Uncovering the Role of Natural and Synthetic Small Molecules in Counteracting the Burden of α-Synuclein Aggregates and Related Toxicity in Different Models of Parkinson’s Disease

A proteostasis network represents a sophisticated cellular system that controls the whole process which leads to properly folded functional proteins. The imbalance of proteostasis determines a quantitative increase in misfolded proteins prone to aggregation and elicits the onset of different diseases. Among these, Parkinson's Disease (PD) is a progressive brain disorder characterized by motor and non-motor signs. In PD pathogenesis, alpha-Synuclein (α-Syn) loses its native structure, triggering a polymerization cascade that leads to the formation of toxic inclusions, the PD hallmark. Because molecular chaperones represent a "cellular arsenal" to counteract protein misfolding and aggregation, the modulation of their expression represents a compelling PD therapeutic strategy. This review will discuss evidence concerning the effects of natural and synthetic small molecules in counteracting α-Syn aggregation process and related toxicity, in different in vitro and in vivo PD models. Firstly, the role of small molecules that modulate the function(s) of chaperones will be highlighted. Then, attention will be paid to small molecules that interfere with different steps of the protein-aggregation process. This overview would stimulate in-depth research on already-known small molecules or the development of new ones, with the aim of developing drugs that are able to modify the progression of the disease

The down-regulation of clusterin expression enhances the αsynuclein aggregation process

Parkinson’s Disease (PD) is a progressive neurodegenerative disease characterized by the presence of proteinaceous aggregates of αSynuclein (αSyn) in the dopaminergic neurons. Chaperones are key components of the proteostasis network that are able to counteract αSyn’s aggregation, as well as its toxic effects. Clusterin (CLU), a molecular chaperone, was consistently found to interfere with Aβ aggregation in Alzheimer’s Disease (AD). However, its role in PD pathogenesis has yet to be extensively investigated. In this study, we assessed the involvement of CLU in the αSyn aggregation process by using SH-SY5Y cells stably overexpressing αSyn (SH-Syn). First, we showed that αSyn overexpression caused a strong increase in CLU expression without affecting levels of Hsp27, Hsp70, and Hsp90, which are the chaperones widely recognized to counteract αSyn burden. Then, we demonstrated that αSyn aggregation, induced by proteasome inhibition, determines a strong increase of CLU in insoluble aggregates. Remarkably, we revealed that CLU down-regulation results in an increase of αSyn aggregates in SH-Syn without significantly affecting cell viability and the Unfolded Protein Response (UPR). Furthermore, we demonstrated the direct molecular interaction between CLU and αSyn via a co-immunoprecipitation (co-IP) assay. All together, these findings provide incontrovertible evidence that CLU is an important player in the response orchestrated by the cell to cope with αSyn burden

Antioxidant and pro-oxidant phytochemicals in ultrasound and microwave assisted extracts from hop cones: a statistical modelling approach

The present study investigated the relationships between different green extracts from hop cones (HGEs) and their cytoprotective/cytotoxic effects on human cultured colonocytes, using a multivariate statistical approach. HGEs were obtained by ultrasound (US) and microwave (MW) assisted extraction, using food grade solvents (ethanol and ethanol : water = 50 : 50 mixture). Their chemical fingerprinting showed the presence of 21 bioactive compounds belonging to the classes of polyphenols, prenylcalcones and floroacylglucinols, which were more abundant in MW ethanolic extracts. All the extracts, except for the US hydroalcoholic one, exerted a cytotoxic effect in a dose-dependent manner. HGEs did not alter the cellular redox status at low doses, while at the highest concentrations considered they displayed a pro-oxidant or antioxidant activity. Chemometric analysis revealed the compounds most correlated with cellular toxicity and/or ROS production and that the differences observed in Caco2 cells could be adequately explained by 2D statistical models including inhibitor-promoting agent pairs

Systematic review on strength training in Parkinson’s disease: an unsolved question

Ileana Ramazzina,1 Benedetta Bernazzoli,2 Cosimo Costantino1 1Department of Biomedical, Biotechnological and Translational Sciences, 2Department of Clinical and Experimental Medicine, Graduate School of Rehabilitation and Physical Medicine, University of Parma, Parma, Italy Abstract: The purpose of this study was to investigate the effectiveness of strength training, performed against a different resistance from body weight, in improving motor and nonmotor symptoms in patients with Parkinson’s disease (PD). The following electronic databases were searched: PubMed, Physiotherapy Evidence Database, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science. The review was conducted and reported in accordance with the PRISMA statement. Thirteen high-quality randomized controlled trials were included. Strength training performed against external resistance is well tolerated and appears to be a suitable physical activity to improve both physical parameters and quality of life parameters of PD subjects. However, although the study intervention included strength training, only a few selected studies assessed the improvement of muscle strength. Despite the encouraging results, it is difficult to establish a correlation between strength training and the improvements made. Our review highlights the lack of common intent in terms of study design and the presence of different primary and secondary outcomes. Accordingly, further studies are needed to support the beneficial effects of different types of strength training in PD subjects and to underline the superiority of strength training in PD patients with respect to other training. Keywords: Parkinson’s disease, strength training, muscle strengt

Procede de conversion d'acide urique en allantoine et enzymes associees

L'invention concerne une molécule de polypeptide capable de moduler de manière sélective la conversion d'acide urique en S(+)-allantoïne. L'invention concerne également une composition pharmaceutique permettant de traiter des troubles relatifs à l'acide urique et un procédé permettant de moduler de manière sélective la conversion d'acide urique en S(+)-allantoïne

Method for conversion of uric acid to allantoin and related enzymes

A polypeptide molecule able to selectively modulate uric acid conversion into S(+)- allantoin is described. A pharmaceutical composition for treating uric acid related disorders and a process to selectively modulate uric acid conversion into S(+)-allantoin are also disclosed