Neurodegenerative diseases are one of the leading causes of disability and death worldwide. Intracellular transduction pathways that end in the activation of specific transcription factors are highly implicated in the onset and progression of pathological changes related to neurodegeneration, of which those related to oxidative stress (OS) and neuroinflammation are particularly important. Here, we provide a brief overview of the key concepts related to OS- and neuroinflammation-mediated neuropathological changes in neurodegeneration, together with the role of transcription factors nuclear factor erythroid 2–related factor 2 (Nrf2) and nuclear factor-κB (NF-κB). This review is focused on the transcription factor p53 that coordinates the cellular response to diverse genotoxic stimuli, determining neuronal death or survival. As current pharmacological options in the treatment of neurodegenerative disease are only symptomatic, many research efforts are aimed at uncovering efficient disease-modifying agents. Natural polyphenolic compounds demonstrate powerful anti-oxidative, anti-inflammatory and anti-apoptotic effects, partially acting as modulators of signaling pathways. Herein, we review the current understanding of the therapeutic potential and limitations of flavonols in neuroprotection, with emphasis on their anti-oxidative, anti-inflammatory and anti-apoptotic effects along the Nrf2, NF-κB and p53 pathways. A better understanding of cellular and molecular mechanisms of their action may pave the way toward new treatments.

The structural integrity, elasticity, and fluidity of lipid membranes are critical for cellular activities such as communication between cells, exocytosis, and endocytosis. Unsaturated lipids, the main components of biological membranes, are particularly susceptible to the oxidative attack of reactive oxygen species. The peroxidation of unsaturated lipids, in our case 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), induces the structural reorganization of the membrane. We have employed a multi-technique approach to analyze typical properties of lipid bilayers, i.e., roughness, thickness, elasticity, and fluidity. We compared the alteration of the membrane properties upon initiated lipid peroxidation and examined the ability of flavonols, namely quercetin (QUE), myricetin (MCE), and myricitrin (MCI) at different molar fractions, to inhibit this change. Using Mass Spectrometry (MS) and Fourier Transform Infrared Spectroscopy (FTIR), we identified various carbonyl products and examined the extent of the reaction. From Atomic Force Microscopy (AFM), Force Spectroscopy (FS), Small Angle X-Ray Scattering (SAXS), and Electron Paramagnetic Resonance (EPR) experiments, we concluded that the membranes with inserted flavonols exhibit resistance against the structural changes induced by the oxidative attack, which is a finding with multiple biological implications. Our approach reveals the interplay between the flavonol molecular structure and the crucial membrane properties under oxidative attack and provides insight into the pathophysiology of cellular oxidative injury.

Flavonoids, polyphenols with anti-oxidative activity have high potential as novel therapeutics for neurodegenerative disease, but their applicability is rendered by their poor water solubility and chemical instability under physiological conditions. In this study, this is overcome by delivering flavonoids to model cell membranes (unsaturated DOPC) using prepared and characterized biodegradable mesoporous silica nanoparticles, MSNs. Quercetin, myricetin and myricitrin have been investigated in order to determine the relationship between flavonoid structure and protective activity towards oxidative stress, i.e., lipid peroxidation induced by the addition of hydrogen peroxide and/or Cu²⁺ ions. Among investigated flavonoids, quercetin showed the most enhanced and prolonged protective anti-oxidative activity. The nanomechanical (Young modulus) measurement of the MSNs treated DOPC membranes during lipid peroxidation confirmed attenuated membrane damage. By applying a combination of experimental techniques (atomic force microscopy—AFM, force spectroscopy, electrophoretic light scattering—ES and dynamic light scattering—DLS), this work generated detailed knowledge about the effects of flavonoid loaded MSNs on the elasticity of model membranes, especially under oxidative stress conditions. Results from this study will pave the way towards the development of innovative and improved markers for oxidative stress-associated neurological disorders. In addition, the obtained could be extended to designing effective delivery systems of other high potential bioactive molecules with an aim to improve human health in general.

Oxidative stress (OS) induced by the disturbed homeostasis of metal ions is one of the pivotal factors contributing to neurodegeneration. The aim of the present study was to investigate the effects of flavonoid myricetin on copper-induced toxicity in neuroblastoma SH-SY5Y cells. As determined by the MTT method, trypan blue exclusion assay and measurement of ATP production, myricetin heightened the toxic effects of copper and exacerbated cell death. It also increased copper-induced generation of reactive oxygen species, indicating the prooxidative nature of its action. Furthermore, myricetin provoked chromatin condensation and loss of membrane integrity without caspase-3 activation, suggesting the activation of both caspase-independent programmed cell death and necrosis. At the protein level, myricetin-induced upregulation of PARP-1 and decreased expression of Bcl-2, whereas copper-induced changes in the expression of p53, p73, Bax and NME1 were not further affected by myricetin. Inhibitors of ERK1/2 and JNK kinases, protein kinase A and L-type calcium channels exacerbated the toxic effects of myricetin, indicating the involvement of intracellular signaling pathways in cell death. We also employed atomic force microscopy (AFM) to evaluate the morphological and mechanical properties of SH-SY5Y cells at the nanoscale. Consistent with the cellular and molecular methods, this biophysical approach also revealed a myricetin-induced increase in cell surface roughness and reduced elasticity. Taken together, we demonstrated the adverse effects of myricetin, pointing out that caution is required when considering powerful antioxidants for adjuvant therapy in copper-related neurodegeneration.

Superparamagnetic magnetite nanoparticles (MNPs) with excellent biocompatibility and negligible toxicity were prepared by solvothermal method and stabilized by widely used and biocompatible polymer poly(ethylene glycol) PEG-4000 Da. The unique properties of the synthesized MNPs enable them to host the unstable and water-insoluble quercetin as well as deliver and localize quercetin directly to the desired site. The chemical and physical properties were validated by X-ray powder diffraction (XRPD), field emission scanning electron microscopy (FE–SEM), atomic force microscopy (AFM), superconducting quantum interference device (SQUID) magnetometer, FTIR spectroscopy and dynamic light scattering (DLS). The kinetics of in vitro quercetin release from MNPs followed by UV/VIS spectroscopy was controlled by employing combined stationary and alternating magnetic fields. The obtained results have shown an increased response of quercetin from superparamagnetic MNPs under a lower stationary magnetic field and s higher frequency of alternating magnetic field. The achieved findings suggested that we designed promising targeted quercetin delivery with fine-tuning drug release from magnetic MNPs.

The formation of polyelectrolyte multilayers on silica surfaces was investigated in the presence of binary 1:1 sodium salts (NaCl, NaBr and NaNO3) at various salt concentrations. The build-up of multilayers was monitored using electrophoretic light scattering and quartz crystal microbalance with dissipation monitoring techniques. As cationic polyelectrolyte poly(diallyldimethylammonium chloride) was used and as anionic poly(sodium 4-styrene sulfonate). The counterion specific formation of multilayers was observed at higher electrolyte concentrations and the more pronounced influence was observed in the case of nitrate and bromide than in the case of chloride salt. These results confirm that solely by adjusting the appropriate ionic strength and by choosing the electrolyte type, polyelectrolyte multilayers with various properties and structure can be obtained. This work is licensed under a Creative Commons Attribution 4.0 International License