Uric acid-lowering effect of harpagoside and its protective effect against hyperuricemia-induced renal injury in mice.

Hyperuricemia (HUA) is caused by increased synthesis and/or insufficient excretion of uric acid (UA). Long-lasting HUA may lead to a number of diseases including gout and kidney injury. Harpagoside (Harp) is a bioactive compound with potent anti-inflammatory activity from the roots of Scrophularia ningpoensis. Nevertheless, its potential effect on HUA was not reported. The anti-HUA and nephroprotective effects of Harp on HUA mice were assessed by biochemical and histological analysis. The proteins responsible for UA production and transportation were investigated to figure out its anti-HUA mechanism, while proteins related to NF-κB/NLRP3 pathway were evaluated to reveal its nephroprotective mechanism. The safety was evaluated by testing its effect on body weight and organ coefficients. The results showed that Harp significantly reduced the SUA level and protected the kidney against HUA-induced injury but had no negative effect on safety. Mechanistically, Harp significantly reduced UA production by acting as inhibitors of xanthine oxidase (XOD) and adenosine deaminase (ADA) and decreased UA excretion by acting as activators of ABCG2, OAT1 and inhibitors of GLUT9 and URAT1. Moreover, Harp markedly reduced infiltration of inflammatory cells and down-regulated expressions of TNF-α, NF-κB, NLRP3 and IL-1ß in the kidney. Harp was a promising anti-HUA agent.

Phomopsterone B Alleviates Liver Fibrosis through mTOR-Mediated Autophagy and Apoptosis Pathway.

Liver fibrosis is the initial pathological process of many chronic liver diseases. Targeting hepatic stellate cell (HSC) activation is an available strategy for the therapy of liver fibrosis. We aimed to explore the anti-liver fibrosis activity and potential mechanism of phomopsterone B (PB) in human HSCs. The results showed that PB effectively attenuated the proliferation of TGF-ß1-stimulated LX-2 cells in a concentration-dependent manner at doses of 1, 2, and 4 µM. Quantitative real-time PCR and Western blot assays displayed that PB significantly reduced the expression levels of α-SMA and collagen I/III. AO/EB and Hoechst33342 staining and flow cytometry assays exhibited that PB promoted the cells' apoptosis. Meanwhile, PB diminished the number of autophagic vesicles and vacuolated structures, and the LC3B fluorescent spots indicated that PB could effectively inhibit the accretion of autophagosomes in LX-2 cells. Moreover, rapamycin and MHY1485 were utilized to further investigate the effect of mTOR in autophagy and apoptosis. The results demonstrated that PB regulated autophagy and apoptosis via the mTOR-dependent pathway in LX-2 cells. In summary, this is the first evidence that PB effectively alleviates liver fibrosis in TGF-ß1-stimulated LX-2 cells, and PB may be a promising candidate for the prevention of liver fibrosis.

Three New Selaginellin Derivatives from Selaginella pulvinata and Their α-Glucosidase Inhibitory Activity.

Three new selaginellin derivatives, selaginpulvilins V-X (1-3), together with seven known analogs (4-10) were isolated from whole plants of Selaginella pulvinata. Their structures were determined by extensive spectroscopic methods including 1D and 2D NMR, HR-ESI-MS and chemical derivatization method. Compound 1 represents a rare example of naturally occurring selaginellin with an alkynylphenol-trimmed skeleton. Biological evaluation showed that compounds 2, 6 and 8 displayed moderate inhibition against α-glucosidase with IC50 values of 3.71, 2.04 and 4.00 µM, respectively.

Insights into the Inhibitory Mechanism of Viniferifuran on Xanthine Oxidase by Multiple Spectroscopic Techniques and Molecular Docking.

Viniferifuran was investigated for its potential to inhibit the activity of xanthine oxidase (XO), a key enzyme catalyzing xanthine to uric acid. An enzyme kinetics analysis showed that viniferifuran possessed a strong inhibition on XO in a typical anti-competitive manner with an IC50 value of 12.32 µM (IC50 for the first-line clinical drug allopurinol: 29.72 µM). FT-IR and CD data analyses showed that viniferifuran could induce a conformational change of XO with a decrease in the α-helix and increases in the ß-sheet, ß-turn, and random coil structures. A molecular docking analysis revealed that viniferifuran bound to the amino acid residues located within the activity cavity of XO by a strong hydrophobic interaction (for Ser1214, Val1011, Phe914, Phe1009, Leu1014, and Phe649) and hydrogen bonding (for Asn768, Ser876, and Tyr735). These findings suggested that viniferifuran might be a promising XO inhibitor with a favorable mechanism of action.

New Meroterpenoid and Isocoumarins from the Fungus Talaromyces amestolkiae MST1-15 Collected from Coal Area.

Three new compounds including a meroterpenoid (1) and two isocoumarins (8 and 9), together with thirteen known compounds (2-7, 10-16) were isolated from the metabolites of Talaromyces amestolkiae MST1-15. Their structures were identified by a combination of spectroscopic analysis. The absolute configuration of compound 1 was elucidated on the basis of experimental and electronic circular dichroism calculation, and compounds 8 and 9 were determined by Mo2(OAc)4-induced circular dichroism experiments. Compounds 7-16 showed weak antibacterial activities against Stenotrophomonas maltophilia with MIC values ranging from 128 to 512 µg/mL (MICs of ceftriaxone sodium and levofloxacin were 128 and 0.25 µg/mL, respectively).

Total Synthesis of Isorosthin†L and Isoadenolin†I.

Total syntheses of two Isodon diterpenes, isorosthin L and isoadenolin I, are reported. The synthetic strategy features a quick assembly of two simple building blocks through a diastereoselective intermolecular aldol reaction and a subsequent radical cyclization for efficient construction of a rather complex advanced intermediate bearing a quaternary stereocenter present in all Isodon diterpenes. Oxidative cleavage of the C-C bond in the cyclopentane enabled the conversion to a lactone moiety which is desired for the construction of the molecular skeleton through reductive coupling with an aldehyde carbonyl group.

Synthetic Studies toward Leucosceptroid Family of Natural Products.

Leucosceptroids are sesterterpenoids with potent antifeedant and antifungal activities. In this paper, efforts on two synthetic strategies toward stereoselective total synthesis of the leucosceptroid family of natural products are reported. Intramolecular addition cyclization strategy could lead to a stereochemically mismatched core structure, while intermolecular addition/ring-closing metathesis cyclization strategy successfully furnished an advanced common intermediate bearing eight contiguous stereogenic centers, including three tetra-substituted ones, which fully matches all the stereochemistry on the tricyclic framework in leucosceptroid H. Late-stage transformation of this intermediate to leucosceptroid H encountered difficulty in oxidizing the secondary hydroxyl group to a carbonyl group in the target. Instead of the desired oxidation, an interesting tricyclic spiral product originating from a C-C bond cleavage was observed.

Withanolides from the active extract of Physalis angulate and their anti-hepatic fibrosis effects.

ETHNOPHARMACOLOGICAL RELEVANCE: Physalis angulata L., a traditional Chinese medicine called "Kuzhi" in China, was used traditionally to treat liver diseases (eg. icterus, hepatitis) as well as malaria, asthma, and rheumatism. AIM OF THE STUDY: Our study aimed to investigate the withanolides with anti-hepatic fibrosis effect from P. angulate. MATERIALS AND METHODS: Withanolides were obtained from the EtOH extract of P. angulate by bioassay-molecular networking analysis-guided isolation using column chromatography and normal/reversed-phase semipreparative HPLC. The structures of new withanolides were elucidated by combinations of spectroscopic techniques with NMR and ECD calculations. MTT cell viability assay, AO/EB staining method, cell wound healing assay, ELISA and Western blot experiments were employed to evaluate the anti-hepatic fibrosis activity and to uncover related mechanism. Molecular docking analysis and cellular thermal shift assay were used to evaluate and verify the interaction between the active withanolides and their potential targets. RESULTS: Eight unreported withanolides, withagulides A-H (1-8), along with twenty-eight known ones were obtained from P. angulate. Withanolides 6, 9, 10, 24, 27, and 29-32 showed marked anti-hepatic fibrosis effect with COL1A1 expression inhibition above 50 %. Physalin F (9), the main component in the active fraction, significantly decreased the TGF ß1-stimulated expressions of collagen I and α-SMA in LX-2 cells. Mechanism study revealed that physalin F exerted its anti-hepatic fibrosis effect via the PI3K/AKT/mTOR signaling pathway. CONCLUSION: This study suggested that withanolides were an important class of natural products with marked anti-hepatic fibrosis effect. The main withanolide physalin F might be a promising candidate for hepatic fibrosis treatment. The work provided experimental foundation for the use of P. angulate to treat hepatic fibrosis.

Stereoselective Construction of the Highly Congested Tricyclic Core Structure in Leucosceptroid H.

Leucosceptroids are sesterterpenoids with potent antifeedant and antifungal activities. An efficient stereoselective construction of the highly congested [5,6,5] tricyclic framework of leucosceptroid H is presented. This framework bearing eight contiguous stereogenic centers, including three tetrasubstituted ones, could serve as a common intermediate for the collective total synthesis of the leucosceptroid family of natural products.