Emodin, a Phytotherapeutic Anthraquinone, Potently Attenuates Synaptic Redox Pathology in Aged Rats.

It is well appreciated that reactive oxygen species (ROS) are deleterious to mammals, including humans, especially when generated in abnormally large quantities from cellular metabolism. Whereas the mechanisms leading to the production of ROS are rather well delineated, the mechanisms underlying tissue susceptibility or tolerance to oxidant stress remain elusive. Through an experimental selection over many generations, we have previously generated Drosophila melanogaster flies that tolerate tremendous oxidant stress and have shown that the family of antimicrobial peptides (AMPs) is over-represented in these tolerant flies. Furthermore, we have also demonstrated that overexpression of even one AMP at a time (e.g. Diptericin) allows wild-type flies to survive much better in hyperoxia. In this study, we used a number of experimental approaches to investigate the potential mechanisms underlying hyperoxia tolerance in flies with AMP overexpression. We demonstrate that flies with Diptericin overexpression resist oxidative stress by increasing antioxidant enzyme activities and preventing an increase in ROS levels after hyperoxia. Depleting the GSH pool using buthionine sulfoximine limits fly survival, thus confirming that enhanced survival observed in these flies is related to improved redox homeostasis. We conclude that 1) AMPs play an important role in tolerance to oxidant stress, 2) overexpression of Diptericin changes the cellular redox balance between oxidant and antioxidant, and 3) this change in redox balance plays an important role in survival in hyperoxia.

Growing scientific evidence suggests that oxidative stress plays an important role in human health and disease. Under oxidative stress, the excess levels of reactive oxygen species (ROS) may lead to modification of cellular nucleic acids. Oxidatively damaged DNA has been recognized in association with the development of aging, cancer, and some degenerative diseases. The topics covered in this special edition give some insight into how oxidatively damaged DNA is involved in human disease and its health impacts. This special issue contains five papers. Two papers are related to human disease, including Keshan disease and chronic kidney disease, while two papers cover the underlying mechanisms of inflammation-related carcinogenesis and the association between DNA damage and antioxidant capacity in humans. Finally, a paper summarizes the literature regarding the effect of phytoagents on nucleic acid oxidation in cancer cells. Keshan disease (KD) is an endemic cardiomyopathy of unknown etiology affecting inhabitants of a narrow belt between Northeast China and Southwest China. This region is known for low levels of selenium in the environment as well as in food. In an original research article entitled “Oxidative stress is involved in the pathogenesis of Keshan disease (an endemic dilated cardiomyopathy) in China,” J. Pei et al. demonstrate that oxidative stress in the myocardium may play a crucial role in KD. The authors found elevated 8-oxodG levels in myocardial nuclei of the KD patients. Moreover, the expression of glutathione peroxidase 1 and thioredoxin reductases 1 (selenoproteins) was important in the antioxidant system of the organism and higher in the control group than in patients suffering from KD. In a review article entitled “Oxidative stress and nucleic acid oxidation in patients with chronic kidney disease,” C.-C. Sung et al. provide a systematic review of the role of oxidative stress in chronic kidney disease (CKD). It begins with the mechanisms of radical production, antioxidant defense, pathogenesis, and recent biomarkers of oxidative stress in CKD patients. The authors also summarized and evaluated the potential benefit of antioxidant therapies in CKD patients, although their value as useful therapeutic tools is being tested and future studies are necessary to validate their prospective beneficial effects on CKD. Infectious agents (e.g., parasites and viruses) have been identified as carcinogenic to humans (IARC, group 1). The underlying mechanism of their carcinogenicity includes inflammation accompanied by generation of reactive oxygen (ROS) and nitrogen species (RNS). In a review article entitled “DNA damage in inflammation-related carcinogenesis and cancer stem cells,” S. Ohnishi et al. propose a model by which chronic inflammation by infectious agents induces generation of cancer stem cells. The authors suggest that tissue injury caused by ROS/RNS may activate progenitor/stem cells for regeneration. Oxidative stress may then cause multiple mutations which may result in the formation of mutant stem cells and cancer stem cells thus leading to carcinogenesis. In an original research article entitled “Is the oxidative DNA damage level of human lymphocyte correlated with the antioxidant capacity of serum or the base excision repair activity of lymphocyte?,” Y.-C. Tsai et al. investigate the individual levels of oxidative DNA base damage in the human lymphocyte from different donors (healthy and infected patients) and its correlation with total antioxidant levels in the serum and the DNA base excision repair capacity. The most important finding is that antioxidant serum levels may not change the steady state levels of the oxidative base damage in the DNA. One should also consider that antioxidants in our body protect us in acute and highly stressful situations when we have high levels of ROS in a short time period rather than decrease the steady state levels. In a review article entitled “Phytoagents for cancer management: regulation of nucleic acid oxidation, ROS, and related mechanisms,” W.-L. Lee et al. present a detailed review of the role of phytoagents as redox regulators of nucleic acid oxidation in carcinogenesis. On the concept of genetic heterogeneity caused by nucleic acid oxidation as a major driving force of cancer progression, the authors highlight how and why phytoagents induce or prevent oxidative stress and their potential use in cancer prevention or therapy.

Increased seminal reactive oxygen species levels in patients with varicoceles correlate with varicocele grade but not with testis size

Ischemia/reperfusion (I/R) injury is a common clinical problem. Although the pathophysiological mechanisms underlying I/R injury are unclear, oxidative damage is considered a key factor in the initiation of I/R injury. Findings from preclinical studies consistently show that quenching reactive oxygen and nitrogen species (RONS), thus limiting oxidative damage, alleviates I/R injury. Results from clinical intervention studies on the other hand are largely inconclusive. In this study, we systematically evaluated the release of established biomarkers of oxidative and nitrosative damage during planned I/R of the kidney and heart in a wide range of clinical conditions. Sequential arteriovenous concentration differences allowed specific measurements over the reperfused organ in time. None of the biomarkers of oxidative and nitrosative damage (i.e., malondialdehyde, 15(S)-8-iso-prostaglandin F2α, nitrite, nitrate, and nitrotyrosine) were released upon reperfusion. Cumulative urinary measurements confirmed plasma findings. As of these negative findings, we tested for oxidative stress during I/R and found activation of the nuclear factor erythroid 2-related factor 2 (Nrf2), the master regulator of oxidative stress signaling. This comprehensive, clinical study evaluates the role of RONS in I/R injury in two different human organs (kidney and heart). Results show oxidative stress, but do not provide evidence for oxidative damage during early reperfusion, thereby challenging the prevailing paradigm on RONS-mediated I/R injury. Findings from this study suggest that the contribution of oxidative damage to human I/R may be less than commonly thought and propose a re-evaluation of the mechanism of I/R.

Muscle dysfunction is a common complication and an important prognostic factor in chronic obstructive pulmonary disease (COPD). As therapeutic strategies are still needed to treat this complication, gaining more insight into the process that leads to skeletal muscle decline in COPD appears to be an important issue. This review focuses on mitochondrial involvement in limb skeletal muscle alterations (decreased muscle mass, strength, endurance and power and increased fatigue) in COPD. Mitochondria are the main source of energy for the cells; they are involved in production of reactive oxygen species and activate an important pathway that leads to apoptosis. In COPD patients, skeletal muscles are characterized by decreased mitochondrial density and biogenesis, impaired activity and coupling of mitochondrial respiratory chain complexes, increased mitochondrial production of reactive oxygen species and, possibly, increased apoptosis. Of particular interest, a sedentary lifestyle, hypoxia, hypercapnia, tobacco smoking, corticosteroid therapy and, possibly, inflammation participate in this mitochondrial dysfunction, which is accessible to conventional therapies, such as exercise and tobacco cessation, as well as, potentially, to more innovative approaches, such as antioxidant treatment and supplementation with polyunsaturated fatty acids.

Cigarette smoking in infertile men is highly correlated with leukocytospermia and oxidative stress.

Mn Porphyrin-Based Redox Active Drugs Improve Anemia and Reduce Organ Damage in a Murine Model of Sickle Cell Disease

IntroductionAlectinib is a widely used first-line ALK inhibitor for fusion-positive non-small cell lung cancer. However, its clinical use is limited by hepatotoxicity, and its mechanism remains unclear. This study aims to elucidate how alectinib induces liver injury and to explore a potential protective strategy.MethodsIn vitro, AML-12 hepatocytes were incubated with alectinib to determine cell viability and morphology by using CCK-8 assay and optical microscopy, respectively. Necrosis was assessed by flow cytometry after Annexin V-FITC/PI staining. Mitochondrial damage was analyzed by measuring membrane potential, ultrastructure, and respiratory chain complex activities using JC-1 staining under fluorescence microscopy, transmission electron microscopy, and assay kits, respectively. Intracellular reactive oxygen species (ROS) levels were detected using DCFH-DA staining and flow cytometry. Pyroptosis- and oxidative stress-related proteins (NLRP3, GSDMD-N, P20, cleaved IL-1β, Nrf2, HO-1) were quantified by Western blot. In vivo, C57BL/6J mice were divided into control, alectinib treatment, and alectinib plus magnesium isoglycyrrhizinate (MgIG) treatment groups. Serum ALT and AST were measured to assess liver function. Hepatic oxidative stress was evaluated by SOD and MDA levels. Inflammatory cytokines including IL-1β and TNF-α were measured by corresponding kits. Liver histopathology was examined by hematoxylin-eosin staining.ResultsWe found alectinib could induce the death of AML-12 hepatocytes. Alectinib impaired both the function and structure of mitochondria and caused a significant increase in ROS levels. The excessive accumulation of ROS triggered oxidative stress and finally resulted in cell pyroptosis in AML-12 cells. MgIG was found to alleviate mitochondrial damage and reduce ROS levels, restore the Nrf2/HO-1 signaling pathway, thereby inhibiting oxidative stress and pyroptosis caused by alectinib.ConclusionAlectinib induces elevated ROS levels in hepatocytes by damaging mitochondria and causing oxidative stress in hepatocytes, which results in cell pyroptosis and ultimately hepatotoxicity, whereas MgIG can treat alectinib-induced hepatic injury by restoring mitochondrial function and structure.

The anthocyanin cyanidin-3- O-β-glucoside, a flavonoid, increases hepatic glutathione synthesis and protects hepatocytes against reactive oxygen species during hyperglycemia: Involvement of a cAMP–PKA-dependent signaling pathway

Mercury is a well-known toxicant and found to increase the production of reactive oxygen species (ROS) thereby leading to oxidative stress and cellular damage. The brain being the oxygen metabolizing organ is extremely sensitive to oxidative damage produced by mercury because of its relatively lower levels of antioxidant mechanisms resulting in brain damage/cerebrotoxicity. The increase in ROS levels may lead to increased oxidative stress, mitochondrial damage, and inflammatory responses resulting in aging, and neurodegenerative and neuropsychiatric diseases. Nrf2 is a key transcriptional factor that induces the expression of various antioxidants and detoxifying enzymes thereby protecting against oxidative stress. Imperatorin is an active natural furanocoumarin compound extracted from Qianghuo, and Angelica having many biological properties such as antioxidant, anti-inflammatory, and anticancer and acts as calcium channel blockers. This study explores the role of imperatorin against mercury-induced oxidative damage in the brain through the activation of the Nrf2-signaling pathway. Rat models were treated with mercury chloride and imperatorin, and the tissue morphology, lipid-peroxidation, antioxidant, acetylcholinesterase, and corticotropin releasing hormone levels were analyzed to confirm the treatment effects. The potential effects of imperatorin on Nrf2 signaling were analyzed through molecular docking studies using Fangchinoline and 1VV as controls in Autodock vina and visualized in Biovia Discovery studio, followed by ADME analysis in SwissADME. The results were validated using molecular dynamic simulation using GROMACS. The histopathology, antioxidant, and lipid peroxidation results showed its ability to activate the Nrf2 pathway and increase antioxidant levels in the mercury chloride-treated group evidenced by elevated antioxidant levels. The binding affinity score of Imperatorin (- 8.2) < Fangchinoline (- 9.1) < 1VV (- 10.9) indicates lesser binding affinity of Imperatorin; however, MM-PBSA showed Imperatorin had better binding energy compared to Fangchinoline. ADME results showed that imperatorin showed 0 Lipinski violation, the ability to cross the blood-brain barrier, and lower synthetic accessibility, serving as a potential drug of interest compared to the controls. The protective mechanism of imperatorin arises from its antioxidant, anti-inflammatory, and antiapoptotic properties.

System χc- overexpression prevents 2-deoxy-d-ribose-induced β-cell damage

Studies have demonstrated that the induction of oxidative stress may be involved in brain tumor induction in rats by acrylonitrile. The present study examined whether acrylonitrile induces oxidative stress and DNA damage in rats and whether blood can serve as a valid surrogate for the biomonitoring of oxidative stress induced by acrylonitrile in the exposed population. Male Sprague-Dawley rats were treated with 0, 3, 30, 100, and 200 ppm acrylonitrile in drinking water for 28 days. One group of rats were also coadministered N-acetyl cysteine (NAC) (0.3% in diet) with acrylonitrile (200 ppm in drinking water) to examine whether antioxidant supplementation was protective against acrylonitrile-induced oxidative stress. Direct DNA strand breakage in white blood cells (WBC) and brain was measured using the alkaline comet assay. Oxidative DNA damage in WBC and brain was evaluated using formamidopyrimidine DNA glycosylase (fpg)-modified comet assay and with high-performance liquid chromatography-electrochemical detection. No significant increase in direct DNA strand breaks was observed in brain and WBC from acrylonitrile-treated rats. However, oxidative DNA damage (fpg comet and 8'hydroxyl-2-deoxyguanosine) in brain and WBC was increased in a dose-dependent manner. In addition, plasma levels of reactive oxygen species (ROS) increased in rats administered acrylonitrile. Dietary supplementation with NAC prevented acrylonitrile-induced oxidative DNA damage in brain and WBC. A slight, but significant, decrease in the GSH:GSSG ratio was seen in brain at acrylonitrile doses > 30 ppm. These results provide additional support that the mode of action for acrylonitrile-induced astrocytomas involves the induction of oxidative stress and damage. Significant associations were seen between oxidative DNA damage in WBC and brain, ROS formation in plasma, and the reported tumor incidences. Since oxidative DNA damage in brain correlated with oxidative damage in WBC, these results suggest that monitoring WBC DNA damage maybe a useful tool to assess acrylonitrile-induced oxidative stress in humans.

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Stress proteins and oxidative damage in a renal derived cell line exposed to inorganic mercury and lead

Exploiting cancer's antioxidative weakness through p53 with nanotoxicology.