Sildenafil reduces signs of oxidative stress in pulmonary arterial hypertension: Evaluation by fatty acid composition, level of hydroxynonenal and heart rate variability

AbstractPulmonary arterial hypertension (PAH) is a rare multifactorial disease with an unfavorable prognosis. Sildenafil therapy can improve functional capacity and pulmonary hemodynamics in PAH patients. Nowadays, it is increasingly recognized that the effects of sildenafil are pleiotropic and may also involve changes of the pro-/antioxidant balance, lipid peroxidation and autonomic control. In present study we aimed to assess the effects of sildenafil on the fatty acids (FAs) status, level of hydroxynonenal (HNE) and heart rate variability (HRV) in PAH patients. Patients with PAH were characterized by an increase in HNE and changes in the FAs composition with elevation of linoleic, oleic, docosahexanoic acids in phospholipids as well as reduced HRV with sympathetic predominance. Sildenafil therapy improved exercise capacity and pulmonary hemodynamics and reduced NT-proBNP level in PAH. Antioxidant and anti-inflammatory effects of sildenafil were noted from the significant lowering of HNE level and reduction of the phopholipid derived oleic, linoleic, docosahexanoic, docosapentanoic FAs. That was also associated with some improvement of HRV on account of the activation of the neurohumoral regulatory component. Incomplete recovery of the functional metabolic disorders in PAH patients may be assumed from the persistent increase in free FAs, reduced HRV with the sympathetic predominance in the spectral structure after treatment comparing to control group. The possibilities to improve PAH treatment efficacy through mild stimulation of free radical reactions and formation of hormetic reaction in the context of improved NO signaling are discussed

Clinical Prognosis for SAH Consistent with Redox Imbalance and Lipid Peroxidation

Subarachnoid hemorrhage (SAH) accounts for 3% of all strokes. As more and more data indicates the role of oxidative stress in acute brain damage caused by SAH, an attempt was made to correlate the clinical status of patients with systemic level of antioxidants and lipid peroxidation products. The hemorrhage was diagnosed with brain computed tomography (CT) and aneurysm with angio-CT and angiography, while the vasospasm was monitored with transcranial Doppler. Plasma glutathione peroxidase activity (GSH-Px) and vitamin A, E, and C levels were determined spectrophotometrically and by HPLC, respectively. The levels of polyunsaturated fatty acids (PUFAs) cyclization products were determined by GC–MS, while F2-isoprostanes and neuroprostanes (NP) were determined by LC–MS. SAH was accompanied by changes in antioxidant capacity in blood plasma, including initially (day 1) an increase in GSH-Px activity, followed by its decrease and a progressive decrease in glutathione (GSH) levels and vitamins A, E, and C. On the other hand, levels of PUFAs cyclization products, F2-isoprostanes, and neuroprostanes were highest on day 1 (two and eight times higher, respectively) and decreased over time. The levels of 4-HNE (4-hydroxynonenal), 4-ONE (4-oxononenal), and MDA (malondialdehyde) changed similarly. In contrast, the 4-HHE (4-hydroxyhexenal) level reduced after SAH increased significantly after a week. It was found that the deterioration of the overall clinical and neurological condition of SAH patients due to cerebral edema, intracranial hemorrhage, or vasoconstriction corresponded to reduced antioxidant defense and, as a consequence, increased lipid peroxidation and slower observed changes in regression. It can be concluded that monitoring the level of lipid peroxidation products (neuroprostanes, 4-ONE, and MDA) can support the monitoring of the clinical status of patients, especially with regard to the assessment of vasospasm

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

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

Cytoprotective Effect of Ascorbic Acid and Rutin against Oxidative Changes in the Proteome of Skin Fibroblasts Cultured in a Three-Dimensional System

The combination of ascorbic acid and rutin, commonly used in oral preparations for their antioxidant and anti-inflammatory properties, can also be used to protect skin cells from the effects of UV radiation in sunlight. Here, we tested the potential protective effect of ascorbic acid and rutin used together in UVB-irradiated human skin fibroblasts, and assessed the proteomic profile of these cells, grown in a three-dimensional (3D) system. Proteomic findings revealed a combined effect of ascorbic acid and rutin in UV-irradiated fibroblasts against overexpression of pro-inflammatory signaling proteins and DNA reorganization/expression. These effects were not observed when cells were treated with either compounds alone. The antioxidant effects of ascorbic acid and rutin also prevented protein modifications by lipid peroxidation products. Further, ascorbic acid stimulated rutin-protein adduct formation, which supports intra/extracellular signaling and the Nrf2/ARE antioxidant pathway, contributing to the protective effects against UV-induced oxidative stress. The combined effect of ascorbic acid and rutin suggests that this combination of compounds is potentially effective against skin damage caused by UV radiation

Antioxidative and Anti-Inflammatory Properties of Cannabidiol

Cannabidiol (CBD) is one of the main pharmacologically active phytocannabinoids of Cannabis sativa L. CBD is non-psychoactive but exerts a number of beneficial pharmacological effects, including anti-inflammatory and antioxidant properties. The chemistry and pharmacology of CBD, as well as various molecular targets, including cannabinoid receptors and other components of the endocannabinoid system with which it interacts, have been extensively studied. In addition, preclinical and clinical studies have contributed to our understanding of the therapeutic potential of CBD for many diseases, including diseases associated with oxidative stress. Here, we review the main biological effects of CBD, and its synthetic derivatives, focusing on the cellular, antioxidant, and anti-inflammatory properties of CBD

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

Phytocannabinoids in the Pharmacotherapy of Psoriasis

Phytocannabinoids are naturally occurring compounds, the main source of which is Cannabis sativa L. Through direct action or interaction with G protein-coupled receptors, they affect ROS and pro-inflammatory cytokines levels and modify the effectiveness of transcription factor responsible for the biosynthesis of antioxidants which lead to oxidative stress and its consequences. Due to the modification of the redox balance and inflammation, phytocannabinoids are used in the treatment of various diseases, including autoimmune dermatoses, such as atopic dermatitis and psoriasis. Psoriasis is one of the most common dermatoses, and one of unknown etiology. A disturbed redox balance with a shift towards the oxidation leads to oxidative stress, resulting in oxidative modifications, mainly of lipids and proteins, and prolonged activation of immune cells and increased generation of pro-inflammatory cytokines, resulting in chronic inflammation. Given the biological activity of phytocannabinoids, they have become the focus of research as components of pharmacotherapy for psoriasis. Beneficial effects were shown by various representatives of phytocannabinoids, but the effect of cannabidiol (CBD) on skin cells (in vitro and ex vivo) and on blood cells from patients with psoriasis vulgaris and psoriatic arthritis has been most often evaluated in recent years

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