Nanomaterials alleviating redox stress in neurological diseases: mechanisms and applications.

Overproduced reactive oxygen and reactive nitrogen species (RONS) in the brain are involved in the pathogenesis of several neurological diseases, such as Alzheimer's disease, Parkinson's disease, traumatic brain injury, and stroke, as they attack neurons and glial cells, triggering cellular redox stress. Neutralizing RONS, and, thus, alleviating redox stress, can slow down or stop the progression of neurological diseases. Currently, an increasing number of studies are applying nanomaterials (NMs) with anti-redox activity and exploring the potential mechanisms involved in redox stress-related neurological diseases. In this review, we summarize the anti-redox mechanisms of NMs, including mimicking natural oxidoreductase activity and inhibiting RONS generation at the source. In addition, we propose several strategies to enhance the anti-redox ability of NMs and highlight the challenges that need to be resolved in their application. In-depth knowledge of the mechanisms and potential application of NMs in alleviating redox stress will help in the exploration of the therapeutic potential of anti-redox stress NMs in neurological diseases.

Neurotoxicity of nanoparticles entering the brain via sensory nerve-to-brain pathways: injuries and mechanisms.

Nanoparticles induce neurotoxicity following inhalation, oral administration, intravenous administration, or injection. Different pathways have various corresponding characteristics. Among them, the sensory nerve-to-brain pathways, which are direct neural pathways, bypass barriers such as the blood-brain barrier, which prevents the entry of the majority of nanoparticles into the brain. Subsequently, nanoparticles exert effects on sensory neuroreceptors and sensory nerves, causing central neurotoxicity. However, no studies have summarized sensory nerve-to-brain pathways for transporting nanoparticles. Here, we review recent findings on the potential sensory nerve pathways that promote nanoparticle entry into the brain, the effects of NPs on sensory receptors and sensory nerves, the central neurotoxicity induced by nanoparticles via sensory nerve pathways, and the possible mechanisms underlying these effects. In addition, the limitations of current research and possible trends for future research are also discussed. In summary, we hope that this review will serve as a reference, inspire ideas for further research into the neurotoxicity of nanoparticles, and facilitate the development of protective measures and treatment schemes for nanoparticle-induced neurotoxicity.

Key Role of Microtubule and Its Acetylation in a Zinc Oxide Nanoparticle-Mediated Lysosome-Autophagy System.

Autophagy is a biological process that has attracted considerable attention as a target for novel therapeutics. Recently, nanomaterials (NMs) have been reported to modulate autophagy, which makes them potential agents for the treatment of autophagy-related diseases. In this study, zinc oxide nanoparticles (ZNPs) are utilized to evaluate NM-induced autophagy and debate the mechanisms involved. It is found that ZNPs undergo pH-dependent ion shedding and that intracellular zinc ions (Zn2+ ) play a crucial role in autophagy. Autophagy is activated with ZNPs treatment, which is inhibited after Zn2+ sequestration via ethylenediamine tetra-acetic acid. Lysosome-based autophagic degradation is halted after ZNPs treatment for more than 3 h and is accompanied by blockage of lysophagy, which renews impaired lysosomes. Furthermore, the microtubule (MT) system participates in ZNP-induced lysosome-autophagy system changes, especially in the fusion between autophagosomes and lysosomes. MT acetylation is helpful for protecting from ZNP-induced MT disruption, and it promotes the autophagic degradation process. In conclusion, this study provides valuable information on NM-induced lysosome-autophagy system changes, particularly with respect to the role of lysophagy and the MT system, which point to some attractive targets for the design of engineered nanoparticles.

The lysosome-mitochondrion crosstalk engaged in silver nanoparticles-disturbed mitochondrial homeostasis.

Given their increasing industrial and biomedical applications, silver nanoparticles (AgNPs) have become widely present in the environment. However, to date, studies on their potential health risks have been far from sufficient, especially those regarding their neurotoxic effects. This study investigated the neurotoxic effects of AgNPs on neural PC-12 cells in the context of mitochondria, which play an important role in AgNP-induced cellular metabolism disturbance and even cell death. Our results show that the endocytosed AgNPs, and not extracellular Ag+, appear to directly determine cell fate. Importantly, endocytosed AgNPs led to mitochondrial swelling and vacuolation without direct interaction. Although mitophagy, a selective autophagy process, was invoked to rescue damaged mitochondria, it failed to function in mitochondrial degradation and recycling. Discovery of the underlying mechanism showed that the endocytosed AgNPs could directly translocate into lysosomes and then cause lysosome perturbation, which is the main factor leading to mitophagy blockade and the subsequent accumulation of defective mitochondria. After lysosomal reacidification via cyclic adenosine monophosphate (cAMP), AgNP-induced dysfunctional autolysosome formation and disturbed mitochondrial homeostasis were reversed. In summary, this study reveals that lysosome-mitochondrion crosstalk is a main mechanism for AgNP-induced neurotoxic effects, offering an inspiring perspective on the neurotoxic effects of AgNPs.

Protective effect of zinc oxide nanoparticles on spinal cord injury.

The microenvironmental changes in the lesion area of spinal cord injury (SCI) have been extensively studied, but little is known about the whole-body status after injury. We analyzed the peripheral blood RNA-seq samples from 38 SCI and 10 healthy controls, and identified 10 key differentially expressed genes in peripheral blood of patients with SCI. Using these key gene signatures, we constructed a precise and available neural network diagnostic model. More importantly, the altered transcriptome profiles in peripheral blood reflect the similar negative effects after neuronal damage at lesion site. We revealed significant differential alterations in immune and metabolic processes, therein, immune response, oxidative stress, mitochondrial metabolism and cellular apoptosis after SCI were the main features. Natural agents have now been considered as promising candidates to alleviate/cure neuronal damage. In this study, we constructed an in vitro neuronal axotomy model to investigate the therapeutic effects of zinc oxide nanoparticles (ZnO NPs). We found that ZnO NPs could act as a neuroprotective agent to reduce oxidative stress levels and finally rescue the neuronal apoptosis after axotomy, where the PI3K-Akt signaling probably be a vital pathway. In conclusion, this study showed altered transcriptome of peripheral blood after SCI, and indicated the neuroprotective effect of ZnO NPs from perspective of oxidative stress, these results may provide new insights for SCI diagnosis and therapeutics.

Nano-graphene oxide depresses neurotransmission by blocking retrograde transport of mitochondria.

The application of graphene-family nanomaterials (GFNs) in neuromedicine has recently gained increased attention, but the associated exposure risk for synaptic function and the underlying mechanism remains obscure. The results of this study utilizing nanosized graphene oxide (nGO) suggest that they exert depressive effects on neurotransmission, mainly due to energy deficiency at synaptic contacts. Mitophagy is activated but fails to renew mitochondria and maintain mitochondrial-mediated energy metabolism because of blockage of autophagosome transport through the microtubule system from the axonal terminal to the soma. Further investigation of the underlying mechanism indicates that nGO increases the level of microtubule detyrosination, which restrains loading of the dynactin-dynein motor complex onto microtubules and subsequently inhibits the efficacy of the retrograde transport route. Thus, our study reveals the underlying mechanism by which nGO depresses neurotransmission, and contributes to our understanding of the neurobiological effects of GFNs.

Understanding the interactions between inorganic-based nanomaterials and biological membranes.

The interactions between inorganic-based nanomaterials (NMs) and biological membranes are among the most important phenomena for developing NM-based therapeutics and resolving nanotoxicology. Herein, we introduce the structural and functional effects of inorganic-based NMs on biological membranes, mainly the plasma membrane and the endomembrane system, with an emphasis on the interface, which involves highly complex networks between NMs and biomolecules (such as membrane proteins and lipids). Significant efforts have been devoted to categorizing and analyzing the interaction mechanisms in terms of the physicochemical characteristics and biological effects of NMs, which can directly or indirectly influence the effects of NMs on membranes. Importantly, we summarize that the biological membranes act as platforms and thereby mediate NMs-immune system contacts. In this overview, the existing challenges and potential applications in the areas are addressed. A strong understanding of the discussed concepts will promote therapeutic NM designs for drug delivery systems by leveraging the NMs-membrane interactions and their functions.

Oxidation of Reduced Graphene Oxide via Cellular Redox Signaling Modulates Actin-Mediated Neurotransmission.

Neurotransmission is the basis of brain functions, and controllable neurotransmission tuning constitutes an attractive approach for interventions in a wide range of neurologic disorders and for synapse-based therapeutic treatments. Graphene-family nanomaterials (GFNs) offer promising advantages for biomedical applications, particularly in neurology. Our study suggests that reduced graphene oxide (rGO) serves as a neurotransmission modulator and reveals that the cellular oxidation of rGO plays a crucial role in this effect. We found that rGO could be oxidized via cellular reactive oxygen species (ROS), as evidenced by an increased number of oxygen-containing functional groups on the rGO surface. Cellular redox signaling, which involves NADPH oxidases and mitochondria, was initiated and subsequently intensified rGO oxidation. The study further shows that the blockage of synaptic vesicle docking and fusion induced through a disturbance of actin dynamics is the underlying mechanism through which oxidized rGO exerts depressant effects on neurotransmission. Importantly, this depressant effect could be modulated by restricting the cellular ROS levels and stabilizing the actin dynamics. Taken together, our results identify the complicated biological effects of rGO as a controlled neurotransmission modulator and can provide helpful information for the future design of graphene materials for neurobiological applications.

Interactions of nanomaterials with ion channels and related mechanisms.

The pharmacological potential of nanotechnology, especially in drug delivery and bioengineering, has developed rapidly in recent decades. Ion channels, which are easily targeted by external agents, such as nanomaterials (NMs) and synthetic drugs, due to their unique structures, have attracted increasing attention in the fields of nanotechnology and pharmacology for the treatment of ion channel-related diseases. NMs have significant effects on ion channels, and these effects are manifested in many ways, including changes in ion currents, kinetic characteristics and channel distribution. Subsequently, intracellular ion homeostasis, signalling pathways, and intracellular ion stores are affected, leading to the initiation of a range of biological processes. However, the effect of the interactions of NMs with ion channels is an interesting topic that remains obscure. In this review, we have summarized the recent research progress on the direct and indirect interactions between NMs and ion channels and discussed the related molecular mechanisms, which are crucial to the further development of ion channel-related nanotechnological applications.

Zinc oxide nanoparticles induce toxic responses in human neuroblastoma SHSY5Y cells in a size-dependent manner.

Due to the widespread applications of zinc oxide nanoparticles (ZnO NPs), the potential exposure of workers, consumers, and scientists to these particles has increased. This potential for exposure has attracted extensive attention in the science community. Many studies have examined the toxicological profile of ZnO NPs in the immune system, digestive system, however, information regarding the toxicity of ZnO NPs in the nervous system is scarce. In this study, we detected the cytotoxicity of two types of ZnO NPs of various sizes - ZnOa NPs and ZnOb NPs - and we characterized the shedding ability of zinc ions within culture medium and the cytoplasm. We found that reactive oxygen species played a crucial role in ZnO NP-induced cytotoxicity, likely because zinc ions were leached from ZnO NPs. Apoptosis and cytoskeleton changes were also toxic responses induced by the ZnO NPs, and ZnOb NPs induced more significant toxic responses than ZnOa NPs in SHSY5Y cells. In conclusion, ZnO NPs induced toxic responses in SHSY5Y cells in a size-dependent manner, which can probably be attributed to their ion-shedding ability.