CYP2J2-produced epoxyeicosatrienoic acids attenuate ischemia/reperfusion-induced acute kidney injury by activating the SIRT1-FoxO3a pathway

Zhu, Ye; Ding, Ao; Yang, Dongliang; Cui, Tongxia; Yang, Hui; Zhang, Hua; Wang, Cheng

doi:10.1016/j.lfs.2020.117327

Cited by 20 publications

(13 citation statements)

References 32 publications

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“…Exogenous 11,12-EET addition suppresses I/Rinduced apoptosis through SIRT1-FoxO3a signaling activation. These results suggest that CYP2J2-produced EETs activate the SIRT1-FoxO3a signaling pathway to bring about their beneficial actions [144]. 15-HETE promotes the transcription and translation of SIRT1 to increase viability of pulmonary arterial smooth muscle cells by promoting the expression of Bcl-2 and Bcl-xL [145].…”

Section: Regulatory Action Of Bioactive Lipids On Sirtuinsmentioning

confidence: 97%

“Cell Membrane Theory of Senescence” and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications

Das

2021

Biomolecules

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Lipids are an essential constituent of the cell membrane of which polyunsaturated fatty acids (PUFAs) are the most important component. Activation of phospholipase A2 (PLA2) induces the release of PUFAs from the cell membrane that form precursors to both pro- and ant-inflammatory bioactive lipids that participate in several cellular processes. PUFAs GLA (gamma-linolenic acid), DGLA (dihomo-GLA), AA (arachidonic acid), EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are derived from dietary linoleic acid (LA) and alpha-linolenic acid (ALA) by the action of desaturases whose activity declines with age. Consequently, aged cells are deficient in GLA, DGLA, AA, AA, EPA and DHA and their metabolites. LA, ALA, AA, EPA and DHA can also be obtained direct from diet and their deficiency (fatty acids) may indicate malnutrition and deficiency of several minerals, trace elements and vitamins some of which are also much needed co-factors for the normal activity of desaturases. In many instances (patients) the plasma and tissue levels of GLA, DGLA, AA, EPA and DHA are low (as seen in patients with hypertension, type 2 diabetes mellitus) but they do not have deficiency of other nutrients. Hence, it is reasonable to consider that the deficiency of GLA, DGLA, AA, EPA and DHA noted in these conditions are due to the decreased activity of desaturases and elongases. PUFAs stimulate SIRT1 through protein kinase A-dependent activation of SIRT1-PGC1α complex and thus, increase rates of fatty acid oxidation and prevent lipid dysregulation associated with aging. SIRT1 activation prevents aging. Of all the SIRTs, SIRT6 is critical for intermediary metabolism and genomic stability. SIRT6-deficient mice show shortened lifespan, defects in DNA repair and have a high incidence of cancer due to oncogene activation. SIRT6 overexpression lowers LDL and triglyceride level, improves glucose tolerance, and increases lifespan of mice in addition to its anti-inflammatory effects at the transcriptional level. PUFAs and their anti-inflammatory metabolites influence the activity of SIRT6 and other SIRTs and thus, bring about their actions on metabolism, inflammation, and genome maintenance. GLA, DGLA, AA, EPA and DHA and prostaglandin E2 (PGE2), lipoxin A4 (LXA4) (pro- and anti-inflammatory metabolites of AA respectively) activate/suppress various SIRTs (SIRt1 SIRT2, SIRT3, SIRT4, SIRT5, SIRT6), PPAR-γ, PARP, p53, SREBP1, intracellular cAMP content, PKA activity and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1-α). This implies that changes in the metabolism of bioactive lipids as a result of altered activities of desaturases, COX-2 and 5-, 12-, 15-LOX (cyclo-oxygenase and lipoxygenases respectively) may have a critical role in determining cell age and development of several aging associated diseases and genomic stability and gene and oncogene activation. Thus, methods designed to maintain homeostasis of bioactive lipids (GLA, DGLA, AA, EPA, DHA, PGE2, LXA4) may arrest aging process and associated metabolic abnormalities.

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Section: Regulatory Action Of Bioactive Lipids On Sirtuinsmentioning

confidence: 97%

“Cell Membrane Theory of Senescence” and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications

Das

2021

Biomolecules

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“…Multiple studies demonstrated that both EETs and HETEs play a role in lung injury and kidney injury (Hoff et al, 2019;Zhu et al, 2020). Consequently, it is considered that therapeutic strategies related to specific CYP inhibitors or inducers that improve AA metabolism may be beneficial in COVID-19 (Shoieb et al, 2020).…”

Section: Arachidonic Acid Pathwaymentioning

confidence: 99%

The Role of Cytochrome P450 Enzymes in COVID-19 Pathogenesis and Therapy

et al. 2022

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Coronavirus disease 2019 (COVID-19) has become a new public health crisis threatening the world. Dysregulated immune responses are the most striking pathophysiological features of patients with severe COVID-19, which can result in multiple-organ failure and death. The cytochrome P450 (CYP) system is the most important drug metabolizing enzyme family, which plays a significant role in the metabolism of endogenous or exogenous substances. Endogenous CYPs participate in the biosynthesis or catabolism of endogenous substances, including steroids, vitamins, eicosanoids, and fatty acids, whilst xenobiotic CYPs are associated with the metabolism of environmental toxins, drugs, and carcinogens. CYP expression and activity are greatly affected by immune response. However, changes in CYP expression and/or function in COVID-19 and their impact on COVID-19 pathophysiology and the metabolism of therapeutic agents in COVID-19, remain unclear. In this analysis, we review current evidence predominantly in the following areas: firstly, the possible changes in CYP expression and/or function in COVID-19; secondly, the effects of CYPs on the metabolism of arachidonic acid, vitamins, and steroid hormones in COVID-19; and thirdly, the effects of CYPs on the metabolism of therapeutic COVID-19 drugs.

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“…Instead, the increased EET levels shift ARA metabolism to other pro-inflammatory pathways (e.g., ω-hydrolase-LOX pathways), and this counteracts the increase in EETs [ 11 ]. Other approaches, such as CYP2J2 overexpression, EET analog treatment, and exogenous EET treatment, are widely used [ 9 , 12 , 13 , 14 ]. Moreover, the in vivo overexpression of CYP2J2 could increase EET synthesis, and EET analogs could then lower the metabolism and improve solubility.…”

Section: Introductionmentioning

confidence: 99%

“…The details of sEHI have been reviewed elsewhere [15]. [9,[12][13][14]. Moreover, the in vivo overexpression of CYP2J2 could increase EET synthesis, and EET analogs could then lower the metabolism and improve solubility.…”

Section: Introductionmentioning

confidence: 99%

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

Guan

Rao

Liu

et al. 2021

IJMS

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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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CYP2J2-produced epoxyeicosatrienoic acids attenuate ischemia/reperfusion-induced acute kidney injury by activating the SIRT1-FoxO3a pathway

Cited by 20 publications

References 32 publications

“Cell Membrane Theory of Senescence” and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications

“Cell Membrane Theory of Senescence” and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications

The Role of Cytochrome P450 Enzymes in COVID-19 Pathogenesis and Therapy

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

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