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.Antioxidants 2020, 9, 21 2 of 20 Moreover, this phytocannabinoid accelerated wound healing in a diabetic rat model by protecting the endothelial growth factor (VEGF) [11]. In addition, by preventing the formation of oxidative stress in the retina neurons of diabetic animals, CBD counteracted tyrosine nitration, which can lead to glutamate accumulation and neuronal cell death [12].This review summarizes the chemical and biological effects of CBD and its natural and synthetic derivatives. Particular attention was paid to the antioxidant and anti-inflammatory effects of CBD and its derivatives, bearing in mind the possibilities of using this phytocannabinoid to protect against oxidative stress and the consequences associated with oxidative modifications of proteins and lipids. Although CBD demonstrates safety and a good side effect profile in many clinical trials [4], all of the therapeutic options for CBD discussed in this review are limited in a concentration-dependent manner. Molecular Structure of CBDCBD is a terpenophenol compound containing twenty-one carbon atoms, with the formula C 21 H 30 O 2 and a molecular weight of 314.464 g/mol (Figure 1). The chemical structure of cannabidiol, 2-[1R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1, 3-benzenediol, was determined in 1963 [13]. The current IUPAC preferred terminology is 2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol. Naturally occurring CBD has a (−)-CBD structure [14]. The CBD molecule contains a cyclohexene ring (A), a phenolic ring (B) and a pentyl side chain. In addition, the terpenic ring (A) and the aromatic ring (B) are located in planes that are almost perpendicular to each other [15]. There are four known CBD side chain homologs, which are methyl, n-propyl, n-butyl, and n-pentyl [16]. All known CBD forms (Table 1) have absolute trans configuration in positions 1R and 6R [16].
The current understanding of the complex role of ROS in the organism and pathological sequelae of oxidative stress points to the necessity of comprehensive studies of antioxidant reactivities and interactions with cellular constituents. Studies of antioxidants performed within the COST B-35 action has concerned the search for new natural antioxidants, synthesis of new antioxidant compounds and evaluation and elucidation of mechanisms of action of both natural and synthetic antioxidants. Representative studies presented in the review concern antioxidant properties of various kinds of tea, the search for new antioxidants of herbal origin, modification of tocopherols and their use in combination with selenium and properties of two promising groups of synthetic antioxidants: derivatives of stobadine and derivatives of 1,4-dihydropyridine.
Colorectal carcinogenesis is associated with serious oxidative stress and confirms that gradual advancement of oxidative-antioxidative disorders is followed by progression of colorectal cancer.
Cancer development is essentially a tissue remodeling process in which normal tissue is substituted with cancer tissue. A crucial role in this process is attributed to proteolytic degradation of the extracellular matrix (ECM). Degradation of ECM is initiated by proteases, secreted by different cell types, participating in tumor cell invasion and increased expression or activity of every known class of proteases (metallo-, serine-, aspartyl-, and cysteine) has been linked to malignancy and invasion of tumor cells. Proteolytic enzymes can act directly by degrading ECM or indirectly by activating other proteases, which then degrade the ECM. They act in a determined order, resulting from the order of their activation. When proteases exert their action on other proteases, the end result is a cascade leading to proteolysis. Presumable order of events in this complicated cascade is that aspartyl protease (cathepsin D) activates cysteine proteases (e.g. cathepsin B) that can activate pro-uPA. Then active uPA can convert plasminogen into plasmin. Cathepsin B as well as plasmin are capable of degrading several components of tumor stroma and may activate zymogens of matrix metalloproteinases, the main family of ECM degrading proteases. The activities of these proteases are regulated by a complex array of activators, inhibitors and cellular receptors. In physiological conditions the balance exists between proteases and their inhibitors. Proteolytic-antiproteolytic balance may be of major significance in the cancer development. One of the reasons for such a situation is enhanced generation of free radicals observed in many pathological states. Free radicals react with main cellular components like proteins and lipids and in this way modify proteolytic-antiproteolytic balance and enable penetration damaging cellular membrane. All these lead to enhancement of proteolysis and destruction of ECM proteins and in consequence to invasion and metastasis.
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.
Inflammatory granulocytes are characterized by an oxidative burst, which may promote oxidative stress and lipid modification both in affected tissues and on a systemic level. On the other hand, redox signaling involving lipid peroxidation products acting as second messengers of free radicals play important yet not fully understood roles in the pathophysiology of inflammation and various stress-associated disorders. Therefore, the aim of this study was to evaluate the onset of oxidative stress and alterations of enzyme-dependent lipid metabolism resulting from redox imbalance in granulocytes and plasma obtained from patients with psoriasis vulgaris or psoriatic arthritis in comparison to the healthy subjects. The results obtained revealed enhanced activity of pro-oxidant enzymes nicotinamide adenine dinucleotide phosphate (NADPH) and xanthine oxidases in granulocytes with a decrease of enzymatic and non-enzymatic antioxidants in the plasma of psoriatic patients. The nuclear factor erythroid 2–related factor 2 (Nrf2) and its regulators were increased in both forms of psoriasis while heme oxygenase 1 levels were increased only in psoriasis vulgaris. The redox imbalance was associated with decreased levels of phospholipids and of free polyunsaturated fatty acids but with enhanced activity of enzymes involved in lipid metabolism (phospholipase A2, acetylhydrolase PAF, cyclooxygenases 1 and 2) and increased lipid peroxidation products 4-hydroxynonenal, isoprostanes, and neuroprostanes. Increased endocannabinoids and G protein-coupled receptor 55 were observed in both forms of the disease while expression of the cannabinoid type 1 receptor (CB1) was increased only in patients with psoriatic arthritis, which is opposite to the cannabinoid type 2 receptor. This receptor was increased only in psoriasis vulgaris. Changes in protein expression promoted the apoptosis of granulocytes by increased caspases mainly in psoriasis vulgaris. This study indicates that inhibition of the Nrf2 pathway in psoriatic arthritis promotes a redox imbalance. In addition, increased expression of CB1 receptors leads to increased oxidative stress, lipid modifications, and inflammation, which, in turn, may promote the progression of psoriasis into the advanced, arthritic form of the disease.
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