Dataset Information

Cannabinoid-mediated Modulation of Oxidative Stress and Early Inflammatory Response after Hypoxia-Ischemia.

ABSTRACT: In the process of neonatal encephalopathy, oxidative stress and neuroinflammation have a prominent role after perinatal asphyxia. With the exception of therapeutic hypothermia, no therapeutic interventions are available in the clinical setting to target either the oxidative stress or inflammation, despite the high prevalence of neurological sequelae of this devastating condition. The endocannabinoid system (ECS), recently recognized as a widespread neuromodulatory system, plays an important role in the development of the central nervous system (CNS). This study aims to evaluate the potential effect of the cannabinoid (CB) agonist WIN 55,212-2 (WIN) on reactive oxygen species (ROS) and early inflammatory cytokine production after hypoxia-ischemia (HI) in fetal lambs. Hypoxic-ischemic animals were subjected to 60 min of HI by partial occlusion of the umbilical cord. A group of lambs received a single dose of 0.01 μg/kg WIN, whereas non-asphyctic animals served as controls. WIN reduced the widespread and notorious increase in inflammatory markers tumor necrosis factor (TNF)-α and interleukin (IL)-1β and IL-6 induced by HI, a modulatory effect not observed for oxidative stress. Our study suggests that treatment with a low dose of WIN can alter the profile of pro-inflammatory cytokines 3 h after HI.

SUBMITTER: Alonso-Alconada D

PROVIDER: S-EPMC7072925 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Cannabinoid-mediated Modulation of Oxidative Stress and Early Inflammatory Response after Hypoxia-Ischemia.

Alonso-Alconada Daniel D Álvarez Francisco José FJ Goñi-de-Cerio Felipe F Hilario Enrique E Álvarez Antonia A

International journal of molecular sciences 20200214 4

In the process of neonatal encephalopathy, oxidative stress and neuroinflammation have a prominent role after perinatal asphyxia. With the exception of therapeutic hypothermia, no therapeutic interventions are available in the clinical setting to target either the oxidative stress or inflammation, despite the high prevalence of neurological sequelae of this devastating condition. The endocannabinoid system (ECS), recently recognized as a widespread neuromodulatory system, plays an important role ...[more]

PMID: 32074976

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Project description:Hypoxia-induced miR-210 is a crucial component of the tissue response to ischemia, stimulating angiogenesis and improving tissue regeneration. Previous analysis of miR-210 impact on the transcriptome in a mouse model of hindlimb ischemia showed that miR-210 regulated not only vascular regeneration functions, but also inflammation. To investigate this event, doxycycline-inducible miR-210 transgenic mice (Tg-210) and anti-miR-210 LNA-oligonucleotides were used. It was found that global miR-210 expression decreased inflammatory cells density and macrophages accumulation in the ischemic tissue. To dissect the underpinning cell mechanisms, Tg-210 mice were used in bone marrow (BM) transplantation experiments and chimeric mice underwent hindlimb ischemia. MiR-210 overexpression in the ischemic tissue was sufficient to increase capillary density and tissue repair, and to reduce inflammation in the presence of Wt-BM infiltrating cells. Conversely, when Tg-210-BM cells migrated in a Wt ischemic tissue, dysfunctional angiogenesis, inflammation, and impaired tissue repair, accompanied by fibrosis were observed. The fibrotic regions were positive for α-SMA, Vimentin, and Collagen V fibrotic markers and for phospho-Smad3, highlighting the activation of TGF-β1 pathway. Identification of Tg-210 cells by in situ hybridization showed that BM-derived cells contributed directly to fibrotic areas, where macrophages co-expressing fibrotic markers were observed. Cell cultures of Tg-210 BM-derived macrophages exhibited a pro-fibrotic phenotype and were enriched with myofibroblast-like cells, which expressed canonical fibrosis markers. Interestingly, inhibitors of TGF-β type-1-receptor completely abrogated this pro-fibrotic phenotype. In conclusion, a context-dependent regulation by miR-210 of the inflammatory response was identified. miR-210 expression in infiltrating macrophages is associated to improved angiogenesis and tissue repair when the ischemic recipient tissue also expresses high levels of miR-210. Conversely, when infiltrating an ischemic tissue with mismatched miR-210 levels, macrophages expressing high miR-210 levels display a pro-fibrotic phenotype, leading to impaired tissue repair, fibrosis, and dysfunctional angiogenesis.

Project description:Uterus transplantation is a complex surgical procedure. Uterine ischemia reperfusion (I/R) injury that occurs during this process may cause a loss of function of the uterus and the failure of transplantation. Resveratrol (RSV) is a naturally occurring polyphenol found abundantly in the skin of grapes and red wine, and it has also been used as a dietary supplement in clinical practice. RSV possesses strong anti-inflammatory and anti-oxidative effects, and exhibits a role in immune system regulation. However, the role of RSV in protecting the uterus against I/R-induced injury is yet to be fully elucidated. The aim of the present study was to investigate the effects and mechanisms underlying RSV in I/R-induced uterus injury. A total of 48 Sprague-Dawley rats were randomly divided into four groups: Control (sham operation) group, the uterus I/R group, the 20 mg/kg RSV-pre-treated I/R (I/R+RSV/20) group and the 40 mg/kg RSV-pre-treated I/R (I/R+ RSV/40) group. A regular I/R model was established to induce uterus injury in rats. RSV at 20 or 40 mg/kg was intraperitoneally administrated into rats in both I/R+ RSV groups once per day for five consecutive days prior to ischemia. The control and I/R only groups received an intraperitoneal injection of the vehicle (ethanol) for the same period prior to ischemia. Samples from blood and uterine horns were collected 3 h after reperfusion. Changes in the levels of malondialdehyde, interleukin (IL)-6, tumor necrosis factor-α, IL-10 and IL-37 were determined using ELISA, the activity levels of myeloperoxidase, catalase, and superoxidase dismutase were also determined using ELISA, the protein expression levels of PI3K, phosphorylated (p)-PI3K, AKT and p-AKT were determined using western blot analysis, and the uterine histology was investigated using H&E staining. Results of the present study demonstrated that treatment with RSV increased the capacity of antioxidants and suppressed uterine oxidative injury induced by I/R. Moreover, treatment with RSV decreased the levels of pro-inflammatory cytokines and increased the levels of anti-inflammatory cytokines. In addition, RSV promoted the phosphorylation of PI3K and AKT, thus activating the PI3K-AKT signaling pathway. Therefore, administration of RSV prior to uterine I/R effectively alleviated inflammatory response and oxidative stress via activation of the PI3K-AKT pathway, suggesting that RSV may play a protective role in I/R-induced uterus injury.

Dataset Information

Cannabinoid-mediated Modulation of Oxidative Stress and Early Inflammatory Response after Hypoxia-Ischemia.

Publications

Cannabinoid-mediated Modulation of Oxidative Stress and Early Inflammatory Response after Hypoxia-Ischemia.

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