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Inhibition of soluble epoxide hydrolase (sEH) is considered to be an effective treatment for inflammation-related diseases, and small molecules origin from natural products show promising activity against sEH. Two undescribed protostanes, 3β-hydroxy-25-anhydro-alisol F (1) and 3β-hydroxy-alisol G (2) were isolated from Alisma orientale and identified as new sEH inhibitors with IC 50 values of 10.06 and 30.45 μM, respectively. Potential lead compound 1 was determined as an uncompetitive inhibitor against sEH, which had a K i value of 5.13 μM. In-depth molecular docking and molecular dynamics simulations revealed that amino acid residue Ser374 plays an important role in the inhibition of 1, which also provides an idea for the development of sEH inhibitors based on protostane-type triterpenoids., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Soluble epoxide hydrolase (sEH) is an α/β hydrolase fold protein and widely distributed in numerous organs including the liver, kidney, and brain. The inhibition of sEH can effectively maintain endogenous epoxyeicosatrienoic acids (EETs) levels and reduce dihydroxyeicosatrienoic acids (DHETs) levels, resulting in therapeutic potentials for cardiovascular, central nervous system, and metabolic diseases. Therefore, since the beginning of this century, the development of sEH inhibitors is a hot research topic. A variety of potent sEH inhibitors have been developed by chemical synthesis or isolated from natural sources. In this review, we mainly summarized the interconnected aspects of sEH with cardiovascular, central nervous system, and metabolic diseases and then focus on representative inhibitors, which would provide some useful guidance for the future development of potential sEH inhibitors.

The phytochemical investigation of Andrographis paniculata resulted in the isolation of a novel 15-spiro diterpenoid dimer bisandrographolide G (1). Its structure was determined by 1D and 2D NMR, HRESIMS, electronic circular dichroism (ECD), and TD DFT calculations of ECD spectra. It showed potent inhibitory activity against human carboxylesterase 2 (CES 2) with an IC 50 value of 4.61 ± 0.23 μM, and it was defined as a mixed-competitive type inhibitor with a Ki value of 8.88 μM based on the inhibition kinetics result. This finding gave us a hit to develop new generation of human CES 2 inhibitors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The inhibition of soluble epoxide hydrolase (sEH) is a promising therapeutic approach to treat inflammation and other disorders. In our present investigation on searching for sEH inhibitors from traditional Chinese medicines, we found that Alisma orientale displayed inhibition of sEH. We constructed a small library of protostane-type triterpenoids (1-25) isolated from A. orientale, and screened their inhibitory activities. Alismanin B (1), 11-deoxy-25-anhydro alisol E (4), 11-deoxy alisol B (5), and 25-O-ethyl alisol A (15) displayed concentration-dependently inhibitory activities against sEH with IC 50 values from 3.40 ± 0.57 μM to 9.57 ± 0.88 μM. 11-Deoxy-25-anhydro alisol E (4) and 11-deoxy alisol B (5) were defined as mixed-type competitive inhibitors with Ki values of 12.6 and 3.48 μM, respectively, based on the result of inhibition kinetics. The potential interaction mechanism of 11-deoxy alisol B (5) with sEH was analyzed by molecular docking and molecular dynamics, revealing that amino acid residues Trp336 and Tyr466 were vital for its inhibitory activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

β-Glucuronidase plays a vital role in the metabolism of drugs and endogenous substance. Herein, we assayed the inhibitory effects of thirty-six flavonoids (1-36) toward β-glucuronidase (Escherichia coli) using the probe reaction of DDAO-glu hydrolysis. The results showed that kushenol X (6), (2S)-farrerol (10), 5,7,2'-trihydroxy-8,6'-dimethoxy flavone (20), demethylbellidifolin (31), and gentisin (32) exhibited potent inhibitory activities toward β-glucuronidase with the IC 50 values of 2.07 ± 0.26, 8.95 ± 0.74, 4.97 ± 0.61, 0.91 ± 0.11, and 0.68 ± 0.10 μM, respectively. Furthermore, the inhibition kinetics studies indicated that demethylbellidifolin (31) and gentisin (32) exhibited mixed-type inhibiton toward β-glucuronidase, the K i values were caculated to be 4.05 and 2.02 μM, respectively. Additionally, the circular change of dichroism (CD) spectrum verified the interaction between demethylbellidifolin (31) and gentisin (32) with β-glucuronidase; following by the molecular docking and molecular dynamics further revealed the potential interaction amino acid site in β-glucuronidase. All our findings not only developed some potent novel β-glucuronidase inhibitors but also indicated the potential herb drug interaction (HDI) effects of flavonoids with some clinical drugs which had enterohepatic circulation and further revealed the vital pharamcophoric requirement of natural flavonoids for β-glucuronidase inhibition activity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

As a part of our searching for natural human carboxylesterase 2 (human CES 2) inhibitors from traditional Chinese medicine, we found that the extract of Alisma orientale significantly inhibited human CES 2 in vitro. The investigation on A. orientale led to the isolation of a new protostane-type triterpenoid alismanin I (1). Its structure was determined according to HRESIMS, 1D and 2D NMR spectra. Alismanin I (1) displayed significantly inhibitory activity against human CES 2 with IC 50 value of 1.31 ± 0.09 μM assayed by human CES 2-mediated DDAB hydrolysis. According to its inhibition kinetic result, compound 1 was a noncompetitive type inhibitor, and its Ki was 3.65 μM. Its inhibitory effect was confirmed in living cell level through a visual manner. The potential interaction mechanism of compound 1 with human CES 2 was also analyzed by circular dichroism (CD) spectrum and molecular docking., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In our search for natural human carboxylesterase 2 (hCE 2) inhibitors from natural products, we investigated inhibitory effects and mechanisms of flavonoids (1-16) against hCE 2. The results demonstrated that kurarinone (1), baicalein (2), 2-[(2'-(1-hydroxy-1-methylethyl)-7'-(3-methyl-2-butenyl)-2',3'-dihydrobenzofuran)-5-yl]-7-hydroxy-8-(3-methyl-2-butenyl)chroman-4-one (5), luteolin (6), kushenol X (9), and kushenol C (11) displayed significantly inhibitory effects against hCE 2 with IC 50 values of 1.46 ± 0.43, 5.22 ± 0.89, 1.13 ± 0.19, 9.78 ± 0.98, 3.05 ± 0.46, and 2.61 ± 0.52 μM, respectively. Compounds 1, 5, 6, 9, and 11 were all uncompetitive inhibitors with Ki values of 1.73, 1.59, 16.89, 1.72, and 0.79 μM, respectively, and their Km values ranged from 2.08 μM to 5.41 μM. Furthermore, molecular docking was conducted for investigating mechanisms of compounds 1, 5, 6, 9, and 11 with hCE 2. These results suggested that compounds 1, 5, 6, 9, and 11 could be served as lead compounds for the development of novel hCE 2 inhibitors., (Copyright © 2019. Published by Elsevier B.V.)

Background: Carboxylesterases (CEs) belong to the serine hydrolase family, and are in charge of hydrolyzing chemicals with carboxylic acid ester and amide functional groups via Ser-His-Glu. Uncaria rhynchophylla (Miq.) Miq. ex Havil. is a famous traditional Chinese medicine used in managing hyperpyrexia, epilepsy, preeclampsia, and hypertension in China., Hypothesis/purpose: To discover the potential natural human carboxylesterase 2 (hCE 2) inhibitors from U. rhynchophylla., Methods: Compounds were obtained from the hooks of U. rhynchophylla by silica gel and preparative HPLC. Their structures were elucidated by using HRESIMS, 1D and 2D NMR spectra. Their inhibitory activeties and inhibition kinetics against hCE 2 were assayed by the fluorescent probe, and potential mechanisms were also investigated by molecular docking., Results: Twenty-three compounds, including a new phenolic acid uncariarhyine A (1), eight known triterpenoids (2-9), and ten known aromatic derivatives (10, 13-16, and 19-23), were isolated from U. rhynchophylla. Compounds 1-5, 7, 9, and 15 showed significant inhibitory activities against hCE 2 with IC 50 values from 4.01  ± 0.61 µM to 18.60 ± 0.21 µM, and their inhibition kinetic analysis results revealed that compounds 1, 5, 9, and 15 were non-competitive; compounds 3 and 4 were mixed-type, and compounds 2 and 7 were uncompetitive. Molecular docking studies indicated inhibition mechanisms of compounds 1-5, 7, 9, and 15 against hCE 2., Conclusion: Our present findings highlight potential natural hCE 2 inhibitors from U. rhynchophylla., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

The inhibition of soluble epoxide hydrolase (sEH) is a promising therapeutic approach to treat inflammation and other disorders. In our present investigation on searching for sEH inhibitors from traditional Chinese medicines, we found that Alisma orientale displayed inhibition of sEH. We constructed a small library of protostane-type triterpenoids (1-25) isolated from A. orientale, and screened their inhibitory activities. Alismanin B (1), 11-deoxy-25-anhydro alisol E (4), 11-deoxy alisol B (5), and 25-O-ethyl alisol A (15) displayed concentration-dependently inhibitory activities against sEH with IC50 values from 3.40 ± 0.57 μM to 9.57 ± 0.88 μM. 11-Deoxy-25-anhydro alisol E (4) and 11-deoxy alisol B (5) were defined as mixed-type competitive inhibitors with Ki values of 12.6 and 3.48 μM, respectively, based on the result of inhibition kinetics. The potential interaction mechanism of 11-deoxy alisol B (5) with sEH was analyzed by molecular docking and molecular dynamics, revealing that amino acid residues Trp336 and Tyr466 were vital for its inhibitory activity.