Size-effect on the intracellular antioxidative activity of Prussian blue nanoparticles investigated by atomic force microscopy

Ischemic stroke is caused by cerebrovascular stenosis or occlusion. Excessive reactive oxygen species (ROS) are the focus-triggering factor of irreversible injury in ischemic regions, which result in harmful cascading effects to brain tissue, such as inflammation and microthrombus formation. In the present work, we designed nanodelivery systems (NDSs) based on MnO2 loaded with Ginkgolide B (GB) for restoring the intracerebral microenvironment in ischemic stroke, such as ROS scavenging, O2 elevation, thrombus inhibition and damage repair. GB can activate the endogenous antioxidant defense of cells by enhancing the nuclear factor-E2-related factor 2 (Nrf2) signalling pathway, thus protecting brain tissue from oxidative damage. However, the blood-brain barrier (BBB) is also a therapeutic obstacle for the delivery of these agents to ischemic regions. MnO2 nanoparticles have an inherent BBB penetration effect, which enhances the delivery of therapeutic agents within brain tissue. MnO2 , with mimicking enzymatic activity, can catalyze the decomposition of overproduced H2 O2 in the ischemic microenvironment to O2 , meanwhile releasing platelet-antagonizing GB molecules, thus alleviating cerebral hypoxia, oxidative stress damage, and microthrombus generation. This study may provide a promising therapeutic route for regulating the microenvironment of ischemic stroke through a combined function of ROS scavenging, microthrombus inhibition, and BBB penetration.

The accumulation of intracellular reactive oxygen species (ROS) is widely recognized to stimulate the development of osteoclasts, a crucial factor in the onset of osteoporosis. The ROS scavenging capability of Prussian blue nanoparticles (PBNPs) is exceptional, and they possess excellent biocompatibility. However, the effects of PBNPs on osteoporosis remain unknown. Present study aimed to investigate whether PBNPs could inhibit osteoclast differentiation and prevent ovariectomy (OVX)-induced bone loss by suppressing ROS. Invitro experiments demonstrated that PBNPs attenuated osteoclastogenesis and downregulated the expression of osteoclast-related genes. Mechanistically, PBNPs reduce cellular ROS by blocking RANKL-induced ROS generation and increasing the expression of ROS scavenging enzymes, which in turn block the NF-κB, ERK, JNK, and p38 pathways, thereby reducing NFATc1 signaling. According to invivo experimental results, OVX caused a significant rise in ROS in the bone marrow, an increase in osteoclastic number on the bone surface, and substantial bone loss; however, PBNPs significantly reduced ROS and successfully protected OVX-induced bone damages. In conclusion, this study showed for the first time that PBNPs prevented OVX-induced bone loss and attenuate osteoclastogenesis, indicating that PBNPs may be a viable alternative therapy for the management of osteoclast-associated bone disorders.

Intracellular antioxidant activity and apoptosis inhibition capacity of PEF-treated KDHCH in HepG2 cells.

ROS scavenging and immunoregulative EGCG@Cerium complex loaded in antibacterial polyethylene glycol-chitosan hydrogel dressing for skin wound healing.

Diabetic foot ulcer is a serious complication in diabetes patients, imposing a serious physical and economic burden to patients and to the healthcare system as a whole. Oxidative stress is thought to be a key driver of the pathogenesis of such ulcers. However, no antioxidant drugs have received clinical approval to date, underscoring the need for the further development of such medications. Hydrogels can be applied directly to the wound site, wherein they function to prevent infection and maintain local moisture concentrations, in addition to serving as a reservoir for the delivery of a range of therapeutic compounds with the potential to expedite wound healing in a synergistic manner. Herein, we synthesized Prussian blue nanoparticles (PBNPs) capable of efficiently scavenging reactive oxygen species (ROS) owing to their ability to mimic the activity of catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD). In the context of in vitro oxidative stress, these PBNPs were able to protect against cytotoxicity, protect mitochondria from oxidative stress-related damage, and restore nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) pathway activity. To expand on these results in an in vivo context, we prepared a thermosensitive poly (d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide) (PDLLA-PEG-PDLLA) hydrogel (PLEL)-based wound dressing in which PBNPs had been homogenously incorporated, and we then used this dressing as a platform for controlled PBNP release. The resultant PBNPs@PLEL wound dressing was able to improve diabetic wound healing, decrease ROS production, promote angiogenesis, and reduce pro-inflammatory interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels within diabetic wounds. Overall, our results suggest that this PBNPs@PLEL platform holds great promise as a treatment for diabetic foot ulcers.

Prussian blue (PB) nanoparticles protected by poly(vinylpyrrolidone) (PVP) were prepared by mixing aqueous Fe2+, Fe(CN)63-, and PVP solutions together and were characterized by UV-vis, IR, XRPD, and TEM. Averaged dimensions of the nanoparticles were controlled between 12 and 27 nm depending on initial Fe ion concentrations and feed ratios of Fe ion to PVP. Solubility of PB bulk in organic solvents is considerably low; nevertheless, formations of the PB nanoparticles dramatically increase the solubility in a variety of organic solvents. It is noteworthy that the PVP-protected PB nanoparticles stably maintain the cluster formations without further aggregations and dissociation in CHCl3 over 1 month. Measurement of the critical temperature (Tc) where PB nanoparticles exhibit a ferromagnetic property showed a gradual decrease of Tc for the nanoparticles as the particle sizes become smaller. This result could be ascribed to the reduction of the averaged numbers of magnetic interacted neighbors.

Coordination polymer (CP) nanoparticles (NPs) formed by a self-assembly of organic ligands and metal ions are one of the attractive materials for molecular capture and deliver/release in aqueous media. Control of particle size and prevention of aggregation among CP NPs are important factors for improving their adsorption capability in water. We demonstrate here the potential of a liposome incorporating an antibiotic ion channel as a vessel for synthesizing Prussian blue (PB) NPs, being a typical CP. In the formation of PB NPs within liposomes, the influx rate of Fe2+ ions into liposome encapsulated [Fe(CN)6]3- through channels was fundamental for the change of NPs' sizes. The optimized PB NP-liposome composite showed higher adsorption capacity of Cs+ ions than that of aggregated PB NPs that are prepared without liposome in aqueous media.

Harnessing Ferroptosis and Photothermal Effects: A New Paradigm in Aggressive Lymphoma Therapy

Leukemia is a common and lethal disease. In recent years, iron-based nanomedicines have been developed as a new ferroptosis inducer to leukemia. However, the cytotoxicity of iron nanoparticles to leukemia cells at the transcriptomic level remains unclear. This study investigated the effects of two kinds of iron nanoparticles, 2,3-Dimercaptosuccinic acid (DMSA)-coated Fe3O4 nanoparticles (FeNPs) as a reactive oxygen species (ROS) inducer and Prussian blue nanoparticles (PBNPs) as an ROS scavenger, on the transcriptomic profiles of two leukemia cells (KG1a and HL60) by RNA-Seq. As a result, 470 and 1690 differentially expressed genes (DEGs) were identified in the FeNP-treated HL60 and KG1a cells, respectively, and 2008 and 2504 DEGs were found in the PBNP-treated HL60 and KG1a cells, respectively. Among them, 14 common upregulated and 4 common downregulated DEGs were found, these genes were representative genes that play key roles in lipid metabolism (GBA and ABCA1), iron metabolism (FTL, DNM1, and TRFC), antioxidation (NQO1, GCLM, and SLC7A11), vesicle traffic (MCTP2, DNM1, STX3, and BIN2), and innate immune response (TLR6, ADGRG3, and DDX24). The gene ontology revealed that the mineral absorption pathway was significantly regulated by PBNPs in two cells, whereas the lipid metabolism and HIF-1 signaling pathways were significantly regulated by FeNPs in two cells. This study established the gene signatures of two kinds of nanoparticles in two leukemia cells, which revealed the main biological processes regulated by the two kinds of iron nanoparticles. These data shed new insights into the cytotoxicity of iron nanoparticles that differently regulate ROS in leukemia cells with variant stemness.

Reactive oxygen species generated by activated neutrophils can cause oxidative stress and tissue damage. S100A8 (A8) and S100A9 (A9), abundant in neutrophil cytoplasm, are exquisitely sensitive to oxidation, which may alter their functions. Murine A8 is a neutrophil chemoattractant, but it suppresses leukocyte transmigration in the microcirculation when S-nitrosylated. Glutathione (GSH) modulates intracellular redox, and S-glutathionylation can protect susceptible proteins from oxidative damage and regulate function. We characterized S-glutathionylation of A9; GSSG and GSNO generated S-glutathionylated A8 (A8-SSG) and A9 (A9-SSG) in vitro, whereas only A9-SSG was detected in cytosol of neutrophils activated with phorbol myristate acetate (PMA) but not with fMLP or opsonized zymosan. S-Glutathionylation exposed more hydrophobic regions in Zn(2+)-bound A9 but did not alter Zn(2+) binding affinity. A9-SSG had reduced capacity to form heterocomplexes with A8, but the arachidonic acid binding capacities of A8/A9 and A8/A9-SSG were similar. A9 and A8/A9 bind endothelial cells; S-glutathionylation reduced binding. We found little effect of A9 or A9-SSG on neutrophil CD11b/CD18 expression or neutrophil adhesion to endothelial cells. However, A9, A9-SSG and A8/A9 promoted neutrophil adhesion to fibronectin but, in the presence of A8, A9-mediated adhesion was abrogated by glutathionylation. S-Glutathionylation of A9 may protect its oxidation to higher oligomers and reduce neutrophil binding to the extracellular matrix. This may regulate the magnitude of neutrophil migration in the extravasculature, and together with the functional changes we reported for S-nitrosylated A8, particular oxidative modifications of these proteins may limit tissue damage in acute inflammation.

Photodynamic therapy (PDT) is recognized as a promising therapeutic modality for cancer, psoriasis, bacterial infection, atherosclerosis, and other diseases, yet confronts persistent challenges of oxygen dependency, limited diversity of reactive oxygen species (ROS), and collateral photodamage to healthy tissues. Here, we report that unlike traditional PDT, near-infrared-activated Prussian blue nanoparticles (PBs) uniquely interact with hydrogen peroxide (H2O2) to concurrently generate hydroxyl radicals (·OH), hydroperoxyl radicals (·OOH), and singlet oxygen (1O2) through an oxygen-independent pathway, thereby compensating for the damage and selectivity differences between distinct ROS. PB, H2O2, and light are the three essential factors for producing ROS. Furthermore, PBs exhibit the ability to scavenge H2O2, ·OH, and ·OOH, thereby maintaining the redox homeostasis and showing negligible phototoxicity in normal tissues. Intriguingly, light irradiation enables PBs to selectively regulate both generation and scavenging of ROS. PB shows a powerful capability to selectively regulate the generation and scavenging of ROS at the designated location and time. Proof-of-concept validation through an infected wound murine model reveals that PBs' exceptional therapeutic efficacy, achieving unprecedented healing outcomes. The discovery of PB as a special photosensitizer holds promise for enriching the fundamental understanding of PDT, overcoming its inherent limitations, and advancing the development of next-generation PDT strategies.

We have explored interfacial electrochemical electron transfer (ET) and electrocatalysis of 5–6 nm Prussian Blue nanoparticles (PBNPs) immobilized on Au(111)-electrode surfaces via molecular wiring with variable-length, and differently functionalized thiol-based self-assembled molecular monolayers (SAMs). The SAMs contain positively (−NH3 +) or negatively charged (–COO–) terminal group, as well an electrostatically neutral hydrophobic terminal group (–CH3). The surface microscopic structures of the immobilized PBNPs were characterized by high-resolution atomic force microscopy (AFM) directly in aqueous electrolyte solution under the same conditions as for electrochemical measurements. The PBNPs displayed fast and reversible interfacial ET on all the surfaces, notably in multi-ET steps as reflected in narrow voltammetric peaks. The ET kinetics can be controlled by adjusting the length of the SAM forming linker molecules. The interfacial ET rate constants were found to depend exponentially on the ET distance for distances longer than a few methylene groups in the chain, with decay factors (β) of 0.9, 1.1, and 1.3 per CH2, for SAMs terminated by −NH3 +,–COO–, and–CH3, respectively. This feature suggests, first that the interfacial ET processes follow a tunneling mechanism, resembling that of metalloproteins in a similar assembly. Secondly, the electronic contact of the SAM terminal groups that anchor non-covalently the PBNP are crucial as reported for other types of molecular junctions. Highly efficient PBNP electrocatalysis of H2O2 reduction was also observed for the three linker groups, and the electrocatalytic mechanisms analyzed.

Skin, our first interface to the external environment, is subjected to oxidative stress caused by a variety of factors such as solar ultraviolet, infrared and visible light, environmental pollution, including ozone and particulate matters, and psychological stress. Excessive reactive species, including reactive oxygen species and reactive nitrogen species, exacerbate skin pigmentation and aging, which further lead to skin tone unevenness, pigmentary disorder, skin roughness and wrinkles. Besides these, skin microbiota are also a very important factor ensuring the proper functions of skin. While environmental factors such as UV and pollutants impact skin microbiota compositions, skin dysbiosis results in various skin conditions. In this review, we summarize the generation of oxidative stress from exogenous and endogenous sources. We further introduce current knowledge on the possible roles of oxidative stress in skin pigmentation and aging, specifically with emphasis on oxidative stress and skin pigmentation. Meanwhile, we summarize the science and rationale of using three well-known antioxidants, namely vitamin C, resveratrol and ferulic acid, in the treatment of hyperpigmentation. Finally, we discuss the strategy for preventing oxidative stress-induced skin pigmentation and aging.

The generation of reactive oxygen species (ROS) is an important mechanism of nanomaterial toxicity. We found that Prussian blue nanoparticles (PBNPs) can effectively scavenge ROS via multienzyme-like activity including peroxidase (POD), catalase (CAT), and superoxide dismutase (SOD) activity. Instead of producing hydroxyl radicals (•OH) through the Fenton reaction, PBNPs were shown to be POD mimetics that can inhibit •OH generation. We theorized for the first time that the multienzyme-like activities of PBNPs were likely caused by the abundant redox potentials of their different forms, making them efficient electron transporters. To study the ROS scavenging ability of PBNPs, a series of in vitro ROS-generating models was established using chemicals, UV irradiation, oxidized low-density lipoprotein, high glucose contents, and oxygen glucose deprivation and reperfusion. To demonstrate the ROS scavenging ability of PBNPs, an in vivo inflammation model was established using lipoproteins in Institute for Cancer Research (ICR) mice. The results indicated that PBNPs hold great potential for inhibiting or relieving injury induced by ROS in these pathological processes.

Iron-based nanomaterials are thought to be cytotoxic in recent researches due to the mechanism that they can produce hydroxyl radical (•OH) in cells via Fenton reaction. However, we found Prussian blue nanoparticles (PBNPs) possess reactive oxygen species (ROS) scavenging ability due to their peroxidase (POD), catalase (CAT), super-oxide dismutase (SOD)-like activities and affinity for •OH. We theorized the multienzyme-like activities of PBNPs were caused by their abundant redox potentials in different forms: Prussian White (PW), Prussian blue (PB), Berlin Green (BG) and Prussian Yellow (PY), what makes them admirable electron transporters. The reported PBNPs show anti-inflammation ability in lipopolysaccharide (LPS)-induced cell and animal inflammation research endeavors.