Nanomaterials-induced programmed cell death: Focus on mitochondria.

Nanomaterials are widely utilized in several domains, such as everyday life, societal manufacturing, and biomedical applications, which expand the potential for nanomaterials to penetrate biological barriers and interact with cells. Multiple studies have concentrated on the particular or improper utilization of nanomaterials, resulting in cellular death. The primary mode of cell death caused by nanotoxicity is programmable cell death, which includes apoptosis, ferroptosis, necroptosis, and pyroptosis. Based on our prior publications and latest research, mitochondria have a vital function in facilitating programmed cell death caused by nanomaterials, as well as initiating or transmitting death signal pathways associated with it. Therefore, this review takes mitochondria as the focal point to investigate the internal molecular mechanism of nanomaterial-induced programmed cell death, with the aim of identifying potential targets for prevention and treatment in related studies.

Graphene-Based Material-Mediated Immunomodulation in Tissue Engineering and Regeneration: Mechanism and Significance.

Tissue engineering and regenerative medicine hold promise for improving or even restoring the function of damaged organs. Graphene-based materials (GBMs) have become a key player in biomaterials applied to tissue engineering and regenerative medicine. A series of cellular and molecular events, which affect the outcome of tissue regeneration, occur after GBMs are implanted into the body. The immunomodulatory function of GBMs is considered to be a key factor influencing tissue regeneration. This review introduces the applications of GBMs in bone, neural, skin, and cardiovascular tissue engineering, emphasizing that the immunomodulatory functions of GBMs significantly improve tissue regeneration. This review focuses on summarizing and discussing the mechanisms by which GBMs mediate the sequential regulation of the innate immune cell inflammatory response. During the process of tissue healing, multiple immune responses, such as the inflammatory response, foreign body reaction, tissue fibrosis, and biodegradation of GBMs, are interrelated and influential. We discuss the regulation of these immune responses by GBMs, as well as the immune cells and related immunomodulatory mechanisms involved. Finally, we summarize the limitations in the immunomodulatory strategies of GBMs and ideas for optimizing GBM applications in tissue engineering. This review demonstrates the significance and related mechanism of the immunomodulatory function of GBM application in tissue engineering; more importantly, it contributes insights into the design of GBMs to enhance wound healing and tissue regeneration in tissue engineering.

MDM2 upregulation induces mitophagy deficiency via Mic60 ubiquitination in fetal microglial inflammation and consequently neuronal DNA damage caused by exposure to ZnO-NPs during pregnancy.

During pregnancy, the human body is quite vulnerable to external stimuli. Zinc oxide nanoparticles (ZnO-NPs) are widely used in daily life, and they enter the human body via environmental or biomedical exposure, thus having potential risks. Although accumulating studies have demonstrated the toxic effects of ZnO-NPs, few studies have addressed the effect of prenatal ZnO-NP exposure on fetal brain tissue development. Here, we systematically studied ZnO-NP-induced fetal brain damage and the underlying mechanism. Using in vivo and in vitro assays, we found that ZnO-NPs could cross the underdeveloped bloodbrain barrier and enter fetal brain tissue, where they could be endocytosed by microglia. ZnO-NP exposure impaired mitochondrial function and induced autophagosome overaccumulation by downregulation of Mic60, thus inducing microglial inflammation. Mechanistically, ZnO-NPs increased Mic60 ubiquitination by activating MDM2, resulting in imbalanced mitochondrial homeostasis. Inhibition of Mic60 ubiquitination by MDM2 silencing significantly attenuated the mitochondrial damage induced by ZnO-NPs, thereby preventing autophagosome overaccumulation and reducing ZnO-NP-mediated inflammation and neuronal DNA damage. Our results demonstrate that ZnO-NPs are likely to disrupt mitochondrial homeostasis, inducing abnormal autophagic flux and microglial inflammation and secondary neuronal damage in the fetus. We hope the information provided in our study will improve the understanding of the effects of prenatal ZnO-NP exposure on fetal brain tissue development and draw more attention to the daily use of and therapeutic exposure to ZnO-NPs among pregnant women.

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.

How Nanoparticles Open the Paracellular Route of Biological Barriers: Mechanisms, Applications, and Prospects.

Biological barriers are essential physiological protective systems and obstacles to drug delivery. Nanoparticles (NPs) can access the paracellular route of biological barriers, either causing adverse health impacts on humans or producing therapeutic opportunities. This Review introduces the structural and functional influences of NPs on the key components that govern the paracellular route, mainly tight junctions, adherens junctions, and cytoskeletons. Furthermore, we evaluate their interaction mechanisms and address the influencing factors that determine the ability of NPs to open the paracellular route, which provides a better knowledge of how NPs can open the paracellular route in a safer and more controllable way. Finally, we summarize limitations in the research models and methodologies of the existing research in the field and provide future research direction. This Review demonstrates the in-depth causes for the reversible opening or destruction of the integrity of barriers generated by NPs; more importantly, it contributes insights into the design of NP-based medications to boost paracellular drug delivery efficiency.

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.

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.

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.

Nanomaterials and hepatic disease: toxicokinetics, disease types, intrinsic mechanisms, liver susceptibility, and influencing factors.

The widespread use of nanomaterials (NMs) has raised concerns that exposure to them may introduce potential risks to the human body and environment. The liver is the main target organ for NMs. Hepatotoxic effects caused by NMs have been observed in recent studies but have not been linked to liver disease, and the intrinsic mechanisms are poorly elucidated. Additionally, NMs exhibit varied toxicokinetics and induce enhanced toxic effects in susceptible livers; however, thus far, this issue has not been thoroughly reviewed. This review provides an overview of the toxicokinetics of NMs. We highlight the possibility that NMs induce hepatic diseases, including nonalcoholic steatohepatitis (NASH), fibrosis, liver cancer, and metabolic disorders, and explore the underlying intrinsic mechanisms. Additionally, NM toxicokinetics and the potential induced risks in the livers of susceptible individuals, including subjects with liver disease, obese individuals, aging individuals and individuals of both sexes, are summarized. To understand how NM type affect their toxicity, the influences of the physicochemical and morphological (PCM) properties of NMs on their toxicokinetics and toxicity are also explored. This review provides guidance for further toxicological studies on NMs and will be important for the further development of NMs for applications in various fields.

Tantalum Particles Induced Cytotoxic and Inflammatory Effects in Human Monocytes.

The aim of this study is to evaluate the biological safety of tantalum (Ta) particles and to further explore the effects of Ta particles on human monocyte toxicity and inflammatory cytokine expression. Human monocyte leukemia (THP-1) cells were cultured with Ta and hydroxyapatite (HA) particles. Cell counting kit-8 method was used to evaluate the cytotoxicity of Ta and HA particles. The apoptosis effects were evaluated by flow cytometry, and the protein expression levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were evaluated by ELISA. The protein levels of inflammation-related signaling pathways including nuclear factor-kappa B (NF-κB) and extracellular regulated kinase (ERK) were detected by western blotting. The cytotoxicity test showed that the toxicity level of Ta in vitro was grade l, which is within the clinically acceptable range. Compared with the HA control, Ta had no significant effect on THP-1 cell apoptosis, IL-6, and TNF-α release. The phosphorylated levels of NF-κB and ERK at 3 h in the Ta group were lower than those in the HA and control groups (P < 0.001 both). These results reveal Ta particles behave good biosafety properties and provide some new insights for the future clinical use of Ta.

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.

Rapamycin-Induced Autophagy Promotes the Chondrogenic Differentiation of Synovium-Derived Mesenchymal Stem Cells in the Temporomandibular Joint in Response to IL-1ß.

Cartilage defects in temporomandibular disorders (TMD) lead to chronic pain and seldom heal. Synovium-derived mesenchymal stem cells (SMSCs) exhibit superior chondrogenesis and have become promising seed cells for cartilage tissue engineering. However, local inflammatory conditions that affect the repair of articular cartilage by SMSCs present a challenge, and the specific mechanism through which the function remains unclear. Thus, it is important to explore the chondrogenesis of SMSCs under inflammatory conditions of TMD such that they can be used more effectively in clinical treatment. In this study, we obtained SMSCs from TMD patients with severe cartilage injuries. In response to stimulation with IL-1ß, which is well known as one of the most prevalent cytokines in TMD, MMP13 expression increased, while that of SOX9, aggrecan, and collagen II decreased during chondrogenic differentiation. At the same time, IL-1ß upregulated the expression of mTOR and decreased the ratio of LC3-II/LC3-I and the formation of autophagosomes. Further study revealed that rapamycin pretreatment promoted the migration of SMSCs and the expression of chondrogenesis-related markers in the presence of IL-1ß by inducing autophagy. 3-Benzyl-5-((2-nitrophenoxy)methyl)-dihydrofuran-2(3H)-one (3BDO), a new activator of mTOR, inhibited autophagy and increased the expression of p-GSK3ßser9 and ß-catenin, simulating the effect of IL-1ß stimulation. Furthermore, rapamycin reduced the expression of mTOR, whereas the promotion of LC3-II/LC3-I was blocked by the GSK3ß inhibitor TWS119. Taken together, these results indicate that rapamycin enhances the chondrogenesis of SMSCs by inducing autophagy, and GSK3ß may be an important regulator in the process of rapamycin-induced autophagy. Thus, inducing autophagy may be a useful approach in the chondrogenic differentiation of SMSCs in the inflammatory microenvironment and may represent a novel TMD treatment.

Dual effects of JNK activation in blood-milk barrier damage induced by zinc oxide nanoparticles.

Zinc oxide nanoparticles (ZnO-NPs) have been extensively applied in our daily life. Humans are at high risk of being exposed to ZnO-NPs, which induce potentially adverse health effects. Although a growing number of studies have investigated the toxic effects of ZnO-NPs, the available data concerning ZnO-NP interactions with the blood-milk barrier (BMB) remain highly limited. Herein, we systematically investigated the damage to BMB integrity induced by ZnO-NPs and the mechanisms involved. ZnO-NPs that were intravenously injected into lactating dams accumulated in the mammary gland and entered into the breast milk, inducing disruption to BMB integrity and changes in the tight junction (TJ) and adherens junction (AJ) components. Furthermore, using an in vitro BMB model composed of EpH4-Ev cells, we verified that ZnO-NP-triggered ROS generation and the activation of MKK4 and JNK are the main mechanism of cell-cell junction damage. More interestingly, JNK activation played different roles in inducing changes in the TJ and AJ complex, and these effects did not need to activate the downstream c-Jun. These data provide more information for understanding ZnO-NP interactions with the BMB and raise concern for the daily use and the intravenous use of ZnO-NPs by lactating mothers.

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.

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.