Natural soluble epoxide hydrolase inhibitors from Inula britanica and their potential interactions with soluble epoxide hydrolase: Insight from inhibition kinetics and molecular dynamics

Zhao, Wen‐Yu; Yan, Jing; Zhang, Min; Wang, Chao; Feng, Lei; Lv, Xia; Huo, Xiaokui; Sun, Cheng‐Peng; Chen, Lixia; Ma, Xiaochi

doi:10.1016/j.cbi.2021.109571

Cited by 20 publications

(16 citation statements)

References 55 publications

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“…Secondary metabolites of medicinal plants play important roles in drug discovery by providing lead scaffolds that can then be optimized by synthetic and medicinal chemists. So far, research has been conducted to develop sEH inhibitors from natural products, and, as a result, flavonoids [ 19 ], triterpenoids [ 20 ], and macamides [ 21 ] are representative compounds.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Soluble Epoxide Hydrolase Activity by Components of Glycyrrhiza uralensis

Kim

Huh

Hur

et al. 2023

IJMS

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Soluble epoxide hydrolase (sEH) is a target enzyme for the treatment of inflammation and cardiovascular disease. A Glycyrrhiza uralensis extract exhibited ~50% inhibition of sEH at 100 μg/mL, and column chromatography yielded compounds 1–11. Inhibitors 1, 4–6, 9, and 11 were non-competitive; inhibitors 3, 7, 8, and 10 were competitive. The IC50 value of inhibitor 10 was below 2 μM. Molecular simulation was used to identify the sEH binding site. Glycycoumarin (10) requires further evaluation in cells and animals.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Soluble Epoxide Hydrolase Activity by Components of Glycyrrhiza uralensis

Kim

Huh

Hur

et al. 2023

IJMS

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“…Among bioactive derivatives of AA, epoxy fatty acids (EpFAs) represented by epoxyeicosatrienoic acids (EETs), produced by several CYP450 oxidases (e.g., CYP2J and CYP2C), have received great attention from scientists because of their outstanding physiological effects, especially anti-inflammatory, antioxidant, and antalgesic activities. − However, EETs are rapidly metabolized in the presence of epoxide hydrolases (EHs) represented by soluble epoxide hydrolase (sEH), which causes the loss of their multiple effects. ,− sEH, encoded by Ephx2 , is a bifunctional enzyme with 555 amino acid residues, and its C-terminal mediates the hydrolysis of bioactive epoxy fatty acids (EpFAs), such as EETs and epoxydocosapentaenoic acids (EDPs), , while the role of the N-terminal phosphatase is poorly understood. Recently, sEH inhibition to enhance levels of EETs has become an attractive research strategy to treat diseases related to inflammation, such as lung injury and diabetes. − …”

Section: Introductionmentioning

confidence: 99%

“…An effective approach to discover innovative drugs involves probing natural products for possible drugs or leads because of their complex and changeable structures and multiple biological activities. , Increasing evidence supports the therapeutic effects of natural products and traditional Chinese medicines, such as kuraninone, alisol B, (2 S ,3 S )-britanicafanin A, 3β-hydroxy-25-anhydro-alisol F, and Inula japonica . ,,− Wedelolactone (WED), first isolated from Wedelia calendulacea by Govindachari and co-workers in 1956, is a polyphenol sharing a coumarin skeleton with a benzofuran moiety at C-3 and C-4 . Emerging evidence demonstrates multiple pharmacological responses of WED, including anti-inflammatory, anticancer, and hepatoprotective effects, as well as the remission of Parkinson’s disease (PD) and kidney injury. − Recent research focused on WED has indicated that it attenuates lung collagen deposition and fibrotic pathology in bleomycin-mediated pulmonary fibrosis .…”

Section: Introductionmentioning

confidence: 99%

Macrophage Inactivation by Small Molecule Wedelolactone via Targeting sEH for the Treatment of LPS-Induced Acute Lung Injury

Zhang

Huo

et al. 2023

ACS Cent. Sci.

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Soluble epoxide hydrolase (sEH) plays a critical role in inflammation by modulating levels of epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids (EpFAs). Here, we investigate the possible role of sEH in lipopolysaccharide (LPS)-mediated macrophage activation and acute lung injury (ALI). In this study, we found that a small molecule, wedelolactone (WED), targeted sEH and led to macrophage inactivation. Through the molecular interaction with amino acids Phe362 and Gln384, WED suppressed sEH activity to enhance levels of EETs, thus attenuating inflammation and oxidative stress by regulating glycogen synthase kinase 3beta (GSK3β)-mediated nuclear factor-kappa B (NF-κB) and nuclear factor E2-related factor 2 (Nrf2) pathways in vitro. In an LPS-stimulated ALI animal model, pharmacological sEH inhibition by WED or sEH knockout (KO) alleviated pulmonary damage, such as the increase in the alveolar wall thickness and collapse. Additionally, WED or sEH genetic KO both suppressed macrophage activation and attenuated inflammation and oxidative stress in vivo. These findings provided the broader prospects for ALI treatment by targeting sEH to alleviate inflammation and oxidative stress and suggested WED as a natural lead candidate for the development of novel synthetic sEH inhibitors.

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“…creatinine (Cr) and blood urea nitrogen (BUN)) in Cis-induced AKI 29 , 34 , 35 . Therefore, sEH inhibition to enhance the level of EETs has become an attractive strategy to treat diseases related to inflammation, such as AKI and lung injury 36 , 37 .…”

Section: Introductionmentioning

confidence: 99%

Direct targeting of sEH with alisol B alleviated the apoptosis, inflammation, and oxidative stress in cisplatin-induced acute kidney injury

Zhang¹,

Luan²,

Huo³

et al. 2023

Int. J. Biol. Sci.

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Acute kidney injury (AKI) is a pathological condition characterized by a rapid decrease in glomerular filtration rate and nitrogenous waste accumulation during hemodynamic regulation. Alisol B, from Alisma orientale, displays anti-tumor, anti-complement, and anti-inflammatory effects. However, its effect and action mechanism on AKI is still unclear. Herein, alisol B significantly attenuated cisplatin (Cis)-induced renal tubular apoptosis through decreasing expressions levels of cleaved-caspase 3 and cleaved-PARP and the ratio of Bax/Bcl-2 depended on the p53 pathway. Alisol B also alleviated Cis-induced inflammatory response (e.g. the increase of ICAM-1, MCP-1, COX-2, iNOS, IL-6, and TNF-α) and oxidative stress (e.g. the decrease of SOD and GSH, the decrease of HO-1, GCLC, GCLM, and NQO-1) through the NF-κB and Nrf2 pathways. In a target fishing experiment, alisol B bound to soluble epoxide hydrolase (sEH) as a direct cellular target through the hydrogen bond with Gln384, which was further supported by inhibition kinetics and surface plasmon resonance (equilibrium dissociation constant, KD = 1.32 µM). Notably, alisol B enhanced levels of epoxyeicosatrienoic acids and decreased levels of dihydroxyeicosatrienoic acids, indicating that alisol B reduced the sEH activity in vivo. In addition, sEH genetic deletion alleviated Cis-induced AKI and abolished the protective effect of alisol B in Cis-induced AKI as well. These findings indicated that alisol B targeted sEH to alleviate Cis-induced AKI via GSK3β-mediated p53, NF-κB, and Nrf2 signaling pathways and could be used as a potential therapeutic agent in the treatment of AKI.

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Natural soluble epoxide hydrolase inhibitors from Inula britanica and their potential interactions with soluble epoxide hydrolase: Insight from inhibition kinetics and molecular dynamics

Cited by 20 publications

References 55 publications

Inhibition of Soluble Epoxide Hydrolase Activity by Components of Glycyrrhiza uralensis

Inhibition of Soluble Epoxide Hydrolase Activity by Components of Glycyrrhiza uralensis

Macrophage Inactivation by Small Molecule Wedelolactone via Targeting sEH for the Treatment of LPS-Induced Acute Lung Injury

Direct targeting of sEH with alisol B alleviated the apoptosis, inflammation, and oxidative stress in cisplatin-induced acute kidney injury

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