Uncommon Epoxyquinols Pyrrolocytosporin A and Cytosporin E2 from the Fungus Eutypella sp. D-1.

Two uncommon epoxyquinols, pyrrolocytosporin A (1) and cytosporin E2 (2), along with the known cytosporin Y1 (3), were isolated from the solid defined medium of the Arctic-derived fungus Eutypella sp. D-1. Their structures were established through comprehensive analyses of spectroscopic and electronic circular dichroism data. Structurally, compound 1 represented the first nitrogen-containing epoxyquinol characterized by a pyrrole fused cytosporin framework, while compound 2 contained an uncommon cyclic carbonate functionality. The antibacterial, immunosuppressive, anti-inflammatory, and cytotoxic activities of all compounds were evaluated. Among the three metabolites, only compound 1 exhibited inhibitory effects on nitric oxide production induced by lipopolysaccharide with an IC50 value of 6.55 µM. Additionally, only compound 2 displayed inhibitory activity against ConA-induced T-cell proliferation with an IC50 value of 9.85 µM.

Eutypellaolides A-J, Sesquiterpene diversity expansion of the polar fungus Eutypella sp. D-1.

Eight new 12,8-eudesmanolide sesquiterpenes, eutypellaolides A-H (1-8), and two new eudesmane-type sesquiterpenes, eutypellaolides I-J (9-10), along with four known 12,8-eudesmanolide compounds 11-14, were isolated from the culture extract of the polar fungus Eutypella sp. D-1 by one strain many compounds (OSMAC) approach. The structures of these compounds were determined through comprehensive spectroscopic data and experimental and calculated ECD analysis. Antibacterial, immunosuppressive, and PTP1B inhibition activities of these compounds were evaluated. Compounds 1 and 11 exhibited strong inhibitory activities against Bacillus subtilis and Staphylococcus aureus, with each showing an MIC value of 2 µg/mL. Compound 9 displayed weak immunosuppressive activity against ConA-induced T-cell proliferation with an inhibitory rate of 61.7% at a concentration of 19.8 µM. Compounds 5, 11, and 14 exhibited weak PTP1B inhibition activities with IC50 values of 44.8, 43.2, and 49.5 µM, respectively.

Phyllofenones F-M, Scalarane Sesterterpenes from the Marine Sponge Phyllospongia foliascens.

Eight new scalarane sesterterpenes, phyllofenones F-M (1-8), together with two known analogues, carteriofenones B and A (9-10), were isolated from the marine sponge Phyllospongia foliascens collected from the South China Sea. The structures of these compounds were determined based on extensive spectroscopic and quantum chemical calculation analysis. The antibacterial and cytotoxic activity of these compounds was evaluated. Among them, only compounds 4 and 6 displayed weak inhibitory activity against Staphylococcus aureus and Escherichia coli, with MIC values of 16 µg/mL and 8 µg/mL, respectively. Compounds 1-10 exhibited cytotoxic activity against the HeLa, HCT-116, H460, and SW1990 cancer cell lines, with IC50 values ranging from 3.4 to 19.8 µM.

Cytosporin Derivatives from Arctic-Derived Fungus Eutypella sp. D-1 via the OSMAC Approach.

A chemical investigation of the Arctic-derived fungus Eutypella sp. D-1 based on the OSMAC (one strain many compounds) approach resulted in the isolation of five cytosporin polyketides (compounds 1-3 and 11-12) from rice medium and eight cytosporins (compounds 2 and 4-11) from solid defined medium. The structures of the seven new compounds, eutypelleudesmane A (1), cytosporin Y (2), cytosporin Z (3), cytosporin Y1 (4), cytosporin Y2 (5), cytosporin Y3 (6), and cytosporin E1 (7), were elucidated by analyzing their detailed spectroscopic data. Structurally, cytosporin Y1 (4) may be a key intermediate in the biosynthesis of the isolated cytosporins, rather than an end product. Compound 1 contained a unique skeleton formed by the ester linkage of two moieties, cytosporin F (12) and the eudesmane-type sesquiterpene dihydroalanto glycol. Additionally, the occurrence of cyclic carbonate moieties in compounds 6 and 7 was found to be rare in nature. The antibacterial, immunosuppressive, and cytotoxic activities of all compounds derived from Eutypella sp. D-1 were evaluated. Unfortunately, only compounds 3, 6, 8, and 10-11 displayed immunosuppressive activity, with inhibitory rates of 62.9%, 59.5%, 67.8%, 55.8%, and 68.7%, respectively, at a concentration of 5 µg/mL.

Phyllospongianes A-E, Dinorscalarane Sesterterpenes from the Marine Sponge Phyllospongia foliascens.

Phyllospongianes A-E (1-5), five new scalarane derivatives featuring an unprecedented 6/6/6/5 tetracyclic dinorscalarane scaffold, along with the known probable biogenetic precursor, 12-deacetylscalaradial (6), were isolated from the marine sponge Phyllospongia foliascens. The structures of the isolated compounds were determined by analysis of spectroscopic data and electronic circular dichroism experiments. Compounds 1-5 are the first 6/6/6/5 tetracyclic scalarane derivatives to be reported within the scalarane family. Compounds 1, 2, and 4 exhibited antibacterial activity against Vibrio vulnificus, Vibrio parahemolyticus, Escherichia coli, Staphylococcus aureus, Enterococcus faecalis, Bacillus subtilis, and Pseudomonas aeruginosa with MIC values ranging from 1 to 8 µg/mL. Furthermore, compound 3 exhibited significant cytotoxic activity on MDA-MB-231, HepG2, C4-2-ENZ, MCF-7, H460, and HT-29 cancer cell lines with IC50 values in the range between 0.7 and 13.2 µM.

Quality by design driven development and evaluation of thermosensitive hydrogel loaded with IgY and LL37-SLNs to combat experimental periodontitis.

Egg yolk immunoglobulin (IgY) and LL37, potent antibacterial substances, can fight against periodontitis. This work aimed to develop a locally injectable hydrogel for potential co-delivery of special IgY and LL37-loaded solid lipid nanoparticles (LL37-SLNs) to synergistically inhibit the proliferation of oral pathogens, thus relieving periodontal inflammation and redness. The formulation of thermosensitive hydrogel loaded with IgY and LL37-SLNs was developed by adopting the Quality by Design approach. Then the formulations were optimized by two-factor three-level full factorial design by Design-Expert software. Finally, the optimized formulation was characterized and estimated in vitro and in vivo. In vitro release and antibacterial activity studies have revealed that the optimized formulation was homogeneous and can be released slowly, with sustainably antibacterial power. And the physical and chemical composition analysis and morphological observations further confirmed the sustained-release capability. On the other hand, in vivo studies proved that the optimized formulation significantly decreased gingival redness, bleeding, and plaque formation, avoided excessive resorption of alveolar bone, and reduced the levels of inflammatory factor in periodontitis rats. In conclusion, the optimized thermosensitive hydrogel loaded with IgY and LL37-SLNs may be a promising local sustained-release preparation for the effective treatment of periodontal diseases.

Bioactive Scalarane-Type Sesterterpenoids from Marine Sources.

Scalarane-type sesterterpenoids have received considerable attention in the scientific literature due to their diverse carbon skeletons and various biological activities and pharmacological properties. Among all these derivatives are commonly isolated from marine sponges and are occasionally derived from shell-less mollusks, such as nudibranchs. This review comprehensively discusses the marine-derived natural sources that give rise to these scalarane-type sesterterpenoids, providing the names, their chemical structures, biological properties, with emphasis on anticancer activity and literature references related to these metabolites. A critical summary of the 221 compounds generated from January 2010 up to December 2021 for their potential as anticancer agents is presented.

Palitantin derivatives from the Antarctic fungus Geomyces sp. 3-1.

Two new polyketides, palitantins B and C (1 and 2), along with one known related compound (+)-palitantin (3) were obtained from the culture of the Antarctic fungus Geomyces sp. 3-1. The structures of the new compounds were elucidated by detailed analysis of HRESIMS, NMR, CD, and ECD data. Compound 3 showed potent PTP1B inhibitory activity with an IC50 value of 7.9 µM (ursolic acid as positive control, IC50 = 8.3 µM).

Eutypellacytosporins A-D, Meroterpenoids from the Arctic Fungus Eutypella sp. D-1.

The Arctic fungus Eutypella sp. D-1, previously found to produce a variety of cytotoxic cyclopropyl-fused and cyclobutyl-fused pimarane diterpenoids when grown in the defined medium, was induced to produce unusual metabolites by growing on solid rice medium. A chemical investigation on the rice medium extract led to the isolation of four new meroterpenoids, eutypellacytosporins A-D (1-4), along with the known biogenetically related compound cytosporin D (5). The structures of the new compounds were elucidated by their detailed spectroscopic analysis and modified Mosher's method. Compounds 1-4 may be formed by the 12,32-ester linkage of two moieties, cytosporin D (5) and decipienolide A or B. All isolated compounds, except 5, showed weak cytotoxicity against DU145, SW1990, Huh7, and PANC-1 cell lines with IC50 values ranging from 4.9 to 17.1 µM.

Cytotoxic Microcolin Lipopeptides from the Marine Cyanobacterium Moorea producens.

Nine new linear lipopeptides, microcolins E-M (1-9), together with four known related compounds, microcolins A-D (10-13), were isolated from the marine cyanobacterium Moorea producens using bioassay-guided and LC-MS/MS molecular networking approaches. Catalytic hydrogenation of microcolins A-D (10-13) yielded two known compounds, 3,4-dihydromicrocolins A and B (14, 15), and two new derivatives, 3,4-dihydromicrocolins C and D (16, 17), respectively. The structures of these new compounds were determined by a combination of spectroscopic and advanced Marfey's analysis. Structurally unusual amino acid units, 4-methyl-2-(methylamino)pent-3-enoic (Mpe) acid and 2-amino-4-methylhexanoic acid (N-Me-homoisoleucine), in compounds 1-3 and 8, respectively, are rare residues in naturally occurring peptides. These metabolites showed significant cytotoxic activity against H-460 human lung cancer cells with IC50 values ranging from 6 nM to 5.0 µM. The variations in structure and attendant biological activities provided fresh insights concerning structure-activity relationships for the microcolin class of lipopeptides.

Libertellenones O-S and Eutypellenones A and B, Pimarane Diterpene Derivatives from the Arctic Fungus Eutypella sp. D-1.

Seven new pimarane-type diterpene derivatives, libertellenones O-S (1-5) and eutypellenones A and B (6 and 7), together with two known compounds (8 and 9), were isolated from the culture of Eutypella sp. D-1 obtained from high-latitude soil of the Arctic. Their structures were elucidated from spectroscopic data, as well as experimental and calculated electronic circular dichroism (ECD) analysis. Structurally, compounds 1-5 possess a cyclopropyl-fused pimarane diterpene moiety, whereas compounds 6 and 7 share an unusual cyclobutyl-fused pimarane diterpene skeleton. Compounds 1-9 exhibited cytotoxicities against HeLa, MCF-7, HCT-116, PANC-1, and SW1990 cells, with IC50 values in the range of 0.3 to 29.4 µM. Compounds 6 and 7 could dose-dependently inhibit the activity of NF-κB and exhibited significantly inhibitory effects on nitric oxide production induced by lipopolysaccharide.

Biotransformation of total coumarins of Radix Glehniae by Lecanicillium attenuatum W-1-9.

The biotransformation of total coumarins of Radix Glehniae by Lecanicillium attenuatum W-1-9 yielded three new products, lecaniside A (1), lecaniside B (2), and lecaniside C (3). The chemical structures of these metabolites were elucidated based on extensive spectral data, including 2D NMR and HRMS. The hydrogenation, dealkylation, glycosylation, and O-methylation reactions of these metabolites were observed in the present study. In the in vitro assays, compound 1 displayed a little PTP1B inhibitory activity.

Furanone derivative and sesquiterpene from Antarctic marine-derived fungus Penicillium sp. S-1-18.

A new furanone derivative, butanolide A (1), and a new sesquiterpene, guignarderemophilane F (2), together with six known compounds, were isolated from the fungus Penicillium sp. S-1-18 derived from Antarctic marine. The new structures were determined by spectroscopic studies such as 1D- and 2D-NMR and MS analyses. The absolute configuration of 1 was determined by the modified Mosher's method, while the absolute configuration of 2 was determined by calculated ECD spectroscopy. The isolated secondary metabolites were evaluated for their protein tyrosine phosphatase 1B (PTP1B) inhibitory activity. Compound 1 showed moderate inhibitory activity against PTP1B with IC50 value of 27.4 µM.

A new sesquiterpene lactone from fungus Eutypella sp. D-1.

We isolated and identified a new sesquiterpene lactone which we named eut-Guaiane sesquiterpene (1), along with four cytochalasins from the fungus Eutypella sp. derived from the soil of high latitude of Arctic. The new structure was determined by spectroscopic studies such as 1D and 2D NMR and MS analyses, while the known compounds were identified by comparison of the NMR data with those in literatures. New compound 1 exhibited strong antibacterial activity against Escherichia coli, Bacillus subtilis and Staphylococcus aureus. Besides, it showed a little cytotoxicity against SGC7901 cell line.

Marine Antibody-Drug Conjugates: Design Strategies and Research Progress.

Antibody-drug conjugates (ADCs), constructed with monoclonal antibodies (mAbs), linkers, and natural cytotoxins, are innovative drugs developed for oncotherapy. Owing to the distinctive advantages of both chemotherapy drugs and antibody drugs, ADCs have obtained enormous success during the past several years. The development of highly specific antibodies, novel marine toxins' applications, and innovative linker technologies all accelerate the rapid R&D of ADCs. Meanwhile, some challenges remain to be solved for future ADCs. For instance, varieties of site-specific conjugation have been proposed for solving the inhomogeneity of DARs (Drug Antibody Ratios). In this review, the usages of various natural toxins, especially marine cytotoxins, and the development strategies for ADCs in the past decade are summarized. Representative ADCs with marine cytotoxins in the pipeline are introduced and characterized with their new features, while perspective comments for future ADCs are proposed.

[Antibody-drug conjugates: design and clinical progress].

Antibody-drug conjugates, constructed with monoclonal antibodies, linker and cytotoxins, have distinctive advantages over chemotherapy drugs and antibody drugs in cancer therapy. In this review, the strategy of developing ADCs, and the important progress in past decade are well summarized. The representative ADCs in the pipeline are introduced and characterized with their new features. While, perspective for future directions of ADCs is proposed.

Loss of function of Notch1 identifies a poor prognosis group of early stage hepatocellular carcinoma following hepatectomy.

Notch1 has previously been implicated in the carcinogenesis of hepatocellular carcinoma (HCC). The present study aimed to investigate the prognostic value of Notch1 in early stage HCC patients after hepatectomy. The differential expression of Notch1 in paired tumor and non-tumorous tissue was evaluated by RT-PCR, western blotting and immunohistochemistry. The correlation between Notch1 expression and the surgical outcome of patients at BCLC stage 0/A and its ≤5 cm subgroup was retrospectively investigated in 206 patients from the Eastern Hepatobiliary Surgery Hospital (training cohort), and prospectively validated in 185 patients from the same center and retrospectively verified in 129 patients from the Fujian Medical University (validation cohort 1 and 2, respectively). Compared with paired non-tumorous tissues, loss of Notch1 was observed in tumor tissue. Patients with normal Notch1 had better prognosis than those with loss of Notch1 in the training cohort and ≤5 cm subgroup (time to recurrence: 38.5±6.1 vs. 16.0±3.2 months, P<0.001 and 53.0±6.1 vs. 21.7±3.5 months, P=0.004; 1-, 3-, 5-year survival rates: 91, 64 and 49% vs. 73, 31 and 22%, P<0.001 and 93, 71, 57% vs. 76, 39, 24%, P<0.001). Notch1 expression was an independent factor for recurrence and survival (hazard ratio: 1.901, 2.154; 2.038 and 2.337). Moreover, Notch1 status affected early tumor recurrence, as the 2-year recurrence rate was 61.2 vs. 26.9% (P<0.001) and 51.2 vs. 21.3% (P=0.002) in tumors with reduced or increased Notch1 expression in this cohort and subgroup. These results were fully confirmed by the study in our prospective and retrospective validation cohorts. The status of Notch1 is useful for predicting the prognosis of patients with early stage HCC undergoing hepatectomy.

Traditional Chinese medicine--sea urchin.

The sea urchin is an ancient, common, seafloor-dwelling marine invertebrate that belongs to the phylum Echinodermata. There are multiple species of sea urchin with resources that are widely distributed in China, where they were used in ancient times as Traditional Chinese Medicine for treating a variety of diseases. At present, it is known that the shell, spine and gonad of the sea urchin have many medicinal values determined through modern research. In this paper, we summarized the major chemical constituents and medicinal value of the sea urchin.

S5a binds to death receptor-6 to induce THP-1 monocytes to differentiate through the activation of the NF-κB pathway.

Analyses of supernatants from apoptotic cells have helped in the identification of many signals that modulate the states of cell activation and differentiation. However, the current knowledge about the soluble factors that are released during apoptosis is rather limited. Previous studies have shown that S5a and angiocidin (both encoded by PSMD4) induce human acute monocytic leukemia cells (THP-1 cells) to differentiate into macrophages, but the cell-surface receptor of S5a has not been identified. In this study, we show that apoptotic THP-1 cells release endogenous S5a that binds to death receptor-6 (DR6, also known as TNFRSF1), which was identified as an orphan receptor, to induce THP-1 cells to differentiate. Furthermore, we found that the NF-κB pathway is activated, and that the transcription factors WT1 (Wilms' tumor 1) and c-myb mediate S5a-induced THP-1 differentiation. We also show that differentiation is blocked by anti-DR6 antibody, DR6 siRNA, DR6-Fc, NF-κB inhibitor or WT1 siRNA treatment. Our findings indicate that the interaction between cells can determine their differentiation, and we provide evidence for a functional interaction between S5a and DR6, which provides a novel potential mechanism to induce the differentiation of cancer cells, especially during biotherapy for leukemia.

Bioactive tyrosine-derived cytochalasins from fungus Eutypella sp. D-1.

Three new cytochalasins Z24 , Z25 , Z26 (1-3, resp.) and one known compound, scoparasin B (4), were isolated from the fungus Eutypella sp. D-1 isolated from the soil of high latitude of the Arctic. The structures of 1-3 were elucidated from spectroscopic data (NMR, MS). These compounds were evaluated for cytotoxic activities against several human tumor cell lines. Among them, compound 1 exhibited moderate cytotoxicity toward human breast cancer MCF-7 cell line with IC50 of 9.33 µM.