Epoxyeicosatrienoic Acids and Fibrosis: Recent Insights for the Novel Therapeutic Strategies

Organ fibrosis often ends in eventual organ failure and leads to high mortality. Although researchers have identified many effector cells and molecular pathways, there are few effective therapies for fibrosis to date and the underlying mechanism needs to be examined and defined further. Epoxyeicosatrienoic acids (EETs) are endogenous lipid metabolites of arachidonic acid (ARA) synthesized by cytochrome P450 (CYP) epoxygenases. EETs are rapidly metabolized primarily via the soluble epoxide hydrolase (sEH) pathway. The sEH pathway produces dihydroxyeicosatrienoic acids (DHETs), which have lower activity. Stabilized or increased EETs levels exert several protective effects, including pro-angiogenesis, anti-inflammation, anti-apoptosis, and anti-senescence. Currently, intensive investigations are being carried out on their anti-fibrotic effects in the kidney, heart, lung, and liver. The present review provides an update on how the stabilized or increased production of EETs is a reasonable theoretical basis for fibrosis treatment.

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Protective effects of epoxyeicosatrienoic acids on human endothelial cells from the pulmonary and coronary vasculature

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00953.2005 ◽

2006 ◽

Vol 291 (2) ◽

pp. H517-H531 ◽

Cited By ~ 49

Author(s):

Anuradha Dhanasekaran ◽

Rula Al-Saghir ◽

Bernardo Lopez ◽

Daling Zhu ◽

David D. Gutterman ◽

...

Keyword(s):

Endothelial Cells ◽

Cell Survival ◽

Kinase Inhibitor ◽

Protective Action ◽

Underlying Mechanism ◽

Mitogen Activated Protein Kinase ◽

Epoxyeicosatrienoic Acids ◽

Protective Effects ◽

Human Coronary Artery ◽

Mitogen Activated Protein

Epoxyeicosatrienoic acids (EETs) are cytochrome P-450 (CYP) metabolites synthesized from the essential fatty acid arachidonic acid to generate four regioisomers, 14,15-, 11,12-, 8,9-, and 5,6-EET. Cultured human coronary artery endothelial cells (HCAECs) contain endogenous EETs that are increased by stimulation with physiological agonists such as bradykinin. Because EETs are known to modulate a number of vascular functions, including angiogenesis, we tested each of the four regioisomers to characterize their effects on survival and apoptosis of HCAECs and cultured human lung microvascular endothelial cells (HLMVECs). A single application of physiologically relevant concentration of 14,15-, 11,12-, and 8,9-EET but not 5,6-EET (0.75–300 nM) promoted concentration-dependent increase in cell survival of HLMVECs and HCAECs after removal of serum. The lipids also protected the same cells from death via the intrinsic, as well as extrinsic, pathways of apoptosis. EETs did not increase intracellular calcium concentration ([Ca2+]i) or phosphorylate mitogen-activated protein kinase p44/42 when applied to these cells, and their protective action was attenuated by the phosphotidylinositol-3 kinase inhibitor wortmannin (10 μM) but not the cyclooxygenase inhibitor indomethacin (20 μM). Our results demonstrate for the first time the capacity of EETs to enhance human endothelial cell survival by inhibiting both the intrinsic, as well as extrinsic, pathways of apoptosis, an important underlying mechanism that may promote angiogenesis and endothelial survival during atherosclerosis and related cardiovascular ailments.

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Protective Effect of Fluorofenidone Against Acute Lung Injury Through Suppressing the MAPK/NF-κB Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.772031 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xin Lv ◽

Tingting Yao ◽

Rongling He ◽

Yijun He ◽

Mengyu Li ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Severe Disease ◽

Underlying Mechanism ◽

Lavage Fluid ◽

Pharmacological Therapy ◽

Protective Effects ◽

Cell Accumulation ◽

Tnf Α ◽

Anti Inflammation

Acute lung injury (ALI) is a severe disease that presents serious damage and excessive inflammation in lungs with high mortality without effective pharmacological therapy. Fluorofenidone (AKFPD) is a novel pyridone agent that has anti-fibrosis, anti-inflammation, and other pharmacological activities, while the effect of fluorofenidone on ALI is unclarified. Here, we elucidated the protective effects and underlying mechanism of fluorofenidone on lipopolysaccharide (LPS)-induced ALI. In this study, fluorofenidone alleviated lung tissue structure injury and reduced mortality, decreased the pulmonary inflammatory cell accumulation and level of inflammatory cytokines IL-1β, IL-6, and TNF-α in the bronchoalveolar lavage fluid, and attenuated pulmonary apoptosis in LPS-induced ALI mice. Moreover, fluorofenidone could block LPS-activated phosphorylation of ERK, JNK, and P38 and further inhibited the phosphorylation of IκB and P65. These results suggested that fluorofenidone can significantly contrast LPS-induced ALI through suppressing the activation of the MAPK/NF-κB signaling pathway, which indicates that fluorofenidone could be considered as a novel therapeutic candidate for ALI.

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Upregulation of miR-150-5p alleviates LPS-induced inflammatory response and apoptosis of RAW264.7 macrophages by targeting Notch1

Open Life Sciences ◽

10.1515/biol-2020-0058 ◽

2020 ◽

Vol 15 (1) ◽

pp. 544-552

Author(s):

Xiaoyan Deng ◽

Zhixing Lin ◽

Chao Zuo ◽

Yanjie Fu

Keyword(s):

Inflammatory Response ◽

Underlying Mechanism ◽

Notch Receptor ◽

Raw264.7 Cells ◽

Luciferase Reporter ◽

Raw264.7 Macrophages ◽

Factor Α ◽

Anti Inflammation ◽

Necrosis Factor ◽

Dual Luciferase Reporter Assay

AbstractCirculating miR-150-5p has been identified as a prognostic marker in patients with critical illness and sepsis. Herein, we aimed to further explore the role and underlying mechanism of miR-150-5p in sepsis. Quantitative real-time-PCR assay was performed to detect the expression of miR-150-5p upon stimulation with lipopolysaccharide (LPS) in RAW264.7 cells. The levels of tumor necrosis factor-α, interleukin (IL)-6 and IL-1β were measured by ELISA assay. Cell apoptosis was determined using flow cytometry. Western blot was used to assess notch receptor 1 (Notch1) expression in LPS-induced RAW264.7 cells. Dual-luciferase reporter assay was employed to validate the target of miR-150-5p. Our data showed that miR-150-5p was downregulated and Notch1 was upregulated in LPS-stimulated RAW264.7 cells. miR-150-5p overexpression or Notch1 silencing alleviated LPS-induced inflammatory response and apoptosis in RAW264.7 cells. Moreover, Notch1 was a direct target of miR-150-5p. Notch1 abated miR-150-5p-mediated anti-inflammation and anti-apoptosis in LPS-induced RAW264.7 cells. miR-150-5p alleviated LPS-induced inflammatory response and apoptosis at least partly by targeting Notch1 in RAW264.7 cells, highlighting miR-150-5p as a target in the development of anti-inflammation and anti-apoptosis drugs for sepsis treatment.

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Protective effects of crude chalaza hydrolysates against liver fibrogenesis via antioxidation, anti-inflammation/anti-fibrogenesis, and apoptosis promotion of damaged hepatocytes

Poultry Science ◽

10.1016/j.psj.2021.101175 ◽

2021 ◽

pp. 101175

Author(s):

Yi-Ling Lin ◽

Ching-Fu Lu ◽

Yi-Hsieng Samuel Wu ◽

Kuo-Tai Yang ◽

Wen-Yuan Yang ◽

...

Keyword(s):

Protective Effects ◽

Liver Fibrogenesis ◽

Anti Inflammation

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UVB protective effects of Sargassum horneri through the regulation of Nrf2 mediated antioxidant mechanism

Scientific Reports ◽

10.1038/s41598-021-88949-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Eui Jeong Han ◽

Seo-Young Kim ◽

Hee-Jin Han ◽

Hyun-Soo Kim ◽

Kil-Nam Kim ◽

...

Keyword(s):

Skin Barrier ◽

Human Keratinocytes ◽

Underlying Mechanism ◽

Ultraviolet B ◽

Sargassum Horneri ◽

Cellular Damage ◽

Protective Effects ◽

Skin Damage ◽

Antioxidant Mechanism ◽

Induced Apoptosis

AbstractThe present study aimed to evaluate the protective effect of a methanol extract of Sargassum horneri (SHM), which contains 6-hydroxy-4,4,7a-trimethyl-5,6,7,7a-tetrahydrobenzofuran-2(4H)-one (HTT) and apo-9′-fucoxanthinone, against ultraviolet B (UVB)-induced cellular damage in human keratinocytes and its underlying mechanism. SHM significantly improved cell viability of UVB-exposed human keratinocytes by reducing the generation of intracellular reactive oxygen species (ROS). Moreover, SHM inhibited UVB exposure-induced apoptosis by reducing the formation of apoptotic bodies and the populations of the sub-G1 hypodiploid cells and the early apoptotic cells by modulating the expression of the anti- and pro-apoptotic molecules, Bcl-2 and Bax, respectively. Furthermore, SHM inhibited NF-κB p65 activation by inducing the activation of Nrf2/HO-1 signaling. The cytoprotective and antiapoptotic activities of SHM are abolished by the inhibition of HO-1 signaling. In further study, SHM restored the skin dryness and skin barrier disruption in UVB-exposed human keratinocytes. Based to these results, our study suggests that SHM protects the cells against UVB-induced cellular damages through the Nrf2/HO-1/NF-κB p65 signaling pathway and may be potentially useful for the prevention of UVB-induced skin damage.

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Reno-protective mechanisms of epoxyeicosatrienoic acids in cardiovascular disease

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00606.2011 ◽

2012 ◽

Vol 302 (3) ◽

pp. R321-R330 ◽

Cited By ~ 23

Author(s):

Ahmed A. Elmarakby

Keyword(s):

Blood Pressure ◽

Cardiovascular Disease ◽

Animal Models ◽

Vascular Function ◽

Organ Damage ◽

Reduce Blood Pressure ◽

Experimental Models ◽

Epoxyeicosatrienoic Acids ◽

Protective Effects ◽

Protective Mechanisms

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, and it is well known that end-stage renal disease (ESRD) is a profound consequence of the progression of CVD. Present treatments only slow CVD progression to ESRD, and it is imperative that new therapeutic strategies are developed to prevent the incidence of ESRD. Because epoxyeicosatrienoic acids (EETs) have been shown to elicit reno-protective effects in hypertensive animal models, the current review will focus on addressing the reno-protective mechanisms of EETs in CVD. The cytochrome P-450 epoxygenase catalyzes the oxidation of arachidonic acid to EETs. EETs have been identified as endothelium-derived hyperpolarizing factors (EDHFs) with vasodilatory, anti-inflammatory, antihypertensive, and antiplatelet aggregation properties. EETs also have profound effects on vascular migration and proliferation and promote angiogenesis. The progression of CVD has been linked to decreased EETs levels, leading to the concept that EETs should be therapeutically targeted to prevent end-organ damage associated with CVD. However, EETs are quickly degraded by the enzyme soluble epoxide hydrolase (sEH) to their less active diols, dihydroxyeicosatrienoic acids (DHETs). As such, one way to increase EETs level is to inhibit their degradation to DHETs by using sEH inhibitors. Inhibition of sEH has been shown to effectively reduce blood pressure and organ damage in experimental models of CVD. Another approach to target EETs is to develop EET analogs with improved solubility and resistance to auto-oxidation and metabolism by sEH. For example, stable ether EET analogs dilate afferent arterioles and lower blood pressure in hypertensive rodent animal models. EET agonists also improve insulin signaling and vascular function in animal models of metabolic syndrome.

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The Novel Pan-PIM Kinase Inhibitor, PIM447, Displays Dual Antimyeloma and Bone-Protective Effects, and Potently Synergizes with Current Standards of Care

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-16-0230 ◽

2016 ◽

Vol 23 (1) ◽

pp. 225-238 ◽

Cited By ~ 24

Author(s):

Teresa Paíno ◽

Antonio Garcia-Gomez ◽

Lorena González-Méndez ◽

Laura San-Segundo ◽

Susana Hernández-García ◽

...

Keyword(s):

Kinase Inhibitor ◽

Standards Of Care ◽

Protective Effects ◽

The Novel ◽

Current Standards

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Zingerone Alleviates Myocardial Ischemia/Reperfusion Injury

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:543-549 ◽

2021 ◽

Vol 19 (4) ◽

pp. 543-549

Author(s):

Fanglin Luo ◽

Shunxiang Luo ◽

Yanqing Wu

Keyword(s):

Myocardial Infarction ◽

Proinflammatory Cytokine ◽

Myocardial Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Underlying Mechanism ◽

Protective Effects ◽

Cytokine Release ◽

Myocardial Ischemia Reperfusion Injury ◽

Myocardial Ischemia Reperfusion

Using a rat model, we have explored the underlying mechanism of ischemia/reperfusion (I/R)-mediated myocardial infarction and assessed the protective potential of zingerone. The results show that zingerone exhibits not only the myocardial protective effect, but also antioxidative and anti-inflammatory effects by suppression of markers of oxidation and proinflammatory cytokine release. Zingerone promotes protective effects against I/R-induced myocardial infarction by regulating Nrf2/HO-1 and NF-κB signaling pathways. These findings provide novel insights into the effects of zingerone on the cardioprotective mechanism of myocardial injury after I/R and may open new avenues for myocardial infarction treatment.

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The Protective Effect of Total Flavones from Rhododendron simsii Planch. on Myocardial Ischemia/Reperfusion Injury and Its Underlying Mechanism

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/6139372 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Sheng-Yong Luo ◽

Qing-Hua Xu ◽

Gong Peng ◽

Zhi-Wu Chen

Keyword(s):

Myocardial Infarction ◽

Protective Effect ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Underlying Mechanism ◽

Assay Method ◽

Protective Effects ◽

Rhododendron Simsii ◽

Rhoa Activity ◽

Protein Expressions

Objectives. Total flavones from Rhododendron simsii Planch. (TFR) are the effective part extracted from the flowers of Rhododendron simsii Planch. and have obvious protective effects against cerebral ischemic or myocardial injuries in rabbits and rats. However, their mechanism of cardioprotection is still unrevealed. Therefore, the present study was designed to investigate the effect of TFR on myocardial I/R injury and the underlying mechanism. Methods. TFR groups were treated by gavage once a day for 3 days at a dose of 20, 40, and 80 mg/kg, respectively, and then the model of myocardial I/R injury was established. Myocardial infarction, ST-segment elevation, and the expression of UTR, ROCK1, ROCK2, and p-MLC protein in rat myocardium were determined at 90 min after reperfusion. UTR siRNA in vivo transfection and competition binding assay method were used to study the relationship between the protective effect of TFR and UTR. Results. The expression of UTR protein markedly decreased in myocardium of UTR siRNA transfection group rats. TFR could significantly reduce the infarct size and inhibit the increase of RhoA activity and ROCK1, ROCK2, and p-MLC protein expressions both in WT and UTR knockdown rats. The reducing rate of TFR in myocardial infarction area, RhoA activity, and ROCK1, ROCK2, and p-MLC protein expressions in UTR knockdown rats decreased markedly compared with that in WT rats. In addition, TFR had no obvious effect on the increase of ΣST in UTR knockdown rats in comparison with that in model group. In particular, TFR could significantly inhibit the combination of [I125]-hu-II and UTR, and IC50 was 0.854 mg/l. Conclusions. The results indicate that the protective effect of TFR on I/R injury may be correlated with its blocking UTR and the subsequent inhibition of RhoA/ROCK signaling pathway.

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