The growing number of antibiotic-resistant bacteria necessitates the search for new antimicrobial agents and the principles by which they work. We report that cell membrane-permeant rhodamine B (RhB)-conjugated peptides based on the phosphatidylinositol-4,5-bisphosphate binding site of gelsolin can kill the gram-negative organisms Escherichia coli and Pseudomonas aeruginosa and the gram-positive organism Streptococcus pneumoniae. RhB linkage to the QRLFQVKGRR sequence in gelsolin was essential for the antibacterial function, since the unconjugated peptide had no effect on the bacteria tested. Because RhB-QRLFQVKGRR (also termed PBP10), its scrambled sequence (RhB-FRVKLKQGQR), and PBP10 synthesized from D-isomer amino acids show similar antibacterial properties, the physical and chemical properties of these derivatives appear to be more important than specific peptide folding for their antibacterial functions. The similar activities of PBP10 and all-D-amino-acid PBP10 also indicate that a specific interaction between RhB derivatives and bacterial proteins is unlikely to be involved in the bacterial killing function of PBP10. By using a phospholipid monolayer system, we found a positive correlation between the antibacterial function of PBP10, as well as some naturally occurring antibacterial peptides, and the intrinsic surface pressure activity at the hydrophobic-hydrophilic interface. Surprisingly, we observed little or no dependence of the insertion of these peptides into lipid monolayers on the phospholipid composition. These studies show that an effective antimicrobial agent can be produced from a peptide sequence with specificity to a phospholipid not found in bacteria, and comparisons with other antimicrobial agents suggest that the surface activities of these peptides are more important than specific binding to bacterial proteins or lipids for their antimicrobial functions.Antimicrobial peptides are nonadaptive host defense molecules that provide a first line of defense against a wide spectrum of pathogens. They are found in all species ranging from protozoa to vertebrates. In mammals, these peptides are stored in granules of leukocytes and are present on mucosal surfaces and skin (31). In the last decade, they have become an important focus of study due to their possible applications as a new source of antibiotics, anticancer drugs, food preservatives, and antiseptic agents (32). It has been proposed that a variety of antimicrobial peptides kill bacteria by interacting with the anionic phospholipid of the bacterial inner membrane or with the hydrophilic lipopolysaccharide (LPS) of the cell wall of gramnegative bacteria. As a result of this relatively nonspecific interaction, insertion of antibacterial peptides in the bacterial membrane occurs, resulting in either its permeabilization or disruption. This leads to changes in secondary messenger systems that further augment the abnormal electrical activity and that disrupt signal transduction, causing bacterial death (14). However, understanding of the peptid...

GLUT4 (glucose transporter 4) plays a pivotal role in insulin-induced glucose uptake to maintain normal blood glucose levels. Here, we report that a cell-permeable phosphoinositide-binding peptide induced GLUT4 translocation to the plasma membrane without inhibiting IRAP (insulin-responsive aminopeptidase) endocytosis. However, unlike insulin treatment, the peptide treatment did not increase glucose uptake in 3T3-L1 adipocytes, indicating that GLUT4 translocation and activation are separate events. GLUT4 activation can occur at the plasma membrane, since insulin was able to increase glucose uptake with a shorter time lag when inactive GLUT4 was first translocated to the plasma membrane by pretreating the cells with this peptide. Inhibition of phosphatidylinositol (PI) 3-kinase activity failed to inhibit GLUT4 translocation by the peptide but did inhibit glucose uptake when insulin was added following peptide treatment. Insulin, but not the peptide, stimulated GLUT1 translocation. Surprisingly, the peptide pretreatment inhibited insulin-induced GLUT1 translocation, suggesting that the peptide treatment has both a stimulatory effect on GLUT4 translocation and an inhibitory effect on insulin-induced GLUT1 translocation. These results suggest that GLUT4 requires translocation to the plasma membrane, as well as activation at the plasma membrane, to initiate glucose uptake, and both of these steps normally require PI 3-kinase activation.

No abstract

The strong association between ACR and allospecific CD154+TcM may be useful in minimizing protocol biopsies among recipients at reduced rejection risk.

There is great variability in life-expectancy, physical, cognitive, and functional domains in cancer patients of similar chronologic age. Nowhere is this more apparent than among middle-aged and older patients. However, even in younger patients of similar age, extensive exposure to environmental stressors can cause great variability in health status. A biomarker that would reflect biologic age and any and all health deficits in a cancer patient at a distinct point in time might help predict long term outcomes related to treatment, especially toxicity and overall survival. p16 INK4a (hereafter referred to as p16) expression represents an ideal biomarker that reflects both cellular senescence and biologic aging. In murine models, p16 expression reflects biologic aging in almost all organs. Preliminary findings in patients with cancer support p16 measurement as a marker of physiologic aging and predictor of toxicity in patients treated with chemotherapy. This review describes the role of p16 in cell senescence, the methodology of p16 measurement in humans, preliminary studies of p16 in humans, and the potential clinical utility of p16 in guiding treatment for cancer patients.