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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]

Intestinal commensal fungi are vital to human health, and their metabolites play a key role in the reciprocal relationship. In the present work, eighteen alkaloids and seven monoterpenoids were isolated from the fermentation of the human intestinal fungus Penicillium oxalicum SL2, including seven undescribed alkaloids (penicilloxalines A-G), three undescribed monoterpenoids (penicilloxalines H-J), and fifteen reported compounds. The structures of the isolated compounds were identified by HRESIMS, 1D and 2D NMR, electronic circular dichroism spectra and quantum chemical calculations. Some metabolites displayed moderate agonistic effects against the pregnane X receptor (PXR), whereas (6 R)3,7-dimethyl-6,7-dihydroxy-2(Z)-octenoic acid displayed a significant agonistic effect against the farnesoid X receptor (FXR) with an EC 50 value of 0.43 μ M, which was verified by investigating FXR downstream target genes and proteins, such as small heterodimer partner 1 (SHP1), fibroblast growth factor (FGF), and bile salt export pump (BSEP). 25 metabolites were identified from the human intestinal fungus Penicillium oxalicum SL2. [Display omitted] • Twenty-five metabolites were obtained from gut fungus Penicillium oxalicum. • Seven undescribed alkaloids (penicilloxalines A-G) were identified. • Three undescribed monoterpenoids (penicilloxalines H-J) were identified. • Some metabolites activated pregnane X receptor significantly. • One metabolite displayed agonistic effect against FXR (EC 50 0.43 μM). [ABSTRACT FROM AUTHOR]

Farnesoid X receptor (FXR) is a key regulator in charge of bile acid synthesis, transport, and metabolism. Activation of FXR represses bile acid synthesis and increases its excretion and transport, consequently protecting the liver functions. Thus, FXR is considered as a critical therapeutic target of cholestasis and nonalcoholic steatohepatitis. Herein, we isolated and identified fourteen new protostane-type triterpenoids (1–14) and four known analogues (15–18) from Alisma orientale , and finally constructed a small library of protostane-type triterpenoids (1–70) to investigate their structure-activity relationship with FXR, further leading to obtain compound 15 with potent agonistic activity against FXR (EC 50 = 90 nM). Extensive in vitro investigation confirmed high efficacy of compound 15 against FXR in living cell, and revealed its underlying mechanism for FXR activation (amino acid residues Arg331 and Ser332) by molecular docking and site-directed mutagenesis technology. Image 1 • Fourteen new protostane-type triterpenoids were isolated from A. orientale. • The structure-activity relationship of protostanes with FXR was investigated. • Compound 15 displayed potent agonistic activity against FXR (EC 50 = 90 nM). • High efficacy of compound 15 against FXR in living cell was confirmed. • Compound 15 had interaction with amino acid residues Arg331 and Ser332 of FXR. [ABSTRACT FROM AUTHOR]