Search

Main observation and conclusion: The investigation of Morinda officinalis led to the isolation of twelve compounds (1—12), including three new iridoid glycosides morindalins A—C (1—3) and nine known compounds (4—12). Their structural identifications were conducted using HRMS, 1D and 2D NMR, and electronic circular dichroism (ECD) spectra as well as quantum chemical computations. Compound 6 displayed the most significantly agonistic activity against farnesoid X receptor (FXR) with an EC50 value of 7.18 μM, and its agonistic effect was verified through the investigation of FXR downstream target genes including small heterodimer partner 1 (SHP1), bile salt export pump (BSEP), and organic solute transporter subunit alpha and beta (OSTα and OSTβ). The potential interaction of compound 6 with FXR was analyzed by molecular docking and molecular dynamics stimulation, revealing that amino acid residues Leu287, Thr288, and Ser332 played a crucial role in the activation of compound 6 towards FXR. These findings suggested that compound 6 could be regarded as a potential candidate for the development of FXR agonists. [ABSTRACT FROM AUTHOR]

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), (2 S)-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. • The inhibitory effects of 36 kind nature flavonoids toward β -Glucuronidase were assayed; • The mixed-type inhibition behaviour and inhibition parameter was illustrated and obtained by inhibition kinetics; • The potential interaction between flavonoids and β -Glucuronidase were illustrated by molecular docking and dynamics; [ABSTRACT FROM AUTHOR]

[Display omitted] • Rare diterpenoid dimers with nonacyclic skeleton were obtained from E. fischeriana. • Novel dimers 1 and 2 exhibited inhibitory activities against soluble epoxide hydrolase. • The inhibition kinetics and molecular dynamics of 1 and 2 with sEH were studied. Two undescribed ent -abietane-type diterpenoid dimers with nonacyclic backbone formed by intermolecular [4 + 2] cycloaddition into a spirocyclic skeleton, bisfischoids A (1) and B (2), along with a known one fischdiabietane A (3), were identified from Euphorbia fischeriana Steud. Their structures were elucidated by extensive spectroscopic analysis, ECD and NMR calculation combined with DP4+ probability analysis, as well as X-ray diffraction. The anti-inflammatory potential of dimers 1 – 3 were examined using their inhibitory effects on soluble epoxide hydrolase (sEH), which revealed that 1 and 2 exhibited promising activities with inhibition constant (K i) of 3.20 and 1.95 μM, respectively. Further studies of molecular docking and molecular dynamics indicated that amino acid residue Tyr343 in the catalytic cavity of sEH was the key site for their inhibitory function. [ABSTRACT FROM AUTHOR]

• A small library of protostane-type triterpenoids (1 – 25) were isolated from A. orientale. • Compounds 1 , 4 , 5 , and 15 showed potential inhibitory activities against sEH. • The interaction of compound 5 with sEH were investigated by molecular docking and dynamics. • The Ki value of compound 5 was 3.48 μM. 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. [ABSTRACT FROM AUTHOR]

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, 3 β -hydroxy-25-anhydro-alisol F (1) and 3 β -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. [ABSTRACT FROM AUTHOR]

Gut bacterial β -glucuronidase (GUS) plays a pivotal role in the metabolism and reactivation of a vast of glucuronide conjugates of both endogenous and xenobiotic compounds in the gastrointestinal tract of human, which has been implicated in certain drug-induced gastrointestinal tract (GI) toxicity in clinic. Inhibitors of gut microbial GUS exhibited great potentials in relieving the drug-induced GI toxicity. In this study, Selaginella tamariscina and its major biflavonoid amentoflavone (AMF) were evaluated for their inhibitory activity against Escherichia coli GUS. Two selective probe substrates for GUS (a specific fluorescent probe substrate for GUS, DDAOG and a classical drug substrate for GUS, SN38G) were used in parallel for charactering the inhibition behaviors. Both the extract of S. tamariscina and its major biflavonoid AMF displayed evident inhibitory effects on GUS, and the IC 50 values of AMF against GUS mediated DDAOG and SN-38G hydrolysis were 0.62 and 0.49 μM, respectively. Inhibition kinetics studies indicated that AMF showed mixed type inhibition for GUS-mediated DDAOG hydrolysis, while displayed competitive type inhibition against GUS-mediated SN-38G hydrolysis, with the K i values of 0.24 and 1.25 μM, respectively. Molecular docking studies and molecular dynamics stimulation results clarified the role of amino acid residues Leu361, Ile363, and Glu413 in the inhibition of AMF on GUS. These results provided some foundations for the potential clinical utility of S. tamariscina and its major biflavonoid AMF for treating drug-induced enteropathy. [Display omitted] • Selaginell a tamariscina extract displayed strong inhibitory effects on GUS. •.►Amentoflavone was identified as the key inhibitory component in S. tamariscina. •.►The inhibition constant and the inhibition mechanism were well-characterized. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases, such as hypertension and cardiac failure, have become the most major and global cause for threatening human health in recent years. Uncaria rhynchophylla as a traditional Chinese medicine is widely used to treat hypertension for a long history, whereas its medicinal effective components and potential action mechanism are uncertain. Therefore, twenty-four alkaloids (1–24) isolated from U. rhynchophylla were assayed for their relaxant effects against phenylephrine (Phe)-induced contraction of rat mesenteric arteries. Among them, we surprisingly found that uncarialin A (21) exhibited most potent relaxation effect against Phe-induced contraction (IC 50 = 0.18 μM) in the manner of independent on endothelium-derived vasorelaxing factors and endothelium. All the experiments including measurement of Ca2+ in vascular smooth muscle cells (VSMCs) by fluorescence microscopy, whole-cell path clamp, molecular docking, and molecular dynamics, demonstrated that uncarialin A (21) could significantly inhibit L-type calcium channel subunit alpha-1C (Cav1.2) via the hydrogen bond interaction with amino acid residue Met1186, allowing the inhibition of Ca2+ inward current. Our results suggested that uncarialin A (21) could be served as a potential L-type Cav1.2 blocker in the effective treatment of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Soluble epoxide hydrolase (sEH) serves as a potential target in inflammation-related diseases. Based on the bioactivity-guided separation, a new sesquiterpenoid inulajaponoid A (1) was isolated from Inula japonica with a sEH inhibitory effect, together with five known compounds, such as 1- O -acetyl-6- O -isobutyrylbritannilactone (2), 6 β -hydroxytomentosin (3), 1 β ,8 β -dihydroxyeudesma-4(15),11(13)-dien-12,6 α -olide (4), (4 S ,6 S ,7 S ,8 R)-1- O -acetyl-6- O -(3-methylvaleryloxy)-britannilactone (5), and 1-acetoxy-6 α -(2-methylbutyryl)eriolanolide (6). Among them, compounds 1 and 6 were assigned as mixed and uncompetitive inhibitors, respectively. The result of immunoprecipitation (IP)-MS demonstrated the specific binding of compound 6 to sEH in the complex system, which was further confirmed by the fluorescence-based binding assay showing its equilibrium dissociation constant (K d = 2.43 μM). The detail molecular stimulation revealed the mechanism of action of compound 6 with sEH through the hydrogen bond of amino acid residue Gln384. Furthermore, this natural sEH inhibitor (6) could suppress the MAPK/NF-κB activation to regulate inflammatory mediators, such as NO, TNF-α, and IL-6, which confirmed the anti-inflammatory effect of inhibition of sEH by 6. These findings provided a useful insight to develop sEH inhibitors upon the sesquiterpenoids. [ABSTRACT FROM AUTHOR]

Soluble epoxide hydrolase (sEH) is a potential drug target to treat inflammation and neurodegenerative diseases. In this study, we found that the extract of Inula britanica exhibited significantly inhibitory effects against sEH, therefore, we investigated its phytochemical constituents to obtain seven new compounds together with sixteen known ones (1-20), including two pairs of novel enantiomers, (2S,3S)-britanicafanin A (1a), (2R,3R)-britanicafanin A (1b), (2R,3S)-britanicafanin B (2a), and (2S,3R)-britanicafanin B (2b), and three new lignans britanicafanins C-E (3–5). Their structures were determined by HRESIMS, 1D and 2D NMR, and electronic circular dichroism (ECD) spectra as well as quantum chemical computations. All the isolates were evaluated for their inhibitory effects against sEH, compounds 1 – 3 , 5 – 7 , 9 , 10 , 13 , 14 , and 17 – 20 showed significant inhibitory effects against sEH with IC 50 values from 3.56 μM to 26.93 μM. The inhibition kinetics results indicated that compounds 9 , 10 , 13 , and 19 were all uncompetitive inhibitors, and their inhibition constants (K i) values were 7.11, 1.99, 4.06, and 8.78 μM, respectively. Their potential interactions were analyzed by molecular docking and molecular dynamics (MD), which suggested that amino acid residues Asp335 and Asn359, especially Gln384, played an important role in the inhibition of compounds 10 and 13 on sEH, and compounds 10 and 13 could be considered as the potential candidates for the development of sEH inhibitors. • Seven new lignans together with 16 known ones were obtained from I. britanica. • Some of the isolates showed inhibitory effects against sEH with potential. • The inhibition kinetics and molecular dynamics of active compounds with sEH were studied. [ABSTRACT FROM AUTHOR]