Salt sensitivity of antimicrobial peptides poses a major obstacle in their development as novel antibiotics. Here we report the use of helix-capping motifs to confer salt resistance upon helical antimicrobial peptides. The helical content of the template peptide [RLLR] 5 was almost completely destroyed at salt concentrations over 200 mM NaCl, leading to a 8 -32-fold decrease in antimicrobial activity. However, the introduction of helixcapping motifs at the helix termini resulted in a structurally stable peptide, which retained membrane-permeabilizing and antimicrobial activities upon exposure to salt. Furthermore, the peptide with helix-capping motifs directly inhibited the in vivo growth of Streptococcus pyogenes, which causes localized fasciitis in mice, and prevented the necrosis of the epidermis, dermis, and subcutaneous muscle layers. Results indicate that the adoption of helix-capping motifs into salt-sensitive antimicrobial peptides provides the necessary structural stability for the peptides to permeabilize cell membranes and cause cell death at physiological salt concentrations.

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Alzheimer disease (AD) is a progressive neurodegenerative disease, which is characterized by loss of memory and cognitive function. In AD patients dysfunction of the cholinergic system is the main cause of cognitive disorders, and decreased activity of choline acetyltransferase (ChAT), an enzyme responsible for acetylcholine (ACh) synthesis, is observed. In the present study we investigated if brain transplantation of human neural stem cells (NSCs) genetically modified to encode ChAT gene improves cognitive function of kainic acid (KA)-induced learning deficit rats. Intrahippocampal injection of KA to hippocampal CA3 region caused severe neuronal loss, resulting in profound learning and memory deficit. F3.ChAT human NSCs transplanted intracerebroventricularly improved fully the learning and memory function of KA-induced learning deficit animals, in parallel with the elevation of ACh levels in cerebrospinal fluid. F3.ChAT human NSCs migrated to the KA-induced injury site (CA3) and differentiated into neurons and astrocytes. The present study demonstrates that human NSCs expressing ChAT have lesion-tropic property and improve cognitive function of learning deficit model rats with hippocampal injury by increasing ACh level.

Brain ageing leads to atrophy and degeneration of the cholinergic nervous system, resulting in profound neurobehavioral and cognitive dysfunction from decreased acetylcholine biosynthesis and reduced secretion of growth and neurotrophic factors. Human adipose tissue-derived mesenchymal stem cells (ADMSCs) were intravenously (1 3 10 6 cells) or intracerebroventricularly (4 3 10 5 cells) transplanted into the brains of 18-month-old mice once or four times at 2-week intervals. Transplantation of ADMSCs improved both locomotor activity and cognitive function in the aged animals, in parallel with recovery of acetylcholine levels in brain tissues. Transplanted cells differentiated into neurons and, in part, into astrocytes and produced choline acetyltransferase proteins. Transplantation of ADMSCs restored microtubule-associated protein 2 in brain tissue and enhanced Trk B expression and the concentrations of brain-derived neurotrophic factor and nerve growth factor. These results indicate that human ADMSCs differentiate into neural cells in the brain microenvironment and can restore physical and cognitive functions of aged mice not only by increasing acetylcholine synthesis but also by restoring neuronal integrity that may be mediated by growth/neurotrophic factors. V V C 2013 Wiley Periodicals, Inc.

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