Roles and Functions of ROS and RNS in Cellular Physiology and Pathology

Our common knowledge on oxidative stress has evolved substantially over the years, being focused mostly on the fundamental chemical reactions and the most relevant chemical species involved in human pathophysiology of oxidative stress-associated diseases. Thus, reactive oxygen species and reactive nitrogen species (ROS and RNS) were identified as key players in initiating, mediating, and regulating the cellular and biochemical complexity of oxidative stress either as physiological (acting pro-hormetic) or as pathogenic (causing destructive vicious circles) processes. The papers published in this particular Special Issue of Cells show an impressive range on the pathophysiological relevance of ROS and RNS, including the relevance of second messengers of free radicals like 4-hydroxynonenal, allowing us to assume that the future will reveal even more detailed mechanisms of their positive and negative effects that might improve the monitoring of major modern diseases, and aid the development of advanced integrative biomedical treatments

4-Hydroxynonenal in Redox Homeostasis of Gastrointestinal Mucosa: Implications for the Stomach in Health and Diseases

Maintenance of integrity and function of the gastric mucosa (GM) requires a high regeneration rate of epithelial cells during the whole life span. The health of the gastric epithelium highly depends on redox homeostasis, antioxidant defense, and activity of detoxifying systems within the cells, as well as robustness of blood supply. Bioactive products of lipid peroxidation, in particular, second messengers of free radicals, the bellwether of which is 4-hydroxynonenal (HNE), are important mediators in physiological adaptive reactions and signaling, but they are also thought to be implicated in the pathogenesis of numerous gastric diseases. Molecular mechanisms and consequences of increased production of HNE, and its protein adducts, in response to stressors during acute and chronic gastric injury, are well studied. However, several important issues related to the role of HNE in gastric carcinogenesis, tumor growth and progression, the condition of GM after eradication of Helicobacter pylori, or the relevance of antioxidants for HNE-related redox homeostasis in GM, still need more studies and new comprehensive approaches. In this regard, preclinical studies and clinical intervention trials are required, which should also include the use of state-of-the-art analytical techniques, such as HNE determination by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), as well as modern mass-spectroscopy methods

Controversy about pharmacological modulation of Nrf2 for cancer therapy

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

Chemistry and personalized medicine – the research and development future of Europe

Personalized medicine may represent a dramatic change of paradigm in the medium-term future. For a chemist, personalized medicine means the definition and understanding of any disease on molecular level for each individual or group of individuals (personalized diagnosis) ideally leading to the design of a drug that efficiently counteracts or prevents any molecular dysfunction, ie, a personalized drug without side effects. The interdisciplinary research required for personalized medicine should overcome a myriad of obstacles not the least being to find specific biomarkers and targets for each individual or group of individuals suffering from a given disease. Chemists enter then into action and will model/ design drugs and drug delivery pathways for a personalized therapy. They will either tap into the numerous drugs candidates, which were abandoned at some stage of clinical trials, or synthesize new drugs, mainly those “small molecules” mimicking the activity of natural products. This view has obvious economic, ethical, and social implications, beyond scientific challenges. All stakeholders will have to take them into account. Policy makers will have to examine all disciplines of regulatory science among which the thorny economics (cost-benefit analysis of specific research and development projects) are of paramount importance and critical to the development of personalized medicine

Chemistry and personalized medicine – the research and development future of Europe

Personalized medicine may represent a dramatic change of paradigm in the medium-term future. For a chemist, personalized medicine means the definition and understanding of any disease on molecular level for each individual or group of individuals (personalized diagnosis) ideally leading to the design of a drug that efficiently counteracts or prevents any molecular dysfunction, ie, a personalized drug without side effects. The interdisciplinary research required for personalized medicine should overcome a myriad of obstacles not the least being to find specific biomarkers and targets for each individual or group of individuals suffering from a given disease. Chemists enter then into action and will model/ design drugs and drug delivery pathways for a personalized therapy. They will either tap into the numerous drugs candidates, which were abandoned at some stage of clinical trials, or synthesize new drugs, mainly those “small molecules” mimicking the activity of natural products. This view has obvious economic, ethical, and social implications, beyond scientific challenges. All stakeholders will have to take them into account. Policy makers will have to examine all disciplines of regulatory science among which the thorny economics (cost-benefit analysis of specific research and development projects) are of paramount importance and critical to the development of personalized medicine

Association between aryl hydrocarbon receptor and 4-hydroxynonenal in oxidative stress-mediated chronic rhinosinusitis with nasal polyps

Background: Сhronic rhinosinusitis with nasal polyps (CRSwNPs) is a distinct entity within the chronic rhinosinusitis group of diseases, which are chronic upper airway diseases with several pheno- and endotypes. Oxidative stress plays an important role in the pathogenesis of CRSwNPs. Aim: The aim was to assess the association between the expression of the aryl hydrocarbon receptor (AhR) and 4-hydroxynonenal (4-HNE) in patients with CRSwNPs. Methods: The study included 26 patients who underwent endoscopic sinus surgery – 14 patients with CRSwNPs, and 12 controls with healthy sinus mucosa. The expression of AhR and 4-HNE was assessed in tissue samples using immunohistochemistry. The level of 4-HNE in serum samples was measured using the ELISA assay. The total oxidative capacity (TOC) was assessed by measuring the peroxidase activity. Results: Higher levels of 4-HNE expression were observed in tissues (3, range 1-3 vs. 0, range 0-0, p<0.001) and serum (27.7±11.5 vs. 9.8±7.7 pmol/mg, p<0.001) samples of CRSwNPs patients, as compared to healthy controls. A higher expression of AhR was found in inflammatory cells (plasma cells, lymphocytes, eosinopholes) of CRSwNPs patients, compared to controls (3, range 1-3 vs. 2, range 1-2, p=0.001). There were no differences in TOC across groups (0.0285±0.0207 vs. 0.02978±0.0197 µM H2O2 eq., p=0.848). Patients with bronchial asthma (57%) had abundant eosinophiles in tissue samples. Patients with recalcitrant CRSwNPs had higher 4-HNE serum levels, compared to non-recalcitrant cases (27.3 vs. 24.2 pmol/mg, p=0.339). Conclusion: Patients suffering from CRSwNPs have oxidative stress mediated overexpression of AhR, which is linked to a chronic inflammatory response in the paranasal sinus tissues

Involvement of Metabolic Lipid Mediators in the Regulation of Apoptosis

Apoptosis is the physiological mechanism of cell death and can be modulated by endogenous and exogenous factors, including stress and metabolic alterations. Reactive oxygen species (ROS), as well as ROS-dependent lipid peroxidation products (including isoprostanes and reactive aldehydes including 4-hydroxynonenal) are proapoptotic factors. These mediators can activate apoptosis via mitochondrial-, receptor-, or ER stress-dependent pathways. Phospholipid metabolism is also an essential regulator of apoptosis, producing the proapoptotic prostaglandins of the PGD and PGJ series, as well as the antiapoptotic prostaglandins of the PGE series, but also 12-HETE and 20-HETE. The effect of endocannabinoids and phytocannabinoids on apoptosis depends on cell type-specific differences. Cells where cannabinoid receptor type 1 (CB1) is the dominant cannabinoid receptor, as well as cells with high cyclooxygenase (COX) activity, undergo apoptosis after the administration of cannabinoids. In contrast, in cells where CB2 receptors dominate, and cells with low COX activity, cannabinoids act in a cytoprotective manner. Therefore, cell type-specific differences in the pro- and antiapoptotic effects of lipids and their (oxidative) products might reveal new options for differential bioanalysis between normal, functional, and degenerating or malignant cells, and better integrative biomedical treatments of major stress-associated diseases