Caenorhabditis elegans RAC1/ced-10 mutants as a new animal model to study very early stages of Parkinson's disease.

Patients with Parkinson's disease (PD) display non-motor symptoms arising prior to the appearance of motor signs and before a clear diagnosis. Motor and non-motor symptoms correlate with progressive deposition of the protein alpha-synuclein (Asyn) both within and outside of the central nervous system, and its accumulation parallels neurodegeneration. The genome of Caenorhabditis elegans does not encode a homolog of Asyn, thus rendering this nematode an invaluable system with which to investigate PD-related mechanisms in the absence of interference from endogenous Asyn aggregation. CED-10 is the nematode homolog of human RAC1, a small GTPase needed to maintain the function and survival of dopaminergic neurons against human Asyn-induced toxicity in C. elegans. Here, we introduce C. elegans RAC1/ced-10 mutants as a predictive tool to investigate early PD symptoms before neurodegeneration occurs. Deep phenotyping of these animals reveals that, early in development, they displayed altered defecation cycles, GABAergic abnormalities and an increased oxidation index. Moreover, they exhibited altered lipid metabolism evidenced by the accumulation of lipid droplets. Lipidomic fingerprinting indicates that phosphatidylcholine and sphingomyelin, but not phosphatidylethanolamine or phosphatidylserine, were elevated in RAC1/ced-10 mutant nematodes. These collective characteristics reflect the non-motor dysfunction, GABAergic neurotransmission defects, upregulation of stress response mechanisms, and metabolic changes associated with early-onset PD. Thus, we put forward an easy-to-manipulate preclinical animal model to deepen our understanding of early-stage PD and accelerate the translational path for therapeutic target discovery.

Metallosomes for biomedical applications by mixing molybdenum carbonyl metallosurfactants and phospholipids.

New supramolecular systems have been prepared by mixing molybdenum organometallic metallosurfactants M(CO)5L and M(CO)4L2 {L = Ph2P(CH2)6SO3Na} with the phospholipid phosphatidylcholine. The analysis of the resulting supramolecular structures using dynamic light scattering and cryo-transmission electron microscopy has shown the formation of different aggregates depending on the metallosurfactant/phospholipid ratio, as well as a significantly different behaviour between the two studied metallosurfactants. Mixed vesicles, with properties very similar to liposomes, can be obtained with both compounds, and are called metallosomes. The formation of the mixed aggregates has also been studied by microfluidics using MeOH and EtOH as organic solvents, and it has been observed that the size of the aggregates is strongly dependent on the organic solvent used. In order to analyse the viability of these mixed systems as CO Releasing Molecules (CORMs) for biomedical applications, the CO release was studied by FT-IR spectroscopy, showing that they behave as photo-CORMs with visible and ultraviolet light. Toxicity studies of the different mixed aggregate systems have shown that metallosomes exhibit a very low toxicity, similar to liposomes that do not contain metallosurfactants, which is well below the results observed for pure metallosurfactants. Micro-FTIR microscopy using synchrotron radiation has shown the presence of metallosurfactants in cells. The results of this study show the influence of the length of the hydrocarbon chain on the properties of these mixed systems, compared with previously reported data.

Low-toxicity metallosomes for biomedical applications by self-assembly of organometallic metallosurfactants and phospholipids.

A new and convenient strategy for the preparation of metallosomes has been developed by mixing organometallic metallosurfactants and phospholipids. These aggregates show the characteristic properties of liposomes (stability upon dilution and low toxicity) and the toxicity is at least ten-fold lower than that of the metallosurfactant aggregates without phospholipids.

Effect of poly(propylene imine) glycodendrimers on ß-amyloid aggregation in vitro and in APP/PS1 transgenic mice, as a model of brain amyloid deposition and Alzheimer's disease.

Poly(propylene imine) (PPI) glycodendrimers are promising candidates as drug carriers and antiamyloidogenic and antiprionic agents. In this study the anti-ß-amyloid capacity of PPI glycodendrimers of the fourth and fifth generations was investigated in vitro and in vivo. We assessed distinct PPI glycodendrimers including G4mDS and G5mDS, with electroneutral maltose shell, and G4mOS and G4m-IIIOS, with cationic maltose or maltotriose shell. Our results show that in vitro PPI maltose dendrimers reduce the toxicity of Aß(1-42). However, only the electroneutral maltose dendrimers G4mDS and G5mDS reduce the toxicity of Alzheimer's disease brain extracts in SH-SY5Y neuroblastoma cells. PPI maltose dendrimers with electroneutral or cationic surface penetrate the cytoplasm of cultured cells, and they reach the brain when administered intranasally. Both cationic G4mOS and electroneutral G4mDS are able to modify the total burden of ß-amyloid in APP/PS1 mice. The studied dendrimers did not reverse memory impairment in APP/PS1 mice following chronic administration; moreover, cationic G4mOS caused cognitive decline in nontransgenic mice. In spite of the capacity of G4mDS and G4mOS to cross the blood-brain barrier and modulate Aß aggregation in APP/PS1 mice, further studies are needed to learn how to reduce the harmful effects of maltose dendrimers in vivo.

Differential response of plasma and immune cell's vitamin E levels to physical activity and antioxidant vitamin supplementation.

OBJECTIVE: To assess the differential response of plasma, lymphocyte and neutrophil vitamin E levels to high-intensity physical activity and to vitamin C and E supplementation. SUBJECTS: In all, 14 male trained amateur runners (32-36 y old) were randomly divided in two groups (supplemented and placebo), and participated in a half marathon race. The subjects did not take any other supplements than the ones provided for this study. INTERVENTION: Vitamin C (152 mg/day) and E (50 mg/day) supplementation was administrated to athletes for a month, using a new almond-based isotonic and energetic beverage (supplemented group). The usual dietary habits of participants were assessed using a self-reported 7-day 24-h recall before the day of the study. To avoid the beverage influence, nonenriched vitamin C and E almond-based isotonic and energetic beverage was given to the placebo group. After 1 month, subjects participated in a half marathon race (21 km run). Vitamin E concentration was determined in plasma, neutrophils and lymphocytes before and immediately after the race, and 3 h after finishing the race. RESULTS: Daily energy intake and caloric profile of supplemented and placebo group were not different except for vitamin C and E supplementation. Vitamin supplementation and exercise had no effect on vitamins E levels in plasma. The exercise significantly (P<0.05) increased the lymphocyte vitamin E concentration both in the placebo (+119%) and supplemented groups (+128%), and neutrophil vitamin E content in the supplemented group (+88%). These levels remained significantly (P<0.05) high after the short recovery. After exercise, vitamin E levels in lymphocytes and neutrophils of supplemented subjects were practically twice the levels before exercise, whereas neutrophil vitamin E content of the placebo group was close to those in plasma. CONCLUSION: After endurance exercise, lymphocytes increased their vitamin E content in the supplemented and placebo subjects whereas this trend in neutrophils was just observed in the supplemented group. The determination of vitamin E content in lymphocytes and neutrophils after exercise is a useful tool to assess the functional status of vitamin E.