ROS-mediated Diseases Research Articles

Bilirubin Nanomedicines for the Treatment of Reactive Oxygen Species (ROS)-Mediated Diseases

Bilirubin, a natural product of heme catabolism, has recently emerged as a promising candidate in nanomedicine for the treatment of Reactive Oxygen Species (ROS)-mediated diseases. ROS, including free radicals and other oxygen-derived molecules, play a pivotal role in various pathological conditions such as inflammation, neurodegenerative disorders, and cardiovascular diseases. Bilirubin's potent antioxidant properties make it an attractive therapeutic agent, and recent advancements in nanotechnology have paved the way for its effective delivery and application in treating ROS-related ailments.This abstract delves into the potential of bilirubin-based nanomedicines in combating ROS-induced damage. The encapsulation of bilirubin within nanocarriers enhances its stability, bioavailability, and targeted delivery to affected tissues. The utilization of nanoscale systems not only safeguards bilirubin from degradation but also allows for controlled release, ensuring sustained therapeutic effects.The multifaceted mechanisms of bilirubin action include its ability to scavenge free radicals, modulate inflammatory responses, and protect cellular components from oxidative stress. The encapsulation of bilirubin in nanoparticles further improves its pharmacokinetics, enabling efficient distribution and accumulation at disease sites. Moreover, the nanocarrier systems can be engineered to respond to specific stimuli, facilitating site-specific release of bilirubin in response to the elevated ROS levels characteristic of pathological conditions.This abstract also highlights the versatility of bilirubin nanomedicines in addressing diverse ROS-mediated diseases. From neuroprotection in conditions like Alzheimer's and Parkinson's diseases to alleviating oxidative stress in cardiovascular disorders, bilirubin-based nanotherapeutics exhibit a broad spectrum of applications. The tailored design of nanocarriers allows for personalized treatment approaches, catering to the unique characteristics of each disease state.

Transferrin-Targeted Iridium Nanoagglomerates with Multi-Enzyme Activities for Cerebral Ischemia-Reperfusion Injury Therapy.

Cerebral ischemia-reperfusion injury (CIRI) is a complex pathological condition with high mortality. In particular, reperfusion can stimulate overproduction of reactive oxygen species (ROS) and activation of inflammation, causing severe secondary injuries to the brain. Despite tremendous efforts, it remains urgent to rationally design antioxidative agents with straightforward and efficient ROS scavenging capability. Herein, a potent antioxidative agent was explored based on iridium oxide nano-agglomerates (Tf-IrO2 NAs) via the facile transferrin (Tf)-templated biomineralization approach, and innovatively applied to treat CIRI. Containing some small-size IrO2 aggregates, these NAs possess intrinsic hydroxyl radicals (•OH)-scavenging ability and multifarious enzyme activities, such as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx). Moreover, they also showed improved blood-brain barrier (BBB) penetration and enhanced accumulation in the ischemic brain via Tf receptor-mediated transcytosis. Therefore, Tf-IrO2 NAs achieved robust in vitro anti-inflammatory and cytoprotection effects against oxidative stress. Importantly, mice were effectively protected against CIRI by enhanced ROS scavenging activity in vivo, and the therapeutic mechanism was systematically verified. These findings broaden the idea of expanding Ir-based NAs as potent antioxidative agents to treat CIRI and other ROS-mediated diseases. STATEMENT OF SIGNIFICANCE: : (1) The ROS-scavenging activities of IrO2 are demonstrated comprehensively, which enriched the family of nano-antioxidants. (2) The engineering Tf-IrO2 nano-agglomerates present unique multifarious enzyme activities and simultaneous transferrin targeting and BBB crossing ability for cerebral ischemia-reperfusion injury therapy. (3) This work may open an avenue to enable the use of IrO2 to alleviate ROS-mediated inflammatory and brain injury diseases.

Therapy of spinal cord injury by zinc pyrogallol modified nanozyme via anti-inflammatory strategies

ROS-mediated treatment is a potential strategy that can reduce the risk of spinal cord injury (SCI)-related obvious adverse effects, but at the cost of therapeutic efficacy. Considering the significant reactive oxygen species (ROS) scavenging ability and biocompatibility of natural enzyme such as superoxide dismutase (SOD) and catalase (CAT), zinc pyrogallol nanozyme (PA-Zn) was developed to treat the injured spinal cord, in which zinc as metal center was coupled to pyrogallol through the Zn-O-C bridge to form a zinc four-coordination structure that can mimic enzyme-like behaviors of SOD and CAT for SCI treatment. In vitro tests demonstrated that PA-Zn could efficiently inhibit the expression of ROS and M1-related markers (IL-1β), and upregulate the expression of M2-related markers (Arg-1). Furthermore, PA-Zn could significantly promote ventral horn neurons survival and locomotor functional recovery in vivo, while inhibit injured spinal cord damage, and decrease the infiltration of macrophages in the lesion. PA-Zn had a better therapeutic effect on SCI animals at extremely low dosage (0.1 mg kg−1) and shorter time (2 weeks). The working dosage of PA-Zn was even 100-fold lower than some previous reported nanomedicines for SCI treatment. The PA-Zn with muti-enzymatic activities and biocompatibility showed reliable and efficient treatment efficiency for not only SCI but also other ROS-mediated diseases.

Effects Of Aerobic Training On Pentraxin 3/Toll-like Receptor 4 And Oxidative Status In Elderly Adults

PURPOSE: The consequence of reactive oxygen and nitrogen species (ROS/RNS)-mediated cellular aging has been linked to various diseases, such as atherothrombosis and cancer. One of the possible mechanisms for these ROS-mediated diseases is through the activation of intracellular pattern recognition receptors (PRR), thereby contributing to a chronic low-grade pro-inflammatory systemic state in aging. Pentraxin 3 (PTX3) is a soluble PRR mainly released from endothelial cells and immunes cells and utilizes its counter-regulatory function in promoting the anti-inflammatory response via the inhibition of toll-like receptor 4 (TLR4). Although increased level of PTX3 has been shown following stimulation of oxidative stress and is also associated with aging-related diseases, the relationship between PTX3 and oxidative stress in aging remains to be elucidated. However, exercise has been proposed as the key intervention for the maintenance of health in the elderly. Therefore, this study was to examine whether or not the level of PTX3 on TLR4-dependent inflammation would be associated with changes in oxidative stress in both plasma and peripheral blood mononuclear cells (PBMCs) following 8 weeks of aerobic training in the elderly. METHODS: Fourteen elderly subjects (9 trained and 5 controls) were recruited to participate in an 8-week aerobic training. The ELISA and western blot analyses were used to determine the levels of PTX3 and biomarkers of oxidative stress in both plasma and PBMCs prior to and following training. RESULTS: No changes in plasma levels of PTX3 and oxidative stress markers (GSH, TEAC, and ROS/RNS) were observed in trained vs. control groups. However, our analyses showed a downregulation of PTX3 expression in PBMCs (P = 0.017) following aerobic training, along with decreased ratio of PTX3/TLR4 (P = 0.047). Furthermore, the tendency of oxidative stress response in PBMCs remained unchanged as shown in plasma levels. Finally, no correlation was observed between PTX3 and any oxidative stress biomarkers following training protocol. CONCLUSIONS: These findings demonstrate the downregulation of PTX3 and PTX3/TLR4 ratio in PBMCs of elderly subjects, irrespective of changes in oxidative stress following 8 weeks of aerobic training.

Bilirubin Nanomedicines for the Treatment of Reactive Oxygen Species (ROS)-Mediated Diseases.

Reactive oxygen species (ROS) are chemically reactive species that are produced in cellular aerobic metabolism. They mainly include superoxide anion, hydrogen peroxide, hydroxyl radicals, singlet oxygen, ozone, and nitric oxide and are implicated in many physiological and pathological processes. Bilirubin, a cardinal pigment in the bile, has been increasingly investigated to treat cancer, diabetes, ischemia-reperfusion injury, asthma, and inflammatory bowel diseases (IBD). Indeed, bilirubin has been shown to eliminate ROS production, so it is now considered as a promising therapeutic agent for ROS-mediated diseases and can be used for the development of antioxidative nanomedicines. This review summarizes the current knowledge of the physiological mechanisms of ROS production and its role in pathological changes and focuses on discussing the antioxidative effects of bilirubin and its application in the experimental studies of nanomedicines. Previous studies have shown that bilirubin was mainly used as a responsive molecule in the microenvironment of ROS overproduction in neoplastic tissues for the development of anticancer nanodrugs; however, it could also exert powerful ROS scavenging activity in chronic inflammation and ischemia-reperfusion injury. Therefore, bilirubin, as an inartificial ROS scavenger, is expected to be used for the development of nanomedicines against more diseases due to the universality of ROS involvement in human pathological conditions.

Saffron carotenoids change the superoxide dismutase activity in breast cancer: In vitro, in vivo and in silico studies

Superoxide dismutase (SOD) is an important member of the antioxidant defense system and is proposed as a therapeutic agent against the ROS-mediated diseases, and a therapeutic target for cancer treatment. Saffron carotenoids, crocin (Cro) and crocetin (Crt), are antioxidants with anticancer activity. In the present study, we investigated the effects of Cro/Crt on the SOD activity in both in vivo and in vitro models of breast cancer. Both Cro and Crt showed strong radical scavenging activity and SOD inhibition in the MCF-7 breast cancer cell line. The UVVis, circular dichroism and fluorometry studies proposed the binding of both Cro and Crt with SOD; the ΔG° of binding at 310 °K was −8.6 and −4.4 kcal/mol, respectively. The docking analysis predicted the Cro/Crt binding near the active site channel, but in different sites. According to the obtained data, Cro inhibits SOD activity by scavenging superoxide radical (O2), while Crt inhibits SOD by affecting the copper-binding site. In contrast to the in vitro data, both Cro and Crt effectively increased SOD activity in breast tumors of BALB/c mice, after one month of treatment. The mechanism that is important to compensate for the SOD decreased activity in cancer.

MicroRNA Targeting Nicotinamide Adenine Dinucleotide Phosphate Oxidases in Cancer.

Significance: Reactive oxygen species (ROS) production occurs primarily in the mitochondria as a by-product of cellular metabolism. ROS are also produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases in response to growth factors and cytokines by normal physiological signaling pathways. NADPH oxidase, a member of NADPH oxidase (NOX) family, utilizes molecular oxygen (O2) to generate ROS such as hydrogen peroxide and superoxide. Imbalance between ROS production and its elimination is known to be the major cause of various human diseases. NOX family proteins are exclusively involved in ROS production, which makes them attractive target(s) for the treatment of ROS-mediated diseases including cancer. Recent Advances: Molecules such as Keap1/nuclear factor erythroid 2-related factor 2 (Nrf2), N-methyl-d-aspartic acid (NMDA) receptors, nuclear factor-kappaB, KRAS, kallistatin, gene associated with retinoic-interferon-induced mortality-19, and deregulated metabolic pathways are involved in ROS production in association with NADPH oxidase. Critical Issues: Therapeutic strategies targeting NADPH oxidases in ROS-driven cancers are not very effective due to its complex regulatory circuit. Tumor suppressor microRNAs (miRNAs) viz. miR-34a, miR-137, miR-99a, and miR-21a-3p targeting NADPH oxidases are predominantly downregulated in ROS-driven cancers. miRNAs also regulate other cellular machineries such as Keap1/Nrf2 pathway and NMDA receptors involved in ROS production and consequently drug resistance. Here, we discuss the structure, function, and metabolic role of NADPH oxidase, NOX family protein-protein interaction, their association with other pathways, and NADPH oxidase alteration by miRNAs. Moreover, we also discuss and summarize studies on NADPH oxidase associated with various malignancies and their therapeutic implications. Future Directions: Targeting NADPH oxidases through miRNAs appears to be a promising strategy for the treatment of ROS-driven cancer.

Ascorbic Acid Attenuates Hyperoxia-Compromised Host Defense against Pulmonary Bacterial Infection.

Supraphysiological concentrations of oxygen (hyperoxia) can compromise host defense and increase susceptibility to bacterial infections, causing ventilator-associated pneumonia. The phagocytic activity of macrophages is impaired by hyperoxia-induced increases in the levels of reactive oxygen species (ROS) and extracellular high-mobility group box protein B1 (HMGB1). Ascorbic acid (AA), an essential nutrient and antioxidant, has been shown to be beneficial in various animal models of ROS-mediated diseases. The aim of this study was to determine whether AA could attenuate hyperoxia-compromised host defense and improve macrophage functions against bacterial infections. C57BL/6 male mice were exposed to hyperoxia (≥98% O2, 48 h), followed by intratracheal inoculation with Pseudomonas aeruginosa, and simultaneous intraperitoneal administration of AA. AA (50 mg/kg) significantly improved bacterial clearance in the lungs and airways, and significantly reduced HMGB1 accumulation in the airways. The incubation of RAW 264.7 cells (a macrophage-like cell line) with AA (0-1,000 μM) before hyperoxic exposure (95% O2) stabilized the phagocytic activity of macrophages in a concentration-dependent manner. The AA-enhanced macrophage function was associated with significantly decreased production of intracellular ROS and accumulation of extracellular HMGB1. These data suggest that AA supplementation can prevent or attenuate the development of ventilator-associated pneumonia in patients receiving oxygen support.

Real-time quantification of oxidative stress and the protective effect of nitroxide antioxidants

Nitroxides have been exploited as profluorescent probes for the detection of oxidative stress. In addition, they deliver potent antioxidant action and attenuate reactive oxygen species (ROS) in various models of oxidative stress, with these results ascribed to superoxide dismutase or redox and radical-scavenging actions. Our laboratory has developed a range of novel, biostable, isoindoline nitroxide-based antioxidants, DCTEIO and CTMIO. In this study we compared the efficiency of these novel compounds as antioxidant therapies in reducing ROS both in vivo (rat model) and in vitro (661W photoreceptor cells), with the established antioxidant resveratrol. By assessing changes in fluorescence intensity of a unique redox-responsive probe in the rat retina in vivo, we evaluated the ability of antioxidant therapy to (1) ameliorate ROS production and (2) reverse the accumulation of ROS after complete, acute ischemia followed by reperfusion (I/R). I/R injury induced a marked decrease in fluorescence intensity over 60 min of reperfusion, which was successfully ameliorated with each of the antioxidants. DCTEIO and CTMIO reversed the accumulation of ROS when administered intraocularly post ischemic insult, whereas, the effect of resveratrol was not significant. We also investigated our novel agents’ capacity to prevent ROS-mediated metabolic dysfunction in the 661W photoreceptor cell line. Cellular stress induced by the oxidant, tert-butyl hydroperoxide, resulted in a loss of spare mitochondrial respiratory capacity (SMRC) and in the extracellular acidification rate in 661W cells. DCTEIO antioxidant administration successfully reduced the loss of SMRC. Together, these findings show we can quantify dynamic changes in cellular oxidative status in vivo and suggest that nitroxide-based antioxidants may provide greater protection against oxidative stress than the current state-of-the-art antioxidant treatments for ROS-mediated diseases.

Gene manipulation based selenium-containing peptide exhibiting synergism of SOD and GPx

In this paper, we constructed a novel bifunctional superoxide dismutase(SOD)/glutathione peroxidase(GPx) mimic, a selenium-, copper-containing 35-mer peptide conjugate(Se-Cu-35P) in which a three-amino acid linker(Gly-Asn-Gly) connects the C-terminus of 17-mer polypeptide SOD mimic with the N-terminus of 15-mer polypeptide GPx mimic. The SOD and GPx activities of Se-Cu-35P are two orders of magnitude lower than those of natural SOD and GPx, respectively. It provides a GPx activity 56-fold higher than Ebselen(a well-known GPx mimic). The glutathione(GSH) binding constant is 5.6×102 L·mol−1. Se-Cu-35P synergistically resists against the inactivation by H2O2 and protects the mitochondria from oxidative damage in a dose dependent manner. These results highlight the challenge of generating an efficient SOD/GPx synergism mimic. It could facilitate the studies of the cooperation of GPx and SOD and could be a potential therapeutic agent for the treatment of ROS-mediated diseases.

Preventing UV induced cell damage by scavenging reactive oxygen species with enzyme-mimic Au–Pt nanocomposites

We have prepared enzyme-mimic Au-Pt nanocomposites (NCs) for catalyzing the decomposition of reactive oxygen species. After surface modification, the Au-Pt NCs can be readily internalized and retained by human skin cells and also can effectively reduce cellular oxidative stress. We have demonstrated that the active and biocompatible Au-Pt nanocomposites can be applied for preventing cell damages by scavenging cellular reactive oxygen species induced by ultraviolet irradiation, indicating potential uses for the prevention and therapy of ROS-mediated diseases.

Cyclodextrin-derived chalcogenides as glutathione peroxidase mimics and their protection of mitochondria against oxidative damage

A series of novel glutathione peroxidase (GPx) mimics based on organochalcogen cyclodextrin (CD) dimer were synthesized. Their GPx-like antioxidant activities were studied using hydrogen peroxide H2O2, tert-butylhydroperoxide (BHP), and cumene hydroperoxide (CHP) as substrates and glutathione as thiol co-substrate. The results showed that 6A,6B-ditelluronic acid-A,6B′-tellurium bridged γ-cyclodextrin (6-diTe-γ-CD) had the highest peroxidase activity, which was ~670-fold higher than ebselen, a well-known GPx mimic. Reduction of lipophilic CHP often proceeded much faster than reduction of the more hydrophilic H2O2 or BHP, which cannot bind into the hydrophobic interior of the CD. The biological activities were also evaluated for their capacity to protect mitochondria against ferrous sulfate/ascorbate-induced oxidative damage. 6-diTe-γ-CD was the best inhibitor which significantly suppressed ferrous sulfate/ascorbate-induced cytotoxicity as determined by swelling of mitochondria, lipid peroxidation and cytochrome c oxidase activity. Our data suggests that 6-diTe-γ-CD has potential pharmaceutical application in the treatment of ROS-mediated diseases.

Inactive extracellular superoxide dismutase disrupts secretion and function of active extracellular superoxide dismutase

Extracellular superoxide dismutase (EC-SOD) is an antioxidant enzyme that protects cells and tissues from extracellular damage by eliminating superoxide anion radicals produced during metabolism. Two different forms of EC-SOD exist, and their different enzyme activities are a result of different disulfide bond patterns. Although only two folding variants have been discovered so far, five folding variants are theoretically possible. Therefore, we constructed five different mutant EC-SOD expression vectors by substituting cysteine residues with serine residues and evaluated their expression levels and enzyme activities. The mutant EC-SODs were expressed at lower levels than that of wild-type EC-SOD, and all of the mutants exhibited inhibited extracellular secretion, except for C195S ECSOD. Finally, we demonstrated that co-expression of wild-type EC-SOD and any one of the mutant EC-SODs resulted in reduced secretion of wild-type EC-SOD. We speculate that mutant EC-SOD causes malfunctions in systems such as antioxidant systems and sensitizes tissues to ROS-mediated diseases.

Free-radical-scavenging effect of carbazole derivatives on AAPH-induced hemolysis of human erythrocytes

Since the research on antioxidants provides theoretical information for the medicinal development, and supplies some in vitro methods for quick-optimizing drugs, it attracts more scientific attention from bioorganic and medicinal chemists. In addition to the traditional O–H bond-type antioxidant, carbazole and its related tricyclic amines (Ar 2NHs), in which N–H bond functioned as the antioxidant, have attracted much research attention because Ar 2NHs have always been the central structure in many currently used drugs. Thus, the investigation on the structure–activity relationship (SAR) between Ar 2NHs and their free-radical-scavenging capacities in detail will benefit the development of novel radical-scavenging drugs containing Ar 2NHs as the central structure. Therefore, carbazole (CazNH) and its structural analogues including phenoxazine (PozNH), phenothiazine (PtzNH), iminostilbene (IsbNH) together with diphenylamine (DpaNH) were applied to protect human erythrocytes against 2,2′-azobis(2-amidinopropane hydrochloride) (AAPH)-induced hemolysis in vitro. By introducing the chemical kinetic formula related to free radical reaction, namely, the quantitative relationship between inhibition period ( t inh) and the concentration of antioxidant (AH), t inh = ( n/ R i)[AH], into AAPH-induced hemolysis, the values of stoichiometric factor ( n) of Ar 2NHs indicated that the free-radical-scavenging sequence of Ar 2NHs is PozNH > DpaNH > CazNH > IsbNH > PtzNH > α-tocopherol (TocH). Another aim of this work was to investigate the antioxidative effect of Ar 2NHs used together with other antioxidants including Trolox (TroH), VC, l-ascorbyl-6-laurate (VC-12), and TocH. The obtained data revealed that n value of PozNH when used together with all the other antioxidants decreases, whereas, n values of CazNH, DpaNH, IsbNH, and PtzNH when used in combination with TroH increase, demonstrating that two different interaction styles existed in the case of Ar 2NHs used with other antioxidants. These findings may be useful for the development of agents for various ROS-mediated diseases in vivo.

A novel dicyclodextrinyl ditelluride compound with antioxidant activity

Reactive oxygen species (ROS) primarily arise from products of normal metabolic activities and are thought to be the etiology of many diseases. A novel dicyclodextrinyl ditelluride (2-TeCD) compound was designed to be a functional mimic of the glutathione peroxidase that normally removes ROS. 2-TeCD exhibited highly catalytic efficiency and good water solubility. Antioxidant activity was studied by using ferrous sulfate/ascorbate-induced mitochondria damage model system. 2-TeCD protected the mitochondria against oxidative damage in a dose-dependent manner and exhibited also great antioxidant ability in comparison with 2-phenyl-1,2-benziososelenazol-3(2H)-one. The mimic may result in better clinical therapies for the treatment of ROS-mediated diseases.