Cytokine-, Neurotrophin-, and Motor Rehabilitation-Induced Plasticity in Parkinson's Disease.

Neuroinflammation and cytokine-dependent neurotoxicity appear to be major contributors to the neuropathology in Parkinson's disease (PD). While pharmacological advancements have been a mainstay in the treatment of PD for decades, it is becoming increasingly clear that nonpharmacological approaches including traditional and nontraditional forms of exercise and physical rehabilitation can be critical adjunctive or even primary treatment avenues. Here, we provide an overview of preclinical and clinical research detailing the biological role of proinflammatory molecules in PD and how motor rehabilitation can be used to therapeutically modulate neuroinflammation, restore neural plasticity, and improve motor function in PD.

Senolytic effects of quercetin in an in vitro model of pre-adipocytes and adipocytes induced senescence.

The dysfunction of adipose tissue with aging and the accumulation of senescent cells has been implicated in the pathophysiology of chronic diseases. Recently interventions capable of reducing the burden of senescent cells and in particular the identification of a new class of drugs termed senolytics have been object of extensive investigation. We used an in vitro model of induced senescence by treating both pre-adipocytes as well as mature adipocytes with hydrogen peroxide (H2O2) at a sub-lethal concentration for 3 h for three consecutive days, and hereafter with 20 uM quercetin at a dose that in preliminary experiments resulted to be senolytic without cytotoxicity. H2O2 treated pre-adipocytes and adipocytes showed typical senescence-associated features including increased beta-galactosidase activity (SA-ß-gal) and p21, activation of ROS and increased expression of pro-inflammatory cytokines. The treatment with quercetin in senescent pre-adipocytes and adipocytes was associated to a significant decrease in the number of the SA-ß-gal positive cells along with the suppression of ROS and of inflammatory cytokines. Besides, quercetin treatment decreased miR-155-5p expression in both models, with down-regulation of p65 and a trend toward an up-regulation of SIRT-1 in complete cell extracts. The senolytic compound quercetin could affect AT ageing by reducing senescence, induced in our in vitro model by oxidative stress. The downregulation of miRNA-155-5p, possibly through the modulation of NF-κB and SIRT-1, could have a key role in the effects of quercetin on both pre-adipocytes and adipocytes.

In vitro model of chronological aging of adipocytes: Interrelationships with hypoxia and oxidation.

Aging is a physiological process characterized by an age-progressive decline in intrinsic physiological functions, with an increased risk of developing chronic metabolic conditions, such as insulin resistance and diabetes. Furthermore, from a physiopathological point of view, several authors describe an association between oxidative stress, hypoxia and these metabolic conditions. It had been suggested that adipose tissue (AT) dysfunction, senescent cell accumulation and proinflammatory pathways may be involved in this processes. The purpose of this study was to develop an in vitro model to study the progressive morphological and functional changes of adipocytes with aging, in standard culture conditions and after severe hypoxia and hydrogen peroxide treatment. We evaluated the degree of apoptosis and intracellular reactive oxygen species (ROS) accumulation as well as the gene expression profile of aging adipocytes. Our results show that aged adipocytes become senescent, undergo apoptosis, accumulate ROS, and present an inflammatory profile with an increase in mRNA expression level of key proteins related to the remodeling of the extracellular matrix (ECM). Aged adipocytes present increased levels of p53, p21 and p16, key regulators of senescence, and a decrease in SIRT-1 protein compared to younger cells. Moreover, adipocytes aged in hypoxia or in oxidative stress conditions represent a model of accelerated aging with a decrease in their area, a greater proportion of apoptotic and of intracellular ROS accumulation compared to controls. This study characterizes the progressive morphological and functional changes in aging adipocytes during prolonged cell cultures and explores the addictive effects of hypoxia and oxidation, given at different stages of cellular maturation and senescence.