Are cationic antimicrobial peptides also 'double-edged swords'?

The present view focuses on the possibility that cationic antimicrobial peptides (CAMPs) might, in addition to their killing effects due to permeabilization of microbial membranes, also function similarly to beta-lactam antibiotics to activate nascent autolytic wall enzymes, leading to bacteriolysis. Since the massive release of microbial cell wall components is a major cause of postinfectious sequelae, the in vivo process of bacteriolysis must be controlled. Due to the emergence of antibiotic resistance in pathogenic bacteria, CAMPs might be useful as an alternative to antibiotics. However, they should be used with caution, since they might also function as a 'double-edged sword' by injuring both the bacteria and host.     

Regulation of cancer-related gene expression by galectin-3 and the molecular mechanism of its nuclear import pathway

Galectin-3 (Gal-3), a member of the β-galactoside-binding gene family, distributes inside and outside the cell and has pleiotropic biological functions such as cell growth, cell adhesion, cell–cell interaction, and mRNA processing in a specific situation. In particular, Gal-3 in the nucleus plays a pivotal role in the regulation of cancer-related gene expression, including cyclin D1, TTF-1 and MUC2, presumably associated with tumor progression. Therefore, to understand the mechanism of nuclear import of Gal-3 is very significant and might be developed to the new approach for the cancer treatment. In this review, we focus on the role of Gal-3 in the nucleus and the molecular mechanism of nuclear import pathways of Gal-3, providing the hints for the inhibition of Gal-3 function.     

Fragmented pictures revisited: long-term changes in repetition priming, relation to skill learning, and the role of cognitive resources

BACKGROUND: Whereas age-related declines in declarative memory have been demonstrated in multiple cross-sectional and longitudinal studies, the effect of age on non-declarative manifestations of memory, such as repetition priming and perceptual skill learning, are less clear. The common assumption, based on cross-sectional studies, is that these processes are only mildly (if at all) affected by age. OBJECTIVE: To investigate long-term changes in repetition priming and age-related differences in identification of fragmented pictures in a 5-year longitudinal design. METHOD: Healthy adults (age 28-82 years) viewed drawings of objects presented in descending order of fragmentation. The identification threshold (IT) was the highest fragmentation level at which the object was correctly named. After a short interval, old pictures were presented again along with a set of similar but novel pictures. Five years later the participants repeated the experiment. RESULTS: At baseline and 5-year follow-up alike, one repeated exposure improved IT for old (priming) and new (skill acquisition) pictures. However, long-term retention of priming gains was observed only in young adults. Working memory explained a significant proportion of variance in within-occasion priming, long-term priming, and skill learning. CONCLUSION: Contrary to cross-sectional results, this longitudinal study suggests perceptual repetition priming is not an age-invariant phenomenon and advanced age and reduced availability of cognitive resources may contribute to its decline.     

Possible association between diabetes and bisphosphonate-related jaw osteonecrosis

CONTEXT: Bisphosphonate-related osteonecrosis (BON) of the jaws is a newly identified condition for which the exact mechanism involved in its pathogenesis remains obscure. OBJECTIVE: The objective of the study was to evaluate whether diabetes mellitus (DM) may be a contributing factor in the development of BON. DESIGN: From 2004 to 2006, 31 patients were diagnosed with BON. The diagnosis of BON was based on the medical and dental history of each patient as well as the observation of clinical signs and symptoms of this pathological process. DM was based on two consecutive fasting blood glucose levels above 7 mmol/liter. SETTING: The study was completed in the Hebrew University-Hadassah Hospital referral center. RESULTS: Of the 31 patients with BON, 18 (58%) were found to have DM or impaired fasting glucose. The proportion of diabetic patients was much higher than expected relative to the incidence of DM in the general population (14%) and compared with the proportion of diabetic patients in a control group of oncological patients treated with bisphosphonates and without BON (12%) (P = 0.00003). CONCLUSIONS: This finding indicates that DM may be a risk factor for BON and that DM patients treated with bisphosphonates should be carefully monitored. We discuss here the bone metabolic pathways characteristic of DM patients and the way in which these pathways can augment the effects of bisphosphonates.     

Consequences of Delayed Ciprofloxacin and Doxycycline Treatment Regimens against Francisella tularensis Airway Infection

This study examines the efficacy, bacterial load, and humoral response of extensively delayed ciprofloxacin or doxycycline treatments following airway exposure of mice to Francisella tularensis subsp. holarctica (strain LVS) or to the highly virulent F. tularensis subsp. tularensis (strain SchuS4). A delay in onset of both antibiotic treatments allowed the rescue of all LVS-infected animals. However, for animals infected with SchuS4, only ciprofloxacin was efficacious and prolongation of treatment rescued all animals.     

Multifunctional PEGylated 2C5-immunoliposomes containing pH-sensitive bonds and TAT peptide for enhanced tumor cell internalization and cytotoxicity

pH-sensitive PEGylated (with PEG-PE) long-circulating liposomes (HSPC:cholesterol and Doxil?), modified with cell-penetrating TAT peptide (TATp) moieties and cancer-specific mAb 2C5 were prepared. A degradable pH-sensitive hydrazone bond between a long shielding PEG chains and PE (PEG(2k)-Hz-PE) was introduced. TATp was conjugated with a short PEG(1k)-PE spacer and mAb 2C5 was attached to a long PEG chain (2C5-PEG(3.4k)-PE). The "shielding" effect of TATp by long PEG chains was investigated using three liposomal models. At normal pH, surface TATp moieties are "hidden" by the long PEG chains. Upon the exposure to lowered pH, this multifunctional carrier exposes TATp moieties after the degradation of the hydrazone bond and removal of the long PEG chains. Enhanced cellular uptake of the TATp-containing immunoliposomes was observed in vitro after pre-treatment at lowered pH (using flow cytometry and fluorescence microscopy techniques). The presence of mAb 2C5 on the liposome surface further enhanced the interaction between the carrier and tumor cells but not normal cells. Furthermore, multifunctional immuno-Doxil? preparation showed increased cellular cytotoxicity of B16-F10, HeLa and MCF-7 cells when pre-incubated at lower pH, indicating TATp exposure and activity. In conclusion, a multifunctional immunoliposomal nanocarrier containing a pH-sensitive PEG-PE component, TATp, and the cancer cell-specific mAb 2C5 promotes enhanced cytotoxicity and carrier internalization by cancer cells and demonstrates the potential for intracellular drug delivery after exposure to lowered pH environment, typical of solid tumors.