Oxygen free radicals and lungs

Some of the metabolites resulting from the monovalent reduction of O₂, superoxide anion and hydroxyl radical, are O₂ radicals, whereas H₂O₂, which is not a radical since having no unpaired electron, is also an active O₂ intermediate. These O₂ metabolites are formed intracellularly as a result of normal metabolism. Their production can increase following exposure to high O₂ concentration, radiations or certain drugs. An increased amount of extracellular O₂ metabolites occurs after activation of certain inflammatory cells or during the course of the hypoxanthine-xanthine oxidase reaction. To counteract this oxidative stress, antioxidant defenses exist, whether enzymatic (superoxide dismutase, glutathione peroxidase, catalase, etc.) or nonenzymatic (GSH, vitamin E and C, etc.). Oxidative injury can result from an imbalance between oxidative stress and the defense mechanisms. The main targets are protein, DNA and lipids. The cellular response of the lung is stereotyped and involves cell injury (especially endothelial c cells and type I pneumocytes), inflammatory reaction and repair processes.     

Targeted modulation of reactive oxygen species in the vascular endothelium

'Endothelial cells lining vascular luminal surface represent an important site of signaling and injurious effects of reactive oxygen species (ROS) produced by other cells and endothelium itself in ischemia, inflammation and other pathological conditions. Targeted delivery of ROS modulating enzymes conjugated with antibodies to endothelial surface molecules (vascular immunotargeting) provides site-specific interventions in the endothelial ROS, unattainable by other formulations including PEG-modified enzymes. Targeting of ROS generating enzymes (e.g., glucose oxidase) provides ROS- and site-specific models of endothelial oxidative stress, whereas targeting of antioxidant enzymes SOD and catalase offers site-specific quenching of superoxide anion and H₂O₂. These targeted antioxidant interventions help to clarify specific role of endothelial ROS in vascular and pulmonary pathologies and provide basis for design of targeted therapeutics for treatment of these pathologies. In particular, antibody/catalase conjugates alleviate acute lung ischemia/reperfusion injury, whereas antibody/SOD conjugates inhibit ROS-mediated vasoconstriction and inflammatory endothelial signaling. Encapsulation in protease-resistant, ROS-permeable carriers targeted to endothelium prolongs protective effects of antioxidant enzymes, further diversifying the means for targeted modulation of endothelial ROS.     

Cold preservation-induced changes in oxygen radical generation between parenchymal and nonparenchymal cells in rat liver

Many of the reports implicating the contribution of oxygen radicals to preservation-reperfusion injury have been based largely on indirect experiments demonstrating the effects or the consumption of various antioxidants. Investigations based on the direct measurement of the amounts of oxygen radicals that are actually formed during reoxygenation after preservation have not given satisfactory results. In this study, we attempted direct measurement of H₂O₂ from hepatocellular mitochondria and superoxide (O₂ ^?) from Kupffer cells, using the HRP method and cytochromec perfusion method, respectively, for quantitative comparison of the cold preservation-induced changes in radical generation activity between these sources. H₂O₂ generation in mitochondria isolated after 24 h cold preservation decreased to 8% of non-preserved liver, but in the mitochondria isolated from the livers that were reperfused for 30 min after 24 h preservation H₂O₂ generation recovered to 60%. The respiratory control ratio also decreased significantly after 24 h preservation, and similarly recovered after an additional 30 min reperfusion. By contrast, O₂ ^?, from Kupffer cells increased in time-dependent fashion until 12 h preservation and decreased after 24 h preservation. Although 12 h preservation did not cause an increase in LDH release, the lipid peroxide in the perfusate significantly increased after 12 h preservation, which indicated the occurrence of lipid peroxidation in the sinusoidal area. These results suggested that mitochondrial H₂O₂ was dependent upon the activity of respiratory function and so did not cause hepatocellular injury and that O₂ ^? from Kupffer cells contributed to oxidative injury to the sinusoidal lining cells. Our data support reports demonstrating the vulnerability of nonparenchymal cells.     

Synthesis of caffeic acid sulfonamide derivatives and their protective effect against H2O2 induced oxidative damage in A549 cells

Exogenous antioxidants are considered as important therapeutic tools for oxidative stress associated disorders as they can regulate the redox state, which is associated with cell and organ function. Inspired by natural polyphenols, six new caffeic acid sulfonamide derivatives were synthesized by coupling sulfonamides to the backbone of caffeic acid with good yields. Their structure and lipophilicity were characterized by 1H nuclear magnetic resonance (NMR), ¹³C{¹H} NMR, infrared spectroscopy (IR) and oil–water partition coefficient assay. Their free radical scavenging activity and antioxidant activity were assessed by DPPH assay and hydrogen peroxide (H₂O₂) induced oxidative stress in human lung carcinoma A549 cells. The oil–water partition coefficient results indicate that the conjugation of sulfonamides increases the lipophilicity of caffeic acid. The CASMD, CASDZ and CASN results show higher free radical scavenging effects compared with vitamin C. The derivatives do not show any inhibitory effect on the proliferation of A549 cells up to a concentration of 200 μM, except CASDZ which significantly inhibits the growth of A549 cells at a concentration of 200 μM. In addition, the obtained derivatives markedly attenuate H₂O₂ induced decrease of cell viability, inhibit the production of ROS and MDA, and promote the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). Besides, treatment of H₂O₂ stimulated A549 cells with caffeic acid sulfonamide derivatives further increases mRNA expression of NF-E2-related factor 2 (Nrf2) and its target genes, including heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1) and thioredoxin reductase 1 (TXNRD1). These results suggest that these new caffeic acid sulfonamide derivatives have higher lipophilicity and better antioxidant activities than the parent caffeic acid, and they might be able to control the antioxidant response in cells via the Nrf2 pathway.

Synthesized caffeic acid derivatives exhibit protective effect on H₂O₂ induced oxidative injury in A549 cells via Nrf2 pathway.     

Association of oxidative stress and paraoxonase status with PROCAM risk score

ObjectivesOxidative stress and paraoxonase activity play a significant role in the pathogenesis of cardiovascular disease (CVD). The Prospective Cardiovascular Münster (PROCAM) study evaluated the prevalence of CVD risk factors and postulated the prediction of future CVD events. We therefore investigated the association between plasma markers of oxidative stress and paraoxonase status with PROCAM risk score.Design and methodsOxidative stress status parameters [lipid peroxidation measured as thiobarbituric acid-reacting substances (TBARS), superoxide anion (O₂^?), superoxide dismutase (SOD) activity, total sulphydryl group content] and paraoxonase (PON1) status were assessed in 211 participants. The predicted 10-year risk was calculated according to the PROCAM algorithm.ResultsAs expected subjects with high PROCAM risk score (high CVD risk) had significantly higher concentrations of oxidative stress parameters (TBARS and O₂^? P < 0.001 and P < 0.05, respectively). The PON1₁₉₂ phenotype distribution among CVD risk groups was not significantly different. Logistic regression analyses revealed significant associations of all the examined oxidative stress status parameters with calculated CVD risk score. The potential of the parameters for CVD risk prediction was tested via multivariate analysis. Only the O₂^? level retained a strong association with high CVD risk.ConclusionsOur study demonstrated that high PROCAM risk score is associated with increased oxidative stress, indicating for the first time that elevated O₂^? is independently associated with high CVD risk.     

Oxygen: How Do We Stand It?

The electronic structure of ground state oxygen, which is essential for the life of all aerobic organisms, makes it potentially dangerous for those organisms. Atmospheric oxygen contains two unpaired electrons with parallel spin states, which predisposes it to reduction by a univalent pathway. As a consequence, normal aerobic metabolism generates dangerous reactive intermediates of the reduction of O₂. These include superoxide radical (O₂^–), hydrogen peroxide (H₂O₂), and hydroxyl radical (HO). These reactive oxygen species and others that they can engender can damage all cellular macromolecules and unless opposed by cellular defenses, would make aerobic life impossible. Such defenses include superoxide dismutases, catalases, and peroxidases, enzymes that decrease the concentration of the reactive oxygen species that are their substrates, and others that repair or recycle oxidatively damaged macromolecules. Any factor that stimulates reactive oxygen species production or suppresses the antioxidant systems would inevitably cause cell damage. The role of such oxidative damage in various diseases is well documented. In vivo detection of O^2– and other reactive oxygen species is however hampered by the lack of easy, specific, and sensitive analytical methods. Potential artifacts and limitations of the most common detection methods currently in use are briefly discussed.Key Words: Reactive oxygen species, Superoxide, Singlet oxygen, Hydrogen peroxide, Nitric oxide, Free radical, Oxidative stress, Superoxide dismutase, Superoxide assay     

A mitochondrial superoxide theory for oxidative stress diseases and aging

Fridovich identified CuZnSOD in 1969 and manganese superoxide dismutase (MnSOD) in 1973, and proposed ”the Superoxide Theory,” which postulates that superoxide (O₂^•−) is the origin of most reactive oxygen species (ROS) and that it undergoes a chain reaction in a cell, playing a central role in the ROS producing system. Increased oxidative stress on an organism causes damage to cells, the smallest constituent unit of an organism, which can lead to the onset of a variety of chronic diseases, such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis and other neurological diseases caused by abnormalities in biological defenses or increased intracellular reactive oxygen levels. Oxidative stress also plays a role in aging. Antioxidant systems, including non-enzyme low-molecular-weight antioxidants (such as, vitamins A, C and E, polyphenols, glutathione, and coenzyme Q₁₀) and antioxidant enzymes, fight against oxidants in cells. Superoxide is considered to be a major factor in oxidant toxicity, and mitochondrial MnSOD enzymes constitute an essential defense against superoxide. Mitochondria are the major source of superoxide. The reaction of superoxide generated from mitochondria with nitric oxide is faster than SOD catalyzed reaction, and produces peroxynitrite. Thus, based on research conducted after Fridovich’s seminal studies, we now propose a modified superoxide theory; i.e., superoxide is the origin of reactive oxygen and nitrogen species (RONS) and, as such, causes various redox related diseases and aging.     

Effect of 3-keto-1,5-bisphosphonates on obese-liver’s rats

Obesity is associated with an oxidative stress status, which is defined by an excess of reactive oxygen species (ROS) vs. the antioxidant defense system. We report in this present work, the link between fat deposition and oxidative stress markers using a High Fat Diet-(HFD) induced rat obesity and liver-oxidative stress. We further determined the impact of chronic administration of 3-keto-1, 5-BPs 1 (a & b) (40 μg/kg/8 weeks/i.p.) on liver’s level.In fact, exposure of rats to HFD during 16 weeks induced body and liver weight gain and metabolic disruption with an increase on liver Alanine amino transférase (ALAT) and Aspartate aminotransférase (ASAT) concentration. HFD increased liver calcium level as well as free iron, whereas, it provoked a decrease on liver lipase activity. HFD also induced liver-oxidative stress status vocalized by an increase in reactive oxygen species (ROS) as superoxide radical (O₂), hydroxyl radical (OH) and Hydrogen peroxide (H₂O₂). Consequently, different deleterious damages as an increase on Malon Dialdehyde MDA, Carbonyl protein PC levels with a decrease in non-protein sulfhydryls NPSH concentrations, have been detected. Interestingly, our results demonstrate a decrease in antioxidant enzymes activities such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (GPx) and peroxidases (POD).Importantly, 3-keto-1,5-bisphosphonates treatment corrected the majority of the deleterious effects caused by HFD, but it failed to correct some liver’s disruptions as mineral profile, oxidative damages (PC and NPSH levels) as well as SOD and lipase activities.Our investigation point that 3-keto-1,5-bisphosphonates could be considered as safe antioxidant agents on the hepatic level that should also find other potential biological applications.     

Antioxidant effects of antioxidant biofactor on reactive oxygen species in human gingival fibroblasts

The purpose of this study was to investigate the effects of antioxidant biofactor (AOB) on reactive oxygen species (ROS). Generation of superoxide radical (O₂^•−) and hydroxyl radical (^•OH) was determined using an electron spin resonance (ESR) spin-trapping method. AOB was added at different concentrations to these free radical generating systems. The generation of both O₂^•− and ^•OH was scavenged by the addition of AOB in a dose-dependent manner. These results indicate that AOB has strong antioxidant properties against these radicals. We further investigated the anti-oxidative effect of AOB on human gingival fibroblasts (HGFs). HGFs were treated for 3 h with α-MEM containing a combination of AOB and H₂O₂ (AOB + H₂O₂ group), containing H₂O₂ (H₂O₂ group), or containing AOB alone (AOB group). Non-stimulated HGFs were used as a control group. The number of surviving cells was in the order of the AOB group > control group > AOB + H₂O₂ group > H₂O₂ group. The level of expression of type I collagen mRNA and production of collagen were also in the order of the AOB group > control group > AOB + H₂O₂ group > H₂O₂ group. In conclusion, our results suggest that AOB may protect HGFs against oxidative stress by reducing stress-induced ROS.     

Activity of myricetin and other plant-derived polyhydroxyl compounds in human LDL and human vascular endothelial cells against oxidative stress

Studies indicate that oxidative modifications of endothelium and LDL play a preeminent role in atherogenesis; therefore, the preservation of the endothelial antioxidant capacity and the inhibition of LDL oxidation by use of plant-derived compounds are an appealing strategy against several vascular disorders. On this basis, baicalein, eupatorin, galangin, magnolol, myricetin, oleuropein, silibinin and bilobalide were studied against various oxidative conditions. The radical scavenging capacity was analysed using DPPH and ORAC assays. Furthermore, the LDL oxidation was detected by measuring the formation of thiobarbituric acid reactive substances (TBARS) and by monitoring the oxidation kinetics. Further, we used cultured HUVEC to investigate the activities of the polyhydroxyl compounds towards the oxidative stress induced by H₂O₂. The lowest levels of TBARS were observed in the presence of oleuropein and baicalein, while myricetin, magnolol and eupatorin inhibited these ones to a lesser extent. In addition, oleuropein and myricetin exhibited higher protection in copper-induced LDL oxidation kinetics. However, only myricetin and galangin showed significant protective effects against H₂O₂ oxidative injury in HUVEC cells. Taken all together the results indicate myricetin as the most active agent among the selected plant-derived polyhydroxyl compounds, with prominent capacities against ox-LDL and ROS production in HUVEC.     

Evaluation of whole antioxidant defenses of human mononuclear cells by a new in vitro biological test: Lack of correlation between erythrocyte and mononuclear cell resistance to oxidative stress

Objectives:

This work aims to evaluate the resistance of mononuclear cells to oxidative stress using a “KRL” test, formerly utilized to evaluate the resistance of erythrocyte to free radicals.

Methods:

The “KRL” test evaluates the resistance to lysis of cells treated by free radicals generated under standardized conditions.

Results:

We defined new analytical parameters (level of radical production, time course, number of cells) to obtain an accurate assay determining the resistance to oxidative stress of mononuclear cells, in comparison to that of erythrocytes. This test allows the evaluation of change in the redox state of mononuclear cells (improved by an antioxidant mix or deteriorated by antimycin A-induced mitochondrial radical overproduction). Interestingly, our data show that the sensitivity of mononuclear cells to oxidative stress is not correlated with the susceptibility of erythrocytes to oxidative stress.

Conclusions:

The quantification of the susceptibility of mononuclear cells to oxidative stress gives additional information (in addition to erythrocyte resistance) and could be helpful for patients with chronic inflammation.     

Direct evidence for the occurrence of superoxide radicals in the small intestine of the burned rat

To determine if superoxide radicals (O₂⁻) and related metabolites are generated in extradermal tissues of burned animals, 2-methyl-6-[p-methoxyphenyl]-3,7-dihydroimidazol [1,2-å]pyrazin-3-one (MCLA) was infused intravenously into rats, and change in the chemiluminescence (CL) intensity of the small intestine was determined by using a sensitive photodetector. When animals were challenged with burn stress of 40% total body surface area (TBSA), the CL intensity of the intestine gradually increased, reaching a maximum within 1 hour and remaining elevated for up to 3 hours. Pretreatment of animals with a long-acting superoxide dismutase (SOD) derivative (SM-SOD) significantly inhibited the increase in CL intensity. Administration of SM-SOD immediately after inducing burn injury also significantly inhibited the increase in CL. These results suggest that superoxide radicals are generated in extradermal tissues, such as the small intestine, in the early stage after burn injury.     

DNA damage,DNA susceptibility to oxidation and glutathione level in women with polycystic ovary syndrome

Recent studies have addressed the possibility of an association between polycystic ovaries and ovarian cancer. DNA damage is the first step of the carcinogenesis, and susceptibility to cancer, in general, is characterized by high DNA damage. Free radical‐mediated DNA damage and impaired antioxidant defence have been implicated as contributory factors for the development of cancer. This study evaluates DNA damage (strand breakage, base oxidation, formamidopyrimidine DNA glycosylase (Fpg) sensitive sites), H₂O₂‐induced DNA damage, a marker of DNA susceptibility to oxidation and glutathione (GSH) level, a powerful antioxidant, in women with polycystic ovary syndrome (PCOS). Women with PCOS showed a significant decrease in GSH level, a significant increase in DNA strand breakage and H₂O₂‐induced DNA damage. Although Fpg‐sensitive sites were higher in the PCOS group compared to the control group, the difference did not reach a statistically significant level. Significant correlations were found between free testosterone and DNA strand breakage (r = 0.46, p<0.01) and free testosterone and H₂O₂‐induced DNA damage (r = 0.41, p<0.05). The data indicate that DNA damage and susceptibility of DNA to oxidative stress are increased in women with PCOS and may explain the association between PCOS and ovarian cancer.     

Antioxidant activity of SSeCAHK in HepG2 cells: a selenopeptide identified from selenium-enriched soybean protein hydrolysates

This paper is aimed at purifying and identifying selenium (Se)-containing antioxidative peptides from Se-enriched soybean peptides (SSP). In this work, the SSP was separated into five fractions (F1 to F5). Fraction F4, displaying the highest antioxidative activity, was further separated, and sub-fractions F4-1 to F4-5 were selected for antioxidative activity evaluation using 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2-azino-bis-(3-ethylbenzo-thiazoline-6-sulphonic acid)diammonium salt (ABTS), and OH⁻ radical scavenging assays. The Se-containing antioxidative peptides with sequence Ser–SeC–Ala–His–Lys (SSeCAHK) were identified in sub-fraction F4-1 and chemically synthesized. This Se-containing pentapeptide showed a preventive effect against hydrogen peroxide (H₂O₂)-induced oxidative stress in HepG2 cells. Pretreating the cells for 2 h with SSeCAHK (0.13–0.50 mg mL⁻¹) induced strong intracellular, reactive oxygen species (ROS) scavenging activity while preventing a decrease in reduced glutathione (GSH) and an increase in malondialdehyde (MDA). Therefore, SSeCAHK treatment improved H₂O₂-induced oxidative stress in HepG2 cells, demonstrating the significant potential of SSeCAHK as a natural antioxidative functional material for dietary supplementation.

Se-containing antioxidative soybean peptides were isolated and identified as SSeCAHK. The SSeCAHK had protective effects against H₂O₂-induced oxidative stress in HepG2 cells and could be used as a natural food-born antioxidant.     

20(S)-Ginsenoside Rg2 attenuates myocardial ischemia/reperfusion injury by reducing oxidative stress and inflammation: role of SIRT1

Previously we demonstrated that 20(S)-ginsenoside Rg2 protects cardiomyocytes from H₂O₂-induced injury by inhibiting reactive oxygen species (ROS) production, increasing intracellular levels of antioxidants and attenuating apoptosis. We explored the protective effect of 20(S)-ginsenoside Rg2 on myocardial ischemia/reperfusion (MI/R) injury and to clarify its potential mechanism of action. Rats were exposed to 20(S)-ginsenoside Rg2 in the presence/absence of the silent information regulator SIRT(1) inhibitor EX527 and then subjected to MI/R. 20(S)-Ginsenoside Rg2 conferred a cardioprotective effect by improving post-ischemic cardiac function, decreasing infarct size, reducing the apoptotic index, diminishing expression of creatine kinase-MB, aspartate aminotransferase and lactate dehydrogenase in serum, upregulating expression of SIRT1, B-cell lymphoma-2, procaspase-3 and procaspase-9, and downregulating expression of Bax and acetyl (Ac)-p53. Pretreatment with 20(S)-ginsenoside Rg2 also resulted in reduced myocardial superoxide generation, gp91^phox expression, malondialdehyde content, cardiac pro-inflammatory markers and increased myocardial activities of superoxide dismutase, catalase and glutathione peroxidase. These results suggested that MI/R-induced oxidative stress and inflammation were attenuated significantly by 20(S)-ginsenoside Rg2. However, these protective effects were blocked by EX527, indicating that SIRT1 signaling may be involved in the pharmacological action of 20(S)-ginsenoside Rg2. Our results demonstrated that 20(S)-ginsenoside Rg2 attenuates MI/R injury by reducing oxidative stress and inflammatory responses via SIRT1 signaling.

20(S)-Ginsenoside Rg2 confers a protective effect against MI/R injury via SIRT1 signaling, by alleviating oxidative stress and reducing myocardium inflammation.     

Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage

Patients with inflammatory bowel disease are at increased risk for colon cancer due to augmented oxidative stress. These patients also have compromised antioxidant defenses as the result of nutritional deficiencies. The micronutrient selenium is essential for selenoprotein production and is transported from the liver to target tissues via selenoprotein P (SEPP1). Target tissues also produce SEPP1, which is thought to possess an endogenous antioxidant function. Here, we have shown that mice with Sepp1 haploinsufficiency or mutations that disrupt either the selenium transport or the enzymatic domain of SEPP1 exhibit increased colitis-associated carcinogenesis as the result of increased genomic instability and promotion of a protumorigenic microenvironment. Reduced SEPP1 function markedly increased M2-polarized macrophages, indicating a role for SEPP1 in macrophage polarization and immune function. Furthermore, compared with partial loss, complete loss of SEPP1 substantially reduced tumor burden, in part due to increased apoptosis. Using intestinal organoid cultures, we found that, compared with those from WT animals, Sepp1-null cultures display increased stem cell characteristics that are coupled with increased ROS production, DNA damage, proliferation, decreased cell survival, and modulation of WNT signaling in response to H₂O₂-mediated oxidative stress. Together, these data demonstrate that SEPP1 influences inflammatory tumorigenesis by affecting genomic stability, the inflammatory microenvironment, and epithelial stem cell functions.     

Carvedilol protects bone marrow stem cells against hydrogen peroxide-induced cell death via PI3K-AKT pathway

Carvedilol, a nonselective β-adrenergic receptor blocker, has been reported to exert potent anti-oxidative activities. In the present study, we aimed to investigate the effects of carvedilol against hydrogen peroxide (H₂O₂)-induced bone marrow-derived mesenchymal stem cells (BMSCs) death, which imitate the microenvironment surrounding transplanted cells in the injured spinal cord in vitro. Carvedilol significantly reduced H₂O₂-induced reactive oxygen species production, apoptosis and subsequent cell death. LY294002, the PI3K inhibitor, blocked the protective effects and up-regulation of Akt phosphorylation of carvedilol. Together, our results showed that carvedilol protects H₂O₂-induced BMSCs cell death partly through PI3K-Akt pathway, suggesting carvedilol could be used in combination with BMSCs for the treatment of spinal cord injury by improving the cell survival and oxidative stress microenvironments.     

Ultrasmall copper nanoclusters with multi-enzyme activities

Reactive oxygen species (ROS) as a key messenger of signal transduction mediate physiological activities, however, oxidative stress produced by excessive ROS can cause the destruction of cell homeostasis, which will result in a series of diseases. Therefore, effective control of ROS level is critical to the homeostasis of the cell. Here, we reported that glutathione (GSH)-stabilized copper nanoclusters (CuNCs) with about 9 Cu atoms can functionally mimic three major antioxidant enzymes, namely catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD). The rate of H₂O₂ decomposition was calculated to be ∼0.23 mg L⁻¹ s⁻¹ when the concentration of CuNCs was 100 μg mL⁻¹. The SOD-like activity by catalyzing the disproportionation of superoxide to H₂O₂ and O₂ reached 25.6 U mg⁻¹ when the effective inhibition rate was ∼55.4%. Intracellular ROS scavenging studies further identified that CuNCs can obviously protect cells from oxidative stress and the cell viability recovered to above 90%. Hence, we expect that ultrasmall CuNCs will provide good therapeutic potential in the future treatment of ROS-related diseases.

Ultrasmall copper nanoclusters (CuNCs) can functionally mimic three major antioxidant enzymes, showing impressive intracellular ROS scavenging abilities.     

Oxidative Stress Enhances Cephalosporin Resistance of Enterococcus faecalis through Activation of a Two-Component Signaling System

Enterococcus faecalis is a low-GC Gram-positive bacterium, a normal resident of the gastrointestinal (GI) tract, and an important hospital-acquired pathogen. An important risk factor for hospital-acquired enterococcal infections is prior therapy with broad-spectrum cephalosporins, antibiotics that impair cell wall biosynthesis by inhibiting peptidoglycan cross-linking. Enterococci are intrinsically resistant to cephalosporins; however, environmental factors that modulate cephalosporin resistance have not been described. While searching for the genetic determinants of cephalosporin resistance in E. faecalis, we unexpectedly discovered that oxidative stress, whether from external sources or derived from endogenous metabolism, drives enhanced intrinsic resistance to cephalosporins. A particular source of oxidative stress, H₂O₂, activates signaling through the CroR-CroS two-component signaling system, a known determinant of cephalosporin resistance in E. faecalis. We find that CroR-CroS is required for adaptation to H₂O₂ stress and that H₂O₂ potentiates the activities of cephalosporins against E. faecalis when the CroR-CroS signaling system is nonfunctional. Rather than directly detecting H₂O₂, our data suggest that the CroR-CroS system responds to cell envelope damage caused by H₂O₂ exposure in order to promote cell envelope repair and enhanced cephalosporin resistance.