Antioxidants and Second Messengers of Free Radicals

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. [...].

identifying several known but also many new OxPAPC-binding proteins, thus presenting an important analytical breakthrough. This supports previous research by the Austrian pioneers in the field as Hermann Esterbauer and collaborators who discovered HNE, thus, constructing the fundaments for the modern scientific arena of lipid peroxidation [11].
The pathophysiological aspects of lipid peroxidation were further reviewed from two complementary aspects; by summarizing findings on HNE in redox homeostasis of gastrointestinal mucosa with possible implications for the stomach in health and in gastrointestinal diseases [12] and by reviewing options for modulation of oxidative stress and lipid peroxidation by endocannabinoids and their lipid analogues [13]. In the former article, the authors point to pathophysiological relevance of the HNE-protein adducts in digestive system of humans, especially stressing increased accumulation of HNE-modified proteins in gastric mucosa during infection and even after eradication of H. pillory infection. However, the authors of the later review paper suggest that a link between the endocannabinoid system (ECS) and redox homeostasis impairment could be crucial for cellular and tissue damages occurring in redox-dependent processes involving reactive oxygen and nitrogen species as well as lipid peroxidation-derived reactive aldehydes including acrolein, MDA and HNE.
Consistent with that are the findings on the bioactivities or natural and synthetic antioxidants targeting reactive aldehydes as second messengers of free radicals in vitro or in vivo presented in the remaining papers of this Special Issue [14][15][16][17]. The authors of one review and two original papers were studying the structure-activity relations of particular plant extracts on their chemical composition. This might help us to better understand their activity principles [14][15][16], while in the last article of this Special Issue, the authors studied the relationship between antioxidant and growth regulating effects of synthetic chemical substances, notably of 1,4-dihydropyridine derivatives (DHS) [17]. Namely, various DHPs are known for their pleiotropic activity, some also act as antioxidants that are already used for UV-protection or as antihypertensive agents. In their original in vitro study using several well-known or newly synthesized DHPs to treat human osteoblast-like cells, the authors revealed some DHPs as possible therapeutic agents for osteoporosis. However, further research is needed to elucidate their bioactivity mechanisms in respect to signaling pathways involving HNE and related second messengers of free radicals [17].
Similarly, although working on a very different in vitro model of human skin cells treated with sea buckthorn seed oil, another group analyzed the effects of the particular oil on the redox balance and lipid metabolism in UV irradiated skin cells. This research aimed to examine whether the plant oil can have the UV-protective effect [16]. By doing so, the authors found beneficial effects of the buckthorn seed oil, which decreased the production of lipid peroxidation products (including HNE) simultaneously decreasing the cannabinoid receptor expression in UV-irradiated keratinocytes and fibroblasts.
Another in vitro study used several cell lines to test if HNE might be a relevant factor of beneficial effects of the widely used Aloe vera extracts (AV) [15]. This study found that the cell-type specific effects of AV, by itself was not toxic for any type of cells, while it modulated the cellular response to oxidative stress induced by hydrogen peroxide. Of particular relevance, it was found that high antioxidant levels of the AV did not interfere with enhanced cellular accumulation of the HNE-protein adducts in human endothelial cells, as revealed by the genuine cell-based ELISA specific for HNE-His, which was used for the first time. The authors concluded that these findings might help in understanding the activity principles of AV, particularly if used for the promotion of wound healing and/or for adjuvant cancer treatments.
Some options for the modulation of lipid peroxidation pathophysiology by plant extracts reach in antioxidants were eventually summarized in the review on the relationship between biological activities of such extracts and their chemical composition in the article focusing on the evening primrose extracts [14]. The authors of this review point to the biomedical use of the evening primrose oil (EPO) rich in linoleic acid (70-74%) and linolenic acid (8-10%), which are precursors of anti-inflammatory eicosanoids. Thus, EPO supplementation may result in an increase in plasma levels of linolenic acid and its metabolite dihomo-linolenic acid, which is oxidized by lipoxygenase (15-LOX) to 15-hydroxyeicosatrienoic acid  or can be, under the influence of cyclooxygenase (COX), metabolized to series 1 prostaglandins, which exert anti-inflammatory and anti-proliferative properties. In addition, linolenic acid itself may suppress the production of inflammatory cytokines. Since linoleic acid is also a major source of HNE, one may assume that lipid peroxidation generating HNE could be also important for the multiple biological effects of EPO, as suggested for the Aloe vera extract in the paper described above [15].
In conclusion, more research is needed to evaluate, using advanced analytical methods and translation models, how the natural and/or synthetic antioxidants interfere with the pathophysiology of lipid peroxidation. Yet, by doing so, we could increase not only our understanding of this important field but also support the development of the modern integrative biomedicine for which both antioxidants and second messengers of free radicals, represented by HNE, are of highest importance.

Conflicts of Interest:
The author declares no conflict of interest.