The heritability and structural correlates of resting-state fMRI complexity.

The complexity of fMRI signals quantifies temporal dynamics of spontaneous neural activity, which has been increasingly recognized as providing important insights into cognitive functions and psychiatric disorders. However, its heritability and structural underpinnings are not well understood. Here, we utilize multi-scale sample entropy to extract resting-state fMRI complexity in a large healthy adult sample from the Human Connectome Project. We show that fMRI complexity at multiple time scales is heritable in broad brain regions. Heritability estimates are modest and regionally variable. We relate fMRI complexity to brain structure including surface area, cortical myelination, cortical thickness, subcortical volumes, and total brain volume. We find that surface area is negatively correlated with fine-scale complexity and positively correlated with coarse-scale complexity in most cortical regions, especially the association cortex. Most of these correlations are related to common genetic and environmental effects. We also find positive correlations between cortical myelination and fMRI complexity at fine scales and negative correlations at coarse scales in the prefrontal cortex, lateral temporal lobe, precuneus, lateral parietal cortex, and cingulate cortex, with these correlations mainly attributed to common environmental effects. We detect few significant associations between fMRI complexity and cortical thickness. Despite the non-significant association with total brain volume, fMRI complexity exhibits significant correlations with subcortical volumes in the hippocampus, cerebellum, putamen, and pallidum at certain scales. Collectively, our work establishes the genetic basis and structural correlates of resting-state fMRI complexity across multiple scales, supporting its potential application as an endophenotype for psychiatric disorders.

Altered asymmetry of functional connectome gradients in major depressive disorder.

Introduction: Major depressive disorder (MDD) is a debilitating disease involving sensory and higher-order cognitive dysfunction. Previous work has shown altered asymmetry in MDD, including abnormal lateralized activation and disrupted hemispheric connectivity. However, it remains unclear whether and how MDD affects functional asymmetries in the context of intrinsic hierarchical organization. Methods: Here, we evaluate intra- and inter-hemispheric asymmetries of the first three functional gradients, characterizing unimodal-transmodal, visual-somatosensory, and somatomotor/default mode-multiple demand hierarchies, to study MDD-related alterations in overarching system-level architecture. Results: We find that, relative to the healthy controls, MDD patients exhibit alterations in both primary sensory regions (e.g., visual areas) and transmodal association regions (e.g., default mode areas). We further find these abnormalities are woven in heterogeneous alterations along multiple functional gradients, associated with cognitive terms involving mind, memory, and visual processing. Moreover, through an elastic net model, we observe that both intra- and inter-asymmetric features are predictive of depressive traits measured by BDI-II scores. Discussion: Altogether, these findings highlight a broad and mixed effect of MDD on functional gradient asymmetry, contributing to a richer understanding of the neurobiological underpinnings in MDD.

Targeting VDAC: A potential therapeutic approach for mitochondrial dysfunction in Alzheimer's disease.

Mitochondrial dysfunction has been implicated in the pathogenesis of Alzheimer's disease, a neurodegenerative disorder characterized by progressive cognitive decline. Voltage-dependent anion channel (VDAC), a protein located in the outer mitochondrial membrane, plays a critical role in regulating mitochondrial function and cellular energy metabolism. Recent studies have identified VDAC as a potential therapeutic target for Alzheimer's disease. This article aims to provide an overview of the role of VDAC in mitochondrial dysfunction, its association with Alzheimer's disease, and the potential of targeting VDAC for developing novel therapeutic interventions. Understanding the involvement of VDAC in Alzheimer's disease may pave the way for the development of effective treatments that can restore mitochondrial function and halt disease progression.

Multicolor vision perception of flexible optoelectronic synapse with high sensitivity for skin sunburn warning.

The development of flexible synaptic devices with multicolor signal response is important to exploit advanced artificial visual perception systems. The Sn vacancy-dominant memory and narrow gap characteristics of PEA2SnI4 make it suitable as a functional layer in ultraviolet-visible (UV-Vis) light-stimulated synaptic devices. However, such device tends to have high dark current and poor sensitivity, which is not conducive to subsequent information processing. Here, we proposed a self-powered flexible optoelectronic synapse based on PEA2SnI4 films. By introducing the electron transport layer (ETL), the dark current of the device is decreased by 5 orders of magnitude as compared to the Au/PEA2SnI4/ITO device, and the sensitivity is increased from 10.3% to 99.2% at 1.25 mW cm-2 light illumination (520 nm), indicating the vital role of the introduced ETL in promoting the separation of excitons in the interface and inhibiting the free carrier transfer. On this basis, the optoelectronic synaptic functions with integrated sensing, recognition, and memory features were realized. The array device exhibits UV-Vis light sensitivity and tunable synaptic plasticity, enabling its application for multicolor visual sensing and skin sunburn warning. This work provides an effective strategy for fabricating multicolor intelligent sensors and artificial vision systems, which facilitate the practical application of artificial optoelectronic synapses.

Titanium dioxide nanoparticles induce apoptosis through ROS-Ca2+-p38/AKT/mTOR pathway in TM4 cells.

Titanium dioxide nanoparticles (TiO2 NPs) can cause apoptosis in TM4 cells; however, the underlying mechanism has not been entirely elucidated. The purpose of this study was to investigate the effects of TiO2 NPs on ROS, Ca2+ level, p38/AKT/mTOR pathway, and apoptosis in TM4 cells and to evaluate the role of Ca2+ in p38/AKT/mTOR pathway and apoptosis. After exposure to different concentrations (0, 50, 100, 150, and 200 µg/mL) of TiO2 NPs for 24 h, cell viability, ROS, Ca2+ level, Ca2+-ATPase activity, p38/AKT/mTOR pathway-related proteins, apoptosis rate, and apoptosis-related proteins (Bax, Bcl-2, Caspase 3, Caspase 9, and p53) were detected. The ROS scavenger NAC was used to determine the effect of ROS on Ca2+ level. The Ca2+ chelator BAPTA-AM was used to evaluate the role of Ca2+ in p38/AKT/mTOR pathway and apoptosis. TiO2 NPs significantly inhibited cell viability, increased ROS level, and elevated Ca2+ level while suppressing Ca2+-ATPase activity. TiO2 NPs regulated the p38/AKT/mTOR pathway via increasing p-p38 level and decreasing p-AKT and p-mTOR levels. TiO2 NPs significantly enhanced the apoptosis. NAC attenuated Ca2+ overload and reduction in Ca2+-ATPase activity caused by TiO2 NPs. BAPTA-AM alleviated TiO2 NPs-induced abnormal expression of p38/AKT/mTOR pathway-related proteins. BAPTA-AM assuaged the apoptosis caused by TiO2 NPs. Altogether, this study revealed that TiO2 NPs elevated intracellular Ca2+ level through ROS accumulation. Subsequently, the heightened intracellular Ca2+ level was observed to exert regulation over the p38/AKT/mTOR pathway, ultimately culminating in apoptosis. These results provides a complementary understanding to the mechanism of TiO2 NPs-induced apoptosis in TM4 cells.

Eigenmode-based approach reveals a decline in brain structure-function liberality across the human lifespan.

While brain function is supported and constrained by the underlying structure, the connectome-based link estimated by current approaches is either relatively moderate or accompanied by high model complexity, with the essential principles underlying structure-function coupling remaining elusive. Here, by proposing a mapping method based on network eigendecomposition, we present a concise and strong correspondence between structure and function. We show that the explanation of functional connectivity can be significantly improved by incorporating interactions between different structural eigenmodes. We also demonstrate the pronounced advantage of the present mapping in capturing individual-specific information with simple implementation. Applying our methodology to the human lifespan, we find that functional diversity decreases with age, with functional interactions increasingly dominated by the leading functional mode. We also find that structure-function liberality weakens with age, which is driven by the decreases in functional components that are less constrained by anatomy, while the magnitude of structure-aligned components is preserved. Overall, our work enhances the understanding of structure-function coupling from a collective, connectome-oriented perspective and promotes a more refined identification of functional portions relevant to human aging, holding great potential for mechanistic insights into individual differences associated with cognition, development, and neurological disorders.

Enhanced brain structure-function tethering in transmodal cortex revealed by high-frequency eigenmodes.

While the link between brain structure and function remains an ongoing challenge, the prevailing hypothesis is that the structure-function relationship may itself be gradually decoupling from unimodal to transmodal cortex. However, this hypothesis is constrained by the underlying models which may neglect requisite information. Here we relate structural and functional connectivity derived from diffusion and functional MRI through orthogonal eigenmodes governing frequency-specific diffusion patterns. We find that low-frequency eigenmodes contribute little to functional interactions in transmodal cortex, resulting in divergent structure-function relationships. Conversely, high-frequency eigenmodes predominantly support neuronal coactivation patterns in these areas, inducing structure-function convergence along a unimodal-transmodal hierarchy. High-frequency information, although weak and scattered, could enhance the structure-function tethering, especially in transmodal association cortices. Our findings suggest that the structure-function decoupling may not be an intrinsic property of brain organization, but can be narrowed through multiplexed and regionally specialized spatiotemporal propagation regimes.

Graphene oxide affects the symbiosis of legume-rhizobium and associated rhizosphere rhizobial communities.

The large-scale production and utilization of graphene oxide (GO) have raised concerns regarding its environmental exposure and potential risks. However, existing research on GO toxicity has primarily focused on individual organisms. Little attention has been given to the interaction between GO and the nitrogen-fixing symbiosis of legume-rhizobium. In this study, we focused on alfalfa (Medicago sativa L.), a typical leguminous nitrogen-fixing plant, to investigate the effects of GO on various aspects of this symbiotic relationship, including root nodulation, rhizobial viability, nodule nitrogen fixation, DNA damage, and the composition of the rhizobial community in the rhizosphere. As the dosage of GO increased, a significant inhibition in nodulation development was observed. Exposure to GO resulted in decreased growth and viability of rhizobia, as well as induced DNA damage in nodule cells. Furthermore, with increasing GO dosage, there were significant reductions in nitrogenase activity, leghemoglobin level, and cytoplasmic ammonia content within the root nodules. Additionally, the presence of GO led to notable changes in the rhizobial community in the rhizosphere. Our findings support the existence of the damage promoted by GO in the symbiosis of nitrogen fixing rhizobia with legumes. This underscores the importance of careful soil GO management.

Exploring the potential of treating chronic liver disease targeting the PI3K/Akt pathway and polarization mechanism of macrophages.

Chronic liver disease is a significant public health issue that can lead to considerable morbidity and mortality, imposing an enormous burden on healthcare resources. Understanding the mechanisms underlying chronic liver disease pathogenesis and developing effective treatment strategies are urgently needed. In this regard, the activation of liver resident macrophages, namely Kupffer cells, plays a vital role in liver inflammation and fibrosis. Macrophages display remarkable plasticity and can polarize into different phenotypes according to diverse microenvironmental stimuli. The polarization of macrophages into M1 pro-inflammatory or M2 anti-inflammatory phenotypes is regulated by complex signaling pathways such as the PI3K/Akt pathway. This review focuses on investigating the potential of using plant chemicals targeting the PI3K/Akt pathway for treating chronic liver disease while elucidating the polarization mechanism of macrophages under different microenvironments. Studies have demonstrated that inhibiting M1-type macrophage polarization or promoting M2-type polarization can effectively combat chronic liver diseases such as alcoholic liver disease, non-alcoholic fatty liver disease, and liver fibrosis. The PI3K/Akt pathway acts as a pivotal modulator of macrophage survival, migration, proliferation, and their responses to metabolism and inflammatory signals. Activating the PI3K/Akt pathway induces anti-inflammatory cytokine expression, resulting in the promotion of M2-like phenotype to facilitate tissue repair and resolution of inflammation. Conversely, inhibiting PI3K/Akt signaling could enhance the M1-like phenotype, which exacerbates liver damage. Targeting the PI3K/Akt pathway has tremendous potential as a therapeutic strategy for regulating macrophage polarization and activity to treat chronic liver diseases with plant chemicals, providing new avenues for liver disease treatment.

Noise improves the association between effects of local stimulation and structural degree of brain networks.

Stimulation to local areas remarkably affects brain activity patterns, which can be exploited to investigate neural bases of cognitive function and modify pathological brain statuses. There has been growing interest in exploring the fundamental action mechanisms of local stimulation. Nevertheless, how noise amplitude, an essential element in neural dynamics, influences stimulation-induced brain states remains unknown. Here, we systematically examine the effects of local stimulation by using a large-scale biophysical model under different combinations of noise amplitudes and stimulation sites. We demonstrate that noise amplitude nonlinearly and heterogeneously tunes the stimulation effects from both regional and network perspectives. Furthermore, by incorporating the role of the anatomical network, we show that the peak frequencies of unstimulated areas at different stimulation sites averaged across noise amplitudes are highly positively related to structural connectivity. Crucially, the association between the overall changes in functional connectivity as well as the alterations in the constraints imposed by structural connectivity with the structural degree of stimulation sites is nonmonotonically influenced by the noise amplitude, with the association increasing in specific noise amplitude ranges. Moreover, the impacts of local stimulation of cognitive systems depend on the complex interplay between the noise amplitude and average structural degree. Overall, this work provides theoretical insights into how noise amplitude and network structure jointly modulate brain dynamics during stimulation and introduces possibilities for better predicting and controlling stimulation outcomes.

Air-Stable Flexible Photodetector Based on MXene-Cs3Bi2I9 Microplate Schottky Junctions for Weak-Light Detection.

Weak-light detection technology is widely used in various fields, including industry, high-energy physics, precision analysis, and reflection imaging. Metal-semiconductor-metal (MSM) photodetectors demonstrate high detectivity and high response speed and are one of the suitable structures for the preparation of weak-light detectors. However, traditional MSM photodetectors tend to exhibit high dark currents, which are not conducive to performance improvement. Here, a MXene-Cs3Bi2I9-MXene weak-light detector is proposed. Based on the MXene-Cs3Bi2I9 Schottky junctions, the dark current is reduced by 2 orders of magnitude and the responsivity is significantly improved compared with the traditional Cr/Au-Cs3Bi2I9-Cr/Au MSM photodetector. The device demonstrates excellent photodetection capacity with a photoresponsivity of 6.45 A W-1, a specific detectivity of 9.45 × 1011 Jones, and a fast response speed of 0.27/2.32 ms. Especially, the device yielded a superior weak-light detectable limit of 10.66 nW cm-2 and demonstrated excellent optical communication capability. Moreover, such a flexible device shows little degradation in photodetection performance after extreme bending for 4500 cycles, proving remarkable bending endurance and flexibility. The obtained results highlight the great potential of such Cs3Bi2I9/MXene devices as a stable and environmentally friendly candidate for weak-light detection.

Effects of nano-titanium dioxide on calcium homeostasis in vivo and in vitro: a systematic review and meta-analysis.

With the extensive application of titanium dioxide nanoparticles (TiO2 NPs), their impacts on calcium homeostasis have aroused extensive attention from scholars. However, there are still some controversies in relevant reports. Therefore, a systematic review was performed followed by a meta-analysis to explore whether TiO2 NPs could induce the imbalance in calcium homeostasis in vivo and in vitro through Revman5.4 and Stata15.0 in this research. Fourteen studies were included through detailed database retrieval and literature screening. Results indicated that the calcium levels were significantly increased and the activity of Ca2+-ATPase was significantly decreased by TiO2 NPs in vivo and in vitro. Subgroup analysis of the studies in vivo showed that TiO2 NPs exposure caused a significant increase in calcium levels in rats, exposure to large-sized TiO2 NPs (>10 nm) and long-term (>30 days) exposure could significantly increase calcium levels, and the activity of Ca2+-ATPase showed a concentration-dependent downward trend. Subgroup analysis of the studies in vitro revealed that intracellular calcium levels increased significantly in animal cells, exposure to small-sized TiO2 NPs (≤10 nm) and high concentration (>10 µg/mL) exposure could induce a significant increase in Ca2+ concentration, and the activity of Ca2+-ATPase also showed a concentration-dependent downward trend. This research showed that the physicochemical properties of TiO2 NPs and the experimental scheme could affect calcium homeostasis.

In Situ Grown Vertically Oriented Graphene Coating on Copper by Plasma-Enhanced CVD to Form Superhydrophobic Surface and Effectively Protect Corrosion.

Graphene exhibits great potential for the corrosion protection of metals, because of its low permeability and high chemical stability. To enhance the anticorrosion ability of Cu, we use plasma-enhanced chemical vapor deposition (PECVD) to prepare a vertically oriented few-layer graphene (VFG) coating on the surface of Cu. The Cu coated with VFG shows superhydrophobic surface with a contact angle of ~150°. The VFG coating is used to significantly increase the anticorrosion ability, enhanced by the chemical stability and the unique geometric structure of vertically oriented graphene. The corrosion rate of VFG-Cu was about two orders of magnitude lower than that of bare Cu. This work highlights the special synthesized way of PECVD and superhydrophobic surface of vertical structures of graphene as coatings for various applications.

Effect of Titanium Dioxide Nanoparticles on Mammalian Cell Cycle In Vitro: A Systematic Review and Meta-Analysis.

Although most studies that explore the cytotoxicity of titanium dioxide nanoparticles (nano-TiO2) have focused on cell viability and oxidative stress, the cell cycle, a basic process of cell life, can also be affected. However, the results on the effects of nano-TiO2 on mammalian cell cycle are still inconsistent. A systematic review and meta-analysis were therefore performed in this research based on the effects of nano-TiO2 on the mammalian cell cycle in vitro to explore whether nano-TiO2 can induce cell cycle arrest. Meanwhile, the impact of physicochemical properties of nano-TiO2 on the cell cycle in vitro was investigated, and the response of normal cells and cancer cells was compared. A total of 33 articles met the eligibility criteria after screening. We used Review Manager 5.4 and Stata 15.1 for analysis. The results showed an increased percentage of cells in the sub-G1 phase and an upregulation of the p53 gene after being exposed to nano-TiO2. Nevertheless, nano-TiO2 had no effect on cell percentage in other phases of the cell cycle. Furthermore, subgroup analysis revealed that the cell percentage in both the sub-G1 phase of normal cells and S phase of cancer cells were significantly increased under anatase-form nano-TiO2 treatment. Moreover, nano-TiO2 with a particle size <25 nm or exposure duration of nano-TiO2 more than 24 h induced an increased percentage of normal cells in the sub-G1 phase. In addition, the cell cycle of cancer cells was arrested in the S phase no matter if the exposure duration of nano-TiO2 was more than 24 h or the exposure concentration was over 50 µg/mL. In conclusion, this study demonstrated that nano-TiO2 disrupted the cell cycle in vitro. The cell cycle arrest induced by nano-TiO2 varies with cell status and physicochemical properties of nano-TiO2.

Insertion of carbon skeleton in Ni/MoO2 heterojunction with porous hollow sphere for efficient alkaline electrochemical hydrogen production.

The catalyst morphology has a strong impact on the activity of electrocatalytic hydrogen production. Considering the effect, we design and fabricate hollow spherical Ni/MoO2 heterojunction. In addition, an amorphous carbon skeleton is inserted into the hollow sphere, which makes the structure more stable and porous. Compared with other morphological Ni/MoO2, the porous hollow spherical Ni/MoO2 (H-Ni/MoO2) with an internal carbon skeleton shows better hydrogen evolution reaction (HER) activity with a small overpotential of 58 mV to reach 10 mA cm-2 and a tafel value of 44.8 mV dec-1 in alkaline media. The developed HER performance of H-Ni/MoO2 can be attributed to the larger active surface area of porous hollow spherical structure and the faster electron transfer and better stability of carbon skeleton. Undoubtedly, the urea plays a crucial role to construct the hollow spherical morphology and being decomposed to form holes and amorphous carbon in the synthesized steps. The soft-template strategy using urea as the addition for forming the porous hollow structure with carbon skeleton can be extended to explore superior non-noble metal for hydrogen production.

Efficient assembly of long DNA fragments and multiple genes with improved nickase-based cloning and Cre/loxP recombination.

Functional genomics, synthetic biology and metabolic engineering require efficient tools to deliver long DNA fragments or multiple gene constructs. Although numerous DNA assembly methods exist, most are complicated, time-consuming and expensive. Here, we developed a simple and flexible strategy, unique nucleotide sequence-guided nicking endonuclease (UNiE)-mediated DNA assembly (UNiEDA), for efficient cloning of long DNAs and multigene stacking. In this system, a set of unique 15-nt 3' single-strand overhangs were designed and produced by nicking endonucleases (nickases) in vectors and insert sequences. We introduced UNiEDA into our modified Cre/loxP recombination-mediated TransGene Stacking II (TGSII) system to generate an improved multigene stacking system we call TGSII-UNiE. Using TGSII-UNiE, we achieved efficient cloning of long DNA fragments of different sizes and assembly of multiple gene cassettes. Finally, we engineered and validated the biosynthesis of betanin in wild tobacco (Nicotiana benthamiana) leaves and transgenic rice (Oryza sativa) using multigene stacking constructs based on TGSII-UNiE. In conclusion, UNiEDA is an efficient, convenient and low-cost method for DNA cloning and multigene stacking, and the TGSII-UNiE system has important application prospects for plant functional genomics, genetic engineering and synthetic biology research.

Age-Related Changes in Micro Brain Characteristics Based on Relaxed Mean-Field Model.

Brain health is an important research direction of neuroscience. In addition to the effects of diseases, we cannot ignore the negative effect of aging on brain health. There have been many studies on brain aging, but only a few have used dynamic models to analyze differences in micro brain characteristics in healthy people. In this article, we use the relaxed mean-field model (rMFM) to study the effects of normal aging. Two main parameters of this model are the recurrent connection strength and subcortical input strength. The sensitivity of the rMFM to the initial values of the parameters has not been fully discussed in previous research. We examine this issue through repeated numerical experiments and obtain a reasonable initial parameter range for this model. Differences in recurrent connection strength and subcortical input strength due to aging have also not been studied previously. We use statistical methods to find the regions of interest (ROIs) exhibiting significant differences between young and old groups. Further, we carry out a difference analysis on the process of change of these ROIs on a more detailed timescale. We find that even with the same final results, the trends of change in these ROIs are different. This shows that to develop possible methods to prevent or delay brain damage due to aging, more attention needs to be paid to the trends of change of different ROIs, not just the final results.

Nanosized Titanium Dioxide Induced Apoptosis and Abnormal Expression of Blood-Testis Barrier Junction Proteins Through JNK Signaling Pathway in TM4 Cells.

Nanosized titanium dioxide (nano-TiO2) has been widely used in consumer products. It can cross the blood-testis barrier (BTB), and it has adverse effects on the male reproductive system. However, the specific mechanism has not been fully elucidated. The purpose of this study was to understand the role of the JNK signaling pathway in the apoptosis and abnormal expression of BTB junction proteins induced by nano-TiO2 in TM4 cells. After different concentration of nano-TiO2 treatments, the cell viability, apoptosis, mitochondrial membrane potential (Δψm), BTB junction proteins (Claudin-11, ZO-1, ß-catenin), apoptosis-related proteins (Bax, Bcl-2, cleaved caspase-9, cleaved caspase-3), and phosphorylated (p)-JNK protein were examined. The results showed that cell viability, apoptosis rates, Δψm, and apoptosis-related protein levels changed in a concentration-dependent manner. Cell viability decreased significantly from 100 µg/mL nano-TiO2 group. Apoptosis rates increased significantly from 150 µg/mL nano-TiO2 group, and Δψm decreased significantly from 150 µg/mL nano-TiO2 group. The protein levels of Bax, cleaved caspase-9, and cleaved caspase-3 increased significantly from 150 µg/mL nano-TiO2 group, and the protein level of Bcl-2 decreased significantly from 100 µg/mL nano-TiO2 group. The protein level of p-JNK increased significantly from 100 µg/mL nano-TiO2 group. Abnormal expression of ZO-1 and ß-catenin started from 150 µg/mL nano-TiO2 group, and abnormal expression of Claudin-11 started from 100 µg/mL nano-TiO2 group. Cells were treated with JNK inhibitor SP100625 to determine whether the changes of the above indicators in the concentration of 150 µg/mL nano-TiO2 group can be reversed. We found that SP100625 at 20 µM significantly reversed these effects. These results highlighted that nano-TiO2 could activate the JNK signaling pathway to induce mitochondria-mediated apoptosis and abnormal expression of BTB junction proteins in TM4 cells.

Genotoxicity evaluation of silica nanoparticles in murine: a systematic review and meta-analysis.

Silica nanoparticles (SiNPs) have been widely used in nanotechnology, and more attention has been paid to their safety evaluation. However, there are still inconsistent conclusions about the genotoxicity of SiNPs. A systematic review was conducted to explore whether SiNPs have genotoxicity followed by a meta-analysis of in vivo and in vitro murine genotoxicity tests. A total of 26 eligible studies were identified in this meta-analysis through a detailed process of inclusion and exclusion, which included 9 in vivo studies, 15 in vitro studies, and 2 in both. The results of in vitro studies showed that SiNPs exposure significantly increased the indicators of the comet assay, such as tail DNA content (T DNA%), tail length (TL), and olive tail moment (OTM). Indicators of mutagenicity had not been affected in vitro studies, such as mutation frequency (MF) and micronucleus (MN) frequency. There was a significant increase in MN frequency, but there was no influence on T DNA% in vivo. Results of subgroup analysis indicated that size and treatment time of SiNPs were the associated factors in vitro genotoxicity. The size of SiNPs, <21 nm, induced more DNA damage than larger sized SiNPs. It could induce MN formation when the treatment time of SiNPs was <12 h, and even more DNA damage when the exposure time over 12 h. SiNPs can induce genotoxicity both in vivo and in vitro. Comet assay may be more sensitive to detect in vitro genotoxicity, and MN frequency may be more suitable to detect in vivo genotoxicity.

Mitochondria-targeted and ultrasound-responsive nanoparticles for oxygen and nitric oxide codelivery to reverse immunosuppression and enhance sonodynamic therapy for immune activation.

Background: Sonodynamic therapy (SDT) is a promising strategy to inhibit tumor growth and activate antitumor immune responses for immunotherapy. However, the hypoxic and immunosuppressive tumor microenvironment limits its therapeutic efficacy and suppresses immune response. Methods: In this study, mitochondria-targeted and ultrasound-responsive nanoparticles were developed to co-deliver oxygen (O2) and nitric oxide (NO) to enhance SDT and immune response. This system (PIH-NO) was constructed with a human serum albumin-based NO donor (HSA-NO) to encapsulate perfluorodecalin (FDC) and the sonosensitizer (IR780). In vitro, the burst release of O2 and NO with US treatment to generate reactive oxygen species (ROS), the mitochondria targeting properties and mitochondrial dysfunction were evaluated in tumor cells. Moreover, in vivo, tumor accumulation, therapeutic efficacy, the immunosuppressive tumor microenvironment, immunogenic cell death, and immune activation after PIH-NO treatment were also studied in 4T1 tumor bearing mice. Results: PIH-NO could accumulate in the mitochondria and relive hypoxia. After US irradiation, O2 and NO displayed burst release to enhance SDT, generated strongly oxidizing peroxynitrite anions, and led to mitochondrial dysfunction. The release of NO increased blood perfusion and enhanced the accumulation of the formed nanoparticles. Owing to O2 and NO release with US, PIH-NO enhanced SDT to inhibit tumor growth and amplify immunogenic cell death in vitro and in vivo. Additionally, PIH-NO promoted the maturation of dendritic cells and increased the number of infiltrating immune cells. More importantly, PIH-NO polarized M2 macrophages into M1 phenotype and depleted myeloid-derived suppressor cells to reverse immunosuppression and enhance immune response. Conclusion: Our findings provide a simple strategy to co-deliver O2 and NO to enhance SDT and reverse immunosuppression, leading to an increase in the immune response for cancer immunotherapy.