recently as a new and effective anticancer drug. In this study, magnetic iron oxide nanoparticles (IONPs) were utilized as a drug carrier for salinomycin for potential use in glioblastoma (GBM) chemotherapy. The biocompatible polyethylenimine (PEI)-polyethylene glycol (PEG)-IONPs (PEI-PEG-IONPs) exhibited an efficient uptake in both mouse brain-derived microvessel endothelial (bEnd.

Acute upregulation of bone morphogenetic protein-4 regulates endogenous cell response and promotes cell death in spinal cord injury.

Traumatic spinal cord injury (SCI) elicits a cascade of secondary injury mechanisms that induce profound changes in glia and neurons resulting in their activation, injury or cell death. The resultant imbalanced microenvironment of acute SCI also negatively impacts regenerative processes in the injured spinal cord. Thus, it is imperative to uncover endogenous mechanisms that drive these acute injury events.

Simple, Hackable, Size-Selective, Amine-Functionalized Fe-Oxide Nanoparticles for Biomedical Applications.

A facile one-pot method for synthesizing amine-functionalized nonspherical FeO nanoparticles in gram-scale quantities is presented using just a single source of iron (iron(II) chloride) and an amine (triethylamine). The amine not only transforms iron salt to FeO, but also directs the morphology of the nanoparticles along with the temperature of the reaction and functionalizes them, making the synthesis very economical. By modifying the surface further, these nanoparticles promise to offer useful biomedical applications.

Neuregulin-1 promotes remyelination and fosters a pro-regenerative inflammatory response in focal demyelinating lesions of the spinal cord.

Oligodendroglial cell death and demyelination are hallmarks of neurotrauma and multiple sclerosis that cause axonal damage and functional impairments. Remyelination remains a challenge as the ability of endogenous precursor cells for oligodendrocyte replacement is hindered in the unfavorable milieu of demyelinating conditions. Here, in a rat model of lysolecithin lysophosphatidyl-choline (LPC)-induced focal demyelination, we report that Neuregulin-1 (Nrg-1), an important factor for oligodendrocytes and myelination, is dysregulated in demyelinating lesions and its bio-availability can promote oligodendrogenesis and remyelination.

Perturbation of redox balance after thioredoxin reductase deficiency interrupts autophagy-lysosomal degradation pathway and enhances cell death in nutritionally stressed SH-SY5Y cells.

Oxidative damage and aggregation of cellular proteins is a hallmark of neuronal cell death after neurotrauma and chronic neurodegenerative conditions. Autophagy and ubiquitin protease system are involved in degradation of protein aggregates, and interruption of their function is linked to apoptotic cell death in these diseases. Oxidative modification of cysteine groups in key molecular proteins has been linked to modification of cellular systems and cell death in these conditions.

Differential internalization of brick shaped iron oxide nanoparticles by endothelial cells.

Nanoparticles targeting endothelial cells to treat diseases such as cancer, oxidative stress, and inflammation have traditionally relied on ligand-receptor based delivery. The present studies examined the influence of nanoparticle shape in regulating preferential uptake of nanoparticles in endothelial cells. Spherical and brick shaped iron oxide nanoparticles (IONPs) were synthesized with identical negatively charged surface coating.

Pelota Regulates Epidermal Differentiation by Modulating BMP and PI3K/AKT Signaling Pathways.

The depletion of evolutionarily conserved pelota protein causes impaired differentiation of embryonic and spermatogonial stem cells. In this study, we show that temporal deletion of pelota protein before epidermal barrier acquisition leads to neonatal lethality due to perturbations in permeability barrier formation. Further analysis indicated that this phenotype is a result of failed processing of profilaggrin into filaggrin monomers, which promotes the formation of a protective epidermal layer.

Biodistribution of negatively charged iron oxide nanoparticles (IONPs) in mice and enhanced brain delivery using lysophosphatidic acid (LPA).

Effective treatment of brain disorders requires a focus on improving drug permeability across the blood-brain barrier (BBB). Herein, we examined the pharmacokinetic properties of negatively charged iron oxide nanoparticles (IONPs) and the capability of using lysophosphatidic acid (LPA) to transiently disrupt the tight junctions and allow IONPs to enter the brain. Under normal conditions, IONPs had a plasma half-life of six minutes, with the liver and spleen being the major organs of deposition.

Modulation of intercellular junctions by cyclic-ADT peptides as a method to reversibly increase blood-brain barrier permeability.

It is challenging to deliver molecules to the brain for diagnosis and treatment of brain diseases. This is primarily because of the presence of the blood-brain barrier (BBB), which restricts the entry of many molecules into the brain. In this study, cyclic-ADT peptides (ADTC1, ADTC5, and ADTC6) have been shown to modify the BBB to enhance the delivery of marker molecules [e.

The FGF-2-triggered protection of cardiac subsarcolemmal mitochondria from calcium overload is mitochondrial connexin 43-dependent.

Aims: Fibroblast growth factor 2 (FGF-2) protects the heart from ischaemia- and reperfusion-induced cell death by a mechanism linked to protein kinase C (PKC)ε-mediated connexin 43 (Cx43) phosphorylation. Cx43 localizes predominantly to gap junctions, but has also been detected at subsarcolemmal (SSM), but not interfibrillar (IFM), mitochondria, where it is considered important for cardioprotection. We have now examined the effect of FGF-2 administration to the heart on resistance to calcium-induced permeability transition (mPTP) of isolated SSM vs.

Caspase 3 activity in isolated fetal rat lung fibroblasts and rat periodontal ligament fibroblasts: cigarette smoke induced alterations.

Background: Cigarette smoking is the leading cause of preventable death and has been implicated in pathogenesis of pulmonary, oral and systemic diseases. Smoking during pregnancy is a risk factor for the developing fetus and may be a major cause of infant mortality. Moreover, the oral cavity, and all cells within are the first to be exposed to cigarette smoke and may be a possible source for the spread of toxins to other organs of the body.

One-pot synthesis of iron oxide nanoparticles with functional silane shells: a versatile general precursor for conjugations and biomedical applications.

Iron oxide nanoparticles (IONPs) and their surface modifications with therapeutic or diagnostic (theranostic, TN) agents are of great interest. Here we present a novel one-pot synthesis of a versatile general TN precursor (aminosilane-coated IONPs [IONP-Sil(NH2)]) with surface amine groups. Surface functional group conversion to carboxylic acid was accomplished by conjugating poly(ethylene glycol) diacid to IONP-Sil(NH2).

Characterization of cellular uptake and toxicity of aminosilane-coated iron oxide nanoparticles with different charges in central nervous system-relevant cell culture models.

Background: Aminosilane-coated iron oxide nanoparticles (AmS-IONPs) have been widely used in constructing complex and multifunctional drug delivery systems. However, the biocompatibility and uptake characteristics of AmS-IONPs in central nervous system (CNS)-relevant cells are unknown. The purpose of this study was to determine the effect of surface charge and magnetic field on toxicity and uptake of AmS-IONPs in CNS-relevant cell types.

A tea/vanadate decoction delivered orally over 14 months to diabetic rats induces long-term glycemic stability without organ toxicity.

Vanadium can induce potent hypoglycemic effects in type 1 and type 2 diabetes mellitus animals, but toxic adverse effects have inhibited the translation of these findings. Administration of vanadate in a black tea decoction has shown impressive hypoglycemic effects without evidence of toxicity in short-term studies. The purpose of this study was to investigate the hypoglycemic action and the toxic adverse effects of a tea/vanadate (T/V) decoction in diabetic rats over a 14-month treatment period.

Hyaluronidase 3 (HYAL3) knockout mice do not display evidence of hyaluronan accumulation.

Hyaluronidases are endoglycosidases that initiate the breakdown of hyaluronan (HA), an abundant component of the vertebrate extracellular matrix. In humans, six paralogous genes encoding hyaluronidase-like sequences have been identified on human chromosomes 3p21.3 (HYAL2-HYAL1-HYAL3) and 7q31.

Caveolae facilitate muscarinic receptor-mediated intracellular Ca2+ mobilization and contraction in airway smooth muscle.

Contractile responses of airway smooth muscle (ASM) determine airway resistance in health and disease. Caveolae microdomains in the plasma membrane are marked by caveolin proteins and are abundant in contractile smooth muscle in association with nanospaces involved in Ca(2+) homeostasis. Caveolin-1 can modulate localization and activity of signaling proteins, including trimeric G proteins, via a scaffolding domain.

Effect of NQO1 induction on the antitumor activity of RH1 in human tumors in vitro and in vivo.

NQO1 is a reductive enzyme that is important for the activation of many bioreductive agents and is a target for an enzyme-directed approach to cancer therapy. It can be selectively induced in many tumor types by a number of compounds including dimethyl fumarate and sulforaphane. Mitomycin C is a bioreductive agent that is used clinically for treatment of solid tumors.

A comparison of biologically variable ventilation to recruitment manoeuvres in a porcine model of acute lung injury.

Background: Biologically variable ventilation (return of physiological variability in rate and tidal volume using a computer-controller) was compared to control mode ventilation with and without a recruitment manoeuvre - 40 cm H2O for 40 sec performed hourly; in a porcine oleic acid acute lung injury model.

Methods: We compared gas exchange, respiratory mechanics, and measured bronchoalveolar fluid for inflammatory cytokines, cell counts and surfactant function. Lung injury was scored by light microscopy.

Gonadal dysgenesis with X-monosomy in a cynomolgus monkey (Macaca fascicularis).

A 3-year-old female cynomolgus monkey (Macaca fascicularis) was found to have inappropriately high circulating immunoassayable follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels compatible with primary gonadal failure. Hypergonadotropic hypogonadism was confirmed by the findings of persistently high serum gonadotropin levels by both LH bioassay and FSH and LH radioimmunoassays and low levels of serum estradiol. In addition, circhoral gonadotropin pulsatility and an exaggerated response to a gonadotropin-releasing hormone challenge were demonstrated.