JOTROL, a Novel Formulation of Resveratrol, Shows Beneficial Effects in the 3xTg-AD Mouse Model.

BACKGROUND: Alzheimer's disease (AD) has minimally effective treatments currently. High concentrations of resveratrol, a polyphenol antioxidant found in plants, have been reported to affect several AD-related and neuroprotective genes. To address the low bioavailability of resveratrol, we investigated a novel oral formulation of resveratrol, JOTROL™, that has shown increased pharmacokinetic properties compared to non-formulated resveratrol in animals and in humans. OBJECTIVE: We hypothesized that equivalent doses of JOTROL, compared to non-formulated resveratrol, would result in greater brain exposure to resveratrol, and more efficacious responses on AD biomarkers. METHODS: For sub-chronic reversal studies, 15-month-old male triple transgenic (APPSW/PS1M146V/TauP301L; 3xTg-AD) AD mice were treated orally with vehicle or 50 mg/kg JOTROL for 36 days. For prophylactic studies, male and female 3xTg-AD mice were similarly administered vehicle, 50 mg/kg JOTROL, or 50 mg/kg resveratrol for 9 months starting at 4 months of age. A behavioral battery was run, and mRNA and protein from brain and blood were analyzed for changes in AD-related gene and protein expression. RESULTS: JOTROL displays significantly increased bioavailability over non-formulated resveratrol. Treatment with JOTROL resulted in AD-related gene expression changes (Adam10, Bace1, Bdnf, Psen1) some of which were brain region-dependent and sex-specific, as well as changes in inflammatory gene and cytokine levels. CONCLUSION: JOTROL may be effective as a prophylaxis and/or treatment for AD through increased expression and/or activation of neuroprotective genes, suppression of pro-inflammatory genes, and regulation of central and peripheral cytokine levels.

Developing a Web Platform to Optimize the Self-Management of People Living with a Chronic Respiratory Disease.

Purpose: The purpose of this article is to describe the development of a new Web platform to optimize self-management after pulmonary rehabilitation (PR) for persons living with a chronic respiratory disease (CRD) and to present data on its usability. Method: The Web platform is informed by a theoretical framework of behaviour changes and concepts of self-management and self-efficacy. It uses breathing exercises and a logbook and is meant to be a self-management tool. Usability was tested for 8 months after PR with a group consisting of five patients with chronic obstructive pulmonary disease and one with pulmonary fibrosis. We evaluated adherence (e.g., number of exercise/weeks), quality of life, dyspnoea, and functional capacity. We measured frequency count for adherence and pre-post differences per patient for clinical outcomes. Results: Four participants' adherence was higher than 50% of completed exercises (72 exercise/weeks). Five of six participants showed maintenance of functional capacity (6-minute walk test) 8 months after PR. Four participants showed maintenance of their quality of life. Four participants showed a deterioration in dyspnoea on the Borg Scale of Perceived Exertion. Conclusions: We developed a new theory-informed Web platform to optimize self-management after PR for persons living with a CRD. The pilot Web platform appears to optimize adherence to self-management techniques and possibly stabilize people's health outcomes.

Objectif : décrire la création d'une nouvelle plateforme en ligne pour optimiser l'autogestion après la réadaptation pulmonaire (RP) des personnes vivant avec une maladie pulmonaire chronique et présenter des données sur sa facilité d'utilisation. Méthodologie : la plateforme repose sur une structure théorique de changements de comportement et de concepts d'autogestion et d'autoefficacité. Elle se veut un outil d'autogestion faisant appel à des exercices respiratoires et à un journal. Les chercheurs en ont évalué la facilité d'utilisation auprès d'un groupe de cinq patients atteints d'une maladie pulmonaire obstructive chronique et d'un patient atteint de fibrose pulmonaire pendant huit mois après la RP. Ils ont évalué l'adhésion (p. ex., nombre d'exercices par semaine), la qualité de vie, la dyspnée et la capacité fonctionnelle. Ils ont également mesuré la fréquence pour déterminer l'adhésion et la différence avant-après de chaque patient pour évaluer les résultats cliniques. Résultats : quatre participants ont présenté une adhésion supérieure à 50 % pour ce qui est des exercices complétés (72 exercices par semaine). Quatre des six participants avaient maintenu leur capacité fonctionnelle (test de marche de six minutes) huit mois après la RP, et quatre participants avaient maintenu leur qualité de vie. Cependant, quatre participants ont présenté une détérioration de leur dyspnée à l'échelle de Borg. Conclusion : les chercheurs ont créé une nouvelle plateforme reposant sur des critères théoriques pour optimiser l'autogestion après une RP chez les personnes vivant avec une maladie pulmonaire chronique. Le projet-pilote de plateforme en ligne semble optimiser l'adhésion aux techniques d'autogestion et pourrait stabiliser l'état de santé des patients.

Matriptase proteolytically activates influenza virus and promotes multicycle replication in the human airway epithelium.

Influenza viruses do not encode any proteases and must rely on host proteases for the proteolytic activation of their surface hemagglutinin proteins in order to fuse with the infected host cells. Recent progress in the understanding of human proteases responsible for influenza virus hemagglutinin activation has led to the identification of members of the type II transmembrane serine proteases TMPRSS2 and TMPRSS4 and human airway trypsin-like protease; however, none has proved to be the sole enzyme responsible for hemagglutinin cleavage. In this study, we identify and characterize matriptase as an influenza virus-activating protease capable of supporting multicycle viral replication in the human respiratory epithelium. Using confocal microscopy, we found matriptase to colocalize with hemagglutinin at the apical surface of human epithelial cells and within endosomes, and we showed that the soluble form of the protease was able to specifically cleave hemagglutinins from H1 virus, but not from H2 and H3 viruses, in a broad pH range. We showed that small interfering RNA (siRNA) knockdown of matriptase in human bronchial epithelial cells significantly blocked influenza virus replication in these cells. Lastly, we provide a selective, slow, tight-binding inhibitor of matriptase that significantly reduces viral replication (by 1.5 log) of H1N1 influenza virus, including the 2009 pandemic virus. Our study establishes a three-pronged model for the action of matriptase: activation of incoming viruses in the extracellular space in its shed form, upon viral attachment or exit in its membrane-bound and/or shed forms at the apical surface of epithelial cells, and within endosomes by its membrane-bound form where viral fusion takes place.