Polyketides from the mangrove-derived fungus Penicillium robsamsonii HNNU0006.

Seven polyketides, including an undescribed depsidone (1) and six previously reported 3,6,8-trihydroxy-1-methylxanthone (2), 7-hydroxy-2-(2-hydroxypropyl)-5-methylchromone (3), methyl3-chloro-6-hydroxy-2-(4-hy-droxy-2-methoxy-6-methylphenoxy)-4- methoxybenzoate (4), xylarianin A (5), 4,5-dihydroxy-6-(6'-methylsalicyloxy)-2-hydro-xymethyl-2-cyclohexen-1-one (6) and alternariol (7), have been isolated from cultures of the mangrove-derived fungus Penicillium robsamsonii HNNU0006. The structure of compound 1 was elucidated by extensive spectroscopic analysis and X-ray crystallography. Furthermore, all the compounds were evaluated their cytotoxic activities, and compounds 1 and 7 showed weak cytotoxicity against two cell lines Vero and A549 with IC50 values ranging from 95.6 and 296.5 µM, relative to the positive control Etoposide phosphate with IC50 values of 24.5 and 18.7 µM, respectively.

Recent Discovery of Nitrogen Heterocycles from Marine-Derived Aspergillus Species.

Nitrogen heterocycles have drawn considerable attention because of their structurally novel and significant biological activities. Marine-derived fungi, especially the Aspergillus species, possess unique metabolic pathways to produce secondary metabolites with novel structures and potent biological activities. This review prioritizes the structural diversity and biological activities of nitrogen heterocycles that are produced by marine-derived Aspergillus species from January 2019 to January 2024, and their relevant biological activities. A total of 306 new nitrogen heterocycles, including seven major categories-indole alkaloids, diketopiperazine alkaloids, quinazoline alkaloids, isoquinoline alkaloids pyrrolidine alkaloids, cyclopeptide alkaloids, and other heterocyclic alkaloids-are presented in this review. Among these nitrogen heterocycles, 52 compounds had novel skeleton structures. Remarkably, 103 compounds showed various biological activities, such as cytotoxic, antimicrobial, anti-inflammatory, antifungal, anti-virus, and enzyme-inhibitory activities, and 21 compounds showed potent activities. This paper will guide further investigations into the structural diversity and biological activities of nitrogen heterocycles derived from the Aspergillus species and their potential contributions to the future development of new natural drug products in the medicinal and agricultural fields.

[Two new pinophol derivatives from endophytic fungus Penicillium herquei JX4 hosted in Ceriops tagal].

An OSMAC strategy was used to study secondary metabolites and anti-inflammatory activities of the endophytic fungus Penicillium herquei JX4 hosted in Ceriops tagal. The PDB ferment of fungus P. herquei JX4 was isolated, purified, and identified by using silica gel column chromatography, gel column chromatography, octadecylsilyl(ODS) column chromatography, and semi-preparative high-performance liquid chromatography. Two new pinophol derivatives, pinophol H(1) and pinophol I(2) were isolated and identified, and they were evaluated in terms of the inhibitory activities against the nitric oxide(NO) production induced by lipopolysaccharide(LPS) in mouse macrophage RAW264.7 cells. The results showed that compound 1 had significant inhibitory activity on NO production, with an IC_(50) value of 8.12 µmol·L~(-1).

Hexadecanoic acid produced in the co-culture of S. cerevisiae and E.coli promotes oxidative stress tolerance of the S.cerevisiae cells.

Co-fermentation performed by Saccharomyces cerevisiae and Escherichia coli or other microbes has been widely used in industrial fermentation. Meanwhile, the co-cultured microbes might regulate each other's metabolisms or cell behaviors including oxidative stress tolerance through secreting molecules. Here, results based on the co-culture system of S. cerevisiae and E. coli suggested the promoting effect of E. coli on the oxidative stress tolerance of S. cerevisiae cells. The co-cultured E. coli could enhance S. cerevisiae cell viability through improving its membrane stability and reducing the oxidized lipid level. Meanwhile, promoting effect of the co-cultured supernatant on the oxidative stress tolerance of S. cerevisiae illustrated by the supernatant substitution strategy suggested that secreted compounds contained in the co-cultured supernatant contributed to the higher oxidative stress tolerance of S. cerevisiae. The potential key regulatory metabolite (i.e., hexadecanoic acid) with high content difference between co-cultured supernatant and the pure-cultured S. cerevisiae supernatant was discovered by GC-MS-based metabolomics strategy. And exogenous addition of hexadecanoic acid did suggest its contribution to higher oxidative stress tolerance of S. cerevisiae. Results presented here would contribute to the understanding of the microbial interactions and provide the foundation for improving the efficiency of co-fermentation performed by S. cerevisiae and E. coli.

Isolation, Identification and Chemical Modification of Bufadienolides from Bufo melanostictus Schneider and Their Cytotoxic Activities against Prostate Cancer Cells.

The traditional Chinese medicine toad venom (Venenum bufonis) has been extensively used to treat various diseases, including cancers, in China and other Southeast Asian countries. The major constituents of toad venom, e.g., bufadienolides and alkaloids, exhibit broad-spectrum pharmacological effects in cancers. Herein, two new bufadienolides (1 and 2), along with eleven known compounds (3-13) were successfully isolated from Bufo melanostictus Schneider. Their structures were elucidated by extensive spectroscopic data and X-ray diffraction analysis. Furthermore, four lactam derivatives were synthesized through the transformation of bufadienolides lactones. The inhibitory effects of these compounds against human prostate cancer cell lines PC-3 and DU145 were evaluated. The outcomes indicated a notable trend, with a substantial subset displaying nanomolar range IC50 values against PC-3 and DU145 cells, underscoring their pronounced cytotoxicity. Moreover, a noteworthy distinction surfaces, wherein lactones consistently outperformed their lactam counterparts, further validating their heightened potency for the treatment of prostate cancer. This study contributes significant preclinical evidence substantiating the therapeutic viability of bufadienolides and toad venom as intervention strategies for prostate cancer.

Structures and Biological Activities of Secondary Metabolites from Xylaria spp.

The fungus genus Xylaria is an important source of drug discoveries in scientific fields and in the pharmaceutical industry due to its potential to produce a variety of structured novel and bioactive secondary metabolites. This review prioritizes the structures of the secondary metabolites of Xylaria spp. from 1994 to January 2024 and their relevant biological activities. A total of 445 new compounds, including terpenoids, nitrogen-containing compounds, polyketides, lactones, and other classes, are presented in this review. Remarkably, among these compounds, 177 compounds show various biological activities, including cytotoxic, antimicrobial, anti-inflammatory, antifungal, immunosuppressive, and enzyme-inhibitory activities. This paper will guide further investigations into the structures of novel and potent active natural products derived from Xylaria and their potential contributions to the future development of new natural drug products in the agricultural and medicinal fields.

Regulation of the PFK1 gene on the interspecies microbial competition behavior of Saccharomyces cerevisiae.

Saccharomyces cerevisiae is a widely used strain for ethanol fermentation; meanwhile, efficient utilization of glucose could effectively promote ethanol production. The PFK1 gene is a key gene for intracellular glucose metabolism in S. cerevisiae. Our previous work suggested that although deletion of the PFK1 gene could confer higher oxidative tolerance to S. cerevisiae cells, the PFK1Δ strain was prone to contamination by other microorganisms. High interspecies microbial competition ability is vital for the growth and survival of microorganisms in co-cultures. The result of our previous studies hinted us a reasonable logic that the EMP (i.e., the Embden-Meyerhof-Parnas pathway, the glycolytic pathway) key gene PFK1 could be involved in regulating interspecies competitiveness of S. cerevisiae through the regulation of glucose utilization and ethanol production efficiency. The results suggest that under 2% and 5% glucose, the PFK1Δ strain showed slower growth than the S288c wild-type and TDH1Δ strains in the lag and exponential growth stages, but realized higher growth in the stationary stage. However, relative high supplement of glucose (10%) eliminated this phenomenon, suggesting the importance of glucose in the regulation of PFK1 in yeast cell growth. Furthermore, during the lag growth phase, the PFK1Δ strain displayed a decelerated glucose consumption rate (P < 0.05). The expression levels of the HXT2, HXT5, and HXT6 genes decreased by approximately 0.5-fold (P < 0.05) and the expression level of the ZWF1 exhibited a onefold increase in the PFK1Δ strain compared to that in the S. cerevisiae S288c wild-type strain (P < 0.05).These findings suggested that the PFK1 inhibited the uptake and utilization of intracellular glucose by yeast cells, resulting in a higher amount of residual glucose in the medium for the PFK1Δ strain to utilize for growth during the reverse overshoot stage in the stationary phase. The results presented here also indicated the potential of ethanol as a defensive weapon against S. cerevisiae. The lower ethanol yield in the early stage of the PFK1Δ strain (P < 0.001) and the decreased expression levels of the PDC5 and PDC6 (P < 0.05), which led to slower growth, resulted in the strain being less competitive than the wild-type strain when co-cultured with Escherichia coli. The lower interspecies competitiveness of the PFK1Δ strain further promoted the growth of co-cultured E. coli, which in turn activated the ethanol production efficiency of the PFK1Δ strain to antagonize it from E. coli at the stationary stage. The results presented clarified the regulation of the PFK1 gene on the growth and interspecies microbial competition behavior of S. cerevisiae and would help us to understand the microbial interactions between S. cerevisiae and other microorganisms. KEY POINTS: • PFK1Δ strain could realize reverse growth overshoot at the stationary stage • PFK1 deletion decreased ethanol yield and interspecific competitiveness • Proportion of E. coli in co-culture affected ethanol yield capacity of yeast cells.

XQZ3, a Chlorella pyrenoidosa polysaccharide suppresses cancer progression by restraining mitochondrial bioenergetics via HSP90/AKT signaling pathway.

The mitochondria are known to exert significant influence on various aspects of cancer cell physiology. The suppression of mitochondrial function represents a novel avenue for the advancement of anti-cancer pharmaceuticals. The heat shock protein HSP90 functions as a versatile regulator of mitochondrial metabolism in cancer cells, rendering as a promising target for anticancer interventions. In this work, a novel acid polysaccharide named as XQZ3 was extracted from Chlorella pyrenoidosa and purified by DEAE-cellulose and gel-filtration chromatography. The structural characteristic of XQZ3 was evaluated by monosaccharides composition, methylation analysis, TEM, FT-IR, and 2D-NMR. It was found that XQZ3 with a molecular weight of 29.13 kDa was a complex branched polysaccharide with a backbone mainly composed of galactose and mannose. It exhibited good antitumor activity in vitro and in vivo by patient-derived 3D organoid models and patient-derived xenografts models. The mechanistic investigations revealed that XQZ3 specifically interacted with HSP90, impeding the activation of the HSP90/AKT/mTOR signaling cascade. This, in turn, led to the induction of mitochondrial dysfunction, autophagy, and apoptosis, ultimately resulting in the demise of cancer cells due to nutrient deprivation. This study offers a comprehensive theoretical foundation for the advancement of XQZ3, a novel polysaccharide inhibitor targeting HSP90, with potential as an effective therapeutic agent against cancer.

Alkaloid-metabolites from the mangrove-derived fungus Penicillium robsamsonii HNNU0006.

Nine metabolites, including three undescribed alkaloids pyripyropenes VW (1-2), penicioxa A (4), two previously reported pyripyropene A (3), oxaline (5), three grisephenone-type xanthone derivatives (6-8), and a diphenyl ether derivative 4-chloro-7,4'-dihydroxy-5,2'-dimethoxy-2-methylformate-6'-methybenzophone (9), were isolated from cultures of the mangrove-derived fungus Penicillium robsamsonii HNNU0006. Their structures were determined by spectroscopic analysis, ECD calculations, together with DP4+ probability analysis. Furthermore, all the isolated compounds were tested for cytotoxicity and anti-phytopathogenic fungal activities. Compounds 6-8 showed moderate cytotoxicity against tumor cell lines A549, with IC50 values ranging from 5.68 ± 0.21 to 9.71 ± 0.34 µg/mL, respectively.

Bioactive polyketides and meroterpenoids from the mangrove-derived fungus Talaromyces flavus TGGP35.

Six new polyketides, which includes three new lactones (talarotones A-C) (1-3), one new polyketide (talarotide A) (4), two new polyenes (talaroyenes A, B) (5, 6), together with one new meroterpenoid (talaropenoid A) (7) and 13 known compounds (8-20) were isolated from the mangrove-derived fungus Talaromyces flavus TGGP35. The structure and configuration of the compounds 1-7 were elucidated from the data obtained from HR-ESI-MS, IR, 1D/2D NMR spectroscopy, Mo2 (OAc)4-induced electronic circular dichroism (ECD), CD spectroscopy, and modified Mosher's method. Compounds 5 and 20 displayed antioxidant activity with IC50 values of 0.40 and 1.36 mM, respectively. Compounds 3, 6, 11, 16, and 17 displayed cytotoxic activity against human cancer cells Hela, A549, and had IC50 values ranging from 28.89 to 62.23 µM. Compounds 7, 10-12, and 14-18 exhibited moderate or potent anti-insect activity against newly hatched larvae of Helicoverpa armigera Hubner, with IC50 values in the range 50-200 µg/mL. Compound 18 showed antibacterial activity against Ralstonia solanacearum with the MIC value of 50 µg/mL.

Drimane-type sesquiterpenoids and their anti-inflammatory evaluation from Pyrrhoderma noxium HNNU0524.

Chemical investigation of a culture broth from the marine-derived fungus Pyrrhoderma noxium HNNU0524 yielded two new compounds including a drimane-type sesquiterpenoid named pyrrnoxin A (1) and a benzoic acid derivative, pyrrnoxin B (5), together with three related known analogues (2-4). The chemical structures of 1 and 5 were determined by detailed analysis of spectroscopic data, single-crystal X-ray crystallography, quantum mechanics-based DP4+ and ECD calculations. Compounds 2 and 3 moderately inhibited NO production of lipopolysaccharide-induced microglia cells BV2 with IC50 values of 26.6 and 60.5 µM, respectively.

Four New Polyhydroxy Cyclohexanes from the Stems of Fissistigma tientangense.

Four undescribed polyhydroxy cyclohexanes, fissoxhydrylenes A-D (1-4), together with two known biogenetically related polyhydroxy cyclohexanes (5 and 6) were isolated from the stems of Fissistigma tientangense Tsiang et P. T. Li. Their structures were elucidated by detailed analysis of NMR, HR-ESI-MS, IR, UV and Optical rotations data. The absolute configuration of 1 was confirmed by X-ray crystallographic. The absolute configurations of 2-4 were confirmed by chemical reaction and optical rotations. Compound 4 represent the first example of a no substituent polyhydroxy cyclohexanes from natural products. All isolated compounds were evaluated for their anti-inflammatory activities against the lipopolysaccharide-induced nitric oxide (NO) production in mouse macrophage RAW 264.7 cells in vitro. Compounds 3 and 4 showed inhibitory activities with the IC50 values of 16.63±0.06 µM and 14.38±0.08 µM, respectively.

Toad venom-derived bufadienolides and their therapeutic application in prostate cancers: Current status and future directions.

Cancer is the second leading cause of death worldwide. Specially, the high incidence rate and prevalence of drug resistance have rendered prostate cancer (PCa) a great threat to men's health. Novel modalities with different structures or mechanisms are in urgent need to overcome these two challenges. Traditional Chinese medicine toad venom-derived agents (TVAs) have shown to possess versatile bioactivities in treating certain diseases including PCa. In this work, we attempted to have an overview of bufadienolides, the major bioactive components in TVAs, in the treatment of PCa in the past decade, including their derivatives developed by medicinal chemists to antagonize certain drawbacks of bufadienolides such as innate toxic effect to normal cells. Generally, bufadienolides can effectively induce apoptosis and suppress PCa cells in-vitro and in-vivo, majorly mediated by regulating certain microRNAs/long non-coding RNAs, or by modulating key pro-survival and pro-metastasis players in PCa. Importantly, critical obstacles and challenges using TVAs will be discussed and possible solutions and future perspectives will also be presented in this review. Further in-depth studies are clearly needed to decipher the mechanisms, e.g., targets and pathways, toxic effects and fully reveal their application. The information collected in this work may help evoke more effects in developing bufadienolides as therapeutic agents in PCa.

Bioactive secondary metabolites from tomato-derived bacterium Bacillus velezensis Hnu24.

A series of secondary metabolites have been isolated from the genus of Bacillus velezensis, most of which show antibacterial and insecticidal activities. In order to find more bioactive secondary metabolites from B. velezensis, one new natural component aminoindole dimer baciindole A (1), together with seven known compounds (2-8) were isolated from the tomato-derived bacterium Bacillus velezensis Hnu24. The structure of compound 1 was elucidated by its HR-ESI-MS spectral data and 1 D/2D NMR spectroscopic analysis. Compound 3 showed antibacterial activity against Staphylococcus aureus, S. epidermidis and Ralstonia solanacearum with the MIC values of 3.125, 12.5 and 50 µg/mL, respectively. Compound 4 showed antibacterial activity against S. aureus with the MIC value of 12.5 µg/mL. Compound 3 showed cytotoxic activity for human colon cancer HTC116 cancer cells with the IC50 value of 8.42 ± 0.48 µM. Five compounds (1-4 and 8) were obtained from the strain of B. velezensis for the first time. These results indicated that 3 will be useful in developing antimicrobial and treatment of colon cancer agents.

Targeted isolation of prenylated indole alkaloids from the marine-derived fungus Penicillium janthinellum HK1­6 using molecular networking.

Four prenylated indole alkaloids (1-4) were targeted isolated from the mangrove rhizosphere soil-derived fungus Penicillium janthinellum HK1-6 by using molecular networking strategies. Among them, the planar structure and relative configuration of notoamide X (1) were elucidated by detailed analysis of the spectroscopic data especially the NOESY spectrum for the first time and its absolute configuration was determined by ECD spectrum. Furthermore, curated molecular networks of MS/MS data were generated with GNPS which allowed highlighting six prenylated indole alkaloids (5, 6, 8, 9, 11, 12) that had not previously been identified in this fungus and two (7, 10) that had never been observed in any fungus. The MS/MS fragmentation pathway of these prenylated indole alkaloids was summarized.

Three new long-chain polyenes from the mangrove-derived fungus Penicillium herquei JX4.

One new epimer pair of long-chain polyenes penicilqueis E (1) and F (2), and one new long-chain polyene pinophol G (3), along with one known compound (4), were obtained from EtOAc extract of the mangrove-derived fungus Penicillium herquei JX4. Their structures were elucidated by detailed analysis of comprehensive spectroscopic data. The inhibitory activities of all compounds against the nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells in vitro were evaluated.

Exopolysaccharides from Marine Microbes: Source, Structure and Application.

The unique living environment of marine microorganisms endows them with the potential to produce novel chemical compounds with various biological activities. Among them, the exopolysaccharides produced by marine microbes are an important factor for them to survive in these extreme environments. Up to now, exopolysaccharides from marine microbes, especially from extremophiles, have attracted more and more attention due to their structural complexity, biodegradability, biological activities, and biocompatibility. With the development of culture and separation methods, an increasing number of novel exopolysaccharides are being found and investigated. Here, the source, structure and biological activities of exopolysaccharides, as well as their potential applications in environmental restoration fields of the last decade are summarized, indicating the commercial potential of these versatile EPS in different areas, such as food, cosmetic, and biomedical industries, and also in environmental remediation.

Oxalierpenes A and B, Unusual Indole-Diterpenoid Derivatives with Antiviral Activity from a Marine-Derived Strain of the Fungus Penicillium oxalicum.

Oxalierpenes A and B (1 and 2), two unusual indole-diterpenoid derivatives, were obtained from the marine-derived fungus Penicillium oxalicum. The absolute configurations of 1 and 2 were elucidated by calculated TDDFT ECD and DP4plus methods. Oxalierpene A (1) represents the first indole-diterpenoid derivative with a five-membered ring of 4-hydroxy-5,5-dimethyldihydrofuran-3-one as a side chain. Oxalierpene B (2) has a unique 6/5/6/5/5/6/6/5/5 ring system. Compounds 1 and 2 showed antiviral activity against the H1N1 virus and respiratory syncytial virus (RSV), with IC50 values ranging from 2.8 to 9.4 µM.

Talaromarins A-F: Six New Isocoumarins from Mangrove-Derived Fungus Talaromyces flavus TGGP35.

Six new isocoumarin derivative talaromarins A-F (1-6), along with 17 known analogues (7-23), were isolated from the mangrove-derived fungus Talaromyces flavus (Eurotiales: Trichocomaceae) TGGP35. Their structures were identified by detailed IR, UV, 1D/2D NMR and HR-ESI-MS spectra. The absolute configurations of new compounds were determined by the modified Mosher's method and a comparison of their CD spectra with dihydroisocoumarins described in the literature. The antioxidant, antibacterial, anti-phytopathogenic and inhibitory activity against α-glucosidase of all the isolated compounds were tested. Compounds 6-11, 17-19 and 21-22 showed similar or better antioxidant activity than the IC50 values ranging from 0.009 to 0.27 mM, compared with the positive control trolox (IC50 = 0.29 mM). Compounds 10, 18, 21 and 23 exhibited strong inhibitory activities against α-glucosidase with IC50 values ranging from 0.10 to 0.62 mM, while the positive control acarbose had an IC50 value of 0.5 mM. All compounds showed no antibacterial or anti-phytopathogenic activity at the concentrations of 50 µg/mL and 1 mg/mL, respectively. These results indicated that isocoumarins will be useful to developing antioxidants and as diabetes control agents.

A Mini-Review of Flavone Isomers Apigenin and Genistein in Prostate Cancer Treatment.

The initial responses to standard chemotherapies among prostate cancer (PCa) patients are usually significant, while most of them will finally develop drug resistance, rendering them with limited therapies. To discover new regimens for the treatment of PCa including resistant PCa, natural products, the richest source of bioactive compounds, can serve as a library for screening and identifying promising candidates, and flavones such as apigenin and genistein have been used in lab and clinical trials for treating PCa over decades. In this mini-review, we take a look into the progress of apigenin and genistein, which are isomers, in treating PCa in the past decade. While possessing very similar structure, these two isomers can both target the same signaling pathways; they also are found to work differently in PCa cells. Given that more combinations are being developed and tested, genistein appears to be the more promising option to be approved. The anticancer efficacies of these two flavones can be confirmed by in-vitro and in-vivo studies, and their applications remain to be validated in clinical trials. Information gained in this work may provide important information for new drug development and the potential application of apigenin and genistein in treating PCa.