Free radicals and oxidative stress: signaling mechanisms, redox basis for human diseases, and cell cycle regulation

2021 ◽  
Vol 22 ◽  
Author(s):  
Idris Zubairu Sadiq
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Free Radicals ◽  
Cell Cycle Progression ◽  
Redox Regulation ◽  
Second Messengers ◽  
Living System ◽  
Detoxification Enzymes ◽  
Antioxidant Defenses ◽  
Human Pathology

: Free radical contained one or more unpaired electrons in its valence shell, thus making it unstable, short-lived and highly reactive specie. Excessive generation of these free radicals ultimately leads to oxidative stress causing oxidation and damage to significant macromolecules in the living system and essentially disrupting signal transduction pathways and antioxidants equilibrium. At lower concentrations, ROS serves as “second messengers” influencing many physiological processes in the cell. However, at higher concentrations beyond cell capacity causes oxidative stress, which contributes to much human pathology such as diabetes, cancer, Parkinson’s disease, cardiovascular diseases, cataract, asthma, hypertension, atherosclerosis, arthritis and Alzheimer’s disease. Signaling pathways such as NF-κB, MAPKs, PI3K/Akt/ mTOR and Keap1-Nrf2-ARE modulates the detrimental effects of oxidative stress by increasing the expression of cellular antioxidant defenses, phase II detoxification enzymes and decreased production of ROS. Free radicals such as H2O2 are indeed needed for the advancement of cell cycle as these molecules influences DNA, proteins and enzymes in the cell cycle pathway. In the course of cell cycle progression, the cellular redox environment becomes more oxidized moving from G1 phase, becomes higher in G2/M and moderate in S phase. Signals in the form of an increase in cellular pro-oxidant levels are required and these signals are often terminated by a rise in the amount of antioxidants and MnSOD with a decrease in the level of cyclin D1 proteins. Therefore, understanding the mechanism of cell cycle redox regulation will help in therapy of many diseases.

scholarly journals Oxidative stress in dogs

2016 ◽  
Vol 37 (3) ◽  
pp. 1431 ◽  
Author(s):  
Claudia Russo ◽  
Ana Paula F. Rodrigues Loureiro Bracarense
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Free Radicals ◽  
Cell Membrane ◽  
The Body ◽  
Antioxidant Defenses ◽  
Cellular Respiration ◽  
Bodily Fluids ◽  
Cellular Components ◽  
Harmful Effects

Reactive oxygen species (ROS), also known as free radicals, are generated during cellular respiration. Under normal conditions, the body has the ability to neutralize the effects of free radicals by using its antioxidant defenses. In the case of an imbalance between oxidants and antioxidants, free radical production exceeds the capacity of organic combustion, resulting in oxidative stress. Of all the cellular components compromised by the harmful effects of ROS, the cell membrane is the most severely affected owing to lipid peroxidation, which invariably leads to changes in the membrane structure and permeability. With lipid peroxidation of the cell membrane, some by-products can be detected and measured in tissues, blood, and other bodily fluids. The measurement of biomarkers of oxidative stress is commonly used to quantify lipid peroxidation of the cell membrane in humans, a species in which ROS can be considered as a cause or consequence of oxidative stress-related diseases. In dogs, few studies have demonstrated this correlation. The present review aims to identify current literature knowledge relating to oxidative stress diseases and their detection in dogs.

scholarly journals Disrupted mitochondrial homeostasis coupled with mitotic arrest generates antineoplastic oxidative stress

Oncogene ◽  
2021 ◽  
Author(s):  
Xiaohe Hao ◽  
Wenqing Bu ◽  
Guosheng Lv ◽  
Limei Xu ◽  
Dong Hou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Oxidative Dna Damage ◽  
Underlying Mechanism ◽  
Mitochondrial Oxidative Stress ◽  
Mitochondrial Homeostasis ◽  
Mitochondrial Superoxide ◽  
Antineoplastic Effect ◽  
M Phase

AbstractReactive oxygen species (ROS) serve as critical signals in various cellular processes. Excessive ROS cause cell death or senescence and mediates the therapeutic effect of many cancer drugs. Recent studies showed that ROS increasingly accumulate during G2/M arrest, the underlying mechanism, however, has not been fully elucidated. Here, we show that in cancer cells treated with anticancer agent TH287 or paclitaxel that causes M arrest, mitochondria accumulate robustly and produce excessive mitochondrial superoxide, which causes oxidative DNA damage and undermines cell survival and proliferation. While mitochondrial mass is greatly increased in cells arrested at M phase, the mitochondrial function is compromised, as reflected by reduced mitochondrial membrane potential, increased SUMOylation and acetylation of mitochondrial proteins, as well as an increased metabolic reliance on glycolysis. CHK1 functional disruption decelerates cell cycle, spares the M arrest and attenuates mitochondrial oxidative stress. Induction of mitophagy and blockade of mitochondrial biogenesis, measures that reduce mitochondrial accumulation, also decelerate cell cycle and abrogate M arrest-coupled mitochondrial oxidative stress. These results suggest that cell cycle progression and mitochondrial homeostasis are interdependent and coordinated, and that impairment of mitochondrial homeostasis and the associated redox signaling may mediate the antineoplastic effect of the M arrest-inducing chemotherapeutics. Our findings provide insights into the fate of cells arrested at M phase and have implications in cancer therapy.

scholarly journals Circ_0124644 Serves as a ceRNA for miR-590-3p to Promote Hypoxia-Induced Cardiomyocytes Injury via Regulating SOX4

2021 ◽  
Vol 12 ◽  
Author(s):  
Juan Tan ◽  
Weinan Pan ◽  
Huilin Chen ◽  
Yafang Du ◽  
Peiyong Jiang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Circular Rna ◽  
Suppressive Effect ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Protein Levels ◽  
Stress Markers ◽  
Transcription Factor 4

Circular RNA (circRNA) is an important factor for regulating the progression of many cardiovascular diseases, including acute myocardial infarction (AMI). However, the role of circ_0124644 in AMI progression remains unclear. Hypoxia was used to induce cardiomyocytes injury. The expression of circ_0124644, microRNA (miR)-590-3p, and SRY-box transcription factor 4 (SOX4) mRNA was measured by qRT-PCR. Cell counting kit 8 (CCK8) assay and flow cytometry were utilized to detect cell viability, cell cycle progression, and apoptosis. The protein levels of apoptosis markers and SOX4 were determined by western blot (WB) analysis, and the levels of oxidative stress markers were assessed using commercial Assay Kits. Dual-luciferase reporter assay, RIP assay, and RNA pull-down assay were employed to confirm the interaction between miR-590-3p and circ_0124644 or SOX4. Circ_0124644 was upregulated in AMI patients and hypoxia-induced cardiomyocytes. Hypoxia could inhibit cardiomyocytes viability, cell cycle process, and promote apoptosis and oxidative stress, while silencing circ_0124644 could alleviate hypoxia-induced cardiomyocytes injury. In terms of mechanism, circ_0124644 could target miR-590-3p. MiR-590-3p overexpression could relieve hypoxia-induced cardiomyocytes injury. Also, the suppressive effect of circ_0124644 knockdown on hypoxia-induced cardiomyocytes injury could be reversed by miR-590-3p inhibitor. Moreover, SOX4 was found to be a target of miR-590-3p, and its overexpression also could reverse the regulation of miR-590-3p on hypoxia-induced cardiomyocytes injury. Circ_0124644 silencing could alleviate hypoxia-induced cardiomyocytes injury by regulating the miR-590-3p/SOX4 axis, suggesting that it might be a target for alleviating AMI.

scholarly journals Paradoxical Enhancement of Leukemogenesis in Acute Myeloid Leukemia Cells with Moderately Attenuated RUNX1 Expressions

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2710-2710
Author(s):  
Kensho Suzuki ◽  
Ken Morita ◽  
Shintaro Maeda ◽  
Hiroki Kiyose ◽  
Souichi Adachi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Myeloid Leukemia ◽  
Free Radicals ◽  
Protein Level ◽  
Myeloid Leukemia ◽  
Cell Cycle Progression ◽  
Leukemia Cells ◽  
Cycle Progression ◽  
Runx1 Expression ◽  
Acute Myeloid

Abstract Although Runt-related transcription factor 1 (RUNX1), a member of RUNX transcription family, is known for its oncogenic role in the development of acute myeloid leukemia (AML), evidence from other groups support the oncosuppressive property of RUNX1 in leukemia cells, casting a question over the bidirectional function of RUNX1 and it is currently highly controversial. Here we report that the dual function of RUNX1 possibly arise from the total level of RUNX family expressions. To examine the precise mechanism of RUNX1 expression in leukemogenesis, we first prepared several tetracycline-inducible short hairpin RNAs (shRNAs) which could attenuate the expressions of RUNX1 at different levels in AML cells (MV4-11 and MOLM-13 cells). Intriguingly, while AML cells transduced with shRNAs which could down-regulate RUNX1 expression below 10% at protein level (sh_Rx1_profound) deteriorated the proliferation speed of AML cells, AML cells transduced with shRNAs which could moderately down-regulate RUNX1 expression to 70% at protein level (sh_Rx1_moderate) paradoxically promoted the cell cycle progression and doubled the growth rate of AML cells. Besides, RUNX1-moderately expressing AML patient cohort exhibited the worse outcome compared to RUNX1-high or RUNX1-low expressing cohorts (n = 187), indicating an underlying mechanism that confer growth advantage to AML cells with moderately inhibited RUNX1 expressions. To further investigate the correspondent gene in this paradoxical enhancement of oncogenesis in sh_Rx1_moderate-transduced AML cells, we performed comprehensive gene expression array and extracted genes that are highly up-regulated in RUNX1 moderate inhibition and down-regulated in AML cells transduced with sh_Rx1_profound. We hereafter focused on the top-listed gene glutathione S-transferase alpha 2 (GSTA2) and addressed the interaction of RUNX1 and GSTA2 and their functions in AML cells. Real time quantitative PCR (RT-qPCR) and immunoblotting revealed that the expression of GSTA2 was actually up-regulated in sh_Rx1_moderate-transduced AML cells and down-regulated in AML cells transduced with sh_Rx1_profound. Interestingly, equivalent level of compensatory up-regulation of RUNX2 and RUNX3 were observed in sh_Rx1_moderate- and sh_Rx1_profound-transduced AML cells, creating an absolute gap in the expression of total amount of RUNX (RUNX1 + RUNX2 + RUNX3), which was confirmed by RT-qPCR (total amount of RUNX expressions were estimated by primers amplifying the specific sequence common to all RUNX family members). Luciferase reporter assay of GSTA2 promoter and chromatin immunoprecipitation (ChIP) assay in the proximal promoter region of GSTA2 gene proved the association of RUNX family members with this genomic region. These results indicated that total amount of RUNX family expressions modulate the expression of GSTA2 in AML cells, which might results in a paradoxical outbursts of RUNX1 moderately-inhibited AML cells. Since GSTA2 catabolizes and scavenges free radicals such as hydrogen peroxide (H2O2), and decreased intracellular free radicals promote acceleration of cell cycle progression, we next measured the intracellular accumulation of H2O2 in RUNX1 inhibited AML cells. As we have expected, intracellular amount of H2O2 was decreased in sh_Rx1_moderate-transduced AML cells and increased in AML cells transduced with sh_Rx1_profound. Additive transduction of sh_RNAs targeting GSTA2 to AML cells with sh_Rx1_moderate reverted the proliferation speed to the control level, underpinning that growth advantage of moderate RUNX1 inhibition could be attributed to the GSTA2 overexpressions. Taken together, these findings indicate that moderately attenuated RUNX1 expressions paradoxically enhance leukemogenesis in AML cells through intracellular environmental change via GSTA2, which could be a novel therapeutic target in anti-leukemia strategy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Antioxidant Drug Design: Historical and Recent Developments

2021 ◽  
pp. 36-56
Author(s):  
Melford C. Egbujor ◽  
Samuel A. Egu ◽  
Vivian I. Okonkwo ◽  
Alifa D. Jacob ◽  
Pius I. Egwuatu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Free Radicals ◽  
Drug Design ◽  
The Body ◽  
Antioxidant Defenses ◽  
Cell Aging ◽  
High Demand ◽  
Chain Reactions ◽  
Single Piece ◽  
Recent Developments

The sustained interest in the design of potent antioxidants drugs over the years can be attributed to the indispensable roles antioxidants play in the mitigation of oxidative stress and its concomitant diseases. The high demand for exogenous antioxidants has been ascribed to the prevalence of oxidative stress-mediated diseases such as cancer, diabetes, stroke, cell aging, arteriosclerosis and central nervous system disorders occasioned by a biochemical disequilibrium between the production of free radicals and the body’s ability to eliminate these reactive species from the biological system. COVID-19 severity and death have been linked to a free radical generating process known as the cytokine storm. In an attempt to maintain optimal body function, antioxidant supplementation has increasingly become a wide spread practice because of antioxidants’ ability to directly scavenge free radicals, inhibit oxidative chain reactions thereby increasing the antioxidant defenses of the body. Recent data showed that researchers had made significant efforts to demonstrate the importance and timeliness of antioxidant therapy based on drug design from natural and synthetic sources. Therefore this review presents antioxidant drug design methodologies, identifying the lead and hits to provide a historical and up-to-date collection of research briefs on antioxidant drug design into a single piece in order to ensure easy accessibility, motivate readership and inspire future researches.

scholarly journals Day/Night Separation of Oxygenic Energy Metabolism and Nuclear DNA Replication in the Unicellular Red AlgaCyanidioschyzon merolae

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Shin-ya Miyagishima ◽  
Atsuko Era ◽  
Tomohisa Hasunuma ◽  
Mami Matsuda ◽  
Shunsuke Hirooka ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Dna Replication ◽  
Energy Metabolism ◽  
Cell Cycle Progression ◽  
Nuclear Dna ◽  
S Phase ◽  
Cycle Progression ◽  
Content Type

ABSTRACTThe transition from G1to S phase and subsequent nuclear DNA replication in the cells of many species of eukaryotic algae occur predominantly during the evening and night in the absence of photosynthesis; however, little is known about how day/night changes in energy metabolism and cell cycle progression are coordinated and about the advantage conferred by the restriction of S phase to the night. Using a synchronous culture of the unicellular red algaCyanidioschyzon merolae, we found that the levels of photosynthetic and respiratory activities peak during the morning and then decrease toward the evening and night, whereas the pathways for anaerobic consumption of pyruvate, produced by glycolysis, are upregulated during the evening and night as reported recently in the green algaChlamydomonas reinhardtii. Inhibition of photosynthesis by 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU) largely reduced respiratory activity and the amplitude of the day/night rhythm of respiration, suggesting that the respiratory rhythm depends largely on photosynthetic activity. Even when the timing of G1/S-phase transition was uncoupled from the day/night rhythm by depletion of retinoblastoma-related (RBR) protein, the same patterns of photosynthesis and respiration were observed, suggesting that cell cycle progression and energy metabolism are regulated independently. Progression of the S phase under conditions of photosynthesis elevated the frequency of nuclear DNA double-strand breaks (DSB). These results suggest that the temporal separation of oxygenic energy metabolism, which causes oxidative stress, from nuclear DNA replication reduces the risk of DSB during cell proliferation inC. merolae.IMPORTANCEEukaryotes acquired chloroplasts through an endosymbiotic event in which a cyanobacterium or a unicellular eukaryotic alga was integrated into a previously nonphotosynthetic eukaryotic cell. Photosynthesis by chloroplasts enabled algae to expand their habitats and led to further evolution of land plants. However, photosynthesis causes greater oxidative stress than mitochondrion-based respiration. In seed plants, cell division is restricted to nonphotosynthetic meristematic tissues and populations of photosynthetic cells expand without cell division. Thus, seemingly, photosynthesis is spatially sequestrated from cell proliferation. In contrast, eukaryotic algae possess photosynthetic chloroplasts throughout their life cycle. Here we show that oxygenic energy conversion (daytime) and nuclear DNA replication (night time) are temporally sequestrated inC. merolae. This sequestration enables “safe” proliferation of cells and allows coexistence of chloroplasts and the eukaryotic host cell, as shown in yeast, where mitochondrial respiration and nuclear DNA replication are temporally sequestrated to reduce the mutation rate.

scholarly journals Genistein contributes to cell cycle progression and regulates oxidative stress in primary culture of osteoblasts along with osteoclasts attenuation

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Sahabjada Siddiqui ◽  
Abbas Ali Mahdi ◽  
Md Arshad
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cathepsin K ◽  
Neonatal Rat ◽  
Calcium Deposition ◽  
Tartrate Resistant Acid Phosphatase ◽  
Antioxidant Ability ◽  
Cycle Progression ◽  
Trap Staining

Abstract Background The present study was designed to examine the role of isoflavone genistein (GS) on bone formation, regulating oxidative stress and cell cycle in primary osteoblasts, as well as attenuation of osteoclast formation. Methods Primary calvaria osteoblasts were isolated from 2 to 3 days old neonatal rat pups (n = 6–8) of Sprague Dawley rats. Osteoblasts were incubated with varying concentrations of GS and different assays viz. cell proliferation, differentiation, calcium deposition, cell cycle progression, antioxidant ability, and osteogenic gene expression were performed. Tartrate-resistant acid phosphatase (TRAP) staining and immunolocalization of cathepsin K protein were assessed in bone marrow-derived osteoclasts. Results Results revealed that GS markedly induced cell growth and osteoblast differentiation depending upon dose. The fluorescent dye DCFH-DA staining data proved the antioxidant ability of GS, which reduced the H2O2- induced intracellular oxidative stress in osteoblasts. Quantitative real-time PCR analysis revealed that GS treatment upregulated the expression of osteoblastic genes of Runt-related transcription factor 2 (Runx2), bone morphogenetic proteins 2 (BMP2), and osteocalcin. Immunolocalization of BMP2 also indicated the osteogenic efficacy of GS. Furthermore, TRAP staining and cathepsin K expression depicted that GS inhibited multinucleated osteoclasts formation. Conclusions In conclusion, GS isoflavone might impart protective effects against oxidative stress-induced bone loss and thus, could maintain skeletal growth.

Redox factor-1 contributes to the regulation of progression from G0/G1 to S by PDGF in vascular smooth muscle cells

2003 ◽  
Vol 285 (2) ◽  
pp. H804-H812 ◽  
Author(s):  
Tongrong He ◽  
Neal L. Weintraub ◽  
Prabhat C. Goswami ◽  
Papri Chatterjee ◽  
Dawn M. Flaherty ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Smooth Muscle ◽  
Dna Binding ◽  
Cell Cycle Progression ◽  
Redox Regulation ◽  
Excision Repair ◽  
Chemical Reduction ◽  
Cell Cycle Control ◽  
S Phase ◽  
Nuclear Extracts

Redox factor-1 (Ref-1/APE), a multifunctional DNA base excision repair and redox regulation enzyme, plays an important role in oxidative signaling, transcription factor regulation, and cell cycle control. We hypothesized that Ref-1 plays a regulatory role in smooth muscle cell (SMC) proliferation induced by PDGF. Ref-1 antisense oligodeoxynucleotides (AODN), which diminished the level of Ref-1 protein in SMCs by ∼50%, inhibited PDGF-BB (composed of the homodimer of B-polypeptide chain)-induced [3H]thymidine incorporation compared with control oligodeoxynucleotides. Ref-1 AODN inhibited PDGF-BB-induced S phase entry by ∼63%, which was overcome by overexpression of Ref-1 by adenoviral-mediated gene transfer. Overexpression of Ref-1 alone without PDGF enhanced SMC entry into the S phase. Furthermore, decreasing Ref-1 protein by treatment of SMCs with Ref-1 AODN, or by immunodepletion of Ref-1 from nuclear extracts, inhibited PDGF-BB-induced activator protein-1 (AP-1) DNA binding activity. Chemical reduction restored the AP-1 DNA binding in Ref-1-depleted nuclear extracts. These results suggest that Ref-1 contributes to the regulation of PDGF-BB-stimulated cell cycle progression from G0/G1 to S in SMCs, with one of the possible steps being redox-regulation of AP-1 by Ref-1 protein.

scholarly journals Antioxidants and Second Messengers of Free Radicals

Antioxidants ◽  
2018 ◽  
Vol 7 (11) ◽  
pp. 158 ◽  
Author(s):  
Neven Zarkovic
Keyword(s):  
Oxidative Stress ◽  
Clinical Trials ◽  
Free Radicals ◽  
Second Messengers ◽  
Experimental Models ◽  
Redox Signaling

In the recent years, numerous research on the pathology of oxidative stress has been completed by intense studies on redox signaling implementing various experimental models and clinical trials. [...]

scholarly journals Mitochondrial Dysfunctions and Altered Metals Homeostasis: New Weapons to Counteract HCV-Related Oxidative Stress

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Mario Arciello ◽  
Manuele Gori ◽  
Clara Balsano
Keyword(s):  
Oxidative Stress ◽  
Free Radicals ◽  
Metabolic Pathways ◽  
Energy Production ◽  
Power Plants ◽  
Focal Point ◽  
Antioxidant Defenses ◽  
Host Organism ◽  
Mitochondrial Dysfunctions

The hepatitis C virus (HCV) infection produces several pathological effects in host organism through a wide number of molecular/metabolic pathways. Today it is worldwide accepted that oxidative stress actively participates in HCV pathology, even if the antioxidant therapies adopted until now were scarcely effective. HCV causes oxidative stress by a variety of processes, such as activation of prooxidant enzymes, weakening of antioxidant defenses, organelle damage, and metals unbalance. A focal point, in HCV-related oxidative stress onset, is the mitochondrial failure. These organelles, known to be the “power plants” of cells, have a central role in energy production, metabolism, and metals homeostasis, mainly copper and iron. Furthermore, mitochondria are direct viral targets, because many HCV proteins associate with them. They are the main intracellular free radicals producers and targets. Mitochondrial dysfunctions play a key role in the metal imbalance. This event, today overlooked, is involved in oxidative stress exacerbation and may play a role in HCV life cycle. In this review, we summarize the role of mitochondria and metals in HCV-related oxidative stress, highlighting the need to consider their deregulation in the HCV-related liver damage and in the antiviral management of patients.

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