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Brasiliamides are a class of piperazine-containing alkaloids produced by Penicillium brasilianum with a range of pharmaceutical activities. The mechanism of brasiliamide biosynthesis, including piperazine ring formation and multiple tailoring modifications, still remains unclear. In this study, the biosynthetic gene cluster of brasiliamides, brs, was identified from the marine-derived fungal strain Penicillium brasilianum WZXY-M122-9. Deletion of a histone deacetylase–encoding gene using a CRISPR/Cas9 gene editing system led to the production of a new compound, namely brasiliamide I (1). The brs-encoded single-module nonribosomal peptide synthetase (NRPS) BrsA is involved in the formation of the piperazine skeleton of brasiliamides. Full-length BrsA protein (113.6 kDa) was purified, and reconstitution of enzymatic activity in vitro confirmed that BrsA stereoselectively accepts l-phenylalanine as the substrate. Multiple deletion of tailoring genes and analysis of purified proteins in vitro enabled us to propose a brasiliamide biosynthetic pathway. In the tailoring steps, an α-ketoglutarate (KG)-dependent nonheme iron dioxygenase, BrsJ, was identified to catalyze piperazine ring cleavage during biosynthesis of brasiliamide A (2).Key PointsThe gene cluster encoding brasiliamide biosynthesis, brs, is identified.Deletion of a histone deacetylase–encoding gene produces brasiliamide I.BrsA catalyzes brasiliamide piperazine skeleton formation.BrsJ catalyzes piperazine ring cleavage to produce brasiliamide A.

Two tetrahydrofurofurano lignans (1 and 2), four phenylpropanoids (3–6), and two alkamides (7 and 8) were isolated from the EtOAc-soluble fraction of the roots of Asarum sieboldii. The chemical structures of the isolates were identified by analysis of spectroscopic data measurements, and by a comparison of their data with published values. The isolates (1, 2, 4–8) were evaluated for their cytotoxicity against human ovarian cancer cells (A2780 and SKOV3) and immortalized ovarian surface epithelial cells (IOSE80PC) using a MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) assay. Of the isolates, (−)-asarinin (1) exhibited the most potent cytotoxicity to both A2780 and SKOV3 cells. A propidium iodide/annexin V-fluorescein isothiocyanate (V-FITC) double staining assay showed that (−)-asarinin (1) induces apoptotic cell death in ovarian cancer cells. In addition, (−)-asarinin (1) increased the activation of caspase-3, caspase-8, and caspase-9 in ovarian cancer cells. Pretreatment with caspase inhibitors attenuated the cell death induced by (−)-asarinin (1). In conclusion, our findings show that (−)-asarinin (1) from the roots of A. sieboldii may induce caspase-dependent apoptotic cell death in human cancer cells.

Aim： The nuclear factor erythroid 2-related factor 2 （NRF2） acts through the antioxidant response element （ARE） to regulate the expression of many detoxifying and antioxidant genes responsible for cytoprotective processes. We previously reported that schisandrol B （SolB） isolated from Schisandra sphenanthera produced a protective effect against acetaminophen （APAP）-induced liver injury. In this study we investigated whether the NRF2/ARE signaling pathway was involved in this hepato-protective effect. Methods： Male C57BL/6 mice were treated with SolB （200 mg.kg-l.d-1, ig） for 3 d before injection of APAP （400 mg/kg, ip）. Serum and liver tissue samples were collected 6 h later. The mRNA and protein expression were measured using qRT-PCR and Western blot assay, respectively. The activation of NRF2 was examined in HepG2 cells using luciferase reporter gene assay. Results： SolB pretreatment significantly alleviated the hepatic injury （large patchy necrosis and hyperemia of the hepatic sinus）, the increase of serum AST, ALT levels and hepatic MDA contents, and the decrease of liver and mitochondrial glutathione levels in APAP- treated mice. Furthermore, SolB pretreatment significantly increased nuclear accumulation of NRF2 and increased hepatic expression of NRF2 downstream proteins, including GCLC, GSR, NQ01, GSTs, MRP2, MRP3 and MRP4 in APAP-treated mice. Moreover, treatment with SolB （2.5-20 pmol/L） dose-dependently increased the activity of NRF2 reporter gene in HepG2 cells. Conclusion： SolB exhibits a remarkable protective effect against APAP-induced hepatotoxicity, partially via activation of the NRF2/ARE pathway and regulation of NRF2 target genes, which induce detoxification and increase antioxidant capacity.

Surveys of foliar endophytes from the Acadian forest region over the past three decades have identified numerous phylogenetically diverse fungi producing natural products toxic to forest pests and diseases. The life histories of some conifer endophytes can be restricted to plant foliage or may include saprotrophic phases on other plants tissues or even alternate hosts. Considering the potentially broad host preferences of conifer endophytes we explored fungi isolated from understory species and their metabolites as part of an ongoing investigation of fungal biodiversity from the Acadian forest. We report a hitherto unidentified Xylariomycetidae species isolated from symptomatic Labrador tea (Rhododendron groenlandicum) leaves and mountain laurel (Kalmia latifolia) collected in coastal southern New Brunswick, Canada. Morphological and phylogenetic evidence demonstrated the unknown species was a novel Synnemapestaloides (Sporocadaceae) species, described here as Syn. ericacearum. A preliminary screening assay indicated that the culture filtrate extract of the new species was potently antifungal towards the biotrophic pathogen Microbotryum violaceum, warranting an investigation of its natural products. Two natural products possessing a rare 1,3-benzodioxin-4-one scaffold, synnemadoxins A-B (1-2), and their postulated precursor, synnemadiacid A (3), were characterized as new structures and assessed for antimicrobial activity. All isolated compounds elicited in vitro inhibitory antifungal activity towards M. violaceum at 2.3 μg mL-1 and moderate antibiotic activity. Further, the characterization of synnemadoxins A-B provided a perspective on the biosynthesis of some related 1,3-benzodioxin-4-ones produced by other fungi within the Xylariales.

Herb–drug interaction (HDI) limits clinical application of herbs and drugs, and inhibition of herbs towards uridine diphosphate (UDP)-glucuronosyltransferases (UGTs) has gained attention as one of the important reasons to cause HDIs. Sauchinone, an active lignan isolated from aerial parts of Saururus chinensis (Saururacease), possesses anti-oxidant, anti-inflammatory, and anti-viral activities. In pharmacokinetics of sauchinone, sauchinone is highly distributed to the liver, forming extensive metabolites of sauchinone via UGTs in the liver. Thus, we investigated whether sauchinone inhibited UGTs to explore potential of sauchinone–drug interactions. In human liver microsomes (HLMs), sauchinone inhibited activities of UGT1A1, 1A3, 1A6, and 2B7 with IC50 values of 8.83, 43.9, 0.758, and 0.279 μM, respectively. Sauchinone also noncompetitively inhibited UGT1A6 and 2B7 with Ki values of 1.08 and 0.524 μM, respectively. In in vivo interaction study using mice, sauchinone inhibited UGT2B7-mediated zidovudine metabolism, resulting in increased systemic exposure of zidovudine when sauchinone and zidovudine were co-administered together. Our results indicated that there is potential HDI between sauchinone and drugs undergoing UGT2B7-mediated metabolism, possibly contributing to the safe use of sauchinone and drug combinations.

Brasilamides K-N (1–4), four new bergamotane sesquiterpenoids; with 4-oxatricyclo (3.3.1.0 2,7)nonane (1)and 9-oxatricyclo(4.3.0.0 4,7)nonane (2–4) skeletons; were isolated from the scale-up fermentation cultures of the plant endophytic fungus Paraconiothynium brasiliense Verkley. The previously identified sesquiterpenoids brasilamides A and C (5 and 6) were also reisolated in the current work. The structures of 1–4 were elucidated primarily by interpretation of NMR spectroscopic data. The absolute configurations of 1–3 were deduced by analogy to the co-isolated metabolites 5 and 6; whereas that of C-12 in 4 was assigned using the modified Mosher method. The cytotoxicity of all compounds against a panel of eight human tumor cell lines were assayed.

Sauchinone, an active lignan isolated from the aerial parts of Saururus chinensis (Saururaceae), exhibits anti-inflammatory, anti-obesity, anti-hyperglycemic, and anti-hepatic steatosis effects. As herb–drug interaction (HDI) through cytochrome P450s (CYPs)-mediated metabolism limits clinical application of herbs and drugs in combination, this study sought to explore the enzyme kinetics of sauchinone towards CYP inhibition in in vitro human liver microsomes (HLMs) and in vivo mice studies and computational molecular docking analysis. In in vitro HLMs, sauchinone reversibly inhibited CYP2B6, 2C19, 2E1, and 3A4 activities in non-competitive modes, showing inhibition constant (Ki) values of 14.3, 16.8, 41.7, and 6.84 μM, respectively. Also, sauchinone time-dependently inhibited CYP2B6, 2E1 and 3A4 activities in vitro HLMs. Molecular docking study showed that sauchinone could be bound to a few key amino acid residues in the active site of CYP2B6, 2C19, 2E1, and 3A4. When sibutramine, clopidogrel, or chlorzoxazone was co-administered with sauchinone to mice, the systemic exposure of each drug was increased compared to that without sauchinone, because sauchinone reduced the metabolic clearance of each drug. In conclusion, when sauchinone was co-treated with drugs metabolized via CYP2B6, 2C19, 2E1, or 3A4, sauchinone–drug interactions occurred because sauchinone inhibited the CYP-mediated metabolic activities.

Sixteen compounds were extracted and purified from the leaves of Liriodendron tulipifera. These compounds include aporphines, oxoaporphine, coumarin, sesquiterpene lactone, benzenoids, cyclitol and steroids. (+)-Norstephalagine (2) (an aporphine) and scopoletin (8) (a coumarin) were isolated from Liriodendron tulipifera leaves from the first time. The identified compounds were screened for their antiradical scavenging, metal chelating and ferric reducing power activities. The results have showed that these compounds have antioxidative activity. The study has also examined the chemopreventive property of the isolated compounds against human melanoma cells A375. The results shown that (−)-anonaine (1), (−)-liridinine (3), (+)-lirinidine (6), lysicamine (7) and epitulipinolide diepoxide (9) significantly inhibited the proliferation of melanoma cells. These results revealed that these compounds have antioxidative activity and chemopreventive activity in skin melanoma cells.

Peperomia pellucida is a plant used in traditional medicine to treat gastric ulcers. Although this gastroprotective activity was reported, the active compounds have not been identified. Therefore, the aim herein was to identify the most active compound in the gastroprotective activity of P. pellucida using an ethanol-induced gastric ulcer experimental rat model. A gastroprotective effect was observed when the hexane and dichloromethane extracts were tested, with the higher effect being obtained with the dichloromethane extract (82.3 ± 5.6%) at 100 mg/kg. Dillapiole was identified as the most active compound in this extract. Although there have been previous reports on dillapiole, this is the first on its gastroprotective activity. Rats treated with this compound at 3, 10, 30 and 100 mg/kg showed 23.1, 56.1, 73.2 and 85.5% gastroprotection, respectively. The effect elicited by dillapiole at 100 mg/kg was not attenuated by pretreatment with indomethacin (10 mg/kg, s.c.), a prostaglandin synthesis blocker, NG-nitro-l-arginine methyl ester (70 mg/kg, i.p.), a nitric oxide (NO) synthase inhibitor, or N-ethylmaleimide (10 mg/kg, s.c.), a blocker of sulfhydryl groups. This suggests that the gastroprotective mechanism of action of dillapiole does not involve prostaglandins, NO or sulfhydryl groups.

Niranthin, a lignan isolated from the aerial parts of the plant Phyllanthus amarus , exhibits a wide spectrum of pharmacological activities. In the present study, we have shown for the first time that niranthin is a potent anti‐leishmanial agent. The compound induces topoisomerase I‐mediated DNA–protein adduct formation inside Leishmania cells and triggers apoptosis by activation of cellular nucleases. We also show that niranthin inhibits the relaxation activity of heterodimeric type IB topoisomerase of L. donovani and acts as a non‐competitive inhibitor interacting with both subunits of the enzyme. Niranthin interacts with DNA–protein binary complexes and thus stabilizes the ‘cleavable complex’ formation and subsequently inhibits the religation of cleaved strand. The compound inhibits the proliferation of Leishmania amastigotes in infected cultured murine macrophages with limited cytotoxicity to the host cells and is effective against antimony‐resistant Leishmania parasites by modulating upregulated P‐glycoprotein on host macrophages. Importantly, besides its in vitro efficacy, niranthin treatment leads to a switch from a Th2‐ to a Th1‐type immune response in infected BALB/c mice. The immune response causes production of nitric oxide, which results in almost complete clearance of the liver and splenic parasite burden after intraperitoneal or intramuscular administration of the drug. These findings can be exploited to develop niranthin as a new drug candidate against drug‐resistant leishmaniasis.