Biodistribution and in vivo activities of tumor-associated macrophage-targeting nanoparticles incorporated with doxorubicin.

Tumor-associated macrophages (TAMs) are increasingly considered a viable target for tumor imaging and therapy. Previously, we reported that innovative surface-functionalization of nanoparticles may help target them to TAMs. In this report, using poly(lactic-co-glycolic) acid (PLGA) nanoparticles incorporated with doxorubicin (DOX) (DOX-NPs), we studied the effect of surface-modification of the nanoparticles with mannose and/or acid-sensitive sheddable polyethylene glycol (PEG) on the biodistribution of DOX and the uptake of DOX by TAMs in tumor-bearing mice. We demonstrated that surface-modification of the DOX-NPs with both mannose and acid-sensitive sheddable PEG significantly increased the accumulation of DOX in tumors, enhanced the uptake of the DOX by TAMs, but decreased the distribution of DOX in mononuclear phagocyte system (MPS), such as liver. We also confirmed that the acid-sensitive sheddable PEGylated, mannose-modified DOX-nanoparticles (DOX-AS-M-NPs) targeted TAMs because depletion of TAMs in tumor-bearing mice significantly decreased the accumulation of DOX in tumor tissues. Furthermore, in a B16-F10 tumor-bearing mouse model, we showed that the DOX-AS-M-NPs were significantly more effective than free DOX in controlling tumor growth but had only minimum effect on the macrophage population in mouse liver and spleen. The AS-M-NPs are promising in targeting cytotoxic or macrophage-modulating agents into tumors to improve tumor therapy.

Emotional Distress May Increase Risk for Self-Medication and Lower Risk for Mood-related Drinking Consequences in Adolescents.

The current study examines indicators of emotional distress and coping that may define sub-populations of adolescents at risk for two potential affect-related mechanisms underlying substance misuse: self-medication and mood-related drinking consequences. Although theory and empirical evidence point to the salience of affect-related drinking to current and future psychopathology, we have little knowledge of whether or for whom such mood-related processes exist in adolescents because few studies have used methods that optimally match the phenomenon to the level of analysis. Consequently, the current study uses multilevel modeling in which daily reports of negative mood and alcohol use are nested within individuals to examine whether adolescents with more emotional distress and poorer coping skills are more likely to evidence self-medication and mood-related drinking consequences. Seventy-five adolescents participated in a multi-method, multi-reporter study in which they completed a 21-day experience sampling protocol assessing thrice daily measures of mood and daily measures of alcohol use. Results indicate that adolescents reporting greater anger are more likely to evidence self-medication. Conversely, adolescents displaying lower emotional distress and more active coping are more likely to evidence mood-related drinking consequences. Implications for identifying vulnerable sub-populations of adolescents at risk for these mechanisms of problematic alcohol use are discussed.

Expression of neprilysin in skeletal muscle reduces amyloid burden in a transgenic mouse model of Alzheimer disease.

Neprilysin (NEP) is a zinc metallopeptidase that efficiently degrades the amyloid beta (Abeta) peptides believed to be involved in the etiology of Alzheimer disease (AD). The focus of this study was to develop a new and tractable therapeutic approach for treating AD using NEP gene therapy. We have introduced adeno-associated virus (AAV) expressing the mouse NEP gene into the hindlimb muscle of 6-month-old human amyloid precursor protein (hAPP) (3X-Tg-AD) mice, an age which correlates with early stage AD. Overexpression of NEP in muscle decreased brain soluble Abeta peptide levels by approximately 60% and decreased amyloid deposits by approximately 50%, with no apparent adverse effects. Expression of NEP on muscle did not affect the levels of a number of other physiological peptides known to be in vitro substrates. These findings demonstrate that peripheral expression of NEP and likely other peptidases represents an alternative to direct administration into brain and illustrates the potential for using NEP expression in muscle for the prevention and treatment of AD.

The association between observed parental emotion socialization and adolescent self-medication.

The current study examined the moderating influence of observed parental emotion socialization (PES) on self-medication in adolescents. Strengths of the study include the use of a newly developed observational coding system further extending the study of PES to adolescence, the use of an experience sampling method to assess the daily covariation between negative affect and substance use, and a focus on PES styles defined by the interaction of emotion-dismissing and emotion-coaching behaviors. Using multi-leveling modeling, we tested PES as a moderator of daily negative mood-substance use relation in a sample of 65 elevated-risk adolescents (48% male, 58% Caucasian, with a median age of 14). Results showed a three-way interaction between emotion-coaching PES, emotion-dismissing PES and daily negative mood in predicting daily substance use. Results are discussed in terms of the importance of PES styles and their effects on self-medication through compromised emotion regulation and interpersonal processes.

Conduct problems moderate self-medication and mood-related drinking consequences in adolescents.

OBJECTIVE: We tested whether conduct problems moderate the relation between negative mood and drinking in adolescents as consistent with either a self-medication or a drinking consequences model. METHOD: The sample included 75 rising ninth graders (i.e., in the summer before starting ninth grade) who completed a two-stage, multimethod, multireporter study. We used experience sampling to assess negative mood and drinking across 21 days and hierarchical linear modeling to test our hypotheses. RESULTS: Counter to predictions, both self-medication and drinking consequence mechanisms were evident only in youth with fewer conduct problems. CONCLUSIONS: Findings provide support for the importance of considering multiple mechanisms as underlying the relation between negative mood and drinking as pertaining to subpopulations of vulnerable youth. Implications for prevention and understanding negative mood-drinking relations in adolescents are discussed.

Cellular and molecular characterization of oxidative stress in olfactory epithelium of Harlequin mutant mouse.

Oxidative stress in the olfactory system is a major factor associated with age-related olfactory impairment, although the mechanisms by which this occurs are not completely understood. The Harlequin mutant mouse (Hq/Y), which carries an X-linked recessive mutation in the Aifm1 gene, is a model of progressive oxidative stress-induced neurodegeneration in the cerebellum and retina. To determine whether the Hq/Y mutant mouse is a suitable model of oxidative stress-associated olfactory aging, we investigated cellular and molecular changes in the olfactory epithelium (OE) and olfactory bulb (OB) of 6-month-old male Hq/Y mice compared to those in sex-matched littermate controls (+/Y) and in age- and sex-matched C57BL/6 mice. Immunoreactivity for apoptosis-inducing factor, the protein product of Aifm1, was localized in mature olfactory sensory neurons (mOSNs) in +/Y mice but was rarely detected in Hq/Y mice. Hq/Y mice also exhibited increased lipofuscin autofluorescence and increased immunoreactivity for an oxidative DNA/RNA damage marker in mOSNs and in mitral/tufted cells in the OB and an increased number of cleaved caspase-3 immunoreactive apoptotic cells in the OE. Microarray analysis demonstrated that Aifm1 expression was down-regulated by 80% in the OE of Hq/Y mice compared to that in +/Y mice. Most significantly, regulated genes were classified into functional categories of cell signaling/apoptosis/cell cycle, oxidative stress/aging, and cytoskeleton/extracellular matrix/transport-associated. Analysis with EASE software indicated that the functional categories significantly overrepresented in Hq/Y mice included up-regulated mitochondrial genes and down-regulated cytoskeletal organization- and neurogenesis-related genes. Our results strongly support the Hq/Y mutant mouse being a novel model for mechanistic studies of oxidative stress-associated olfactory aging.