Reactive Oxygen Species Scavenger Research Articles

Reactive oxygen-scavenging polydopamine nanoparticle coated 3D nanofibrous scaffolds for improved osteogenesis: Toward an aging in vivo bone regeneration model.

Tissue engineered scaffolds aimed at the repair of critical-sized bone defects lack adequate consideration for our aging society. Establishing an effective aged in vitro model that translates to animals is a significant unmet challenge. The in vivo aged environment is complex and highly nuanced, making it difficult to model in the context of bone repair. In this work, 3D nanofibrous scaffolds generated by the thermally-induced self-agglomeration (TISA) technique were functionalized with polydopamine nanoparticles (PD NPs) as a tool to improve drug binding capacity and scavenge reactive oxygen species (ROS), an excessive build-up that dampens the healing process in aged tissues. PD NPs were reduced by ascorbic acid (rPD) to further improve hydrogen peroxide (H2O2) scavenging capabilities, where we hypothesized that these functionalized scaffolds could rescue ROS-affected osteoblastic differentiation in vitro and improve new bone formation in an aged mouse model. rPDs demonstrated improved H2O2 scavenging activity compared to neat PD NPs, although both NP groups rescued the alkaline phosphatase activity (ALP) of MC3T3-E1 cells in presence of H2O2. Additionally, BMP2-induced osteogenic differentiation, both ALP and mineralization, was significantly improved in the presence of PD or rPD NPs on TISA scaffolds. While in vitro data showed favorable results aimed at improving osteogenic differentiation by PD or rPD NPs, in vivo studies did not note similar improvements in ectopic bone formation an aged model, suggesting that further nuance in material design is required to effectively translate to improved in vivo results in aged animal models.

Loss of the DNA repair protein, polynucleotide kinase/phosphatase, activates the type 1 interferon response independent of ionizing radiation.

DNA damage has been implicated in the stimulation of the type 1 interferon (T1IFN) response. Here, we show that downregulation of the DNA repair protein, polynucleotide kinase/phosphatase (PNKP), in a variety of cell lines causes robust phosphorylation of STAT1, upregulation of interferon-stimulated genes and persistent accumulation of cytosolic DNA, all of which are indicators for the activation of the T1IFN response. Furthermore, this did not require damage induction by ionizing radiation. Instead, our data revealed that production of reactive oxygen species (ROS) synergises with PNKP loss to potentiate the T1IFN response, and that loss of PNKP significantly compromises mitochondrial DNA (mtDNA) integrity. Depletion of mtDNA or treatment of PNKP-depleted cells with ROS scavengers abrogated the T1IFN response, implicating mtDNA as a significant source of the cytosolic DNA required to potentiate the T1IFN response. The STING signalling pathway is responsible for the observed increase in the pro-inflammatory gene signature in PNKP-depleted cells. While the response was dependent on ZBP1, cGAS only contributed to the response in some cell lines. Our data have implications for cancer therapy, since PNKP inhibitors would have the potential to stimulate the immune response, and also to the neurological disorders associated with PNKP mutation.

Reactive oxygen species-responsive nanotherapy for the prevention and treatment of cerebral ischemia–reperfusion injury

Vascular recanalization intervention is the primary recommended approach for the treatment of ischemic stroke. However, the damage caused by cerebral ischemia-reperfusion (I/R) poses a significant challenge for effective treatment. The aim of this study was to address this challenge by developing multifunctional nanoparticles (NPs). Cu4.6O NP was encapsulated by zein-Se-Se-DHA (Dz), the diselenide bond-conjugated zein and docosahexaenoic acid (DHA), and then coated by platelet membrane (PLTM) to form Cu4.6O@Dz@PLTM (MDzCu) NP. MDzCu with the PLTM coating showed strong targeting ability to the cerebral ischemic lesions in the rat model of cerebral I/R injury. Furthermore, in the reactive oxygen species (ROS)-rich brain microenvironment, both Cu4.6O and DHA are released from MDzCu, exerting ROS scavenging, promoting microglia polarization, and providing neuroprotective effects, ultimately alleviating cerebral I/R injury. This study presents several novel findings, such as the use of Cu0/Cu+ NPs for brain-related diseases, ROS scavenger-assisted DHA therapy for the central nervous system (CNS), and the application of stimuli-responsive NPs with diselenides to treat I/R injuries. This study provides insights into the development of stimuli-responsive nanomedicines with cell membrane coatings for the targeted treatment of brain diseases.

Light-activated nanoclusters with tunable ROS for wound infection treatment

Infected wounds pose a significant clinical challenge due to bacterial resistance, recurrent infections, and impaired healing. Reactive oxygen species (ROS)-based strategies have shown promise in eradicating bacterial infections. However, the excess ROS in the infection site after treatments may cause irreversible damage to healthy tissues. To address this issue, we developed bovine serum albumin-iridium oxide nanoclusters (BSA-IrOx NCs) which enable photo-regulated ROS generation and scavenging using near infrared (NIR) laser. Upon NIR laser irradiation, BSA-IrOx NCs exhibit enhanced photodynamic therapy, destroying biofilms and killing bacteria. When the NIR laser is off, the nanoclusters' antioxidant enzyme-like activities prevent inflammation and repair damaged tissue through ROS clearance. Transcriptomic and metabolomic analyses revealed that BSA-IrOx NCs inhibit bacterial nitric oxide synthase, blocking bacterial growth and biofilm formation. Furthermore, the nanoclusters repair impaired skin by strengthening cell junctions and reducing mitochondrial damage in a fibroblast model. In vivo studies using rat infected wound models confirmed the efficacy of BSA-IrOx NCs. This study presents a promising strategy for treating biofilm-induced infected wounds by regulating the ROS microenvironment, addressing the challenges associated with current ROS-based antibacterial approaches.

Lactobacillus rhamnosus GG coating with nanocomposite ameliorates intestinal inflammation

The steady increase in the prevalence of inflammatory bowel disease (IBD) is regarded as a worldwide health issue. Gut microorganisms could modulate host immune and metabolic status and are associated with health effects. Probiotics, Lactobacillus rhamnosus GG (LGG), are beneficial microorganisms that ameliorate disease and exert advantageous effects on intestinal homeostasis. However, the viability of probiotics will suffer from various risk factors in the digestive tract. In this view, we developed a probiotic coating with nanocomposite using tannic acid (TA) and casein phosphopeptide (CPP) through layer-by-layer technology to overcome the challenges after oral administration. LGG showed an improved survival rate in simulated gastrointestinal conditions after coated. The coating (LGG/TA-Mg2+/CPP) had potent reactive oxygen species (ROS) scavenging ability and improved the survival rate of colorectal epithelial cells after H2O2 stimulation. In DSS-induced colitis, administration of LGG/TA-Mg2+/CPP ameliorated intestinal inflammation and reduced the disruption of barrier function. Furthermore, LGG/TA-Mg2+/CPP increased the abundance and diversity of the gut microbiota. In the mouse model of DSS colitis, LGG/TA-Mg2+/CPP can better activate the EGFR/AKT signaling pathway, thereby protecting the epithelial barrier function of the colon epithelium. In conclusion, the probiotic coating with nanocomposite may become a delivery platform for probiotics applied to IBD.

A phased small interfering RNA-derived pathway mediates lead stress tolerance in maize.

Phased small interfering RNAs (phasiRNAs) are a distinct class of endogenous small interfering RNAs, which regulate plant growth, development and environmental stress response. To determine the effect of phasiRNAs on maize (Zea mays L.) tolerance to lead (Pb) stress, the roots of 305 maize lines under Pb treatment were subjected to generation of individual databases of small RNAs. We identified 55 high-confidence phasiRNAs derived from 13 PHAS genes (genes producing phasiRNAs) in this maize panel, of which 41 derived from nine PHAS loci were negatively correlated with Pb content in the roots. The potential targets of the 41 phasiRNAs were enriched in ion transport and import. Only the expression of PHAS_1 (ZmTAS3j, Trans-Acting Short Interference RNA3) was regulated by its cis-expression quantitative trait locus and thus affected the Pb content in the roots. Using the Nicotiana benthamiana (N. benthamiana) transient expression system, 5'-rapid amplification of cDNA ends, and Arabidopsis heterologously expressed, we verified that ZmTAS3j was cleaved by zma-miR390 and thus generated tasiRNA targeting ARF genes (tasiARFs), and that the 5' and 3' zma-miR390 target sites of ZmTAS3j were both necessary for efficient biosynthesis and functional integrity of tasiARFs. We validated the involvement of the zma-miR390-ZmTAS3j-tasiARF-ZmARF3-ZmHMA3 pathway in Pb accumulation in maize seedlings using genetic, molecular, and cytological methods. Moreover, the increased Pb tolerance in ZmTAS3j-overexpressed lines was likely attributed to the zma-miR390-ZmTAS3j-tasiARF-ZmARF3-SAURs pathway, which elevated indole acetic acid levels and thus reactive oxygen species scavenging capacity in maize roots. Our study reveals the importance of the TAS3-derived tasiRNA pathway in plant adaptation to Pb stress.

A nanozyme-functionalized bilayer hydrogel scaffold for modulating the inflammatory microenvironment to promote osteochondral regeneration

BackgroundThe incidence of osteochondral defects caused by trauma, arthritis or tumours is increasing annually, but progress has not been made in terms of treatment methods. Due to the heterogeneous structure and biological characteristics of cartilage and subchondral bone, the integration of osteochondral repair is still a challenge.ResultsIn the present study, a novel bilayer hydrogel scaffold was designed based on anatomical characteristics to imitate superficial cartilage and subchondral bone. The scaffold showed favourable biocompatibility, and the addition of an antioxidant nanozyme (LiMn2O4) promoted reactive oxygen species (ROS) scavenging by upregulating antioxidant proteins. The cartilage layer effectively protects against chondrocyte degradation in the inflammatory microenvironment. Subchondral bionic hydrogel scaffolds promote osteogenic differentiation of rat bone marrow mesenchymal stem cells (BMSCs) by regulating the AMPK pathway in vitro. Finally, an in vivo rat preclinical osteochondral defect model confirmed that the bilayer hydrogel scaffold efficiently promoted cartilage and subchondral bone regeneration.ConclusionsIn general, our biomimetic hydrogel scaffold with the ability to regulate the inflammatory microenvironment can effectively repair osteochondral defects. This strategy provides a promising method for regenerating tissues with heterogeneous structures and biological characteristics.Graphical abstract

Enhanced In Vitro Efficacy of Verbascoside in Suppressing Hepatic Stellate Cell Activation via ROS Scavenging with Reverse Microemulsion

Numerous approaches targeting hepatic stellate cells (HSCs) have emerged as pivotal therapeutic strategies to mitigate liver fibrosis and are currently undergoing clinical trials. The investigation of herbal drugs or isolated natural active compounds is particularly valuable, due to their multifaceted functions and low risk of side effects. Recent studies have hinted at the potential efficacy of verbascoside (VB) in ameliorating renal and lung fibrosis, yet its impact on hepatic fibrosis remains to be elucidated. This study aims to evaluate the potential effects of VB on liver fibrosis by assessing its ability to inhibit HSC activation. VB demonstrated significant efficacy in suppressing the expression of fibrogenic genes in activated LX-2 cells. Additionally, VB inhibited the migration and proliferation of these activated HSCs by scavenging reactive oxygen species (ROS) and downregulating the AMPK pathway. Furthermore, a biosafe reverse microemulsion loaded with VB (VB-ME) was developed to improve VB’s instability and low bioavailability. The optimal formulation of VB-ME was meticulously characterized, revealing substantial enhancements in cellular uptake, ROS-scavenging capacity, and the suppression of HSC activation.

A multifunctional injectable, self-healing, and adhesive hydrogel-based wound dressing stimulated diabetic wound healing with combined reactive oxygen species scavenging, hyperglycemia reducing, and bacteria-killing abilities

The proficient handling of diabetic wounds, a rising issue coinciding with the global escalation of diabetes cases, poses significant clinical difficulties. A range of biofunctional dressings have been engineered and produced to expedite the healing process of diabetic wounds. This study proposes a multifunctional hydrogel dressing for diabetic wound healing, which is composed of Polyvinyl Alcohol (PVA) and N1-(4-boronobenzyl)-N3-(4-boronophenyl)-N1, N1, N3, N3-teramethylpropane-1, 3-diaminium (TSPBA), and a dual-drug loaded Gelatin methacryloyl (GM) microgel. The GM microgel is loaded with sodium fusidate (SF) and nanoliposomes (LP) that contain metformin hydrochloride (MH). Notably, adhesive and self-healing properties the hydrogel enhance their therapeutic potential and ease of application. In vitro assessments indicate that SF-infused hydrogel can eliminate more than 98% of bacteria within 24 h and maintain a sustained release over 15 days. Additionally, MH incorporated within the hydrogel has demonstrated effective glucose level regulation for a duration exceeding 15 days. The hydrogel demonstrates a sustained ability to neutralize ROS throughout the entire healing process, predominantly by electron donation and sequestration. This multifunctional hydrogel dressing, which integrated biological functions of efficient bactericidal activity against both MSSA and MRSA strains, blood glucose modulation, and control of active oxygen levels, has successfully promoted the healing of diabetic wounds in rats in 14 days. The hydrogel dressing exhibited significant effectiveness in facilitating the healing process of diabetic wounds, highlighting its considerable promise for clinical translation.Graphical

Targeted nanoparticles triggered by plaque microenvironment for atherosclerosis treatment through cascade effects of reactive oxygen species scavenging and anti-inflammation

Inflammatory factors and reactive oxygen species (ROS) are risk factors for atherosclerosis. Many existing therapies use ROS-sensitive delivery systems to alleviate atherosclerosis, which achieved certain efficacy, but cannot eliminate excessive ROS. Moreover, the potential biological safety concerns of carrier materials through chemical synthesis cannot be ignored. Herein, an amphiphilic low molecular weight heparin- lipoic acid conjugate (LMWH-LA) was used as a ROS-sensitive carrier material, which consisted of injectable drug molecules used clinically, avoiding unknown side effects. LMWH-LA and curcumin (Cur) self-assembled to form LLC nanoparticles (LLC NPs) with LMWH as shell and LA/Cur as core, in which LMWH could target P-selectin on plaque endothelial cells and competitively block the migration of monocytes to endothelial cells to inhibit the origin of ROS and inflammatory factors, and LA could be oxidized to trigger hydrophilic-hydrophobic transformation and accelerate the release of Cur. Cur released within plaques further exerted anti-inflammatory and antioxidant effects, thereby suppressing ROS and inflammatory factors. We used ultrasound imaging, pathology and serum analysis to evaluate the therapeutic effect of nanoparticles on atherosclerotic plaques in apoe−/− mice, and the results showed that LLC showed significant anti-atherosclerotic effects. Our finding provided a promising therapeutic nanomedicine for the treatment of atherosclerosis.

Antioxidant and Immunomodulatory Polymer Vesicles for Effective Diabetic Wound Treatment through ROS Scavenging and Immune Modulating.

Chronic diabetic wound patients usually show high glucose levels and systemic immune disorder, resulting in high reactive oxygen species (ROS) levels and immune cell dysfunction, prolonged inflammation, and delayed wound healing. Herein, we prepared an antioxidant and immunomodulatory polymer vesicle for diabetic wound treatment. This vesicle is self-assembled from poly(ε-caprolactone)36-block-poly[lysine4-stat-(lysine-mannose)22-stat-tyrosine)16] ([PCL36-b-P[Lys4-stat-(Lys-Man)22-stat-Tyr16]). Polytyrosine is an antioxidant polypeptide that can scavenge ROS. d-Mannose was introduced to afford immunomodulatory functions by promoting macrophage transformation and Treg cell activation through inhibitory cytokines. The mice treated with polymer vesicles showed 23.7% higher Treg cell levels and a 91.3% higher M2/M1 ratio than those treated with PBS. Animal tests confirmed this vesicle accelerated healing and achieved complete healing of S. aureus-infected diabetic wounds within 8 days. Overall, this is the first antioxidant and immunomodulatory vesicle for diabetic wound healing by scavenging ROS and regulating immune homeostasis, opening new avenues for effective diabetic wound healing.

VvLBD39, a grape LBD transcription factor, regulates plant response to salt and drought stress

Grape (Vitis vinifera L.), as an important deciduous perennial fruit tree, constantly confronts various abiotic stresses such as salinity and drought. The lateral organ boundaries domain (LBD) proteins are a class of plant-specific transcription factors that play pivotal roles in regulating plant growth and responding to abiotic stress. However, the biological function of the LBD transcription factor in grape remains poorly understood. Here, we cloned and characterized the VvLBD39 gene from grape, which contained a highly conserved LBD domain and localized to the cell nucleus. qRT-PCR analyses showed that the expression of VvLBD39 was downregulated upon exposure to NaCl, polyethylene glycol 6000 (PEG6000) and abscisic acid (ABA) treatments, respectively. Overexpression of VvLBD39 in grape calli and Arabidopsis resulted in hypersensitivity to PEG6000 and NaCl stress. Moreover, VvLBD39-overexpressing transgenic tobacco exhibited decreased tolerance to drought and salt stress, as well as insensitivity to exogenous ABA. After drought and salt stress treatments, the chlorophyll content, root length and antioxidant enzyme activity of the transgenic tobacco were lower than those of the wild-type (WT). Conversely, malonic dialdehyde (MDA) content, electronic conductivity, hydrogen peroxide (H2O2) content and superoxide anion (O2-) productivity were markedly elevated in the transgenic tobacco compared to the WT. Further investigations found that VvLBD39 had a negative impact on stomatal closure, ABA biosynthesis and ABA signaling under drought and salt treatments. In addition, the expression of genes related to reactive oxygen species (ROS) scavenging and stress response were significantly downregulated in VvLBD39 transgenic tobacco. Taken together, these results indicated that VvLBD39 functions as a negative regulator of salt and drought tolerance, making it a promising target for drought and salt resistance breeding.

Biocompatible and nondegradable microcapsules using an ethylamine-bridged EGCG dimer for successful therapeutic cell transplantation

Conventional alginate microcapsules are widely used for encapsulating therapeutic cells to reduce the host immune response. However, the exchange of monovalent cations with divalent cations for crosslinking can lead to a sol-gel phase transition, resulting in gradual degradation and swelling of the microcapsules in the body. To address this limitation, we present a biocompatible and nondegradable epigallocatechin-3-gallate (EGCG)-based microencapsulation with ethylamine-bridged EGCG dimers (EGCG(d)), denoted as ‘Epi-Capsules’. These Epi-Capsules showed increased physical properties and Ca2+ chelating resistance compared to conventional alginate microcapsules. Horseradish peroxidase (HRP) treatment is very effective in increasing the stability of Epi-Capsule((+)HRP) due to the crosslinking between EGCG(d) molecules. Interestingly, the Epi-Capsules(oxi) using a pre-oxidized EGCG(d) can support long-term survival (>90 days) of xenotransplanted insulin-secreting islets in diabetic mice in vivo, which is attributed to its structural stability and reactive oxygen species (ROS) scavenging for lower fibrotic activity. Collectively, this EGCG-based microencapsulation can create Ca2+ chelating-resistance and anti-oxidant activity, which could be a promising strategy for cell therapies for diabetes and other diseases.

Carbon Dots with Integrated Photothermal Antibacterial and Heat-Enhanced Antioxidant Properties for Diabetic Wound Healing.

Diabetic wounds pose a persistent challenge due to their slow healing nature, primarily caused by bacterial infection and excessive reactive oxygen species (ROS)-induced inflammation. In this study, carbon dots with synergistic antibacterial and antioxidant properties, referred to as AA-CDs, are developed specifically for diabetic wound healing using a straightforward solvothermal method. By utilizing cost-effective precursors like citric acid and ascorbic acid, AA-CDs are engineered to possess tailored functions of photothermal sterilization and ROS scavenging. The resulting AA-CDs demonstrats broad-spectrum antibacterial activity, particularly against multidrug-resistant strains, along with efficient ROS scavenging both in solution and within cells. Additionally, AA-CDs exhibits a protective effect against oxidative stress-induced damage. Notably, with a high photothermal conversion efficiency (41.18%), AA-CDs displays heat-enhanced antioxidant performance, providing not only augmented ROS scavenging but also additional protection against oxidative stress, yielding a true "1 + 1 > 2" effect. To facilitate their use in vivo, AA-CDs are incorporated into a thermally responsive hydrogel, which exhibits evident anti-inflammatory properties by modulating inflammatory factors and significantly promots the healing of diabetic wounds. This study underscores the value of integrated platforms for diabetic wound healing and highlights the potential of versatile CDs as promising therapeutic agents in biomedical applications.

Exogenous expression of PGC-1α during in vitro maturation impairs the developmental competence of porcine oocytes

Objectives of the current study were to examine the effects of exogenous expression of PGC-1α, which is a transcription factor responsive for controlling mitochondrial DNA (mtDNA) replication, mitochondria quantity control, mitochondrial biogenesis, and reactive oxygen species (ROS) maintenance, in porcine oocytes during in-vitro maturation (IVM) on the developmental competence, as well as mitochondrial quantity and function. Exogenous over-expression of PGC-1α by injection of the mRNA construct into oocytes 20 h after the start of IVM culture significantly increased the copy number of mtDNA in the oocytes, but reduced the incidences of oocytes matured to the metaphase-II stage after the IVM culture for totally 44 h and completely suppressed the early development in vitro to the blastocyst stage following parthenogenetic activation. The exogenous expression of PGC-1α also significantly induced spindle defects and chromosome misalignments. Furthermore, markedly higher ROS levels were observed in the PGC-1α-overexpressed mature oocytes, whereas mRNA level of SOD1, encoded for a ROS scavenging enzyme, was decreased. These results conclude that forced expression of PGC-1α successfully increase mtDNA copy number but led to increased ROS production, evidently by downregulation of SOD1 gene expression, inducement of spindle aberration/chromosomal misalignment, and consequently reduction in the meiotic and developmental competences of porcine oocytes.

A multifunctional carbon quantum dot overcoming the BBB for modulating amyloid aggregation and scavenging reactive oxygen species

The abnormal aggregation of β-amyloid (Aβ), the accumulation of reactive oxygen species (ROS), and the presence of the blood-brain barrier (BBB) cause the prevention and treatment of Alzheimer’s disease (AD) extremely difficult. In this study, we report multifunctional carbon quantum dots (CQDs) with red emission (RCQDs) for targeting Aβ42, modulating Aβ42 aggregation, overcoming the BBB, and scavenging ROS. RCQDs demonstrate exceptional targeting affinity for Aβ42 species, and exhibit high inhibition and disaggregation efficiencies against Aβ42 aggregates. Moreover, RCQDs possess outstanding scavenging abilities against the ROS in cells, thus resulting in the mitigation of cellular oxidative damages. RCQDs also exhibited strong penetration through the BBB in both in vitro and in vivo models, highlighting their potential for brain-targeted treatment. Further investigations using primary microglial cells confirm the anti-neuroinflammation properties of RCQDs. This study unprecedently demonstrates the therapeutic potential of unmodified pure CQDs for overcoming the BBB, targeting Aβ42 species, modulating Aβ42 aggregation and scavenging ROS, offering a promising candidate for the treatment of AD.

Molecular identification of two thioredoxin genes and their function in antioxidant defense in Arma chinensis diapause

Thioredoxin (Trx), an important part of thioredoxin systems, plays crucial role in maintaining the intracellular redox balance by scavenging reactive oxygen species (ROS). However, few Trxs have been functionally characterized in Arma chinensis, especially in diapause. In this study, diapause induction condition promoted hydrogen peroxide accumulation and increased CAT enzymatic activity and ascorbate content, suggesting that A. chinensis was exposed to high level of ROS. Therefore, we identified AcTrx2 and AcTrx-like, and investigated the relationship with antioxidant defense. It was found that AcTrx2 expression was significantly induced, whereas AcTrx-like expression was the highest on day 10 under diapause conditions. The expression of AcTrx2 and AcTrx-like in fat body, a central metabolic organ of resisting oxidative stress, was significantly increased under diapause conditions, and was significantly improved by 5/15°C (diapause temperature). We investigated the knockdown of AcTrx2 and AcTrx-like in A. chinensis and found that some selected antioxidant genes were upregulated, indicating that the upregulated genes may be functional compensation for AcTrx2 and AcTrx-like silencing. We also found that the enzymatic activities of SOD and CAT, and the metabolite contents of hydrogen peroxide, ascorbate increased after AcTrx2 and AcTrx-like knockdown. These results suggested the AcTrx2 and AcTrx-like may play critical roles in antioxidant defense of A. chinensis diapause.

Differentiated management of ROS level in tumor and kidney to alleviate Cis-platinum induced acute kidney injury with improved efficacy

Cisplatin (DDP) is a prevalent chemotherapeutic agent used in tumor therapy, yet DDP-induced acute kidney injury (AKI) severely limits its clinical application. Antioxidants as reactive oxygen species (ROS) scavengers can circumvent this adverse effect while leading to the decrease of efficacy to tumor. Herein, we report ultrasmall ruthenium nanoparticles (URNPs) as switchable ROS scavengers/generators to alleviate DDP-induced AKI and improve its therapeutic efficacy. In the physiological environment of the kidney, URNPs mimic multi-enzyme activities, such as superoxide dismutase and catalase, effectively protecting the renal cell and tissue by down-regulating the increased ROS level caused by DDP and alleviating AKI. Specifically, URNPs are oxidized by high levels of H2O2 in the tumor microenvironment (TME), resulting in the generation of oxygen vacancies and Ru3+/Ru4+ ions. This unique structure transformation endows URNPs to generate singlet oxygen (1O2) under laser irradiation and hydroxyl radicals (∙OH) through a Fenton-like reaction in tumor cell and tissue. The simultaneous generation of multifarious ROS effectively improves the efficacy of DDP in vitro and in vivo. This TME-responsive ROS scavenger/generator acts as an adjuvant therapeutic agent to minimize side effects and improve the efficacy of chemotherapy drugs, providing a new avenue to chemotherapy and facilitating clinical tumor therapy.Graphical

Vasoconstrictor Effects of Trace Amine Associated Receptor Agonists in the Isolated Perfused Rat Kidney.

Endogenous trace amines such as tryptamine and 3-iodothyronamine (T1AM) are present in mammalian tissues at very low concentrations. They produce their actions by activating surface G protein-coupled receptors known as trace amine-associated receptors (TAARs). The study was designed to investigate the possible vasoconstrictor effects of tryptamine, T1AM, and the selective TAAR1 agonist RO5263397 in isolated perfused rat kidney. Renal vascular reactivity experiment using Male Wistar Kyoto (WKY, n = 82) and Spontaneously Hypertensive Rats (SHR, n = 89) were used in this study. Tryptamine, T1AM, and RO5263397 increased perfusion pressure in preparations from WKY rats and SHRs in a dose-dependent manner, with no significant difference between the agonist's pD2 values (P > 0.05). EPPTB, a selective TAAR1 antagonist (1ηM), significantly (P < 0.05) reduced agonist-induced increase in perfusion pressure in both WKY and SHRs, suggesting a role for TAAR1 activation in these responses. The vasoconstrictor responses in both groups were significantly reduced by L-type dihydropyridine calcium channel blocker, Rho-kinase, and PKC inhibitors suggesting the involvement of extracellular calcium and enhanced calcium sensitization. Reactive oxygen species (ROS) scavenger significantly inhibited the agonist-induced increase in perfusion pressure in preparations from SHRs but not WKY. The agonist-induced increase in perfusion pressure in the kidney involves the influx of extracellular calcium, increased calcium sensitization, and ROS in SHRs only.

Diselenide-Bridged Mesoporous Silica-Based Nanoplatform with a Triple ROS-Scavenging Effect for Intracerebral Hemorrhage Treatment.

Oxidative stress (OS) is a major mediator of secondary brain injury following intracerebral hemorrhage (ICH). Thus, antioxidant therapy is emerging as an attractive strategy to combat ICH. To achieve both reactive oxygen species (ROS) scavenging ability and on-demand drug release ability, we constructed a novel polydopamine (PDA)-coated diselenide-bridged mesoporous silica nanoparticle (DSeMSN) drug delivery system (PDA-DSeMSN). Edaravone (Eda) was blocked in the pores of DSeMSN by covering the pores with PDA as a gatekeeper. The drug maintained nearly "zero release" before reaching the lesion site, while in the ROS-enriched circumstances, the PDA shell went through degradation and the doped diselenide bonds broke up, triggering the disintegration of nanoparticles and leading to Eda release. Interestingly, the ROS-degradable property of the PDA shell and diselenide bond endowed the system with enhanced ROS-eliminating capacity. The synergistic effect of ROS-responsive drug delivery and ROS-scavenging PDA-DSeMSN showed efficient antioxidative and mitochondria protective performance without apparent toxicity in vitro. Importantly, PDA-DSeMSN@Eda through intravenous administration specifically accumulated in perihematomal sites and demonstrated robust neuroprotection in an ICH mouse model through antioxidative and antiapoptotic effects with high biological safety. Thus, the PDA-DSeMSN platform holds tremendous potential as an excellent carrier for on-demand delivery of drugs and provides a new and effective strategy for the clinical treatment of ICH.