Penicilloneines A and B, Quinolone-Citrinin Hybrids from a Starfish-Derived Penicillium sp.

Penicilloneines A (1) and B (2) are the first reported quinolone-citrinin hybrids. They were isolated from the starfish-derived fungus Penicillium sp. GGF16-1-2, and their structures were elucidated using spectroscopic, chemical, computational, and single-crystal X-ray diffraction methods. Penicilloneines A (1) and B (2) share a common 4-hydroxy-1-methyl-2(1H)-quinolone unit; however, they differ in terms of citrinin moieties, and these two units are linked via a methylene bridge. Penicilloneines A (1) and B (2) exhibited antifungal activities against Colletotrichum gloeosporioides, with lethal concentration 50 values of 0.02 and 1.51 µg/mL, respectively. A mechanistic study revealed that 1 could inhibit cell growth and promote cell vacuolization and consequent disruption of the fungal cell walls via upregulating nutrient-related hydrolase genes, including putative hydrolase, acetylcholinesterase, glycosyl hydrolase, leucine aminopeptidase, lipase, and beta-galactosidase, and downregulating their synthase genes 3-carboxymuconate cyclase, pyruvate decarboxylase, phosphoketolase, and oxalate decarboxylase.

Preliminary investigation on the analysis of the whole components of Pogejiuxin decoction and its formulation pattern based on ultrahigh-performance liquid chromatography with quadrupole time-of-flight mass spectrometry.

RATIONAL: Pogejiuxin decoction (PGJXD) is one of the most important formulas for the treatment of heart failure. However, there is a great lack of research on the material basis of this formula, especially research on its compatibility laws, which restricts its clinical use. Studying the complete ingredients and compatibility rules of PGJXD has great significance for guiding clinical medication. METHODS: The entire formula, the major single herbs, the drug pairs and the disassembled formula were analyzed by ultrahigh-performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UHPLC/QTOFMS/MS), matching the chemical composition database and global natural product social molecular networking to explain the chemical composition as well as the combination pattern of PGJXD. RESULTS: A total of 1048 chemical constituents were fully analyzed from the major single herbs, the drug pairs and the disassembled formula and 188 chemical constituents, including 13 potential novel compounds, were firstly identified from the whole formula. We found that the chemical compositions were reduced after the single herbs were matched to the other herbs, especially the significant reduction of highly toxic diester alkaloids after compatibility, indicating that the medicines of PGJXD were interdependent and controlled by each other. CONCLUSION: This study innovatively researches and compares the compositional differences between the entire formula of PGJXD, the single, paired and separated formulas, greatly extending our understanding of the chemical substance basis of these compounds, and preliminarily explores the compatibility laws of PGJXD, providing some theoretical guidance for clinical medication.

Discovery of Anti-Hypercholesterolemia Agents Targeting LXRα from Marine Microorganism-Derived Natural Products.

A strategy integrating in silico molecular docking with LXRα and phenotypic assays was adopted to discover anti-hypercholesterolemia agents in a small library containing 205 marine microorganism-derived natural products, collected by our group in recent years. Two fumitremorgin derivatives, 12R,13S-dihydroxyfumitremorgin C (1) and tryprostatin A (3), were identified as potential LXRα agonists, by real-time qPCR and Western blot (WB) analysis, together with a surface plasmon resonance (SPR) assay. The anti-hypercholesterolemic effects of 1 and 3, together with their mechanisms, were investigated in depth using different cell and mouse models, among which the study of LXRα is of crucial importance. Compound 1 or 3 exhibited the capacity to effectively reverse excessive lipid accumulation in a hepatic steatosis cell model and significantly reduce liver damage and blood cholesterol levels in high cholesterol diet (HCD)-fed wild-type mice, whereas those beneficial effects were completely nullified in HCD-fed LXRα-knockout mice. Furthermore, 1 and 3 outperformed common LXRα agonists by suppressing the expression of sterol regulatory element-binding protein 1 (SREBP1) in HCD-fed mice, mitigating lipotoxicity. Thus, this study highlights the discovery of two marine microorganism-derived anti-hypercholesterolemia agents targeting LXRα.

New polyketides from the starfish-derived symbiotic fungus Penicillium sp. GGF16-1-2.

One new rare carbon-bridged citrinin dimer quinocitrindimer C (1) as a pair of epimers, two new polyketide penicilliodes D (3) and E (4) together with nine known citrinin derivatives, were isolated from the fermentation broth of starfish-derived symbiotic fungus Penicillium sp. GGF16-1-2. Their structures and configurations were elucidated by comprehensively spectroscopic data analysis and electronic circular dichroism calculations. Eleven citrinin derivatives were tested by Colletotrichum gloeosporioides, and compound 2 played a significant antifungal activity against Colletotrichum gloeosporioides with LC50 value of 0.27 µg/ml.

The marine Penicillium sp. GGF16-1-2 metabolite dicitrinone G inhibits pancreatic angiogenesis by regulating the activation of NLRP3 inflammasome.

Citrinin derivatives have been found to have various pharmacological activities, such as anti-inflammatory, anti-tumor, and antioxidant effects. Dicitrinone G (DG) was a new citrinin dimer isolated from marine-derived fungus Penicillium sp. GGF 16-1-2 which has potential activity. Here, we aim to investigate whether DG has anti-pancreatic cancer activity. In xenograft tumor model, 2 × 106 BXPC-3 cells were injected into the hind flank of NU/NU nude mice by subcutaneously for 2 weeks followed by treating with DG (0.25, 0.5, 1 mg/kg) and 5-FU (30 mg/kg) for 4 weeks. Tumor volume and weight were measured, and the expression of CD31, IL-18, NLRP3, and Caspase-1 in tumor tissue were detected. In vitro, HUVECs were treated with conditioned medium (CM) derived from BXPC-3 cells, the effects of DG on angiogenesis were detected by tube formation and western blot analysis. In vivo studies showed that the tumor growth and angiogenesis were greatly suppressed. The tumor weight inhibition rates of DG and 5-FU groups were about 42.36%, 38.94%, 43.80%, and 31.88%. Furthermore, the expression of CD31 and Caspase-1 were decreased. In vitro, CM derived from BXPC-3 cells which treated with DG could inhibit the tube formation and expression of pro-angiogenic NICD in HUVECs. Our study suggests that DG could suppress angiogenesis via the NLRP3/IL-18 pathway and may have the potential to inhibit tumor development.

Bioactive Aspergteroids G-J from Soft-Coral-Associated Symbiotic and Epiphytic Fungus Aspergillus terreus EGF7-0-1.

Two new disubstituted maleimides, aspergteroids G-H (1-2), and two trisubstituted butenolides aspergteroids I-J (3-4), along with four known analogs, were isolated and structurally identified from the fermentation extract of soft-coral-associated symbiotic and epiphytic fungus Aspergillus terreus EGF7-0-1. The structures of the new compounds were established mainly via spectroscopic data analyses, and their absolute configurations were determined via X-ray diffraction analysis and comparison of the calculated and experimental electronic circular dichroism. Myocardial protection assays showed that compounds 1, 2, 5, and 6 possess protective effects against tert-butyl hydroperoxide (TBHP)-induced H9c2 (rat myocardial cells) apoptosis at low concentrations. Based on the analyses of the protein-protein interaction (PPI) network and Western blotting, compound 1 may inhibit the apoptosis and inflammatory response of cardiomyocytes after TBHP induction and improve the antioxidant capacity of cardiomyocytes. We speculate that the anti-inflammatory response of compound 1 is suppressed by the glycogen synthase kinase-3 beta (GSK-3ß), downregulated by the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation, and suppressed by the expression of cysteinyl aspartate specific proteinase-3 (caspase-3) and B-cell lymphoma-2 associated X protein (Bax).

New Indole Diketopiperazine Alkaloids from Soft Coral-Associated Epiphytic Fungus Aspergillus versicolor CGF 9-1-2.

Two new indole diketopiperazine alkaloids (IDAs), (+)19-epi-sclerotiamide (1) and (-)19-epi-sclerotiamide (2), along with 13 known analogs (3-15), were isolated from a soft coral-associated epiphytic fungus Aspergillus versicolor CGF 9-1-2. The structures of two new compounds were established based on the combination of HR-ESI-MS, 1D and 2D NMR spectroscopy, optical rotation measurements and quantum chemical 13 C-NMR, the absolute configurations were determined by experimental and electronic circular dichroism (ECD) calculations. The results of molecular docking showed that all the compounds had a good binding with TDP1, TDP2, TOP1, TOP2, Ache, NLRP3, EGFR, EGFR L858R, EGFR T790M and EGFR T790/L858. Biological evaluation of compounds 3, 6, 8, 11 showed that 3 exerted a strong inhibitory effect on TDP2 with a rate of 81.72 %.

Investigate the metabolic profile and potential active compounds of Fructus Corni in the treatment of heart failure by applying ultra-performance liquid chromatography with quadrupole time-of-flight mass spectrometry and network pharmacology.

Fructus Corni has been reported to contain a wide variety of pharmacological effects and previous studies had revealed that Fructus Corni might protect the cardiac indices. However, the all-encompassing metabolic profile of Fructus Corni has not been well illuminated. In this research, high-sensitivity ultra-performance liquid chromatography with quadrupole time-of-flight mass spectrometry method was adopted to identify the metabolic profile after oral administration of Fructus Corni extract, especially the metabolic characterization of serum and heart, for which the targets and signaling pathways about heart failure were hunted through compound-target-disease-pathway intersection network. Ultimately, 37 ingredients were identified in Fructus Corni extract, and 22 prototypes and 134 metabolites that were identified in serum, heart, feces, and urine were tentatively characterized, which contained iridoids, flavonoids, tannins, organic acids, and others. Additionally, 10 putative key compounds including four prototypes and six phase I metabolites were screened by network pharmacology and molecular docking, among which, secoxyloganin (P7), loganin (P14), cornuside III (P17) and cornuside (P20) were the absorbed compounds to represent the potential active ingredients of Fructus Corni engaged in heart failure condition. In general, this method provided the combined strategy to preliminarily settle the complex of Fructus Corni's metabolic profiling and anti-heart failure pharmacologic activities.

Explore the Potential Ingredients for Detoxification of Honey-Fired Licorice (ZGC) Based on the Metabolic Profile by UPLC-Q-TOF-MS.

Licorice is well known for its ability to reduce the toxicity of the whole prescription in traditional Chinese medicine theory. However, honey-fired licorice (ZGC for short), which is made of licorice after being stir-fried with honey water, is more commonly used for clinical practice. The metabolism in vivo and detoxification-related compounds of ZGC have not been fully elucidated. In this work, the chemical constituents in ZGC and its metabolic profile in rats were both identified by high ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). The network pharmacology was applied to predict the potential detoxifying ingredients of ZGC. As a result, a total of 115 chemical compounds were identified or tentatively characterized in ZGC aqueous extract, and 232 xenobiotics (70 prototypes and 162 metabolites) were identified in serum, heart, liver, kidneys, feces, and urine. Furthermore, 41 compounds absorbed in serum, heart, liver, and kidneys were employed for exploring the detoxification of ZGC by network pharmacology. Ultimately, 13 compounds (five prototypes including P5, P24, P30, P41 and P44, and 8 phase Ⅰ metabolites including M23, M47, M53, M93, M100, M106, M118, and M134) and nine targets were anticipated to be potential mediums regulating detoxification actions. The network pharmacology analysis had shown that the ZGC could detoxify mainly through regulating the related targets of cytochrome P450 and glutathione. In summary, this study would help reveal potential active ingredients in vivo for detoxification of ZGC and provided practical evidence for explaining the theory of traditional Chinese medicine with modern technology.

Rare Carbon-Bridged Citrinin Dimers from the Starfish-Derived Symbiotic Fungus Penicillium sp. GGF16-1-2.

Four novel, rare carbon-bridged citrinin dimers, namely dicitrinones G-J (1-4), and five known analogs (5-9) were isolated from the starfish-derived fungus Penicillium sp. GGF 16-1-2. Their structures were elucidated by extensive spectroscopic analysis and quantum chemical calculations. Compounds 1-9 exhibited strong antifungal activities against Colletotrichum gloeosporioides with LD50 values from 0.61 µg/mL to 16.14 µg/mL. Meanwhile, all compounds were evaluated for their cytotoxic activities against human pancreatic cancer BXPC-3 and PANC-1 cell lines; as a result, compound 1 showed more significant cytotoxicities than the positive control against both cell lines. In addition, based on the analyses of the protein-protein interaction (PPI) network and Western blot, 1 could induce apoptosis by activating caspase 3 proteins (CASP3).

γ-Aromatic Butenolides of Microbial Source - A Review of Their Structures, Biological Activities and Biosynthesis.

γ-Aromatic butenolides (γ-AB) are an important type of structures found in many bioactive microbial secondary metabolites (SMs). γ-AB refer to a group of natural products (NPs) containing five-membered (unsaturated) lactones with 3-phenyl and 4-benzyl substituents. Their wide-range biological activities have inspired pharmaceutical chemists to explore its biosynthesis mechanisms and design strategies to construct the γ-AB skeleton. Recently, there are a great deal of interesting research progress on the structures, biological activities and biosynthesis of γ-AB. This review will focus on these aspects and summarize the important achievements of γ-AB from 1975 to 2021.

Synthesis and biological evaluation of marine natural product, Cryptoechinuline D derivatives as novel antiangiogenic agents.

Tumor angiogenesis is an important biological process involved in the proliferation and migration of endothelial cells, regulated by Ang/Tie-2 signaling pathways, which is essential for tumor growth and metastasis. Therefore, blocking Ang/Tie-2 signaling pathways is a promising anti-angiogenic strategy for tumor treatment. 2,5-Diketopiperazines (DKPs) are a kind of bioactive compounds derived from marine fungi and they present a wide spectrum of pharmacological properties, particularly in the field of cancer treatment. Herein, a DKP marine natural product, Cryptoechinuline D (Cry D) was applied to structural modification and twelve derivatives were synthesized. Among which, compound 5 showed significant inhibitory activity against HUVECs with an IC50 value of 12.6 µmol/L, which weakened the proliferation, migration and invasion of HUVECs by inhibiting the Ang2/Tie-2 signaling pathway. The results of these evaluations indicated that compound 5 might be a promising anti-angiogeneic agent and worth further optimization and development for cancer therapy.

Pyranodipyran Derivatives with Tyrosyl DNA Phosphodiesterase 1 Inhibitory Activities and Fluorescent Properties from Aspergillus sp. EGF 15-0-3.

Four new benzodipyran racemates, namely (±)-aspergiletals A-D (3-6), representing a rare pyrano[4,3-h]chromene scaffold were isolated together with eurotiumide G (1) and eurotiumide F (2) from the soft-coral-derived fungus Aspergillus sp. EGF 15-0-3. All the corresponding optically pure enantiomers were successfully separated by a chiral HPLC column. The structures and configurations of all the compounds were elucidated based on the combination of NMR and HRESIMS data, chiral separation, single-crystal X-ray diffraction, quantum chemical 13C NMR, and electronic circular dichroism calculations. Meanwhile, the structure of eurotiumide G was also revised. The TDP1 inhibitor activities and photophysical properties of the obtained compounds were evaluated. In the TDP1 inhibition assay, as a result of synergy between (+)-6 and (-)-6, (±)-6 displayed strong inhibitory activity to TDP1 with IC50 values of 6.50 ± 0.73 µM. All compounds had a large Stokes shift and could be utilized for elucidating the mode of bioactivities by fluorescence imaging.

Probing Indole Diketopiperazine-Based Hybrids as Environmental-Induced Products from Aspergillus sp. EGF 15-0-3.

Comprehensive analyses of the metabolite spectra of Aspergillus sp. EGF 15-0-3 under different culture conditions revealed the presence of unique environmental-induced metabolites exclusively from the rice medium. Subsequent target isolation afforded four unprecedented indole diketopiperazine-based hybrids with a pyrano[3',2':7,8]isochromeno[4,3-b]pyrazino[2,1-i]indole core (1 and 2) or a spiro[piperazine-2,2'-pyrano[3,4,5-de]chromene] scaffold (3 and 4). Putative biosynthetic pathways for 1-4, with Diels-Alder cycloadditions as key steps, were proposed. 1-4 exhibited selective cytotoxicities among several human cancer cells.

Chemical Constituents from Sargassum fusiforme (Harv.) Setch.

Phytochemical investigation of Sargassum fusiforme (Harv.) Setch. led to the discovery of fifteen secondary metabolites, including three sterols, three monoterpenes, five nitrogenous compounds, two fatty acids, and two others. Among them, two compounds are new, while the other thirteen compounds were isolated from S. fusiforme for the first time. The structures of the two new compounds were identified by NMR and HR-ESI-MS data analyses, and the absolute configurations were established by comparing the calculated and experimental ECD spectroscopic data.

New Indole Diketopiperazine Alkaloids from Soft Coral-Associated Epiphytic Fungus Aspergillus sp. EGF 15-0-3.

Three new indole diketopiperazine alkaloids, 11-methylneoechinulin E and variecolorin M, and (+)-variecolorin G, along with 12 known analogs, were isolated from a soft coral-associated epiphytic fungus Aspergillus sp. EGF 15-0-3. The structures of the new compounds were unambiguously established by extensive spectroscopic analyses including HR-ESI-MS, 1D and 2D NMR spectroscopy and optical rotation measurements. The absolute configurations of (+)- and (-)-variecolorin G were determined by experimental and quantum-chemical ECD investigations and single-crystal X-ray diffraction analysis. Variecolorin G is a pair of enantiomeric mixtures with a ratio of 1 : 2. Moreover, (+)-neoechinulin A is firstly reported as a natural product. The cytotoxic activities of all the isolated compounds against NCI-H1975 gefitinib resistance (NCI-H1975/GR) cell lines were preliminarily evaluated by MTT method.

Structural characterization and discrimination of Paris polyphylla var. yunnanensis by a molecular networking strategy coupled with ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry.

RATIONALE: Paris polyphylla var. yunnanensis (Franch) Hand Mazz (PPY) is a traditional Chinese medicine with antitumor, antibacterial, hemostatic, and anthelmintic activities. Identification of the chemical composition in PPY is helpful to discover its active ingredients and can be used to establish its quality control protocols. METHODS: The composition of PPY was identified using ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UHPLC/QTOF-MS/MS) coupled with a molecular networking strategy. First, the UHPLC/QTOF-MS/MS approach was optimized for chemical compound profiling. Then, the MS data were processed using PeakView™ combined with an in-house database to quickly characterize the secondary metabolites. Finally, molecular networking excavated new molecular weights to discover unknown or trace natural products based on the characteristics of each cluster. RESULTS: A total of 222 compounds, including 77 isospirostanols, 2 spirostanols, 19 furostanols, 10 pseudospirostanols, 6 cholesterols, 10 C21 steroids, 5 insect metamorphosis hormones, 3 plant sterols, 6 five-ring triterpenoids, 4 flavonoids, 8 fatty acids, 2 phenylpropanoids, and 8 other compounds, were characterized in PPY by comparing their main fragmentation characteristics and pathways with the literature data, and 62 of them, 54 steroidals and 8 phenylpropanoids, were discovered or tentatively identified for the first time. CONCLUSIONS: This study extended the application of a molecular networking strategy to traditional herbal medicines and developed a molecular networking based screening approach with a significant increase in efficiency for the discovery and identification of trace novel natural products.

High Specific Capacitance of the Electrodeposited MnO2 on Porous Foam Nickel Soaked in Alcohol and its Dependence on Precursor Concentration.

In this work, we used the mixed solution of manganese acetate and sodium sulfate to deposit manganese dioxide on the three-dimensional porous nickel foam that was previously soaked in alcohol, and then the effects of solution concentrations on their capacitance properties were investigated. The surface morphology, microstructure, elemental valence and other information of the material were observed by scanning electron microscope (SEM), Transmission Electron Microscope (TEM), X-ray photoelectron spectroscopy (XPS), etc. The electrochemical properties of the material were tested by Galvanostatic charge-discharge (GCD), Cyclic Voltammetry (CV), Chronoamperometry (CA), Electrochemical impedance spectroscopy (EIS), etc. The MnO2 electrode prepared at lower concentrations can respectively reach a specific capacitance of 529.5 F g-1 and 237.3 F g-1 at the current density of 1 A g-1 and 10 A g-1, and after 2000 cycles, the capacity retention rate was still 79.8% of the initial capacitance, and the energy density can even reach 59.4 Wh Kg-1, while at the same time, it also has a lower electrochemical impedance (Rs = 1.18 Ω, Rct = 0.84 Ω).

New glycosylsphingolipids from Psychotria serpens L.

In clinical, Psychotria serpens L. was often substitute for Caulis trachelospermi to treat cancer in China. Meanwhile, EtOAc and n-BuOH fractions of MeOH extract of P. serpens L. show power activity against H460, HepG2, Hela, and PC9/GR cell lines, and no toxic effects against normal 16HBE cell lines. In our ongoing search for bioactive novel compounds from Chinese material medica, one new type of glycosylsphingolipids Psychotramide (1a-1c) were isolated from P. serpens L., and their structures were identified through spectroscopic techniques including NMR (1D and 2D) and MS (LC-MS, and GC-MS).

Enantiomeric Polyketides from the Starfish-Derived Symbiotic Fungus Penicillium sp. GGF16-1-2.

One new racemic mixture, penicilliode A (1) and four pairs of enantiomeric polyketides, penicilliode B and C (2 and 3) and coniochaetone B and C (4 and 5), were obtained from the starfish-derived symbiotic fungus Penicillium sp. GGF16-1-2. Interestingly, the strain GGF16-1-2 can produce enantiomers. The absolute configuration of 1 was determined by X-ray diffraction (XRD) analysis, and the absolute configurations of 2-4 were determined by the optical rotation (OR) values and electronic circular dichroism (ECD) calculations. Compounds 1-5 were firstly isolated from the marine-derived fungus Penicillium as racemates, and 2-5 were separated by HPLC with a chiral stationary phase. All the compounds were evaluated for their antibacterial, cytotoxic and inhibitory activities against PDE4D2.