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Last update 23 Jan 2025

EPHX2

Last update 23 Jan 2025

Basic Info

Synonyms

ABHD20, Bifunctional epoxide hydrolase 2, CEH

+ [9]

Introduction

Bifunctional enzyme (PubMed:12574510). The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides (PubMed:12869654, PubMed:12574510, PubMed:22798687). Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides (By similarity). Also determines steady-state levels of physiological mediators (PubMed:12869654, PubMed:12574510, PubMed:22798687, PubMed:21217101). Bifunctional enzyme (PubMed:12574510). The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo-9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro-9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy-octadec-9Z-enoic acid and 12-phosphonooxy-octadec-9E-enoic acid (PubMed:12574510). Has phosphatase activity toward lyso-glycerophospholipids with also some lower activity toward lysolipids of sphingolipid and isoprenoid phosphates (PubMed:22217705, PubMed:22387545).

Drugs associated with EPHX2

TMS-007

Target

EPHX2 x PLPP

Mechanism

EPHX2 inhibitors [+1]

Active Org.

Corxel Pharmaceuticals (Shanghai) Co., Ltd [+1]

Originator Org.

TMS Co., Ltd.

Active Indication

Acute Ischemic Stroke

Inactive Indication-

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

GSK-2256294

Target

EPHX2

Mechanism

EPHX2 inhibitors

Active Org.

Originator Org.

Active Indication

Inactive Indication

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

EC-5026

Target

EPHX2

Mechanism

EPHX2 inhibitors

Active Org.

Eicosis Human Health, Inc. [+1]

Originator Org.

University Of California - Davis Branch (513968)

Active Indication

Pain [+2]

Inactive Indication-

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with EPHX2

NCT06438471

/ Not yet recruitingPhase 1

Development of a Novel Soluble Epoxide Hydrolase Inhibitor as a Strategy for Treating Neuropathic Pain in Patients With SCI

The goal of this clinical trial is to evaluate safety and tolerability of multiple oral doses of EC5026 in male and female patients with neuropathic pain due to spinal cord injury. The main question it aims to answer is whether EC5026 is safe and well tolerated in SCI patients with neuropathic pain. In addition, this trial will also study the effects of EC5026 on pain.
Researchers will compare EC5026 to placebo.
Participants will be asked to:
* Take EC5026 or placebo in a masked fashion, once daily, for 14 consecutive days.
* Undergo physical exams, vital signs assessments, ECGs, and blood draws
* Complete assessments of pain, sleep, functional status, and perception of change

Start Date01 Dec 2024

Sponsor / Collaborator

Eicosis Human Health, Inc.

NCT05764122

/ WithdrawnPhase 2

A Multicenter, Operationally Seamless, Double-Blind, Dose-Ranging, Placebo-Controlled, Randomized, Parallel-Group, Phase 2b Study to Evaluate the Efficacy and Safety of Intravenous BIIB131 for Participants With Ischemic Stroke Between 4.5 and 24 Hours After Last Known Well

The primary objective of the study is to evaluate the effects of BIIB131 on arterial revascularization (Part 1) and to determine if BIIB131 improves functional outcome as measured by the Modified Rankin Scale (mRS) when compared with placebo following acute ischemic stroke (AIS) (Part 2). The secondary objectives are to evaluate the effects of BIIB131 on angiographic reperfusion and infarct evolution, to determine if BIIB131 improves functional outcome, pharmacokinetic profile of BIIB131 (Part 1); to evaluate the effects of BIIB131 on acute and 90-day clinical outcomes (Part 2).

Start Date29 Mar 2024

Sponsor / Collaborator

Biogen, Inc.

NCT06089837

/ CompletedPhase 1

A Phase 1b Multiple Ascending Dose (MAD) Study of EC5026 in Healthy Volunteers

EC5026 has been shown to be effective in preclinical pain models of pain, including inflammatory and neuropathic pain subtypes. Two Phase 1a studies - a Phase 1a single ascending dose (SAD) study and a Phase 1a fed-fasted study - have been conducted, evaluating the safety, tolerability, PK, and food effects of single oral doses of EC5026 ranging 0.5 to 24 mg. The present study will evaluate the safety, tolerability, and PK of 2 sequential ascending dose regimens of EC5026, administered once daily for 7 consecutive days, in healthy volunteers.

Start Date28 Nov 2023

Sponsor / Collaborator

Eicosis Human Health, Inc.

100 Clinical Results associated with EPHX2

100 Translational Medicine associated with EPHX2

0 Patents (Medical) associated with EPHX2

672

Literatures (Medical) associated with EPHX2

31 Dec 2024·Renal Failure

Novel immune cross-talk between inflammatory bowel disease and IgA nephropathy

Article

Author: Liu, Dongwei ; Pan, Shaokang ; Liu, Zhangsuo ; Duan, Jiayu ; Zhao, Zihao ; Yan, Qianqian ; Li, Jia

The mechanisms underlying the complex correlation between immunoglobulin A nephropathy (IgAN) and inflammatory bowel disease (IBD) remain unclear. This study aimed to identify the optimal cross-talk genes, potential pathways, and mutual immune-infiltrating microenvironments between IBD and IgAN to elucidate the linkage between patients with IBD and IgAN. The IgAN and IBD datasets were obtained from the Gene Expression Omnibus (GEO). Three algorithms, CIBERSORTx, ssGSEA, and xCell, were used to evaluate the similarities in the infiltrating microenvironment between the two diseases. Weighted gene co-expression network analysis (WGCNA) was implemented in the IBD dataset to identify the major immune infiltration modules, and the Boruta algorithm, RFE algorithm, and LASSO regression were applied to filter the cross-talk genes. Next, multiple machine learning models were applied to confirm the optimal cross-talk genes. Finally, the relevant findings were validated using histology and immunohistochemistry analysis of IBD mice. Immune infiltration analysis showed no significant differences between IBD and IgAN samples in most immune cells. The three algorithms identified 10 diagnostic genes, MAPK3, NFKB1, FDX1, EPHX2, SYNPO, KDF1, METTL7A, RIDA, HSDL2, and RIPK2; FDX1 and NFKB1 were enhanced in the kidney of IBD mice. Kyoto Encyclopedia of Genes and Genomes analysis showed 15 mutual pathways between the two diseases, with lipid metabolism playing a vital role in the cross-talk. Our findings offer insights into the shared immune mechanisms of IgAN and IBD. These common pathways, diagnostic cross-talk genes, and cell-mediated abnormal immunity may inform further experimental studies.

01 Dec 2024·Alzheimer's & Dementia

Alzheimer’s disease genetics and real‐world patient data fuel target and drug discovery in European and African American Ancestries using AI/ML approaches

Article

Author: Haines, Jonathan L. ; Hou, Yuan ; Cummings, Jeffrey L. ; Fan, Fan ; Pieper, Andrew A. ; McReynolds, Cindy ; Leverenz, James B ; Cheng, Feixiong ; Hammock, Bruce D. ; Zhang, Pengyue

AbstractBackgroundAlthough high‐throughput DNA/RNA sequencing technologies have generated massive genetic and genomic data in human disease, translation of these findings into new patient treatment has not materialized by lack of effective approaches, such as Artificial Intelligence (AL) and Machine Learning (ML) tools.MethodTo address this problem, we have used AI/ML approaches, Mendelian randomization (MR), and large patient’s genetic and functional genomic data to evaluate druggable targets using Alzheimer’s disease (AD) as a prototypical example. We utilized the genomic instruments from 9 expression quantitative trait loci (eQTL) and 3 protein quantitative trait loci (pQTL) datasets across five human brain regions from three biobanks. We tested the outcome of Mendelian randomization across genome‐wide association studies (GWAS) datasets of European‐American (EA) and African‐American (AA) ancestries, with 275,540 AD cases and 1.55 million controls. We searched repurposable drugs using AI‐assistant drugome‐wide association studies from ∼80 million electronic health records.ResultWe identified 25 drug targets in EAs and 6 new drug targets in AAs. Among 6 AA‐specific targets, TRPV3 is a potent drug target and replicated in AA‐specific eQTL data from the Metabrain cohort. We pinpointed that an anti‐inflammatory AD target of epoxide hydrolase 2 (EPHX2): (1) a pQTL lead SNP rs2741342 (PGWAS = 5.72 × 10‐13; PpQTL = 1.19 × 10‐16) located in an enhancer of EPHX2; and (2) a protein‐coding variant of rs751141 (p.Arg287Gln) was associated with reduced EPHX2 protein expression (PpQTL = 5.50 × 10‐16) from the AD knowledge portal. We demonstrated that TPPU (a nanomolar‐EPHX2 inhibitor) blocked deterioration in hippocampal‐dependent cognitive ability in a TgF344‐AD rat model and EC5026 (a first‐in‐class, picomolar EPHX2 inhibitor) improves cognition in a 5xFAD mouse model. We identified 23 candidate drugs associated with reduced risk of AD in mild cognitive impairment patients. We found that usage of either apixaban (hazard ratio [HR] = 0.74, 95% confidence interval [CI] 0.69–0.80) and amlodipine (HR = 0.91, 95%CI 0.88–0.94) were significantly associated with reduced progression to AD.ConclusionCombining genetics and real‐world patient data identifies ancestry‐specific therapeutic targets and medicines for AD. Further functional and clinical validation of candidate targets and drugs in ethnically diverse population are warranted.

01 Dec 2024·Biochemical Genetics

Antioxidant Genes Variants and Their Association with Sperm DNA Fragmentation

Article

Author: Ismail, Soher ; Suleiman, Raed ; Abuwarda, Hadeer N ; Hassouna, Nora ; Ashour, Mohammed J ; Sharif, Fadel A ; Salem, Noor

Semen possesses a variety of antioxidant defense mechanisms which protect sperm DNA from the damaging effects of oxidative stress. Correlation between antioxidant genes variants and sperm DNA fragmentation (SDF) level is not sufficiently studied. Therefore, we investigated the association between several single nucleotide polymorphisms (SNPs): CYP1A1 (rs1048943A > G), CYP4F2 (rs2108622G > A), NRF2 (rs6721961C > A), PON1 (rs662A > G), NOS3 (rs1799983G > T), GSTM1 (null), CAT (rs1001179C > T), SOD2 (rs4880A > G), GSTP1 (rs1695A > G), PON2 (rs7493G > C), EPHX2 (rs1042064T > C), and AHR (rs2066853G > A) and elevated SDF. The study employed a case-control design where, the allele and genotype frequencies of the selected SNPs were compared between 75 semen samples with abnormal SDF (the cases) and 75 samples with normal SDF (the controls). DNA was extracted from the semen samples and allele-specific PCR (AS-PCR) was used for genotyping the SNPs. Relevant data were collected from the patients' records et al.-Basma Fertility Center. Suitable statistical tests and multifactorial dimensionality reduction (MDR) test were used to anticipate SNP-SNP interactions. Comparison of semen parameters revealed significant differences between cases and controls in terms of liquefaction time, sperm total motility, and normal form. Genotype frequencies of NOS3 G > T (GT), SOD2 A > G (AA and AG), EPHX2 T > C (CC and CT), and AHR G > A (GA and GG) were significantly different between cases and controls. Allele frequencies of SOD2 (G-allele), and EPHX2 (T-allele) also significantly varied between cases and controls. MDR analysis revealed that the NOS3, SOD2, and EPHX2 SNPs combination has the highest impact on SDF. The study findings suggest that genetic variations in genes involved antioxidant defenses contribute to abnormal SDF.

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EPHX2

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