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-1β, IL-6, IL-33, TNF-α, TGF-β, 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

Quercetin Inhibits Peripheral and Spinal Cord Nociceptive Mechanisms to Reduce Intense Acute Swimming-Induced Muscle Pain in Mice.

The present study aimed to evaluate the effects of the flavonoid quercetin (3,3´,4´,5,7-pentahydroxyflavone) in a mice model of intense acute swimming-induced muscle pain, which resembles delayed onset muscle soreness. Quercetin intraperitoneal (i.p.) treatment dose-dependently reduced muscle mechanical hyperalgesia. Quercetin inhibited myeloperoxidase (MPO) and N-acetyl-β-D- glucosaminidase (NAG) activities, cytokine production, oxidative stress, cyclooxygenase-2 (COX-2) and gp91phox mRNA expression and muscle injury (creatinine kinase [CK] blood levels and myoblast determination protein [MyoD] mRNA expression) as well as inhibited NFκB activation and induced Nrf2 and HO-1 mRNA expression in the soleus muscle. Beyond inhibiting those peripheral effects, quercetin also inhibited spinal cord cytokine production, oxidative stress and glial cells activation (glial fibrillary acidic protein [GFAP] and ionized calcium-binding adapter molecule 1 [Iba-1] mRNA expression). Concluding, the present data demonstrate that quercetin is a potential molecule for the treatment of muscle pain conditions related to unaccustomed exercise

Quercetin reduces in a dose-dependent manner intense acute swimming-induced muscle mechanical hyperalgesia and did not affect glucose levels, time spent in swimming behavior or immobility behavior during the intense acute swimming session.

<p>Mice received vehicle (2% DMSO in saline) or quercetin (1–30 mg/kg, i.p.) 30 min before plus reinforcements 12 h after the intense acute swimming session. The intensity of muscle mechanical hyperalgesia was evaluated 6–48 h after the intense acute swimming session (Panel A). Glucose plasmatic levels were determined immediately after and 24 h (peak of the hyperalgesia) after the swimming session (Panel B). Time spent in swimming behavior (Panel C) and immobility behavior (Panel D) were measured during the period of 2 h of the intense acute swimming session in quercetin (30 mg/kg, i.p., 30 min before) and vehicle treated groups. Results are presented as intensity of hyperalgesia (Δ reaction, in grams), glucose (mg/dL of plasma), time spent in swimming behavior and immobility behavior in minutes (Panels A-D) (<i>n</i> = 6 mice per group per experiment, representative of two independent experiments). *P<0.05 compared with naïve and sham groups, #P<0.05 compared with vehicle group, **P<0.05 compared with vehicle and 1 mg/kg groups, ##P<0.05 compared with vehicle, 1 and 3 mg/kg groups, ***P<0.05 compared with vehicle, 1, 3 and 10 mg/kg groups (Two-way ANOVA followed by Tukey’s <i>post hoc</i>).</p

Quercetin reduces intense acute swimming-induced increases in cytokine production, oxidative stress and glial cells activation in the spinal cord.

<p>Mice were treated with vehicle or quercetin (30 mg/kg, i.p.) 30 min before (for cytokine production and oxidative stress determination) plus reinforcements 12 h after the intense acute swimming session (for glial cells activation assessment). Samples of the spinal cord (L4-L6) were collected 2 h after the intense acute swimming session for evaluation of cytokine production (TNF-α, IL-1β and IL-10) (Panel A) and oxidative stress (GSH and TBARS) (Panels B and C). GFAP and Iba-1 mRNA expression in spinal cord samples was determined 24 h after the swimming session (Panels D and E). Results are presented as cytokines (picograms per 100 mg), GSH (mmol/mg) and TBARS (nmol of MDA/mg of protein) of spinal cord samples, and GFAP and Iba-1 mRNA expression (normalized to Gapdh) (<i>n</i> = 6 mice per group per experiment, representative of two independent experiments). *P<0.05 compared to the naïve and sham groups, #P<0.05 compared with vehicle group (One-way ANOVA followed by Tukey’s <i>post hoc</i>).</p

Quercetin reduces intense acute swimming-induced COX-2 and gp91^phox mRNA expression in the soleus muscle.

<p>Mice were treated with vehicle or quercetin (30 mg/kg, i.p.) 30 min before plus reinforcements 12 h after the intense acute swimming session. Samples of soleus muscle were collected 24 h after the intense acute swimming session. COX-2 (Panel A) and gp91^phox (Panel B) mRNA expression were determined by qPCR. Results are presented as COX-2 and gp91^phox mRNA expression (normalized to Gapdh) (<i>n</i> = 6 mice per group per experiment, representative of two independent experiments). *P<0.05 compared to the naïve and sham groups, #P<0.05 compared with vehicle group (One-way ANOVA followed by Tukey’s <i>post hoc</i>).</p

Quercetin inhibits NFκB activation and induces Nrf2 and HO-1 mRNA expression in the soleus muscle after intense acute swimming.

<p>Mice were treated with vehicle or quercetin (30 mg/kg, i.p.) 30 min before plus reinforcements 12 h after the intense acute swimming session. NFκB activation (total NFκB/phosphorylated NFκB ratio, Panel A), and Nrf2 (Panel B) and HO-1 (Panel C) mRNA expression in the soleus muscle were assessed 24 h after the intense acute swimming session. Results are presented as NFκB activation (total-p65/phosphotrilated-p65 ratio)/mg of soleus muscle, and Nrf2 and HO-1 mRNA expression (normalized to Gapdh) (<i>n</i> = 6 mice per group per experiment, representative of two independent experiments). *P<0.05 compared to the vehicle treated group (One-way ANOVA followed by Tukey’s <i>post hoc</i>).</p

Quercetin reduces intense acute swimming-induced increases in plasmatic concentrations of CK and MyoD mRNA expression in the soleus muscle.

<p>Mice were treated with vehicle or quercetin (30 mg/kg, i.p.) 30 min before plus reinforcements 12 h after the intense acute swimming session. At 2 or 24 h after the intense acute swimming session, blood samples were collected for determination of plasmatic levels of CK (Panel A). Samples of the soleus muscle were collected 24 h after the intense acute swimming session for evaluation of MyoD mRNA expression (Panel B). Results are presented as creatine kinase (total) (U/L of plasma) and MyoD mRNA expression (normalized to Gapdh) (<i>n</i> = 6 mice per group per experiment, representative of two independent experiments). *P<0.05 compared to the naïve and sham groups, #P<0.05 compared with vehicle group (One-way ANOVA followed by Tukey’s <i>post hoc</i>).</p

Quercetin reduces intense acute swimming-induced TNF-α, IL-1β and IL-10 production in the soleus muscle, but not in the gastrocnemius muscle.

<p>Mice were treated with vehicle or quercetin (30 mg/kg, i.p.) 30 min before intense acute swimming session. The TNF-α, IL-1β and IL-10 concentration in the soleus (Panel A) and gastrocnemius (Panel B) muscles were quantified immediately after the end of intense acute swimming session by ELISA. Results are presented as picograms (pg) per 100 mg of soleus and gastrocnemius muscles samples (<i>n</i> = 6 mice per group per experiment, representative of two independent experiments). *P<0.05 compared to the naïve and sham groups, #P<0.05 compared with vehicle group (One-way ANOVA followed by Tukey’s <i>post hoc</i>).</p

Quercetin reduces intense acute swimming-induced increase in MPO and NAG activities in the soleus muscle but not in the gastrocnemius muscle.

<p>Mice were treated with vehicle or quercetin (30 mg/kg, i.p.) 30 min before plus reinforcements 12 h after the intense acute swimming session. MPO (Panels A and B) and NAG (Panels C and D) activities were measured 24 h after the intense acute swimming session. Results are presented as MPO (Neutrophils x 10¹⁰) and NAG (Macrophages x 10⁴) activity per milligram of the soleus and gastrocnemius muscles (<i>n</i> = 6 mice per group per experiment, representative of two independent experiments). *P<0.05 compared to the naïve and sham groups, #P<0.05 compared with vehicle group (One-way ANOVA followed by Tukey’s <i>post hoc</i>).</p