Diversified Effects of COVID-19 as a Consequence of the Differential Metabolism of Phospholipids and Lipid Peroxidation Evaluated in the Plasma of Survivors and Deceased Patients upon Admission to the Hospital.

As a result of SARS-CoV-2 infection, inflammation develops, which promotes oxidative stress, leading to modification of phospholipid metabolism. Therefore, the aim of this study is to compare the effects of COVID-19 on the levels of phospholipid and free polyunsaturated fatty acids (PUFAs) and their metabolites produced in response to reactions with reactive oxygen species (ROS) and enzymes (cyclooxygenases-(COXs) and lipoxygenase-(LOX)) in the plasma of patients who either recovered or passed away within a week of hospitalization. In the plasma of COVID-19 patients, especially of the survivors, the actions of ROS and phospholipase A2 (PLA2) cause a decrease in phospholipid fatty acids level and an increase in free fatty acids (especially arachidonic acid) despite increased COXs and LOX activity. This is accompanied by an increased level in lipid peroxidation products (malondialdehyde and 8-isoprostaglandin F2α) and lipid mediators generated by enzymes. There is also an increase in eicosanoids, both pro-inflammatory as follows: thromboxane B2 and prostaglandin E2, and anti-inflammatory as follows: 15-deoxy-Δ-12,14-prostaglandin J2 and 12-hydroxyeicosatetraenoic acid, as well as endocannabinoids (anandamide-(AEA) and 2-arachidonylglycerol-(2-AG)) observed in the plasma of patients who recovered. Moreover, the expression of tumor necrosis factor α and interleukins (IL-6 and IL-10) is increased in patients who recovered. However, in the group of patients who died, elevated levels of N-oleoylethanolamine and N-palmitoylethanolamine are found. Since lipid mediators may have different functions depending on the onset of pathophysiological processes, a stronger pro-inflammatory response in patients who have recovered may be the result of the defensive response to SARS-CoV-2 in survivors associated with specific changes in the phospholipid metabolism, which could also be considered a prognostic factor.

The Impact of Severe COVID-19 on Plasma Antioxidants.

Several studies suggested the association of COVID-19 with systemic oxidative stress, in particular with lipid peroxidation and vascular stress. Therefore, this study aimed to evaluate the antioxidant signaling in the plasma of eighty-eight patients upon admission to the Clinical Hospital Dubrava in Zagreb, of which twenty-two died within a week, while the other recovered. The differences between the deceased and the survivors were found, especially in the reduction of superoxide dismutases (SOD-1 and SOD-2) activity, which was accompanied by the alteration in glutathione-dependent system and the intensification of the thioredoxin-dependent system. Reduced levels of non-enzymatic antioxidants, especially tocopherol, were also observed, which correlated with enhanced lipid peroxidation (determined by 4-hydroxynonenal (4-HNE) and neuroprostane levels) and oxidative modifications of proteins assessed as 4-HNE-protein adducts and carbonyl groups. These findings confirm the onset of systemic oxidative stress in patients with severe SARS-CoV-2, especially those who died from COVID-19, as manifested by strongly reduced tocopherol level and SOD activity associated with lipid peroxidation. Therefore, we propose that preventive and/or supplementary use of antioxidants, especially of lipophilic nature, could be beneficial for the treatment of COVID-19 patients.

The Importance of 6-Aminohexanoic Acid as a Hydrophobic, Flexible Structural Element.

6-aminohexanoic acid is an ω-amino acid with a hydrophobic, flexible structure. Although the ω-amino acid in question is mainly used clinically as an antifibrinolytic drug, other applications are also interesting and important. This synthetic lysine derivative, without an α-amino group, plays a significant role in chemical synthesis of modified peptides and in the polyamide synthetic fibers (nylon) industry. It is also often used as a linker in various biologically active structures. This review concentrates on the role of 6-aminohexanoic acid in the structure of various molecules.

Therapeutic Potential of Jasmonic Acid and Its Derivatives.

A modern method of therapeutic use of natural compounds that would protect the body are jasmonates. The main representatives of jasmonate compounds include jasmonic acid and its derivatives, mainly methyl jasmonate. Extracts from plants rich in jasmonic compounds show a broad spectrum of activity, i.e., anti-cancer, anti-inflammatory and cosmetic. Studies of the biological activity of jasmonic acid and its derivatives in mammals are based on their structural similarity to prostaglandins and the compounds can be used as natural therapeutics for inflammation. Jasmonates also constitute a potential group of anti-cancer drugs that can be used alone or in combination with other known chemotherapeutic agents. Moreover, due to their ability to stimulate exfoliation of the epidermis, remove discoloration, regulate the function of the sebaceous glands and reduce the visible signs of aging, they are considered for possible use in cosmetics and dermatology. The paper presents a review of literature data on the biological activity of jasmonates that may be helpful in treatment and prevention.

Jasmonate Compounds and Their Derivatives in the Regulation of the Neoplastic Processes.

Cancer is a serious problem in modern medicine, mainly due to the insufficient effectiveness of currently available therapies. There is a particular interest in compounds of natural origin, which can be used in the prophylaxis, as well as in the treatment and support of cancer treatment. One such compound is jasmonic acid (3-oxo-2-(pent-2'-enyl)cyclopentane acetic acid; isolated active form: trans-(-)-(3R,7R)- and cis-(+)-(3R,7S)-jasmonic acid) and its derivatives, which, due to their wide range of biological activities, are also proposed as potential therapeutic agents. Therefore, a review of literature data on the biological activity of jasmonates was prepared, with particular emphasis on the mechanisms of jasmonate action in neoplastic diseases. The anti-tumor activity of jasmonate compounds is based on altered cellular ATP levels; induction of re-differentiation through the action of Mitogen Activated Protein Kinases (MAPKs); the induction of the apoptosis by reactive oxygen species. Jasmonates can be used in anti-cancer therapy in combination with other known drugs, such as cisplatin, paclitaxel or doxorubicin, showing a synergistic effect. The structure-activity relationship of novel jasmonate derivatives with anti-tumor, anti-inflammatory and anti-aging effects is also shown.

Cannabidiol Effects on Phospholipid Metabolism in Keratinocytes from Patients with Psoriasis Vulgaris.

Psoriasis is a chronic inflammatory skin disease characterized by dysregulated keratinocyte differentiation, but oxidative stress also plays an important role in the pathogenesis of this disease. Here, we examined the effect of cannabidiol (CBD), a phytocannabinoid with antioxidant and anti-inflammatory properties, on the redox balance and phospholipid metabolism in UVA/UVB-irradiated keratinocytes isolated from the skin of psoriatic patients or healthy volunteers. CBD accumulates mainly in membrane keratinocytes, especially from patients with psoriasis. This phytocannabinoid reduces the redox imbalance observed in the UV-irradiated keratinocytes of healthy subjects. It does so by decreasing reactive oxygen species (ROS) generation, increasing the Trx-dependent system efficiency, and increasing vitamin A and E levels. Consequently, a reduction in lipid peroxidation products, such as 8-isoprostanes and 4-hydroxynonenal, was also observed. Moreover, CBD modifies redox balance and lipid peroxidation in psoriatic patient keratinocytes following UV-irradiation. Interestingly, these changes are largely in the opposite direction to the case of keratinocytes from healthy subjects. CBD also regulates metabolic changes by modulating the endocannabinoid system that is disturbed by psoriasis development and UV irradiation. We observed a decrease in anandamide level in the UV-irradiated keratinocytes of healthy controls following CBD treatment, while in keratinocytes from patients treated with CBD, anandamide level was increased. However, the level of palmitoylethanolamide (PEA) was decreased in both groups treated with CBD. We further demonstrate that CBD increases CB1 receptor expression, primarily in the keratinocytes of patients, and increases CB2 receptor expression in both the psoriatic and control groups. However, CBD decreases CB2 receptor expression in UV-irradiated keratinocytes taken from patients. The UV- and psoriasis-induced activity of transmembrane transporters (Multidrug-Resistance (MDR) and breast cancer resistance protein (BCRP)) is normalized after CBD treatment. We conclude that CBD partially reduces oxidative stress in the keratinocytes of healthy individuals, while showing a tendency to increase the oxidative and inflammatory state in the keratinocytes of patients with psoriasis, especially following UV-irradiation.

Synergistic Cytoprotective Effects of Rutin and Ascorbic Acid on the Proteomic Profile of 3D-Cultured Keratinocytes Exposed to UVA or UVB Radiation.

The combination of ascorbic acid and rutin, often used in oral preparations, due to antioxidant and anti-inflammatory properties, can be used to protect skin cells against the effects of UV radiation from sunlight. Therefore, the aim of this study was to investigate the synergistic effect of rutin and ascorbic acid on the proteomic profile of UVA and UVB irradiated keratinocytes cultured in a three-dimensional (3D) system. Results showed that the combination of rutin and ascorbic acid protects skin cells against UV-induced changes. In particular, alterations were observed in the expression of proteins involved in the antioxidant response, DNA repairing, inflammation, apoptosis, and protein biosynthesis. The combination of rutin and ascorbic acid also showed a stronger cytoprotective effect than when using either compound alone. Significant differences were visible between rutin and ascorbic acid single treatments in the case of protein carboxymethylation/carboxyethylation. Ascorbic acid prevented UV or rutin-induced protein modifications. Therefore, the synergistic effect of rutin and ascorbic acid creates a potentially effective protective system against skin damages caused by UVA and UVB radiation.

Rutin and ascorbic acid cooperation in antioxidant and antiapoptotic effect on human skin keratinocytes and fibroblasts exposed to UVA and UVB radiation.

The combination of ascorbic acid and rutin is frequently used in oral preparations. However, despite numerous protective effects of each component individually, their combined effect on ultraviolet (UV)-irradiated skin cells has never been evaluated. The aim of this study was to evaluate the combined effect of ascorbic acid and rutin on human keratinocytes and fibroblasts exposed to UVA and UVB radiation. Skin keratinocytes and fibroblasts exposed to UVA and UVB radiation were treated with ascorbic acid or/and rutin. The total antioxidant properties of both components, as well as their effect on cellular pro- and antioxidant status, lipid and protein oxidation, transmembrane transport, and pro-inflammatory and pro/antiapoptotic protein expression were measured. The combination of ascorbic acid and rutin had higher antioxidant properties compared to the activity of the single compound alone, and showed a stronger effect against UV-induced reactive oxygen species generation. The ascorbic acid and rutin combination also showed increased antioxidant enzyme activity (catalase, superoxide dismutase, thioredoxin reductase), which was impaired following UV irradiation. Moreover, ascorbic acid additional stimulated UV-induced bilitranslocase activity responsible for rutin transport, and therefore favored rutin effect on Nrf2 pathway, simultaneously differentiating the reaction of keratinocytes and fibroblasts. In keratinocytes, Nrf2 is strongly activated, while in fibroblasts decreased Nrf2 activity was observed. Used mixture, also significantly silenced UV-induced expression of pro-inflammatory factor NFκB and pro-apoptotic proteins such as caspases 3, 8, and 9. These results showed that ascorbic acid and rutin are complementary in their antioxidant actions, transport and signaling functions. Their combined antioxidant, antiinflammatory and antiapoptotic actions suggest rutin and ascorbic acid are a potentially cytoprotective team against UV-induced skin damage.

The Effect of Sea Buckthorn (Hippophae rhamnoides L.) Seed Oil on UV-Induced Changes in Lipid Metabolism of Human Skin Cells.

Lipids and proteins of skin cells are the most exposed to harmful ultraviolet (UV) radiation contained in sunlight. There is a growing need for natural compounds that will protect these sensitive molecules from damage, without harmful side effects. The aim of this study was to investigate the effect of sea buckthorn seed oil on the redox balance and lipid metabolism in UV irradiated cells formed different skin layers to examine whether it had a protective effect. Human keratinocytes and fibroblasts were subjected to UVA (ultraviolet type A; 30 J/cm² and 20 J/cm²) or UVB (ultraviolet type B; 60 mJ/cm² and 200 mJ/cm², respectively) radiation and treated with sea buckthorn seed oil (500 ng/mL), and the redox activity was estimated by reactive oxygen species (ROS) generation and enzymatic/non-enzymatic antioxidants activity/level (using electron spin resonance (ESR), high-performance liquid chromatography (HPLC), and spectrophotometry). Lipid metabolism was measured by the level of fatty acids, lipid peroxidation products, endocannabinoids and phospholipase A2 activity (GC/MS (gas chromatography/mass spectrometry), LC/MS (liquid chromatography/mass spectrometry), and spectrophotometry). Also, transcription factor Nrf2 (nuclear erythroid 2-related factor) and its activators/inhibitors, peroxisome proliferator-activated receptors (PPAR) and cannabinoid receptor levels were measured (Western blot). Sea buckthorn oil partially prevents UV-induced ROS generation and enhances the level of non-enzymatic antioxidants such as glutathione (GSH), thioredoxin (Trx) and vitamins E and A. Moreover, it stimulates the activity of Nrf2 leading to enhanced antioxidant enzyme activity. As a result, decreases in lipid peroxidation products (4-hydroxynonenal, 8-isoprostaglandin) and increases in the endocannabinoid receptor levels were observed. Moreover, sea buckthorn oil treatment enhanced the level of phospholipid and free fatty acids, while simultaneously decreasing the cannabinoid receptor expression in UV irradiated keratinocytes and fibroblasts. The main differences in sea buckthorn oil on various skin cell types was observed in the case of PPARs-in keratinocytes following UV radiation PPAR expression was decreased by sea buckthorn oil treatment, while in fibroblasts the reverse effect was observed, indicating an anti-inflammatory effect. With these results, sea buckthorn seed oil exhibited prevention of UV-induced disturbances in redox balance as well as lipid metabolism in skin fibroblasts and keratinocytes, which indicates it is a promising natural compound in skin photo-protection.

Sweet grass protection against oxidative stress formation in the rat brain.

The aims of this study were to investigate the influences of sweet grass on chronic ethanol-induced oxidative stress in the rat brain. Chronic ethanol intoxication decreased activities and antioxidant levels resulting in enhanced lipid peroxidation. Administration of sweet grass solution to ethanol-intoxicated rats partially normalized the activity activities of Cu,Zn-superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, as well as levels of reduced glutathione and vitamins C, E, and A. Sweet grass also protected unsaturated fatty acids (arachidonic and docosahexaenoic) from oxidations and decreased levels of lipid peroxidation products: 4-hydroxynonenal, isoprostanes, and neuroprostanes. The present in vivo study confirms previous in vitro data demonstrating the bioactivity of sweet grass and suggests a possible role for sweet grass in human health protection from deleterious consequences associated with oxidative stress formation.