Superoxide Dismutase Mimetics Research Articles

Mitochondria-targeting Cu2-xSe-TPP with dual enzyme activity alleviates Alzheimer's disease by modulating oxidative stress

Mitochondrial dysfunction in microglia has been implicated as a key pathogenesis of most neurodegenerative diseases including Alzheimer's disease (AD). Abnormal production of reactive oxygen species (ROS) and neuroinflammation caused by mitochondrial oxidative stress are important factors leading to neuronal death in AD. Herein, a "dual brake" strategy to synergistically halt mitochondrial dysfunction and neuroinflammation targeting mitochondria in microglia is proposed. To achieve this goal, (3-carboxypropyl) triphenyl-phosphonium bromide (TPP)-modified Cu2-xSe nanozymes (Cu2-xSe-TPP NPs) with dual enzyme-like activities was designed. Cu2-xSe-TPP NPs with superoxide dismutase-mimetic (SOD) and catalase-mimetic (CAT) activities can effectively scavenge ROS in the mitochondria of microglia and relieve mitochondrial oxidative stress. In vivo studies demonstrated that Cu2-xSe-TPP NPs can alleviate oxidative stress and promote neuroprotection in the hippocampus of AD model mice. In addition, Cu2-xSe-TPP NPs can regulate the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, promote Aβ phagocytosis and reshape the AD inflammatory microenvironment, thus effectively attenuating AD neuropathology and rescuing cognitive deficits in AD model mice. Taken together, this strategy preventing mitochondrial damage and remodeling the inflammatory microenvironment will provide a new perspective for AD therapy.

Exploring research trends and hotspots on oxidative stress and bronchopulmonary dysplasia: Insights from bibliometric and visualized study.

Bronchopulmonary dysplasia (BPD) is a severe chronic lung disease primarily affecting premature infants, often resulting from prolonged mechanical ventilation and oxygen therapy. Oxidative stress plays a critical role in the pathogenesis of BPD, contributing to lung injury, inflammation, and impaired lung development. Despite extensive research, there is a need to systematically map out the research trends and hotspots in this field to inform future studies and therapeutic strategies. This study utilized bibliometric and visualized analysis to explore global research trends and hotspots on oxidative stress and BPD from 2004 to 2024. A comprehensive literature search was conducted in the Web of Science Core Collection, focusing on publications related to oxidative stress and BPD. Tools such as VOSviewer, Citespace, and the R package Bibliometrix were employed to analyze Coauthorship, co-citation, and keyword co-occurrence networks, as well as to identify emerging research fronts and influential studies. The analysis identified 597 relevant publications, showing a steady increase in research output over the 20-year period, with a significant surge in the last decade. The United States led in research contributions, followed by China and Germany, with notable collaborations among these countries. Coauthorship analysis highlighted key research institutions, such as Harvard University and the University of California, as central nodes in the research network. Thematic clustering revealed five major research areas: antioxidant mechanisms, inflammation, molecular pathways, lung development, and therapeutic interventions. The keyword co-occurrence analysis showed a shift in research focus over time. Early studies concentrated on basic pathophysiological mechanisms, while recent research has increasingly focused on advanced molecular techniques, such as gene expression and targeted therapies. Notably, the study identified emerging research hotspots, including the role of extracellular vesicles and cellular senescence in BPD, as well as the potential therapeutic applications of antioxidants like superoxide dismutase mimetics. This bibliometric study provides a comprehensive overview of the research landscape on oxidative stress and BPD, identifying key trends, influential authors, and emerging research topics. The findings underscore the importance of continued research in this field, particularly in translating basic scientific insights into clinical applications to improve outcomes for infants affected by BPD. The study also highlights potential areas for future investigation, including the development of novel therapeutic strategies targeting oxidative stress in BPD.

Unlocking Selective Anticancer Mechanisms: Dinuclear Manganese Superoxide Dismutase Mimetics Combined with Pt(II) Complexes.

We conducted an in-depth exploration of the in vitro activities of the dinuclear Mn2L2Ac and Mn2L2 complexes (where HL=2-{[di(2-pyridyl)methylamino]-methyl}phenol), possessing dual superoxide dismutase (SOD) and catalase (CAT) activity. We investigated these complexes both individually and in conjunction with various Pt(II)-complexes, either as mixtures or as the Mn2-Pt adducts. Our findings revealed a notable up to 50 % enhancement in the viability of healthy human breast cells, contrasted with a viability decrease as low as 50 % in breast cancer cells upon combined treatments with Mn2 SOD mimics and Pt(II) complexes. Specifically, we synthesized and characterized the self-assembled Mn2-Pt adducts (isolated Mn2L2Pt and in situ Mn2L2Pt'), linking Mn2L2-core with the carboxylate group of PtDAPCl2 (dichloro(2,3-diaminopropionic acid) platinum(II)). The SOD activity of the isolated Mn2L2Pt adduct (kSOD=1.7×107 M-1 s-1) remained intact. Through in vitro cell viability assessments, ROS levels, cellular Mn uptake and proteomics measurements, we elucidated key mechanisms underlying the observed biological effects. We demonstrated that Mn2-containing formulations predominantly target mitochondrial processes, differently affecting the proteome of cancerous and healthy cells. They induced downregulation of H2S signaling and expression of mitochondrial complex I and III, as well as increased oxidative phosphorylation pathways and upregulation of EGFR in cancer cells. In contrast, healthy cells showed a decrease in EGFR expression and a moderate enrichment in oxidative phosphorylation pathways.

Balanced Duality: H2O2-Based Therapy in Cancer and Its Protective Effects on Non-Malignant Tissues.

Conventional cancer therapy strategies, although centered around killing tumor cells, often lead to severe side effects on surrounding normal tissues, thus compromising the chronic quality of life in cancer survivors. Hydrogen peroxide (H2O2) is a secondary signaling molecule that has an array of functions in both tumor and normal cells, including the promotion of cell survival pathways and immune cell modulation in the tumor microenvironment. H2O2 is a reactive oxygen species (ROS) crucial in cellular homeostasis and signaling (at concentrations maintained under nM levels), with increased steady-state levels in tumors relative to their normal tissue counterparts. Increased steady-state levels of H2O2 in tumor cells, make them vulnerable to oxidative stress and ultimately, cell death. Recently, H2O2-producing therapies-namely, pharmacological ascorbate and superoxide dismutase mimetics-have emerged as compelling complementary treatment strategies in cancer. Both pharmacological ascorbate and superoxide dismutase mimetics can generate excess H2O2 to overwhelm the impaired H2O2 removal capacity of cancer cells. This review presents an overview of H2O2 metabolism in the physiological and malignant states, in addition to discussing the anti-tumor and normal tissue-sparing mechanism(s) of, and clinical evidence for, two H2O2-based therapies, pharmacological ascorbate and superoxide dismutase mimetics.

Distinct concentration-dependent oxidative stress profiles by cadmium in a rat kidney proximal tubule cell line

Levels and chemical species of reactive oxygen/nitrogen species (ROS/RNS) determine oxidative eustress and distress. Abundance of uptake pathways and high oxygen consumption for ATP-dependent transport makes the renal proximal tubule particularly susceptible to cadmium (Cd2+)-induced oxidative stress by targeting ROS/RNS generation or antioxidant defence mechanisms, such as superoxide dismutase (SOD) or H2O2-metabolizing catalase (CAT). Though ROS/RNS are well-evidenced, the role of distinct ROS profiles in Cd2+ concentration-dependent toxicity is not clear. In renal cells, Cd2+ (10–50 µM) oxidized dihydrorhodamine 123, reaching a maximum at 2–3 h. Increases (up to fourfold) in lipid peroxidation by TBARS assay and H2O2 by Amplex Red were evident within 30 min. ROS and loss in cell viability by MTT assay with 50 µM Cd2+ could not be fully reversed by SOD mimetics Tempol and MnTBAP nor by SOD1 overexpression, whereas CAT expression and α-tocopherol were effective. SOD and CAT activities were attenuated below controls only with >6 h 50 µM Cd2+, yet augmented by up to 1.5- and 1.2-fold, respectively, by 10 µM Cd2+. Moreover, 10 µM, but not 25–50 µM Cd2+, caused 1.7-fold increase in superoxide anion (O2•−), detected by dihydroethidium, paralled by loss in cell viability, that was abolished by Tempol, MnTBAP, α-tocopherol and SOD1 or CAT overexpression. H2O2-generating NADPH oxidase 4 (NOX4) was attenuated by ~50% with 10 µM Cd2+ at 3 h compared to upregulation by 50 µM Cd2+ (~1.4-fold, 30 min), which was sustained for 24 h. In summary, O2•− predominates with low–moderate Cd2+, driving an adaptive response, whereas oxidative stress by elevated H2O2 at high Cd2+ triggers cell death signaling pathways.HighlightsDifferent levels of reactive oxygen species are generated, depending on cadmium concentration.Superoxide anion predominates and H2O2 is suppressed with low cadmium representing oxidative eustress.High cadmium fosters H2O2 by inhibiting catalase and increasing NOX4 leading to oxidative distress.Superoxide dismutase mimetics and overexpression were less effective with high versus low cadmium.Oxidative stress profile could dictate downstream signalling pathways.

Angiotensin II acts through Rac1 to upregulate pendrin: role of NADPH oxidase.

Angiotensin II increases apical plasma membrane pendrin abundance and function. This study explored the role of the small GTPase Rac1 in the regulation of pendrin by angiotensin II. To do this, we generated intercalated cell (IC) Rac1 knockout mice and observed that IC Rac1 gene ablation reduced the relative abundance of pendrin in the apical region of intercalated cells in angiotensin II-treated mice but not vehicle-treated mice. Similarly, the Rac1 inhibitor EHT 1864 reduced apical pendrin abundance in angiotensin II-treated mice, through a mechanism that does not require aldosterone. This IC angiotensin II-Rac1 signaling cascade modulates pendrin subcellular distribution without significantly changing actin organization. However, NADPH oxidase inhibition with APX 115 reduced apical pendrin abundance in vivo in angiotensin II-treated mice. Moreover, superoxide dismutase mimetics reduced Cl- absorption in angiotensin II-treated cortical collecting ducts perfused in vitro. Since Rac1 is an NADPH subunit, Rac1 may modulate pendrin through NADPH oxidase-mediated reactive oxygen species production. Because pendrin gene ablation blunts the pressor response to angiotensin II, we asked if pendrin blunts the angiotensin II-induced increase in kidney superoxide. Although kidney superoxide was similar in vehicle-treated wild-type and pendrin knockout mice, it was lower in angiotensin II-treated pendrin-null kidneys than in wild-type kidneys. We conclude that angiotensin II acts through Rac1, independently of aldosterone, to increase apical pendrin abundance. Rac1 may stimulate pendrin, at least partly, through NADPH oxidase. This increase in pendrin abundance contributes to the increment in blood pressure and kidney superoxide content seen in angiotensin II-treated mice.NEW & NOTEWORTHY This study defines a new signaling mechanism by which angiotensin II modulates oxidative stress and blood pressure.

Enhanced Peroxide Fluxes and Radiosensitization in Colorectal Tumors but Not Normal Enterocytes from the Combination of Superoxide Dismutase Mimetics and Pharmacological Ascorbate

Selective superoxide dismutase mimetics (DMs), including GC4419 and GC4711, are radiation (RT) modulators which induce opposite effects in tumors and normal tissues and may be ideally suited for locally advanced rectal cancer. However, their tumor radiosensitization effect is limited at RT doses relevant to rectal cancer (2-5 Gy). Over this dose range, they protect normal mucosal tissues, but we and others have shown they do not reliably enhance tumor radiosensitization at doses < 8-15 Gy. We hypothesize that combining DMs and other therapies which also target redox metabolism may effectively sensitize tumors to clinically relevant RT doses for rectal cancer while maintaining their normal tissue sparing effects. Like DMs, pharmacological ascorbate (P-AscH) selectively increases lethal hydrogen peroxide (H2O2) fluxes in tumors, but it does so through distinct mechanisms which are potentially complimentary with DMs (particularly at low RT doses). Human HCT116, SW480, and HT29 colorectal tumor models and non-malignant FHs74 intestinal epithelial cells were used. Clonogenic survival was assessed following single-fraction RT (2-5 Gy) +/- P-AscH (5 pmol/cell) +/- GC4711 (20 µM). Dependency on H202 fluxes was tested by adding bovine catalase with drug and RT treatments. Oxygen consumption in culture media was measured using a Clark electrode. Rectal toxicity was assessed in vivo using IHC in fixed rectal tissues following fractionated, image-guided rectal RT (5-9 Gy x 3). Tumor growth delay was assessed following RT (5 Gy x 3) +/- P-AscH (4 g/kg) +/- GC4419 (10 mg/kg) in animals with unilateral HCT116 flank tumors. Combination therapy with P-AscH and GC4711 potently radiosensitized all tumor lines in vitro whereas neither agent significantly decreased clonogenic survival as a monotherapy. Neither drug nor combination treatment sensitized FHs74 epithelial cells. P-AscH increased oxygen consumption and H2O2 production in culture media and the addition of GC4711 significantly increased both more than P-AscH alone. Co-treatment with exogenous catalase inhibited cancer cell killing with combination therapy +/- RT. In vivo, combination therapy significantly enhanced tumor growth delay and survival. Both agents significantly decreased markers of acute rectal RT injury as monotherapies. Co-treatment with DMs and P-AscH selectively enhanced tumor radiosensitization by increasing oxygen consumption and H202 fluxes even in tumor models which are known to be resistant to oxidative stressors (HT29). In contrast, each agent conferred a radioprotective effect in the rectum. Combination therapy with DMs and P-AscH may represent a novel, potent approach to target dysregulated redox metabolism in colorectal tumors.

A Redox Modulatory SOD Mimetic Nanozyme Prevents the Formation of Cytotoxic Peroxynitrite and Improves Nitric Oxide Bioavailability in Human Endothelial Cells.

The endothelium-derived signalling molecule nitric oxide (NO) in addition to controlling multifarious servo-regulatory functions, suppresses key processes in vascular lesion formation and prevents atherogenesis and other vascular abnormalities. The conversion of NO into cytotoxic and powerful oxidant peroxynitrite (ONOO- ) in a superoxide (O2 .- )-rich environment has emerged as a major reason for reduced NO levels in vascular walls, leading to endothelial dysfunction and cardiovascular complications. So, designing superoxide dismutase (SOD) mimetics that can selectively catalyze the dismutation of O2 .- in the presence of NO, considering their rapid reaction is challenging and is of therapeutic relevance. Herein, the authors report that SOD mimetic cerium vanadate (CeVO4 ) nanozymes effectively regulate the bioavailability of both NO and O2 .- , the two vital constitutive molecules of vascular endothelium, even in the absence of cellular SOD enzyme. The nanozymes optimally modulate the O2 .- level in endothelial cells under oxidative stress conditions and improve endogenously generated NO levels by preventing the formation of ONOO- . Furthermore, nanoparticles exhibit size- and morphology-dependent uptake into the cells and internalize via the clathrin-mediated endocytosis pathway. Intravenous administration of CeVO4 nanoparticles in mice caused no definite organ toxicity and unaltered haematological and biochemical parameters, indicating their biosafety and potential use in biological applications.

The cardioprotective effects of pharmacological postconditioning with mangafodipir in ST-elevation myocardial infarction, a 4–7 years follow up study

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Futurum - the academy for health and care, Jönköping. Background/Introduction The prevalence of heart failure is increasing as more patients survive a myocardial infarction (MI). MI scar extent is a strong predictor of the development of heart failure due to left ventricular adverse remodeling. Reperfusion injury occurs in the early phase of reperfusion and is linked to the increase of reactive oxygen species (ROS) with calcium overload disrupting the mitochondrial structure, which in turn results in further cell necrosis. Manganese dipyridoxyl diphosphate (mangafodipir) has superoxide dismutase mimetics and may act as a ROS scavenger in the acute phase of myocardial ischemia, hence supporting the myocardial cells in the neutralization of the chemically reactive molecules reducing the MI extent [1–3]. Purpose Our aim was to investigate the cardioprotective role of pharmacological postconditioning with mangafidipir in patients with ST-elevation myocardial infarction (STEMI). Methods Twenty patients with acute STEMI were enrolled between 2009–2014 and followed up 2017. The subjects were randomized in the cath lab into blinded treatment with i.v mangafodipir or control treatment receiving i.v saline prior to restoration of blood flow in the occluded coronary artery. Cardiac magnetic resonance imaging (CMR) at baseline and at follow-up (4–7 years) was performed to evaluate MI scar, LV end diastolic volume (LVEDV), LV end systolic volume (LVESV), LV stroke volume (LVSV), LV ejection fraction (LVEF) and LV mass (LVM). The study was approved by the ethical review board in Linkoping (Dnr 2016/212-31) and registered in the public database at clinicaltrials.gov (NCT 00966563). Results There was no significant difference between the groups in MI scar or LV geometrical and functional properties at baseline, although the duration of ischemia was significantly longer in the mangafodipir group (206 min vs. 144 min, p &amp;lt; 0.05) and a better TIMI grade before pPCI was observed in the control group. The group that underwent pharmacological postconditioning with mangafodipir had lower volumes and higher LVEF (p &amp;lt; 0.05) at follow-up, while the placebo group showed increased LV volumes, see Table 1 and Figure 1. Conclusion Pharmacological postconditioning with mangafodipir in STEMI may have a cardioprotective role in the development of left ventricular adverse remodeling. Due to the limited number of participants, the benefit of mangafodipir needs confirmation in larger studies.

Abstract 4787: The cancer targeting synergy of tertbutylhydroquinone and a manganese porphyrin

Abstract Cancer cells utilize high basal levels of reactive oxygen species (ROS) to create conditions that facilitate rapid cell proliferation. This creates an Achilles heel, making cancer cells more susceptible than normal cells to cell death caused by a bolus dose of ROS. The common food preservative, tert-butylhydroquinone (tBHQ), generates ROS intracellularly via redox cycling. Herein, we tested the effect of combining tBHQ with a manganese porphyrin, compounds originally designed as super oxide dismutase mimetics which can also generate ROS intracellularly in cancer cells and have radioprotective effects under clinical investigation. We find that the combination treatment of tBHQ and the commercially available Mn(III) tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP) is much more toxic to leukemic Jurkat lymphocytes than either compound alone, e.g., lowering the LC50 of tBHQ by two orders of magnitude to 1.0 μM. MnTMPyP acts as a catalyst to oxidize tBHQ, shown by UV-Vis spectroscopy. Flow cytometry analysis revealed that while 5 μM tBHQ decreases cell viability by less than 10% in 4 hours, the combination of 5 μM tBHQ and 12 μM MnTMPyP decreases viability by 60%, primarily by apoptosis. A clinically tested manganese porphyrin, Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin (Mn2BuOE), was as effective and more potent than MnTMPyP. We evaluated the cancer-targeting effect of tBHQ and Mn2BuOE in both Jurkats and a matched primary CD4 T cell line. The combination treatment induced significantly more cell death in cancerous Jurkats than in the normal CD4 cells. With the promise Mn2BuOE shows in pre-clinical studies and early clinical trials as adjunctive to radiotherapy, and the wide use of tBHQ in prepared food, the results shown here in CD4 cells suggest their combination may be an effective therapy to target cancer cells. Citation Format: Joseph P. LaMorte, Sandra Tamarin, Margueritte Lalo, David J. Sokoloski, Jared J. Paul, Aimee L. Eggler. The cancer targeting synergy of tertbutylhydroquinone and a manganese porphyrin. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4787.

SOD2 in platelets: with age comes responsibility

SOD2 in platelets: with age comes responsibility

A New Manganese Superoxide Dismutase Mimetic Improves Oxaliplatin-Induced Neuropathy and Global Tolerance in Mice.

Reactive oxygen species (ROS) are produced by every aerobic cell during mitochondrial oxidative metabolism as well as in cellular response to xenobiotics, cytokines, and bacterial invasion. Superoxide Dismutases (SOD) are antioxidant proteins that convert superoxide anions (O2•-) to hydrogen peroxide (H2O2) and dioxygen. Using the differential in the level of oxidative stress between normal and cancer cells, SOD mimetics can show an antitumoral effect and prevent oxaliplatin-induced peripheral neuropathy. New Pt(IV) conjugate prodrugs (OxPt-x-Mn1C1A (x = 1, 1-OH, 2)), combining oxaliplatin and a Mn SOD mimic (MnSODm Mn1C1A) with a covalent link, were designed. Their stability in buffer and in the presence of sodium ascorbate was studied. In vitro, their antitumoral activity was assessed by the viability and ROS production of tumor cell lines (CT16, HCT 116, KC) and fibroblasts (primary culture and NIH 3T3). In vivo, a murine model of colorectal cancer was created with subcutaneous injection of CT26 cells in Balb/c mice. Tumor size and volume were measured weekly in four groups: vehicle, oxaliplatin, and oxaliplatin associated with MnSODm Mn1C1A and the bis-conjugate OxPt-2-Mn1C1A. Oxaliplatin-induced peripheral neuropathy (OIPN) was assessed using a Von Frey test reflecting chronic hypoalgesia. Tolerance to treatment was assessed with a clinical score including four items: weight loss, weariness, alopecia, and diarrhea. In vitro, Mn1C1A associated with oxaliplatin and Pt(IV) conjugates treatment induced significantly higher production of H2O2 in all cell lines and showed a significant improvement of the antitumoral efficacy compared to oxaliplatin alone. In vivo, the association of Mn1C1A to oxaliplatin did not decrease its antitumoral activity, while OxPt-2-Mn1C1A had lower antitumoral activity than oxaliplatin alone. Mn1C1A associated with oxaliplatin significantly decreased OIPN and also improved global clinical tolerance of oxaliplatin. A neuroprotective effect was observed, associated with a significantly improved tolerance to oxaliplatin without impairing its antitumoral activity.

Acceleration of Singlet Oxygen Evolution by Superoxide Dismutase Mimetics in Lithium–Oxygen Batteries

AbstractSide reactions caused by reactive oxygen species (e.g., superoxide and singlet oxygen) are limiting factors in the lithium–oxygen batteries (LOBs). Superoxide dismutase mimetics (SODms), which suppress superoxide‐triggered side reactions by accelerating the disproportionation reaction during discharge, are introduced as soluble additives in the LOBs. However, although SODms promote the disproportionation reaction, which is the main pathway for singlet oxygen evolution, the correlation between SODms and singlet oxygen has not been verified. Here, 4‐carboxy‐TEMPO is selected as a representative SODm that effectively promotes the disproportionation reaction and chemically verifies acceleration of singlet oxygen evolution. Furthermore, by using quencher, it is reported that the release of singlet oxygen evolved by the SODm is decreased. Because this study closely examines the relationship between the additives and singlet oxygen, it is believed that this study provides an important reference for the development of additives for the practical application of LOBs.

PH-responsive theranostic nanoplatform of ferrite and ceria co-engineered nanoparticles for anti-inflammatory.

Multiple component integration to achieve both therapy and diagnosis in a single theranostic nanosystem has aroused great research interest in the medical investigator. This study aimed to construct a novel theranostic nanoplatform ferrite and ceria co-engineered mesoporous silica nanoparticles (Fe/Ce-MSN) antioxidant agent though a facile metal Fe/Ce-codoping approach in the MSN framework. The resulted Fe3+-incorporated ceria-based MSN nanoparticles possessing a higher Ce3+-to-Ce4+ ratio than those revealed by ceria-only nanoparticles. The as-prepared Fe/Ce-MSN nanoparticles exhibited an excellent efficiency in scavenging reactive oxygen species (ROS), which is attributed to improving the superoxide dismutase (SOD) mimetics activity by increasing Ce3+ content and maintaining a higher activity of catalase (CAT) mimetics via including ferrite ion in nanoparticles. The fast Fe/Ce-MSN biodegradation, which is sensitive to the mild acidic microenvironment of inflammation, can accelerate Fe/Ce ion release, and the freed Fe ions enhanced T2-weighted magnetic resonance imaging in the inflammation site. PEGylated Fe/Ce-MSN nanoparticles in vitro cell models significantly attenuated ROS-induced inflammation, oxidative stress, and apoptosis in macrophages by scavenging overproduced intracellular ROS. More importantly, Fe/Ce-MSN-PEG NPs exhibited significant anti-inflammatory effects by inhibiting lipopolysaccharide (LPS)-induced expression of tumor necrosis factor-α (TNF-α) and interleukin-1 beta (IL-1β) levels in vitro. Additionally, it can promote the macrophages polarization of pro-inflammatory M1 phenotype towards an anti-inflammatory M2 phenotype. Thus, the novel pH-responsive theranostic nanoplatform shows great promise for inflammation and oxidative stress-associated disease treatment.

Therapeutic Potential of Small Molecules Targeting Oxidative Stress in the Treatment of Chronic Obstructive Pulmonary Disease (COPD): A Comprehensive Review.

Chronic obstructive pulmonary disease (COPD) is an increasing and major global health problem. COPD is also the third leading cause of death worldwide. Oxidative stress (OS) takes place when various reactive species and free radicals swamp the availability of antioxidants. Reactive nitrogen species, reactive oxygen species (ROS), and their counterpart antioxidants are important for host defense and physiological signaling pathways, and the development and progression of inflammation. During the disturbance of their normal steady states, imbalances between antioxidants and oxidants might induce pathological mechanisms that can further result in many non-respiratory and respiratory diseases including COPD. ROS might be either endogenously produced in response to various infectious pathogens including fungi, viruses, or bacteria, or exogenously generated from several inhaled particulate or gaseous agents including some occupational dust, cigarette smoke (CS), and air pollutants. Therefore, targeting systemic and local OS with therapeutic agents such as small molecules that can increase endogenous antioxidants or regulate the redox/antioxidants system can be an effective approach in treating COPD. Various thiol-based antioxidants including fudosteine, erdosteine, carbocysteine, and N-acetyl-L-cysteine have the capacity to increase thiol content in the lungs. Many synthetic molecules including inhibitors/blockers of protein carbonylation and lipid peroxidation, catalytic antioxidants including superoxide dismutase mimetics, and spin trapping agents can effectively modulate CS-induced OS and its resulting cellular alterations. Several clinical and pre-clinical studies have demonstrated that these antioxidants have the capacity to decrease OS and affect the expressions of several pro-inflammatory genes and genes that are involved with redox and glutathione biosynthesis. In this article, we have summarized the role of OS in COPD pathogenesis. Furthermore, we have particularly focused on the therapeutic potential of numerous chemicals, particularly antioxidants in the treatment of COPD.

Abstract 218: Novel SOD mimetics GC4419 &amp; GC4711 induce synergistic tumoricidal effects combined with radiotherapy in lung cancer models

Abstract Introduction: Superoxide dismutase mimetics (SODm) synergize with radiation (IR) by converting radiolytically produced superoxide to hydrogen peroxide. Cancer cells lacking catalase function fail to clear H2O2 resulting in increased tumoricidal load. In addition, complex interactions through redox signaling and immune interplay are suggested mechanisms of action. Our pre-clinical studies with the SODm GC4419 (AVA) indicated that increased inflammatory, TNFα, and apoptosis signaling contribute to treatment synergy that was most effective at hypofractionation (Sci Transl Med. 13:593). The analogue GC4711 (GC) is currently in clinical trials for SBRT against NSCLC and pancreatic cancer. However, optimal combination schedules and molecular mechanisms are largely unknown. Here, we present optimized combination schedules using human lung tumor xenografts regarding drug administration timing and dosage, as well as local and abscopal tumor control in a syngeneic lung tumor model. Further, we tested various cell stress and immune pathways to identify targets of synergistic IR-drug interaction. Methods: Female athymic nude and C57BL/6 mice were inoculated with H1299 and LLC, respectively. H1299 tumors were irradiated with 10-15 Gy and GC was given once or twice daily (24 or 2x20 mg/kg, respectively) over 5 days, including untreated controls. LLC tumors were set up as an abscopal model and mice received combination treatment with GC and 15 Gy, 15 Gy only, or GC only, including untreated controls. In vitro, lung cancer cell lines were pre-treated with AVA or GC 30 min prior to IR and assayed for various immune or DNA damage-related endpoints. Results: The anti-tumor efficacy of single or double GC administration showed nonlinear dose-dependence indicating complex drug-IR interplay. Optimal drug administration appears to be around 3 hours prior to irradiation while time-of-day of treatment has no observable effect in this model. In the LLC double tumor model, GC in combination with IR induced significant and pronounced abscopal tumor control. In vitro, analysis revealed GC action related to e.g. 53BP1, yH2AX, Akt, R-loop formation and replication stress, and interaction with various immune pathways. Discussion and Conclusions: The radiotherapeutic effect can be vastly increased with superoxide dismutase mimetics, both within and outside the treatment field. Combination therapy requires screening of schedules regarding timing, drug dosage, and IR dose and fractionation to achieve optimal tumoricidal effects. SODm synergize with IR acting on various molecular targets that can be harnessed to overcome treatment resistance. Secondary tumor control is a promising new venue for IR-SODm combination therapy. Moreover, redox-immune interaction opens new therapeutic applications with combined immune checkpoint inhibitors for unprecedented tumor control and cure rate. Citation Format: Britta Langen, Laurentiu Pop, Zengfu Shang, Moito Iijima, James Nicholson, Mingming Yang, Michael D. Story. Novel SOD mimetics GC4419 &amp; GC4711 induce synergistic tumoricidal effects combined with radiotherapy in lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 218.

Inertness of Superoxide Dismutase Mimics Mn(II) Complexes Based on an Open-Chain Ligand, Bioactivity, and Detection in Intestinal Epithelial Cells.

Oxidative stress is known to play a major role in the pathogenesis of inflammatory bowel diseases (IBDs), and, in particular, superoxide dismutase (SODs) defenses were shown to be weakened in patients suffering from IBDs. SOD mimics, also called SOD mimetics, as low-molecular-weight complexes reproducing the activity of SOD, constitute promising antioxidant catalytic metallodrugs in the context of IBDs. A Mn(II) complex SOD mimic (Mn1) based on an open-chain diaminoethane ligand exerting antioxidant and anti-inflammatory effects on an intestinal epithelial cellular model was shown to experience metal exchanges between the manganese center and metal ions present in the biological environment (such as Zn(II)) to some degrees. As the resulting complexes (mainly Zn(II)) were shown to be inactive, improving the kinetic inertness of Mn(II) complexes based on open-chain ligands is key to improve their bioactivity in a cellular context. We report here the study of three new Mn(II) complexes resulting from Mn1 functionalization with a cyclohexyl and/or a propyl group meant to limit, respectively, (a) metal exchanges and (b) deprotonation of an amine from the 1,2-diaminoethane central scaffold. The new manganese-based SOD mimics display a higher intrinsic SOD activity and also improved kinetic inertness in metal ion exchange processes (with Zn(II), Cu(II), Ni(II), and Co(II)). They were shown to provide anti-inflammatory and antioxidant effects in cells at lower doses than Mn1 (down to 10 μM). This improvement was due to their higher inertness against metal-assisted dissociation and not to different cellular overall accumulations. Based on its higher inertness, the SOD mimic containing both the propyl and the cyclohexyl moieties was suitable for intracellular detection and quantification by mass spectrometry, quantification, that was achieved by using a 13C-labeled Co-based analog of the SOD mimics as an external heavy standard.

Malonic-acid-functionalized fullerene enables the interfacial stabilization of Ni-rich cathodes in lithium-ion batteries

High-capacity LiNi 1-x-y Co x Mn y O 2 (NCM) (x + y ≤ 0.2) is a potential candidate for realizing high-energy-density lithium-ion batteries (LIBs). However, successful application of this cathode requires overcoming the irreversible phase transition (layered-to-spinel/rock-salt), interfacial instability caused by residual lithium compounds, and the electrolyte oxidation promoted by highly oxidized Ni 4+ . In this study, we investigate the roles of fullerene with malonic acid moieties (MA-C 60 ) as a superoxide dismutase mimetic (SODm) electrolyte additive in LIBs to deactivate reactive radical species (O 2 •- , LiOCO 3 • , and Li(CO 3 ) 2 • ) induced by electrochemical oxidation of residual lithium compound, Li 2 CO 3 on the LiNi 0.8 Co 0.1 Mn 0.1 O 2 (NCM811) cathode surface and to scavenge trace water to avoid undesirable hydrolysis of LiPF 6 . Further, MA-C 60 maintains the structural stability of NCM811 cathodes and mitigates the parasitic reaction of residual lithium compounds with LiPF 6 through the formation of a stable cathode–electrolyte interface. Our findings showed that MA-C 60 helps overcome the challenges associated with Li 2 CO 3 oxidation at the NCM811 cathode, which produces CO 2 gas and O 2 •- that react with the solvent molecules. • Electrochemical oxidation of Li 2 CO 3 generates superoxide radicals and CO 2 . • MA-C 60 is capable of scavenge superoxide radical and water molecule. • MA-C 60 -derived cathode interfaces ensure structural stability of NCM811 cathode.

Abstract WP253: Increased Hydrogen Sulfide As A New Mechanism For Hyperglycemic Worsening Of Stroke Outcome

Introduction: Hyperglycemia at stroke onset worsens outcome and reduces the effectiveness of reperfusion therapies. Increased oxidative and mitochondrial injury likely contribute. To treat this mechanism, we synthesized (PEG)-ylated carbon nanoparticles (CNPs) from acid oxidation of activated charcoal (OAC) generating 3 nm discs, catalytic superoxide dismutase mimetics that protect mitochondrial complexes. Cellular uptake is rapid and delayed I.V. PEG-CNPs are highly protective in reversible MCAO in hyperglycemic rats. Hydrogen sulfide (H 2 S) is an essential gaseous transmitter with a narrow therapeutic index associated with many disorders e.g., diabetes. Its synthesis is influenced by radicals. Excess H 2 S is toxic to mitochondrial complex IV. H 2 S is endogenously oxidized to polysulfides (PS), potent antioxidants also needed for protein persulfidation. We hypothesized that OAC’s favorable redox potential will catalyze H 2 S oxidization to PS, acute hyperglycemia will increase H 2 S and PEG-OACs will blunt the increase. Methods: b.End3 brain endothelial and HEK293 cultured cells were employed. SSP4 fluorescence measured PS levels with increasing concentrations of PEG-OACs. AzMC fluorescence detected H 2 S levels in cells incubated in 100 mg/dL glucose media followed by glucose 500 mg/dL with or without PEG-OACs, first in normoxia followed by anoxia/normoxia. Results: PEG-OACs dose dependently increased cellular PS levels (Fig 1a). High glucose increased H 2 S levels especially during anoxia/normoxia (Fig 1b). PEG-OACs completely eliminated the glucose-induced increase in H 2 S (Fig 1c). Conclusions: Acute hyperglycemia increased H 2 S production especially under conditions mimicking ischemia/reperfusion, an effect eliminated by PEG-OACs. Because of mitochondrial toxicity, an H 2 S increase may contribute to worsened outcome in hyperglycemic stroke. These results suggest a new therapeutic target for this important cause of poor stroke outcome.

Carbon monoxide activation of delayed rectifier potassium currents of human cardiac fibroblasts through diverse pathways.

To identify the effect and mechanism of carbon monoxide (CO) on delayed rectifier K+ currents (IK) of human cardiac fibroblasts (HCFs), we used the whole-cell mode patch-clamp technique. Application of CO delivered by carbon monoxide-releasing molecule-3 (CORM3) increased the amplitude of outward K+ currents, and diphenyl phosphine oxide-1 (a specific IK blocker) inhibited the currents. CORM3-induced augmentation was blocked by pretreatment with nitric oxide synthase blockers (L-NG-monomethyl arginine citrate and L-NG-nitro arginine methyl ester). Pretreatment with KT5823 (a protein kinas G blocker), 1H-[1,-2,-4] oxadiazolo-[4,-3-a] quinoxalin-1-on (ODQ, a soluble guanylate cyclase blocker), KT5720 (a protein kinase A blocker), and SQ22536 (an adenylate cyclase blocker) blocked the CORM3 stimulating effect on IK. In addition, pretreatment with SB239063 (a p38 mitogen-activated protein kinase [MAPK] blocker) and PD98059 (a p44/42 MAPK blocker) also blocked the CORM3’s effect on the currents. When testing the involvement of S-nitrosylation, pretreatment of N-ethylmaleimide (a thiol-alkylating reagent) blocked CO-induced IK activation and DL-dithiothreitol (a reducing agent) reversed this effect. Pretreatment with 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)-21H,23H porphyrin manganese (III) pentachloride and manganese (III) tetrakis (4-benzoic acid) porphyrin chloride (superoxide dismutase mimetics), diphenyleneiodonium chloride (an NADPH oxidase blocker), or allopurinol (a xanthine oxidase blocker) also inhibited CO-induced IK activation. These results suggest that CO enhances IK in HCFs through the nitric oxide, phosphorylation by protein kinase G, protein kinase A, and MAPK, S-nitrosylation and reduction/oxidation (redox) signaling pathways.