Carbon Nanotubes in Biomedical Applications: Factors, Mechanisms, and Remedies of Toxicity

Carbon nanotubes (CNTs) represent one of the most studied allotropes of carbon. The unique physicochemical properties of CNTs make them among prime candidates for numerous applications in biomedical fields including drug delivery, gene therapy, biosensors, and tissue engineering applications. However, toxicity of CNTs has been a major concern for their use in biomedical applications. In this review, we present an overview of carbon nanotubes in biomedical applications; we particularly focus on various factors and mechanisms affecting their toxicity. We have discussed various parameters including the size, length, agglomeration, and impurities of CNTs that may cause oxidative stress, which is often the main mechanism of CNTs' toxicity. Other toxic pathways are also examined, and possible ways to overcome these challenges have been discussed. 2016 American Chemical Society.Scopu

Elastin-Dependent Aortic Heart Valve Leaflet Curvature Changes During Cyclic Flexure

The progression of calcific aortic valve disease (CAVD) is characterized by extracellular matrix (ECM) remodeling, leading to structural abnormalities and improper valve function. The focus of the present study was to relate aortic valve leaflet axial curvature changes as a function of elastin degradation, which has been associated with CAVD. Circumferential rectangular strips (L × W = 10 × 2.5 mm) of normal and elastin-degraded (via enzymatic digestion) porcine AV leaflets were subjected to cyclic flexure (1 Hz). A significant increase in mean curvature (p < 0.05) was found in elastin-degraded leaflet specimens in comparison to un-degraded controls at both the semi-constrained (50% of maximum flexed state during specimen bending and straightening events) and fully-constrained (maximally-flexed) states. This significance did not occur in all three flexed configurations when measurements were performed using either minimum or maximum curvature. Moreover, the mean curvature increase in the elastin-degraded leaflets was most pronounced at the instance of maximum flexure, compared to un-degraded controls. We conclude that the mean axial curvature metric can detect distinct spatial changes in aortic valve ECM arising from the loss in bulk content and/or structure of elastin, particularly when there is a high degree of tissue bending. Therefore, the instance of maximum leaflet flexure during the cardiac cycle could be targeted for mean curvature measurements and serve as a potential biomarker for elastin degradation in early CAVD remodeling

Mistargeting of peroxisomal EHHADH and inherited renal Fanconi's syndrome

BACKGROUND In renal Fanconi's syndrome, dysfunction in proximal tubular cells leads to renal losses of water, electrolytes, and low-molecular-weight nutrients. For most types of isolated Fanconi's syndrome, the genetic cause and underlying defect remain unknown. METHODS We clinically and genetically characterized members of a five-generation black family with isolated autosomal dominant Fanconi's syndrome. We performed genomewide linkage analysis, gene sequencing, biochemical and cell-biologic investigations of renal proximal tubular cells, studies in knockout mice, and functional evaluations of mitochondria. Urine was studied with the use of proton nuclear magnetic resonance (1H-NMR) spectroscopy. RESULTS We linked the phenotype of this family's Fanconi's syndrome to a single locus on chromosome 3q27, where a heterozygous missense mutation in EHHADH segregated with the disease. The p.E3K mutation created a new mitochondrial targeting motif in the N-terminal portion of EHHADH, an enzyme that is involved in peroxisomal oxidation of fatty acids and is expressed in the proximal tubule. Immunocytofluorescence studies showed mistargeting of the mutant EHHADH to mitochondria. Studies of proximal tubular cells revealed impaired mitochondrial oxidative phosphorylation and defects in the transport of fluids and a glucose analogue across the epithelium. 1H-NMR spectroscopy showed elevated levels of mitochondrial metabolites in urine from affected family members. Ehhadh knockout mice showed no abnormalities in renal tubular cells, a finding that indicates a dominant negative nature of the mutation rather than haploinsufficiency. CONCLUSIONS Mistargeting of peroxisomal EHHADH disrupts mitochondrial metabolism and leads to renal Fanconi's syndrome; this indicates a central role of mitochondria in proximal tubular function. The dominant negative effect of the mistargeted protein adds to the spectrum of monogenic mechanisms of Fanconi's syndrome. (Funded by the European Commission Seventh Framework Programme and others.