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Modern analytical methods combined with the modern concepts of redox signaling revealed 4- hydroxy-2- nonenal (4-HNE) as particular growth regulating factor involved in redox signaling under physiological and pathophysiological circumstances. In this review current knowledge of the relevance of 4-HNE as "the second messenger of reactive oxygen species" (ROS) in redox signaling of representative major stress- associated diseases is briefly summarized. The findings presented allow for 4-HNE to be considered not only as second messenger of ROS, but also as one of fundamental factors of the stress- and age- associated diseases. While standard, even modern concepts of molecular medicine and respective therapies in majority of these diseases target mostly the disease- specific symptoms. 4-HNE, especially its protein adducts, might appear to be the bioactive markers that would allow better monitoring of specific pathophysiological processes reflecting their complexity. Eventually that could help development of advanced integrative medicine approach for patients and the diseases they suffer from on the personalized basis implementing biomedical remedies that would optimize beneficial effects of ROS and 4-HNE to prevent the onset and progression of the illness, perhaps even providing the real cure.

Conventional anticancer therapies such as radiotherapy and chemotherapies are associated with oxidative stress generating reactive oxygen species (ROS) and reactive aldehydes like 4-hydroxynonenal in cancer cells that govern them to die. The main mechanism activated due to exposure of the cell to these reactive species is the Nrf2-Keap1 pathway. Although Nrf2 was firstly perceived as a tumor suppressor that inhibits tumor initiation and cancer metastasis, more recent data reveal its role also as a pro-oncogenic factor. Discovery of the upregulation of Nrf2 in different types of cancer supports such undesirable pathophysiological roles of Nrf2. The upregulation of Nrf2 leads to activation of cytoprotective genes thus helping malignant cells to withstand high levels of ROS and to avoid apoptosis, eventually becoming resistant to conventional anticancer therapy. Therefore, new treatment strategies are needed for eradication of cancer and in this review, we will explore two opposing approaches for modulation of Nrf2 in cancer treatments., Graphical abstract fx1, Highlights • Nrf2-Keap1 pathway is the main pathway activated upon redox imbalance. • Nrf2 and oxidative stress products (e.g. ROS, HNE) play dual role in carcinogenesis. • Nrf2 is both, a tumor suppressor and a proto-oncogene. • Usage of Nrf2 activators or inhibitors depends upon the stage of the cancer.

International audience; The end products of polyunsaturated fatty acid (PUFA) peroxidation, such as malondialdehyde (MDA), 4-hydroxynonenal (HNE), and isoprostanes (8-iso-PGF2alpha), are widely used as systemic lipid oxidation/oxidative stress biomarkers. However, some of these compounds have also a dietary origin. Thus, replacing dietary saturated fat by PUFAs would improve health but could also increase the formation of such compounds, especially in the case of a pro-oxidant/antioxidant imbalanced diet. Hence, the possible impact of dietary fatty acids and pro-oxidant compounds was studied in rats given diets allowing comparison of the effects of heme iron vs. ferric citrate and of omega-6- vs. omega-3-rich oil on the level of lipid peroxidation/oxidative stress biomarkers. Rats given a heme iron-rich diet without PUFA were used as controls. The results obtained have shown that MDA and the major urinary metabolite of HNE (the mercapturic acid of dihydroxynonane, DHN-MA) were highly dependent on the dietary factors tested, while 8-iso-PGF2alpha was modestly but significantly affected. Intestinal inflammation and tissue fatty acid composition were checked in parallel and could only explain the differences we observed to a limited extent. Thus, the differences in biomarkers were attributed to the formation of lipid oxidation compounds in food or during digestion, their intestinal absorption, and their excretion into urine. Moreover, fecal extracts from the rats fed the heme iron or fish oil diets were highly toxic for immortalized mouse colon cells. Such toxicity can eventually lead to promotion of colorectal carcinogenesis, supporting the epidemiological findings between red meat intake and colorectal cancer risk. Therefore, the analysis of these biomarkers of lipid peroxidation/oxidative stress in urine should be used with caution when dietary factors are not well controlled, while control of their possible dietary intake is needed also because of their pro-inflammatory, toxic, and even cocarcinogenic effects.

Polystyrene (PS) foils were exposed to oxygen plasma in order to improve the ability of human osteosarcoma cells (HOS) proliferation. Plasma was created in an electrodeless radio-frequency (RF) discharge in pure oxygen. Plasma treatment time of 30 s allowed for saturation of the surface with oxygen rich functional groups. Incubation of proteins from cell culture media was studied versus incubation time for untreated and plasma treated PS by X-ray photoelectron spectroscopy (XPS). Then HOS cells were cultivated according to a standard procedure, applied on the PS substrates and incubated. The proliferation was studied qualitatively by optical microscopy, scanning electron microscopy (SEM) and quantitatively by MTT assay. All techniques revealed significant differences in HOS cells proliferation on untreated and oxygen plasma treated PS. The differences were most pronounced after 24 h of incubation when the cells have already stared to proliferate on plasma treated PS, while they were still in quiescence on untreated PS. The confluency was achieved till the 6th day on plasma treated PS, while on untreated PS such confluency has never been achieved. The cell viability assay revealed that HOS cells grew better on plasma treated PS for various incubation times. Similar trend was observed regarding the adhesion of proteins. They adhered better on plasma treated PS causing better environment for further cell proliferation. The results clearly show that oxygen plasma treatment allows for much better proliferation of HOS cells on plasma treated PS as compared to the untreated PS substrates.

Otosclerosis is a complex disease characterized by an abnormal bone turnover of the otic capsule resulting in conductive hearing loss. Recent findings have shown that angiotensin II (Ang II), a major effector peptide of the renin–angiotensin system, plays an important role in the pathophysiology of otosclerosis, most likely by its proinflammatory effects on the bone cells. Because reactive oxygen species play a role both in inflammation and in the cellular signaling pathway of Ang II, the appearance of protein adducts of the “second messenger of free radicals,” the aldehyde 4-hydroxynonenal (HNE), in otosclerotic bone has been analyzed. Immunohistochemical analysis of HNE-modified proteins in tissue samples of the stapedial bones performed on 15 otosclerotic patients and 6 controls revealed regular HNE–protein adducts present in the subperiosteal parts of control bone specimens, whereas irregular areas of a pronounced HNE–protein adduct presence were found within stapedial bone in cases of otosclerosis. To study possible interference by HNE and Ang II in human bone cell proliferation, differentiation, and induction of apoptosis we used an in vitro model of osteoblast-like cells. HNE interacted with Ang II in a dose-dependent manner, both by forming HNE–Ang II adducts, as revealed by immunoblotting, and by modifying its effects on cultured cells. Namely, treatment with 0.1 nM Ang II and 2.5 μM HNE stimulated proliferation, whereas treatment with 10 μM HNE or in combination with Ang II (0.1, 0.5, and 1 nM) decreased cell proliferation. Moreover, 10 μM HNE alone and with Ang II (except if 1 nM Ang II was used) increased cellular differentiation and apoptosis. HNE at 5 μM did not affect differentiation nor significantly change apoptosis. On the other hand, when cells were treated with lower concentrations of HNE and Ang II we observed a decrease in cellular differentiation (combination of 1.0 or 2.5 μM HNE with 0.1 nM Ang II) and decrease in apoptosis (0.1 and 0.5 nM Ang II). Cellular necrosis was increased with 5 and 10 μM HNE if given alone or combined with Ang II, whereas 0.5 nM Ang II and combination of 1 μM HNE with Ang II (0.1 and 0.5 nM) reduced necrosis. These results indicate that HNE and Ang II might act mutually dependently in the regulation of bone cell growth and in the pathophysiology of otosclerosis.

Cancer stem cells are a subpopulation of cancer cells with great plasticity, slow cell cycle and are capable of dormating for long time. Today, these cells are recognized as a major factor of malignancy causing metastasis, relapse, failure of cancer treatment and therapy resistance. The mechanisms which keep in control or activate these cells are still not fully revealed, but microenvironment certainly has a specific role. Proteins of the extracellular matrix can modify proccesses which cells are undergoing and changes of these proteins consequently affect cell. In addition to the environmental signals, oxidative stress may modulate and change signals cells are recieving thereby creating different outcome. Among the molecules produced during oxidative stress, 4-hydroxynonenal (HNE) was shown to modulate many signaling pathways thereby inducing differentiation, proliferation or apoptosis. Here, we provide evidence that HNE can change cancer stem cell responce to chronic oxidative stress through interactions with collagen, representative of extracellular matrix protein. Hence, HNE may be the factor that modulates cellular responce to stress or therapy via interactions with extracellular proteins and thereby changing the outcome of the disease.

Oxidative stress is an important factor in carcinogenesis. In addition, radiotherapy, chemotherapy and inflammation increase oxidative stress in tumors. Lipid peroxidation end product, a reactive aldehyde 4-hydroxy-2-nonenal (HNE), is considered to be second messenger of oxidative stress. HNE modifies the metabolism of cancer cells by interacting with proteins, lipids and DNA. Along with oxidative stress, cancer stem cells have been recognized as the crucial factor in cancer malignancy and are considered responsible for metastasis occurrence, therapy resistance and, finally, recurrence of the disease. For these reasons we examined the effect of HNE induced oxidative stress and HNE modulation of the extracellular matrix on cancer stem cells metabolism, proliferation and their antioxidative mechanisms. Collagen was used as a representative protein of extracellular matrix and was modified with HNE. Cells were plated on native and HNE-modified collagen as well as polystyrene surface and were additionally treated with HNE every second day. Afterwards, we determined viability and proliferation with MTT and 3HT test. Antioxidant cell capacity was assessed by glutathione and catalase assay. Dot-blot analysis was performed in order to quantify Nrf2 and HNE histidine conjugates. We confirmed specificity of dot-blot findings by performing western blot analysis of Nrf2. The results suggest that the aggressive cancer stem cell phenotype is enhanced during chronic oxidative stress. Extracellular matrix alterations resulting from oxidative stress may cause an adaptation of cancer stem cells, enabling them to survive increased oxidative stress.