Aspirin-Triggered Resolvin D1 (AT-RvD1) Protects Mouse Skin against UVB-Induced Inflammation and Oxidative Stress.

Intense exposure to UVB radiation incites excessive production of reactive oxygen species (ROS) and inflammation. The resolution of inflammation is an active process orchestrated by a family of lipid molecules that includes AT-RvD1, a specialized proresolving lipid mediator (SPM). AT-RvD1 is derived from omega-3, which presents anti-inflammatory activity and reduces oxidative stress markers. The present work aims to investigate the protective effect of AT-RvD1 on UVB-induced inflammation and oxidative stress in hairless mice. Animals were first treated with 30, 100, and 300 pg/animal AT-RvD1 (i.v.) and then exposed to UVB (4.14 J/cm2). The results showed that 300 pg/animal of AT-RvD1 could restrict skin edema, neutrophil and mast cell infiltration, COX-2 mRNA expression, cytokine release, and MMP-9 activity and restore skin antioxidant capacity as per FRAP and ABTS assays and control O2•- production, lipoperoxidation, epidermal thickening, and sunburn cells development. AT-RvD1 could reverse the UVB-induced downregulation of Nrf2 and its downstream targets GSH, catalase, and NOQ-1. Our results suggest that by upregulating the Nrf2 pathway, AT-RvD1 promotes the expression of ARE genes, restoring the skin's natural antioxidant defense against UVB exposition to avoid oxidative stress, inflammation, and tissue damage.

Rosmarinus officinalis extract-loaded emulgel prevents UVB irradiation damage to the skin.

UVB-irradiation increases the risk of various skin disorders, therefore leading to inflammation and oxidative stress. In this sense, antioxidant-rich herbs such as Rosmarinus officinalis may be useful in minimizing the damage promoted by reactive oxygen species. In this work, we report the efficacy of a R. officinalis hydroethanolic extract (ROe)-loaded emulgel in preventing UVB-related skin damage. Total phenols were determined using Folin-Ciocalteu assay, and the main phytocomponents in the extract were identified by UHPLC-HRMS. Moreover, in vitro sun protection factor (SPF) value of ROe was also assessed, and we investigated the in vivo protective effect of an emulgel containing ROe against UVB-induced damage in an animal model. The ROe exhibited commercially viable SPF activity (7.56 ± 0.16) and remarkable polyphenolic content (24.15 ± 0.11 mg (Eq.GA)/g). HPLC-MS and UHPLC-HRMS results showcased that the main compounds in ROe were: rosmarinic acid, carnosic acid and carnosol. The evaluation of the in vitro antioxidant activity demonstrated a dose-dependent effect of ROe against several radicals and the capacity to reduce iron. Therefore, we demonstrated that topical application of the formulation containing ROe inhibited edema formation, myeloperoxidase activity, GSH depletion and maintained ferric reducing (FRAP) and ABTS scavenging abilities of the skin after UVB exposure.

Protection against UVB deleterious skin effects in a mouse model: effect of a topical emulsion containing Cordia verbenacea extract.

Cordia verbenacea DC (Boraginaceae) is a flowering shrub found along the Brazilian Atlantic Forest, Brazilian coast, and low areas of the Amazon. The crude extract of its leaves is widely used in Brazilian folk medicine as an anti-inflammatory, both topically and orally. The aim of this study is to evaluate the activity of C. verbenacea ethanolic leaves extract (CVE) against UVB-triggered cutaneous inflammation and oxidative damage in hairless mice. CVE treatment recovered cutaneous antioxidant capacity demonstrated by scavenging ABTS+ free radical and iron-reducing antioxidant potential evaluated by FRAP. CVE also controlled the following UV-triggered events in the skin: reduced glutathione (GSH) depletion, catalase activity decrease, and superoxide anion (O⋅-) build-up. Furthermore, mice treated with CVE exhibited less inflammation, shown by the reduction in COX-2 expression, TNF-α, IL-1ß, IL-6, edema, and neutrophil infiltration. CVE also regulated epidermal thickening and sunburn cells, reduced dermal mast cells, and preserved collagen integrity. The best results were obtained using 5% CVE-added emulsion. The present data demonstrate that topical administration of CVE presents photochemoprotective activity in a mouse model of UVB inflammation and oxidative stress. Because of the intricate network linking inflammation, oxidative stress, and skin cancer, these results also indicate the importance of further studies elucidating a possible role of C. verbenacea in the prevention of UVB-induced skin cancer and evaluating a potential synergy between CVE and sunscreens in topical products against UVB damaging effects to the skin.

Topical Administration of 15-Deoxy-Δ 12,14-Prostaglandin J2 Using a Nonionic Cream: Effect on UVB-Induced Skin Oxidative, Inflammatory, and Histopathological Modifications in Mice.

UVB radiation is certainly one of the most important environmental threats to which we are subjected to. This fact highlights the crucial protective role of the skin. However, the skin itself may not be capable of protecting against UVB depending on irradiation intensity and time of exposition. Sun blockers are used to protect our skin, but they fail to fully protect it against oxidative and inflammatory injuries initiated by UVB. To solve this issue, topical administration of active molecules is an option. 15-Deoxy-Δ 12,14-prostaglandin J2 (15d-PGJ2) is an arachidonic acid-derived lipid with proresolution and anti-inflammatory actions. However, as far as we are aware, there is no evidence of its therapeutic use in a topical formulation to treat the deleterious events initiated by UVB, which was the aim of the present study. We used a nonionic cream to vehiculate 15d-PGJ2 (30, 90, and 300 ng/mouse) (TFcPGJ2) in the skin of hairless mice. UVB increased skin edema, myeloperoxidase activity, metalloproteinase-9 activity, lipid peroxidation, superoxide anion production, gp91phox and COX-2 mRNA expression, cytokine production, sunburn and mast cells, thickening of the epidermis, and collagen degradation. UVB also diminished skin ability to reduce iron and scavenge free radicals, reduced glutathione (GSH), sulfhydryl proteins, and catalase activity. TFcPGJ2 inhibited all these pathological alterations in the skin caused by UVB. No activity was observed with the unloaded topical formulation. The protective outcome of TFcPGJ2 indicates it is a promising therapeutic approach against cutaneous inflammatory and oxidative pathological alterations.

The Lipoxin Receptor/FPR2 Agonist BML-111 Protects Mouse Skin Against Ultraviolet B Radiation.

Excessive exposure to UV, especially UVB, is the most important risk factor for skin cancer and premature skin aging. The identification of the specialized pro-resolving lipid mediators (SPMs) challenged the preexisting paradigm of how inflammation ends. Rather than a passive process, the resolution of inflammation relies on the active production of SPMs, such as Lipoxins (Lx), Maresins, protectins, and Resolvins. LXA4 is an SPM that exerts its action through ALX/FPR2 receptor. Stable ALX/FPR2 agonists are required because SPMs can be quickly metabolized within tissues near the site of formation. BML-111 is a commercially available synthetic ALX/FPR2 receptor agonist with analgesic, antioxidant, and anti-inflammatory properties. Based on that, we aimed to determine the effect of BML-111 in a model of UVB-induced skin inflammation in hairless mice. We demonstrated that BML-111 ameliorates the signs of UVB-induced skin inflammation by reducing neutrophil recruitment and mast cell activation. Reduction of these cells by BML-111 led to lower number of sunburn cells formation, decrease in epidermal thickness, collagen degradation, cytokine production (TNF-α, IL-1ß, IL-6, TGF, and IL-10), and oxidative stress (observed by an increase in total antioxidant capacity and Nrf2 signaling pathway), indicating that BML-111 might be a promising drug to treat skin disorders.

Resolvin D5 Protects Female Hairless Mouse Skin from Pathological Alterations Caused by UVB Irradiation.

Resolvin D5 (RvD5) is a lipid mediator that has been reported to present anti-inflammatory and pro-resolution properties. Evidence also supports its capability to enhance reactive oxygen species (ROS) production during bacterial infections, which would be detrimental in diseases driven by ROS. The biological activity of RvD5 and mechanisms against UVB irradiation skin pathology have not been investigated so far. Female hairless mice were treated intraperitoneally with RvD5 before UVB stimulus. RvD5 reduced skin edema in a dose-dependent manner as well as oxidative stress by increasing antioxidants (endogenous tissue antioxidant scavenging of cationic radical, iron reduction, catalase activity and reduced glutathione levels) and decreasing pro-oxidants (superoxide anion and lipid peroxidation). RvD5 antioxidant activity was accompanied by enhancement of Nrf2, HO-1 and NQO1 mRNA expression. RvD5 reduced the production of IL-1ß, TNF-α, TGF-ß, and IL-10. RvD5 also reduced the inflammatory cell counts, including mast cells and neutrophils/macrophages. The reduction of oxidative stress and inflammation resulted in diminished matrix metalloproteinase 9 activity, collagen degradation, epidermal thickening and sunburn cell development. Therefore, this study demonstrates, to our knowledge, the first body of evidence that RvD5 can be used to treat UVB skin pathology and unveils, at least in part, its mechanisms of action.

Topiramate treatment in Wistar rats during childhood induces sex-specific vascular dysfunction in adulthood.

The present study determined whether treatment during childhood with topiramate (TPM), a new generation antiepileptic drug, results in altered aortic reactivity in adult male and female rats. We also sought to understand the role of endothelium-derived contractile factors in TPM-induced vascular dysfunction. Male and female Wistar rats were treated with TPM (41 mg/kg/day) or water (TPM vehicle) by gavage during childhood (postnatal day, 16-28). In adulthood, thoracic aorta reactivity to phenylephrine (phenyl), as well as aortic thickness and expression of cyclooxygenases (COX-1 and COX-2), NOX2, and p47phox were evaluated. The aortic response to phenyl was increased in male and female rats from the TPM group when compared with the control group. In TPM male rats, the hyperreactivity to phenyl was abrogated by the inhibition of NADPH oxidase and COX-2, while in female rats, responses were restored only by inhibition of COX-2. In addition, TPM male rats presented aortic hypertrophy and increased expression of NOX-2 and p47phox, while TPM female rats showed increased COX-2 aortic expression. Taken together, for the first-time, the present study provides evidence that treatment with TPM during childhood causes vascular dysfunction in adulthood, and that the mechanism underlying the vascular effects of TPM is sex-specific.

Photochemoprotective Potential of the Ethyl Acetate Fraction from Eugenia hiemalis Leaves and Its 2,6-Di-O-galloylarbutin Isolate Against UVB-Induced Photodamage.

Intense and constant exposure to UVB radiation can lead to inflammation and oxidative stress, which are associated with many cutaneous disorders, including photoaging and skin cancer. Antioxidant plant materials that are rich in polyphenols, such as the ethyl acetate fraction (EAF) from Eugenia hiemalis leaves, and phenolic compounds represent a promising approach to protect the skin against UVB-induced damage. The present study evaluated the photochemoprotective potential of the EAF and its 2,6-di-O-galloylarbutin (1) isolate. The EAF and the phenolic antioxidant (1) reduced UVB-induced L929 fibroblast death. The EAF prevented UVB-induced damage in fibroblasts by inhibiting the intracellular production of reactive oxygen species and lipid peroxidation, especially in pretreated cells. Topical treatment with an emulsion with 1% EAF prevented/attenuated UVB-induced inflammation and oxidative stress in the skin in hairless mice by controlling the increase in myeloperoxidase activity, reducing superoxide anion production, maintaining radical-scavenging ability and ferric reducing power, and controlling the depletion of reduced glutathione and catalase levels. The EAF also inhibited the increase in epidermal thickness, mast cell infiltration, the number of sunburn cells and collagen fiber destruction that were triggered by UVB. The in vitro and in vivo results indicated that the EAF is a bioactive agent that is able to protect the skin against the harmful effects of UVB.

Protective effect of oral treatment with Cordia verbenacea extract against UVB irradiation deleterious effects in the skin of hairless mouse.

Photochemoprotection of the skin can be achieved by inhibiting inflammation and oxidative stress, which we tested using Cordia verbenacea extract, a medicinal plant known for its rich content of antioxidant molecules and anti-inflammatory activity. In vitro antioxidant evaluation of Cordia verbenacea leaves ethanolic extract (CVE) presented the following results: ferric reducing antioxidant power (886.32 µM equivalent of Trolox/g extract); IC50 of 19.128 µg/ml for scavenging 2,2-diphenyl-1-picrylhydrazyl; IC50 of 12.48 µg/mL for scavenging 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid); decrease of hydroperoxides from linoleic acid (IC50 of 10.20 µg/mL); inhibition of thiobarbituric acid reactive substances (IC50 8.90 µg/mL); iron-chelating ability in bathophenanthroline iron assay (IC50 47.35 µg/mL); chemiluminescence triggered by free radicals in the H2O2/horseradish peroxidase/luminol (IC50 0.286 µg/mL) and xanthine/xanthine oxidase/luminol (IC50 0.42 µg/mL) methods. CVE (10-100 mg per kg, 30 min before and immediately after UVB exposure) treatment was performed by gavage in hairless mice. CVE inhibited skin edema, neutrophil infiltration, and overproduction of MMP-9; reduced levels of TNF-α, IL-1ß, and IL- 6; numbers of skin mast cells, epidermal thickening, number of epidermal apoptotic keratinocytes, and collagen degradation. CVE increased the skin's natural antioxidant defenses as observed by Nrf-2, NAD(P)H quinone oxidoreductase 1, and heme oxygenase 1 mRNA expression enhancement. Furthermore, CVE inhibited lipid peroxidation and superoxide anion production and recovered antioxidant reduced glutathione, catalase activity, and ROS scavenging capacity of the skin. Concluding, CVE downregulates the skin inflammatory and oxidative damages triggered by UVB, demonstrating its potentialities as a therapeutic approach.

The Lipid Mediator Resolvin D1 Reduces the Skin Inflammation and Oxidative Stress Induced by UV Irradiation in Hairless Mice.

UV irradiation-induced oxidative stress and inflammation contribute to the development of skin diseases. Therefore, targeting oxidative stress and inflammation might contribute to reduce skin diseases. Resolvin D1 (RvD1) is a bioactive metabolite generated during inflammation to actively orchestrate the resolution of inflammation. However, the therapeutic potential of RvD1 in UVB skin inflammation remains undetermined, which was, therefore, the aim of the present study. The intraperitoneal treatment with RvD1 (3-100 ng/mouse) reduced UVB irradiation-induced skin edema, myeloperoxidase activity, matrix metalloproteinase 9 activity, and reduced glutathione depletion with consistent effects observed with the dose of 30 ng/mouse, which was selected to the following experiments. RvD1 inhibited UVB reduction of catalase activity, and hydroperoxide formation, superoxide anion production, and gp91phox mRNA expression. RvD1 also increased the Nrf2 and its downstream targets NQO1 and HO-1 mRNA expression. Regarding cytokines, RvD1 inhibited UVB-induced production of IL-1ß, IL-6, IL-33, TNF-α, TGF-ß, and IL-10. These immuno-biochemical alterations by RvD1 treatment had as consequence the reduction of UVB-induced epidermal thickness, sunburn and mast cell counts, and collagen degradation. Therefore, RvD1 inhibited UVB-induced skin oxidative stress and inflammation, rendering this resolving lipid mediator as a promising therapeutic agent.