Cytotoxic Compounds from Marine Fungi: Sources, Structures, and Bioactivity.

Marine fungi, such as species from the Penicillium and Aspergillus genera, are prolific producers of a diversity of natural products with cytotoxic properties. These fungi have been successfully isolated and identified from various marine sources, including sponges, coral, algae, mangroves, sediment, and seawater. The cytotoxic compounds derived from marine fungi can be categorized into five distinct classes: polyketides, peptides, terpenoids and sterols, hybrids, and other miscellaneous compounds. Notably, the pre-eminent group among these compounds comprises polyketides, accounting for 307 out of 642 identified compounds. Particularly, within this collection, 23 out of the 642 compounds exhibit remarkable cytotoxic potency, with IC50 values measured at the nanomolar (nM) or nanogram per milliliter (ng/mL) levels. This review elucidates the originating fungal strains, the sources of isolation, chemical structures, and the noteworthy antitumor activity of the 642 novel natural products isolated from marine fungi. The scope of this review encompasses the period from 1991 to 2023.

Phytochemistry and Biological Studies of Endemic Hawaiian Plants.

The Hawaiian Islands are renowned for their exceptional biodiversity and are host to a plethora of endemic plant species, which have been utilized in traditional Hawaiian medicine. This scientific review provides an in-depth analysis of the phytochemistry and biological studies of selected endemic Hawaiian plants, highlighting their medicinal properties and therapeutic potential. A literature search was conducted, utilizing major academic databases such as SciFinder, Scopus, Web of Science, PubMed, Google Scholar, Science Direct, and the Scientific Information Database. The primary objective of this search was to identify relevant scholarly articles pertaining to the topic of the review, which focused on the phytochemistry and biological studies of endemic Hawaiian plants. Utilizing these databases, a comprehensive range of literature was obtained, facilitating a comprehensive examination of the subject matter. This review emphasizes the rich phytochemical diversity and biological activities found in Endemic Hawaiian plants, showcasing their potential as sources of novel therapeutic agents. Given the unique biodiversity of Hawaii and the cultural significance of these plants, continued scientific exploration, conservation, and sustainable utilization of these valuable resources is necessary to unlock the full potential of these plant species in drug discovery and natural product-based therapeutics.

Hawaiian Plants with Beneficial Effects on Sleep, Anxiety, and Mood, etc.

Diverse chemical messengers are responsible for maintaining homeostasis in the human body, for example, hormones and neurotransmitters. Various Hawaiian plant species produce compounds that exert effects on these messengers and the systems of which they are a part. The main purpose of this review article is to evaluate the potential effects of Hawaiian plants on reducing pain and anxiety and improving sleep and mood. A comprehensive literature search was conducted in SciFinder, PubMed, Science Direct, Scopus, Google Scholar, and Scientific Information Database between 2019 and 2023 to identify related articles. Results indicate that several Hawaiian plant species, such as M. citrifolia and P. methysticum, have medicinal properties associated with these effects. These plants have been used in traditional Hawaiian cultural practices for centuries, suggesting their potential to benefit human health and well-being. This review presents a comprehensive analysis of the available evidence concerning the potential impacts of Hawaiian plants on sleep, anxiety, mood, and pain.

A Comprehensive Insight into Mamaki (Pipturus albidus): Its Ethnomedicinal Heritage, Human Health Research, and Phytochemical Properties.

In Hawaii, the plants P. albidus, P. forbesii, P. kauaiensis, and P. ruber are collectively known as mamaki in ethnomedicine, where P. albidus predominates. Farmed mamaki is becoming increasingly popular in Hawaii and the United States. Mamaki teas (such as bottled Shaka tea) are the dominant product. Historically, mamaki has been utilized for its medicinal properties, promoting well-being and good health through consuming tea made from its leaves, ingesting its fruit, and incorporating it into ointments. Mamaki holds cultural significance among Native Hawaiians and is widely used in ethnic medicine, having been incorporated into traditional practices for centuries. However, the scientific mechanisms behind its effects remain unclear. This review consolidates current knowledge of mamaki, shedding light on its potential therapeutic properties, physical properties, nutritional and mineral composition, and active phytochemicals. We also highlight recent research advances in mamaki's antibacterial, anti-viral, chemopreventive, anti-inflammatory, and antioxidant activities. Additionally, we discuss future prospects in this field.

Exploring Diversity through Dimerization in Natural Products by a Rational Tandem Mass-Based Molecular Network Strategy.

The step- and atom-efficient dimerization strategy is frequently used in nature to build structural complexity and diversity. We propose the rationale and structural features of the versatile monomers that are responsible for "diversity through dimerization". Using 5-FAM-maleimide combined with a UHPLC-MS/MS-FBMN workflow, we successfully identified a diverse set of dimeric natural products from fungus Panus rudis F01315, in which all four complex 4'5-ring scaffolds are derived from one monomeric epoxyquinol and endowed with functional diversity.

Chemical Stability of Petrichorins.

The structure of petrichorin C1 (4) converted from petrichorin C (3) was determined using NMR spectroscopy and X-ray crystallography. The chemical stability of petrichorins A and C (1 and 3) was investigated by NMR spectroscopy, X-ray crystallography, and calculations.

Dual Beneficial Effects of Methylnissolin-3-O-ß-d-Glucopyranoside on Obesity-Induced Inflammatory Responses in Adipocyte-Macrophage Co-Culture.

Methylnissolin-3-O-ß-d-glucopyranoside (MNG) is a pterocarpan analog, which protects EA.hy926 cells against oxidative damage through the Nrf2/HO-1 pathway. However, the effects of MNG on obesity-induced inflammatory responses in adipocyte-macrophage co-culture remain unclear. A differentiated murine preadipocyte cell line (3T3-L1) was co-cultured with a murine macrophage cell line (RAW264.7). Intracellular lipid accumulation was determined using Oil Red O staining. Western blotting was performed to investigate the expression of adipogenesis- and inflammation-associated proteins. Cell culture supernatants were assayed using ELISA kits to measure the levels of proinflammatory cytokines such as interleukin 6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1). MNG inhibited lipid accumulation and the production of IL-6 and MCP-1 in the 3T3-L1 and RAW264.7 cell co-culture. Moreover, MNG inhibited the protein expression of CCAAT/enhancer-binding protein alpha (C/EBPα), C/EBPß, peroxisome proliferator-activated receptor γ (PPARγ), cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS) under the same co-culture conditions. MNG also inhibited IL-6 and MCP-1 production compared with the co-culture control. These findings demonstrate that MNG inhibited lipid accumulation and inflammatory response by downregulating IL-6 and MCP-1 production and protein expression of C/EBPß, C/EBPα, PPARγ, COX-2, and iNOS in co-culture conditions with 3T3-L1 and RAW264.7 cells. These results suggest that MNG may be beneficial in preventing obesity-related inflammatory status.

Sulfur-Containing Compounds from Endophytic Fungi: Sources, Structures and Bioactivities.

Endophytic fungi have attracted increasing attention as an under-explored source for the discovery and development of structurally and functionally diverse secondary metabolites. These microorganisms colonize their hosts, primarily plants, and demonstrate diverse ecological distribution. Among endophytic fungal natural products, sulfur-containing compounds feature one or more sulfur atoms and possess a range of bioactivities, e.g., cytotoxicity and antimicrobial activities. These natural products mainly belong to the classes of polyketides, nonribosomal peptides, terpenoids, and hybrids. Here, we reviewed the fungal producers, plant sources, chemical structures, and bioactivities of 143 new sulfur-containing compounds that were reported from 1985 to March 2022.

Fusarium fruiting body microbiome member Pantoea agglomerans inhibits fungal pathogenesis by targeting lipid rafts.

Plant-pathogenic fungi form intimate interactions with their associated bacterial microbiota during their entire life cycle. However, little is known about the structure, functions and interaction mechanisms of bacterial communities associated with fungal fruiting bodies (perithecia). Here we examined the bacterial microbiome of perithecia formed by Fusarium graminearum, the major pathogenic fungus causing Fusarium head blight in cereals. A total of 111 shared bacterial taxa were identified in the microbiome of 65 perithecium samples collected from 13 geographic locations. Within a representative culture collection, 113 isolates exhibited antagonistic activity against F. graminearum, with Pantoea agglomerans ZJU23 being the most efficient in reducing fungal growth and infectivity. Herbicolin A was identified as the key antifungal compound secreted by ZJU23. Genetic and chemical approaches led to the discovery of its biosynthetic gene cluster. Herbicolin A showed potent in vitro and in planta efficacy towards various fungal pathogens and fungicide-resistant isolates, and exerted a fungus-specific mode of action by directly binding and disrupting ergosterol-containing lipid rafts. Furthermore, herbicolin A exhibited substantially higher activity (between 5- and 141-fold higher) against the human opportunistic fungal pathogens Aspergillus fumigatus and Candida albicans in comparison with the clinically used fungicides amphotericin B and fluconazole. Its mode of action, which is distinct from that of other antifungal drugs, and its efficacy make herbicolin A a promising antifungal drug to combat devastating fungal pathogens, both in agricultural and clinical settings.

Biochemical and structural characterization of Haemophilus influenzae nitroreductase in metabolizing nitroimidazoles.

Nitroheterocycle antibiotics, particularly 5-nitroimidazoles, are frequently used for treating anaerobic infections. The antimicrobial activities of these drugs heavily rely on the in vivo bioactivation, mainly mediated by widely distributed bacterial nitroreductases (NTRs). However, the bioactivation can also lead to severe toxicities and drug resistance. Mechanistic understanding of NTR-mediated 5-nitroimidazole metabolism can potentially aid addressing these issues. Here, we report the metabolism of structurally diverse nitroimidazole drug molecules by a NTR from a human pathogen Haemophilus influenzae (HiNfsB). Our detailed bioinformatic analysis uncovered that HiNfsB represents a group of unexplored oxygen-insensitive NTRs. Biochemical characterization of the recombinant enzyme revealed that HiNfsB effectively metabolizes ten clinically used nitroimidazoles. Furthermore, HiNfsB generated not only canonical nitroreduction metabolites but also stable, novel dimeric products from three nitroimidazoles, whose structures were proposed based on the results of high resolution MS and tandem MS analysis. X-ray structural analysis of the enzyme coupled with site-directed mutagenesis identified four active site residues important to its catalysis and broad substrate scope. Finally, transient expression of HiNfsB sensitized an E. coli mutant strain to 5-nitroimidazoles under anaerobic conditions. Together, these results advance our understanding of the metabolism of nitroimidazole antibiotics mediated by a new NTR group and reinforce the research on the natural antibiotic resistome for addressing the antibiotic resistance crisis.

Discovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster.

Rare actinomycetes represent an underexploited source of new bioactive compounds. Here, we report the use of a targeted metabologenomic approach to identify piperazyl compounds in the rare actinomycete Lentzea flaviverrucosa DSM 44664. These efforts to identify molecules that incorporate piperazate building blocks resulted in the discovery and structural elucidation of two dimeric biaryl-cyclohexapeptides, petrichorins A and B. Petrichorin B is a symmetric homodimer similar to the known compound chloptosin, but petrichorin A is unique among known piperazyl cyclopeptides because it is an asymmetric heterodimer. Due to the structural complexity of petrichorin A, solving its structure required a combination of several standard chemical methods plus in silico modeling, strain mutagenesis, and solving the structure of its biosynthetic intermediate petrichorin C for confident assignment. Furthermore, we found that the piperazyl cyclopeptides comprising each half of the petrichorin A heterodimer are made via two distinct nonribosomal peptide synthetase (NRPS) assembly lines, and the responsible NRPS enzymes are encoded within a contiguous biosynthetic supercluster on the L. flaviverrucosa chromosome. Requiring promiscuous cytochrome p450 crosslinking events for asymmetric and symmetric biaryl production, petrichorins A and B exhibited potent in vitro activity against A2780 human ovarian cancer, HT1080 fibrosarcoma, PC3 human prostate cancer, and Jurkat human T lymphocyte cell lines with IC50 values at low nM levels. Cyclic piperazyl peptides and their crosslinked derivatives are interesting drug leads, and our findings highlight the potential for heterodimeric bicyclic peptides such as petrichorin A for inclusion in future pharmaceutical design and discovery programs.

Bacterial lipopolysaccharide induces settlement and metamorphosis in a marine larva.

How larvae of the many phyla of marine invertebrates find places appropriate for settlement, metamorphosis, growth, and reproduction is an enduring question in marine science. Biofilm-induced metamorphosis has been observed in marine invertebrate larvae from nearly every major marine phylum. Despite the widespread nature of this phenomenon, the mechanism of induction remains poorly understood. The serpulid polychaete Hydroides elegans is a well established model for investigating bacteria-induced larval development. A broad range of biofilm bacterial species elicit larval metamorphosis in H. elegans via at least two mechanisms, including outer membrane vesicles (OMVs) and complexes of phage-tail bacteriocins. We investigated the interaction between larvae of H. elegans and the inductive bacterium Cellulophaga lytica, which produces an abundance of OMVs but not phage-tail bacteriocins. We asked whether the OMVs of C. lytica induce larval settlement due to cell membrane components or through delivery of specific cargo. Employing a biochemical structure­function approach with a strong ecological focus, the cells and OMVs produced by C. lytica were interrogated to determine the class of the inductive compounds. Here, we report that larvae of H. elegans are induced to metamorphose by lipopolysaccharide produced by C. lytica. The widespread prevalence of lipopolysaccharide and its associated taxonomic and structural variability suggest it may be a broadly employed cue for bacterially induced larval settlement of marine invertebrates.

New and bioactive polyketides from Hawaiian marine-derived fungus Trichoderma sp. FM652.

Two new sorbicillinoid derivatives (1 and 2), together with ten other related compounds (3-12) were isolated from a Hawaiian marine fungal strain Trichoderma sp. FM652. The structures of compounds 1 and 2, including the absolute configuration, were elucidated by extensive analysis of NMR spectroscopy, HRESIMS and electronic circular dichroism (ECD) data. Compounds 6-12 exhibited significant anti-proliferative activity against ovarian cancer cell line A2780, with the IC50 values ranging from 0.5 to 8.07 µM. Moreover, compounds 1, 7 and 8 showed significant inhibition against NF-κB with IC50 values of 13.83, 24.40 and 14.63 µM, respectively. Compounds 6, 9 and 12 also demonstrated moderate inhibitory activity against S. aureus and methicillin resistant S. aureus with the MIC values in the range of 10-40 µg/mL.

New phenalenone derivatives from the Hawaiian volcanic soil-associated fungus Penicillium herquei FT729 and their inhibitory effects on indoleamine 2,3-dioxygenase 1 (IDO1).

Phenalenone derivatives sourced from fungi are polyketides that have attracted significant interest because of their diverse chemical structures and potential bioactivities. As part of our ongoing quest to discover novel natural products with biological properties from diverse natural resources, three unreported phenalenone derivatives (1-3), named ent-12-methoxyisoherqueinone (1), (-)-scleroamide (2), and (+)-scleroamide (3), together with four known phenalenone derivatives, ent-atrovenetinone (4), isoherqueinone (5), herqueinone (6), and ent-peniciherquinone (7) were isolated from the Hawaiian soil fungus Penicillium herquei FT729, collected on the Big Island, Hawaii. Compounds 2 and 3 were enantiomers, which were separated using a chiral-phase HPLC column, which provided optically pure compounds 2 and 3. The structures of the novel compounds were established by extensive spectroscopic analyses, including 1D and 2D NMR and high-resolution ESIMS. Their absolute configurations were determined using quantum chemical electronic circular dichroism (ECD) calculations. The inhibitory activity of the isolated compounds (1-7) against indoleamine 2,3-dioxygenase 1 (IDO1) was assessed. Compounds 1, 5-7 inhibited IDO1, with IC50 values of 32.59, 36.86, 19.05, and 24.18 µM, respectively. These findings demonstrated that the phenalenone derivatives 1 and 5-7, as IDO1 inhibitors, are promising anticancer immunotherapeutic agents.

Polyketides, diketopiperazines and an isochromanone from the marine-derived fungal strain Fusarium graminearum FM1010 from Hawaii.

The fungal strain Fusarium graminearum FM1010 was isolated from a shallow-water volcanic rock known as "live rock" at the Richardson's Beach, Hilo, Hawaii. Eleven specialised metabolites, including two undescribed diketopiperazines, three undescribed polyketides, and one undescribed isochromanone, along with five known fusarielin derivatives were obtained from F. graminearum FM1010. The structures of the six undescribed compounds were elucidated by extensive analysis of NMR spectroscopy, HRESIMS, chemical reactions, and electronic circular dichroism (ECD) data. Kaneoheoic acids G-I showed mild inhibitory activity against S. aureus with the MIC values in the range of 20-40 µg/mL when assayed in combination with chloramphenicol (half of the MIC, 1 µg/mL), an FDA approved antibiotic. Kaneoheoic acid I exhibited both anti-proliferative activity against ovarian cancer cell line A2780 and TNF-α induced NF-κB inhibitory activity with the IC50 values of 18.52 and 15.86 µM, respectively.

Lemnalemnanes A-C, Three Rare Rearranged Sesquiterpenoids from the Soft Corals Paralemnalia thyrsoides and Lemnalia sp.

Three novel sesquiterpenoids, lemnalemnanes A-C (1-3), were obtained from marine soft corals Paralemnalia thyrsoides and Lemnalia sp. Their structures were determined by 1D/2D NMR spectroscopy, HRESIMS, single-crystal X-ray diffraction analysis (Cu Kα), Mosher's method, and ECD quantum chemistry calculations. Lemnalemnane A (1) possessed an intriguing basket-like structure with a spiro[bicyclo[3.3.1]nonane-furan core, while lemnalemnanes B (2) and C (3) exhibited unusual 6/6/5 and 6/5/5 carbon skeletons, respectively. In the proposed biosynthesis pathway, 1-3 were suspected to originate from the same precursor, 4-O-deacetylparalemnolin D (4), a compound coisolated from both aforementioned species. Furthermore, lemnalemnane C (3) exhibited strong in vivo promoting-angiogenesis activity.

Cytotoxic compounds from marine actinomycetes: Sources, Structures and Bioactivity.

Marine actinomycetes produce a substantial number of natural products with cytotoxic activity. The strains of actinomycetes were isolated from different sources like fishes, coral, sponges, seaweeds, mangroves, sediments etc. These cytotoxic compounds can be categorized briefly into four classes: polyketides, non-ribosomal peptides and hybrids, isoprenoids and hybrids, and others, among which majority are polyketides (146). Twenty two out of the 254 compounds showed potent cytotoxicity with IC50 values at ng/mL or nM level. This review highlights the sources, structures and antitumor activity of 254 natural products isolated from marine actinomycetes, which were new when they were reported from 1989 to 2020.

18:0 Lyso PC Derived by Bioactivity-Based Molecular Networking from Lentil Mutant Lines and Its Effects on High-Fat Diet-Induced Obese Mice.

Lentil (Lens culinaris; Fabaceae), one of the major pulse crops in the world, is an important source of proteins, prebiotics, lipids, and essential minerals as well as functional components such as flavonoids, polyphenols, and phenolic acids. To improve crop nutritional and medicinal traits, hybridization and mutation are widely used in plant breeding research. In this study, mutant lentil populations were generated by γ-irradiation for the development of new cultivars by inducing genetic diversity. Molecular networking via Global Natural Product Social Molecular Networking web platform and dipeptidyl peptide-IV inhibitor screening assay were utilized as tools for structure-based discovery of active components in active mutant lines selected among the lentil population. The bioactivity-based molecular networking analysis resulted in the annotation of the molecular class of phosphatidylcholine (PC) from the most active mutant line. Among PCs, 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine (18:0 Lyso PC) was selected for further in vivo study of anti-obesity effect in a high-fat diet (HFD)-induced obese mouse model. The administration of 18:0 Lyso PC not only prevented body weight gain and decreased relative gonadal adipose tissue weight, but also attenuated the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and leptin in the sera of HFD-induced obese mice. Additionally, 18:0 Lyso PC treatment inhibited the increase of adipocyte area and crown-like structures in adipose tissue. Therefore, these results suggest that 18:0 Lyso PC is a potential compound to have protective effects against obesity, improving obese phenotype induced by HFD.

NF-κB inhibitory, antimicrobial and antiproliferative potentials of compounds from Hawaiian fungus Aspergillus polyporicola FS910.

Bioassay-guided experimental design and chromatographic analysis led to the isolation and identification of ten compounds (1-10) including two unusual sulfur-containing curvularin macrolides (1 and 2) from a Hawaiian fungal strain Aspergillus polyporicola FS910. Compounds 1 and 2 are rare curvularin macrolides each with a five-membered cyclic sulfur-containing moiety. The structures of the compounds were identified by HRESIMS, NMR spectroscopy, X-ray crystallography, ECD and DFT energy calculation, as well as comparing with previous literatures. Compounds 4, 6 and 8 were active against TNF-α-induced NF-κB inhibitory activity with IC50 values of 26.45, 5.41 and 15.8 µM, respectively. Compounds 3 and 5-8 exhibited anti-proliferative activity against HT1080, T46D, and A2780S cell lines, with IC50 values ranging from 2.48 to 29.17 µM. Additionally, Compound 3 showed promising antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), Bacillus subtilis, Escherichia coli and Candida albicans. Moreover, when tested in combination with antibiotic adjuvant disulfiram [4 µg/mL], compounds 4, 5 and 10 also displayed significant antibacterial activity against S. aureus. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-021-02877-7.