PM2.5 induce neurotoxicity via iron overload and redox imbalance mediated-ferroptosis in HT22 cells.

PM2.5 is an important risk factor for the development and progression of cognitive impairment-related diseases. Ferroptosis, a new form of cell death driven by iron overload and lipid peroxidation, is proposed to have significant implications. To verify the possible role of ferroptosis in PM2.5-induced neurotoxicity, we investigated the cytotoxicity, intracellular iron content, iron metabolism-related genes, oxidative stress indices and indicators involving in Nrf2 and ferroptosis signaling pathways. Neurotoxicity biomarkers as well as the ferroptotic cell morphological changes were determined by Western Blot and TEM analysis. Our results revealed that PM2.5 induced cytotoxicity, lipid peroxidation, as indicated by MDA content, and neurotoxicity via Aß deposition in a dose-related manner. Decreased cell viability and excessive iron accumulation in HT-22 cells can be partially blocked by ferroptosis inhibitors. Interestingly, GPX activity, Nrf2, and its regulated ferroptotic-related proteins (i.e. GPX4 and HO-1) were significantly up-regulated by PM2.5. Moreover, gene expression of DMT1, TfR1, IRP2 and FPN1 involved in iron homeostasis and NCOA4-dependent ferritinophagy were activated after PM2.5 exposure. The results demonstrated that PM2.5 triggered ferritinophagy-dependent ferroptotic cell death due to iron overload and redox imbalance. Activation of Nrf2 signaling pathways may confer a protective mechanism for PM2.5-induced oxidative stress and ferroptosis.

Optimizing a twin-chamber system for direct ozone production rate measurement.

High Ozone Production Rate (OPR) leads to O3 pollution episodes and adverse human health outcomes. OPR observation (Obs-OPR) and OPR modelling (Mod-OPR) have been obtained from observed and modelled peroxy radicals and nitrogen oxides. However, discrepancies between them remind of an imperfect understanding of O3 photochemistry. Direct measurement of OPR (Mea-OPR) by a twin-chamber system emerges. Herein, we optimized Mea-OPR design, i.e., minimizing the chamber surface area to volume ratio (S/V) to 9.8 m-1 from 18 m-1 and the dark uptake coefficient of O3 to 9.9 × 10-9 from 7.1 × 10-8 in the literature. In addition, control experiments further revealed and quantified a photo-enhanced O3 uptake, and therefore recommended an essential correction of Mea-OPR. We finally characterized a measurement uncertainty of ±38% and a detection limit of 3.2 ppbv h-1 (3SD), which suggested that Mea-OPR would be sensitive enough to measure OPR in urban or suburban environments. Further application of this system in urban Beijing during the Beijing 2022 Olympic Winter Games recorded a noontime OPR of 7.3 (±3.3, 1SD) ppbv h-1. These observational results added up to our confidence in future field application of Mea-OPR, to facilitate pollution control policy evaluation and to shed light on O3 photochemistry puzzle.

Silver nanoparticles induce iron accumulation-associated cognitive impairment via modulating neuronal ferroptosis.

Silver nanoparticles (AgNPs) are widely used in daily life and medical fields owing to their unique physicochemical properties. Daily exposure to AgNPs has become a great concern regarding their potential toxicity to human beings, especially to the central nervous system. Ferroptosis, a newly recognized programmed cell death, was recently reported to be associated with the neurodegenerative process. However, whether and how ferroptosis contributes to AgNPs-induced neurotoxicity remain unclear. In this study, we investigated the role of ferroptosis in neurotoxic effects induced by AgNPs using in vitro and in vivo models. Our results showed that AgNPs induced a notable dose-dependent cytotoxic effect on HT-22 cells and cognitive impairment in mice as indicated by a decline in learning and memory and brain tissue injuries. These findings were accompanied by iron overload caused by the disruption of the iron transport system and activation of NCOA4-mediated autophagic degradation of ferritin. The excessive free iron subsequently induced GSH depletion, loss of GPX and SOD activities, differential expression of Nrf2 signaling pathway elements, down-regulation of GPX4 protein and production of lipid peroxides, initiating ferroptosis cascades. The mitigating effects of ferrostatin-1 and deferoxamine on iron overload, redox imbalance, neuronal cell death, impairment of mice learning and memory, Aß deposition and synaptic plasticity reduction suggested ferroptosis as a potential molecular mechanism in AgNPs-induced neurotoxicity. Taken together, these results demonstrated that AgNPs induced neuronal cell death and cognitive impairment with Aß deposition and reduction of synaptic plasticity, which were mediated by ferroptosis caused by iron-mediated lipid peroxidation. Our study provides new insights into the underlying mechanisms of AgNPs-induced neurotoxicity and predicts potential preventive strategies.

Synthesizing evidence for the external cycling of NOx in high- to low-NOx atmospheres.

External cycling regenerating nitrogen oxides (NOx ≡ NO + NO2) from their oxidative reservoir, NOz, is proposed to reshape the temporal-spatial distribution of NOx and consequently hydroxyl radical (OH), the most important oxidant in the atmosphere. Here we verify the in situ external cycling of NOx in various environments with nitrous acid (HONO) as an intermediate based on synthesized field evidence collected onboard aircraft platform at daytime. External cycling helps to reconcile stubborn underestimation on observed ratios of HONO/NO2 and NO2/NOz by current chemical model schemes and rationalize atypical diurnal concentration profiles of HONO and NO2 lacking noontime valleys specially observed in low-NOx atmospheres. Perturbation on the budget of HONO and NOx by external cycling is also found to increase as NOx concentration decreases. Consequently, model underestimation of OH observations by up to 41% in low NOx atmospheres is attributed to the omission of external cycling in models.

Validating HONO as an Intermediate Tracer of the External Cycling of Reactive Nitrogen in the Background Atmosphere.

In the urban atmosphere, nitrogen oxide (NOx═NO + NO2)-related reactions dominate the formation of nitrous acid (HONO). Here, we validated an external cycling route of HONO and NOx, i.e., formation of HONO resulting from precursors other than NOx, in the background atmosphere. A chemical budget closure experiment of HONO and NOx was conducted at a background site on the Tibetan Plateau and provided direct evidence of the external cycling. An external daytime HONO source of 100 pptv h-1 was determined. Both soil emissions and photolysis of nitrate on ambient surfaces constituted likely candidate mechanisms characterizing this external source. The external source dominated the chemical production of NOx with HONO as an intermediate tracer. The OH production was doubled as a result of the external cycling. A high HONO/NOx ratio (0.31 ± 0.06) during the daytime was deduced as a sufficient condition for the external cycling. Literature review suggested the prevalence of high HONO/NOx ratios in various background environments, e.g., polar regions, pristine mountains, and forests. Our analysis validates the prevalence of external cycling in general background atmosphere and highlights the promotional role of external cycling regarding the atmospheric oxidative capacity.

Palladium-Catalyzed Cascade Carbonylative Synthesis of Perfluoroalkyl and Carbonyl-Containing 3,4-Dihydroquinolin-2(1H)-one Derivatives.

A palladium-catalyzed cascade radical cyclization and carbonylation of 1,7-enynes with perfluoroalkyl iodides and alcohols has been described. This procedure provides a facile and efficient approach for the construction of 3,4-dihydroquinolin-2(1H)-one skeletons by using benzene-1,3,5-triyl triformate (TFBen) as the CO source. This method enables the incorporation of both perfluoroalkyl and carbonyl units into the 3,4-dihydroquinolin-2(1H)-one skeletons, producing a variety of 3,4-dihydroquinolin-2(1H)-one derivatives in moderate to high yields and with excellent E/Z selectivity.

Silver Nanoparticles Induce a Size-dependent Neurotoxicity to SH-SY5Y Neuroblastoma Cells via Ferritinophagy-mediated Oxidative Stress.

Silver nanoparticles (AgNPs) are widely used in a variety of consumer products because of their antibacterial and antifungal characteristics, but little is known about their toxicity to the brain. In this study, we investigated AgNP-induced neurotoxicity using the human neuroblastoma cancer (SH-SY5Y) cell line. After a 24 h treatment of AgNPs with two primary sizes (5 and 50 nm labeled as Ag-5 and Ag-50, respectively), a series of toxicological endpoints including cell viability, expression of proteins and genes in amyloid precursor protein (APP) amyloid hydrolysis process and ferritinophagy signaling pathways, oxidative stress, intracellular iron levels, and molecular regulators of iron metabolism were evaluated. Our results showed that both Ag-5 and Ag-50 induced notable neurotoxic effects on SH-SY5Y cells indicated by cell proliferation inhibition, increased BACE1 protein expression, and decreased APP and ADAM10 gene expression. Activation of nuclear receptor coactivator 4-mediated ferritinophagy and blockade of autophagic flux were induced by AgNPs, accompanied by intracellular iron accumulation and overexpression of divalent metal-ion transporter-1 and ferroportin1 in SH-SY5Y cells. In addition, AgNPs significantly decreased glutathione peroxidase 4 protein expression but increased malondialdehyde concentration, suggesting that AgNP-induced iron accumulation may trigger oxidative stress by disruption of the intracellular oxidant and antioxidant systems. In addition, compared with Ag-50, Ag-5 with higher cellular uptake efficiency caused more detrimental effects on SH-SY5Y cells. In conclusion, our findings demonstrated a size-dependent neurotoxicity in SH-SY5Y cells by AgNPs via ferritinophagy-mediated oxidative stress.

A probe-free electrochemical immunosensor for methyl jasmonate based on a Cu-MOF-carboxylated graphene oxide platform.

Methyl jasmonate (MeJA) is an important phytohormone which can regulate plant growth and stress tolerance. It is very necessary to develop sensitive and accurate detection methods for MeJA. In this work, a probe-free electrochemical immunosensor for MeJA detection was developed based on a Cu-MOF-carboxylated graphene oxide (COOH-GO) platform. The Cu2+ in the Cu-MOFs was used to provide redox signals, which avoids the application of an external redox probe in the electrolyte solutions as conventional immunosensors. COOH-GO was used to improve the structural stability and provide more sites for binding MeJA antibodies. The linear range of the MeJA immunosensor is from 10 pM to 100 µM, which can cover the whole concentration range of MeJA in most plants. And its detection limit is very low (0.35 pM), and it can detect very low concentrations of MeJA. This immunosensor is simple, low cost, and does not need redox probe solutions for measurements. It shows remarkable potential for on-site application in precision agriculture.

Association of Preoperative Plasma D-Dimer and Fibrinogen and Osteosarcoma Outcome.

Objective: We aimed to evaluate the utility of preoperative D-dimer and plasma fibrinogen (PF) levels as useful markers for predicting the clinical value of patients with osteosarcoma. Methods: 145 enrolled patients with osteosarcoma were studied retrospectively. We determined the critical values of D-dimer and PF by receiver operating characteristic curve analysis. Cox regression analysis was used to assess prognostic role of the D-dimer and PF levels among osteosarcoma patients. Results: The critical values of D-dimer and PF were calculated to be 0.46 µg/mL and 3.34 mg/mL, respectively. Upregulation of D-dimer and PF showed positive correlations with a higher clinical stage, tumour metastasis and recurrence. Survival curve results confirmed that osteosarcoma patients with higher levels of D-dimer and PF predicted worse overall survival (OS) and progression-free survival (PFS). Moreover, only a high D-dimer level was associated with a shorter OS (P = 0.013) and PFS (P = 0.042) in both the univariate and multivariate analysis. Conclusion: Elevated preoperative D-dimer levels are correlated with aggressive clinicopathological features and poor survival outcomes, which indicates that assessment of the D-dimer could be a useful prognostic marker in osteosarcoma.

PM2.5 induces inflammatory responses via oxidative stress-mediated mitophagy in human bronchial epithelial cells.

BACKGROUND: Fine particulate matter (PM2.5) is a ubiquitous air pollutant, and it has been reported to be closely associated with lung inflammatory injury. In this study, the potential molecular mechanisms underlying PM2.5-induced cellular inflammation in human bronchial epithelial (BEAS-2B) cells were investigated. MATERIALS AND METHODS: Ambient PM2.5 particulates from Suzhou, China, were collected and re-suspended in ultrapure water. Cellular damages, characterized by oxidative stress, mitochondrial injury, and inflammatory cytokine production, were determined in 24 h PM2.5-treated BEAS-2B cells with or without 3-methyladenine (3-MA; autophagy inhibitor) pretreatment. Biomarkers related to oxidative damage, inflammatory injury and autophagy signaling pathways were also measured. RESULTS: Uptake of PM2.5 in BEAS-2B cells induced cellular oxidative damage, mitochondrial injury, and inflammatory responses as indicated by a significant decrease in GSH/GSSG ratio, increased MDA content, dilated mitochondria with loss and rupture of crista, and production of inflammatory cytokines. Activation of Nrf-2/TXNIP-mediated NF-κB and Bnip3L/NIX-dependent mitophagy signaling pathways, as well as accumulation of autophagosomes and autolysosomes, were also observed. A 6 h pretreatment of 3-MA increased PM2.5-induced oxidative damage and cellular inflammation as indicated by increasing protein levels of HO-1, TXNIP, Bnip3L/NIX and IL-8 gene expression. CONCLUSIONS: PM2.5 induced cellular inflammatory injury by oxidative stress, mitochondrial dysfunction, and mitophagy initiation. Although induction of Bnip3L/NIX-mediated mitophagy in BEAS-2B cells appeared to confer protection in response to PM2.5, dysfunction of autophagic flux may be a critical contributor to defective mitophagy and cellular inflammatory response.

Additive-Controlled Divergent Synthesis of Indole and 4H-Benzo[d][1,3]oxazine Derivatives: Palladium-Catalyzed Carbonylative Cyclization of 2-Alkynylanilines and Benzyl Chlorides.

A palladium-catalyzed divergent carbonylative synthesis of indoles and 4H-benzo[d][1,3]oxazines from 2-alkynylanilines and benzyl chlorides with benzene-1,3,5-triyl triformate (TFBen) as the CO source has been developed. The reaction using AlCl3 as the additive produced various indoles in high yields, while a series of 4H-benzo[d][1,3]oxazines was achieved in moderate yields with AcOH as the additive.

ZFC3H1 prevents RNA trafficking into nuclear speckles through condensation.

Controlling proper RNA pool for nuclear export is important for accurate gene expression. ZFC3H1 is a key controller that not only facilitates nuclear exosomal degradation, but also retains its bound polyadenylated RNAs in the nucleus upon exosome inactivation. However, how ZFC3H1 retains RNAs and how its roles in RNA retention and degradation are related remain largely unclear. Here, we found that upon degradation inhibition, ZFC3H1 forms nuclear condensates to prevent RNA trafficking to nuclear speckles (NSs) where many RNAs gain export competence. Systematic mapping of ZFC3H1 revealed that it utilizes distinct domains for condensation and RNA degradation. Interestingly, ZFC3H1 condensation activity is required for preventing RNA trafficking to NSs, but not for RNA degradation. Considering that no apparent ZFC3H1 condensates are formed in normal cells, our study suggests that nuclear RNA degradation and retention are two independent mechanisms with different preference for controlling proper export RNA pool-degradation is preferred in normal cells, and condensation retention is activated upon degradation inhibition.

Palladium-catalyzed carbonylative synthesis of aryl esters from p-benzoquinones and aryl triflates.

A palladium-catalyzed dicarbonylation of p-benzoquinones with aryl triflates has been developed. Using Cr(CO)6 as the CO source, the reaction proceeds smoothly and efficiently to give a series of aryl esters in moderate to good yields (up to 90%).

A probe-free electrochemical immunosensor for methyl jasmonate based on ferrocene functionalized-carboxylated graphene-multi-walled carbon nanotube nanocomposites.

Methyl jasmonate (MeJA) is an endogenous plant hormone, which plays an important role in agriculture production. A novel probe-free electrochemical immunosensor was fabricated for detecting of MeJA. Fc, carboxylated graphene (COOH-GR) and carboxylated multi-walled carbon nanotubes (COOH-MWNT) composite was formed and used to fabricate screen-printed electrode (SPE). Fc was used as the electronic medium. COOH-GR and COOH-MWNT were used to improve the conductivity and catalytic activity of the sensor and to immobilize the MeJA antibody. Thus, the immunosensor can be used to detect MeJA without external redox probe solution. The designed sensor can detect MeJA in a wide range of 100 fM-100 µM, and its detection limit is as low as 31.26 fM (S/N = 3). The as-prepared probe-free immunosensor is simple, low cost, and does not need redox probe solutions for measurements, which shows great promise for future application in precision agriculture.

Supported Palladium-Catalyzed Carbonylative Synthesis of Diaryl Ketones from Aryl Bromides and Arylboronic Acids.

A palladium supported on graphitic carbon nitride (Pd/g-C3 N4 ) catalyzed carbonylative reaction of aryl bromides and arylboronic acids by has been developed for the construction of diaryl ketones. Using benzene-1,3,5-triyl triformate (TFBen) as the CO source, the reaction proceeded well to give various diaryl ketones in moderate to good yields.

Silver nanoparticles: Correlating particle size and ionic Ag release with cytotoxicity, genotoxicity, and inflammatory responses in human cell lines.

The widespread use of silver nanoparticles (AgNPs), their many sources for human exposure, and the ability of AgNPs to enter organisms and induce general toxicological responses have raised concerns regarding their public health and environmental safety. To elucidate the differential toxic effects of polyvinylpyrrolidone-capped AgNPs with different primary particle sizes (i.e. 5, 50, and 75 nm), we performed a battery of cytotoxicity and genotoxicity assays and examined the inflammatory responses in two human cell lines (i.e. HepG2 and A549). Concentration-dependent decreases in cell proliferation and mitochondrial membrane potential and increases in cytokine (i.e. interleukin-6 and interleukin-8) excretion indicated disruption of mitochondrial function and inflammation as the main mediating factors of AgNPs-induced cytotoxicity. An incremental increase in genotoxicity with decreasing AgNPs diameter was noted in HepG2 cells, which was associated with S and G2/M accumulation and transcriptional activation of the GADD45α promoter as reflected by luciferase activity. Dose-related genetic damage, as indicated by Olive tail moment and micronucleus formation, was also observed in A549 cells, but these effects as well as the AgNPs-induced cytotoxicity were more associated with ionic Ag release from nanoparticles (NPs). In summary, the present study addressed different toxicity mechanisms of AgNPs, depending on the cell model, toxicological endpoint, particle size, and degree of Ag+ release from NPs. The results suggest that the GADD45α promoter-driven luciferase reporter cell system provided a rapid screening tool for the identification of genotoxic properties of NPs across a range of different sizes and concentrations.

Cellular effects of PM2.5 from Suzhou, China: relationship to chemical composition and endotoxin content.

Exposure to PM2.5 can cause adverse health outcomes. In this study, we analyzed PM2.5 samples collected from suburban and urban sites, including a traffic tunnel in Suzhou, China, for their physicochemical properties, endotoxin contents, and effects on HepG2 and A549 cells in vitro. The greatest cellular responses, including oxidative stress, cytotoxicity, genotoxicity, inflammatory, and transcriptional activation of stress-responsive genes (i.e., HSPA1A, GADD45α), were observed in cells treated with traffic tunnel PM2.5. Cytokine expression was also measured and closely correlated with endotoxin content, while other toxic effects were largely related to PM2.5-bound metals and polycyclic aromatic hydrocarbons (PAHs). These findings suggested that chemical and biological composition of PM2.5, including adsorbed trace metals, PAHs, and endotoxin, may contribute significantly to their toxicity. In addition to commonly used in vitro toxicity tests, HSPA1A and GADD45α promoter-driven luciferase reporter cells may provide a potential new tool for rapid screening and quantification of PM2.5 toxicity.

Out or decay: fate determination of nuclear RNAs.

In eukaryotes, RNAs newly synthesized by RNA polymerase II (RNAPII) undergo several processing steps prior to transport to the cytoplasm. It has long been known that RNAs with defects in processing or export are removed in the nucleus. Recent studies revealed that RNAs without apparent defects are also subjected to nuclear degradation, indicating that nuclear RNA fate is determined in a more complex and dynamic way than previously thought. Nuclear RNA sorting directly determines the quality and quantity of RNA pools for future translation and thus is of significant importance. In this essay, we will summarize recent studies on this topic, mainly focusing on findings in mammalian system, and discuss about important remaining questions and possible biological relevance for nuclear RNA fate determination.