Cadmium-Induced Kidney Injury: Oxidative Damage as a Unifying Mechanism

Cadmium is a nonessential metal that has heavily polluted the environment due to human activities. It can be absorbed into the human body via the gastrointestinal tract, respiratory tract, and the skin, and can cause chronic damage to the kidneys. The main site where cadmium accumulates and causes damage within the nephrons is the proximal tubule. This accumulation can induce dysfunction of the mitochondrial electron transport chain, leading to electron leakage and production of reactive oxygen species (ROS). Cadmium may also impair the function of NADPH oxidase, resulting in another source of ROS. These ROS together can cause oxidative damage to DNA, proteins, and lipids, triggering epithelial cell death and a decline in kidney function. In this article, we also reviewed evidence that the antioxidant power of plant extracts, herbal medicines, and pharmacological agents could ameliorate cadmium-induced kidney injury. Finally, a model of cadmium-induced kidney injury, centering on the notion that oxidative damage is a unifying mechanism of cadmium renal toxicity, is also presented. Given that cadmium exposure is inevitable, further studies using animal models are warranted for a detailed understanding of the mechanism underlying cadmium induced ROS production, and for the identification of more therapeutic targets.

Evaluation of Leea rubra Leaf Extract for Oxidative Damage Protection and Antitumor and Antimicrobial Potential

Background. The leaves of Leea rubra contain an abundance of phenolic constituents and have medicinal uses as antipyretic and diaphoretic agents and are also used in the treatment of stomach ache, rheumatism, arthritis etc. In spite of the traditional uses, data on the scientific evaluation of the plant are not sufficient. So, the present study was designed to evaluate the protective role of the extract against oxidative damage to DNA and human erythrocytes as well as antitumor and antibacterial activities against some resistant bacteria. Methods. The protective activity of the ethyl acetate fraction (EAF) of the extract was investigated by evaluating the inhibition of oxidative damage of pUC19 plasmid DNA as well as hemolysis and lipid peroxidation damage to human erythrocytes induced by 2,2′-azobis-2-amidinopropane (AAPH). Antitumor activity was assessed by evaluating the percentage inhibition of cell growth, morphological changes of Ehrlich’s ascites carcinoma (EAC) cells, and hematological parameters. Antimicrobial activity was determined by the disc diffusion method against different resistant microorganisms. Results. EAF effectively inhibited AAPH-induced oxidative damage to DNA because it can inhibit the transformation of the supercoiled form of plasmid DNA to open circular and further linear form. The oxidative hemolysis caused by AAPH in human erythrocytes was inhibited by EAF extract in a time-dependent manner, and the production of malondialdehyde (MDA) was significantly reduced, which indicates the prevention of lipid peroxidation. In antitumor assay, 76% growth of inhibition of EAC was observed compared with the control mice ( p < 0.05 ) at a dose of 100 mg/kg body weight. Antimicrobial activity was evaluated against two pathogenic resistant microorganisms (Escherichia coli and Pseudomonas aeruginosa), and the highest antimicrobial activity was observed against Pseudomonas spp. Conclusion. EAF may have great importance in preventing oxidative damage to DNA, erythrocytes, and other cellular components as well as can be a good candidate in cancer chemotherapy and treating infectious diseases caused by antibiotic-resistant bacteria.

Hyperbilirubinemia Maintained by Chronic Supplementation of Unconjugated Bilirubin Improves the Clinical Course of Experimental Autoimmune Arthritis

Rheumatoid arthritis (RA) is a chronic multisystem disease, therapy of which remains a challenge for basic research. The present work examined the effect of unconjugated bilirubin (UCB) administration in adjuvant-induced arthritis (AIA)—an experimental model, in which oxidative stress (OS), inflammation and inadequate immune response are often similar to RA. Male Lewis rats were randomized into groups: CO—control, AIA—untreated adjuvant-induced arthritis, AIA-BIL—adjuvant-induced arthritis administrated UCB, CO-BIL—control with administrated UCB. UCB was administered intraperitoneally 200 mg/kg of body weight daily from 14th day of the experiment, when clinical signs of the disease are fully manifested, to 28th day, the end of the experiment. AIA was induced by a single intradermal immunization at the base of the tail with suspension of Mycobacterium butyricum in incomplete Freund’s adjuvant. Clinical, hematologic, biochemical and histologic examinations were performed. UCB administration to animals with AIA lead to a significant decrease in hind paws volume, plasma levels of C-reactive protein (CRP) and ceruloplasmin, drop of leukocytes, lymphocytes, erythrocytes, hemoglobin and an increase in platelet count. UCB administration caused significantly lowered oxidative damage to DNA in arthritic animals, whereas in healthy controls it induced considerable oxidative damage to DNA. UCB administration also induced atrophy of the spleen and thymus in AIA and CO animals comparing to untreated animals. Histological signs of joint damage assessed by neutrophils infiltration and deposition of fibrin were significantly reduced by UCB administration. The effects of exogenously administered UCB to the animals with adjuvant-induced arthritis might be identified as therapeutic, in contrast to the effects of UCB administration in healthy animals rather classified as toxic.

DNA interstrand cross-links induced by the major oxidative adenine lesion 7,8-dihydro-8-oxoadenine

Oxidative damage to DNA generates 7,8-dihydro-8-oxoguanine (oxoG) and 7,8-dihydro-8-oxoadenine (oxoA) as two major lesions. Despite the comparable prevalence of these lesions, the biological effects of oxoA remain poorly characterized. Here we report the discovery of a class of DNA interstrand cross-links (ICLs) involving oxidized nucleobases. Under oxidative conditions, oxoA, but not oxoG, readily reacts with an opposite base to produce ICLs, highlighting a latent alkylating nature of oxoA. Reactive halogen species, one-electron oxidants, and the myeloperoxidase/H2O2/Cl− system induce oxoA ICLs, suggesting that oxoA-mediated cross-links may arise endogenously. Nucleobase analog studies suggest C2-oxoA is covalently linked to N2-guanine and N3-adenine for the oxoA-G and oxoA-A ICLs, respectively. The oxoA ICLs presumably form via the oxidative activation of oxoA followed by the nucleophilic attack by an opposite base. Our findings provide insights into oxoA-mediated mutagenesis and contribute towards investigations of oxidative stress-induced ICLs and oxoA-based latent alkylating agents.

THE DEGREE OF OXIDATIVE DAMAGE TO DNA IN VITRO AS A MOLECULAR PREDICTOR OF DISORDERS CAUSED BY EPIGENETIC AND EXOGENOUS FACTORS

In this work, we studied the mechanisms of oxidative damage to DNA molecules isolated from whole blood of healthy donors and patients with epigenetic disease (epidermolysis bullosa) when exposed to an alternating magnetic field of low frequency in vitro, associated with the formation of reactive oxygen species.

A multilayered repair system protects the mycobacterial chromosome from endogenous and antibiotic-induced oxidative damage

Oxidative damage to DNA is a threat to the genomic integrity and coding accuracy of the chromosomes of all living organisms. Guanine is particularly susceptible to oxidation, and 8-oxo-dG (OG), when produced in situ or incorporated by DNA polymerases, is highly mutagenic due to mispairing with adenine. In many bacteria, defense against OG depends on MutT enzymes, which sanitize OG in the nucleotide pool, and the MutM/Y system, which counteracts OG in chromosomal DNA. InEscherichia coli, antibiotic lethality has been linked to oxidative stress and the downstream consequences of OG processing. However, in mycobacteria, the role of these systems in genomic integrity and antibiotic lethality is not understood, in part because mycobacteria encode four MutT enzymes and two MutMs, suggesting substantial redundancy. Here, we definitively probe the role of OG handling systems in mycobacteria. We find that, although MutT4 is the only MutT enzyme required for resistance to oxidative stress, this effect is not due to OG processing. We find that the dominant system that defends against OG-mediated mutagenesis is MutY/MutM1, and this system is dedicated to in situ chromosomal oxidation rather than correcting OG incorporated by accessory polymerases (DinB1/DinB2/DinB3/DnaE2). In addition, we uncover that mycobacteria resist antibiotic lethality through nucleotide sanitization by MutTs, and in the absence of this system, accessory DNA polymerases and MutY/M contribute to antibiotic-induced lethality. These results reveal a complex, multitiered system of OG handling in mycobacteria with roles in oxidative stress resistance, mutagenesis, and antibiotic lethality.

OXIDATIVE DAMAGE TO DNA, IONIZING RADIATION AND MAGNETIC FIELDS

In this work, we studied the mechanisms of damage to the structure of DNA extracted from human whole blood after exposure to blood samples of various types of ionizing radiation and a lowfrequency magnetic field. Oxidative damage of nitrogenous bases and single-stranded DNA breaks are caused by the formation of reactive oxygen species generated by radiation.

Graphene oxide-silver nanoparticle nanocomposites induces apoptosis in caprine fetal fibroblast cells via induction of oxidative stress

Background: Graphene oxide (GO) has drawn much attention as excellent platform to which silver nanoparticles (AgNPs) can be anchored for the production of biomedical nanocomposites. Yet, the potential toxicity of GO-AgNPs nanocomposites to animal and human is complex to evaluate and remains largely unknown. Results: Our data indicated that GO-AgNPs caused cytotoxicity in dose-dependent manner. GO-AgNPs induced significant cytotoxicity by the loss of cell viability, production of reactive oxygen species (ROS), cell cycle arrest, increasing leakage of lactate dehydrogenase (LDH) and level of Malondialdehyde (MDA), increasing expression of pro-apoptotic genes and decreasing expression of anti-apoptotic genes. Conclusions: Taken together, our study demonstrated that GO-AgNPs potentially induce oxidative damage to DNA, which result in toxicity and cell apoptosis in caprine fetal fibroblast cell due to an increased generation of ROS. It strongly suggests that applications of GO-AgNPs nanocomposite in animal must be further evaluated.