Development of a Mind Body Program for Obese Knee Osteoarthritis Patients with Comorbid Depression

Knee osteoarthritis (OA) is the most common joint disorder in the U.S. and a leading cause of disability. Depression and obesity are highly comorbid among knee OA patients, and the combination of obesity and depression is associated with decreased physical activity, higher pain and disability, and more rapid cartilage degradation. Depression, obesity and OA exacerbate one another and share a common pathophysiology involving systemic inflammation and pro-inflammatory cytokines, reflecting a complex mind-body interaction. Current treatments for knee OA offer little to no benefit over placebo, and do not emphasize mind-body practices or physical activity to target the underlying pathophysiology. Mind-body interventions to lessen depressive symptoms and increase physical activity offer the ability to target biological, mechanical and psychological mechanisms of OA progression. Our long-term goals are to evaluate the mechanisms by which the Relaxation Response Resiliency Program (3RP) delivered via secure telehealth, and adapted for patients with depression, obesity and knee OA (GetActive-OA) promotes increases in physical activity and improved knee health. We hypothesize that the synergistic interaction between mindfulness, adaptive thinking, positive psychology and healthy living skills of the GetActive-OA will slow the progression of symptomatic knee OA by reducing pro-inflammatory cytokine expression and promoting optimal mechanical loading of the cartilage. Here we present the protocol for a mixed methods study that will adapt the 3RP for the needs of knee OA patients with depression and obesity with a focus on increasing physical activity (GetActive-OA), and iteratively maximize the feasibility, credibility and acceptability of the programs and research procedures

Proteomic analysis of the action of the Mycobacterium ulcerans toxin mycolactone: targeting host cells cytoskeleton and collagen

Buruli ulcer (BU) is a neglected tropical disease caused by Mycobacterium ulcerans. The tissue damage characteristic of BU lesions is known to be driven by the secretion of the potent lipidic exotoxin mycolactone. However, the molecular action of mycolactone on host cell biology mediating cytopathogenesis is not fully understood. Here we applied two-dimensional electrophoresis (2-DE) to identify the mechanisms of mycolactone's cellular action in the L929 mouse fibroblast proteome. This revealed 20 changed spots corresponding to 18 proteins which were clustered mainly into cytoskeleton-related proteins (Dync1i2, Cfl1, Crmp2, Actg1, Stmn1) and collagen biosynthesis enzymes (Plod1, Plod3, P4ha1). In line with cytoskeleton conformational disarrangements that are observed by immunofluorescence, we found several regulators and constituents of both actin- and tubulin-cytoskeleton affected upon exposure to the toxin, providing a novel molecular basis for the effect of mycolactone. Consistent with these cytoskeleton-related alterations, accumulation of autophagosomes as well as an increased protein ubiquitination were observed in mycolactone-treated cells. In vivo analyses in a BU mouse model revealed mycolactone-dependent structural changes in collagen upon infection with M. ulcerans, associated with the reduction of dermal collagen content, which is in line with our proteomic finding of mycolactone-induced down-regulation of several collagen biosynthesis enzymes. Our results unveil the mechanisms of mycolactone-induced molecular cytopathogenesis on exposed host cells, with the toxin compromising cell structure and homeostasis by inducing cytoskeleton alterations, as well as disrupting tissue structure, by impairing the extracellular matrix biosynthesis.The research leading to these results has received funding from the European Community's Seventh Framework Program (FP7/2007-2013) under grant agreement Nu 241500 (BuruliVac), from Fundacao Calouste Gulbenkian and from Projeto Estrategico - LA 26 - 2013-2014 (PEst-C/SAU/LA0026/2013). JBG, TGM and AGF had a personal grant from the Portuguese Science and Technology Foundation (FCT) (SFRH/BD/33573/2009, SFRH/BD/41598/2007 and SFRH/BPD/68547/2010, respectively). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Membrane fluidity matters: Hyperthermia from the aspects of lipids and membranes

Hyperthermia is a promising treatment modality for cancer in combination both with radio- and chemotherapy. In spite of its great therapeutic potential, the underlying molecular mechanisms still remain to be clarified. Due to lipid imbalances and 'membrane defects' most of the tumour cells possess elevated membrane fluidity. However, further increasing membrane fluidity to sensitise to chemo-or radiotherapy could have some other effects. In fact, hyperfluidisation of cell membrane induced by membrane fluidiser initiates a stress response as the heat shock protein response, which may modulate positively or negatively apoptotic cell death. Overviewing some recent findings based on a technology allowing direct imaging of lipid rafts in live cells and lipidomics, novel aspects of the intimate relationship between the 'membrane stress' of tumour cells and the cellular heat shock response will be highlighted. Our findings lend support to both the importance of membrane remodelling and the release of lipid signals initiating stress protein response, which can operate in tandem to control the extent of the ultimate cellular thermosensitivity. Overall, we suggest that the fluidity variable of membranes should be used as an independent factor for predicting the efficacy of combinational cancer therapies

Metabolic synergies in the biotransformation of organic and metallic toxic compounds by a saprotrophic soil fungus

The saprotrophic fungus Penicillium griseofulvum was chosen as model organism to study responses to a mixture of hexachlorocyclohexane (HCH) isomers (α-HCH, β-HCH, γ-HCH, δ-HCH) and of potentially toxic metals (vanadium, lead) in solid and liquid media. The P. griseofulvum FBL 500 strain was isolated from polluted soil containing high concentrations of HCH isomers and potentially toxic elements (Pb, V). Experiments were performed in order to analyse the tolerance/resistance of this fungus to xenobiotics, and to shed further light on fungal potential in inorganic and organic biotransformations. The aim was to examine the ecological and bioremedial potential of this fungus verifying the presence of mechanisms that allow it to transform HCH isomers and metals under different, extreme, test conditions. To our knowledge, this work is the first to provide evidence on the biotransformation of HCH mixtures, in combination with toxic metals, by a saprotrophic non-white-rot fungus and on the metabolic synergies involved