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.

Neuroinflammation is induced by tongue-instilled ZnO nanoparticles via the Ca2+-dependent NF-κB and MAPK pathways.

BACKGROUND: The extensive biological applications of zinc oxide nanoparticles (ZnO NPs) in stomatology have created serious concerns about their biotoxicity. In our previous study, ZnO NPs were confirmed to transfer to the central nervous system (CNS) via the taste nerve pathway and cause neurodegeneration after 30 days of tongue instillation. However, the potential adverse effects on the brain caused by tongue-instilled ZnO NPs are not fully known. METHODS: In this study, the biodistribution of Zn, cerebral histopathology and inflammatory responses were analysed after 30 days of ZnO NPs tongue instillation. Moreover, the molecular mechanisms underlying neuroinflammation in vivo were further elucidated by treating BV2 and PC12 cells with ZnO NPs in vitro. RESULTS: This analysis indicated that ZnO NPs can transfer into the CNS, activate glial cells and cause neuroinflammation after tongue instillation. Furthermore, exposure to ZnO NPs led to a reduction in cell viability and induction of inflammatory response and calcium influx in BV2 and PC12 cells. The mechanism underlying how ZnO NPs induce neuroinflammation via the Ca2+-dependent NF-κB, ERK and p38 activation pathways was verified at the cytological level. CONCLUSION: This study provided a new way how NPs, such as ZnO NPs, induce neuroinflammation via the taste nerve translocation pathway, a new mechanism for ZnO NPs-induced neuroinflammation and a new direction for nanomaterial toxicity analysis.

Supplementation of exogenous phytohormones for enhancing the removal of sulfamethoxazole and the simultaneous accumulation of lipid by Chlorella vulgaris.

In this study, the phytohormone gibberellins (GAs) were used to enhance sulfamethoxazole (SMX) removal and lipid accumulation in the microalgae Chlorella vulgaris. At the concentration of 50 mg/L GAs, the SMX removal achieved by C. vulgaris was 91.8 % while the lipid productivity of microalga was at 11.05 mg/L d-1, which were much higher than that without GAs (3.5 % for SMX removal and 0.52 mg/L d-1 for lipid productivity). Supplementation of GAs enhanced the expression of antioxidase-related genes in C. vulgaris as a direct response towards the toxicity of SMX. In addition, GAs increased lipid production of C. vulgaris by up-regulating the expression of genes related to carbon cycle of microalgal cells. In summary, exogenous GAs promoted the stress tolerance and lipid accumulation of microalgae at the same time, which is conducive to improving the economic benefits of microalgae-based antibiotics removal as well as biofuel production potential.

Tongue-Brain-Transported ZnO Nanoparticles Induce Abnormal Taste Perception.

Nanoparticles (NPs) can be transported to the brain, especially through nerves, because of their small size and high biological activity. Previous studies confirmed that zinc oxide (ZnO) NPs can enter the brain through the tongue-brain pathway, but it is unclear whether they will further affect synaptic transmission and brain perception. In this study, it is found that tongue-brain-transported ZnO NPs can cause a decrease in taste sensitivity and taste aversion learning ability, indicating abnormal taste perception. Moreover, the release of miniature excitatory postsynaptic currents, the frequency of action potential release, and the expression of c-fos are decreased, suggesting that the synaptic transmission is reduced. To further explore the mechanism, protein chip detection of inflammatory factors is carried out and it is found that neuroinflammation occurs. Importantly, it is found that neuroinflammation originated from neurons. The JAK-STAT signaling pathway is activated, which inhibits the Neurexin1-PSD95-Neurologigin1 pathway and c-fos expression. Blocking the activation of the JAK-STAT pathway prevents neuroinflammation and the reduction in Neurexin1-PSD95-Neurologigin1. These results indicate that ZnO NPs can be transported by the tongue-brain pathway and lead to abnormal taste perception by neuroinflammation-induced deficits in synaptic transmission. The study reveals the influence of ZnO NPs on neuronal function and provides a novel mechanism.

Promoting effect of plant hormone gibberellin on co-metabolism of sulfamethoxazole by microalgae Chlorella pyrenoidosa.

In this study, sodium acetate (NaAC) as a co-substrate effectively promoted the metabolism of sulfamethoxazole (SMX) by microalgae Chlorella pyrenoidosa. In the cultivation supplied with 5.0 and 10.0 g L-1 NaAC, 51.1% and 61.2% SMX was removed, respectively. On this basis, the improvement effect of plant hormone gibberellin (GA3) on SMX removal by 5 g L-1 NaAC supplied as co-substrate was further investigated. The results showed that biodegradation played decisive role in the removal of SMX. As a plant hormone, GA3 effectively improved the co-metabolic removal efficiency of SMX by C. pyrenoidosa. Especially when GA3 dosage reached 10.0 and 50.0 mg L-1, C. pyrenoidosa showed a very high SMX removal rate of 83.5% and 95.3%, respectively. Transcriptome analysis showed that GA3 promoted the removal of SMX by C. pyrenoidosa was the result of the combined action of exogenous and endogenous plant hormones.

Improvement of synaptic plasticity by nanoparticles and the related mechanisms: Applications and prospects.

Synaptic plasticity is an important basis of learning and memory and participates in brain network remodelling after different types of brain injury (such as that caused by neurodegenerative diseases, cerebral ischaemic injury, posttraumatic stress disorder (PTSD), and psychiatric disorders). Therefore, improving synaptic plasticity is particularly important for the treatment of nervous system-related diseases. With the rapid development of nanotechnology, increasing evidence has shown that nanoparticles (NPs) can cross the blood-brain barrier (BBB) in different ways, directly or indirectly act on nerve cells, regulate synaptic plasticity, and ultimately improve nerve function. Therefore, to better elucidate the effect of NPs on synaptic plasticity, we review evidence showing that NPs can improve synaptic plasticity by regulating different influencing factors, such as neurotransmitters, receptors, presynaptic membrane proteins and postsynaptic membrane proteins, and further discuss the possible mechanism by which NPs improve synaptic plasticity. We conclude that NPs can improve synaptic plasticity and restore the function of damaged nerves by inhibiting neuroinflammation and oxidative stress, inducing autophagy, and regulating ion channels on the cell membrane. By reviewing the mechanism by which NPs regulate synaptic plasticity and the applications of NPs for the treatment of neurological diseases, we also propose directions for future research in this field and provide an important reference for follow-up research.

mTOR participates in the formation, maintenance, and function of memory CD8+T cells regulated by glycometabolism.

Memory CD8+T cells participate in the fight against infection and tumorigenesis as well as in autoimmune disease progression because of their efficient and rapid immune response, long-term survival, and continuous differentiation. At each stage of their formation, maintenance, and function, the cell metabolism must be adjusted to match the functional requirements of the specific stage. Notably, enhanced glycolytic metabolism can generate sufficient levels of adenosine triphosphate (ATP) to form memory CD8+T cells, countering the view that glycolysis prevents the formation of memory CD8+T cells. This review focuses on how glycometabolism regulates memory CD8+T cells and highlights the key mechanisms through which the mammalian target of rapamycin (mTOR) signaling pathway affects memory CD8+T cell formation, maintenance, and function by regulating glycometabolism. In addition, different subpopulations of memory CD8+T cells exhibit different metabolic flexibility during their formation, survival, and functional stages, during which the energy metabolism may be critical. These findings which may explain why enhanced glycolytic metabolism can give rise to memory CD8+T cells. Modulating the metabolism of memory CD8+T cells to influence specific cell fates may be useful for disease treatment.

Effects of carbon-based nanomaterials on vascular endothelia under physiological and pathological conditions: interactions, mechanisms and potential therapeutic applications.

The endothelium participates in maintaining vascular hemostasis and is involved in multiple pathological processes. Although it is rarely the targeted tissue, the endothelium interacts intimately with applied therapeutic systems. Carbon nanomaterials (CBNs) with editable physiochemical characteristics and outstanding biosafety are believed to have great prospects in the biomedical field. Before reaching their destination, these materials necessarily enter the blood vessels and interact with the vascular endothelium, which strongly affects the biomedical efficiency. In this work, we start with the changes that CBNs cause to physiological endothelial barriers and then organize the potential mechanisms revealed. Subsequently, we discuss the factors influencing the CBN-endothelium interaction and highlight the importance of balancing therapeutic efficiency and biocompatibility. More importantly, this work introduces the heterogeneity of multiple vascular endothelia under both physiological and pathological conditions and the related applications with the hope of promoting improved accuracy and curative effects of future therapeutic systems. Through this manuscript, we hope to help illuminate the current status quo of CBN-vascular research and inspire further exciting progress via the insights we gained from the current outstanding examples.

The Role of Tantalum Nanoparticles in Bone Regeneration Involves the BMP2/Smad4/Runx2 Signaling Pathway.

BACKGROUND: In recent years, nanomaterials have been increasingly developed and applied in the field of bone tissue engineering. However, there are few studies on the induction of bone regeneration by tantalum nanoparticles (Ta NPs) and no reports on the effects of Ta NPs on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and the underlying mechanisms. The main purpose of this study was to investigate the effects of Ta NPs on bone regeneration and BMSC osteogenic differentiation and the underlying mechanisms. MATERIALS AND METHODS: The effects of Ta NPs on bone regeneration were evaluated in an animal experiment, and the effects of Ta NPs on osteogenic differentiation of BMSCs and the underlying mechanisms were evaluated in cell experiments. In the animal experiment, hematoxylin-eosin (HE) staining and hard-tissue section analysis showed that Ta NPs promoted bone regeneration, and immunohistochemistry revealed elevated expression of BMP2 and Smad4 in cells cultured with Ta NPs. RESULTS: The results of the cell experiments showed that Ta NPs promoted BMSC proliferation, alkaline phosphatase (ALP) activity, BMP2 secretion and extracellular matrix (ECM) mineralization, and the expression of related osteogenic genes and proteins (especially BMP2, Smad4 and Runx2) was upregulated under culture with Ta NPs. Smad4 expression, ALP activity, ECM mineralization, and osteogenesis-related gene and protein expression decreased after inhibiting Smad4. CONCLUSION: These data suggest that Ta NPs have an osteogenic effect and induce bone regeneration by activating the BMP2/Smad4/Runx2 signaling pathway, which in turn causes BMSCs to undergo osteogenic differentiation. This study provides insight into the molecular mechanisms underlying the effects of Ta NPs in bone regeneration.

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.

Toxicity Induced by Zirconia Oxide Nanoparticles on Various Organs After Intravenous Administration in Rats.

ZrO2-NPs are widely applied in industry, biomedicine and dentistry, e.g., foundry sands, refractories, ceramics dental prostheses, dental implant coatings and bone defect restorative materials. To date, little information is available on the potential adverse effects and toxic mechanism in human organs associated with exposure to ZrO2-NPs. The biodistribution of ZrO2-NPs and the consequent oxidative stress in the spleen, kidney, heart, brain, and lung at six time points after a single injection of ZrO2-NPs were examined. Histopathological and immunohistochemical changes were also examined. RNA-Seq analysis was conducted in organs with high ZrO2-NPs accumulations or obvious histopathological changes (brain and spleen). Exposure to the ZrO2-NPs led to persistent oxidative stress and cell proliferation promotion/inhibition in various organs. RNA-Seq results of the spleen and brain point to significant gene expression changes. Metabolism was identified as leading pathways in the spleen. This study proves ZrO2-NPs likely have negative impacts on various organs, and exhibit potential disease risks.

Potential adverse effects of nanoparticles on the reproductive system.

With the vigorous development of nanometer-sized materials, nanoproducts are becoming widely used in all aspects of life. In medicine, nanoparticles (NPs) can be used as nanoscopic drug carriers and for nanoimaging technologies. Thus, substantial attention has been paid to the potential risks of NPs. Previous studies have shown that numerous types of NPs are able to pass certain biological barriers and exert toxic effects on crucial organs, such as the brain, liver, and kidney. Only recently, attention has been directed toward the reproductive toxicity of nanomaterials. NPs can pass through the blood-testis barrier, placental barrier, and epithelial barrier, which protect reproductive tissues, and then accumulate in reproductive organs. NP accumulation damages organs (testis, epididymis, ovary, and uterus) by destroying Sertoli cells, Leydig cells, and germ cells, causing reproductive organ dysfunction that adversely affects sperm quality, quantity, morphology, and motility or reduces the number of mature oocytes and disrupts primary and secondary follicular development. In addition, NPs can disrupt the levels of secreted hormones, causing changes in sexual behavior. However, the current review primarily examines toxicological phenomena. The molecular mechanisms involved in NP toxicity to the reproductive system are not fully understood, but possible mechanisms include oxidative stress, apoptosis, inflammation, and genotoxicity. Previous studies have shown that NPs can increase inflammation, oxidative stress, and apoptosis and induce ROS, causing damage at the molecular and genetic levels which results in cytotoxicity. This review provides an understanding of the applications and toxicological effects of NPs on the reproductive system.

The toxicity of silica nanoparticles to the immune system.

Silicon-based materials and their oxides are widely used in drug delivery, dietary supplements, implants and dental fillers. Silica nanoparticles (SiNPs) interact with immunocompetent cells and induce immunotoxicity. However, the toxic effects of SiNPs on the immune system have been inadequately reviewed. The toxicity of SiNPs to the immune system depends on their physicochemical properties and the cell type. Assessments of immunotoxicity include determining cell dysfunctions, cytotoxicity and genotoxicity. This review focuses on the immunotoxicity of SiNPs and investigates the underlying mechanisms. The main mechanisms were proinflammatory responses, oxidative stress and autophagy. Considering the toxicity of SiNPs, surface and shape modifications may mitigate the toxic effects of SiNPs, providing a new way to produce these nanomaterials with less toxic impaction.

Involvement of PINK1/parkin-mediated mitophagy in ZnO nanoparticle-induced toxicity in BV-2 cells.

With the increasing application of zinc oxide nanoparticles (ZnO NPs) in biological materials, the neurotoxicity caused by these particles has raised serious concerns. However, the underlying molecular mechanisms of the toxic effect of ZnO NPs on brain cells remain unclear. Mitochondrial damage has been reported to be a factor in the toxicity of ZnO NPs. PINK1/parkin-mediated mitophagy is a newly emerging additional function of autophagy that selectively degrades impaired mitochondria. Here, a PINK1 gene knockdown BV-2 cell model was established to determine whether PINK1/parkin-mediated mitophagy was involved in ZnO NP-induced toxicity in BV-2 cells. The expression of total parkin, mito-parkin, cyto-parkin, and PINK1 both in wild type and PINK1-/- BV-2 cells was evaluated using Western blot analysis after the cells were exposed to 10 µg/mL of 50 nm ZnO NPs for 2, 4, 8, 12, and 24 h. The findings suggested that the downregulation of PINK1 resulted in a significant reduction in the survival rate after ZnO NP exposure compared with that of control cells. ZnO NPs were found to induce the transportation of parkin from the cytoplasm to the mitochondria, implying the involvement of mitophagy in ZnO NP-induced toxicity. The deletion of the PINK1 gene inhibited the recruitment of parkin to the mitochondria, causing failure of the cell to trigger mitophagy. The present study demonstrated that apart from autophagy, PINK1/parkin-mediated mitophagy plays a protective role in ZnO NP-induced cytotoxicity.

Current understanding of the toxicological risk posed to the fetus following maternal exposure to nanoparticles.

INTRODUCTION: With the broad use of nanotechnology, the number and variety of nanoparticles that humans can be exposed to has further increased. Consequently, there is growing concern about the potential effect of maternal exposure to various nanoparticles during pregnancy on a fetus. However, the nature of this risk is not fully known. Areas covered: In this review, materno-fetal transfer of nanoparticles through the placenta is described. Both prenatal and postnatal adverse effects, such as fetal resorption, malformation and injury to various organs in mice exposed to nanoparticles are reviewed. The potential mechanisms of toxicity are also discussed. Expert opinion: The toxicology and safe application of recently developed nanoparticles has attracted much attention in the past few years. Although many studies have demonstrated the toxicology of nanoparticles in various species, only a small number of studies have examined the effect on a fetus after maternal exposure to nanoparticles. This is particularly important, because the developing fetus is especially vulnerable to the toxic effects of nanoparticles during fetal development due to the unique physical stage of the fetus. Nanoparticles may directly or indirectly impair fetal development and growth after maternal exposure to nanoparticles.

Graphene oxide and reduced graphene oxide induced neural pheochromocytoma-derived PC12 cell lines apoptosis and cell cycle alterations via the ERK signaling pathways.

Given the novel applications of graphene materials in biomedical and electronics industry, the health hazards of these particles have attracted extensive worldwide attention. Although many studies have been performed on graphene material-induced toxic effects, toxicological data for the effect of graphene materials on the nervous system are lacking. In this study, we focused on the biological effects of graphene oxide (GO) and reduced graphene oxide (rGO) materials on PC12 cells, a type of traditional neural cell line. We found that GO and rGO exerted significant toxic effects on PC12 cells in a dose- and time-dependent manner. Moreover, apoptosis appeared to be a response to toxicity. A potent increase in the number of PC12 cells at G0/G1 phase after GO and rGO exposure was detected by cell cycle analysis. We found that phosphorylation levels of ERK signaling molecules, which are related to cell cycle regulation and apoptosis, were significantly altered after GO and rGO exposure. In conclusion, our results show that GO has more potent toxic effects than rGO and that apoptosis and cell cycle arrest are the main toxicity responses to GO and rGO treatments, which are likely due to ERK pathway regulation.

Evaluation of the effect of time on the distribution of zinc oxide nanoparticles in tissues of rats and mice: a systematic review.

To evaluate the time effect on the distribution of zinc oxide nanoparticles (ZnO NPs) in tissues from rats and mice, a search on the PubMed, Embase, SpringerLink, Scopus, Science Direct, Cochrane, CNKI, Wanfang, and vip databases up to September 2014 was performed, followed by screening, data extraction, and quality assessment. Thirteen studies were included. At 24 h, Zn content was mainly distributed in the liver, kidney, and lung. At ≥7 days, Zn content was mainly distributed in the liver, kidney, lung, and brain. ZnO NPs are readily deposited in tissues. Furthermore, as time increases, Zn content decreases in the liver and kidney, but increases in the brain.

Comparing Integrated and Disciplinary Clinical Training Patterns for Dental Interns: Advantages, Disadvantages, and Effect on Students' Self-Confidence.

In China, the five-year program of undergraduate education for stomatology consists of four years of lecture courses and one year of internship focused on clinical training. Dental schools provide this clinical training either in their own clinics (referred to as the one-stage pattern because all forms of practice are completed together) or by placing students in external clinics usually at non-affiliated hospitals (referred to as the three-stage program because the three primary areas are taught separately). The aims of this study were to investigate differences in teaching effect between the one-stage and the three-stage patterns and to evaluate advantages and disadvantages of the two patterns. A three-section, 31-item questionnaire was designed to assess basic and clinic information about the interns' training and their self-confidence in performing clinical procedures. The survey was administered to graduates who finished the fifth-year internship in 2012-14. Of the 356 individuals invited to participate, 303 graduates who spent their intern years in 43 academic dental institutions returned completed surveys (response rate of 85%). The one-stage group (n=121) reported longer independent operation time than the three-stage group (n=182) (p<0.01). No significant difference was found between the groups for assessment of clinic infrastructure (p=0.121). The interns were most confident in oral hygiene instruction and scale and polish (overall median=5), but showed low confidence in rubber dam placement and four other procedures (overall median=2). The one-stage group rated their confidence level higher than the three-stage group on comprehensive skills such as arranging appointments and managing patients and procedures needing long treatment periods such as molar endodontics. The three-stage group showed higher confidence on more specialized procedures such as surgical extractions and suturing. This study found that both of the two intern patterns had advantages and shortcomings in clinical training in various procedures. Combining the two could be a way to improve clinical education in China.