Jing Li

Gastric cancer (GC) is a highly aggressive and fatal disease, with limited treatment options. Altered cellular lipid metabolism is a hallmark of cancer that contributes to GC progression. However, the determinants of lipid metabolism in GC and new agents that target lipid metabolic pathways are poorly defined. The aim of this study was to identify potentially effective lead anti-GC compounds by developing and exploring natural marine products. Furthermore, we sought to uncover viable therapeutic targets for GC through the underlying mechanisms of action of the compounds as an anticancer agent. The chemical structures of the metabolites produced by the crinoid-derived fungus Penicillium brocae SYSU-CJ17 were elucidated using advanced spectroscopic techniques. These metabolites were screened for their growth-inhibitory effects on GC cell lines. Among them, Penicolinate H (Pen-H) demonstrated the most significant anti-cancer activity. High-throughput RNA sequencing of Pen-H-treated GC samples revealed differentially expressed genes, and transcriptomic data integrated with bioinformatics analyses highlighted the potential pathways and target genes through which Pen-H might exert its anti-cancer effects. Further investigations, including rescue experiments, endogenous affinity pull-down assays, cellular thermal shift assays (CETSA), surface plasmon resonance (SPR) assays, molecular docking, and in vitro analyses, confirmed the interaction between Pen-H and SREBP-1. The feasibility of SREBP-1 as a therapeutic target for GC is supported by single-cell transcriptome analysis, bioinformatics evaluation of GC patient data, and in vitro studies. Additionally, the chemosensitization effect of Pen-H was confirmed by in vivo and in vitro experiments. Our findings reveal a novel marine-derived compound, Pen-H, which inhibits GC growth and metastasis both in vitro and in vivo by suppressing SREBP-1 mediated lipogenesis. Bioinformatic analysis indicated that SREBP-1 was highly expressed in GC tissues, and high SREBP-1 transcript levels were negatively correlated with prognosis in GC patients. SREBP-1 depletion significantly inhibits the proliferation, migration, and invasion of GC cells. Mechanistic studies have revealed that targeting SREBP-1 by Pen-H significantly reduces de novo fatty acid synthesis and that the anti-GC efficacy of Pen-H is SREBP-1 dependent. Moreover, combination treatment with Pen-H and 5-fluorouracil (5-Fu) resulted in enhanced inhibition of cell proliferation and tumor growth compared to monotherapy. Taken together, these findings highlight that SREBP-1 is an effective therapeutic target in GC and that Pen-H is a promising SREBP-1 inhibitor and a candidate for GC treatment.

Nitrile groups are vital components of diverse bioactive molecules, however, their enzymatic origins in fungal natural products remain largely unknown. Here, we report the discovery of an argininosuccinate synthetase (AsS)-like enzyme, ArtA, which plays a key role in the biosynthesis of a nitrile-containing nonribosomal peptide, auranthine. Structural and mechanistic studies, including X-ray crystallography, site-directed mutagenesis, docking, and molecular dynamics simulations, reveal that ArtA retains core AsS features, but possesses a remodeled active site that accommodates glutamine and facilitates nitrile formation through a unique mechanism. Furthermore, we demonstrated that ArtA homologs are prevalent across fungi and bacteria, and also demonstrated nitrile synthetase activity of representative homologs from both fungi and bacteria, suggesting a broader distribution of this function. The identification of ArtA and its homologs opens new avenues for genome mining and biotechnological applications targeting nitrile-containing natural products.

Seven new xanthones, diaporthones A−G (1−7), together with 13 known analogues, including five mono- (8−14) and six dimeric xanthones (15−20), were obtained from the ascidian-derived fungus Diaporthe sp. SYSU-MS4722. Their planar structures were established by extensive spectroscopic analyses, including 1D and 2D NMR and high-resolution mass spectrometry (HR-ESIMS). The absolute configurations of 1−7 were clearly identified by X-ray crystallographic analysis and calculation of the ECD Spectra. Compounds 15−20 showed significant anti-inflammatory activity with IC₅₀ values between 6.3 and 8.0 μM. In addition, dimeric xanthones (15−20) showed selective cytotoxicity against T98G cell lines with IC₅₀ values ranging from 19.5 to 78.0 μM.

Six new fusarin derivatives, fusarins G–L (1–6), together with five known compounds (5–11) were isolated from the marine-derived fungus Fusarium solani 7227. The structures of the new compounds were elucidated by means of comprehensive spectroscopic methods (1D and 2D NMR, HRESIMS, ECD, and ORC) and X-ray crystallography. Compounds 5–11 exhibited potent anti-inflammatory activity by inhibiting the production of NO in RAW264.7 cells activated by lipopolysaccharide, with IC₅₀ values ranging from 3.6 to 32.2 μM. The structure–activity relationships of the fusarins are discussed herein.

One new naphthalenone, didymelol A, and three new naphthols, didymelol B–D, together with three known naphthalenones, (3S,4R)‐3,4,6‐trihydroxy‐3,4‐dihydronaphthalen‐1(2H)‐one, (4S)‐4,6‐dihydroxy‐3,4‐dihydronaphthalen‐1(2H)‐one, (4S)‐4‐hydroxy‐3,4‐dihydronaphthalen‐1(2H)‐one, were isolated from the Saussurea laniceps endophytic fungus Didymella glomerata X223. The structures of the isolates were elucidated based on extensive spectroscopic data analysis. The absolute configuration of didymelol A was established through single‐crystal X‐ray diffraction data and didymelols B–D were identified through comparisons of experimental and calculated ECD spectra. All compounds were evaluated for cytotoxic activity against human non‐small cell lung cancer A549 cells and human breast carcinoma MDA‐MB‐435 cells.

Tetramic acid (pyrrolidine-2,4-dione) compounds, isolated from a variety of marine and terrestrial organisms, have attracted considerable attention for their diverse, challenging structural complexity and promising bioactivities. In the past decade, marine-derived microorganisms have become great repositories of novel tetramic acids. Here, we discuss the biological activities of 277 tetramic acids of eight classifications (simple 3-acyl tetramic acids, 3-oligoenoyltetramic acids, 3-decalinoyltetramic acid, 3-spirotetramic acids, macrocyclic tetramic acids, N-acylated tetramic acids, α-cyclopiazonic acid-type tetramic acids, and other tetramic acids) from marine-derived microbes, including fungi, actinobacteria, bacteria, and cyanobacteria, as reported in 195 research studies up to 2019.

Two new cembrane-type diterpenoids, lobophytins A (1) and B (3), and four new prostaglandins, (5E)-PGB₂ (10), (5E)-13,14-dihydro-PGB₂ (11), 13,14-dihydro-PGB₂ (12) and 13,14-dihydro-PGB₂-Me (13), together with ten known compounds were isolated from the soft coral Lobophytum sarcophytoides. The structures of these new secondary metabolites were identified by high resolution mass spectrometry (HR-ESIMS), nuclear magnetic resonance (NMR) and electron circular dichroism (ECD) analyses, as well as the modified Mosher’s method. Compounds 6, 7, 9, 10, 12, 13, 15 and 16 showed potential anti-inflammatory activity by inhibiting the production of nitric oxide (NO) in RAW264.7 cells that were activated by lipopolysaccharide, with IC₅₀ values ranging from 7.1 to 32.1 μM and were better than the positive control indomethacin, IC₅₀ = 39.8 μM.