Prostaglandins & other lipid mediators最新文献

New insights have been gained on the role of platelets beyond thrombosis. Platelets can accumulate in damaged and inflamed tissues, acting as a sentinel to detect and repair tissue damage. However, by releasing several soluble factors, including thromboxane A₂ (TXA₂) and 12-hydroxyeicosatetraenoic acid, and extracellular vesicles (EVs), platelets can activate vascular cells, stromal, such as fibroblasts, immune cells, and cancer cells, leading to atherosclerosis, vascular restenosis, tissue fibrosis, and tumor metastasis. Platelet-derived extracellular vesicles (PEVs) are released when platelets are activated and can transfer their cargo to other cell types, thus contributing to the development of diseases. Inhibitors of the internalization of PEVs can potentially represent novel therapeutic tools. Both platelets and PEVs contain a significant number of different types of molecules, and their omics assessment and integration with clinical data using computational approaches have the potential to detect early disease development and monitor drug treatments.

Immune responses during inflammation involve complex, well-coordinated lipid signaling pathways. Eicosanoids are a class of lipid signaling molecules derived from polyunsaturated fatty acids such as arachidonic acid and constitute a major network that controls inflammation and its subsequent resolution. Arachidonic acid is metabolized by enzymes in three different pathways to form a variety of lipid metabolites that can be either pro- or anti-inflammatory. Therefore, an understanding of the time-dependent gene expression, lipid metabolite profiles and cytokine profiles during the initial inflammatory response is necessary, as it will allow for the design of time-dependent therapeutics. Herein, we investigate the multi-level regulation of this process. After stimulating RAW 264.7 cells, a mouse-derived macrophage cell line commonly used to examine inflammatory responses, we examine the gene expression of 44 relevant lipid metabolizing enzymes from the different eicosanoid synthesizing classes. We also measure the formation of lipid metabolites and production of cytokines at selected time points. Results reveal a dynamic relationship between the time-course of inflammation dependent gene expression of the three eicosanoid synthesizing enzymes.

Since the effects of flaxseed supplementation on lipid profile and liver enzymes are still controversial, a meta-analysis of randomized controlled trials was conducted in the present study to assess the effect of flaxseed supplementation on lipid profile and liver enzymes. The study was designed, conducted, and reported according to the guidelines of the 2020 preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement. A systematic and comprehensive search was performed in several databases from inception up to January 10, 2024. The meta-analysis on the impact of flaxseed supplementation on lipid profile and liver enzymes indicates that the overall effect of flaxseed supplementation on triglycerides, combining different doses, revealed a significant reduction with a WMD of − 230.72 (-53.95, − 27.49) and a P-value of 0.010. High-density lipoprotein (HDL) demonstrated a positive effect, with an overall WMD of 1.82 (0.27, 3.38) and a P-value of 0.021, indicating an increase in HDL levels. The liver enzymes AST and ALT displayed reductions in their levels, with overall WMDs of − 21.18 (-2.95, 0.59) and − 24.83 (-8.74, − 20.91), respectively. Subgroup analysis based on dosage revealed more pronounced reductions in ALT levels for doses below 2000 mg/day. Findings from this study suggest that a flaxseed supplement might be beneficial to modulate the blood lipid profile and liver enzymes.

Pomegranate seed oil shows positive effects by limiting neutrophil activation and lipid peroxidation through its antioxidant and anti-inflammatory activities. This study evaluated the possible ameliorative effects of pomegranate seed oil, its actions on proinflammatory cytokines, and its antioxidant activity using an acute acetic acid-induced colitis model in rats. 32 male Sprague-Dawley rats were divided into 4 groups: control, colitis, 0.4 ml/kg, and 0.8 ml/kg pomegranate seed oil treatment after colitis. At the end of the experiment, histopathological and biochemical analyses of intestinal tissues and blood were performed. The study revealed that administering different doses of pomegranate seed oil dramatically reduced total oxidant levels, nuclear factor kappa B, proinflammatory cytokines, and myeloperoxidase activity and appreciably reduced colitis injury. These findings suggest that pomegranate seed oil may alleviate colitis symptoms effectively and exert protective effects through antioxidant, anti-inflammatory mechanisms.

Dravet syndrome is an intractable epilepsy with a high seizure burden that is resistant to current anti-seizure medications. There is evidence that neuroinflammation plays a role in epilepsy and seizures, however few studies have specifically examined neuroinflammation in Dravet syndrome under conditions of a higher seizure burden. Here we used an established genetic mouse model of Dravet syndrome (Scn1a^+/- mice), to examine whether a higher seizure burden impacts the number and morphology of microglia in the hippocampus. Moreover, we examined whether a high seizure burden influences classical inflammatory mediators in this brain region. Scn1a^+/- mice with a high seizure burden induced by thermal priming displayed a localised reduction in microglial cell density in the granule cell layer and subgranular zone of the dentate gyrus, regions important to postnatal neurogenesis. However, microglial cell number and morphology remained unchanged in other hippocampal subfields. The high seizure burden in Scn1a^+/- mice did not affect hippocampal mRNA expression of classical inflammatory mediators such as interleukin 1β and tumour necrosis factor α, but increased cyclooxygenase 2 (COX-2) expression. We then quantified hippocampal levels of prostanoids that arise from COX-2 mediated metabolism of fatty acids and found that Scn1a^+/- mice with a high seizure burden displayed increased hippocampal concentrations of numerous prostaglandins, notably PGF_2α, PGE₂, PGD₂, and 6-K-PGF_1A, compared to Scn1a^+/- mice with a low seizure burden. In conclusion, a high seizure burden increased hippocampal concentrations of various prostaglandin mediators in a mouse model of Dravet syndrome. Future studies could interrogate the prostaglandin pathways to further better understand their role in the pathophysiology of Dravet syndrome.

Oxysterol, 25-hydroxycholesterol (25HC), is a potent regulator of immune reactions, its synthesis greatly increases by macrophages during inflammation. We hypothesize that 25HC can have cardioprotective effects by limiting consequences of excessive β-adrenoceptor (βAR) stimulation, particularly reactive oxygen species (ROS) production, in mouse atria. Isoproterenol, a βAR agonist, increased extra- and intracellular levels of ROS. This enhancement of ROS production was suppressed by NADPH oxidase antagonists as well as 25HC. Inhibition of β3ARs, Gi protein and protein kinase Cε prevented the effect of 25HC on isoproterenol-dependent ROS synthesis. Furthermore, 25HC suppressed isoproterenol-induced lipid peroxidation and mitochondrial ROS generation as well as ROS-dependent component of positive inotropic response to isoproterenol. Additionally, 25HC decreased mitochondrial ROS production and lipid peroxidation induced by antimycin A, a mitochondrial poison. Thus, 25HC exerts antioxidant properties alleviating mitochondrial dysfunction-induced and βAR-dependent cardiac oxidative damage. In the latter case, 25HC can act via signaling mechanism engaging β3ARs, Gi protein and protein kinase Cε.

Smoking causes several diseases such as chronic obstructive pulmonary disease (COPD). Aspirin-triggered-resolvin D1 (AT-RvD1) is a lipid mediator produced during the resolution of inflammation and demonstrates anti-inflammatory and pro-resolution effects in several inflammatory experimental models including in the airways. Here we evaluated the role of AT-RvD1 (100 nM) in bronchial epithelial cells (BEAS-2B) stimulated by cigarette smoke extract (CSE; 1%; 1 cigarette) for 24 h. CSE induced the productions of IL-1β, TNF-α, IL-10, IL-4 and IFN-γ as well as the activations of NF-κB and STAT3 and the expression of ALX/FPR2 receptor. AT-RvD1 reduced the IL-1β and TNF-α production and increased the production of IFN-γ. These effects were reversed BOC2, an antagonist of ALX/FPR2 receptor for AT-RvD1. The production of IL-4 and IL-10 were not altered by AT-RvD1. In addition, AT-RvD1 reduced the phosphorylation of NF-κB and STAT3 when compared to CSE-stimulated BEAS-2B cells. No alteration of ALX/FPR2 expression was observed by AT-RvD1 when compared to CSE group. In the human monocytic leukemia cell line, the relative number of copies of IL-1β and IL-4 was significantly higher in CSE + AT-RvD1 group compared CSE group, however, the expression of M1 cytokine was more pronounced than M2 profile. AT-RvD1 could be an important target for the reduction of inflammation in the airways associated with smoking.

Atherosclerosis (AS) represents a prevalent initiating factor for cardiovascular events. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) is an oncofetal RNA-binding protein that participates in cardiovascular diseases. This work aimed to elaborate the effects of IGF2BP3 on AS and the probable mechanism by using an oxidized low-density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cells (HUVECs) model. Results indicated that IGF2BP3 expression was declined in the blood of AS patients and ox-LDL-induced HUVECs. IGF2BP3 elevation alleviated ox-LDL-provoked viability loss, apoptosis, oxidative DNA damage and endothelial dysfunction in HUVECs. Moreover, IGF2BP3 bound SESN1 and stabilized SESN1 mRNA. Furthermore, SESN1 interference reversed the impacts of IGF2BP3 overexpression on the apoptosis, oxidative DNA damage and endothelial dysfunction of ox-LDL-challenged HUVECs. Additionally, the activation of Nrf2 signaling mediated by IGF2BP3 up-regulation in ox-LDL-treated HUVECs was blocked by SESN1 absence. Collectively, SESN1 stabilized by IGF2BP3 might protect against AS by activating Nrf2 signaling.

Background

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that leads to joint destruction. Numerous pro-inflammatory mediators, including adipokines, play an important role in the pathogenesis of RA.

Objective

The aim of the study was to investigate the relationships between selected plasma cytokines and expression of adiponectin and its receptors in the synovium and the infrapatellar fat pad in patients with RA and osteoarthritis (OA).

Methods

Blood, synovium and fat pad samples from 18 patients with RA and 18 with OA were collected during joint replacement surgery. Spearman rank correlations between plasma concentrations of selected cytokines (IL-1β, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 p40, IL-13, IL-17, G-CSF and GM-CSF) and the expression of adiponectin and its receptors were determined. Plasma levels of cytokines were determined using a magnetic bead-based multiplex assay, mRNA expression of adiponectin and its receptors were determined by real-time PCR.

Results

In OA patients, there were significant positive correlations between adiponectin expression in the synovial membrane and plasma levels of IL-1β, IL-4, G-CSF and GM-CSF, as well as a significant positive correlation between adiponectin expression in the fat pad and plasma levels of GM-CSF. In addition, OA patients showed significant negative correlations between AdipoR1 and AdipoR2 expression in the synovial membrane and plasma IL-6 levels, as well as between AdipoR2 expression in the synovial membrane and plasma MCP-1 and TNF-α levels. In patients with RA, there were no significant correlations between adiponectin expression in the synovial membrane and infrapatellar fat pad and plasma levels of the cytokines studied. In addition, RA patients showed a statistically significant negative correlation between AdipoR1 expression in the synovial membrane and plasma levels of TNF-α, IL-7, IL-12 and IL-13, and a significant negative correlation between AdipoR1 expression in the infrapatellar fat pad and plasma levels of IL-1β.

Conclusions

Adiponectin and its receptors showed the correlations with several plasma cytokines, however, a thorough understanding of the role of adiponectin in RA and OA requires further investigation.