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Perturbations in mitochondrial dynamics have been observed in most neurodegenerative diseases. Here, we focus on manganese (Mn)-induced Parkinsonism-like neurodegeneration, a disorder associated with the preferential of Mn in the basal ganglia where the mitochondria are considered an early target. Despite the extensive characterization of the clinical presentation of manganism, the mechanism by which Mn mediated mitochondrial toxicity is unclear. In this study we hypothesized whether Mn exposure alters mitochondrial activity, including axonal transport of mitochondria and mitochondrial dynamics, morphology, and network. Using primary neuron cultures exposed to 100 μM Mn (which is considered the threshold of Mn toxicity in vitro) and intraperitoneal injections of MnCl(2) (25mg/kg) in rat, we observed that Mn increased mitochondrial fission mediated by phosphorylation of dynamin-related protein-1 at serine 616 (p-s616-DRP1) and decreased mitochondrial fusion proteins (MFN1 and MFN2) leading to mitochondrial fragmentation, defects in mitochondrial respiratory capacity, and mitochondrial ultrastructural damage in vivo and in vitro. Furthermore, Mn exposure impaired mitochondrial trafficking by decreasing dynactin (DCTN1) and kinesin-1 (KIF5B) motor proteins and increasing destabilization of the cytoskeleton at protein and gene levels. In addition, mitochondrial communication may also be altered by Mn exposure, increasing the length of nanotunnels to reach out distal mitochondria. These findings revealed an unrecognized role of Mn in dysregulation of mitochondrial dynamics providing a potential explanation of early hallmarks of the disorder, as well as a possible common pathway with neurological disorders arising upon chronic Mn exposure.

Nitric oxide (NO), an essential agent of the innate immune system, exhibits multi-mechanistic antimicrobial activity. Previously, NO-releasing nanoparticles (NO-np) demonstrated increased antimicrobial activity when combined with glutathione (GSH) due to formation of S-nitrosoglutathione (GSNO), a transnitrosylating agent. To capitalize on this finding, we incorporated the thiol-containing ACE-inhibitor, captopril, with NO-np to form SNO-CAP-np, nanoparticles that both release NO and form S-nitrosocaptopril. In the presence of GSH, SNO-CAP-np demonstrated increased transnitrosylation activity compared to NO-np, as exhibited by increased GSNO formation. Escherichia coli and methicillin-resistant Staphylococcus aureus were highly susceptible to SNO-CAP-np in a dose-dependent fashion, with E. coli being most susceptible, and SNO-CAP-np were nontoxic in zebrafish embryos at translatable concentrations. Given SNO-CAP-np's increased transnitrosylation activity and increased E. coli susceptibility compared to NO-np, transnitrosylation rather than free NO is likely responsible for overcoming E. coli 's resistance mechanisms and ultimately killing the pathogen. From the Clinical Editor This team of authors incorporated the thiol-containing ACE-inhibitor, captopril, into a nitric oxide releasing nanoparticle system, generating nanoparticles that both release NO and form S-nitrosocaptopril, with pronounced toxic effects on MRSA and E. coli in the presented model system.

Burn wounds are often complicated by bacterial infection, contributing to morbidity and mortality. Agents commonly used to treat burn wound infection are limited by toxicity, incomplete microbial coverage, inadequate penetration, and rising resistance. Curcumin is a naturally derived substance with innate antimicrobial and wound healing properties. Acting by multiple mechanisms, curcumin is less likely than current antibiotics to select for resistant bacteria. Curcumin's poor aqueous solubility and rapid degradation profile hinder usage; nanoparticle encapsulation overcomes this pitfall and enables extended topical delivery of curcumin. In this study, we synthesized and characterized curcumin nanoparticles (curc-np), which inhibited in vitro growth of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa in dose-dependent fashion, and inhibited MRSA growth and enhanced wound healing in an in vivo murine wound model. Curc-np may represent a novel topical antimicrobial and wound healing adjuvant for infected burn wounds and other cutaneous injuries.

A new platform using biocompatible materials is presented for generating powders comprised of nanoparticles that release therapeutic levels of nitric oxide (NO) in a controlled and sustained manner. The capacity of these particles to retain and gradually release NO arises from their having combined features of both glassy matrices and hydrogels. This feature allows both for the generation of NO through the thermal reduction of added nitrite by glucose and for the retention of the generated NO within the dry particles. Exposure of these robust biocompatible nanoparticles to moisture initiates the sustained release of the trapped NO over extended time periods as determined both fluorimetrically and amperometrically. The slow sustained release is in contrast to the much faster release pattern associated with the hydration-initialed NO release in powders derived from glassy matrices. These glasses are prepared using trehalose and sucrose doped with either glucose or tagatose as the source of thermal electrons needed to convert nitrite to gNO. Significantly, the release profiles for the NO in the hydrogel/glass composite materials are found to be an easily tuned parameter that is modulated through the specific additives used in preparing the hydrogel/glass composites. The presented data raise the prospect that these new NO releasing nanoparticles can be easily formulated for use under a wide range of therapeutic circumstances.

The outermost layer ofMycobacterium tuberculosisis composed primarily of two polysaccharides, glucan (GC) and arabinomannan. To analyze the surface polysaccharide composition ofM. tuberculosis, we generated a monoclonal antibody (MAb) that bindsM. tuberculosisGC and is known as MAb 24c5. Immunofluorescence and whole-mount immunoelectron microscopy indicated that GC is on the outermost portion of the bacteria.M. tuberculosisstrains Erdman and CDC 1551 were analyzed for their ability to bind MAb 24c5 after in vitro growth in media with and without the detergent Tween 80. MAb 24c5 bound to Erdman and CDC 1551 at all culture times with only slightly greater apparent affinity after extended culture in the absence of Tween 80, indicating that a stable amount of GC polysaccharide antigen is associated with the cell surface ofM. tuberculosis. An enzyme-linked immunosorbent assay indicated that GC is antigenically similar to glycogen, and the amount of GC antigen increased in the media ofM. tuberculosiscultures grown either with or without the detergent Tween 80. Other nontuberculosis mycobacteria have antigenically similar GCs on their surfaces after in vitro growth. Inoculation of mice with live bacilli but not inoculation with dead bacilli elicited a strong antibody response to GC consistent with production of this antigen in vivo. Our results provide a more comprehensive picture of theM. tuberculosiscell envelope and the conditions that allow expression ofM. tuberculosisGC.