Can dendrimer based nanoparticles fight neurodegenerative diseases? Current situation versus other established approaches

For several decades, the treatment of central nervous system (CNS) disorders such as, for instance, Alzheimer’s disease (AD), Huntington’s disease (HD), and Parkinson’s disease (PD) represented an important challenge due to the difficulty in delivering drug molecules and imaging agents to the brain. Two strategies have been developed aimed at achieving the efficient delivery of drugs to the brain: invasive (e.g., temporary osmotic Blood Brain Barrier (BBB) opening, direct local delivery of nanoparticles with encapsulated CNS drugs etc.) and noninvasive approaches. As a part of the noninvasive approach among systemic delivery of drug molecules across BBB using nanocarriers, dendrimers represent promising therapeutics agents per se or nanocarriers of CNS drugs and for gene therapies. This original review emphasizes and analyzes the use of dendrimers as promising systems in the treatment of AD and PD, ischemia/reperfusion injury, neuroinflammation including cerebral palsy, neurological injury after cardiac surgery and particularly after hypothermic circulatory arrest, and for retinal degeneration purposes.     

Neuroprotective effect of blackberry (Rubus sp.) polyphenols is potentiated after simulated gastrointestinal digestion

Blackberry ingestion has been demonstrated to attenuate brain degenerative processes in rodents with the benefits ascribed to the (poly)phenolic components. The aim of this work was to assess the efficacy of blackberry polyphenolics in a neurodegeneration cell model before and after simulated gastrointestinal digestion.Digested blackberry metabolites protected neuroblastoma cells from H₂O₂-induced death at low, non-toxic levels that approach physiologically-relevant serum concentrations. However, the original extracts were not protective even at fivefold higher concentrations. This potentiation may reflect alterations in the polyphenolic composition caused by the digestion procedure, as detected by liquid-chromatography-mass spectrometric analysis. This protection was not caused by modulation of the intracellular antioxidant capacity or through alteration of glutathione levels, although the original extract influenced both of these parameters. This work reinforces the importance of evaluating digested metabolites in disease cell models and highlights the possible involvement of other mechanisms beyond antioxidant systems.     

Docking,molecular dynamics and free energy studies on aspartoacylase mutations involved in Canavan disease

The disruption of aspartoacylase enzyme’s catalytic activity causes fatal neurodegenerative Canavan disease. By molecular dynamics and docking methods, here we studied two deleterious mutations that have been identified in the Canavan patients’ genotype E285A, F295S, and revealed the possible cause for the enzyme inhibition due to the drastic changes in active site dynamics, loss of interactions among Arg 71, Arg 168 and the substrate and pKa value of critical Glu178 residue. In addition to changes in the enzyme dynamics, free energy calculations show that the binding energy of substrate decreases dramatically up on mutations.     

Phytochemical profile of a blend of black chokeberry and lemon juice with cholinesterase inhibitory effect and antioxidant potential

In this study, black chokeberry concentrate was added (5% w/v) to lemon juice, since previous reports suggested potential health benefits of this blend. The phytochemical composition, antioxidant capacity (scavenging of DPPH, superoxide and hydroxyl radicals, and hypochlorous acid), and inhibitory activity against cholinesterase of the new blend were determined and compared with those of lemon juice and chokeberry in citric acid (5%). The chokeberry concentrate, rich in cyanidin-glycosides, quercetin derivatives, and 3-O-caffeoylquinic acid, and lemon juice, possessing flavones, flavanones, quercetin derivates, and hydroxycinnamic acids, were characterised. The new drink showed a higher antioxidant effect than the chokeberry or lemon controls for all the tested methods, except for hypochlorous acid, in which lemon juice displayed higher activity. Both the lemon juice and chokeberry controls inhibited acetylcholinesterase and butyrylcholinesterase, and this effect was increased in the new mixtures. The results of the different radical scavenging assays indicate that the lemon–black chokeberry (5% w/v) mixture was more antioxidative than the respective controls separately. Moreover, their inhibition of cholinesterase is of interest regarding neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, or senile dementia.     

P-糖蛋白在神经退行性疾病中的作用

神经退行性疾病(neurodegenerative disease)是一种以神经元退行性病变为基础的慢性进行性神经系统疾病,发病机制尚不明了,但一些内源性和外源性物质在脑部的异常聚集和沉积与其病因密切相关,且其往往是P-糖蛋白的底物。近年来研究表明血脑屏障的P-糖蛋白在一些神经退行性疾病发展过程中表达会减少,这可能导致致病性内外源性物质的进一步聚集和沉积,恶化病情。本文对近年来有关P-糖蛋白在神经退行性疾病的发病和病情进展中的作用作一综述。     

Microenvironmental regulation of stem cells injected in the area at risk of neurodegenerative diseases

The complex mechanism of degenerative diseases and the non-specific modulation of regenerative targets are topics that need to be elucidated in order to advance the use of stem cells in improvement of neurodegenerative diseases. From pre-transplantation through post-transplantation, there are many changes in the conditions, both inside and outside of the stem cells that have not been carefully considered. This has hindered development in the field of cell therapy and regeneration. This viewpoint highlights the potential implications of intracellular and extracellular alterations of stem cells in transplanted areas at risk of neurodegenerative disease.     

MSCs derived extracellular vesicles as a therapeutic paragon for neurodegenerative disorders: A viewpoint

Neurodegenerative disorders are a vicious woe to the public health and wellness. Uncertainty in their underlying causes, lack of effective biomarkers for their early detection, existence of only supportive therapy, and their ever rising incidence creates an unmatched need for targeted therapies. Mesenchymal Stem Cells (MSCs) have found to be promising candidates for regenerative and remedial therapy in neurodegenerative disorders, however several biological risks and practical issues impede in their translational utility. Deriving from MSCs are certain Extracellular Vesicles (EVs), which aid in the paracrine action of MSCs and have lately gained the scientific interest for their implacability in diverse set ups. Their cargo is of utmost importance and is being explored in various different diseases like heart diseases, neuronal diseases, respiratory diseases and hepatic diseases. They thereby hold the position of a likely prospective remedial candidate for therapy against neurodegenerative disorders.     

Bovine milk phospholipid fraction protects Neuro2a cells from endoplasmic reticulum stress via PKC activation and autophagy

Endoplasmic reticulum stress commonly causes neuronal damage in a lot of neurodegenerative diseases. In this study, we examined neuroprotective effect of bovine milk phospholipid fraction (mPL) on mouse neuroblastoma Neuro2a cells from endoplasmic reticulum (ER) stress induced cell death. Neuro2a cells were induced cell death by ER stressor tunicamycin (TM) or thapsigargin (TG), and studied whether mPL could attenuate the toxicity. By preincubation with mPL, the cell viabilities were significantly increased in TM or TG treated cells, and caspase-12 activated cells induced by TM or TG treatment were significantly decreased. Protein kinase C inhibitor GF109203x significantly reduced the protective effect on TM induced cell death, and autophagy inhibitor 3-methyladenine reduced the protective effect on TM or TG induced cell death. Moreover, preincubation with mPL significantly stimulated autophagosomes formation observed by dansylcadaverine staining. Our data suggest that mPL will be applicable to prevent neurodegenerative diseases caused by ER stress.     

Effect of graphene oxide on the conformational transitions of amyloid beta peptide: A molecular dynamics simulation study

The interactions between nanomaterials (NMs) and amyloid proteins are central to the nanotechnology-based diagnostics and therapy in neurodegenerative disorders such as Alzheimer's and Parkinson's. Graphene oxide (GO) and its derivatives have shown to modulate the aggregation pattern of disease causing amyloid beta (Aβ) peptide. However, the mechanism is still not well understood. Using molecular dynamics simulations, the effect of graphene oxide (GO) and reduced graphene oxide (rGO) having carbon:oxygen ratio of 4:1 and 10:1, respectively, on the conformational transitions (alpha-helix to beta-sheet) and the dynamics of the peptide was investigated. GO and rGO decreased the beta-strand propensity of amino acid residues in Aβ. The peptide displayed different modes of adsorption on GO and rGO. The adsorption on GO was dominated by electrostatic interactions, whereas on rGO, both van der Waals and electrostatic interactions contributed in the adsorption of the peptide. Our study revealed that the slight increase in the hydrophobic patches on rGO made it more effective inhibitor of conformational transitions in the peptide. Alpha helix-beta sheet transition in Aβ peptide could be one of the plausible mechanism by which graphene oxide may inhibit amyloid fibrillation.     

Closing the gap between brain banks and proteomics to advance the study of neurodegenerative diseases

Neurodegenerative diseases (NDs), such as Alzheimer's disease and Parkinson's disease, are among the most debilitating neurological disorders, and as life expectancy rises quickly around the world, the scientific and clinical challenges of dealing with them will also increase dramatically, putting increased pressure on the biomedical community to come up with innovative solutions for the understanding, diagnosis, and treatment of these conditions. Despite several decades of intensive research, there is still little that can be done to prevent, cure, or even slow down the progression of NDs in most patients. There is an urgent need to develop new lines of basic and applied research that can be quickly translated into clinical application. One way to do this is to apply the tools of proteomics to well-characterized samples of human brain tissue, but a closer partnership must still be forged between proteomic scientists, brain banks, and clinicians to explore the maximum potential of this approach. Here, we analyze the challenges and potential benefits of using human brain tissue for proteomics research toward NDs.