Biopreservation and Reversal of Oxidative Injury During Blood Storage by a Novel Curcumin-based Gel Formulation.

Blood storage lesion induces cytosolic and membrane changes driven in part by hemoglobin (Hb) oxidation reactions within red blood cells (RBCs). A novel gel formulation containing the antioxidant curcuminoids in a biocompatible solvent system was used to deliver curcumin into RBCs. Incubation of peroxide treated RBCs stored in PBS with curcumin gel led to a reduction in prooxidant ferrylHb and recovery in ATP. Curcumin treatment prevented band 3 tyrosine (Y359 and Y21) phosphorylation. RBCs stored in AS-3 solutions for 28, 35, 42 and 49 days, following a single-dose of 100µM curcuminoids at each time points, caused reduction in protein carbonylation and considerable recovery in ATP levels. Proteomic analysis revealed minimal changes in the proteomic landscape in 35 days. However, a downregulation in fibrinogen was observed in the treated samples which may reduce RBC aggregation. Additionally, we used a guinea pig model where the circulation of infused aged RBCs can be extended (approximately 10%) when treated with curcumin gel at the start of storage. Our data therefore provide mechanistic insights and supportive animal data into benefits of treating stored RBCs with a novel curcuminoid formulation based on the biopreservation of RBC membrane integrity, redox balance, and increased longevity in circulation.

Nano-encapsulated anandamide reduces inflammatory cytokines in vitro and lesion severity in a murine model of cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune skin disease which occurs independently and in conjunction with systemic lupus erythematosus. Drug development for CLE is severely lacking. Anandamide (AEA) is a primary endocannabinoid which exhibits immunomodulatory effects through mixed cannabinoid receptor agonism. We evaluated AEA as topical treatment for CLE and assessed benefits of nanoparticle encapsulation (AEA-NP) on cutaneous drug penetration, delivery and biological activity. Compared to untreated controls, AEA-NP decreased IL-6 and MCP-1 in UVB-stimulated keratinocytes (p < 0.05) in vitro. In BALB/c mice, AEA-NP displayed improved cutaneous penetration, extended release and persistence of AEA in the follicular unit extending to the base after 24 h. Utilizing the MRL-lpr lupus murine model, twice weekly treatment of lesions with topical AEA-NP for 10 weeks led to decreased clinical and histologic lesion scores compared to unencapsulated AEA and untreated controls (p < 0.05). Prophylactic application of AEA-NP to commonly involved areas on MRL-lpr mice similarly resulted in decreased clinical and histologic scores when compared to controls (p < 0.05), and reduced C3 and IBA-1 in lesional tissue (p < 0.05). The demonstrated clinical and immunomodulatory effects of treatment with AEA support its potential as therapy for CLE. This work also suggests that encapsulation of AEA improves penetration and treatment efficacy. Future studies will be conducted to assess full therapeutic potential.

Novel transdermal curcumin therapeutic preserves endothelial barrier function in a high-dose LPS rat model.

Sepsis is a devastating complication of infection and injury that, through widespread endothelial dysfunction, can cause perfusion deficits and multi-organ failure. To address the recognised need for therapeutics targetting the endothelial barrier, a topical formulation (CUR; VASCEPTOR™; Vascarta Inc, Summit, NJ) was developed to transdermally deliver bio-active concentrations of curcumin-an anti-inflammatory and nitric oxide promoter. Male, Sprague Dawley rats were treated daily with lipopolysaccharide (LPS, 10 mg/kg, IP) to induce endotoxemia, and topical applications of Vehicle Control (LPS + VC; N = 7) or Curcumin (LPS + CUR; N = 7). A third group received neither LPS nor treatment (No-LPS; N = 8). After 72 h, animals were surgically prepared for measurements of physiology and endothelial dysfunction in the exteriorised spinotrapezius muscle through the extravasation of 67 kDa TRITC-BSA (albumin) and 500 kDa FITC-dextran (dextran). At 72 h, LPS + VC saw weight loss, and increases to pulse pressure, lactate, pCO2, CXCL5 (vs No-LPS) and IL-6 (vs 0 h; p < 0.05). LPS + CUR was similar to No-LPS, but with hypotension. Phenylephrine response was increased in LPS + CUR. Regarding endothelial function, LPS + CUR albumin and dextran extravasation were significantly reduced versus LPS + VC suggesting that Curcumin mitigated endotoxemic endothelial dysfunction. The speculated mechanisms are nitric oxide modulation of the endothelium and/or an indirect anti-inflammatory effect.

Nitric oxide releasing nanoparticles reduce inflammation in a small animal model of ARDS.

Acute respiratory distress syndrome (ARDS) is a condition hallmarked by high permeability pulmonary edema and hypoxemic respiratory failure and is associated with high mortality. Current treatment protocols rely on improving O2 delivery, decreasing O2 consumption, and treating the underlying cause of the initial insult. In this study, we used a small rodent model of ARDS, where we induced lung injury with inhalation of lipopolysaccharide (LPS). We investigated three different treatments, namely inhaled NO at 70 ppm, inhaled NO at 140 ppm, and NO-np (10 mg/mL), compared with untreated rodents 72 h after initial insult. Concurrent with treatment, the fraction of inspired O2 was increased after 30 min from 21% to 40% and finally to 60%. At an FiO2 of 60% and 72 h post induction of ARDS, NO-np treated mice had an arterial PO2 (PaO2) of 142 ± 9 mmHg, higher than mice treated with inhaled NO at 70 ppm (87 ± 5 mmHg, p = 8.4 × 10-8) and inhaled NO at 140 ppm (107 ± 6 mmHg, p = 6.1 × 10-6). Neutrophils in both the periphery (1.6 × 105 ± 0.4 × 105 cells) and bronchoalveolar lavage fluid (BALF; 2.7 × 105 ± 0.8 × 105 cells) were reduced in NO-np treated mice compared to mice treated with inhaled NO at 70 ppm (p = 0.0097, 2.4 × 105 ± 0.5 × 105 cells for periphery, p = 0.0075, 3.8 × 105 ± 0.8 × 105 cells for BALF). In summary, we found that treatment with NO-np improved arterial PO2 at a high FiO2 compared to inhaled NO alone and NO-np reduced both circulating and pulmonary interstitial neutrophil count, while inhaled NO did not. Future studies should aim to elucidate the precise mechanisms behind how NO-np mediate neutrophilic inflammation in ARDS.

Topically delivered nitric oxide acts synergistically with an orally administered PDE5 inhibitor in eliciting an erectile response in a rat model of radical prostatectomy.

Patients undergoing radical prostatectomy (RP) have a high incidence of postoperative erectile dysfunction (ED) refractory to treatment by oral phosphodiesterase-5 inhibitors (PDE5i). In the present studies, we investigated if a topically applied, nitric oxide microparticle delivery system (NO-MP) might act synergistically with an oral PDE5i (sildenafil) to improve erectile function outcomes in a rat model of RP. Thirty-five Sprague-Dawley rats underwent bilateral transection of the cavernous nerve (CN) for 1 week. After 1 week, animals were orally administered 0, 0.05, or 0.005 mg sildenafil/kg and the erectile response following topical application to the penile shaft of 250 or 100 mg NO-MP, or blank-MP, was monitored over a 2-h timeframe by recording the intracorporal pressure normalized to systemic blood pressure (ICP/BP, N = 5 animals/treatment group). Oral treatment with sildenafil by itself resulted in no observable erectile response. However, a combination of orally administered 0.05 sildenafil/kg with topical application of 250 mg NO-MP, compared to 250 mg NO-MP by itself, resulted in significantly more spontaneous erections (4.6 compared to 2 erections per hour, t-test; p value = 0.043), with a significantly faster onset for the first erectile response (11 compared to 22 min; t-test, p value = 0.041). Our results demonstrate a synergistic effect between orally administered PDE5i and topically applied NO-MP in eliciting an erectile response. Furthermore, they suggest a potential novel therapeutic approach to treat men with ED resulting from RP, through combination therapy of a topically applied NO-MP and an orally administered PDE5i.

Nitric Oxide-Releasing Nanoparticles Are Similar to Efinaconazole in Their Capacity to Eradicate Trichophyton rubrum Biofilms.

Filamentous fungi such as Trichophyton rubrum and T. mentagrophytes, the main causative agents of onychomycosis, have been recognized as biofilm-forming microorganisms. Nitric oxide-releasing nanoparticles (NO-np) are currently in development for the management of superficial and deep bacterial and fungal infections, with documented activity against biofilms. In this context, this work aimed to evaluate, for the first time, the in vitro anti-T. rubrum biofilm potential of NO-np using standard ATCC MYA-4438 and clinical BR1A strains and compare it to commonly used antifungal drugs including fluconazole, terbinafine and efinaconazole. The biofilms formed by the standard strain produced more biomass than those from the clinical strain. NO-np, fluconazole, terbinafine, and efinaconazole inhibited the in vitro growth of planktonic T. rubrum cells. Similarly, NO-np reduced the metabolic activities of clinical strain BR1A preformed biofilms at the highest concentration tested (SMIC50 = 40 mg/mL). Scanning electron and confocal microscopy revealed that NO-np and efinaconazole severely damaged established biofilms for both strains, resulting in collapse of hyphal cell walls and reduced the density, extracellular matrix and thickness of the biofilms. These findings suggest that biofilms should be considered when developing and testing new drugs for the treatment of dermatophytosis. Development of a biofilm phenotype by these fungi may explain the resistance of dermatophytes to some antifungals and why prolonged treatment is usually required for onychomycosis.

Fidgetin-like 2 negatively regulates axonal growth and can be targeted to promote functional nerve regeneration.

The microtubule (MT) cytoskeleton plays a critical role in axon growth and guidance. Here, we identify the MT-severing enzyme fidgetin-like 2 (FL2) as a negative regulator of axon regeneration and a therapeutic target for promoting nerve regeneration after injury. Genetic knockout of FL2 in cultured adult dorsal root ganglion neurons resulted in longer axons and attenuated growth cone retraction in response to inhibitory molecules. Given the axonal growth-promoting effects of FL2 depletion in vitro, we tested whether FL2 could be targeted to promote regeneration in a rodent model of cavernous nerve (CN) injury. The CNs are parasympathetic nerves that regulate blood flow to the penis, which are commonly damaged during radical prostatectomy (RP), resulting in erectile dysfunction (ED). Application of FL2-siRNA after CN injury significantly enhanced functional nerve recovery. Remarkably, following bilateral nerve transection, visible and functional nerve regeneration was observed in 7 out of 8 animals treated with FL2-siRNA, while no control-treated animals exhibited regeneration. These studies identify FL2 as a promising therapeutic target for enhancing regeneration after peripheral nerve injury and for mitigating neurogenic ED after RP - a condition for which, at present, only poor treatment options exist.

Inhomogeneous Kondo-lattice in geometrically frustrated Pr2Ir2O7.

Magnetic fluctuations induced by geometric frustration of local Ir-spins disturb the formation of long-range magnetic order in the family of pyrochlore iridates. As a consequence, Pr2Ir2O7 lies at a tuning-free antiferromagnetic-to-paramagnetic quantum critical point and exhibits an array of complex phenomena including the Kondo effect, biquadratic band structure, and metallic spin liquid. Using spectroscopic imaging with the scanning tunneling microscope, complemented with machine learning, density functional theory and theoretical modeling, we probe the local electronic states in Pr2Ir2O7 and find an electronic phase separation. Nanoscale regions with a well-defined Kondo resonance are interweaved with a non-magnetic metallic phase with Kondo-destruction. These spatial nanoscale patterns display a fractal geometry with power-law behavior extended over two decades, consistent with being in proximity to a critical point. Our discovery reveals a nanoscale tuning route, viz. using a spatial variation of the electronic potential as a means of adjusting the balance between Kondo entanglement and geometric frustration.

Curcumin nanoparticles as a photoprotective adjuvant.

With rising skin cancer rates and interest in preventing photoaging, adjuvants for sunscreens are in high demand. The potential of curcumin has been posited due to its anti-inflammatory, antioxidant and wound healing properties. In prior studies, curcumin decreased UV-induced inflammation, apoptotic changes in human keratinocytes and dermal fibroblasts, and the expression of matrix metalloproteinases. However, curcumin's utility has been hindered by poor aqueous solubility and rapid degradation in vivo. To overcome these limitations, we synthesized curcumin nanoparticles (curc-np), which offer sustained topical delivery and enhanced bioavailability. Curc-np and controls were applied to the skin of BALB/c mice prior to UVB irradiation. Twenty-four hours later, mice pretreated with curc-np showed less erythema, induration and scale compared to controls. Histopathology showed fewer sunburn cells, and TUNEL assay indicated decreased apoptosis in curc-np treated mice. Immunohistochemistry illustrated less p53 expression in skin pretreated with curc-np. Furthermore, cytokine analysis revealed significantly less IL-6 and significantly greater anti-inflammatory IL-10 in skin of curc-np-treated mice as compared to controls. Taken together, our results reinforce curcumin's established anti-inflammatory effects in the skin and highlight its potential as a photoprotective adjuvant when delivered through nanoparticles. Further investigation alongside sunscreens against UV-induced damage is warranted.

A Novel Therapeutic Approach to Corneal Alkaline Burn Model by Targeting Fidgetin-Like 2, a Microtubule Regulator.

Purpose: The purpose of this study was to determine the efficacy of nanoparticle-encapsulated Fidgetin-like 2 (FL2) siRNA (FL2-NPsi), a novel therapeutic agent targeting the FL2 gene, for the treatment of corneal alkaline chemical injury. Methods: Eighty 12-week-old, male Sprague-Dawley rats were divided evenly into 8 treatment groups: prednisolone, empty nanoparticles, control-NPsi (1 µM, 10 µM, and 20 µM) and FL2-NPsi (1 µM, 10 µM, and 20 µM). An alkaline burn was induced onto the cornea of each rat, which was then treated for 14 days according to group assignment. Clinical, histopathologic, and immunohistochemical analyses were conducted to assess for wound healing. FL2-NPsi-mediated knockdown of FL2 was confirmed by in vitro quantitative polymerase chain reaction (qPCR). Toxicity assays were performed to assess for apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling [TUNEL] assay) and nerve damage (whole mount immunochemical staining). Statistical analyses were performed using Student's t-test and ANOVA. Results: Compared with controls, FL2-NPsi-treated groups demonstrated enhanced corneal wound healing, with the 10 and 20 µM FL2-NPsi-treated groups demonstrating maximum rates of corneal re-epithelialization as assessed by ImageJ software, enhanced corneal transparency, and improved stromal organization on histology. Immunohistochemical analysis of vascular endothelial cells, macrophages, and neutrophils did not show significant differences between treatment groups. FL2-NPsi was not found to be toxic to nerves or induce apoptosis (p = 0.917). Conclusions: Dose-response studies found both 10 and 20 µM FL2-NPsi to be efficacious in this rat model. FL2-NPsi may offer a novel treatment for corneal alkaline chemical injuries. Translational Relevance: Basic cell biology findings about the microtubule cytoskeleton were used to design a therapeutic to enhance corneal cell migration, highlighting the promise of targeting microtubules to regulate corneal wound healing.

Control of systemic inflammation through early nitric oxide supplementation with nitric oxide releasing nanoparticles.

Amelioration of immune overactivity during sepsis is key to restoring hemodynamics, microvascular blood flow, and tissue oxygenation, and in preventing multi-organ dysfunction syndrome. The systemic inflammatory response syndrome that results from sepsis ultimately leads to degradation of the endothelial glycocalyx and subsequently increased vascular leakage. Current fluid resuscitation techniques only transiently improve outcomes in sepsis, and can cause edema. Nitric oxide (NO) treatment for sepsis has shown promise in the past, but implementation is difficult due to the challenges associated with delivery and the transient nature of NO. To address this, we tested the anti-inflammatory efficacy of sustained delivery of exogenous NO using i.v. infused NO releasing nanoparticles (NO-np). The impact of NO-np on microhemodynamics and immune response in a lipopolysaccharide (LPS) induced endotoxemia mouse model was evaluated. NO-np treatment significantly attenuated the pro-inflammatory response by promoting M2 macrophage repolarization, which reduced the presence of pro-inflammatory cytokines in the serum and slowed vascular extravasation. Combined, this resulted in significantly improved microvascular blood flow and 72-h survival of animals treated with NO-np. The results from this study suggest that sustained supplementation of endogenous NO ameliorates and may prevent the morbidities of acute systemic inflammatory conditions. Given that endothelial dysfunction is a common denominator in many acute inflammatory conditions, it is likely that NO enhancement strategies may be useful for the treatment of sepsis and other acute inflammatory insults that trigger severe systemic pro-inflammatory responses and often result in a cytokine storm, as seen in COVID-19.

Harnessing nitric oxide for preventing, limiting and treating the severe pulmonary consequences of COVID-19.

The ongoing outbreak of COVID-19 has quickly become a daunting challenge to global health. In the absence of targeted therapy and a reported 5.5% case fatality rate in the United States, treatments preventing rapid cardiopulmonary failure are urgently needed. Clinical features, pathology and homology to better understood pathogens suggest that uncontrolled inflammation and a cytokine storm likely drive COVID-19's unrelenting disease process. Interventions that are protective against acute lung injury and ARDS can play a critical role for patients and health systems during this pandemic. Nitric oxide is an antimicrobial and anti-inflammatory molecule with key roles in pulmonary vascular function in the context of viral infections and other pulmonary disease states. This article reviews the rationale for exogenous nitric oxide use for the pathogenesis of COVID-19 and highlights its potential for contributing to better clinical outcomes and alleviating the rapidly rising strain on healthcare capacity.

NO Candida auris: Nitric Oxide in Nanotherapeutics to Combat Emerging Fungal Pathogen Candida auris.

Candida auris (C. auris) is an emerging pathogenic fungal species that is especially worrisome due to its high mortality rates and widespread antifungal resistance. Previous studies have demonstrated the efficacy of nitric oxide (NO) nanoparticles on Candida species, and, to our knowledge, this is the first study to investigate the antifungal effects of a NO-generating nanoparticle on C. auris. Six C. auris strains were incubated with a nanoparticle (NAC-SNO-np), which releases N-acetylcysteine S-nitrosothiol (NAC-SNO) and N-acetylcysteine (NAC), and generates NO, through colony forming unit (CFU) assays, and confocal laser scanning microscopy. NAC-SNO-np effectively eradicates planktonic and biofilm C. auris. Across all six strains, 10 mg/mL NAC-SNO-np significantly reduced the number of CFUs (p < 0.05) and demonstrated a >70% decrease in biofilm viability (p < 0.05). NAC-SNO-np effectively eradicates planktonic C. auris and significantly reduces C. auris biofilm formation. Hence, this novel NO-releasing nanoparticle shows promise as a future therapeutic.

NO-Releasing Nanoparticles Ameliorate Detrusor Overactivity in Transgenic Sickle Cell Mice via Restored NO/ROCK Signaling.

Sickle cell disease (SCD) is associated with overactive bladder (OAB). Detrusor overactivity, a component of OAB, is present in an SCD mouse, but the molecular mechanisms for this condition are not well-defined. We hypothesize that nitric oxide (NO)/ ras homolog gene family (Rho) A/Rho-associated kinase (ROCK) dysregulation is a mechanism for detrusor overactivity and that NO-releasing nanoparticles (NO-nps), a novel NO delivery system, may serve to treat this condition. Male adult SCD transgenic, combined endothelial NO synthases (eNOSs) and neuronal NOS (nNOS) gene-deficient (dNOS-/-), and wild-type (WT) mice were used. Empty nanoparticle or NO-np was injected into the bladder, followed by cystometric studies. The expression levels of phosphorylated eNOS (Ser-1177), protein kinase B (Akt) (Ser-473), nNOS (Ser-1412), and myosin phosphatase target subunit 1 (MYPT1) (Thr-696) were assessed in the bladder. SCD and dNOS-/- mice had a greater (P < 0.05) number of voiding and nonvoiding contractions compared with WT mice, and they were normalized by NO-np treatment. eNOS (Ser-1177) and AKT (Ser-473) phosphorylation were decreased (P < 0.05) in the bladder of SCD compared with WT mice and reversed by NO-np. Phosphorylated MYPT1, a marker of the RhoA/ROCK pathway, was increased (P < 0.05) in the bladder of SCD mice compared with WT and reversed by NO-np. nNOS phosphorylation on positive (Ser-1412) regulatory site was decreased (P < 0.05) in the bladder of SCD mice compared with WT and was not affected by NO-np. NO-nps did not affect any of the measured parameters in WT mice. In conclusion, dysregulation of NO and RhoA/ROCK pathways is associated with detrusor overactivity in SCD mice; NO-np reverses these molecular derangements in the bladder and decreases detrusor overactivity. SIGNIFICANCE STATEMENT: Voiding abnormalities commonly affect patients with sickle cell disease (SCD) but are problematic to treat. Clarification of the science for this condition in an animal model of SCD may lead to improved interventions for it. Our findings suggest that novel topical delivery of a vasorelaxant agent nitric oxide into the bladder of these mice corrects overactive bladder by improving deranged bladder physiology regulatory signaling.

Novel nitric oxide-generating platform using manuka honey as an anti-biofilm strategy in chronic rhinosinusitis.

BACKGROUND: Bacterial biofilms are implicated in the pathogenesis of chronic rhinosinusitis. Nitric oxide (NO) is a key immune effector with potent antimicrobial effects, but a short half-life limits achievement of therapeutic concentrations. We hypothesized that manuka honey (MH) could induce sustained reduction of nitrite to NO causing biofilm disruption and that this effect would be enhanced with the addition of a NO-releasing microparticle. METHODS: Porous organosilica microparticles containing nitrosylated thiol groups were formulated (SNO-MP). MH was combined with serial dilutions of nitrite. NO release was evaluated using a NO analyzer. The susceptibility of 2 strains of Pseudomonas aeruginosa biofilms to these NO-releasing platforms was evaluated using confocal microscopy. Cell viability and biofilm volume were quantified. Statistical analysis was performed using the Mann-Whitney U test with SPSS software. RESULTS: MH with nitrite generated a linear increase in NO formation. SNO-MP induced a bolus release of NO within 5 minutes, followed by a sustained plateau phase. MH with nitrite combined with SNO-MP enhanced NO release during the plateau phase. MH with nitrite reduced biofilm live cells and volume by 88.5% to 96.9% and 95.1% to 95.6%, respectively, vs control (p < 0.0001). SNO-MP reduced live cells and volume by 61.0% to 98.5% and 74.7% to 85.7%, respectively, vs control (p < 0.0001). MH with nitrite combined with SNO-MP nearly eradicated biofilm, with a 98.3% to 99.8% (log 1.8-2.6) reduction in viability and a 91.4% to 97.7% decrease in volume (p < 0.0001 vs control). CONCLUSION: A novel platform that generates NO using MH and nitrite produces a potent anti-biofilm effect, which can be further enhanced with the addition of SNO-MP.

Anti-biofilm activity of garlic extract loaded nanoparticles.

The emergence and widespread distribution of multi-drug resistant bacteria are considered as a major public health concern. The inabilities to curb severe infections due to antibiotic resistance have increased healthcare costs as well as patient morbidity and mortality. Bacterial biofilms formed by drug-resistant bacteria add additional challenges to treatment. This study describes a solgel based nanoparticle system loaded with garlic extract (GE-np) that exhibits: i) slow and sustained release of garlic components; ii) stabilization of the active components; and iii) significant enhancement of antimicrobial and antibiofilm activity relative to the free garlic extract. Also, GE-np were efficient in penetrating and disrupting the well-established methicillin-resistant Staphylococcus aureus (MRSA) biofilms. Overall, the study suggests that GE-np might be a promising candidate for the treatment of chronic infections due to biofilm forming drug-resistant bacteria.

Visualizing Uniaxial-strain Manipulation of Antiferromagnetic Domains in Fe1+ Y Te Using a Spin-polarized Scanning Tunneling Microscope.

The quest to understand correlated electronic systems has pushed the frontiers of experimental measurements toward the development of new experimental techniques and methodologies. Here we use a novel home-built uniaxial-strain device integrated into our variable temperature scanning tunneling microscope that enables us to controllably manipulate in-plane uniaxial strain in samples and probe their electronic response at the atomic scale. Using scanning tunneling microscopy (STM) with spin-polarization techniques, we visualize antiferromagnetic (AFM) domains and their atomic structure in Fe1+yTe samples, the parent compound of iron-based superconductors, and demonstrate how these domains respond to applied uniaxial strain. We observe the bidirectional AFM domains in the unstrained sample, with an average domain size of ~50-150 nm, to transition into a single unidirectional domain under applied uniaxial strain. The findings presented here open a new direction to utilize a valuable tuning parameter in STM, as well as other spectroscopic techniques, both for tuning the electronic properties as for inducing symmetry breaking in quantum material systems.

Reducing Ischemia/Reperfusion Injury by the Targeted Delivery of Nitric Oxide from Magnetic-Field-Induced Localization of S-Nitrosothiol-Coated Paramagnetic Nanoparticles.

Nitric oxide (NO) is an important factor during an ischemia/reperfusion (I/R) injury. Protective actions of NO during I/R are attributed to antioxidant and anti-inflammatory effects, as well as cell-signaling-based inhibition of nuclear proteins. The therapeutic potential of supplemented NO during I/R is nonetheless uncertain, since peroxynitrite formed from NO near superoxide can be potentially harmful due to NF-κB up-regulation and direct cytotoxicity. This study investigates new technology to provide the magnet-assisted delivery of therapeutic levels of localized NO to targeted I/R tissues using biocompatible gadolinium-oxide-based paramagnetic nanoparticles coated with S-nitrosothiols (SNO-PMNPs). Hamsters fitted with a window chamber were subjected to ischemia by application of a tourniquet at the periphery of the window chamber for 1 h. The SNO-PMNPs were intravenously infused (10 mg/kg) during the reperfusion phase, during which time a localized external magnetic field was either applied or not applied to the I/R area. The microvascular hemodynamics, functional capillary density (FCD), rolling and adherent leukocytes, reactive oxygen and nitrogen species, and tissue viability were assessed using intravital microscopy. Control animals did not receive SNO-PMNPs. Treatment with SNO-PMNPs plus a magnet but not without a magnet increased reflow, decreased leukocytes rolling and sticking in postcapillary venules, limited cell death, and restored the FCD. The absence of the magnet resulted in systemic changes in heart rate and mean arterial blood pressure, consistent with the systemic delivery of NO by the SNO-PMNP. These results indicate that the localized delivery of NO during reperfusion counters the deleterious consequences of peroxynitrite and other reactive species generated upon reperfusion as reflected in localized increases in blood flow and tissue viability, all with minimal systemic effects. This technology can provide the basis for a timely treatment of a localized ischemia-associated disease to prevent injury in different tissues and organs.