Soluble Epoxide Hydrolase Inhibitory Activity Research Articles

Tinospora cordifolia ameliorates paclitaxel-induced neuropathic pain in albino rats

Ethnopharmacological relevanceTinospora cordifolia (T. cordifolia) (Willd.) Miers, a member of the Menispermaceae, family documented in the ancient textbooks of the Ayurveda System of Medicine, has been used in the management of sciatica pain and diabetic neuropathy. AimThe study has been designed to evaluate the antinociceptive potential of various extracts of T. cordifolia stem in Paclitaxel (PT)-generated neuropathic pain model in albino rats and explore its possible mechanism employing molecular docking studies. MethodsStems of T. cordifolia were shade dried, grinded in fine powder, and extracted separately with different solvents viz. ethanol, water & hydro-alcoholic and characterized using LCMS/MS. The antinociceptive property of T. cordifolia stem (200 and 400 mg/kg) was examined in albino rats using a PT-induced neuropathic pain model. Further, the effect of these extracts was also observed using different behavioral assays viz. cold allodynia, mechanical hyperalgesia (pin-prick test), locomotor activity test, walking track test, and Sciatic Functional Index (SFI) in rats. Tissue lysate of the sciatic nerve was used to determine various biochemical markers such as GSH, SOD, TBARS, tissue protein, and nitrite. Further to explore the possible mechanism of action, the most abundant and therapeutically active compounds available in aqueous extract were analyzed for binding affinity towards soluble epoxide hydrolase (sEH) enzyme (PDB ID: 3wk4) employing molecular docking studies. ResultsThe results of the LCMS/MS study of different extracts of T. cordifolia indicated presence of alkaloids, glycosides, terpenoids, sterols and sugars such as amritoside A, tinocordin, magnoflorine, N-methylcoclaurine, coridine, 20β-hydroxyecdysone and menaquinone-7 palmatin, cordifolioside A and tinosporine etc. Among all the three extracts, the hydroalcoholic extract (400 mg/kg) showed the highest response followed by aqueous and ethanolic extracts as evident in in vivo behavioral and biochemical evaluations. Furthermore, docking studies also exposed that these compounds viz. N-methylcoclaurine tinosporin, palmatine, tinocordin, 20β-hydroxyecdysone, and coridine exhibited well to excellent affinity towards target sEH protein. ConclusionT. cordifolia stem could alleviate neuropathic pain via soluble epoxide hydrolase inhibitory activity.

Isolation of bioactive components with soluble epoxide hydrolase inhibitory activity from Stachys sieboldii MiQ. by ultrasonic-assisted extraction optimized using response surface methodology

Stachys sieboldii MiQ (SSM) is an important food and medicinal herb in Korea, used to improve memory of patients with senile dementia and cardiovascular diseases. However, little information on bioactive components from SSM or standardized extraction methods for these components is available. This study isolated and purified major components from SSM for the first time, and assessed their ability to inhibit soluble epoxide hydrolase (sEH). The results showed that acteoside is the most potent inhibitor of sEH, with an IC50 of 33.5 ± 0.5 μM. Additional active components, including harpagide, tryptophan, and 8-acetate-harpagide, along with acteoside, were tentatively identified using high‐performance liquid chromatography photodiode array tandem mass spectrometry (HPLC–PDA–MS/MS) and quantified using an ultraviolet detector at 210 nm. Further, an ultrasonic-assisted extraction technique for extraction of four bioactive compounds in SSM was developed and optimized using response surface methodology (RSM). The optimal extraction conditions were: extraction time, 30.46 minutes; extraction temperature, 67.95 °C, and methanol concentration 53.85%. The prediction model of RSM was validated with laboratory experiments. The similarity between predicted and actual values was 97.84%. The extraction method is thus a rapid, environment-friendly, energy-saving method can be applied to extract bioactive components from SSM in large quantities.

Coumarin and Moracin Derivatives from Mulberry Leaves (Morus alba L.) with Soluble Epoxide Hydrolase Inhibitory Activity.

This study identified three coumarins (1–3), and six moracin derivatives (4–9). The structures of these natural compounds were determined by the spectroscopic methods, including 1D and 2D NMR methods, and comparison with previous reported data. All of the isolated compounds were assessed for the effects on the soluble epoxide hydrolase (sEH) inhibitory activity. Among them, compounds 1–7 exhibited significant inhibitory effect with 100% inhibitory, with IC50 values of 6.9, 0.2, 15.9, 1.1, 1.2, 9.9, and 7.7 µM, respectively. A kinetic study revealed that compounds 1–4, and 6 were competitive types of inhibitors, compounds 5 and 7 were mixed types of inhibitors. These results suggest that moracin and coumarin derivatives from mulberry leaves are significant sEH inhibitors.

Nitro derivatives and other compounds from sugar apple (Annona squamosa L.) leaves exhibit soluble epoxide hydrolase inhibitory activity

A phytochemical study for the MeOH extract of Annona squamosa leaves led to the isolation of seven compounds. Among them there were two nitro derivative compounds (1 and 2), two phenolic glucoside compounds (3 and 4), and three sesquiterpenes (5‒7). The structures of these natural compounds were determined by the spectroscopic methods including 1D and 2D NMR methods. All the isolated compounds were assessed for the effects on the sEH inhibitory activity; of all the compounds, thalictoside (1) and arabinothalictoside (2) displayed strong inhibition of sEH activities with IC50 value of 20.2 µM and 47.1 µM, respectively. A kinetic analysis of compounds 1 and 2 revealed that both of them were competitive inhibitory action. The molecular docking increases our understanding of receptor‒ligand binding of all compounds. These results suggested that nitro derivatives from Annona squamosa leaves are potential sEH inhibitors.

Anti-bacterial effects of components from Sanguisorba officinalis L. on Vibrio vulnificus and their soluble epoxide hydrolase inhibitory activity

Sanguisorba officinalis L. is a traditional herbal medicine, which is prevailingly applied to cure hemorrhoids, wounds and ulcers in Eastern Asian countries. The purpose of this study was to investigate the antibacterial and soluble epoxide hydrolase (sEH) inhibitory effects of the extracts and components from S. officinalis. The methanol extract was divided into ethyl acetate (EtOAc), n-butanol (n-BuOH), and water layers. In our screening procedure, the EtOAc and n-BuOH extracts and compounds (1–2) remarkably suppressed the growth of V. vulnificus in a dose-dependent manner. In addition, the EtOAc extract and compound 1 exhibited significant inhibitory effect on the V. vulnificus induced cytotoxicity on HeLa cells. Furthermore, compound 4 displayed an inhibition against sEH with an IC50 value of 7.0 ± 0.5 μM. A kinetic analysis demonstrated that the inhibitory effect of compound 4 was a mixed type, with an inhibitory constant (Ki) 0.22 ± 0.0 μM.

Soluble epoxide hydrolase inhibitory activity of phenolic glycosides from Polygala tenuifolia and in silico approach

The goal of this study was to identify soluble epoxide hydrolase (sEH) inhibitors from plants. Our efforts led to the isolation of nine phenolic glycosides 1–9 from the roots of Polygala tenuifolia Willd. The structures of compounds were determined by spectroscopic methods, including mass spectroscopy and one-dimensional and two-dimensional nuclear magnetic resonance, and compared with published data. All the isolated compounds were evaluated for their inhibitory activity against sEH. The IC50 values for inhibition ranged 6.4 ± 0.4 to 27.2 ± 0.3 µM. Inhibitors 2–9 were confirmed the interaction with receptor as competitive type. Molecular docking demonstrated that inhibitors 2–9 could bind sufficiently to the right pocket. Additionally, potential inhibitors (5, 6, and 8) were confirmed to show the flexible movement with the protein in these sites of receptor.

Prenyl-flavonoids from Epimedium koreanum Nakai and their soluble epoxide hydrolase and tyrosinase inhibitory activities

A new 8-prenyl-flavonoid, epimedokoreanoside III, and 11 other flavonoids, were isolated from the aerial parts of Epimedium koreanum Nakai. Their chemical structures were elucidated by nuclear magnetic resonance and mass analyzes. All isolates were evaluated for their soluble epoxide hydrolase and tyrosinase inhibitory activities. Among the isolates, compounds 1, 5, 9, 10, and 12 exerted soluble epoxide hydrolase inhibitory activity in dose-dependent manner, with IC50 values ranging from 26.0 ± 1.2 to 37.6 ± 1.0 µM, whereas compounds 4 and 9 showed potent inhibition of tyrosinase in a dose-dependent manner, having IC50 values of 16.8 ± 2.7 and 8.7 ± 2.7 µM, respectively.

Soluble epoxide hydrolase inhibitory activity of components from Leonurus japonicus

One new compound, 10-methoxy-leonurine (1), and four known compounds (2-5) were purified by silica gel, C-18, and Sephadex LH-20 column chromatography from Leonurus japonicus. Their structures were elucidated using one-dimensional (1D)/two-dimensional (2D)-nuclear magnetic resonance (NMR), high-resolution (HR)-electrospray ionization (ESI) mass spectrometry (MS). The compounds were evaluated to determine their inhibition of the catalysis of soluble epoxide hydrolase (sEH). According to the results from in vitro analyses, compounds 1 and 2, which contain guanidine and flavonoid (3), were determined to be potential inhibitors of this enzyme. All compounds were revealed to be non-competitive inhibitors according to Lineweaver-Burk plots. Furthermore, in silico molecular docking indicated that compounds 1-3 are bound to sEH in a similar fashion and have stable binding energies, as calculated by AutoDock 4.2. Molecular dynamics determined the root-mean-square deviation (RMSD), total energy, RMS fluctuation (RMSF), hydrogen bonds, and distance of the complex according to time.

Coumarins Isolated from Murraya paniculata in Vietnam and Their Inhibitory Effects against Enzyme Soluble Epoxide Hydrolase (sEH)

In the search for bioactive constituents from Vietnam medicinal plants, the leaves and stems of Murraya paniculata collected in HoaBinh Province, Vietnam were selected for chemical investigation. From the n-hexane fraction, two sterols, including β-sitosterol (6) and stigmasterol (7), and from the chloroform fraction, five coumarins, including mexoticin (1), omphalocarpin (2), murrangatin (3), kimcuongin (4), and murracarpin (5), were obtained. The structures of the isolated compounds were determined from ESI-MS, HR-ESI-MS, and NMR (1D and 2D) spectroscopic data. Coumarins (1–5) were elucidated for inhibitory effects against soluble epoxide hydrolase. Among them, coumarins (2–4) showed soluble epoxide hydrolase inhibitory activity with IC50 values 2.2 ± 4.7, 13.9 ± 6.5, and 3.2 ± 4.5 µM, respectively. A kinetic study of the five coumarins revealed the noncompetitive enzymatic mode for 3 and 4, and a mixture of competitive/noncompetitive enzymatic modes for coumarin 2. Using molecular modelling, the coumarin kimcuongin (4) showed the best binding outline into active sites of human soluble epoxide hydrolase.

Soluble epoxide hydrolase inhibitory activity of anthraquinone components from Aloe

Soluble epoxide hydrolase inhibitory activity of anthraquinone components from Aloe

Soluble epoxide hydrolase inhibitory activity by rhizomes of Kaempferia parviflora Wall. ex Baker

In our search for natural soluble epoxide hydrolase (sEH) inhibitors from plants, we found that the methanolic extract of the rhizomes of Kaempferia parviflora Wall. ex Baker (Zingiberaceae) significantly inhibits sEH in vitro. In a phytochemical investigation of dichloromethane fraction of K. parviflora rhizomes, we isolated sixteen compounds (1–16), including flavonoid derivatives (1–12), anthraquinones (13 and 14), triterpene (15), and triterpene glycoside (16). The structures of the isolated compounds were established in an extensive 1D and 2D NMR, as well as MS analysis. The sEH inhibitory activities of all isolated compounds were evaluated. Among the isolated flavonoid derivatives, 4, 6, 8, 10, and 12 were identified as potent inhibitors of sEH, with IC50 values ranging from 0.9 ± 0.1 to 4.5 ± 0.1 μM. In addition, a kinetic analysis of the flavonoid derivatives (1–12) revealed that the inhibitory activity of flavonoid derivatives 1–4 and 6–12 is mixed with K i values ranging from 0.1 ± 0.0 to 14.3 ± 0.3 μM, whereas compound 8 was a non-competitive with K i = 0.3 ± 0.0 μM. These findings suggest that flavonoid derivatives from K. parviflora rhizomes are potential novel sEH inhibitors.

Alkylphloroglucinol derivatives and triterpenoids with soluble epoxide hydrolase inhibitory activity from Callistemon citrinus

Phytochemical analysis of the leaves and stems of Callistemon citrinus (Curtis) Skeels led to the isolation of two new alkylphloroglucinols, gallomyrtucommulone E and F (1 and 2), along with four other known alkylphloroglucinol derivatives, gallomyrtucommulone A (3), endoperoxide G3 (4), myrtucommulone B (5), callistenone B (6) and five known triterpenoids, including betulinic acid (7), 3β-acetylmorolic acid (8), 3β-hydroxy-urs-11-en-13(28)-olide (9), diospyrolide (10) and ursolic acid (11). The structures of the natural compounds were determined from the spectroscopic evidences including 1D-/2D-NMR and HR-MS spectrometry. All the isolated compounds were assessed for the effects on the sEH inhibitory activity. The acylphloroglucinols myrtucommulone B (5)/callistenone B (6) (in mixture), and two triterpenoids, ursolic acid (11) and 3β-hydroxy-urs-11-en-13(28)-olide (9) displayed strong inhibition of sEH activity, with IC50 values of 0.7, 11.2 and 24.8μM, respectively.

Soluble epoxide hydrolase inhibitory activity of anthraquinone components from Aloe

Aloe is a short-stemmed succulent herb widely used in traditional medicine to treat various diseases and as raw material in cosmetics and heath foods. In this study, we isolated and identified two new anthraquinone derivatives, aloinoside C (6) and aloinoside D (7), together with six known compounds from an aqueous dissolved Aloe exudate. Their structures were identified by spectroscopic analysis. The inhibitory effects of the isolated compounds on soluble epoxide hydrolase (sEH) were evaluated. Compounds 1–8 inhibited sEH activity potently, with IC50 values ranging from 4.1±0.6 to 41.1±4.2μM. A kinetic analysis of compounds 1–8 revealed that the inhibitory actions of compounds 1, 6 and 8 were non-competitive, whereas those of compounds 2–5 and 7 were the mixed-type. Molecular docking increases our understanding of receptor–ligand binding of all compounds. These results demonstrate that compounds 1–8 from Aloe are potential sEH inhibitors.

Soluble epoxide hydrolase inhibitory activity of phenolic components from the rhizomes and roots of Gentiana scabra.

Two new (1 and 2) and seven known phenolic compounds were isolated from a methanol extract of the rhizomes and roots of Gentiana scabra. Their structures were identified by spectroscopic analysis and comparing with reported values. The inhibitory effects of each compound on soluble epoxide hydrolase (sEH) were evaluated. Among them, compounds 2, 6, and 9 potently inhibited sEH activity.

Chemical constituents from the root of Polygonum multiflorum and their soluble epoxide hydrolase inhibitory activity.

Fourteen compounds were isolated from a methanol extract of Polygonum multiflorum roots, and their structures were elucidated by comparing spectroscopic data to published spectra. The inhibitory effects of the isolated compounds on soluble epoxide hydrolase (sEH) were then evaluated. Compounds 1-7 inhibited sEH activity potently, with IC50 values ranging from 6.2 ± 0.5 to 48.6 ± 3.1 μM. Moreover, a kinetic analysis of compounds 1-7 revealed that the inhibitory actions of compounds 1, 3 and 4 were non-competitive, whereas those of compounds 2 and 5-7 were mixed-type.

Sorafenib has soluble epoxide hydrolase inhibitory activity, which contributes to its effect profile in vivo

The advent of multikinase inhibitors targeting the vascular endothelial growth factor (VEGF) receptor has revolutionized the treatment of highly angiogenic malignancies such as renal cell carcinoma. Interestingly, several such inhibitors are commercially available, and they each possess diverse specific beneficial and adverse effect profiles. In examining the structure of sorafenib, it was hypothesized that this compound would possess inhibitory effects on the soluble epoxide hydrolase, an enzyme with pleiotropic effects on inflammation and vascular disease. We now show that sorafenib but not another VEGF receptor targeted inhibitor sunitinib is a potent inhibitor of the human soluble epoxide hydrolase in vitro (K(I) = 17 +/- 4 nmol/L). Furthermore, sorafenib causes the expected in vivo shift in oxylipid profile resulting from soluble epoxide hydrolase inhibition, evidence of a reduction in the acute inflammatory response. Lipopolysaccharide-induced hypotension was reversed with sorafenib but not sunitinib treatment, suggesting that soluble epoxide hydrolase inhibition accounts for at least part of the anti-inflammatory effect of sorafenib. The pharmacokinetic studies presented here in light of the known potency of sorafenib as a soluble epoxide hydrolase inhibitor indicate that the soluble epoxide hydrolase will be largely inhibited at therapeutic doses of sorafenib. Thus, it is likely that soluble epoxide hydrolase inhibition contributes to the beneficial effects from the inhibition of the VEGF receptor and other kinases during treatment with sorafenib.