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Cardiac cells respond to various pathophysiological stimuli, synthesizing inflammatory molecules that allow tissue repair and proper functioning of the heart; however, perpetuation of the inflammatory response can lead to cardiac fibrosis and heart dysfunction. High concentration of glucose (HG) induces an inflammatory and fibrotic response in the heart. Cardiac fibroblasts (CFs) are resident cells of the heart that respond to deleterious stimuli, increasing the synthesis and secretion of both fibrotic and proinflammatory molecules. The molecular mechanisms that regulate inflammation in CFs are unknown, thus, it is important to find new targets that allow improving treatments for HG-induced cardiac dysfunction. NFκB is the master regulator of inflammation, while FoxO1 is a new participant in the inflammatory response, including inflammation induced by HG; however, its role in the inflammatory response of CFs is unknown. The inflammation resolution is essential for an effective tissue repair and recovery of the organ function. Lipoxin A4 (LXA4) is an anti-inflammatory agent with cytoprotective effects, while its cardioprotective effects have not been fully studied. Thus, in this study, we analyze the role of p65/NFκB, and FoxO1 in CFs inflammation induced by HG, evaluating the anti-inflammatory properties of LXA4. Our results demonstrated that HG induces the inflammatory response in CFs, using an in vitro and ex vivo model, while FoxO1 inhibition and silencing prevented HG effects. Additionally, LXA4 inhibited the activation of FoxO1 and p65/NFκB, and inflammation of CFs induced by HG. Therefore, our results suggest that FoxO1 and LXA4 could be novel drug targets for the treatment of HG-induced inflammatory and fibrotic disorders in the heart., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Raul Vivar reports financial support was provided by ANID, Fondecyt 11160531. Guillermo Diaz reports financial support was provided by ANID, Fondecyt 1210627. Juan Diego Maya reports financial support was provided by ANID, Fondecyt 1210359. Raul Vivar reports financial support was provided by Biomedical Sciences Institute (Puente ICBM-2020 Raul Vivar)., (Copyright © 2023. Published by Elsevier Inc.)

An essential component of acute pancreatitis(AP)-induced acute lung injury(ALI) is the inflammation that is part of the body's systemic inflammatory response to a variety of systemic stimuli. Lipoxins(LXs) are considered important endogenous lipids that mediate the resolution of inflammation. In previous studies, we found that Lipoxin A4 (LXA4) reduced AP-induced pulmonary oedema and TNF-α production in lung. However, the underlying mechanism remains unclear. Due to the above studies, we investigated the aquaporin, matrix metalloprotein, apoptosis and PKC/SSeCKS signal pathway in cellular and animal models of AP-associated lung injury following LXA4 intervention. In this study, we first proved LXA4 could effectively promote F-actin reconstruction and regulate its expression in pulmonary microvascular endothelial cells both in vivo and vitro via suppressing PKC/SSeCKS signalling pathway. Next, we found that LXA4 attenuated cell growth inhibition and apoptosis in lung tissues of AP-ALI mice and HPMECs. Additionally, we demonstrated that LXA4 could regulate the expression of AQP-5 and MMP-9 to stabilize the permeability of pulmonary microvascular endothelial cell. In summary, our results suggest that the anti-inflammatory eff ;ects of LXA4 may be due to the inhibition of both the PKC/SSeCKS pathway and apoptosis to reduce alveolar fluid exudation and to the regulation of AQP-5 and MMP-9 expression to maintain the clearance of alveolar fluid. Thus, LXA4 is capable of exerting protective eff ;ects on AP-induced ALI., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Gout is a common inflammatory disease. The activation of NLRP3 inflammasome induced by monosodium urate (MSU) crystals has a critical role in gout, and its prevention is beneficial for patients. Lipoxin A4 (LXA4) is an endogenous lipoxygenase-derived eicosanoid mediator with powerful anti-inflammatory properties. However, whether LXA4 can suppress NLRP3 inflammasome activation induced by MSU crystals remains unclear. This study aimed to investigate the protective effect of LXA4 on MSU-crystal-induced NLRP3 inflammasome activation and its underlying molecular mechanisms. We found that LXA4 inhibited MSU-crystal-induced NLRP3 inflammasome activation, interleukin (IL)-1β maturation, and pyroptosis. More specifically, LXA4 suppressed the assembly of the NLRP3 inflammasome, including oligomerization and speck formation of ASC, and ASC-NLRP3 interaction. Furthermore, LXA4 suppressed oxidative stress, the upstream events for NLRP3 inflammasome activation, as evidenced by the fact that LXA4 eliminated total reactive oxygen species (ROS) generation and alleviated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and mitochondrial dysfunction. However, LXA4 also depressed the Nrf2 activation, a critical molecule in the antioxidant pathway, and then exerted an inhibitory impact on Klf9 expression and promotional impact on TXNRD2 expression, two molecules located downstream of Nrf2 in sequence. Knockdown of TXNRD2 reversed the LXA4-induced depression of ROS and NLRP3 inflammasome. Moreover, LXA4 alleviated joint inflammation and decreased the production of cleaved caspase-1 and matured IL-1b in gouty arthritis rats. Taken together, our findings demonstrate that LXA4 can attenuate MSU-crystal-induced NLRP3 inflammasome activation, probably through suppressing Nrf2 activation to increase TXNRD2 expression. The present study highlights the potential of LXA4 as an attractive new gout treatment candidate. [ABSTRACT FROM AUTHOR]

LipoxinA4 (LXA4) is a well-known key mediator of endogenous anti-inflammation and of the resolution of inflammation. Considerable oxidative stress occurs during inflammation due to the generation of reactive oxidative species (ROS). Moreover, high levels of uric acid (UA) contribute to endothelial cell dysfunction, which can promote disease-related morbidity, and NADPH oxidase-derived ROS are crucial regulatory factors in these responses. However, LXA4 also has the potential to reduce oxidative stress. The aim of the present study was to examine whether LXA4 could suppress UA-induced oxidative stress in human umbilical vein endothelial cells (HUVECs) and to investigate its mechanisms of action in vitro. HUVECs were incubated with or without LXA4, followed by the addition of UA. ROS levels were then measured using 2,7-dichlorodihydrofluorescein diacetate and lucigenin-enhanced chemiluminescence was used to evaluate NADPH oxidase activity. p47phox or p22phox small interfering (si)RNA were transfected into HUVECs and protein levels of p47phox were detected using western blot analysis. LXA4 significantly inhibited UA-induced generation of ROS to the same extent as the NADPH oxidase inhibitor, diphenyleneiodonium chloride. Notably, transfection of p47phox siRNA attenuated the generation of ROS and the activation of NADPH oxidase. Cells transfected with p22phox siRNA demonstrated a significant reduction in the expression of p47phox on the membrane. Further experiments demonstrated that LXA4 interfered with the transfer of p47phox from the cytoplasm to the cell membrane. These findings suggested that LXA4 inhibited the release of NADPH oxidase derived ROS in HUVECs stimulated by UA. A potential mechanism of action underlying this effect could be LXA4-mediated suppression of NADPH oxidase activity, leading to inhibition of p47phox translocation from the cytoplasm to the cell membrane. [ABSTRACT FROM AUTHOR]