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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]

Background: Depression is a pervasive or persistent mental disorder that causes mood, cognitive and memory deficits. Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history, although its efficacy and potential mechanism are still uncertain.Purpose: The present study aimed to investigate anti-depression effect and potential mechanism of U. rhynchophylla extract (URE).Study Design and Methods: A mouse depression model was established using unpredictable chronic mild stress (UCMS). Effects of URE on depression-like behaviours, neurotransmitters, and neuroendocrine hormones were investigated in UCMS-induced mice. The potential target of URE was analyzed by transcriptomics and bioinformatics methods and validated by RT-PCR and Western blot. The agonistic effect on 5-HT1A receptor was assayed by dual-luciferase reporter system.Results: URE ameliorated depression-like behaviours, and modulated levels of neurotransmitters and neuroendocrine hormones, including 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), corticosterone (CORT), corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH), in UCMS-induced mice. Transcriptomics and bioinformatics results indicated that URE could regulate glutamatergic, cholinergic, serotonergic, and GABAergic systems, especially neuroactive ligand-receptor and cAMP signaling pathways, revealing that Htr1a encoding 5-HT1A receptor was a potential target of URE. The expression levels of downstream proteins of 5-HT1A signaling pathway 5-HT1A, CREB, BDNF, and PKA were increased in UCMS-induced mice after URE administration, and URE also displayed an agonistic effect against 5-HT1A receptor with an EC50 value of 17.42 μg/ml.Conclusion: U. rhynchophylla ameliorated depression-like behaviours in UCMS-induced mice through activating 5-HT1A receptor. [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]

• Sidestep cutting is important in sports, but there is no consensus on its biomechanical study. • Kinematics, kinetics and muscle forces were computed using OpenSim. • Athletic performance was affected by limb dominance and movement direction. • Limb dominance and movement direction should be considered to reduce the risk of injury. Sidestep cutting is a critical movement in sports. However, biomechanical research on sidestep cutting has not hitherto reached a consensus. In order to investigate the effects of limb dominance and movement direction on ankle and subtalar joints during sidestep cutting, twelve physically active male participants were recruited in the present study. Trajectory and ground reaction force data were collected by the motion capture system and force platform. Kinematics, kinetics, and muscle forces information were obtained by running OpenSim. Two-way repeated measures ANOVA was performed with movement direction and limb dominance as independent variables. We found that movement direction had a significant effect on ankle dorsiflexion angle. In contrast, the factor of limb dominance had no effect on ankle and subtalar joints angles. For ankle joint moment, the plantarflexion moment was greater by performing a 45° sidestep cutting or using the dominant limb, while the subtalar joint moment was not affected by these two variables. In terms of muscle forces, the soleus of the dominant limb generated greater plantarflexion muscle force on the sagittal plane, while the non-dominant limb tended to contract more strongly (peroneus longus and peroneus brevis) on the frontal plane to stabilize the subtalar joint. Meanwhile, a smaller sidestep cutting angle made participants generate greater plantarflexion muscle forces (soleus and gastrocnemius). In conclusion, our findings indicated that participants should take limb dominance and movement direction into consideration for enhancing athletic performance and reducing the risk of injury during sidestep cutting. [ABSTRACT FROM AUTHOR]