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Single-cell RNA sequencing (scRNA-seq) is one of the most efficient technologies for human tumor research. However, data analysis is still faced with technical challenges, especially the difficulty in efficiently and accurately discriminating cancer/normal cells in the scRNA-seq expression matrix. If we can address these challenges, we can have a deeper understanding of the intratumoral and intertumoral heterogeneity. In this study, we developed a cancer/normal cell discrimination pipeline called pan-Cancer Seeker (CaSee) devoted to scRNA-seq expression matrix, which is based on the traditional high-quality pan-cancer bulk sequencing data using transfer learning. CaSee is the first tool directly used to discriminate cancer/normal cells in the scRNA-seq expression matrix, with much wider application fields and higher efficiency than copy number variation (CNV) method which requires corresponding reference cells. CaSee is user-friendly and can adapt to a variety of data sources, including but not limited to scRNA tissue sequencing data, scRNA cell line sequencing data, scRNA xenograft cell sequencing data and scRNA circulating tumor cell sequencing data. It is compatible with mainstream sequencing technology platforms, 10× Genomics Chromium, Smart-seq2, and Microwell-seq. Here, CaSee pipeline exhibited excellent performance in the multicenter data evaluation of 11 retrospective cohorts and one independent dataset, with an average discrimination accuracy of 96.69%. In general, the development of a deep-learning based, pan-cancer cell discrimination model, CaSee, to distinguish cancer cells from normal cells will be compelling to researchers working in the genomics, cancer, and single-cell fields.

Infrared selective emitters are attracting more and more attention due to their modulation ability of infrared radiance, which provides an efficient ability to blend objects into the surrounding environment. In this paper, an Ag/ZnS/Si/Ag/Si multilayered emitter is proposed by virtue of impedance matching as well as Fabry-Perot cavity effect to achieve selective radiation in the infrared band. The emissivity of the fabricated selective emitter is measured to be ε3–5μm = 0.16 and ε8–14μm = 0.23 in the atmosphere windows, respectively, meeting the requirements of infrared stealth. Meanwhile, the emissivity at the non-atmospheric window (5–8 μm) is as high as 0.78, which allows efficient heat dissipation to achieve radiative cooling. Furthermore, the selective emitter maintains excellent stealth performance until 350 °C, indicating its good heat resistance and dissipation at medium temperature. The proposed emitter with spectral selectivity provides a new strategy for the facile fabrication of mid-/low-temperature infrared stealth devices.

Chemotherapy is a difficult treatment for cancer patients because of the low effective accumulation of chemo-drugs and their detrimental side effects. Nanoparticles have shown promise as a solution to these problems. However, the known differences in the porosity and vascularization of tumor vessels, and other factors, including the potential formation of a "protein crown," the short half-life time in circulation, and the low drug distribution, often limit their application. To address these problems, biomimetic nanoparticles coated with cell membranes have been developed and shown to have advantages such as prolonged circulation, high biocompatibility, and enhanced targeting abilities in drugs and nanoparticles, thus exhibiting good application prospects in cancer therapy for liver, lung, and melanoma cancers. Accordingly, we designed a PH-sensitive biomimetic nanodrug delivery system with a delicate "core-shell" structure based on red blood cell membranes. Briefly, core nanoparticles were synthesized by the self-assembly of natural amphoteric polymers, including hydrophilic carboxymethylcellulose sodium and hydrophobic stearic acid. For the shell structure, red blood cell membranes were modified using folic acid by a lipid tether (1,2-distearoyl-sn-glycero-3-phosphoethanolamine) to increase tumor-targeting ability, whereas polyethylene glycol was inserted to decrease lipid tether modification-induced potential sequestration by either the mononuclear phagocyte system or the reticuloendothelial system. Via a series of formulation optimizations, paclitaxel was packaged into the red blood membrane-based core-shell nanoparticles with an average size of 226.9 ± 2.75 nm and a negative Zeta potential of -14.5 ± 0.3 mV. More importantly, the examinations focusing on CD47, a representative red blood cell membrane protein, revealed not only the successful establishment of the membrane shell but also the right-side-out membrane orientation on our core-shell nanoparticles. Our nanodrug delivery system showed good biocompatibility and sensitivity to acidic tumor microenvironments while effectively prolonging the circulation time of paclitaxel and further enhancing its antitumor effects on epithelial malignancies, including liver, lung, and melanoma cancers. In particular, our nanodrug delivery system significantly alleviated paclitaxel-induced renal toxicity. Taken together, our findings highlight that the red blood membrane-based core-shell nanoparticle is a promising biomimetic nanodrug delivery system for functionally delivering chemotherapeutic drugs, and it has promise in clinical applications.

Adult neurogenesis declines with age due to the less functional neural stem cells (NSCs) and niches, but the underlying molecular bases for this impaired condition remain unclear. Here we analyzed >55,000 single-cell transcriptomes from two discrete neurogenic niches across the mouse lifespan, and identified new features and populations in NSCs, new markers, and neurogenic regional-specific alternations during aging. Intercellular communication analysis revealed defects in brain-derived neurotrophic factor (BDNF)-TrkB signaling cascade in old NSCs. Carboxypeptidase E (CPE) was found to be highly enriched in NSCs, and played a crucial role in mature/proBDNF balance and adult neurogenesis. Diminishment of CPE with aging resulted in impaired generation of BDNF, thus limiting the neurogenesis in old neurogenic niches. Restoring CPE expression markedly rescued the adult neurogenesis by increasing the production of mature BDNF, offering an attractive therapeutic strategy for the treatment of certain disorders in regions associated with constitutive neurogenesis.

Epidemiological data indicate atmospheric particulate matter, especially fine particulate matter (PM2.5), has many negative effects on human health. Of note, people spend about 90% of their time indoors. More importantly, according to the World Health Organization (WHO) statistics, indoor air pollution causes nearly 1.6 million deaths each year, and it is considered as one of the major health risk factors. In order to obtain a deeper understanding of the harmful effects of indoor PM2.5 on human health, we used bibliometric software to summarize articles in this field. In conclusion, since 2000, the annual publication volume has increased year by year. America topped the list for the number of articles, and Professor Petros Koutrakis and Harvard University were the author and institution with the most published in this research area, respectively. Over the past decade, scholars gradually paid attention to molecular mechanisms, therefore, the toxicity can be better explored. Particularly, apart from timely intervention and treatment for adverse consequences, it is necessary to effectively reduce indoor PM2.5 through technologies. In addition, the trend and keywords analysis are favorable ways to find out future research hotspots. Hopefully, various countries and regions strengthen academic cooperation and integration of multi-disciplinary.

The deleterious effects of silica nanoparticles (SiNPs) on human health and the ecological system have gradually gained attention owing to their heavy annual output and extensive global flux. The updated epidemiological or experimental investigations have demonstrated the potential myocardial toxicity triggered by SiNPs, but the underlying mechanisms and long-lasting cardiac effects are still poorly understood. Here, a rat model of sub-chronic respiratory exposure to SiNPs was conducted, and the histopathological analysis and ultrastructural investigation of heart tissues were carried out. More importantly, a comprehensive analysis of whole-genome transcription was utilized in rat heart to uncover key biological and cellular mechanisms triggered by SiNPs. The widening of myocardial space and partial fiber rupture were clearly manifested in rat heart after prolonged SiNPs exposure, particularly accompanied by mitochondrial swelling and cristae rupture. With the aid of Affymetrix GeneChips, 3153 differentially expressed genes (DEGs) were identified after SiNPs exposure, including 1916 down- and 1237 up-regulated genes. GO and KEGG analysis illustrated many important biological processes and pathways perturbed by SiNPs, mainly specializing in cellular stress, energy metabolism, actin filament dynamics and immune response. Signal-net analysis revealed that

In recent years, more and more biochars have been employed to treat dye wastewater. In order to increase the utilization of moringa seed shell resources and enrich the removal method of methylene blue (MB) in solution, in the current study, the magnetic moringa seed shells biochar was prepared through ultrasonic-assisted impregnation and pyrolysis, while Fe3O4 was used to activate the material to obtain adsorption (Fe3O4-MOS). The prepared adsorbents were characterized by SEM-EDS, XRD, XPS, FTIR, N2 adsorption and desorption and VSM. Under the suitable experimental conditions, the removal rate can be close to 100% and the maximum adsorption capacity of MB could be 219.60 mg/g. The Freundlich model provided a good match to the data presented by the adsorption isotherm, and the adsorption of MB on Fe3O4-MOS was a spontaneous and endothermic reaction. Study of the mechanism indicated that pore adsorption, electrostatic interaction, hydrogen bond, and π-π interaction were the major adsorption mechanisms. After five cycles, it was found that Fe3O4-MOS had a high removal rate for MB, which was close to 90%. This work provides a new idea for moringa seed shells and the results confirm that Fe3O4-MOS has substantial potential for dye wastewater treatment.

Silica nanoparticles (SiNPs) are one of the most common inorganic nanomaterials. Autophagy is the predominant biological response to nanoparticles and transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome pathway. Previous studies show that SiNPs induce autophagosome accumulation, yet the precise underlying mechanisms remain uncertain. The present study investigates the role of TFEB during SiNP-induced autophagy. SiNP-induced TFEB nuclear translocation is verified using immunofluorescence and western blot assay. The regulation of TFEB is proved to be via EIF2AK3 pathway. A TFEB knockout (KO) cell line is constructed to validate the TFEB involvement in SiNP-induced autophagy. The transcriptomes of wild-type and TFEB KO cells are compared using RNA-sequencing to identify genes of the TFEB-mediated autophagy and lysosome pathways affected by SiNPs. Based on these data and the Human Autophagy Database, four candidate autophagic genes are identified, including HSPB8, ATG4D, CTSB and CTSD. Specifically, that the chaperone HSPB8 is upregulated through SiNP-mediated TFEB activation and forms a chaperone-assisted selective autophagy (CASA) complex with BAG3 and HSC70, triggering HSPB8-assisted selective autophagy, is found. Thus, this study characterizes a novel mechanism underlying SiNP-induced autophagy that helps pave the way for further research on the toxicity and risk assessment of SiNPs.

The metabolic associated fatty liver disease (MAFLD) is a public health challenge, leading to a global increase in chronic liver disease. The respiratory exposure of silica nanoparticles (SiNPs) has revealed to induce hepatotoxicity. However, its role in the pathogenesis and progression of MAFLD was severely under-studied. In this context, the hepatic impacts of SiNPs were investigated in vivo and in vitro through using ApoE

In this paper, a microdisk resonator (MDR) based on an

SUMMARYEpidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) positively affect the initial control of non-small cell lung cancer (NSCLC). The rapidly acquired TKIs resistance accounts for a major hurdle in successful treatment. However, the mechanisms controlling EGFR-TKIs resistance remain largely unknown. RNA structures have widespread and crucial roles in various biological processes; but, their role in regulating cancer drug resistance remains unclear. Here, the PARIS method is used to establish the higher-order RNA structure maps of EGFR-TKI resistant- and sensitive-cells of NSCLC. According to our results, RNA structural regions are enriched in UTRs and correlate with translation efficiency. Moreover,YRDCfacilitates resistance to EGFR-TKIs in NSCLC cells, and RNA structure formation inYRDC3’UTR suppress ELAVL1 binding leading to EGFR-TKIs sensitivity by impairingYRDCtranslation. A potential cancer therapy strategy is provided by using antisense oligonucleotide (ASO) to perturb the interaction between RNA and protein. Our study reveals an unprecedented mechanism in which the RNA structure switch modulates EGFR-TKIs resistance by controllingYRDCmRNA translation in an ELAVL1-dependent manner.

Ferroptosis, a newly discovered form of regulated cell death dependent on iron and reactive oxygen species, is mainly characterized by mitochondrial shrinkage, increased density of bilayer membranes and the accumulation of lipid peroxidation, causing membrane lipid peroxidation and eventually cell death. Similar with the most forms of regulated cell death, ferroptosis also participated in the pathological metabolism of myocardial infarction and myocardial ischemia/reperfusion injuries, which are still the leading causes of death worldwide. Given the crucial roles ferroptosis played in cardiovascular diseases, such as myocardial infarction and myocardial ischemia/reperfusion injuries, it is considerable to delve into the molecular mechanisms of ferroptosis contributing to the progress of cardiovascular diseases, which might offer the potential role of ferroptosis as a targeted treatment for a wide range of cardiovascular diseases. This review systematically summarizes the process and regulatory metabolisms of ferroptosis, discusses the relationship between ferroptosis and myocardial infarction as well as myocardial ischemia/reperfusion injuries, which might potentially provide novel insights for the pathological metabolism and original ideas for the prevention as well as treatment targeting ferroptosis of cardiovascular diseases such as myocardial infarction and myocardial ischemia/reperfusion injuries.

The relationship between environmental exposure to silica nanoparticles (SiNPs) and adverse cardiac outcomes has received more attention. Our recent work has revealed a size-dependent impact of the intratracheal instilled SiNPs on cardiac health of ApoE

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) positively affect the initial control ratio of non-small cell lung cancer (NSCLC). Rapidly acquired resistance to EGFR-TKI is a major hurdle in successful treatment. However, the mechanisms that control the resistance of EGFR-TKI remain largely unknown. RNA structures have widespread and crucial functions in many biological regulations, however, the functions of RNA structures in regulating cancer drug resistance remain unclear. Here, the psoralen analysis of RNA interactions and structures method (PARIS) is used to establish the higher-order RNA structure maps of EGFR-TKI resistant and sensitive cells of NSCLC. Our results show RNA structural regions are enriched in untranslation regions (UTRs) and correlate with translation efficiency (TE). Moreover, yrdC N

Soluble receptor for advanced glycation end-products (sRAGE) was reported to inhibit cardiac apoptosis through the mitochondrial pathway during myocardial ischemia/reperfusion (I/R) injury. Meanwhile, the proapoptotic protein Bcl2 and adenovirus E1B 19-kDa-interacting protein 3 (Bnip3) was reported to mediate mitochondrial depolarization and be activated by the Forkhead box protein O3 (FoxO3a). Therefore, it is supposed that FoxO3a-Bnip3 pathway might be involved in the inhibiting effects of sRAGE on mitochondrial apoptosis during I/R. I/R surgery or glucose deprivation/reoxygenation was adopted to explore mitochondrial depolarization, apoptosis and related signaling pathways in mice hearts and cultured cardiomyocytes. The results showed that overexpression of sRAGE in cardiomyocytes dramatically improved cardiac function and reduced infarct areas in I/R treated mice. sRAGE inhibited mitochondrial depolarization and cardiac apoptosis during I/R, which correlated with reduced expression of Bnip3, Sirt2, phosphorylation of Akt and FoxO3a which translocated into nucleus in cultured cardiomyocytes. Either Sirt2 or FoxO3a silencing enhanced the inhibiting effects of sRAGE on mitochondrial depolarization induced by I/R in cultured cardiomyocytes. Meanwhile, overexpression or silencing of FoxO3a affected the inhibiting effects of sRAGE on Bnip3 and cleaved caspase-3 in cultured cardiomyocytes. Therefore, it is suggested that sRAGE inhibited I/R injuries via reducing mitochondrial apoptosis through the FoxO3a-Bnip3 pathway.

Background The biosafety concern of silica nanoparticles (SiNPs) is rapidly expanding alongside with its mass production and extensive applications. The cardiovascular effects of SiNPs exposure have been gradually confirmed, however, the interaction between SiNPs exposure and atherosclerosis, and the underlying mechanisms still remain unknown. Thereby, this study aimed to explore the effects of SiNPs on the progression of atherosclerosis, and to investigate related mechanisms. Results We firstly investigated the in vivo effects of SiNPs exposure on atherosclerosis via intratracheal instillation of ApoE−/− mice fed a Western diet. Ultrasound microscopy showed a significant increase of pulse wave velocity (PWV) compared to the control group, and the histopathological investigation reflected a greater plaque burden in the aortic root of SiNPs-exposed ApoE−/− mice. Compared to the control group, the serum levels of total triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) were elevated after SiNPs exposure. Moreover, intensified macrophage infiltration and endoplasmic reticulum (ER) stress was occurred in plaques after SiNPs exposure, as evidenced by the upregulated CD68 and CHOP expressions. Further in vitro, SiNPs was confirmed to activate ER stress and induce lipid accumulation in mouse macrophage, RAW264.7. Mechanistic analyses showed that 4-PBA (a classic ER stress inhibitor) pretreatment greatly alleviated SiNPs-induced macrophage lipid accumulation, and reversed the elevated CD36 expression induced by SiNPs. Conclusions Our results firstly revealed the acceleratory effect of SiNPs on the progression of atherosclerosis in ApoE−/− mice, which was related to lipid accumulation caused by ER stress-mediated upregulation of CD36 expression in macrophage. Graphical abstract

Anthracyclines are a class of conventional and commonly used frontline chemotherapy drugs to treat breast cancer. However, the anthracycline-based regimens can only reduce breast cancer mortality by 20–30%. Furthermore, there is no appropriate biomarker for predicting responses to this kind of chemotherapy currently. Here we report our findings that may fill this gap by showing the AQP1 (Aquaporin1) protein as a potential response predictor in the anthracycline chemotherapy. We showed that breast cancer patients with a high level of AQP1 expression who underwent the anthracycline treatment had a better clinical outcome relative to those with a low level of AQP1 expression. In the exploration of the underlying mechanisms, we found that the AQP1 and glycogen synthase kinase-3β (GSK3β) competitively interacted with the 12 armadillo repeats of β-catenin, followed by the inhibition of the β-catenin degradation that led to β-catenin’s accumulation in the cytoplasm and nuclear translocation. The nuclear β-catenin interacted with TopoIIα and enhanced TopoIIα’s activity, which resulted in a high sensitivity of breast cancer cells to anthracyclines. We also found, the miR-320a-3p can attenuate the anthracycline’s chemosensitivity by inhibiting the AQP1 expression. Taken together, our findings suggest the efficacy of AQP1 as a response predictor in the anthracycline chemotherapy. The application of our study includes, but is not limited to, facilitating screening of the most appropriate breast cancer patients (who have a high AQP1 expression) for better anthracycline chemotherapy and improved prognosis purposes.

ACS (acute coronary syndrome), a subgroup of coronary artery disease (CHD), is a leading cause of death worldwide. Reports shown the association between methylation and CHD, while the abnormal expression of C1QTNF1 (C1q and tumor necrosis factor related protein 1) in CHD patients, but the underlying mechanisms are still unclear. To analyze the methylation of CpG sites of C1QTNF1 in ACS patients. Peripheral blood samples were collected from healthy controls and ACS patients. The methylation of total C1QTNF1, promoter sequence and CpG sites of C1QTNF1 were measured using methylation detection kits. The outcomes were compared between patients and controls based on gender, clinical classification and clinical stages. The promoter sequences from 37 ACS patients and 20 controls indicate that the methylation rate of C1QTNF1 was significantly lower in male patients compared to healthy controls at + 63 CpG sites (p = 0.03). Whereas, the methylation rate of C1QTNF1 in female patients was significantly lower than female health controls at − 89, + 39 and + 167 CpG sites (p = 0.021, 0.042, 0.021). In addition, the methylation rate of C1QTNF1 was significantly higher in male patients than female patients at − 89, − 41 and + 39 CpG sites (p = 0.011, 0.043, 0.006). Moreover, the methylation rate significantly decreased at − 24 sites (p = 0.021), but it significantly increased at − 14 site (p = 0.048) in patients with UA, compared to patients with STEMI (ST-segment elevation myocardial infarction). There were significant differences in the methylation rate + 63 CpG sites between controls and male ACS patients. The − 14 site methylation increased in patients with UA, compared to patients with STEMI.

Soluble receptor for advanced glycation end-products (sRAGE), which exerts cardioprotective effect through inhibiting cardiomyocyte apoptosis and autophagy during ischemia/reperfusion (I/R) injury, is also known to enhance angiogenesis in post-ischemic reperfusion injury-critical limb ischemia (PIRI-CLI) mice. However, whether sRAGE protects the heart from myocardial I/R injury via promoting angiogenesis remains unclear. Myocardial model of I/R injury was conducted by left anterior descending (LAD) ligation for 30 min and reperfusion for 2 weeks in C57BL/6 mice. And I/R injury in cardiac microvascular endothelial cells (CMECs) was duplicated by oxygen and glucose deprivation. The results showed that I/R-induced cardiac dysfunction, inflammation and myocardial fibrosis were all reversed by sRAGE. CD31 immunohistochemistry staining showed that sRAGE increased the density of vessels after I/R injury. The results from cultured CMECs showed that sRAGE inhibited apoptosis and increased proliferation, migration, angiogenesis after exposure to I/R. These effects were dependent on signal transducer and activator of transcription 3 (STAT3) pathway. Together, the present study demonstrated that activation of STAT3 contributed to the protective effects of sRAGE on myocardial I/R injury via promoting angiogenesis.

The genomes of all living cells are under endogenous and exogenous attacks every day, causing diverse genomic lesions. Most of the lesions can be timely repaired by multiple DNA repair pathways. However, some may persist during S-phase, block DNA replication, and challenge genome integrity. Eukaryotic cells have evolved DNA damage tolerance (DDT) to mitigate the lethal effects of arrested DNA replication without prior removal of the offending DNA damage. As one important mode of DDT, translesion DNA synthesis (TLS) utilizes multiple low-fidelity DNA polymerases to incorporate nucleotides opposite DNA lesions to maintain genome integrity. Three different mechanisms have been proposed to regulate the polymerase switching between high-fidelity DNA polymerases in the replicative machinery and one or more specialized enzymes. Additionally, it is known that proliferating cell nuclear antigen (PCNA) mono-ubiquitination is essential for optimal TLS. Given its error-prone property, TLS is closely associated with spontaneous and drug-induced mutations in cells, which can potentially lead to tumorigenesis and chemotherapy resistance. Therefore, TLS process must be tightly modulated to avoid unwanted mutagenesis. In this review, we will focus on polymerase switching and PCNA mono-ubiquitination, the two key events in TLS pathway in mammalian cells, and summarize current understandings of regulation of TLS process at the levels of protein-protein interactions, post-translational modifications as well as transcription and noncoding RNAs. Environ. Mol. Mutagen. 61:680-692, 2020. © 2020 Wiley Periodicals, Inc.

Acute myocardial infarction is mostly caused by coronary atherosclerotic stenosis or thrombosis. Myocardial infarction directly caused by left fascicular pacing is rarely reported.We reported a 60-year-old male patient who accepted left bundle branch pacing (LBBP). After operation, this patient experienced acute myocardial infarction (AMI), Adams-stokes syndrome and was treated successfully at last.

Soluble receptor for advanced glycation end-product (sRAGE) was reported to protect myocardial ischemia/reperfusion (I/R) injuries via directly interacting with cardiomyocytes besides competing with RAGE for AGEs. However, the specific molecule for the interaction between sRAGE and cardiomyocytes are not clearly defined. Integrins which were reported to interact with RAGE on leukocytes were also expressed on myocardial cells, therefore it was supposed that sRAGE might interact with integrins on cardiomyocytes to protect hearts from ischemia/reperfusion injuries. The results showed that sRAGE increased the expression of integrinβ3 but not integrinβ1, β2, β4 or β5 in cardiomyocytes during I/R injuries. Meanwhile, the suppressive effects of sRAGE on cardiac function, cardiac infraction size and apoptosis in mice were cancelled by inhibition of integrinβ3 with cilengitide (CLG, 75 mg/kg). The results from cultured cardiomyocytes also proved that sRAGE attenuated myocardial apoptosis and autophagy through interacting with integrinβ3 to activate Akt and STAT3 pathway during oxygen and glucose deprivation/reperfusion (OGD/R) treatment. Furthermore, the phosphorylation of STAT3 was significantly downregulated by the inhibition of Akt (LY294002, 10 μM) in OGD/R and sRAGE treated cardiomyocytes, which suggested that STAT3 pathway was induced by Akt in I/R and sRAGE treated cardiomyocytes. The present study contributes to the understanding of myocardial I/R pathogenesis and provided a novel integrinβ3-dependent therapy strategy for sRAGE ameliorating I/R injuries.

Transmembrane of coiled-coil domains 1 (TMCO1) plays an important role in maintaining homeostasis of calcium (Ca

Interest is growing to better comprehend the interaction of silica nanoparticles (SiNPs) with the cardiovascular system. In particular, the extremely small size, relatively large surface area and associated unique properties may greatly enhance its toxic potentials compared to larger-sized counterparts. Nevertheless, the underlying mechanisms still need to be evaluated. In this context, the cardiotoxicity of nano-scale (Si-60; particle diameter about 60 nm) and submicro-scale silica particles (Si-300; 300 nm) were examined in ApoE

Exposure to amorphous silica nanoparticles (SiNPs) has increased dramatically, and concerns are growing about their potential health effects. However, their long-term systemic toxicity profile and underlying mechanisms following respiratory exposure still remains unexplored. It is well documented that the inhalation of ultrafine particles is firmly associated with adverse effects in humans. Environmental pollutants may contribute to diverse adverse effect or comorbidity in susceptible individuals. Thereby, we examined the long-term systemic effects of inhaled SiNPs using a sensitive mouse model (ApoE

Silica nanoparticles (SiNPs) are among the most abundantly produced nanosized particles in the global market, and their potential toxicity has aroused a great concern. Increasing epidemiological investigations and experimental evidence revealed the threaten of SiNPs exposure to cardiovascular system. The myocardial toxicity caused by SiNPs was gradually demonstrated, nevertheless, the underlying mechanisms remain unclear. In view of mitochondria serving as the centrality in the prominent of cardiovascular disease, we investigated the role of mitochondria and related mechanisms in SiNPs-induced adverse effects on cardiomyocytes. As a result, SiNPs were found in cytoplasm, accompanied with morphological alterations in mitochondria, such as cristae fracture or disappearance, vacuolation. The induction of mitochondrial dysfunction by SiNPs was confirmed, as indicated by the excessive reactive oxygen species (ROS) formation, and blockage of cellular respiratory and ATP production. Concomitantly, SiNPs activated mitochondria-mediated apoptotic signaling in view of the up-regulated BAX, increased Caspase-9 cleavage and declined Bcl-2, ultimately resulting in myocardial apoptosis. It was noteworthy that SiNPs disturbed mitochondrial dynamics toward fission phenotype, which was supported by the dysregulated fission/fusion regulators. Especially, DRP1 and its phosphorylated level at s616 (p-DRP1

Ischemia-reperfusion injury (IRI) is an inevitable process when reperfusion therapy undergoes in acute myocardial infarction patients, which will lead to cardiac cell death. Many factors have been found to protect the myocardium, one of which was the soluble receptor for advanced glycation end-products (sRAGE) that protected the myocardium from apoptosis and autophagy. However, pyroptosis is also an important form of cell death that occurs during ischemia-reperfusion (I/R), whose critical molecule, NLR family pyrin domain containing 3 (NLRP3), was ever reported to be inhibited by sRAGE; therefore, it is hypothesized that sRAGE may decrease the cardiac pyroptosis induced by I/R. The results showed that sRAGE protected cardiomyocytes from I/R-induced pyroptosis by decreasing the expression level of NLRP3, gasdermin D (GSDMD), interleukin-1β (IL-1β), and interleukin-18 (IL-18). Meanwhile, the results from primary cultured cardiomyocytes showed that the NF-κB pathway mediated the effects of sRAGE on pyroptosis. Therefore, it is concluded that sRAGE protects the heart from pyroptosis through inhibiting the NF-κB pathway during myocardial ischemia-reperfusion.

Silica nanoparticles (SiNPs) are derived from manufactured materials and the natural environment, and they cause detrimental effects on human health via various exposure routes. The liver is proven to be a key target organ for SiNP toxicity; however, the mechanisms causing toxicity remain largely uncertain. Here, we investigated the effects of SiNPs on the metabolic spectrum in hepatocytes via integrative analyses of proteomics and metabolomics. First, a proteomic analysis was used to screen for critical proteins (including RPL3, HSP90AA1, SOD, PGK1, GOT1, and PNP), indicating that abnormal protein synthesis, protein misfolding, oxidative stress, and metabolic dysfunction may contribute to SiNP-induced hepatotoxicity. Next, metabolomic data demonstrated that SiNPs caused metabolic dysfunction by altering vital metabolites (including glucose, alanine, GSH, CTP, and ATP). Finally, a systematic bioinformatic analysis of protein-metabolite interactions showed that SiNPs disturbed glucose metabolism (glycolysis and pentose phosphate pathways, amino acid metabolism (alanine, aspartate, and glutamate), and ribonucleotide metabolism (purine and pyrimidine). These metabolic dysfunctions could exacerbate oxidative stress and lead to liver injury. Moreover, SOD, TKT, PGM1, GOT1, PNP, and NME2 may be key proteins for SiNP-induced hepatotoxicity. This study revealed the metabolic mechanisms underlying SiNP-induced hepatotoxicity and illustrated that integrative omics analyses can be a powerful approach for toxicity evaluations and risk assessments of nanoparticles.