A new secondary metabolite from the marine-derived fungus Phomopsis lithocarpus FS508.

Based on the One Strain-Many Compounds (OSMAC) strategy, the secondary metabolites of Phomopsis lithocarpus FS508 were investigated. As a result, a new secondary metabolite, 4-methoxy-3-[4-(acetyloxy)-3-methyl-2-butenyl]benzoic acid (1) as well as eleven known compounds were isolated from the fermentation product of the strain FS508. Their structures were determined by NMR, IR, UV, and MS spectroscopic data analyses. All the isolated compounds were evaluated for cytotoxic and anti-inflammatory activities. Among them, compounds 3 and 9 displayed potent cytotoxicity against HepG-2 cell line, and compounds 2, 3 and 12 showed significant anti-inflammatory activities.

The biochemical basis of mitochondrial dysfunction in Zellweger Spectrum Disorder.

Peroxisomal biogenesis disorders (PBDs) are genetic disorders of peroxisome biogenesis and metabolism that are characterized by profound developmental and neurological phenotypes. The most severe class of PBDs-Zellweger spectrum disorder (ZSD)-is caused by mutations in peroxin genes that result in both non-functional peroxisomes and mitochondrial dysfunction. It is unclear, however, how defective peroxisomes contribute to mitochondrial impairment. In order to understand the molecular basis of this inter-organellar relationship, we investigated the fate of peroxisomal mRNAs and proteins in ZSD model systems. We found that peroxins were still expressed and a subset of them accumulated on the mitochondrial membrane, which resulted in gross mitochondrial abnormalities and impaired mitochondrial metabolic function. We showed that overexpression of ATAD1, a mitochondrial quality control factor, was sufficient to rescue several aspects of mitochondrial function in human ZSD fibroblasts. Together, these data suggest that aberrant peroxisomal protein localization is necessary and sufficient for the devastating mitochondrial morphological and metabolic phenotypes in ZSDs.

Anti-Inflammatory Phomalones from the Deep-Sea-Derived Fungus Trichobotrys effuse FS522.

Four new phomalones A-D (1-4), together with five known analogues (5-9) were isolated from the deep-sea-derived fungus Trichobotrys effuse FS522. Their structures of the new compounds established by analysis of their NMR and HR-ESI-MS spectroscopic data, and the absolute configurations of 2 was determined by electronic circular dichroism (ECD) calculations. compounds 4, 6 and 8 substantially inhibited the production of nitric oxide (NO) with IC50 values of 4.64, 13.90, and 34.07 µM.

Chevalones H-M: Six New α-Pyrone Meroterpenoids from the Gorgonian Coral-Derived Fungus Aspergillus hiratsukae SCSIO 7S2001.

Six new α-pyrone meroterpenoid chevalones H-M (1-6), together with six known compounds (7-12), were isolated from the gorgonian coral-derived fungus Aspergillus hiratsukae SCSIO 7S2001 collected from Mischief Reef in the South China Sea. Their structures, including absolute configurations, were elucidated on the basis of spectroscopic analysis and X-ray diffraction data. Compounds 1-5 and 7 showed different degrees of antibacterial activity with MIC values of 6.25-100 µg/mL. Compound 8 exhibited potent cytotoxicity against SF-268, MCF-7, and A549 cell lines with IC50 values of 12.75, 9.29, and 20.11 µM, respectively.

Structurally Diverse Polycyclic Salicylaldehyde Derivative Enantiomers from a Marine-Derived Fungus Eurotium sp. SCSIO F452.

To enlarge the chemical diversity of Eurotium sp. SCSIO F452, a talented marine-derived fungus, we further investigated its chemical constituents from a large-scale fermentation with modified culture. Four pairs of new salicylaldehyde derivative enantiomers, euroticins F-I (1-4), as well as a known one eurotirumin (5) were isolated and characterized. Compound 1 features an unprecedented constructed 6/6/6/5 tetracyclic structures, while 2 and 3 represent two new types of 6/6/5 scaffolds. Their structures were established by comprehensive spectroscopic analyses, X-ray diffraction, 13C NMR, and electronic circular dichroism calculations. Selected compounds showed significant inhibitory activity against α-glucosidase and moderate cytotoxic activities against SF-268, MCF-7, HepG2, and A549 cell lines.

Callyspongiolide Is a Potent Inhibitor of the Vacuolar ATPase.

Callyspongiolide is a marine-derived macrolide that kills cells in a caspase-independent manner. NCI COMPARE analysis of human tumor cell line toxicity data for synthetic callyspongiolide indicated that its pattern of cytotoxicity correlated with that seen for concanamycin A, an inhibitor of the vacuolar-type H+-ATPase (V-ATPase). Using yeast as a model system, we report that treatment with synthetic callyspongiolide phenocopied a loss of V-ATPase activity including (1) inability to grow on a nonfermentable carbon source, (2) rescue of cell growth via supplementation with Fe2+, (3) pH-sensitive growth, and (4) a vacuolar acidification defect visualized using the fluorescent dye quinacrine. Crucially, in an in vitro assay, callyspongiolide was found to dose-dependently inhibit yeast V-ATPase (IC50 = 10 nM). Together, these data identify callyspongiolide as a new and highly potent V-ATPase inhibitor. Notably, callyspongiolide is the first V-ATPase inhibitor known to be expelled by Pdr5p.

Cytosporins A-D, novel benzophenone derivatives from the endophytic fungus Cytospora rhizophorae A761.

Four novel benzophenone derivatives, cytosporins A-D (1-4), hemiterpene-conjugated phenolics with an unprecedented benzo[b][1,5]dioxocane skeleton, were isolated from Cytospora rhizophorae A761. The structures of the new compounds were fully characterized on the basis of extensive spectroscopic analysis. The deduced structure represents the first example of natural meroterpenoids which bear a benzo[b][1,5]dioxocane framework embodying hemiterpene and benzophenone moieties. Moreover, compounds 1-4 were evaluated for in vitro antimicrobial activity.

Tersone A-G, New Pyridone Alkaloids from the Deep-Sea Fungus Phomopsis tersa.

Four phenylfuropyridone racemates, (±)-tersones A-C and E (1-3, 5), one phenylpyridone racemate, (±)-tersone D (4), one new pyridine alkaloid, tersone F (6), single new phenylfuropyridone, tersone G (7) and two known analogs 8 and 9 were isolated from the deep-sea fungus Phomopsis tersa. Their structures and absolute configurations were characterized on the basis of comprehensive spectroscopic analyses, single-crystal X-ray diffraction experiments, and electronic circular dichroism (ECD) calculations. Moreover, compounds 1-9 were evaluated for in vitro antimicrobial and cytotoxic activity. Compounds 5b and 8b exhibited antibacterial activity against S. aureus with the MIC value of 31.5 µg/mL, while compound 5b showed cytoxic activities against SF-268, MCF-7, HepG-2 and A549 cell lines with IC50 values of 32.0, 29.5, 39.5 and 33.2 µM, respectively.

Chromone-Derived Polyketides from the Deep-Sea Fungus Diaporthe phaseolorum FS431.

Five new chromone-derived polyketides phaseolorins A-F (1⁻5), together with nine known compounds, were isolated from the deep-sea derived fungus Diaporthe phaseolorum FS431. The structures of new compounds were determined by analysis of their NMR and high-resolution electrospray ionization mass spectroscopy (HRESIMS) spectroscopic data. The absolute configurations were confirmed by chemical transformations, extensively experimental electron capture detection (ECD) calculations, or X-ray crystallography. Among them, compound 2 represented the first example for a new family of chromone derivative possessing an unprecedented recombined five-member γ-lactone ring. Moreover, the new compounds (1⁻5) were evaluated for in vitro cytotoxic activities against a panel of human cancer cell lines.

Two new 12-membered macrolides from the endophytic fungal strain Cladosprium colocasiae A801 of Callistemon viminalis.

Two new polyketide metabolites, the 12-membered macrolides 4-hydroxy-12-methyloxacyclododecane-2,5,6-trione (1) and 12-methyloxacyclododecane-2,5,6-trione (2), were isolated from the endophytic fungal strain Cladosprium colocasiae A801 of the plant Callistemon viminalis, together with five known derivatives. Their structures were fully characterized by means of detailed spectroscopic analysis for new structures, and in comparison with published data for known compounds. The antibacterial, cytotoxic, and α-glucosidase inhibitory activities of the new compounds 1 and 2 were evaluated.

Two new metabolites from Daldinia eschscholtzii, an endophytic fungus derived from Pogostemon cablin.

The chemical investigation of the mycelia of endophytic fungus Daldinia eschscholtzii A630, which was isolated from the medicinal plant Pogostemon cablin, resulted in the isolation of two new compounds, named eschscholin A (1), 3-ene-2-methyl-2H-1-benzopyran-5-ol (2), and one new natural product 3,5-dihydroxy-2-methyl-4H-chromen-4-one (3), along with seven known compounds. Their structures were fully characterized by means of detailed spectroscopic analysis, and in comparison with published data for known compounds. All of the isolated compounds (1-10) were evaluated for their antibacterial activities.

Msp1/ATAD1 maintains mitochondrial function by facilitating the degradation of mislocalized tail-anchored proteins.

The majority of ER-targeted tail-anchored (TA) proteins are inserted into membranes by the Guided Entry of Tail-anchored protein (GET) system. Disruption of this system causes a subset of TA proteins to mislocalize to mitochondria. We show that the AAA+ ATPase Msp1 limits the accumulation of mislocalized TA proteins on mitochondria. Deletion of MSP1 causes the Pex15 and Gos1 TA proteins to accumulate on mitochondria when the GET system is impaired. Likely as a result of failing to extract mislocalized TA proteins, yeast with combined mutation of the MSP1 gene and the GET system exhibit strong synergistic growth defects and severe mitochondrial damage, including loss of mitochondrial DNA and protein and aberrant mitochondrial morphology. Like yeast Msp1, human ATAD1 limits the mitochondrial mislocalization of PEX26 and GOS28, orthologs of Pex15 and Gos1, respectively. GOS28 protein level is also increased in ATAD1(-/-) mouse tissues. Therefore, we propose that yeast Msp1 and mammalian ATAD1 are conserved members of the mitochondrial protein quality control system that might promote the extraction and degradation of mislocalized TA proteins to maintain mitochondrial integrity.

Quetiapine ameliorates collagen-induced arthritis in mice via the suppression of the AKT and ERK signaling pathways.

OBJECTIVE AND DESIGN: To investigate the amelioration effects of quetiapine on rheumatoid arthritis with RAW 264.7 macrophage and collagen-induced arthritis (CIA) DBA/1J mouse model. SUBJECTS: RAW 264.7 macrophage and DBA/1J mice. TREATMENT: Lipopolysaccharide and collagen. METHODS: RAW 264.7 macrophages stimulated by lipopolysaccharide (LPS) followed by quetiapine treatments were investigated. Activations of CD80 and CD86 were analyzed by flow cytometry. Pro-inflammatory cytokines such as IL-6, TNF-α and IL-1ß were analyzed by ELISA. Proteins involved in signaling pathways related to the formation of rheumatoid arthritis were assayed by Western blotting. Therapeutic efficacy of quetiapine in CIA mouse model was also assayed. 18F-FDG/micro-PET was used to monitor the inflammation status in the joints, and the severity of bone erosion was evaluated with micro-CT and H&E staining. RESULTS: The inhibition of pro-inflammatory cytokines by quetiapine was found through the ERK and AKT phosphorylation and subsequent NF-κB and CREB signaling pathways. Pro-inflammatory cytokines such as IL-17, IL-6 and IL-1ß were decreased, while immunosuppressive factors such as TGF-ß and IL-10 were increased in CIA mice treated with quetiapine. Notably, no uptake of 18F-FDG and bone erosion was found with micro-PET images on days 32 and 43 in the quetiapine-treated and normal control groups. However, significant uptake of 18F-FDG could be observed in the CIA group during the same time course. Similar results were further verified with ex vivo autoradiography. CONCLUSION: Taken together, these results suggest that quetiapine is a potential anti-inflammatory drug, and may be used as an adjuvant for the treatment of rheumatoid arthritis.

Geospallins A⁻C: New Thiodiketopiperazines with Inhibitory Activity against Angiotensin-Converting Enzyme from a Deep-Sea-Derived Fungus Geosmithia pallida FS140.

Three new thiodiketopiperazines, geospallins A⁻C (1⁻3), together with nine known analogues (4⁻12), were isolated from the culture of the deep-sea sediment-derived fungus Geosmithia pallida FS140. Among them, geospallins A and B (1 and 2) represent rare examples of thiodiketopiperazines featuring an S-methyl group at C-10 and a tertiary hydroxyl group at C-11. Their structures were determined by high-resolution electrospray mass spectrometry (HRESIMS), spectroscopic analyses, and electronic circular dichroism (ECD) calculations. Their angiotensin-converting enzyme (ACE) inhibitory activity was reported, and geospallins A⁻C (1⁻3) showed inhibitory activity with IC50 values of 29⁻35 µM.

Highly Substituted Benzophenone Aldehydes and Eremophilane Derivatives from the Deep-Sea Derived Fungus Phomopsis lithocarpus FS508.

Five new benzophenone derivatives named tenellones D⁻H (1⁻5), sharing a rare naturally occurring aldehyde functionality in this family, and a new eremophilane derivative named lithocarin A (7), together with two known compounds (6 and 8), were isolated from the deep marine sediment-derived fungus Phomopsis lithocarpus FS508. All of the structures for these new compounds were fully characterized and established on the basis of extensive spectroscopic interpretation and X-ray crystallographic analysis. Compound 5 exhibited cytotoxic activity against HepG-2 and A549 cell lines with IC50 values of 16.0 and 17.6 µM, respectively.

Eurotiumins A⁻E, Five New Alkaloids from the Marine-Derived Fungus Eurotium sp. SCSIO F452.

Three new prenylated indole 2,5-diketopiperazine alkaloids (1⁻3) with nine known ones (5⁻13), one new indole alkaloid (4), and one new bis-benzyl pyrimidine derivative (14) were isolated and characterized from the marine-derived fungus Eurotium sp. SCSIO F452. 1 and 2, occurring as a pair of diastereomers, both presented a hexahydropyrrolo[2,3-b]indole skeleton. Their chemical structures, including absolute configurations, were elucidated by 1D and 2D NMR, HRESIMS, quantum chemical calculations of electronic circular dichroism, and single crystal X-ray diffraction experiments. Most isolated compounds were screened for antioxidative potency. Compounds 3, 5, 6, 7, 9, 10, and 12 showed significant radical scavenging activities against DPPH with IC50 values of 13, 19, 4, 3, 24, 13, and 18 µM, respectively. Five new compounds were evaluated for cytotoxic activities.

Monoterpenes and sesquiterpenes from the marine sediment-derived fungus Eutypella scoparia FS46.

Eutypellol A (1), the first norsesquiterpenoid of sequicarene family, as well as eutypellol B (2), a rare 7-methyl oxidized 2-carene derivative, and one new natural product 2-(2-hydroxy-4-methylcyclohex-3-enyl)propanoic acid (3), along with eight known terpenoids, were isolated from the marine sediment-derived fungus Eutypella scoparia FS46 collected from the South China Sea. Their structures were established on the basis of extensive spectroscopic analysis. Compounds 1-3 were evaluated for their antibacterial activities against Staphylococcus aureus and cytotoxic activities against MCF-7, NCI-H460, and SF-268 tumor cell lines.

Two New Metabolites from the Endophytic Fungus Alternaria sp. A744 Derived from Morinda officinalis.

Two new compounds isobenzofuranone A (1) and indandione B (2), together with eleven known compounds (3-13) were isolated from liquid cultures of an endophytic fungus Alternaria sp., which was obtained from the medicinal plant Morinda officinalis. Among them, the indandione (2) showed a rarely occurring indanone skeleton in natural products. Their structures were elucidated mainly on the basis of extensive spectroscopic data analysis. All of the compounds were evaluated with cytotoxic and α-glucosidase inhibitory activity assays. Compounds 11 and 12 showed significant inhibitory activities against four tumor cell lines; MCF-7, HepG-2, NCI-H460 and SF-268, with IC50 values in the range of 1.91-9.67 µM, and compounds 4, 5, 9, 10, 12 and 13 showed excellent inhibitory activities against α-glucosidase with IC50 values in the range of 12.05-166.13 µM.

[Sesquiterpenoids of endophytic fungus Cerrena sp. from Pogostemon cablin and their cytotoxic activities].

The secondary metabolites of endophytic fungus Cerrena sp.A593 from Pogostemon cablin and their cytotoxic activities were investigated. Eight sesquiterpenoids were isolated from the fermentation broth of the strain A593 by silica gel, reverse phase silica gel, Sephadex LH-20, HPLC and so on. Their structures were identified as chloriolin B(1), chloriolin C(2), pleurocybellone A(3), dihydrohypnophilin(4), cucumin F(5), antrodin A(6), 10α-hydroxyamorphan-4-en-3-one(7), and connatusin A(8). Compounds 1- 8 were firstly found from the genus Cerrena. All isolated sesquiterpenoids were evaluated for in vitro cytotoxic activities against HepG-2, SF-268, MCF-7 and NCI-H460 tumor cell lines. Compounds 1-3 showed inhibitory activities against the four tumor cell lines with IC50 values ranging from 20.33 to 63.13 µmol•L⁻¹.

Dichotocejpins A-C: New Diketopiperazines from a Deep-Sea-Derived Fungus Dichotomomyces cejpii FS110.

Three new diketopiperazines, dichotocejpins A-C (1-3), together with eight known analogues (4-11), were isolated from the culture of the deep-sea sediment derived fungus Dichotomomyces cejpii FS110. Their structures, including absolute configurations, were elucidated by a combination of HRESIMS, NMR, X-ray crystallography, and ECD calculations. Compounds 4-6, 10-11 showed significant cytotoxic activities against MCF-7, NCI-H460, HepG-2, and SF-268 tumor cell lines. Compound 1 exhibited excellent inhibitory activity against α-glucosidase with an IC50 of 138 µM.