Chiral silver nanoparticles with surface-anchored L(D)-Cys exhibit dissimilar biological characteristics in vitro but not in vivo.

This work investigated the influence of surface chirality on cellular internalization, cytotoxicity, and tissue distribution of silver nanoparticles (AgNPs). D-cysteine and L-cysteine are chiral forms of the amino acid cysteine. These enantiomers exhibit distinct spatial arrangements, with D-cysteine having a different configuration from L-cysteine. This structural dissimilarity can lead to variations in how these forms interact with biological systems, potentially impacting their cytotoxic responses. Four distinct types of AgNPs were synthesized, each possessing a unique surface coating: pristine AgNPs (pAgNPs), L-cysteine coated AgNPs (AgNPs@L-Cys), D-cysteine coated AgNPs (AgNPs@D-Cys), and racemic AgNPs coated with both L-Cys and D-Cys (AgNPs@L/D-Cys). We found chiral-dependent cytotoxicity of AgNPs on J774A.1 cells. Specifically, AgNPs@L-Cys exhibited the highest toxicity, and AgNPs@D-Cys exhibited the lowest toxicity. Meanwhile, the cellular uptake of the AgNPs correlated nicely with their cytotoxicity, with AgNPs@L-Cys being internalized to the greatest extent while AgNPs@D-Cys displays the least internalization. Scavenger receptors and clathrin predominantly mediate the cellular internalization of these AgNPs. Strikingly, the dissimilar cellular internalization and cytotoxicity of AgNPs with different chirality were eliminated upon protein corona coverage. Notably, following intravenous injection in mice, these four types of AgNPs showed similar patterns among various organs due to the inevitable protein adsorption in the bloodstream. These findings underscored the pivotal role of surface chirality in governing the biological interactions and toxicity of AgNPs.

A multi-mode Rhein-based nano-platform synergizing ferrotherapy/chemotherapy-induced immunotherapy for enhanced tumor therapy.

Ferroptosis has emerged as a promising strategy for treating triple-negative breast cancer (TNBC) due to bypassing apoptosis and triggering immunogenic cell death (ICD) of tumor cells. However, the antitumor efficacy has been limited by the insufficient intracellular ferrous iron concentration required for ferroptosis and inadequate antitumor immune response. To address these limitations, we designed a multi-mode nano-platform (MP-FA@R-F NPs), which exhibited a synergistic effect of ferroptosis, apoptosis and induced immune response for enhanced antitumor therapy. MP-FA@R-F NPs target folate receptors, which are over-expressed on the tumor cell's surface to promote intracellular uptake. The cargoes, including Rhein and Fe3O4, would be released in intracellular acid, accelerating by NIR laser irradiation. The released Rhein induced apoptosis of tumor cells mediated by the caspase 3 signal pathway, while the released Fe3O4 triggered ferroptosis through the Fenton reaction and endowed the nanoplatform with magnetic resonance imaging (MRI) capabilities. In addition, ferroptosis-dying tumor cells could release damage-associated molecular patterns (DAMPs) to promote T cell activation and infiltration for immune response and induce immunogenic cell death (ICD) for tumor immunotherapy. Together, MP-FA@R-F NPs represent a potential synergistic ferro-/chemo-/immuno-therapy strategy with MRI guidance for enhanced antitumor therapy. STATEMENT OF SIGNIFICANCE: The massive strategies of cancer therapy based on ferroptosis have been emerging in recent years, which provided new insights into designing materials for cancer therapy. However, the antitumor efficacy of ferroptosis is still unsatisfactory, mainly due to insufficient intracellular pro-ferroptotic stimuli. In the current study, we designed a multi-mode nano-platform (MP-FA@R-F NPs), which represented a potential synergistic ferro-/chemo-/immuno-therapy strategy with MRI guidance for enhanced antitumor therapy.

Exosome Heterogeneity Affects the Distal "Barrier-Crossing" Trafficking of Exosome Encapsulated Quantum Dots.

The biological activities of nanoparticles (NPs), which include endocytosis by macrophages and subsequent intracellular degradation and/or release, transfer to other cells, or translocation across tissue barriers, highly depend on their fate in living organisms. Yet, translocation across barriers, especially the distal "barrier-crossing" trafficking of NPs, is still unclear. The exosome (Exo) plays a crucial role in intercellular communication and biological barrier trafficking. Here, we report that ZnCdSe@ZnS quantum dots (QDs), as a representation of NPs in biomedical applications, could cross the blood-brain barrier and approach the mouse brain via active Exo encapsulation. By employing multiple techniques, we demonstrated that QDs were internalized by macrophages (J774A.1) and tumor cells (HeLa) and then released to the extracellular environment along with Exo. Exo encapsulation facilitates the distal barrier-crossing trafficking of QDs in vivo, while Exo biogenesis inhibitor GW4869 suppressed the QDs enriched in the brains of mice with a 4T1-Luc breast cancer xenograft. Interestingly, Exo heterogeneity affects the distal trafficking of enveloped QDs. Exo derived from tumorous HeLa cells, not macrophages, that were enriched in functional proteins with cell adhesion, cell migration, axon guidance, and cell motility, showed a better capacity for the remote trafficking of QDs. This study proposes Exo as a vehicle to deliver exogenous NPs to translocate across the distal barrier and provides further information for biomedical application and the risk assessment of NPs.

Long-term pulmonary iron oxide nanoparticles exposure disrupts hepatic iron-lipid homeostasis and increases plaque vulnerability in ApoE-/- mice.

Iron oxide nanoparticles (Fe3O4 NPs) have attracted great attention due to their extensive applications, which warranted their environmental concerns. Although recent advances have proposed the relevance of Fe3O4 NPs to cardiovascular disease, the intrinsic mechanisms underlying the effects of NPs remain indistinct. ApoE-/- mice were chosen as a long-term exposure model to explore the immanent association between respiratory exposure to Fe3O4 NPs and the development of cardiovascular diseases. Pulmonary exposure to 20 nm and 200 nm Fe3O4 NPS resulted in significant lung injury, and pulmonary histopathological examination displayed inflammatory cell infiltration, septal thickening and alveolar congestion. Intriguingly, liver iron deposition and variations in the hepatic lipid homeostasis were found in Fe3O4 NPs-exposed mice, eventually leading to dyslipidemia, hinting the potential cardiovascular toxicity of Fe3O4 NPs. In addition, we not only found that Fe3O4 NPs exposure increased aortic plaque area, but also increased M1 macrophages in the plaque, which yielding plaque vulnerability in ApoE-/- mice Of note, 20 nm Fe3O4 NPs showed enhanced capability on the progression of atherosclerosis than 200 nm Fe3O4 NPs. This study may propose the potential mechanism for adverse cardiovascular disease induced by Fe3O4 NPs and provide convincing evidence for the safety evaluation of Fe3O4 NPs.

Azo Reductase Activated Magnetic Resonance Tuning Probe with "Switch-On" Property for Specific and Sensitive Tumor Imaging in Vivo.

Cancer remains a threat to human health. However, if tumors can be detected in the early stage, then the effectiveness of cancer treatment could be significantly improved. Therefore, it is worthwhile to develop more sensitive and accurate cancer diagnostic methods. Herein, we demonstrated an azo reductase (AzoR)-activated magnetic resonance tuning (MRET) probe with a "switch-on" property for specific and sensitive tumor imaging in vivo. Specifically, Gd-labeled DNA1 (DNA1-Gd) and cyclodextrin-coated magnetic nanoparticles (MNP-CD) were employed as enhancer and quencher of MRET, respectively, while DNA2, an azobenzene (Azo) group-modified aptamer (AS1411), served as a linker between enhancer and quencher to construct the MRET probe of MNP@DNA(1-2)-Gd. In tumor tissues with high-level AzoR, the T1-weighted magnetic resonance signal of the MRET probe could be restored by intelligently regulating the switch from "OFF" to "ON" after activation with AzoR, thus accurately indicating the location of the tumor accurately. Moreover, the tumor with a 4 times smaller size than that of the normal tumor model could be imaged based on the proposed MRET probe. The as-proposed MRET-based magnetic resonance imaging strategy not only achieves tumor imaging accurately but also shows promise for early diagnosis of tumors, which might improve patients' survival rates and provide an opportunity for image-guided biomedical applications in the future.

Transferrin-Targeted Cascade Nanoplatform for Inhibiting Transcription Factor Nuclear Factor Erythroid 2-Related Factor 2 and Enhancing Ferroptosis Anticancer Therapy.

Ferroptosis, an iron-dependent cell death driven by the lethal levels of lipid peroxidation (LPO), becomes a promising anticancer strategy. However, the anticancer efficacy of ferroptosis is often hindered by the activation of nuclear factor erythrocyte 2-associated factor 2 (Nrf2), which is an indispensable regulator of the cellular antioxidant balance by preventing the accumulation of intracellular reactive oxygen species (ROS). Herein, we present a rational design of a Tf-targeted cascade nanoplatform TPM@AM based on mesoporous polydopamine (MPDA) co-encapsulating a ferroptosis inducer (artesunate, ART) and an Nrf2-specific inhibitor (ML385) to enhance intracellular ROS and therefore amplify ferrotherapy. Transferrin (Tf) can specifically recognize the transferrin receptor (TfR) on the surface of the cell membrane, which binds and transports iron into cells. When TPM@AM is endocytosed, the high-acid tumor microenvironment and laser irradiation trigger the collapse of MPDA to release ART and ML385. Furthermore, MPDA endows the nanoplatform with photothermal capability. The nanoplatform exhibits high efficiency for synergistic tumor suppression, representing a spatiotemporal controllable therapeutic strategy for precise synergistic cancer therapy.

Enzyme-Triggered Transforming of Assembly Peptide-Modified Magnetic Resonance-Tuned Probe for Highly Sensitive Imaging of Bacterial Infection In Vivo.

Confirming bacterial infection at an early stage and distinguishing between sterile inflammation and bacterial infection is still highly needed for efficient treatment. Here, in situ highly sensitive magnetic resonance imaging (MRI) bacterial infection in vivo based on a peptide-modified magnetic resonance tuning (MRET) probe (MPD-1) that responds to matrix metallopeptidase 2 (MMP-2) highly expressed in bacteria-infected microenvironments is achieved. MPD-1 is an assembly of magnetic nanoparticle (MNP) bearing with gadolinium ion (Gd3+ ) modified MMP-2-cleavable self-assembled peptide (P1 ) and bacteria-targeting peptide (P), and it shows T2 -weighted signal due to the assemble of MNP and MRET ON phenomenon between MNP assembly and Gd3+ . Once MPD-1 accumulates at the bacterially infected site, P1 included in MPD-1 is cleaved explicitly by MMP-2, which triggers the T2 contrast agent of MPD-1 to disassemble into the monomer of MNP, leading the recovery of T1 -weighted signal. Simultaneously, Gd3+ detaches from MNP, further enhancing the T1 -weighted signal due to MRET OFF. The sensitive MRI of Staphylococcus aureus (low to 104 CFU) at the myositis site and accurate differentiation between sterile inflammation and bacterial infection based on the proposed MPD-1 probe suggests that this novel probe would be a promising candidate for efficiently detecting bacterial infection in vivo.

Polybrominated diphenyl ether quinone exposure leads to ROS-driven lysosomal damage, mitochondrial dysfunction and NLRP3 inflammasome activation.

Polybrominated diphenyl ethers (PBDEs) are aromatic compounds that containing bromine atoms, which possess high efficiency, good thermal stability. However, PBDEs had various known toxic effects and were characterized as persistent environmental pollutants. Exposure to a quinone-type metabolite of PBDEs (PBDEQ) is linked with excess production of intracellular reactive oxygen species (ROS) in our previous studies. Here, we observed that PBDEQ exposure led to ROS and mitochondrial dysfunction, which promoted canonical and non-canonical Nod-like receptor protein 3 (NLRP3) inflammasome activation. Further experiments demonstrated that PBDEQ exposure activated Toll-like receptors (TLRs), subsequently regulating nuclear factor kappa B (NF-κB) signaling. Moreover, lysosomal damage and K+ efflux were involved in PBDEQ-driven NLRP3 inflammasome activation. Our in vivo study also illustrated that PBDEQ administration induced liver inflammation in male C57BL/6J mice. Cumulatively, our current finding provided novel insights into PBDEQ-induced pro-inflammatory responses.

Synergistic hydroxyl radical formation, system XC- inhibition and heat shock protein crosslinking tango in ferrotherapy: A prove-of-concept study of "sword and shield" theory.

Ferroptosis provide new insights into designing nanomedicines for enhanced cancer therapy; however, its antitumor efficacy is relatively low, mainly due to self-protective mechanism of cancer cells, e.g., heat shock protein (HSP) overexpression. Since HSPs can be modified/inhibited by lipid peroxidation (LPO) ending products, we construct a nanoplatform, namely MPDA@Fe3O4-Era, to amplify intracellular reactive oxygen species (ROS) and LPO for synergistic ferrotherapy. Upon tumor acidic microenvironment and local near-infrared stimuli, this nanoplatform releases Fe3O4 and reacts with intracellular hydrogen peroxide (H2O2) to promote Fenton reaction, and yields significant intracellular ROS (specifically hydroxyl radical, •OH) and LPO. In turn, LPO ending products crosslink HSPs to destroy self-preservation pathways of cancer cells to enhance anticancer effect. Meanwhile, the released erastin inhibits system XC - signal pathway to depletes glutathione. Fe3O4 loading further provides magnetic resonance imaging T2-weighted signal to guide anti-tumor treatment. Together, this nanoplatform not only provides •OH (as a "sword" to attack tumor cells), but also inhibits system XC - signal pathway and crosslinks HSP (break down the "shield" of tumor cells) to maximize synergistic ferro-therapeutic effect. MPDA@Fe3O4-Era plus laser irradiation possessed highly efficient tumor suppression with magnified the levels of •OH and inactive glutathione peroxidase 4 (GPX4), which can promote the development of precise cooperative cancer therapy.

Iron ion and sulfasalazine-loaded polydopamine nanoparticles for Fenton reaction and glutathione peroxidase 4 inactivation for enhanced cancer ferrotherapy.

Ferroptosis shows promising potential in tumor treatment; however, factors that compromise the efficiency of the Fenton catalyst have limited its therapeutic effectiveness. We developed a polydopamine-based nanoplatform constructed with ferric ion and sulfasalazine-loaded nanoparticles (Fe(III)PP@SAS NPs) for dual-functional ferrotherapy strategy of "sword and shield" through enhanced Fenton reaction and inactivation of glutathione peroxidase 4 (GPX4), respectively. Both the Fenton reaction-based hydroxyl radical (·OH) production and sulfasalazine-driven GPX4 inhibition induced ferroptotic cell death, thus achieving synergistic cancer therapy. Near-infrared light irradiation and acidic tumor microenvironment enhanced the release of ferric ions and sulfasalazine from the Fe(III)PP@SAS NPs. In addition, the released iron ions underwent valence state change due to Fenton reaction and thus provided a supplementary T1-weighted signal for in situ visualization of the tumor based on magnetic resonance imaging. The Fe(III)PP@SAS NPs exhibited high pro-ferroptosis performance by utilizing ·OH radicals as a "sword" to attack cancer cells and the GPX4 inhibitor to break down the "shield" of cancer cells, thus showing potential for cancer treatment. STATEMENT OF SIGNIFICANCE: Several strategies of cancer therapy based on ferroptosis have emerged in recent years, which have provided new insights into designing materials for therapeutic applications. The antitumor efficacy of ferroptosis is, however, still unsatisfactory, mainly because of insufficient intracellular pro-ferroptotic stimuli. In the current study, we report a multifunctional theranostic nanoplatform, namely Fe(III)PP@SAS, with three-fold synergistic effect; this nanoplatform has excellent theranostic potential with multifunctional ferrotherapy.

Iron oxide nanoparticles oxidize transformed RAW 264.7 macrophages into foam cells: Impact of pulmonary surfactant component dipalmitoylphosphatidylcholine.

Iron oxide nanoparticles (IONPs) are one of the most important components in airborne particulate matter that originally generated from traffic emission, iron ore mining, coal combustion and melting of engine fragments. Once IONPs entered respiratory tract and deposit in the alveoli, they may interact with pulmonary surfactant (PS) that distributed in the alveolar lining. Thereafter, it is necessary to investigate the interaction of inhaled IONPs and PS, which helps the understanding of health risk of respiratory health induced by IONPs. Using dipalmitoyl phosphatidylcholine (DPPC), the major components of PS, as a lipid model, we explored the interaction of DPPC with typical IONPs, Fe3O4 NPs and amino-functionalized analogue (Fe3O4-NH2 NPs). DPPC was readily adsorbed on the surface of both IONPs. Although DPPC corona depressed the cellular uptake of IONPs, IONPs@DPPC complexes caused higher cytotoxicity toward RAW 264.7 macrophages, compared to pristine IONPs. Mechanistic studies have shown that IONPs react with intracellular hydrogen peroxide, which promotes the Fenton reaction, to generate hydroxyl radicals. Iron ions could oxidize lipids to form lipid peroxides, and lipid hydroperoxides will decompose to generate hydroxyl radicals, which further promote cellular oxidative stress, lipid accumulation, foam cell formation, and the release of inflammatory factors. These findings demonstrated the phenomenon of coronal component oxidation, which contributed to IONPs-induced cytotoxicity. This study offered a brand-new toxicological mechanism of IONPs at the molecular level, which is helpful for further understanding the adverse effects of IONPs.

Polychlorinated Biphenyl Quinone Metabolites Cause Neutrophil Extracellular Traps in Mouse Bone Marrow Neutrophils.

Polychlorinated biphenyls (PCBs) are a group of persistent organic environmental pollutants with various toxic effects. Our previous research found that a highly reactive quinone metabolite of PCBs, namely, PCB29-pQ, causes excessive reactive oxygen species (ROS) production and different toxic actions. Neutrophil extracellular traps (NETs), the product of NETosis, are one of the newly discovered programmed cell deaths. Recent studies have suggested the association of NET formation with excess ROS. The objective of this study was to investigate the influence of PCB29-pQ exposure on NETs and its possible molecular mechanisms. Using scanning electron microscopy, immunofluorescence microscopy, and the quantitative analysis of extracellular DNA, we found that PCB29-pQ exposure induces the formation of NETs in mouse bone marrow. Mechanistically, our results suggested that PCB29-pQ induces histone citrullination and chromatin decondensation, which are necessary processes for NET formation. Moreover, PCB29-pQ exposure increases ROS and autophagy levels, while ROS and autophagy inhibitors significantly reverse NET formation. These results indicated that PCB29-pQ-induced NET formation was mediated by the intracellular ROS level and autophagy signaling. In general, our research uncovered a toxicity mechanism of PCB29-pQ, which suggested the necessity of evaluating its immunotoxicity during the risk assessment of PCB exposure.

Polychlorinated biphenyl quinone exposure promotes breast cancer aerobic glycolysis: An in vitro and in vivo examination.

Polychlorinated biphenyls (PCBs) were classified as group I carcinogenic to humans, as their toxicological mechanisms have been associated with cancer initiation and promotion. However, whether PCBs have effects on cancer progression are still largely veiled. Here, we for the first time discovered that a PCB quinone-type metabolite, namely PCB29-pQ, exposure significantly promoted aerobic glycolysis, a hallmark property of metabolic reprogramming in cancer progression. PCB29-pQ exposure activated corresponding glucose transporter type 1 (GLUT1)/integrin ß1/Src/focal adhesion kinase (FAK) signaling pathway in breast cancer MDA-MB-231 cells. Conversely, the inhibition of GLUT1 reversed this effect, as well as the ability of migration and invasion of MDA-MB-231 cells. In addition, PCB29-pQ-induced breast cancer metastasis in 4T1-luc cell inoculated nude mice is repressed by GLUT1 inhibition. Overall, our results demonstrated a novel mechanism that PCB29-pQ exposure promotes aerobic glycolysis in both in vitro and in vivo breast cancer models in a GLUT1-dependent fashion, which may provide a strategy to prevent breast cancer cell spread.

Delivery of Ultrasmall Nanoparticles to the Cytosolic Compartment of Pyroptotic J774A.1 Macrophages via GSDMDNterm Membrane Pores.

Endosome capture is a major physiological barrier to the successful delivery of nanomedicine. Here, we found a strategy to deliver ultrasmall nanoparticles (<10 nm) to the cytosolic compartment of pyroptotic cells with spontaneous endosomal escape. To mimic pathological pyroptotic cells, J774A.1 macrophages were stimulated with lipopolysaccharide (LPS) plus nigericin (Nig) or adenosine triphosphate (ATP) to form specific gasdermin D protein-driven membrane pores at an N-terminal domain (GSDMDNterm). Through GSDMDNterm membrane pores, both anionic and cationic nanoparticles (NPs) with diameters less than 10 nm were accessed into the cytosolic compartment of pyroptotic cells in an energy- and receptor-independent manner, while NPs larger than the size of GSDMDNterm membrane pores failed to enter pyroptotic cells. NPs pass through GSDMDNterm membrane pores via free diffusion and then access into the cytoplasm of pyroptotic cells in a microtubule-independent manner. Interestingly, we found that LPS-primed NPs may act as Trojan horse, deliver extracellular LPS into normal cells through endocytosis, and in turn induce GSDMDNterm membrane pores, which facilitate further internalization of NPs. This study presented a straightforward method of distinguishing normal and pyroptotic cells through GSDMD membrane pores, implicating their potential application in monitoring the delivery of desired nanomedicines in pyroptosis-related diseases and conditions.

Polybrominated Diphenyl Ether Quinone Exposure Induces Atherosclerosis Progression via CD36-Mediated Lipid Accumulation, NLRP3 Inflammasome Activation, and Pyroptosis.

Polybrominated diphenyl ethers (PBDEs) are used worldwide in brominated flame retardants. Although due to the forbiddance of their application, PBDEs continuously exist in the environment due to their persistence. Therefore, it is important to expand the understanding of their potential toxicities and human risks. The underlying cardiovascular toxicological mechanisms of PBDEs are still largely unknown. Our previous studies indicated that PBDE quinone-type metabolite (PBDEQ) exposure causes reactive oxygen species (ROS)-driven cytotoxicity and various types of programmed cell death. Here, we first reported PBDEQ exposure induces atherosclerosis progression in bone marrow-derived macrophages (BMDMs) isolated from wild-type C57BL/6 or CD36-/- mice and J774A.1 macrophage models. First, we found that PBDEQ exposure induced lipid accumulation in oxidized low-density lipid (Ox-LDL)-treated J774A.1 macrophages. Consistently, in J774A.1 macrophages, PBDEQ exposure resulted in NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and pyroptosis. CD36, a scavenger receptor responsible for the mediation of Ox-LDL uptake, was upregulated upon PBDEQ treatment. On the contrary, genetic knockout of CD36 or CD36 silencing by small interfering RNA efficiently attenuates PBDEQ-promoted lipid accumulation in BMDMs and J774A.1 macrophages. These findings highlight the effect of CD36 on the cardiovascular toxicity of PBDEs, which provides a better understanding of the pro-atherosclerosis effect of PBDEs.

Nucleophilic and redox properties of polybrominated diphenyl ether derived-quinone/hydroquinone metabolites are responsible for their neurotoxicity.

Polybrominated diphenyl ethers (PBDEs) are a category of brominated flame retardants, which were widely used in industrial products since the 1970 s. Our previous studies indicated quinone-type metabolites of PBDEs (PBDE-Qs) cause neurotoxicity, however, their inherent toxicological mechanism remains unclear. Here, we first synthesized PBDE-Qs and corresponding reduced hydroquinone homologous (PBDE-HQs) with different pattern of bromine substitution. Their nucleophilic and redox properties were investigated. PBDE-Qs react with reduced glutathione (GSH) via Michael addition and bromine displacement reaction, whilst PBDE-HQs lack the ability of reacting with GSH. Of note, the displacement reaction only occurs with bromine on the quinone ring of PBDE-Qs but not phenyl ring. Next, electron paramagnetic resonance (EPR) analysis revealed the generation of SQ•-, along with their downstream hydroxyl radical (HO•) and methyl radical (•CH3) through a PBDE quinone/semiquinone/hydroquinone (Q/SQ•-/HQ) futile cycle. In addition, a structure-dependent cytotoxicity pattern was found, the exposure of PBDE-Q/HQ with bromine substitution on the quinone ring resulted in higher level of apoptosis and autophagy in BV2 cells. In conclusion, this work clearly demonstrated that the nucleophilic and redox properties of PBDE-Qs/HQs are responsible for their neurotoxicity, and this finding provide better understanding of neurotoxicity of PBDEs.

Polybrominated diphenyl ethers quinone exhibits neurotoxicity by inducing DNA damage, cell cycle arrest, apoptosis and p53-driven adaptive response in microglia BV2 cells.

Polybrominated diphenyl ethers (PBDEs) are world-wide used flame retardants before they were listed as Persistent Organic Pollutants (POPs) by the Stockholm Convention. Previously, our studies indicated that a quinone type of PBDE metabolite (PBDEQ) exposure was linked with neurotoxicity via excess free radical formation and oxidative stress. However, it is current unknown the effect of PBDEQ on genetic biomacromolecules DNA and corresponding biological consequences in neurological cells. Here, by employing phosphorylated histone H2AX in Serine 139 (γ-H2AX) and comet assay in microglia BV2 cells, our data suggested PBDEQ could triggered DNA damage. Furthermore, PBDEQ exposure led to the caspase 3-dependent cell apoptosis. Moreover, PBDEQ induced G2/M-phase cell arrest in a p53-dependent manner. Notably, p53 activation coordinated cell cycle progression, alleviated DNA damage and ultimately mitigated apoptosis in BV2 cells. Finally, antioxidant N-acetyl-l-cysteine (NAC) inhibited p53 activation upon PBDEQ exposure, and then ameliorated PBDEQ-induced DNA damage, cell cycle arrest and apoptosis, which illustrated that PBDEQ-induced DNA damage and p53 activation were mediated by reactive oxygen species (ROS). Together, the current findings unveil the fundamental toxicological mechanisms of PBDEQ, which propose a potential therapeutic strategy against the adverse effect caused by PBDE exposure.

Iron-bearing nanoparticles trigger human umbilical vein endothelial cells ferroptotic responses by promoting intracellular iron level.

Iron-bearing nanoparticles (IBNPs) were abundant in particulate matter (PM). Due to their high reactivity, IBNPs were considered hazardous to human health, however, their toxic mode-of-action(s) are highly unclear. Ferroptosis is a novel programmed cell death (PCD) that highly associated with intracellular iron. However, the pro-ferroptotic effect of IBNPs has not been characterized. To this end, we ought to investigate whether and how IBNPs (synthetic γ-Fe2O3 and Fe3O4 NPs were selected as the model compounds) are involved in ferroptosis. We found that human umbilical vein endothelial cells (HUVECs) phagocytized large qualities of γ-Fe2O3 and Fe3O4 NPs, resulting in increased intracellular iron level. We further observed the disrupted cystine/glutamate reverse transporter (System Xc-) and glutathione peroxidase 4 (GPX4) signaling in γ-Fe2O3 and Fe3O4 NPs-challenged HUVECs. γ-Fe2O3 and Fe3O4 NPs could also cause mitochondrial fusion and fission dysregulation, activate lipid peroxidation and iron metabolism-related genes in a P53-dependent manner. Together, the ferroptotic activity of IBNPs should be acknowledged for the risk assessment of PM associated health effects.

Polybrominated diphenyl ethers quinone-induced intracellular protein oxidative damage triggers ubiquitin-proteasome and autophagy-lysosomal system activation in LO2 cells.

Polybrominated diphenyl ethers (PBDEs), a kind of flame retardants, were widely used in the furniture, textile and electronics industries. Because of their lipophilic, persistent and bio-accumulative properties, PBDEs were listed on the Stockholm Convention as typical persistent organic pollutants (POPs). We have previously reported that a highly active, quinone-type metabolite of PBDEs (PBDEQ) causes DNA damage and subsequently triggers apoptosis. However, it is remaining unclear whether PBDEQ provokes protein damage and stimulates corresponding signaling cascade. Using human normal liver (LO2) cells as an in vitro model, we demonstrated that PBDEQ causes oxidative protein damage through excess reactive oxygen species (ROS). Consistently, we found PBDEQ exposure causes the depletion of protein thiol group, the appearance of carbonyl group and the accumulation of protein aggregates. Endoplasmic reticulum (ER) stress was involved in the repair of oxidized proteins. Under the scenario of severe damage, LO2 cells degrade oxidized proteins through ubiquitin-proteasome system (UPS) and autophagy. The blockage of these protein degradation pathways aggravates PBDEQ-induced cytotoxicity in LO2 cells, whilst antioxidant N-acetyl-cysteine (NAC) rescues PBDEQ-induced oxidative protein damage conversely. In summary, our current study first demonstrated PBDEQ-induced protein oxidative damage in LO2 cells, which offer a better understanding of the cytotoxicity of PBDEs and corresponding metabolites.

Iron-based nanoparticles for MR imaging-guided ferroptosis in combination with photodynamic therapy to enhance cancer treatment.

Ferroptosis therapy, which applies ferroptotic inducers to produce lethal lipid peroxidation and induce the death of tumor cells, is regarded as a promising therapeutic strategy for cancer treatment. However, there is still a challenge regarding how to increase reactive oxygen species (ROS) accumulation in the tumor microenvironment (TME) to enhance antitumor efficacy. Herein, we designed a nanosystem coated with the FDA approved poly(lactic-co-glycolic acid) (PLGA) containing ferrous ferric oxide (Fe3O4) and chlorin E6 (Ce6) for synergistic ferroptosis-photodynamic anticancer therapy. The Fe3O4-PLGA-Ce6 nanosystem can dissociate in the acidic TME to release ferrous/ferric ions and Ce6. Then, the Fenton reaction between the released ferrous/ferric ions and intracellular excess hydrogen peroxide can occur to produce hydroxyl radicals (˙OH) and induce tumor cell ferroptosis. The released Ce6 can increase the generation and accumulation of ROS under laser irradiation to offer photodynamic therapy, which can boost ferroptosis in 4T1 cells. Moreover, magnetic monodisperse Fe3O4 loading provides excellent T2-weighted magnetic resonance imaging (MRI) properties. The Fe3O4-PLGA-Ce6 nanosystem possesses MRI ability and highly efficient tumor suppression with high biocompatibility in vivo due to the synergism of photodynamic and ferroptosis antitumor therapies.