The triage theory posits that modest micronutrient deficiencies may induce reallocation of nutrients to processes necessary for immediate survival at the expense of long-term health. Neglected processes could in time contribute to the onset of age-related diseases, in which oxidative stress is believed to be a major factor. Vitamin B12 (B12) appears to possess antioxidant properties. This review aims to summarise the potential antioxidant mechanisms of B12 and investigate B12 status in relation to oxidative stress markers. A systematic query-based search of PubMed was performed to identify eligible publications. The potential antioxidant properties of B12 include: (1) direct scavenging of reactive oxygen species (ROS), particularly superoxide; (2) indirect stimulation of ROS scavenging by preservation of glutathione; (3) modulation of cytokine and growth factor production to offer protection from immune response-induced oxidative stress; (4) reduction of homocysteine-induced oxidative stress; and (5) reduction of oxidative stress caused by advanced glycation end products. Some evidence appears to suggest that lower B12 status is related to increased pro-oxidant and decreased antioxidant status, both overall and for subclinically deficient individuals compared to those with normal B12 status. However, there is a lack of randomised controlled trials and prospective studies focusing specifically on the relation between B12 and oxidative stress in humans, resulting in a low strength of evidence. Further work is warranted.

https://www.mdpi.com/2072-6643/11/2/482/pdf

Vitamin B12 in Relation to Oxidative Stress: A Systematic Review.

Gross chromosomal rearrangements (including translocations, deletions, insertions and duplications) are a hallmark of cancer genomes and often create oncogenic fusion genes. An obligate step in the generation of such gross rearrangements is the formation of DNA double-strand breaks (DSBs). Since the genomic distribution of rearrangement breakpoints is non-random, intrinsic cellular factors may predispose certain genomic regions to breakage. Notably, certain DNA sequences with the potential to fold into secondary structures [potential non-B DNA structures (PONDS); e.g. triplexes, quadruplexes, hairpin/cruciforms, Z-DNA and single-stranded looped-out structures with implications in DNA replication and transcription] can stimulate the formation of DNA DSBs. Here, we tested the postulate that these DNA sequences might be found at, or in close proximity to, rearrangement breakpoints. By analyzing the distribution of PONDS-forming sequences within ±500 bases of 19 947 translocation and 46 365 sequence-characterized deletion breakpoints in cancer genomes, we find significant association between PONDS-forming repeats and cancer breakpoints. Specifically, (AT)n, (GAA)n and (GAAA)n constitute the most frequent repeats at translocation breakpoints, whereas A-tracts occur preferentially at deletion breakpoints. Translocation breakpoints near PONDS-forming repeats also recur in different individuals and patient tumor samples. Hence, PONDS-forming sequences represent an intrinsic risk factor for genomic rearrangements in cancer genomes.

/pdf/translocation-and-deletion-breakpoints-in-cancer-genomes-are-tniahxa4hw.pdf

Translocation and deletion breakpoints in cancer genomes are associated with potential non-B DNA-forming sequences.

Background Radiotherapy is a treatment modality for cancer. For better therapeutic efficiency, it could be used in combination with surgery, chemotherapy or immunotherapy. In addition to its beneficial therapeutic effects, exposure to radiation leads to several toxic effects on normal tissues. Also, it may induce some changes in genomic expression of tumor cells, thereby increasing the resistance of tumor cells. These changes lead to the appearance of some acute reactions in irradiated organs, increased risk of carcinogenesis, and reduction in the therapeutic effect of radiotherapy. Discussion So far, several studies have proposed different targets such as cyclooxygenase-2 (COX-2), some toll-like receptors (TLRs), mitogen-activated protein kinases (MAPKs) etc., for the amelioration of radiation toxicity and enhancing tumor response. NADPH oxidase includes five NOX and two dual oxidases (DUOX1 and DUOX2) subfamilies that through the production of superoxide and hydrogen peroxide, play key roles in oxidative stress and several signaling pathways involved in early and late effects of ionizing radiation. Chronic ROS production by NOX enzymes can induce genomic instability, thereby increasing the risk of carcinogenesis. Also, these enzymes are able to induce cell death, especially through apoptosis and senescence that may affect tissue function. ROS-derived NADPH oxidase causes apoptosis in some organs such as intestine and tongue, which mediate inflammation. Furthermore, continuous ROS production stimulates fibrosis via stimulation of fibroblast differentiation and collagen deposition. Evidence has shown that in contrast to normal tissues, the NOX system induces tumor resistance to radiotherapy through some mechanisms such as induction of hypoxia, stimulation of proliferation, and activation of macrophages. However, there are some contradictory results. Inhibition of NADPH oxidase in experimental studies has shown promising results for both normal tissue protection and tumor sensitization to ionizing radiation. Conclusion In this article, we aimed to review the role of different subfamilies of NADPH oxidase in radiation-induced early and late normal tissue toxicities in different organs.

NADPH Oxidase as a Target for Modulation of Radiation Response; Implications to Carcinogenesis and Radiotherapy.

Oxidized extracellular DNA as a stress signal that may modify response to anticancer therapy

Damage-associated molecular patterns in tumor radiotherapy.

Background 
Cell free DNA (cfDNA) circulates throughout the bloodstream of both healthy people and patients with various diseases and acts upon the cells. Response to cfDNA depends on concentrations and levels of the damage within cfDNA. Oxidized extracellular DNA acts as a stress signal and elicits an adaptive response.


Principal Findings 
Here we show that oxidized extracellular DNA stimulates the survival of MCF-7 tumor cells. Importantly, in cells exposed to oxidized DNA, the suppression of cell death is accompanied by an increase in the markers of genome instability. Short-term exposure to oxidized DNA results in both single- and double strand DNA breaks. Longer treatments evoke a compensatory response that leads to a decrease in the levels of chromatin fragmentations across cell populations. Exposure to oxidized DNA leads to a decrease in the activity of NRF2 and an increase in the activity of NF-kB and STAT3. A model that describes the role of oxidized DNA released from apoptotic cells in tumor biology is proposed.


Conclusions/Significance 
Survival of cells with an unstable genome may substantially augment progression of malignancy. Further studies of the effects of extracellular DNA on malignant and normal cells are warranted.

/pdf/an-exposure-to-the-oxidized-dna-enhances-both-instability-of-4dvkjeew77.pdf

An exposure to the oxidized DNA enhances both instability of genome and survival in cancer cells.

We have hypothesized that the adaptive response to low doses of ionizing radiation (IR) is mediated by oxidized cell-free DNA (cfDNA) fragments. Here, we summarize our experimental evidence for this model. Studies involving measurements of ROS, expression of the NOX (superoxide radical production), induction of apoptosis and DNA double-strand breaks, antiapoptotic gene expression and cell cycle inhibition confirm this hypothesis. We have demonstrated that treatment of mesenchymal stem cells (MSCs) with low doses of IR (10 cGy) leads to cell death of part of cell population and release of oxidized cfDNA. cfDNA has the ability to penetrate into the cytoplasm of other cells. Oxidized cfDNA, like low doses of IR, induces oxidative stress, ROS production, ROS-induced oxidative modifications of nuclear DNA, DNA breaks, arrest of the cell cycle, activation of DNA reparation and antioxidant response, and inhibition of apoptosis. The MSCs pretreated with low dose of irradiation or oxidized cfDNA were equally effective in induction of adaptive response to challenge further dose of radiation. Our studies suggest that oxidized cfDNA is a signaling molecule in the stress signaling that mediates radiation-induced bystander effects and that it is an important component of the development of radioadaptive responses to low doses of IR.

/pdf/low-dose-ionizing-radiation-affects-mesenchymal-stem-cells-yec4tsosq5.pdf

Low-Dose Ionizing Radiation Affects Mesenchymal Stem Cells via Extracellular Oxidized Cell-Free DNA: A Possible Mediator of Bystander Effect and Adaptive Response

Background Cell free DNA (cfDNA) circulates throughout the bloodstream of both healthy people and patients with various diseases CfDNA is substantially enriched in its GC-content as compared with human genomic DNA Principal Findings Exposure of haMSCs to GC-DNA induces short-term oxidative stress (determined with H2DCFH-DA) and results in both single- and double-strand DNA breaks (comet assay and γH2AX, foci) As a result in the cells significantly increases the expression of repair genes (BRCA1 (RT-PCR), PCNA (FACS)) and antiapoptotic genes (BCL2 (RT-PCR and FACS), BCL2A1, BCL2L1, BIRC3, and BIRC2 (RT-PCR)) Under the action of GC-DNA the potential of mitochondria was increased Here we show that GC-rich extracellular DNA stimulates adipocyte differentiation of human adipose-derived mesenchymal stem cells (haMSCs) Exposure to GC-DNA leads to an increase in the level of RNAPPARG2 and LPL (RT-PCR), in the level of fatty acid binding protein FABP4 (FACS analysis) and in the level of fat (Oil Red O) Conclusions GC-rich fragments in the pool of cfDNA can potentially induce oxidative stress and DNA damage response and affect the direction of mesenchymal stem cells differentiation in human adipose—derived mesenchymal stem cells Such a response may be one of the causes of obesity or osteoporosis

/pdf/gc-rich-extracellular-dna-induces-oxidative-stress-double-3z0okjgguw.pdf

Sergey V. Stukalov

Papers

An exposure to the oxidized DNA enhances both instability of genome and survival in cancer cells.

Low-Dose Ionizing Radiation Affects Mesenchymal Stem Cells via Extracellular Oxidized Cell-Free DNA: A Possible Mediator of Bystander Effect and Adaptive Response

GC-Rich Extracellular DNA Induces Oxidative Stress, Double-Strand DNA Breaks, and DNA Damage Response in Human Adipose-Derived Mesenchymal Stem Cells.