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Proceedings of the National Academy of... Mar 2022Parkinson's disease (PD) is one of the most common neurodegenerative disorders and is characterized by loss of dopaminergic neurons in the substantia nigra (SN), causing...
Parkinson's disease (PD) is one of the most common neurodegenerative disorders and is characterized by loss of dopaminergic neurons in the substantia nigra (SN), causing bradykinesia and rest tremors. Although the molecular mechanism of PD is still not fully understood, neuroinflammation has a key role in the damage of dopaminergic neurons. Herein, we found that kurarinone, a unique natural product from , alleviated the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits and dopaminergic neurotoxicity, including the losses of neurotransmitters and tyrosine hydroxylase (TH)-positive cells (SN and striatum [STR]). Furthermore, kurarinone attenuated the MPTP-mediated neuroinflammation via suppressing the activation of microglia involved in the nuclear factor kappa B signaling pathway. The proteomics result of the solvent-induced protein precipitation and thermal proteome profiling suggest that the soluble epoxide hydrolase (sEH) enzyme, which is associated with the neuroinflammation of PD, is a promising target of kurarinone. This is supported by the increase of plasma epoxyeicosatrienoic acids (sEH substrates) and the decrease of dihydroxyeicosatrienoic acids (sEH products), and the results of in vitro inhibition kinetics, surface plasmon resonance, and cocrystallization of kurarinone with sEH revealed that this natural compound is an uncompetitive inhibitor. In addition, sEH knockout (KO) attenuated the progression of PD, and sEH KO plus kurarinone did not further reduce the protection of PD in MPTP-induced PD mice. These findings suggest that kurarinone could be a potential natural candidate for the treatment of PD, possibly through sEH inhibition.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Disease Models, Animal; Epoxide Hydrolases; Flavonoids; Gene Deletion; Mice; Microglia; Parkinson Disease; Substrate Specificity
PubMed: 35217618
DOI: 10.1073/pnas.2118818119 -
International Journal of Molecular... Jun 2022Type 2 diabetes mellitus (T2DM) can result in microvascular complications such as neuropathy, retinopathy, nephropathy, and cerebral small vessel disease, and contribute... (Review)
Review
Type 2 diabetes mellitus (T2DM) can result in microvascular complications such as neuropathy, retinopathy, nephropathy, and cerebral small vessel disease, and contribute to macrovascular complications, such as heart failure, peripheral arterial disease, and large vessel stroke. T2DM also increases the risks of depression and dementia for reasons that remain largely unclear. Perturbations in the cytochrome P450-soluble epoxide hydrolase (CYP-sEH) pathway have been implicated in each of these diabetes complications. Here we review evidence from the clinical and animal literature suggesting the involvement of the CYP-sEH pathway in T2DM complications across organ systems, and highlight possible mechanisms (e.g., inflammation, fibrosis, mitochondrial function, endoplasmic reticulum stress, the unfolded protein response and autophagy) that may be relevant to the therapeutic potential of the pathway. These mechanisms may be broadly relevant to understanding, preventing and treating microvascular complications affecting the brain and other organ systems in T2DM.
Topics: Animals; Cytochrome P-450 Enzyme System; Diabetes Complications; Diabetes Mellitus, Type 2; Endoplasmic Reticulum Stress; Epoxide Hydrolases; Inflammation
PubMed: 35682911
DOI: 10.3390/ijms23116232 -
Proceedings of the National Academy of... Jun 2023Traumatic brain injury (TBI) is a pervasive problem worldwide for which no effective treatment is currently available. Although most studies have focused on the...
Traumatic brain injury (TBI) is a pervasive problem worldwide for which no effective treatment is currently available. Although most studies have focused on the pathology of the injured brain, we have noted that the liver plays an important role in TBI. Using two mouse models of TBI, we found that the enzymatic activity of hepatic soluble epoxide hydrolase (sEH) was rapidly decreased and then returned to normal levels following TBI, whereas such changes were not observed in the kidney, heart, spleen, or lung. Interestingly, genetic downregulation of hepatic (which encodes sEH) ameliorates TBI-induced neurological deficits and promotes neurological function recovery, whereas overexpression of hepatic sEH exacerbates TBI-associated neurological impairments. Furthermore, hepatic sEH ablation was found to promote the generation of A2 phenotype astrocytes and facilitate the production of various neuroprotective factors associated with astrocytes following TBI. We also observed an inverted V-shaped alteration in the plasma levels of four EET (epoxyeicosatrienoic acid) isoforms (5,6-, 8,9-,11,12-, and 14,15-EET) following TBI which were negatively correlated with hepatic sEH activity. However, hepatic sEH manipulation bidirectionally regulates the plasma levels of 14,15-EET, which rapidly crosses the blood-brain barrier. Additionally, we found that the application of 14,15-EET mimicked the neuroprotective effect of hepatic sEH ablation, while 14,15-epoxyeicosa-5(Z)-enoic acid blocked this effect, indicating that the increased plasma levels of 14,15-EET mediated the neuroprotective effect observed after hepatic sEH ablation. These results highlight the neuroprotective role of the liver in TBI and suggest that targeting hepatic EET signaling could represent a promising therapeutic strategy for treating TBI.
Topics: Animals; Mice; Neuroprotective Agents; Eicosanoids; Astrocytes; Brain Injuries, Traumatic; Liver; Epoxide Hydrolases
PubMed: 37339206
DOI: 10.1073/pnas.2301360120 -
International Journal of Molecular... Apr 2023Epoxide hydrolases are attractive and industrially important biocatalysts. They can catalyze the enantioselective hydrolysis of epoxides to the corresponding diols as... (Review)
Review
Epoxide hydrolases are attractive and industrially important biocatalysts. They can catalyze the enantioselective hydrolysis of epoxides to the corresponding diols as chiral building blocks for bioactive compounds and drugs. In this review article, we discuss the state of the art and development potential of epoxide hydrolases as biocatalysts based on the most recent approaches and techniques. The review covers new approaches to discover epoxide hydrolases using genome mining and enzyme metagenomics, as well as improving enzyme activity, enantioselectivity, enantioconvergence, and thermostability by directed evolution and a rational design. Further improvements in operational and storage stabilization, reusability, pH stabilization, and thermal stabilization by immobilization techniques are discussed in this study. New possibilities for expanding the synthetic capabilities of epoxide hydrolases by their involvement in non-natural enzyme cascade reactions are described.
Topics: Epoxide Hydrolases; Catalysis; Epoxy Compounds; Hydrolysis; Genetic Techniques; Stereoisomerism
PubMed: 37108499
DOI: 10.3390/ijms24087334 -
Physiological Research Oct 2019Epoxyeicosatrienoic acids (EETs) are also known as epoxyeicosanoids that have renal and cardiovascular actions. These renal and cardiovascular actions can be regulated... (Review)
Review
Epoxyeicosatrienoic acids (EETs) are also known as epoxyeicosanoids that have renal and cardiovascular actions. These renal and cardiovascular actions can be regulated by soluble epoxide hydrolase (sEH) that degrades and inactivates EETs. Extensive animal hypertension studies have determined that vascular, epithelial transport, and anti-inflammatory actions of EETs lower blood pressure and decrease renal and cardiovascular disease progression. Human studies have also supported the notion that increasing EET levels in hypertension could be beneficial. Pharmacological and genetic approaches to increase epoxyeicosanoids in several animal models and humans have found improved endothelial vascular function, increased sodium excretion, and decreased inflammation to oppose hypertension and associated renal and cardiovascular complications. These compelling outcomes support the concept that increasing epoxyeicosanoids via sEH inhibitors or EET analogs could be a valuable hypertension treatment.
Topics: Animals; Antihypertensive Agents; Blood Pressure; Eicosanoids; Enzyme Inhibitors; Epoxide Hydrolases; Humans; Hypertension; Signal Transduction
PubMed: 31475560
DOI: 10.33549/physiolres.934291 -
The Chinese Journal of Physiology 2022Epoxyeicosatrienoic acids (EETs) are fatty acid signaling molecules synthesized by cytochrome P450 epoxygenases from arachidonic acid. The biological activity of EETs is... (Review)
Review
Epoxyeicosatrienoic acids (EETs) are fatty acid signaling molecules synthesized by cytochrome P450 epoxygenases from arachidonic acid. The biological activity of EETs is terminated when being metabolized by soluble epoxide hydrolase (sEH), a process that serves as a key regulator of tissue EETs levels. EETs act through several signaling pathways to mediate various beneficial effects, including anti-inflammation, anti-apoptosis, and anti-oxidation with relieve of endoplasmic reticulum stress, thereby sEH has become a potential therapeutic target in cardiovascular disease and cancer therapy. Enzymes for EET biosynthesis and metabolism are both widely detected in both neuron and glial cells in the central nervous system (CNS). Recent studies discovered that astrocyte-derived EETs not only mediate neurovascular coupling and neuronal excitability by maintaining glutamate homeostasis but also glia-dependent neuroprotection. Genetic ablation as well as pharmacologic inhibition of sEH has greatly helped to elucidate the physiologic actions of EETs, and maintaining or elevating brain EETs level has been demonstrated beneficial effects in CNS disease models. Here, we review the literature regarding the studies on the bioactivity of EETs and their metabolic enzyme sEH with special attention paid to their action mechanisms in the CNS, including their modulation of neuronal activity, attenuation of neuroinflammation, regulation of cerebral blood flow, and improvement of neuronal and glial cells survival. We further reviewed the recent advance on the potential application of sEH inhibition for treating cerebrovascular disease, epilepsy, and pain disorder.
Topics: Brain; Central Nervous System; Epoxide Hydrolases; Homeostasis; Neurons
PubMed: 35229747
DOI: 10.4103/cjp.cjp_80_21 -
Neurotherapeutics : the Journal of the... Jul 2020The role of lipids in pain signaling is well established and built on decades of knowledge about the pain and inflammation produced by prostaglandin and leukotriene... (Review)
Review
The role of lipids in pain signaling is well established and built on decades of knowledge about the pain and inflammation produced by prostaglandin and leukotriene metabolites of cyclooxygenase and lipoxygenase metabolism, respectively. The analgesic properties of other lipid metabolites are more recently coming to light. Lipid metabolites have been observed to act directly at ion channels and G protein-coupled receptors on nociceptive neurons as well as act indirectly at cellular membranes. Cytochrome P450 metabolism of specifically long-chain fatty acids forms epoxide metabolites, the epoxy-fatty acids (EpFA). The biological role of these metabolites has been found to mediate analgesia in several types of pain pathology. EpFA act through a variety of direct and indirect mechanisms to limit pain and inflammation including nuclear receptor agonism, limiting endoplasmic reticulum stress and blocking mitochondrial dysfunction. Small molecule inhibitors of the soluble epoxide hydrolase can stabilize the EpFA in vivo, and this approach has demonstrated relief in preclinical modeled pain pathology. Moreover, the ability to block neuroinflammation extends the potential benefit of targeting soluble epoxide hydrolase to maintain EpFA for neuroprotection in neurodegenerative disease.
Topics: Animals; Epoxide Hydrolases; Humans; Lipid Metabolism; Membrane Lipids; Pain
PubMed: 32875445
DOI: 10.1007/s13311-020-00916-4 -
Cells Jun 2022Cell responses to changes in their redox state are significantly mediated by reversible oxido-reductive post-translational modifications of proteins, potentially... (Review)
Review
Cell responses to changes in their redox state are significantly mediated by reversible oxido-reductive post-translational modifications of proteins, potentially altering their activities or interactions. These modifications are important for the homeostatic responses of cells to environmental changes that alter their redox state. Such redox regulatory mechanisms not only operate to maintain health, but can become dysregulated and contribute to pathophysiology. In this review, we focus on the redox control of soluble epoxide hydrolase (sEH), which is widely expressed, including in blood vessels and cardiomyocytes. We review the different types of oxidative modifications that regulate sEH and how they may alter cardiovascular physiology and affect disease progression during stress.
Topics: Cardiovascular System; Disease Progression; Epoxide Hydrolases; Humans; Oxidation-Reduction
PubMed: 35741062
DOI: 10.3390/cells11121932 -
Cardiovascular Therapeutics Apr 2011Cardiovascular disease remains one of the leading causes of death in the Western societies. Heart failure (HF) is due primarily to progressive myocardial dysfunction... (Review)
Review
Cardiovascular disease remains one of the leading causes of death in the Western societies. Heart failure (HF) is due primarily to progressive myocardial dysfunction accompanied by myocardial remodeling. Once HF develops, the condition is, in most cases, irreversible and is associated with a very high mortality rate. Soluble epoxide hydrolase (sEH) is an enzyme that catalyzes the hydrolysis of epoxyeicosatrienoic acids (EETs), which are lipid mediators derived from arachidonic acid through the cytochrome P450 epoxygenase pathway. EETs have been shown to have vasodilatory, antiinflammatory, and cardioprotective effects. When EETs are hydrolyzed by sEH to corresponding dihydroxyeicosatrienoic acids, their cardioprotective activities become less pronounced. In line with the recent genetic study that has identified sEH as a susceptibility gene for HF, the sEH enzyme has received considerable attention as an attractive therapeutic target for cardiovascular diseases. Indeed, sEH inhibition has been demonstrated to have antihypertensive and antiinflammatory actions, presumably due to the increased bioavailability of endogenous EETs and other epoxylipids, and several potent sEH inhibitors have been developed and tested in animal models of cardiovascular disease including hypertension, cardiac hypertrophy, and ischemia/reperfusion injury. sEH inhibitor treatment has been shown to effectively prevent pressure overload- and angiotensin II-induced cardiac hypertrophy and reverse the pre-established cardiac hypertrophy caused by chronic pressure overload. Application of sEH inhibitors in several cardiac ischemia/reperfusion injury models reduced infarct size and prevented the progressive cardiac remodeling. Moreover, the use of sEH inhibitors prevented the development of electrical remodeling and ventricular arrhythmias associated with cardiac hypertrophy and ischemia/reperfusion injury. The data published to date support the notion that sEH inhibitors may represent a promising therapeutic approach for combating detrimental cardiac remodeling and HF.
Topics: Animals; Cardiomegaly; Enzyme Inhibitors; Epoxide Hydrolases; Heart Failure; Humans; Myocardial Reperfusion Injury; Ventricular Remodeling
PubMed: 20433684
DOI: 10.1111/j.1755-5922.2010.00150.x -
Gene Sep 2013Mammalian soluble epoxide hydrolase (sEH) converts epoxides to their corresponding diols through the addition of a water molecule. sEH readily hydrolyzes lipid signaling... (Review)
Review
Mammalian soluble epoxide hydrolase (sEH) converts epoxides to their corresponding diols through the addition of a water molecule. sEH readily hydrolyzes lipid signaling molecules, including the epoxyeicosatrienoic acids (EETs), epoxidized lipids produced from arachidonic acid by the action of cytochrome p450s. Through its metabolism of the EETs and other lipid mediators, sEH contributes to the regulation of vascular tone, nociception, angiogenesis and the inflammatory response. Because of its central physiological role in disease states such as cardiac hypertrophy, diabetes, hypertension, and pain sEH is being investigated as a therapeutic target. This review begins with a brief introduction to sEH protein structure and function. sEH evolution and gene structure are then discussed before human small nucleotide polymorphisms and mammalian gene expression are described in the context of several disease models. The review ends with an overview of studies that have employed the sEH knockout mouse model.
Topics: Animals; Catalysis; Disease Models, Animal; Epoxide Hydrolases; Evolution, Molecular; Gene Expression; Gene Expression Regulation; Humans; Mice; Mice, Knockout; Polymorphism, Single Nucleotide; Protein Conformation; Sequence Deletion
PubMed: 23701967
DOI: 10.1016/j.gene.2013.05.008