Redox signaling: an evolution from free radicals to aging

Forman, Henry Jay

doi:10.1016/j.freeradbiomed.2016.04.162

Cited by 10 publications

(15 citation statements)

References 58 publications

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“…1). We further relate this specificity to cellular redox regulation, supporting a role for redox conditions and superoxide and NO in regulation of proliferation which was suggested 30 years ago (44, 14, 45 reviewed in 46,47). We hypothesized that the induction of cell proliferation by UVA may be caused by changes in intracellular levels of ROS and RNS (34, 35).…”

Section: Discussionsupporting

confidence: 72%

Cell type-specific differences in redox regulation and proliferation after low UVA doses

Ciesielska

Bil

Gajda

et al. 2018

Preprint

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21Ultraviolet A (UVA) radiation is harmful for living organisms but in low doses may 22 stimulate cell proliferation. Our aim was to examine the relationships between exposure 23 to different low UVA doses, cellular proliferation, and changes in cellular reactive 24 oxygen species levels. In human colon cancer (HCT116) and melanoma (Me45) cells 25 exposed to UVA doses comparable to environmental, the highest doses (30-50 kJ/m 2 ) 26 reduced clonogenic potential but some lower doses (1 and 10 kJ/m 2 ) induced 27 proliferation. This effect was cell type and dose specific. In both cell lines the levels of 28 reactive oxygen species and nitric oxide fluctuated with dynamics which were 29 influenced differently by UVA; in Me45 cells decreased proliferation accompanied the 30 changes in the dynamics of H 2 O 2 while in HCT116 cells those of superoxide. Genes 31 coding for proteins engaged in redox systems were expressed differently in each cell 32 line; transcripts for thioredoxin, peroxiredoxin and glutathione peroxidase showed 33 higher expression in HCT116 cells whereas those for glutathione transferases and 34 copper chaperone were more abundant in Me45 cells. We conclude that these two cell 35 types utilize different pathways for regulating their redox status. Many mechanisms 36 engaged in maintaining cellular redox balance have been described. Here we show that 37 the different cellular responses to a stimulus such as a specific dose of UVA may be 38 consequences of the use of different redox control pathways. Assays of superoxide and 39 hydrogen peroxide level changes after exposure to UVA may clarify mechanisms of 40 cellular redox regulation and help in understanding responses to stressing factors. 41 42 43 44 Ciesielska 3 45 46 48with a wavelength of 100-400 nm, invisible to human sight. The sun is a natural emitter 49 of UV divided into three main fractions UVA (315-400 nm), UVB (280-315 nm), and 50 UVC (100-280 nm), but most of this radiation is blocked by the atmosphere (1,2). UVA 51 constitutes the largest part (∼95%) of UV radiation that reaches the Earth's surface (3), 52whereas UVB represents only 4-5% (1). In irradiated humans UVA reaches the dermis 53 and hypodermis and has no direct impact on DNA, but it can influence cellular 54 structures indirectly by induction of reactive oxygen species (ROS) which can damage 55 macromolecules (4,1). For a long time UV was regarded as damaging for cells and 56 organisms (5), but since a few decades it is known that low doses can also stimulate 57 proliferation of cells; however, the mechanisms underlying this phenomenon are not 58 completely understood (3,1,6,7). 59Studies of signaling pathways in conditions where UVA stimulates cell proliferation 60 show changes in the levels of proteins engaged in controlling proliferation such as 61 cyclin D1 (8,9), Pin1 (3), and Kin17 (10) or activation of epidermal growth factor 62 receptor (EGFR) which is strongly mitogenic in many cell types (8). Experiments on 63 mice showed that UVA can accelerate tumor growth ...

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Section: Discussionsupporting

confidence: 72%

Cell type-specific differences in redox regulation and proliferation after low UVA doses

Ciesielska

Bil

Gajda

et al. 2018

Preprint

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“…35 Nox4-derived ROS are primarily detectable as H 2 O 2 , which unlike superoxide is membrane-permeable and has a longer half-life rendering it an ideal intracellular but also extracellular signaling mediator. 13 Interestingly, TGFb1mediated fibroblast activation requires both intra-and extracellular ROS as membrane-permeable or -impermeable forms of antioxidant enzymes abrogate the induction of different sets of CAF markers by TGFb1 (not shown). Such extracellular functions of ROS have been described previously, for example, TGFb-induced ROS activate latent TGFb and cross-link fibroblast-derived ECM proteins.…”

Section: Discussionmentioning

confidence: 92%

“…However, ROS are also key regulators of diverse physiological processes (e.g., proliferation, apoptosis and differentiation) via reversible thiol modification of redox-sensitive proteins, resulting in conformational changes that alter enzymatic activity (kinases and phosphatases) or DNA binding activity of transcription factors (e.g., NFjB and AP-1). 13 NADPH oxidase (Nox) enzymes are a major source of cellular ROS and thus key regulators of inter-and intracellular redox signaling. 14 The Nox family comprises seven members (Nox1-5 and Duox1-2) that catalyze the transfer of electrons from molecular oxygen across biological membranes using NADPH as electron donor thereby generating superoxide.…”

mentioning

confidence: 99%

Inhibition of Nox4‐dependent ROS signaling attenuates prostate fibroblast activation and abrogates stromal‐mediated protumorigenic interactions

Sampson

Brunner

Weber

et al. 2018

Intl Journal of Cancer

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Carcinoma‐associated fibroblasts (CAFs) play a key onco‐supportive role during prostate cancer (PCa) development and progression. We previously reported that the reactive oxygen species (ROS)‐producing enzyme NADPH oxidase 4 (Nox4) is essential for TGFβ1‐mediated activation of primary prostate human fibroblasts to a CAF‐like phenotype. This study aimed to further investigate the functional relevance of prostatic Nox4 and determine whether pharmacological inhibition of stromal Nox4 abrogates paracrine‐mediated PCa‐relevant processes. RNA in situ hybridization revealed significantly elevated Nox4 mRNA levels predominantly in the peri‐tumoral stroma of clinical PCa with intense stromal Nox4 staining adjacent to tumor foci expressing abundant TGFβ protein levels. At pharmacologically relevant concentrations, the Nox1/Nox4 inhibitor GKT137831 attenuated ROS production, CAF‐associated marker expression and migration of TGFβ1‐activated but not nonactivated primary human prostate fibroblasts. Similar effects were obtained upon shRNA‐mediated silencing of Nox4 but not Nox1 indicating that GKT137831 primarily abrogates TGFβ1‐driven fibroblast activation via Nox4 inhibition. Moreover, inhibiting stromal Nox4 abrogated the enhanced proliferation and migration of PCa cell lines induced by TGFβ1‐activated prostate fibroblast conditioned media. These effects were not restricted to recombinant TGFβ1 as conditioned media from PCa cell lines endogenously secreting high TGFβ1 levels induced fibroblast activation in a stromal Nox4‐ and TGFβ receptor‐dependent manner. Importantly, GKT137831 also attenuated PCa cell‐driven fibroblast activation. Collectively, these findings suggest the TGFβ‐Nox4 signaling axis is a key interface to dysregulated reciprocal stromal–epithelial interactions in PCa pathophysiology and provide a strong rationale for further investigating the applicability of Nox4 inhibition as a stromal‐targeted approach to complement current PCa treatment modalities.

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“…In liver tissue, superoxide anions, hydrogen peroxide and hydroxyl radicals can be converted into stable reactive oxygen species (ROS) with strong toxicity, such as nitric oxide and peroxynitrites. 5 Thus, therapies targeting ROS inhibition are in great demand for inhibiting injury caused by oxidative stress and improving the prognosis of liver cirrhosis. Melatonin (MT), also known as N-acetyl-5-methoxytryptamine, is isolated from the pineal gland and participates in regulating multiple physiological functions including sleep promotion, circadian rhythms and neuroendocrine processes.…”

mentioning

confidence: 99%

Protective role of melatonin in early‐stage and end‐stage liver cirrhosis

Zhao

Tao

et al. 2019

J Cellular Molecular Medi

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The liver is composed of hepatocytes, cholangiocytes, Kupffer cells, sinusoidal endothelial cells, hepatic stellate cells (HSCs) and dendritic cells; all these functional and interstitial cells contribute to the synthesis and secretion functions of liver tissue. However, various hepatotoxic factors including infection, chemicals, high‐fat diet consumption, surgical procedures and genetic mutations, as well as biliary tract diseases such as sclerosing cholangitis and bile duct ligation, ultimately progress into liver cirrhosis after activation of fibrogenesis. Melatonin (MT), a special hormone isolated from the pineal gland, participates in regulating multiple physiological functions including sleep promotion, circadian rhythms and neuroendocrine processes. Current evidence shows that MT protects against liver injury by inhibiting oxidation, inflammation, HSC proliferation and hepatocyte apoptosis, thereby inhibiting the progression of liver cirrhosis. In this review, we summarize the circadian rhythm of liver cirrhosis and its potential mechanisms as well as the therapeutic effects of MT on liver cirrhosis and earlier‐stage liver diseases including liver steatosis, nonalcoholic fatty liver disease and liver fibrosis. Given that MT is an antioxidative and anti‐inflammatory agent that is effective in eliminating liver injury, it is a potential agent with which to reverse liver cirrhosis in its early stage.

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Redox signaling: an evolution from free radicals to aging

Cited by 10 publications

References 58 publications

Cell type-specific differences in redox regulation and proliferation after low UVA doses

Cell type-specific differences in redox regulation and proliferation after low UVA doses

Inhibition of Nox4‐dependent ROS signaling attenuates prostate fibroblast activation and abrogates stromal‐mediated protumorigenic interactions

Protective role of melatonin in early‐stage and end‐stage liver cirrhosis

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