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

Oxidative Stress and Lipid Mediators Modulate Immune Cell Functions in Autoimmune Diseases

Autoimmune diseases, including psoriasis, systemic lupus erythematosus (SLE), and rheumatic arthritis (RA), are caused by a combination of environmental and genetic factors that lead to overactivation of immune cells and chronic inflammation. Since oxidative stress is a common feature of these diseases, which activates leukocytes to intensify inflammation, antioxidants could reduce the severity of these diseases. In addition to activating leukocytes, oxidative stress increases the production of lipid mediators, notably of endocannabinoids and eicosanoids, which are products of enzymatic lipid metabolism that act through specific receptors. Because the anti-inflammatory CB2 receptors are the predominant cannabinoid receptors in leukocytes, endocannabinoids are believed to act as anti-inflammatory factors that regulate compensatory mechanisms in autoimmune diseases. While administration of eicosanoids in vitro leads to the differentiation of lymphocytes into T helper 2 (Th2) cells, eicosanoids are also necessary for the different0iation of Th1 and Th17 cells. Therefore, their antagonists and/or the genetic deletion of their receptors abolish inflammation in animal models of psoriasis—RA and SLE. On the other hand, products of non-enzymatic lipid peroxidation, especially acrolein and 4-hydroxynonenal-protein adducts, mostly generated by an oxidative burst of granulocytes, may enhance inflammation and even acting as autoantigens and extracellular signaling molecules in the vicious circle of autoimmune diseases

The Effect of Cannabidiol on UV-Induced Changes in Intracellular Signaling of 3D-Cultured Skin Keratinocytes

Human epidermal keratinocytes are constantly exposed to UV radiation. As a result, there is a significant need for safe and effective compounds to protect skin cells against this environmental damage. This study aimed to analyze the effect of phytocannabinoid-cannabinoid (CBD)-on the proteome of UVA/B irradiated keratinocytes. The keratinocytes were cultured in a three-dimensional (3D) system, designed to mimic epidermal conditions closely. The obtained results indicate that CBD protected against the harmful effects of UVA/B radiation. CBD decreased the expression of proinflammatory proteins, including TNFα/NFκB and IκBKB complex and decreased the expression of proteins involved in de novo protein biosynthesis, which are increased in UVA/B-irradiated cells. Additionally, CBD enhanced the UV-induced expression of 20S proteasome subunits. CBD also protected protein structures from 4-hydroxynonenal (HNE)-binding induced by UV radiation, which primarily affects antioxidant enzymes. CBD-through its antioxidant/anti-inflammatory activity and regulation of protein biosynthesis and degradation-protects skin cells against UVA/B-induced changes. In the future, its long-term use in epidermal cells should be investigated

The Differences in the Proteome Profile of Cannabidiol-Treated Skin Fibroblasts following UVA or UVB Irradiation in 2D and 3D Cell Cultures

Cannabidiol (CBD), as the only phytocannabinoid that has no psychoactive effect, has both antioxidant and anti-inflammatory effects, and thus might be suggested as a cytoprotective compound against UV-induced metabolic changes in skin cells. Therefore, the aim of this study was to investigate the level of protective CBD activity by evaluating the proteomic profile of 2D and 3D cultured skin fibroblasts models following exposure to UVA and UVB radiation. The CBD cytoprotective effect against UV-induced damage in 2D and 3D cultured fibroblasts were different. The main alterations focus on the range of cell reaction and involved different proteins associated with various molecular functions. In the 2D cultured cells, following UV radiation, the major changes were associated with proteins involved in antioxidant response and inflammation, while, in the 3D cultured fibroblasts, CBD action against UV induced changes were mainly associated with the activation of signalling pathways. Therefore, the knowledge of the CBD action in a multilayer skin cells model allowed for the prediction of changes in cell-cell interactions and skin cell metabolism. Knowledge about the lower protective effect of CBD in 3D cultured fibroblasts should be taken into account during the design of UV light protection

The Role of ABC Transporters in Skin Cells Exposed to UV Radiation

ABC transporters are expressed in skin cells to protect them against harmful xenobiotics. Moreover, these transmembrane proteins have a number of additional functions that ensure skin homeostasis. This review summarizes the current knowledge about the role of specific ABC proteins in the skin, including multi-drug resistance transporters (MDR1/3), the transporter associated with antigen processing 1/2 (TAP1/2), the cystic fibrosis transmembrane conductance regulator (CFTR), sulfonylurea receptors (SUR1/2), and the breast cancer resistance protein (BCRP). Additionally, the effect of UV radiation on ABC transporters is shown. The exposure of skin cells to UV radiation often leads to increased activity of ABC transporters—as has been observed in the case of MDRs, TAPs, CFTR, and BCRP. A different effect of oxidative stress has been observed in the case of mitochondrial SURs. However, the limited data in the literature—as indicated in this article—highlights the limited number of experimental studies dealing with the role of ABC transporters in the physiology and pathophysiology of skin cells and the skin as a whole. At the same time, the importance of such knowledge in relation to the possibility of daily exposure to UV radiation and xenobiotics, used for both skin care and the treatment of its diseases, is emphasized

Antioxidative and Anti-Inflammatory Activity of Ascorbic Acid

Ascorbic acid, as a one of the basic exogenous vitamins, occurs in the body in the form of ascorbate, known for its strong antioxidant and anti-inflammatory properties. The presented review shows not only the importance of ascorbate as a free radical scavenger but also summarizes its antioxidant action based on other mechanisms, including the activation of intracellular antioxidant systems and its effect on the NFκB/TNFα pathway and apoptosis. Ascorbate interacts with small-molecule antioxidants, including tocopherol, glutathione, and thioredoxin; it can also stimulate biosynthesis and the activation of antioxidant enzymes, such as superoxide dismutase, catalase, or glutathione peroxidase. Moreover, ascorbate promotes the activity of transcription factors (Nrf2, Ref-1, AP-1), which enables the expression of genes encoding antioxidant proteins. Additionally, it supports the action of other exogenous antioxidants, mainly polyphenols. In this regard, both DNA, proteins, and lipids are protected against oxidation, leading to an inflammatory reaction and even cell death. Although ascorbate has strong antioxidant properties, it can also have pro-oxidant effects in the presence of free transition metals. However, its role in the prevention of DNA mutation, inflammation, and cell apoptosis, especially in relation to cancer cells, is controversial

The Role of ABC Transporters in Skin Cells Exposed to UV Radiation

ABC transporters are expressed in skin cells to protect them against harmful xenobiotics. Moreover, these transmembrane proteins have a number of additional functions that ensure skin homeostasis. This review summarizes the current knowledge about the role of specific ABC proteins in the skin, including multi-drug resistance transporters (MDR1/3), the transporter associated with antigen processing 1/2 (TAP1/2), the cystic fibrosis transmembrane conductance regulator (CFTR), sulfonylurea receptors (SUR1/2), and the breast cancer resistance protein (BCRP). Additionally, the effect of UV radiation on ABC transporters is shown. The exposure of skin cells to UV radiation often leads to increased activity of ABC transporters—as has been observed in the case of MDRs, TAPs, CFTR, and BCRP. A different effect of oxidative stress has been observed in the case of mitochondrial SURs. However, the limited data in the literature—as indicated in this article—highlights the limited number of experimental studies dealing with the role of ABC transporters in the physiology and pathophysiology of skin cells and the skin as a whole. At the same time, the importance of such knowledge in relation to the possibility of daily exposure to UV radiation and xenobiotics, used for both skin care and the treatment of its diseases, is emphasized

Effects of Natural Antioxidants on Phospholipid and Ceramide Profiles of 3D-Cultured Skin Fibroblasts Exposed to UVA or UVB Radiation

Ultraviolet (UV) radiation is one of the primary factors responsible for disturbances in human skin cells phospholipid metabolism. Natural compounds that are commonly used to protect skin, due to their lipophilic or hydrophilic nature, show only a narrow range of cytoprotective activity, which prompts research on their combined application. Therefore, the aim of this study was to examine the effect of ascorbic acid and rutin on the phospholipid and ceramide profiles in UV-irradiated fibroblasts cultured in a three-dimensional system that approximates the culture conditions to the dermis. An ultra-high-performance liquid chromatograph coupled with a quadrupole time-of-flight mass spectrometer was used for phospholipid and ceramide profiling. As a result of UVA and UVB cells irradiation, upregulation of phosphatidylcholines, ceramides, and downregulation of sphingomyelins were observed, while treatment with ascorbic acid and rutin of UVA/UVB-irradiated fibroblast promoted these changes to provide cells a stronger response to stress. Moreover, an upregulation of phosphatidylserines in cells exposed to UVB and treated with both antioxidants suggests the stimulation of UV-damaged cells apoptosis. Our findings provide new insight into action of rutin and ascorbic acid on regulation of phospholipid metabolism, which improves dermis fibroblast membrane properties