Exploiting PI3K/mTOR signaling to accelerate epithelial wound healing

The molecular circuitries controlling the process of skin wound healing have gained new significant insights in recent years. This knowledge is built on landmark studies on skin embryogenesis, maturation, and differentiation. Furthermore, the identification, characterization, and elucidation of the biological roles of adult skin epithelial stem cells and their influence in tissue homeostasis have provided the foundation for the overall understanding of the process of skin wound healing and tissue repair. Among numerous signaling pathways associated with epithelial functions, the PI3K/Akt/mTOR signaling route has gained substantial attention with the generation of animal models capable of dissecting individual components of the pathway, thereby providing a novel insight into the molecular framework underlying skin homeostasis and tissue regeneration. In this review, we focus on recent findings regarding the mechanisms involved in wound healing associated with the upregulation of the activity of the PI3K/Akt/mTOR circuitry. This review highlights critical findings on the molecular mechanisms controlling the activation of mTOR, a downstream component of the PI3K–PTEN pathway, which is directly involved in epithelial migration and proliferation. We discuss how this emerging information can be exploited for the development of novel pharmacological intervention strategies to accelerate the healing of critical size wounds.     

Protective effects of Mentha piperita Linn on benzo[a]pyrene-induced lung carcinogenicity and mutagenicity in Swiss albino mice

The Editor-in-Chief has retracted the published paper "ProtectiveEffects of     

Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning

STUDY OBJECTIVES: Evidence suggests that, to maintain treatment effects, nasal continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea (OSA) needs to be used every night. What remains unknown is the nightly duration of use required to normalize functioning. This study, employing probit analyses and piecewise regression to estimate dose-response functions, estimated likelihoods of return to normal levels of sleepiness and daily functioning relative to nightly duration of CPAP. DESIGN: Multicenter, quasi-experimental study. SETTING: Seven sleep centers in the United States and Canada. PARTICIPANTS: Patients with severe OSA (total cohort n = 149; the numbers of included participants from 85 - 120, depending on outcome analyzed.) Interventions: CPAP. MEASUREMENTS AND RESULTS: Before treatment and again after 3 months of therapy, participants completed a day of testing that included measures of objective and subjective daytime sleepiness and functional status. There were significant differences in mean nightly CPAP duration between treatment responders and nonresponders across outcomes. Thresholds above which further improvements were less likely relative to nightly duration of CPAP were identified for Epworth Sleepiness Scale score (4 hours), Multiple Sleep Latency Test (6 hours), and Functional Outcomes associated with Sleepiness Questionnaire (7.5 hours). A linear dose-response relationship (P < 0.01) between increased use and achieving normal levels was shown for objective and subjective daytime sleepiness, but only up to 7 hours use for functional status. CONCLUSIONS: Our analyses suggest that a greater percentage of patients will achieve normal functioning with longer nightly CPAP durations, but what constitutes adequate use varies between different outcomes.     

Potent block of Cx36 and Cx50 gap junction channels by mefloquine

Recently, great interest has been shown in understanding the functional roles of specific gap junction proteins (connexins) in brain, lens, retina, and elsewhere. Some progress has been made by studying knockout mice with targeted connexin deletions. For example, such studies have implicated the gap junction protein Cx36 in synchronizing rhythmic activity of neurons in several brain regions. Although knockout strategies are informative, they can be problematic, because compensatory changes sometimes occur during development. Therefore, it would be extremely useful to have pharmacological agents that block specific connexins, without major effects on other gap junctions or membrane channels. We show that mefloquine, an antimalarial drug, is one such agent. It blocked Cx36 channels, expressed in transfected N2A neuroblastoma cells, at low concentrations (IC(50) approximately 300 nM). Mefloquine also blocked channels formed by the lens gap junction protein, Cx50 (IC(50) approximately 1.1 microM). However, other gap junctions (e.g., Cx43, Cx32, and Cx26) were only affected at concentrations 10- to 100-fold higher. To further examine the utility and specificity of this compound, we characterized its effects in acute brain slices. Mefloquine, at 25 microM, blocked gap junctional coupling between interneurons in neocortical slices, with minimal nonspecific actions. At this concentration, the only major side effect was an increase in spontaneous synaptic activity. Mefloquine (25 microM) caused no significant change in evoked excitatory or inhibitory postsynaptic potentials, and intrinsic cellular properties were also mostly unaffected. Thus, mefloquine is expected to be a useful tool to study the functional roles of Cx36 and Cx50.     

Generation of normal human red cell volume, hemoglobin content, and membrane area distributions by "birth" or regulation?

Using flow cytometry and osmotic lysis measurements, we document here the means and coefficients of variation of the following red cell (RBC) properties: hemoglobin (Hb) content, volume, Hb concentration, and relative lytic tonicity distributions in populations of normal human RBCs, before and after density fractionation. The distributions showed a pattern characterized by much larger coefficients of variation of the Hb content and volume distributions than of the Hb concentration and relative lytic tonicity distributions. From analysis of the factors that determine those RBC properties, the patterns were interpreted as reflecting previously unrecognized statistical proportionalities between cell osmolyte content, Hb content, and membrane area. The possible origin of these statistical links was analyzed by considering alternative models with and without the participation of regulatory processes during cell maturation. A model was shown to be feasible in which mature RBC variability with proportional volume, area, and Hb content arises solely from cell size variability at the last erythroid cell division.