Nrf2 activation by hydroxytyrosol and dimethyl fumarate ameliorates skin tissue repair in high-fat diet-fed mice by promoting M2 macrophage polarization and normalizing inflammatory response and oxidative damage.

Hydroxytyrosol (HT) or dimethyl fumarate (DMF), activators of nuclear factor erythroid 2-related factor 2 (Nrf2), may reduce obesity in high-fat diet (HFD)-fed animals; nevertheless, the role of these activators on skin tissue repair of HFD-fed animals was not reported. This study investigated whether HT or DMF could improve skin wound healing of HFD-fed obese animals. Mice were fed with an HFD, treated with HT or DMF, and full-thickness skin wounds were created. Macrophages isolated from control and obese animals were treated in vitro with HT. DMF, but not HT, reduced the body weight of HFD-fed mice. Collagen deposition and wound closure were improved by HT or DMF in HFD-fed animals. HT or DMF increased anti-inflammatory macrophage phenotype and protein Nrf2 levels in wounds of HFD-fed mice. Lipid peroxidation and protein tumor necrosis factor-α levels were reduced by HT or DMF in wounds of HFD-fed animals. In in vitro, HT stimulated Nrf2 activation in mouse macrophages isolated from obese animals. In conclusion, HT or DMF improves skin wound healing of HFD-fed mice by reducing oxidative damage and inflammatory response. HT or DMF may be used as a therapeutic strategy to improve the skin healing process in individuals with obesity.

Chronic psychological stress aggravates psoriasis-like skin inflammation via overactivation of ß2-adrenoceptor and nuclear factor kappa B pathways.

The relationship between psoriasis severity and psychological stress has been described in several studies. However, the mechanism by which chronic stress exacerbates psoriasis is not completely understood. This study aimed at investigating whether chronic psychological stress can aggravate psoriasis-like skin inflammation. Mice were subjected to a restraint stress model and topically treated with imiquimod (IMQ). Differentiated human keratinocytes were treated with high epinephrine levels and IMQ in vitro. Stress aggravated macroscopic features and the increase in epidermal thickness induced by IMQ in mouse skin. The increase in NF-κB and IL-17A expression induced by IMQ was potentiated by chronic stress in mouse skin. The skin of stressed mice treated with IMQ showed higher levels of ß2-adrenergic receptors (ß2-AR). In human keratinocytes, high epinephrine levels exacerbated the increase in the levels of ß2-AR and IL-17A induced by IMQ. ß-AR antagonist reversed the effects of chronic stress in IMQ-induced inflammation both in vivo and in vitro. In conclusion, stress-stimulated overactivation of the ß2-AR and NF-κB pathways potentiates a Th1/Th17 profile leading to an exacerbation of psoriasis.

Dual effects of extra virgin olive oil in acute wounds.

Extra virgin olive oil (EVOO) has proved beneficial effects in skin wound healing of chronic lesions; however, the effects of EVOO in acute wounds are not completely understood. This study investigated the effects of short-term and long-term administration of a diet rich in EVOO on acute wound healing. To check this, mice were fed with a diet rich in EVOO for 1 week (short term), 1 month, or 3 months (long term). The control group received a standard diet. Mouse macrophages were treated in vitro with EVOO or hydroxytyrosol (HT), which is the main EVOO polyphenol. Short-term administration of an EVOO rich diet in vivo increased lipid peroxidation and mRNA levels of pro-inflammatory cytokine levels and impaired acute wound closure. In contrast, long-term administration of an EVOO rich diet resulted in increased mRNA levels of anti-inflammatory cytokines and enhanced acute wound closure. In both in vivo and in vitro assays, the administration of EVOO or HT resulted in a predominantly anti-inflammatory macrophage phenotype. In conclusion, a diet rich in EVOO has a positive effect on acute wound healing that is dependent on the duration of EVOO administration. Short-term EVOO diet supplementation increases oxidative damage and pro-inflammatory responses, which impaired acute wound closure. On the other hand, long-term EVOO supplementation reduces oxidative damage and enhances anti-inflammatory responses, which improved acute wound closure. The effects of EVOO on oxidation and inflammation in acute wounds are linked to the EVOO polyphenol HT.

Imiquimod-induced ex vivo model of psoriatic human skin via interleukin-17A signalling of T cells and Langerhans cells.

Several in vitro models have been developed to study the mechanisms involved in psoriasis and to screen new antipsoriatic drugs. However, most of them use single-cell or reconstructed human skin models that did not have complex anatomy of human skin. Thus, this study aimed to create a new model of psoriasis-like dermatitis using human skin under in vitro conditions. To perform this, human skin explants were topically treated with imiquimod (IMQ) or vehicle for 2, 3 or 6 consecutive days. Some explants were treated with an anti-psoriatic drug or antibody anti-interleukin-17A (IL-17A). Topical application of IMQ increased total epidermal area, epidermal proliferation and keratinocyte differentiation at 3, 4 or 7 days. The protein levels of CD3 were augmented in the IMQ-treated human skin explants at 7 days reflecting the activation of T cells. Topical IMQ promoted a higher protein and mRNA levels of IL-17A in human skin ex vivo. Immunofluorescence analysis showed CD207-positive Langerhans cells (LCs) and CD3-positive T cells expressing IL-17A in IMQ-treated human skin explants at 7 days. In addition, administration of antibody anti-IL-17A or an anti-psoriatic drug inhibited IMQ-induced increase in the epidermal thickness in ex vivo human skin at 7 days. In conclusion, topical IMQ application promotes epidermal changes in ex vivo human skin that resemble to human psoriatic skin lesions. Moreover, IMQ-induced production of IL-17 by LCs and T cells is critical to development of psoriasis-like inflammation in our model. This new model is suitable for in vitro screening of antipsoriatic drugs.

Dermal fibroblast phagocytosis of apoptotic cells: A novel pathway for wound resolution.

The effective clearance of apoptotic cells is an essential step in the resolution of healing wounds. In particular, blood vessel regression during wound resolution produces a significant number of apoptotic endothelial cells (ApoEC) that must be cleared. In considering the fate of ApoEC and the presence of fibroblasts during wound resolution, we hypothesized that fibroblasts might serve as phagocytes involved in endothelial cell removal. The current study investigated whether dermal fibroblasts engulf ApoEC, whether this uptake alters the phenotype of dermal fibroblasts, and the biological molecules involved. In both in vitro and in vivo studies, following ApoEC engulfment, fibroblasts acquired a pro-healing phenotype (increased cell migration, contractility, α-smooth muscle actin expression, and collagen deposition). In addition, fibroblast uptake of ApoEC was shown to be mediated in part by the milk fat globule-EGF factor 8 protein/integrin αv ß5 pathway. Our study demonstrates a novel function of fibroblasts in the clearance of ApoEC and suggests that this capability has significant implications for tissue repair and fibrosis.

Pigment epithelium-derived factor attenuates angiogenesis and collagen deposition in hypertrophic scars.

Scar forming wounds are often characterized by higher levels of vascularity than non-scarring wounds and normal skin, and inhibition of angiogenesis has been shown to inhibit scar formation in some model systems. The rabbit ear hypertrophic scar (HS) model has been widely used to study the mechanisms that underlie the development of HS as well as the effectiveness of various treatments. Although the rabbit ear HS model is well characterized in terms of scar formation, the rate and level of angiogenesis has not been investigated in this model, and the cause-effect relationship between angiogenesis and rabbit HSs has not been examined. In the current study, full-thickness excisional wounds were created on the ventral side of New Zealand White rabbit ears to induce HS formation, and the dynamic pattern of angiogenesis and the expression of angiogenic regulatory factors were examined over time. Blood vessel density was found to peak at 2.7% on day 14 post-wounding, decreasing to 1.7% by day 28. mRNA levels of the proangiogenic factor VEGF-A peaked at day 14, while the expression of the antiangiogenic factors pigment epithelium-derived factor (PEDF) and thrombospondin 1 (TSP1) peaked at day 28 post-wounding. To examine whether inhibition of angiogenesis influences HS formation in this model, wounds were treated with exogenous soluble antiangiogenic agents including recombinant PEDF (rPEDF) and a functional PEDF peptide (PEDF-335). rPEDF and PEDF-335 were administered intradermally from day 4 post-wounding every 3 days until day 19. Intradermal injection of rPEDF or PEDF-335 both led to decreased angiogenesis and decreased collagen deposition at the wound site. The results support the utility of antiangiogenic therapies, including rPEDF/PEDF-335, as a potential new strategy for the prevention or treatment of HSs.

Dimethyl Fumarate Attenuates Lung Inflammation and Oxidative Stress Induced by Chronic Exposure to Diesel Exhaust Particles in Mice.

Air pollution is mainly caused by burning of fossil fuels, such as diesel, and is associated with increased morbidity and mortality due to adverse health effects induced by inflammation and oxidative stress. Dimethyl fumarate (DMF) is a fumaric acid ester and acts as an antioxidant and anti-inflammatory agent. We investigated the potential therapeutic effects of DMF on pulmonary damage caused by chronic exposure to diesel exhaust particles (DEPs). Mice were challenged with DEPs (30 µg per mice) by intranasal instillation for 60 consecutive days. After the first 30 days, the animals were treated daily with 30 mg/kg of DMF by gavage for the remainder of the experimental period. We demonstrated a reduction in total inflammatory cell number in the bronchoalveolar lavage (BAL) of mice subjected to DEP + DMF as compared to those exposed to DEPs alone. Importantly, DMF treatment was able to reduce lung injury caused by DEP exposure. Intracellular total reactive oxygen species (ROS), peroxynitrite (OONO), and nitric oxide (NO) levels were significantly lower in the DEP + DMF than in the DEP group. In addition, DMF treatment reduced the protein expression of kelch-like ECH-associated protein 1 (Keap-1) in lung lysates from DEP-exposed mice, whereas total nuclear factor κB (NF-κB) p65 expression was decreased below baseline in the DEP + DMF group compared to both the control and DEP groups. Lastly, DMF markedly reduced DEP-induced expression of nitrotyrosine, glutathione peroxidase-1/2 (Gpx-1/2), and catalase in mouse lungs. In summary, DMF treatment effectively reduced lung injury, inflammation, and oxidative and nitrosative stress induced by chronic DEP exposure. Consequently, it may lead to new therapies to diminish lung injury caused by air pollutants.

Topical retinol attenuates stress-induced ageing signs in human skin ex vivo, throughEGFR activation viaEGF, but notERK andAP-1 activation.

Stress-induced oxidative damage and the inflammatory response lead to degradation of collagen and elastic fibres and wrinkle formation. Topical retinol (or vitamin A) can be a strategy to attenuate the effects of stress in skin as it promotes collagen and elastic fibre production and reduces protease synthesis. This study investigated the effect of topical retinol in stressed human skin using in vitro and ex vivo models. Human skin explants were treated with high levels of epinephrine (as observed in stressed patients) and topically with retinol for 13 days. Human dermal fibroblasts were treated with conditioned medium of ex vivo retinol-treated and non-stressed (without epinephrine) human skin for 24 hours. In ex vivo human skin, retinol reversed the epinephrine-induced reduction in epidermal proliferation and differentiation, normalizing epidermal thickness. Retinol also inhibited the epinephrine-induced reduction in elastic fibre deposition and organization, restoring dermal thickness. In addition, retinol reversed the epinephrine-induced increase in c-JUN protein expression, but it did not alter extracellular signal-regulated kinase 1/2 (ERK) phosphorylation in ex vivo human skin. Conditioned medium of ex vivo retinol-treated and non-stressed human skin presented an increased protein expression of epidermal growth factor (EGF). In human dermal fibroblasts, conditioned medium of ex vivo retinol-treated and non-stressed human skin increased protein and gene expression of fibrillin-1 and protein expression of EGF receptor (EGFR). In conclusion, topical retinol attenuates stress-induced skin ageing signs in human skin ex vivo, probably through EGFR activation via EGF, but not by the stress-activated ERK 1/2 and c-JUN pathways.

Exercise prior to, but not concomitant with, stress reverses stress-induced delayed skin wound healing.

Stress-induced prolonged inflammation impairs cutaneous wound healing. Exercise may inhibit this effect via an anti-inflammatory mechanism. Our aim was to investigate the effect of moderate exercise on skin wound healing in chronically stressed mice. Mice were trained five times per week on a treadmill or received no training. Mice underwent daily rotational stress from the 6th week until euthanasia. During the 8th week, two wounds were created in the dorsum and collected 10 days later. A control group only received wounds. Exercise was performed prior to and simultaneous with stress for 2 weeks or only prior to stress. Stress increased normetanephrine levels 10 days after wounding, resulting in an increased amount of inflammatory cells and reduced expression of inflammatory cytokines as well as angiogenesis, myofibroblast differentiation and matrix deposition. Concomitant exercise and stress potentiated these effects, intensifying the delayed wound contraction. When exercise was performed only prior to stress, however, the mice showed reduced inflammatory cells in granulation tissue 10 days after wounding and improved wound healing compared with animals with exercise and concomitant stress. Moderate exercise in association with stress potentiates the stress effect; however, when exercise was performed prior to stress, wound healing was improved.

Propolis reversed cigarette smoke-induced emphysema through macrophage alternative activation independent of Nrf2.

Chronic obstructive pulmonary disease (COPD) is an incurable and progressive disease. Emphysema is the principal manifestation of COPD, and the main cause of this condition is cigarette smoke (CS). Natural products have shown antioxidant and anti-inflammatory properties that can prevent acute lung inflammation and emphysema, but there are few reports in the literature regarding therapeutic approaches to emphysema. We hypothesized that supplementation with natural extracts would repair lung damage in emphysema caused by CS exposure. Mice were exposed to 60days of CS and then treated or not with three different natural extracts (mate tea, grape and propolis) orally for additional 60days. Histological analysis revealed significant improvements in lung histoarchitecture, with recovery of alveolar spaces in all groups treated with natural extracts. Propolis was also able to recovery alveolar septa and elastic fibers. Propolis also increased MMP-2 and decreased MMP-12 expression, favoring the process of tissue repair. Additionally, propolis recruited leukocytes, including macrophages, without ROS release. These findings led us to investigate the profile of these macrophages, and we showed that propolis could promote macrophage alternative activation, thus increasing the number of arginase-positive cells and IL-10 levels and favoring an anti-inflammatory microenvironment. We further investigated the participation of Nrf2 in lung repair, but no Nrf2 translocation to the nucleus was observed in lung cells. Proteins and enzymes related to Nrf2 were not altered, other than NQO1, which seemed to be activated by propolis in a Nrf2-independent manner. Finally, propolis downregulated IGF1 expression. In conclusion, propolis promoted lung repair in a mouse emphysema model via macrophage polarization from M1 to M2 in parallel to the downregulation of IGF1 expression in a Nrf2-independent manner.

The influence of 5-lipoxygenase on cigarette smoke-induced emphysema in mice.

BACKGROUND: Pulmonary emphysema is characterized by the loss of lung architecture. Our hypothesis is that the inhibition of 5-lipoxygenase (5-LO) production may be an important strategy to reduce inflammation, oxidative stress, and metalloproteinases in lung tissue resulting from cigarette smoke (CS)-induced emphysema. METHODS: 5-LO knockout (129S2-Alox5(tm1Fun)/J) and wild-type (WT) mice (129S2/SvPas) were exposed to CS for 60days. Mice exposed to ambient air were used as Controls. Oxidative, inflammatory, and proteolytic markers were analyzed. RESULTS: The alveolar diameter was decreased in CS 5-LO(-/-) mice when compared with the WT CS group. The CS exposure resulted in less pronounced pulmonary inflammation in the CS 5-LO(-/-) group. The CS 5-LO(-/-) group showed leukotriene B4 values comparable to those of the Control group. The expression of MMP-9 was decreased in the CS 5-LO(-/-) group when compared with the CS WT group. The expression of superoxide dismutase, catalase, and glutathione peroxidase were decreased in the CS 5-LO(-/-) group when compared with the Control group. The protein expression of nuclear factor (erythroid-derived 2)-like 2 was reduced in the CS 5-LO(-/-) group when compared to the CS WT group. CONCLUSION: In conclusion, we show for the first time that 5-LO deficiency protects 129S2 mice against emphysema caused by CS. We suggest that the main mechanism of pathogenesis in this model involves the imbalance between proteases and antiproteases, particularly the association between MMP-9 and TIMP-1. General significance This study demonstrates the influence of 5-LO mediated oxidative stress, inflammation, and proteolytic markers in CS exposed mice.

Deletion of the α2A/α2C-adrenoceptors accelerates cutaneous wound healing in mice.

The α2-adrenoceptors regulate the sympathetic nervous system, controlling presynaptic catecholamine release. However, the role of the α2-adrenoceptors in cutaneous wound healing is poorly understood. Mice lacking both the α2A/α2C-adrenoceptors were used to evaluate the participation of the α2-adrenoceptor during cutaneous wound healing. A full-thickness excisional lesion was performed on the dorsal skin of the α2A/α2C-adrenoceptor knockout and wild-type mice. Seven or fourteen days later, the animals were euthanized and the lesions were formalin-fixed and paraffin-embedded or frozen. Murine skin fibroblasts were also isolated from α2A/α2C-adrenoceptor knockout and wild-type mice, and fibroblast activity was evaluated. The in vivo study demonstrated that α2A/α2C-adrenoceptor depletion accelerated wound contraction and re-epithelialization. A reduction in the number of neutrophils and macrophages was observed in the α2A/α2C-adrenoceptor knockout mice compared with wild-type mice. In addition, α2A/α2C-adrenoceptor depletion enhanced the levels of nitrite and hydroxyproline, and the protein expression of transforming growth factor-ß and vascular endothelial growth factor. Furthermore, α2A/α2C-adrenoceptor depletion accelerated blood vessel formation and myofibroblast differentiation. The in vitro study demonstrated that skin fibroblasts isolated from α2A/α2C-adrenoceptor knockout mice exhibited enhanced cell migration, α-smooth muscle actin _protein expression and collagen deposition compared with wild-type skin fibroblasts. In conclusion, α2A/α2C-adrenoceptor deletion accelerates cutaneous wound healing in mice.

Gonadal hormones differently modulate cutaneous wound healing of chronically stressed mice.

Gonadal hormones influence physiological responses to stress and cutaneous wound healing. The aim of this study was to investigate the role of gonadal hormones on cutaneous wound healing in chronically stressed mice. Male and female mice were gonadectomized, and after 25 days, they were spun daily at 115 rpm for 15 min every hour until euthanasia. Twenty-eight days after the gonadectomy, an excisional lesion was created. The animals were killed 7 or 14 days after wounding, and the lesions were collected. Myofibroblast density, macrophage number, catecholamine level, collagen deposition, and blood vessel number were evaluated. In the intact and gonadectomized groups, stress increased the plasma catecholamine levels in both genders. In intact groups, stress impaired wound contraction and re-epithelialization and increased the macrophage number in males but not in females. In addition, stress compromised myofibroblastic differentiation and blood vessel formation and decreased collagen deposition in males but not in females. In contrast to intact mice, wound healing in ovariectomized female mice was affected by stress, while wound healing in castrated male mice was not. In conclusion, gender differences contribute to the cutaneous wound healing of chronically stressed mice. In addition, androgens contribute to the stress-induced impairment of the healing of cutaneous wounds but estrogens inhibit it.

Supplementation with olive oil, but not fish oil, improves cutaneous wound healing in stressed mice.

Supplementation with olive and fish oils reverses the effects of stress on behavioral activities and adrenal activation. However, previous studies have not shown whether supplementation with olive and fish oil could inhibit the effects of stress on cutaneous wound healing. Thus, this study investigated the effects of supplementation with fish or olive oil on cutaneous healing in stressed mice. Mice were subjected to rotational stress and treated with olive or fish oil daily until euthanasia. An excisional lesion was created on each mouse, and 14 days later, the lesions were analyzed. In addition, murine skin fibroblasts were exposed to elevated epinephrine levels plus olive oil, and fibroblast activity was evaluated. In the in vivo studies, administration of olive oil, but not fish oil, inhibited stress-induced reduction in wound contraction, reepithelialization, hydroxyproline levels, and blood vessel density. Stress-induced increases in vascular endothelial growth factor expression and the numbers of macrophages and neutrophils were reversed only by olive oil. Both oils reversed stress-induced increase in catecholamine levels and oxidative damage. In in vitro studies, olive oil treatment reversed the reduction in fibroblast migration and collagen deposition and the increase in lipid peroxidation induced by epinephrine. In conclusion, supplementation with olive oil, but not fish oil, improves cutaneous wound healing in chronically stressed mice.

Nicotine affects cutaneous wound healing in stressed mice.

Stress is an important condition of modern life. Nicotine addiction can modulate the physiological response to stress. Cutaneous healing is a complex process resulting in scar formation, which can be delayed by stress. Therefore, the aim of this study was to investigate the effects of nicotine administration on cutaneous wound healing in chronically stressed mice. Male mice were submitted to rotational stress, whereas control animals were not subjected to stress. These stressed and control animals were treated with a transdermal nicotine patch that was changed every day. A full-thickness excisional lesion was also generated, and 14 days later, lesions had recovered. However, the Stress + Nicotine group presented a delay in wound contraction. These wounds showed a decrease in inflammatory cell infiltration and lower expression of transforming growth factor-ß (TGF-ß), whereas there was an increase in angiogenesis and tumor necrosis factor-α (TNF-α) expression. In vitro fibroblast migration was also impaired by the nicotine treatment of stressed-stimulated cells. In conclusion, nicotine administration potentiates the delay in wound closure observed in mice submitted to stress.

Repeated stress-induced crosstalk between the sympathetic nervous system and mast cells contributes to delayed cutaneous wound healing in mice.

The study identifies a link between the neuroimmune interaction and the impairment of wound healing induced by repeated stress. Stress increased mast cell mobilization and degranulation, levels of IL-10, and sympathetic reinnervation in mouse wounds. In contrast to mast cells, macrophage infiltration into wounds was significantly delayed in stressed mice. Chemical sympathectomy and the blockade of mast cell degranulation reversed the effect of stress on skin wound healing in vivo. In vitro, high epinephrine levels stimulated mast cell degranulation and IL-10 release. In conclusion, catecholamines released by the sympathetic nervous system stimulate mast cells to secrete anti-inflammatory cytokines that impair inflammatory cell mobilization, leading to a delay in the resolution of wound healing under stress conditions.

Olive oil promotes the survival and migration of dermal fibroblasts through Nrf2 pathway activation.

Olive oil has beneficial effects on skin wound healing due to its anti-inflammatory and antioxidant properties; however, the mechanism by which olive oil promotes wound healing is unclear. We evaluated the mechanisms involved in Nrf2 pathway activation by olive oil and its role in cell survival and migration in mouse dermal fibroblasts in a short-term exposition. Our data demonstrated that olive oil and oleic acid promoted reactive oxygen species (ROS) production, while olive oil and hydroxytyrosol stimulated nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Olive oil-mediated ROS production increased nuclear factor kappa B p65 expression, while olive oil-stimulated reactive nitrogen species production augmented the levels of Nrf2. Olive oil augmented cell proliferation, cell migration, and AKT phosphorylation, but decreased apoptotic cell number and cleaved caspase-3 levels. The effect of olive oil on cell migration and protein levels of AKT, BCL-2, and Nrf2 were reversed by an Nrf2 inhibitor. In conclusion, the activation of the Nrf2 pathway by olive oil promotes the survival and migration of dermal fibroblasts that are essential for the resolution of skin wound healing.

Microfibril-associated protein 5 and the regulation of skin scar formation.

Many factors regulate scar formation, which yields a modified extracellular matrix (ECM). Among ECM components, microfibril-associated proteins have been minimally explored in the context of skin wound repair. Microfibril-associated protein 5 (MFAP5), a small 25 kD serine and threonine rich microfibril-associated protein, influences microfibril function and modulates major extracellular signaling pathways. Though known to be associated with fibrosis and angiogenesis in certain pathologies, MFAP5's role in wound healing is unknown. Using a murine model of skin wound repair, we found that MFAP5 is significantly expressed during the proliferative and remodeling phases of healing. Analysis of existing single-cell RNA-sequencing data from mouse skin wounds identified two fibroblast subpopulations as the main expressors of MFAP5 during wound healing. Furthermore, neutralization of MFAP5 in healing mouse wounds decreased collagen deposition and refined angiogenesis without altering wound closure. In vitro, recombinant MFAP5 significantly enhanced dermal fibroblast migration, collagen contractility, and expression of pro-fibrotic genes. Additionally, TGF-ß1 increased MFAP5 expression and production in dermal fibroblasts. Our findings suggest that MFAP5 regulates fibroblast function and influences scar formation in healing wounds. Our work demonstrates a previously undescribed role for MFAP5 and suggests that microfibril-associated proteins may be significant modulators of wound healing outcomes and scarring.

Dietary olive oil intake aggravates psoriatic skin inflammation in mice via Nrf2 activation and polyunsaturated fatty acid imbalance.

Psoriasis is a chronic inflammatory skin disease, which does not have effective treatment options. However, olive oil has been suggested as an alternative to treat psoriasis, but no study has evaluated the mechanisms involved in the effects of olive oil on psoriasis. Thus, the current study investigated whether olive oil could ameliorate psoriasiform skin inflammation. To test this, mice received topical application of imiquimod to induce inflammation and were treated orally with olive oil. Human immortalized keratinocytes were also treated with imiquimod and olive oil. Epidermal thickness and keratinocyte proliferation were increased in imiquimod-induced lesions of olive-oil-treated animals. In both in vitro and in vivo studies, protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) were elevated following imiquimod and olive oil administration. Inhibition of Nrf2 abolished the increased proliferation of keratinocytes treated with imiquimod and olive oil, demonstrating the role of Nrf2 in olive oil-mediated exacerbation of psoriasiform skin inflammation. In addition, lower levels of linoleic acid and higher levels of oleic acid were observed in imiquimod- and olive-oil-treated animals, which may also contribute to the adverse effects of olive oil on psoriasis. In conclusion, dietary intake of olive oil aggravates the symptoms of psoriatic skin lesions through the overexpression of Nrf2 and an imbalance in oleic and linoleic acids levels, suggesting that a diet rich in olive oil may have significant negative effects on psoriasis.

Stress-induced epinephrine levels compromise murine dermal fibroblast activity through ß-adrenoceptors.

Stress-induced catecholamine impairs the formation of granulation tissue acting directly in fibroblast activity; however, the mechanism by which high levels of catecholamines alter the granulation tissue formation is still unclear. Thus, the aim of this study was to investigate how high levels of epinephrine compromise the activity of murine dermal fibroblasts. Dermal fibroblasts isolated from the skin of neonatal Swiss mice were preincubated with α- or ß-adrenoceptor antagonists. Thereafter, cells were exposed to physiologically elevated levels of epinephrine or epinephrine plus α- or ß-adrenoceptor antagonists, and fibroblast activity was evaluated. The blockade of ß1- and ß2-adrenoceptors reversed the increase in fibroblast proliferation, ERK 1/2 phosphorylation, myofibroblastic differentiation and the reduction of collagen deposition induced by epinephrine. In addition, the blockade of ß3-adrenoceptors reversed the increase in fibroblast proliferation and nitric oxide synthesis as well as the reduction of fibroblast migration, AKT phosphorylation and active matrix metalloproteinase-2 expression induced by epinephrine. However, the blockade of α1- and α2-adrenoceptors did not alter the effects of epinephrine on the activity of murine dermal fibroblasts. In conclusion, high levels of epinephrine directly compromise the activity of neonatal mouse skin fibroblasts through the activation of ß1-, ß2- and ß3-adrenoceptors, but not through α1- and α2-adrenoceptors.