Reactive oxygen/nitrogen species scavenging and inflammatory regulation by renal-targeted bio-inspired rhodium nanozymes for acute kidney injury theranostics.

Acute kidney injury (AKI) results from the rapid deterioration of renal function, which is mainly treated by transplantation and dialysis, and has a high mortality rate. Inflammation induced by excess reactive oxygen/nitrogen species (RONS) plays a crucial role in AKI. Although small molecule antioxidants have been utilized to alleviate AKI, low bioavailability and side-effect of these drugs tremendously limit their clinical use. Hence, we successfully construct ultra-small (2-4 nm) rhodium nanoparticles modified with l-serine (denoted as Rh-Ser). Our results show that Rh-Ser with multiple enzyme-mimicking activities, allows remove various RONS to protect damaged kidney cells. Additionally, the ultrasmall size of Rh-Ser is conducive to enrichment in the renal tubules, and the modification of l-serine enables Rh-Ser to bind to kidney injury molecule-1, which is highly expressed on the surface of damaged renal cells, thereby targeting the damaged kidney and increasing the retention time. Moreover, Rh-Ser allows the production of oxygen at the inflammatory site, thus further improving hypoxia and inhibiting pro-inflammatory macrophages to relieve inflammation, and increasing the survival rate of AKI mice from 0 to 80%, which exhibits a better therapeutic effect than that of small molecule drug. Photoacoustic and fluorescence imaging can effectively monitor and evaluate the enrichment and therapeutic effect of Rh-Ser. Our study provides a promising strategy for the targeted treatment of AKI via RONS scavenging and inflammatory regulation.

Alendronate-Modified Nanoceria with Multiantioxidant Enzyme-Mimetic Activity for Reactive Oxygen Species/Reactive Nitrogen Species Scavenging from Cigarette Smoke.

Highly toxic radicals including reactive oxygen species (ROS) and reactive nitrogen species (RNS) in cigarette smoke play an important role in oxidative damage of the lungs, which cannot be efficiently scavenged by current filter techniques. Herein, a novel alendronate-coated nanoceria (CeAL) nanozyme is explored for cigarette filter modification for ROS/RNS scavenging. The CeAL nanozyme with an adjustable oxidation state and high thermal stability exhibits an excellent superoxide dismutase (SOD)-like activity, hydroxyl radical elimination capacity, catalase-mimicking activity, and nitric oxide radical scavenging ability. These synergistic antioxidant abilities make the CeAL nanozyme a lucrative additive for cigarette filters. The filter incorporated with the CeAL nanozyme can efficiently scavenge ROS/RNS in the hot smoke generated by burned commercial cigarettes, resulting in reduction of oxidative stress-induced pulmonary injury and acute inflammation of mice. The developed CeAL nanozyme opens up new opportunities for cigarette filter modification to decrease the toxicity of cigarette smoke and expands the application fields of nanoceria.

Environmental impacts of nitrogen emissions in China and the role of policies in emission reduction.

Atmospheric reactive nitrogen (Nr) has been a cause of serious environmental pollution in China. Historically, China used too little Nr in its agriculture to feed its population. However, with the rapid increase in N fertilizer use for food production and fossil fuel consumption for energy supply over the last four decades, increasing gaseous Nr species (e.g. NH3 and NOx) have been emitted to the atmosphere and then deposited as wet and dry deposition, with adverse impacts on air, water and soil quality as well as plant biodiversity and human health. This paper reviews the issues associated with this in a holistic way. The emissions, deposition, impacts, actions and regulations for the mitigation of atmospheric Nr are discussed systematically. Both NH3 and NOx make major contributions to environmental pollution but especially to the formation of secondary fine particulate matter (PM2.5), which impacts human health and light scattering (haze). In addition, atmospheric deposition of NH3 and NOx causes adverse impacts on terrestrial and aquatic ecosystems due to acidification and eutrophication. Regulations and practices introduced by China that meet the urgent need to reduce Nr emissions are explained and resulting effects on emissions are discussed. Recommendations for improving future N management for achieving 'win-win' outcomes for Chinese agricultural production and food supply, and human and environmental health, are described. This article is part of a discussion meeting issue 'Air quality, past present and future'.

Intracellular-molecular changes in plasma-irradiated budding yeast cells studied using multiplex coherent anti-Stokes Raman scattering microscopy.

Interactions between non-equilibrium atmospheric-pressure plasma (NEAPP) and living cells were examined using multiplex coherent anti-Stokes Raman scattering (CARS) microscopy. Our multiplex CARS analyses revealed that NEAPP irradiation generates short-lived radicals that induce a decrease in the mitochondrial activity of budding yeast cells.

Reactive oxygen and nitrogen species: impact on endothelial dysfunction.

BACKGROUND: Reactive oxygen and nitrogen species, known as free radicals, play a key role in the etiology and progression of atherosclerotic cardiovascular disease by creating vascular oxidative stress. PURPOSE: This review will discuss current biological research about the enzymatic and nonenzymatic sources of oxidative stress, free radical chemistry, and how it pertains to endothelial dysfunction-a hallmark of cardiovascular disease. METHODS: An integrative review of the literature was conducted. FINDINGS: Free radicals lower the bioavailability of the potent vasodilator nitric oxide and therefore, through numerous chemical reactions, negatively affect vascular biology and endothelial function. Endothelial dysfunction is considered to be integral in the initiation of atherosclerosis. CONCLUSIONS: The success and failures of current therapies to reduce oxidative stress are discussed in terms of implications for nursing research on exogenous antioxidants, pharmacotherapy, and lifestyle change.

Impact of oxidative/nitrosative stress and inflammation on cognitive functions in patients with recurrent depressive disorders.

Data show that up to 38.2% of the European population have a mental disorder and that recurrent depressive disorder (rDD) is among the most commonly diagnosed disabling diseases. Over the last few years, neurocognitive impairments in rDD have become a new research front focusing on the role of cognitive decline during the course of rDD and in relation to its clinical presentation and prognosis. Both immune-inflammatory and oxidative and nitrosative stress (O&NS) processes potentially play a role in development of cognitive dysfunction in rDD. New evidence shows that chronic inflammatory and O&NS reactions occur in the brains of patients with neurodegenerative disorders and those with rDD. This narrative review presents the current state of knowledge on the possible impact of selected inflammatory and O&NS enzymes on cognitive functioning in patients with rDD. We focus on manganese superoxide dismutase (MnSOD), inducible nitric oxide synthase (iNOS), and myeloperoxidase (MPO).

Radiation-modifying abilities of Nigella sativa and thymoquinone on radiation-induced nitrosative stress in the brain tissue.

To investigate Nigella sativa oil (NSO) and Thymoquinone (TQ) for their antioxidant effects on the brain tissue of rats exposed to ionizing radiation. Fifty-four male albino Wistar rats, divided into six groups, were designed as group I (normal control group) did not receive NSO, TQ or irradiation; group II (control group of TQ) received dimethyl sulfoxide and sham irradiation; group III (control group of NSO) received saline and sham irradiation; group IV (irradiation plus NSO group) received both 5 Gray of gamma irradiation to total cranium and NSO; group V (irradiation plus TQ group) received both irradiation and TQ; group VI (irradiation alone group) received irradiation plus saline. Alterations in nitric oxide (NO·) and peroxynitrite (ONOO(-)) levels, and nitric oxide synthase (NOS) enzyme activity were measured by biochemical methods in homogenized brain tissue of rats. Levels of NO· and ONOO(-), and enzyme activity of NOS in brain tissue of the rats treated with NSO or TQ were found to be lower than in received IR alone (p<0.002) Nigella sativa oil (NSO) and its active component, TQ, clearly protect brain tissue from radiation-induced nitrosative stress.

Voltammetric investigation of DNA damage induced by nitrofurazone and short-lived nitro-radicals with the use of an electrochemical DNA biosensor.

Electrochemical behavior of nitrofurazone (NFZ) was investigated with the use of cyclic voltammetry (CV) and differential pulse voltammetry (DPV) methods. The pH-dependence of NFZ was studied at a glassy carbon electrode (GCE) in ethanol/Britton-Robinson buffer (30:70), and short-lived nitro-radicals were generated by the reduction of NFZ at high pHs (>7.0). In the presence of DNA, the DPV peak current of NFZ decreased and the peak potential shifted negatively, which indicated that there was an electrostatic interaction between NFZ and DNA. An electrochemical dsDNA/GCE biosensor was prepared to study the DNA damage produced in the presence NFZ; this process was followed with the use of the Co(phen)(3)(2+) electroactive probe. Also, the oxidation peaks of guanosine (750 mV) and adenosine (980 mV) indicated that DNA damage was related directly to the nitro-radicals. Experiments demonstrated that DNA damage occurred via two different steps while NFZ was metabolized and nitro-radicals were produced. Novel work with AFM on the NFZ/DNA interaction supported the suggestion that in vivo, the nitro-radicals were more cytotoxic than the NFZ molecules. A linear DPV calibration plot was obtained for NFZ analysis at a modified dsDNA/GCE (concentration range: 2.50 × 10(-6)-3.75 × 10(-5) mol L(-1); limit of detection: 8.0 × 10(-7) mol L(-1)), and NFZ was determined successfully in pharmaceutical samples.

Angiotensin II plays a critical role in diabetic pulmonary fibrosis most likely via activation of NADPH oxidase-mediated nitrosative damage.

Diabetic patients have a high risk of pulmonary disorders that are usually associated with restrictive impairment of lung function, suggesting a fibrotic process (van den Borst B, Gosker HR, Zeegers MP, Schols AM. Chest 138: 393-406, 2010; Ehrlich SF, Quesenberry CP Jr, Van Den Eeden SK, Shan J, Ferrara A. Diabetes Care 33: 55-60, 2010). The present study was undertaken to define whether and how diabetes causes lung fibrosis. Lung samples from streptozotocin-induced type 1 diabetic mice, spontaneously developed type 1 diabetic OVE26 mice, and their age-matched controls were investigated with histopathological and biochemical analysis. Signaling mechanism was investigated with cultured normal human lung fibroblasts in vitro. In both diabetes models, histological examination with Sirius red and hemotoxylin and eosin stains showed fibrosis along with massive inflammatory cell infiltration. The fibrotic and inflammatory processes were confirmed by real-time PCR and Western blotting assays for the increased fibronectin, CTGF, PAI-1, and TNFα mRNA and protein expressions. Diabetes also significantly increased NADPH oxidase (NOX) expression and protein nitration along with upregulation of angiotensin II (Ang II) and its receptor expression. In cell culture, exposure of lung fibroblasts to Ang II increased CTGF expression in a dose- and time-dependent manner, which could be abolished by inhibition of superoxide, NO, and peroxynitrite accumulation. Furthermore, chronic infusion of Ang II to normal mice at a subpressor dose induced diabetes-like lung fibrosis, and Ang II receptor AT1 blocker (losartan) abolished the lung fibrotic and inflammatory responses in diabetic mice. These results suggest that Ang II plays a critical role in diabetic lung fibrosis, which is most likely caused by NOX activation-mediated nitrosative damage.

Reactive species and DNA damage in chronic inflammation: reconciling chemical mechanisms and biological fates.

Chronic inflammation has long been recognized as a risk factor for many human cancers. One mechanistic link between inflammation and cancer involves the generation of nitric oxide, superoxide and other reactive oxygen and nitrogen species by macrophages and neutrophils that infiltrate sites of inflammation. Although pathologically high levels of these reactive species cause damage to biological molecules, including DNA, nitric oxide at lower levels plays important physiological roles in cell signaling and apoptosis. This raises the question of inflammation-induced imbalances in physiological and pathological pathways mediated by chemical mediators of inflammation. At pathological levels, the damage sustained by nucleic acids represents the full spectrum of chemistries and likely plays an important role in carcinogenesis. This suggests that DNA damage products could serve as biomarkers of inflammation and oxidative stress in clinically accessible compartments such as blood and urine. However, recent studies of the biotransformation of DNA damage products before excretion point to a weakness in our understanding of the biological fates of the DNA lesions and thus to a limitation in the use of DNA lesions as biomarkers. This review will address these and other issues surrounding inflammation-mediated DNA damage on the road to cancer.

Bystander effect of vinorelbine alters antitumor immune response.

The bystander effect (BE) is the ability of malignant cells affected by an anticancer agent to induce damage in neighboring cancer cells. In this study, we showed that it could also affect immune cells surrounding the tumor and interfere with the antitumor immune response. We observed that the exposure of human lung cancer cells A549 to vinorelbine induced a BE on neighboring human peripheral blood mononuclear cells (PBMCs) in vitro and on mice splenocytes in vivo. In vitro, the number of PBMCs killed because of their coculture with vinorelbine-pretreated A549 cells was 33% higher than those killed by A549 control cells (p = 0.003). In addition, we showed that when vinorelbine-pretreated A549 cells were injected into immunocompetent mice, splenocyte proliferation ex vivo toward tumor cells decreased by 27% compared with that seen in mice injected with untreated A549 cells (p = 0.03). Finally, in vivo experiment in A549 tumor bearing nude mice showed that adoptive transfer of A549 immune splenocytes was not able to delay tumor growth when vinorelbine-pretreated A549 cells were used for immunization. Inhibition of the BE by the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester, and the superoxide dismutase mimic, mangafodipir, suggested that it was mediated by oxidative and nitrosative stress. In conclusion, exposure of cancer cells to vinorelbine alters the antitumor immune response through a BE mediated by cellular oxidative and nitrosative stress. Our results offer new prospects for using oxidative stress modulators to restore the antitumor immune response in patients treated with anticancer agents.

Reduced UVB-induced corneal damage caused by reactive oxygen and nitrogen species and decreased changes in corneal optics after trehalose treatment.

Trehalose, a nonreducing disaccharide of glucose, produced and stored in many lower and higher organisms, although not in mammals, is synthetized as a stress responsive factor when cells are exposed to various environmental stress conditions. Recently, trehalose has been implicated in various situations in mammals. The aim of this paper was to examine whether trehalose might decrease the damage of the rabbit cornea evoked by UVB rays. During irradiation with UVB rays, consisiting of a daily dose of 0.5 J/cm2 for four days, trehalose was applied in eye drops on the right eye and buffered saline on the left eye. One day after the end of irradiation the animals were sacrificed and the corneas examined spectrophotometrically for light absorption. Another group of corneas similarly treated were examined morphologically and immunohistochemically. Corneal thickness (hydration) was measured using a Pachymeter. The results show that compared to buffered saline, trehalose treated corneas displayed fewer corneal disturbances during UVB irradiation. The increases in corneal hydration and light absorption were less pronounced and intracorneal inflammation and corneal neovascularization were suppressed. Nitric oxide synthases that generate nitric oxide were less expressed in the cornea, and formation of cytotoxic peroxynitrite (demonstrated by nitrotyrosine residues) was decreased. The expression of the antioxidant aldehyde dehydrogenase3A1 was less inhibited in the corneal epithelium, and apoptotic corneal epithelial cell death (detected by immunostaining for active caspase-3) was greatly diminished. In conclusion, trehalose reduced UVB-induced damage caused by reactive oxygen and nitrogen species and decreased changes in the corneal optics.

Protective effects of polyphenolics in red wine on diabetes associated oxidative/nitrative stress in streptozotocin-diabetic rats.

Increased accumulation of NT (3-nitrotyrosine) and PARylated [poly(ADP-ribosyl)ated] proteins in the tissues of diabetics are associated with diabetes complications (diabetes neuropathy, nephropathy and retinopathy). Red wine (its polyphenols are considered to be the main active components) can act as ROS (reactive oxygen species) scavengers, iron chelators and enzyme modulators. This study is novel in investigating the effect of red wine in preventing the accumulation of NT and PARylated proteins in the sciatic nerve, DRG (dorsal root ganglia), spinal cord, kidney and retina of diabetic animals. We have shown that during the experiment the body weight of control and diabetic groups of rats with consumption of red wine was significantly increased, by 52% and 19% accordingly. The significant increase in the content of NT in the sciatic nerve, DRG, spinal cord, kidney and retina, and PARylated proteins in the sciatic nerve, renal glomeruli and retinae of diabetic rats was partly or completely prevented by treatment with red wine. Red wine and its polyphenol preparations might be a promising option in the prevention and treatment of diabetic complications.

Resveratrol as a therapeutic agent for neurodegenerative diseases.

Excess production of reactive oxygen species in the brain has been implicated as a common underlying risk factor for the pathogenesis of a number of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and stroke. In recent years, there is considerable interest concerning investigation of antioxidative and anti-inflammatory effects of phenolic compounds from different botanical sources. In this review, we first describe oxidative mechanisms associated with stroke, AD, and PD, and subsequently, we place emphasis on recent studies implicating neuroprotective effects of resveratrol, a polyphenolic compound derived from grapes and red wine. These studies show that the beneficial effects of resveratrol are not only limited to its antioxidant and anti-inflammatory action but also include activation of sirtuin 1 (SIRT1) and vitagenes, which can prevent the deleterious effects triggered by oxidative stress. In fact, SIRT1 activation by resveratrol is gaining importance in the development of innovative treatment strategies for stroke and other neurodegenerative disorders. The goal here is to provide a better understanding of the mode of action of resveratrol and its possible use as a potential therapeutic agent to ameliorate stroke damage as well as other age-related neurodegenerative disorders.

Calcium in the mechanism of ammonia-induced astrocyte swelling.

Brain edema, due largely to astrocyte swelling, is an important clinical problem in patients with acute liver failure. While mechanisms underlying astrocyte swelling in this condition are not fully understood, ammonia and associated oxidative/nitrosative stress appear to be involved. Mechanisms responsible for the increase in reactive oxygen/nitrogen species (RONS) and their role in ammonia-induced astrocyte swelling, however, are poorly understood. Recent studies have demonstrated a transient increase in intracellular Ca2+ in cultured astrocytes exposed to ammonia. As Ca2+ is a known inducer of RONS, we investigated potential mechanisms by which Ca2+ may be responsible for the production of RONS and cell swelling in cultured astrocytes after treatment with ammonia. Exposure of cultured astrocytes to ammonia (5 mM) increased the formation of free radicals, including nitric oxide, and such increase was significantly diminished by treatment with the Ca2+ chelator 1,2-bis-(o-aminophenoxy)-ethane-N,N,-N',N'-tetraacetic acid tetraacetoxy-methyl ester (BAPTA). We then examined the activity of Ca2+-dependent enzymes that are known to generate RONS and found that ammonia significantly increased the activities of NADPH oxidase (NOX), constitutive nitric oxide synthase (cNOS), and phospholipase A2 (PLA2) and such increases in activity were significantly diminished by BAPTA. Pre-treatment of cultures with 7-nitroindazole, apocyanin, and quinacrine, respective inhibitors of cNOS, NOX, and PLA2, all significantly diminished RONS production. Additionally, treatment of cultures with BAPTA or with inhibitors of cNOS, NOX, and PLA2 reduced ammonia-induced astrocyte swelling. These studies suggest that the ammonia-induced rise in intracellular Ca2+ activates free radical producing enzymes that ultimately contribute to the mechanism of astrocyte swelling.

Effects of cigarette smoke borne reactive nitrogen species on salivary alpha-amylase activity and protein modifications.

Cigarette smoke (CS) is associated with a variety of human pathologies including cardiovascular disease and cancer. Oral squamous cell carcinoma (OSCC) is the most common malignancy of the head and neck. The major inducer of OSCC is exposure to tobacco. Recent studies demonstrated that oxidative and nitrosative stress contributes to the development of oral carcinogenesis through DNA damage. All salivary reactive nitrogen species (RNS) analyzed from OSCC patients are significantly higher in comparison with healthy subjects. Our findings show that CS and external RNS addition induced reduction in alpha-amylase activity and produced some excited carbonyl formation, but to a much less extant than CS. The addition of epigallocatechine-3-gallate (EGCG) to saliva produced no protective effect against damage to alpha-amylase activity. Our proposed mechanism for the decrease in alpha-amylase activity is the formation of adducts at SH groups of the alpha-amylase active site. In this case, EGCG was unable to counteract this phenomenon, as it does not reduce the concentration of disulfides, and does not alter the amount of protein-SH moieties. However, EGCG did reduce the levels of excited carbonyl formation. Our results indicate that although RNS are abundant in CS, a significant decrease in amylase activity is due to other components in CS, probably aldehydes, reacting with the thiol group of proteins by the Michael addition reaction.

Epidemic inflammation: pondering obesity.

Over the past two decades, inflammation has been recognized as a major driver in the pathogenesis of several common diseases, including atherosclerosis, diabetes, cancer, and asthma. Over the same period, there has been a steep rise in the incidence of obesity, a major risk factor for these disorders. Inflammation of adipose tissue is now recognized to accompany obesity and contribute to its sequelae. Thus, whereas obesity is primarily a disorder of energy balance, it may be helpful to consider it also as a form of epidemic inflammation that predisposes to other forms of epidemic inflammation. It is a fundamental biologic challenge to understand how a positive energy balance and inflammation are linked. This work reviews evidence that reactive oxygen and nitrogen intermediates (ROI and RNI) help drive chronic inflammation in the obese. This is proposed to be a maladaptive instance of our evolved dependence on ROI and RNI for both homeostatic signaling and host defense. ROI and RNI are well suited for these seemingly contradictory dual functions by their metabolic origin, high diffusibility in water and lipid, atomic specificity, and large number of molecular targets. When we eat so much and work so little that we repeatedly generate reactive compounds at levels normally reserved for emergencies, we treat our own cells like invading microbes.

Cigarette smoke induces an unfolded protein response in the human lung: a proteomic approach.

Cigarette smoking, which exposes the lung to high concentrations of reactive oxidant species (ROS) is the major risk factor for chronic obstructive pulmonary disease (COPD). Recent studies indicate that ROS interfere with protein folding in the endoplasmic reticulum and elicit a compensatory response termed the "unfolded protein response" (UPR). The importance of the UPR lies in its ability to alter expression of a variety of genes involved in antioxidant defense, inflammation, energy metabolism, protein synthesis, apoptosis, and cell cycle regulation. The present study used comparative proteomic technology to test the hypothesis that chronic cigarette smoking induces a UPR in the human lung. Studies were performed on lung tissue samples obtained from three groups of human subjects: nonsmokers, chronic cigarette smokers, and ex-smokers. Proteomes of lung samples from chronic cigarette smokers demonstrated 26 differentially expressed proteins (20 were up-regulated, 5 were down-regulated, and 1 was detected only in the smoking group) compared with nonsmokers. Several UPR proteins were up-regulated in smokers compared with nonsmokers and ex-smokers, including the chaperones, glucose-regulated protein 78 (GRP78) and calreticulin; a foldase, protein disulfide isomerase (PDI); and enzymes involved in antioxidant defense. In cultured human airway epithelial cells, GRP78 and the UPR-regulated basic leucine zipper, transcription factors, ATF4 and Nrf2, which enhance expression of important anti-oxidant genes, increased rapidly (< 24 h) with cigarette smoke extract. These data indicate that cigarette smoke induces a UPR response in the human lung that is rapid in onset, concentration dependent, and at least partially reversible with smoking cessation. We speculate that activation of a UPR by cigarette smoke may protect the lung from oxidant injury and the development of COPD.

Effects of generated trans-arachidonic acids on retinal capillary during nitrative stress in diabetic rats.

PURPOSE: To investigate whether the trans-arachidonic acids (TAAs) change in diabetic conditions and the effect on capillary cells and its possible mechanism. METHODS: Diabetes was induced by intraperitoneal injection of streptozotocin at 60 mg kg(-1) body weight. The amount of TAAs and arachidonic acid (AA) in serum of diabetic rats was measured by the gas chromatography and mass spectrometry method and the ratio of the peak area of TAAs to AA with a selected ion of 79 was estimated by group t test. The expression level of thrombospondin-1 (TSP-1) in the retina was examined by Western blot. The pericyte apoptotic index was investigated by flow cytometry. RESULT: The ratio of TAAs to AA significantly increased in serum at the time points of 8, 12 and 16 weeks after streptozotocin induction (p < 0.05). The expression of TSP-1 in the retina of diabetic rats elevated with longer duration of diabetes (checking the time points of 2-, 4-, 8-, 12- and 16-week diabetic rats). The expression of TSP-1 tended to be physiologically elevated in relation to age but less significantly than in the diabetic group. TAAs could not induce the apoptosis of retinal pericytes (p > 0.05). CONCLUSION: TAAs were generated associated with nitrative stress in diabetic rats and a possible mechanism of microvascular injury exits in diabetic conditions.