Penicopeptide A (PPA) from the deep-sea-derived fungus promotes osteoblast-mediated bone formation and alleviates ovariectomy-induced bone loss by activating the AKT/GSK-3ß/ß-catenin signaling pathway.

The potential of marine natural products as effective drugs for osteoporosis treatment is an understudied area. In this study, we investigated the ability of lead compounds from deep-sea-derived Penicillium solitum MCCC 3A00215 to promote bone formation in vitro and in vivo. We found that penicopeptide A (PPA) promoted osteoblast mineralization among bone marrow mesenchymal stem cells (BMSCs) in a concentration-dependent manner, and thus, we selected this natural peptide for further testing. Our further experiments showed that PPA significantly promoted the osteogenic differentiation of BMSCs while inhibiting their adipogenic differentiation and not affecting their chondrogenic differentiation. Mechanistic studies showed that PPA binds directly to the AKT and GSK-3ß and activates phosphorylation of AKT and GSK-3ß, resulting in the accumulation of ß-catenin. We also evaluated the therapeutic potential of PPA in a female mouse model of ovariectomy-induced systemic bone loss. In this model, PPA treatment prevented decreases in bone volume and trabecular thickness. In conclusion, our in vitro and in vivo results demonstrated that PPA could promote osteoblast-related bone formation via the AKT, GSK-3ß, and ß-catenin signaling pathways, indicating the clinical potential of PPA as a candidate compound for osteoporosis prevention.

Tetracyclic Steroids Bearing a Bicyclo[4.4.1] Ring System as Potent Antiosteoporosis Agents from the Deep-Sea-Derived Fungus Rhizopus sp. W23.

Chemical investigation of the deep-sea-derived fungus Rhizopus sp. W23 resulted in the identification of six new (1-3, 6, 8, 9) and 12 known (4, 5, 10-19) cyclocitrinol analogues, together with one handling artifact (7), all featuring an unusual 7/7/6/5-tetracyclic scaffold and bicyclo[4.4.1] A/B rings. Norcyclocitrinoic acids A and B (1, 2) represent the second occurrence of 24,25-bisnor cyclocitrinols. Structures were assigned to new steroids on the basis of extensive spectroscopic analysis and X-ray crystallography. Compound 13 significantly enhances osteoblastogenesis and inhibits adipogenesis in mature bone marrow stromal cells at 5 µM, indicating a potential to be an antiosteoporosis lead.

Neotricitrinols A-C, unprecedented citrinin trimers with anti-osteoporosis activity from the deep-sea-derived Penicillium citrinum W23.

Marine fungi are prolific source for the discovery of structurally diverse and bioactive molecules. In our search for new anti-osteoporosis compounds from deep-sea-derived fungi, we prioritized a fungus whose extract exhibited moderate activity and rich chemical diversity. The investigation of this strain afforded a class of citrinins, including three new citrinin trimers, neotricitrinols A-C (1-3), and three known dimeric/monomeric precursors (4-6). Neotricitrinols A-C (1-3) feature a unique octacyclic carbon scaffold among the few reported citrinin trimers with their absolute configurations established by spectroscopic analysis, theoretical-statistical approaches (GIAO-NMR, TDDFT-ECD/ORD calculations), DP4+ probability analysis as well as biogenetic consideration. A plausible biosynthetic pathway linking 1-3 from the common intermediate metabolite penicitrinol A (4) was proposed. Biologically, neotricitrinol B (2) showed potential anti-osteoporosis activity by promoting osteoblastogenesis and inhibiting adipogenic differentiation on primary bone mesenchymal stem cells, while displaying no cytotoxicity.

Penidihydrocitrinins A-C: New Polyketides from the Deep-Sea-Derived Penicillium citrinum W17 and Their Anti-Inflammatory and Anti-Osteoporotic Bioactivities.

Three new polyketides (penidihydrocitrinins A-C, 1-3) and fourteen known compounds (4-17) were isolated from the deep-sea-derived Penicillium citrinum W17. Their structures were elucidated by comprehensive analyses of 1D and 2D NMR, HRESIMS, and ECD calculations. Compounds 1-17 were evaluated for their anti-inflammatory and anti-osteoporotic bioactivities. All isolates exhibited significant inhibitory effects on LPS-stimulated nitric oxide production in murine brain microglial BV-2 cells in a dose-response manner. Notably, compound 14 displayed the strongest effect with the IC50 value of 4.7 µM. Additionally, compounds 6, 7, and 8 significantly enhanced osteoblast mineralization, which was comparable to that of the positive control, purmorphamine. Furthermore, these three compounds also suppressed osteoclastogenesis in a dose-dependent manner under the concentrations of 2.5 µM, 5.0 µM, and 10 µM.

Hepialiamides A-C: Aminated Fusaric Acid Derivatives and Related Metabolites with Anti-Inflammatory Activity from the Deep-Sea-Derived Fungus Samsoniella hepiali W7.

A systematic investigation combined with a Global Natural Products Social (GNPS) molecular networking approach, was conducted on the metabolites of the deep-sea-derived fungus Samsoniella hepiali W7, leading to the isolation of three new fusaric acid derivatives, hepialiamides A-C (1-3) and one novel hybrid polyketide hepialide (4), together with 18 known miscellaneous compounds (5-22). The structures of the new compounds were elucidated through detailed spectroscopic analysis. as well as TD-DFT-based ECD calculation. All isolates were tested for anti-inflammatory activity in vitro. Under a concentration of 1 µM, compounds 8, 11, 13, 21, and 22 showed potent inhibitory activity against nitric oxide production in lipopolysaccharide (LPS)-activated BV-2 microglia cells, with inhibition rates of 34.2%, 30.7%, 32.9%, 38.6%, and 58.2%, respectively. Of particularly note is compound 22, which exhibited the most remarkable inhibitory activity, with an IC50 value of 426.2 nM.

Chemical Constituents of the Deep-Sea-Derived Penicillium citreonigrum MCCC 3A00169 and Their Antiproliferative Effects.

Six new citreoviridins (citreoviridins J-O, 1-6) and twenty-two known compounds (7-28) were isolated from the deep-sea-derived Penicillium citreonigrum MCCC 3A00169. The structures of the new compounds were determined by spectroscopic methods, including the HRESIMS, NMR, ECD calculations, and dimolybdenum tetraacetate-induced CD (ICD) experiments. Citreoviridins J-O (1-6) are diastereomers of 6,7-epoxycitreoviridin with different chiral centers at C-2-C-7. Pyrenocine A (7), terrein (14), and citreoviridin (20) significantly induced apoptosis for HeLa cells with IC50 values of 5.4 µM, 11.3 µM, and 0.7 µM, respectively. To be specific, pyrenocine A could induce S phase arrest, while terrein and citreoviridin could obviously induce G0-G1 phase arrest. Citreoviridin could inhibit mTOR activity in HeLa cells.

Cladosporioles A and B, Two New Indole Derivatives from the Deep-Sea-Derived Fungus Cladosporium cladosporioides 170056.

Two new (cladosporioles A and B, 1 and 2) and fourteen known (3-16) compounds were isolated from the deep-sea-derived fungus Cladosporium cladosporioides 170056. The relative structures of the new compounds were elucidated mainly by detailed analysis of their NMR and HR-ESI-MS spectroscopic data. Their absolute configurations were determined by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. All isolates were tested for antimicrobial activity against Vibrio parahaemolyticus. Compound 15 exhibited weak effect with the MIC value of 156.25 µg/mL.

Solitumergosterol A, a unique 6/6/6/6/5 steroid from the deep-sea-derived Penicillium solitum MCCC 3A00215.

A unique C30 steroid, solitumergosterol A (1), was isolated from the deep-sea-derived fungus Penicillium solitum MCCC 3A00215. The planar structure and relative configuration of 1 were established mainly on the basis of extensive analysis of its 1D and 2D NMR as well as HRESIMS data, while its absolute configuration was clarified by comparison of the experimental and theoretical ECD spectra. Noteworthily, 1 is a Diels-Alder adduct of a heterogeneous steroid bearing a 6/6/6/6/5 pentacyclic carbon skeleton. Solitumergosterol A (1) exhibited weak in vitro anti-tumor activity against MB231 cells by a RXRα-dependent mechanism.

Discovery of andrastones from the deep-sea-derived Penicillium allii-sativi MCCC 3A00580 by OSMAC strategy.

Andrastones are unusual 6,6,6,5-tetracyclic meroterpenoids that are rarely found in nature. Previously, three andrastones were obtained from the rice static fermentation extract of the deep-sea-derived fungus Penicillium allii-sativi MCCC 3A00580. Inspired by one strain many compounds (OSMAC) approach, the oat static fermentation on P. allii-sativi was conducted. As a result, 14 andrastones were isolated by UV-guided isolation. The chemical structures of the nine new compounds (1-9) was established by comprehensive analysis of the NMR, MS, ECD, and X-ray crystallography and the five known ones (10-14) were assigned by comparing their NMR, MS, and OR data with those reported in literature. Compound 1 bears a novel hemiketal moiety while 2 is the first example to possess a novel tetrahydrofuran moiety via C-7 and C-15. All isolates were tested for anti-allergic bioactivity. Compound 10, 3-deacetylcitreohybridonol, significantly decreased degranulation with the IC50 value of 14.8 µM, compared to that of 92.5 µM for the positive control, loratadine. Mechanism study indicated 10 could decrease the generation of histamine and TNF-α by reducing the accumulation of Ca2+ in RBL-2H3 cells. These findings indicate andrastones could be potential to discover new anti-allergic candidate drugs.

Pharmacokinetics and Metabolism Study of Deep-Sea-Derived Butyrolactone I in Rats by UHPLC-MS/MS and UHPLC-Q-TOF-MS.

Butyrolactone I (BTL-I) is a butanolide isolated from the deep-sea-derived fungus, Aspergillus sp. It provides a potential new target for the prevention and treatment of food allergies. This study aimed to investigate the metabolic and pharmacokinetic profile of BTL-I in rats. The metabolic profiles were obtained by UHPLC-Q-TOF-MS. As a result, eleven metabolites were structurally identified, and the proposed metabolic pathways of BTL-I were characterized. The main metabolites were the oxidative and glucuronidative metabolites. In addition, a sensitive UHPLC-MS/MS method was established for the quantitation of BTL-I in rat plasma (LOQ = 2 ng/mL). The method was fully validated and successfully applied to the pharmacokinetic study of BTL-I in rats after oral administration or intravenous administration. The oral bioavailability was calculated as 6.29%, and the maximum plasma concentrations were 9.85 ± 1.54 ng/mL and 17.97 ± 1.36 ng/mL for intravenous and intragastric dosing groups, respectively.

Anti-Food Allergic Compounds from Penicillium griseofulvum MCCC 3A00225, a Deep-Sea-Derived Fungus.

Ten new (1-10) and 26 known (11-36) compounds were isolated from Penicillium griseofulvum MCCC 3A00225, a deep sea-derived fungus. The structures of the new compounds were determined by detailed analysis of the NMR and HRESIMS spectroscopic data. The absolute configurations were established by X-ray crystallography, Marfey's method, and the ICD method. All isolates were tested for in vitro anti-food allergic bioactivities in immunoglobulin (Ig) E-mediated rat basophilic leukemia (RBL)-2H3 cells. Compound 13 significantly decreased the degranulation release with an IC50 value of 60.3 µM, compared to that of 91.6 µM of the positive control, loratadine.

Anti-Food Allergic Alkaloids from the Lotus Seed Pot.

Lotus seed pod (LSP) has been used as traditional herbal cuisine to modulate immunity. From the AcOEt-soluble extract of LSP, one new aporphine alkaloid, N-[2-(2H-phenanthro[3,4-d][1,3]dioxol-5-yl)ethyl]acetamide (nelunucine A, 1) was obtained along with 19 known ones. Their structures were established by detailed analysis of the 1D-, 2D-NMR, and HR-ESI-MS data. N-Nornuciferine (9) and lirinidine (10) showed potent in vitro anti-food allergic activity with IC50 values of 40.0 and 55.4 µM, respectively, compared to 91.4 µM for loratadine, the positive control.

Chemical Constituents of the Marine Fungus Penicillium sp. MCCC 3A00228.

One new (d-arabinitol-anofinicate, 1) and fourteen known (2-15) compounds were isolated from the marine Penicillium sp. MCCC 3A00228. The structure of the new compound was established mainly by extensive spectroscopic analyses. Compound 1 exhibited weak transcriptional effect on Nur77. While compound 13 showed moderate in vitro anti-proliferative effect against QGY7701, H1299, and HCT116 tumor cells with IC50 values of 21.2 µM, 18.2 µM, and 17.6 µM, respectively.

Asperochratides A-J, Ten new polyketides from the deep-sea-derived Aspergillus ochraceus.

Ten new C9 polyketides (asperochratides A-J, 1-10) and 14 known miscellaneous compounds (11-24) were isolated from the deep-sea-derived fungus Aspergillus ochraceus. Structures of the new compounds were elucidated by extensive spectroscopic analyses, modified Mosher's method, Mo2(OAc)4 induced circular dichroism (ICD) experiments, and ECD calculations. Structurally, compounds 1-11 and 16-18 share the same polyketide origin of the skeleton and belong to aspyrone co-metabolites. All isolates were tested for cytotoxic, anti-food allergic, anti-H1N1 virus, anti-microbe, and anti-inflammatory activities in vitro. Results showed that compounds 5-8 and 13-17 exerted significant cytotoxic effects on BV-2 cell line, and compound 16 showed the potential of anti-inflammatory activities.

Chemical Constituents and Bioactivities of Starfishes: An Update.

Starfishes produce various structurally unique secondary metabolites with diverse biological activities. This review is an update summary of the new compounds and their bioactivities from starfish (the Asteroidea Class) with 71 references covering from January 2007 to December 2018. During this period, 216 new compounds were obtained from 36 species. The chemical constituents are mostly steroids, steroidal glycosides, and gangliosides. These components have been found to possess various bioactivities, including anticancer, anti-inflammation, etc.

Cladosporactone A, a Unique Polyketide with 7-Methylisochromen-3-one Skeleton from the Deep-Sea-Derived Fungus Cladosporium cladosporioides.

A unique polyketide cladosporactone A along with eight known compounds were isolated from the deep-sea-derived Cladosporium cladosporioides. The structure of cladosporactone A was established by spectroscopic analyses, and the absolute configuration was clarified by the theoretical ECD calculation. Cladosporactone A is the first member of polyketide with the 7-methylisochromen-3-one skeleton.

Sarocladione, a unique 5,10:8,9-diseco-steroid from the deep-sea-derived fungus Sarocladium kiliense.

A novel ergostane, sarocladione (1), was isolated from the deep-sea-derived fungus Sarocladium kiliense, along with 20 known compounds. The structure of 1 was determined mainly by a detailed analysis of its experimental and calculated NMR spectroscopic data. It is worth noting that 1 was the first steroid bearing a 5,10:8,9-diseco moiety. All 21 compounds were tested for in vitro antitumor activities against five cancer cell lines. ß-Sitostenone (7) and 4,6-dihydroxyeudesmane (20) showed significant effects on HeLa-S3 cells with the IC50 values of 9.2 µM and 9.3 µM, respectively.

Aphidicolin Chemistry of the Deep-Sea-Derived Fungus Botryotinia fuckeliana MCCC 3A00494.

Aphidicolin, a potent DNA polymerase α inhibitor, has been explored in clinical trials for the treatment of cancer. So far, about 300 modified aphidicolins have been discovered. However, none have shown a stronger effect. Herein, we report 71 new (aphidicolins A1-A71, 1-71) and eight known (72-79) aphidicolin congeners from Botryotinia fuckeliana MCCC 3A00494, a fungus isolated from the western Pacific Ocean (-5572 m). The structures of 1-71 were determined through extensive spectroscopic analysis, X-ray crystallography, chemical derivatization, modified Mosher's method, and the ECD exciton chirality method. Compounds 54-57 and 58-64 are novel 6/6/5/6/5 pentacyclic aphidicolins featuring tetrahydrofuran and dihydrofuran rings, respectively, while compounds 65-71 are rare noraphidicolins. Aphidicolin A8 (8) significantly induced apoptosis in T24 (IC50 = 2.5 µM) and HL-60 (IC50 = 6.1 µM) cancer cells by causing DNA damage. By docking its structure to the human DNA polymerase α binding pocket, 8 was found to form tight intermolecular contacts, elaborating aphidicolin A8 as a potently cytotoxic lead compound.

Fusarisolins A⁻E, Polyketides from the Marine-Derived Fungus Fusarium solani H918.

Five new (fusarisolins A⁻E, 1 to 5) and three known (6 to 8) polyketides were isolated from the marine-derived fungus Fusarium solani H918, along with six known phenolics (9 to 14). Their structures were established by comprehensive spectroscopic data analyses, methoxyphenylacetic acid (MPA) method, chemical conversion, and by comparison with data reported in the literature. Compounds 1 and 2 are the first two naturally occurring 21 carbons polyketides featuring a rare ß- and γ-lactone unit, respectively. All isolates (1 to 14) were evaluated for their inhibitory effects against tea pathogenic fungus Pestalotiopsis theae and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase gene expression. Compound 8 showed potent antifungal activity with an ED50 value of 55 µM, while 1, 8, 13, and 14 significantly inhibited HMG-CoA synthase gene expression.

Penigrisacids A-D, Four New Sesquiterpenes from the Deep-Sea-Derived Penicillium griseofulvum.

Four new (penigrisacids A-D, 1-4) and one known (5) carotane sesquiterpenoids were isolated from the deep-sea-derived fungus Penicillium griseofulvum, along with four known compounds (6-9). The planar structures and relative configurations of the new compounds were determined by extensive analysis of the NMR and HRESIMS data. The absolute configurations were established by comparison of the experimental and calculated ECD (electronic circular dichroism) spectra or OR (optical rotation) value. Compound 9 exhibited potent anti-food allergic activity with IC50 value of 28.7 µM, while 4 showed weak cytotoxicity against ECA-109 tumor cells (IC50 = 28.7 µM).