Marine Drugs最新文献

Peptaibols represent a large family of membrane-active, linear fungal peptides, with variable lengths from 5 to 21 α-amino acid residues. As products of nonribosomal peptide synthetase (NRPS) biosynthetic machinery, they encompass several non-proteinogenic amino acids, particularly the Cα-tetrasubstituted residues, such as α-aminoisobutyric acid (Aib) and its homologue isovaline (Iva). Further distinctive features include an N-acyl terminus, such as an acetyl group, and a C-terminus containing an amino alcohol residue (such as phenylalaninol, leucinol, and valinol, among others), which neutralize charges at both termini and confer them a hydrophobic nature. Peptaibols not only represent the most abundant class among nonribosomal peptides, but they have also attracted continuous scientific interest due to their diverse pharmacological properties, including antimicrobial, cytotoxic, antifungal, and antiviral activities. In this review, we present for the first time the recently explored chemodiversity of fungal peptaibiotics derived from marine sources, with a particular focus on peptaibols. We discuss their distinctive structural features, chemical characterization, biosynthetic pathways, and biological activity profiles, with the aim of supporting ongoing research toward their development as potential pharmaceutical agents.

Within the "One Health, One Medicine" and comparative oncology paradigms, algal extracts have attracted attention, containing natural compounds (NCs) with biological activities, including anti-cancer properties. To characterize the biological effects of a Sphaerococcus coronopifolius extract (SCE), two canine mastocytoma and two normal cell lines were used. After a preliminary screening of three algal extracts, SCE cytotoxicity was measured using Alamar Blue, Sulforhodamine B, and Neutral Red Uptake assays. After assessing the selectivity versus tumor cells and its chemical characterization, SCE mechanisms of action were investigated using RNA-seq, quantitative PCR, flow cytometry and immunoblotting approaches. SCE showed an IC₅₀ comprised between 25 and 35 μg/mL in tumor cell lines, but it also affected normal ones (selectivity index < 2.0). RNA-seq and flow cytometry revealed that SCE negatively affected cell cycle and mevalonate pathway in tumor cells. Additional flow cytometry and immunoblotting investigations suggested a concentration- and time-dependent pro-apoptotic effect of SCE and DNA damage events. In conclusion, SCE demonstrated promising anti-cancer activity in mastocytoma cell lines by targeting the mevalonate pathway, arresting the cell cycle, and inducing apoptosis and DNA damage. Furthermore, the results presented here reinforce the idea that NCs may be promising candidates in comparative anti-cancer chemotherapy.

Prorocentrum lima is a widely distributed and major source of diarrhetic shellfish toxins (DSTs); the ecological impact of diol-estered DSTs (eDSTs) compounds on benthic systems is still inadequate. In this study, the acute toxicity of eDSTs was evaluated in Caenorhabditis elegans, and their accumulation capacity and toxic effects were examined in Mytilus galloprovincialis for an ecological risk assessment. The results indicated that larvae 1 (L1) was more sensitive than larvae 4 (L4) of C. elegans, and the eDSTs in P. lima extract lysate were more toxic than the okadaic acid (OA) standard solution. The lowest LC₅₀ values were 0.293 and 0.469 μg/mL for L1 and L4, respectively. The growth, productivity, and intestinal permeability of C. elegans were impaired, and the effect of P. lima extract lysate on C. elegans was greater than that of the OA standard solution. The total toxin concentration in the digestive gland of mussels reached 3230 μg/kg, with esterified DSTs accounting for 76.7-97.1% of total toxins and inducing marked oxidative stress. Diol-estered DSTs exert direct toxic effects, including oxidative damage and growth inhibition, while exhibiting a high accumulation potential. This study revealed the toxicity of eDSTs, necessitating a focused investigation to comprehensively assess their toxicological impact and ecological risks.

The aim of this study is to investigate the A_2BAR-dependence of okhotoside A₁-1 cytotoxic and antiproliferative action on triple-negative MDA-MB-231 breast cancer cells using monolayer and 3D culture approaches. Earlier triterpene glycoside okhotoside A₁-1 (Okh) was isolated from the sea cucumbers Cucumaria djakonovi and C. conicospermium and its selective cytotoxicity against MDA-MB-231 vs. non-tumorigenic MCF-10A cells was reported. Now it has been found that the A_2B adenosine receptor (A_2BAR) is one of the molecular targets for Okh and its antiproliferative effect is A_2BAR-dependent. Molecular docking studies suggested a unique behavior for Okh demonstrating two highly probable binding modes with comparable affinity, when the aglycone is immersed in the binding pocket, or alternatively, the carbohydrate moiety occupies the site. The glycoside modulated cAMP and intracellular Ca²⁺ levels in an A_2BAR-dependent manner, which accompanied by the suppression of p38 MAPK and ERK1/2 phosphorylation, and blocked cell cycle progression. Okh induced mitochondrial dysfunction, characterized by increased ROS production and loss of the mitochondrial membrane potential (ΔΨm), which led to the upregulation of APAF-1 and cytochrome C, activation of caspases-9 and -3, and initiation of apoptosis. The antitumor potential of Okh was confirmed in a 3D culture of MDA-MB-231 cells and was more significant than those of another A_2BAR-targeted triterpene glycoside cucumarioside A₀-1 and cisplatin.

Ten previously undescribed pyrrolidine alkaloids, namely penicipyrrolidines O-X (1-10), were isolated from the mangrove-derived fungus Penicillium sp. DM27, along with five known compounds (11-15). Their structures were determined by comprehensive analysis of HRESIMS and NMR spectroscopic data, and the absolute configurations were established based on biosynthetic considerations and TDDFT-ECD calculations. All isolates were evaluated for their glucose uptake capacity. Notably, penicipyrrolidine P (2) significantly enhanced cellular glucose uptake in L6 myotubes by 3.83-fold, demonstrating activity comparable to that of metformin, whereas penicipyrrolidines Q and R (3 and 4) showed relatively weaker effects.

Triple-negative breast cancer (TNBC) is known for being aggressive and potentially resistant to chemotherapy. This means that new ways to improve cancer treatments are a priority. So, the anticancer effect of binary combinations of fucoidan (FuLt) and the chemotherapeutic agents doxorubicin, paclitaxel, and 5-fluorouracil was evaluated. The Chou-Talalay combination index method was used to do this. This method allows the assessment of interactions between products by determining synergism, additive effect and antagonism with combination index <1, =1 and >1, respectively. Synergistic indices (SIs) were selected and applied to 4T1 homotypic spheroids. Oxidative stress caused by SIs was determined after 72 h by measuring the production of ROS and NO in both homotypic and heterotypic spheroids. Three SIs with an inhibitory effect of at least ≥ 0.50 and a dose reduction index > 1 were selected. Considering the experimental and simulated SI, twelve, nineteen, and seven SIs were found for FuLt with doxorubicin, paclitaxel, and 5-fluorouracil, respectively. The highest levels of ROS and NO occurred at 12 and 72 h, respectively, in homotypic and heterotypic spheroids, indicating an immunomodulatory effect in heterotypic spheroids. These results suggest that the synergistic combination of FuLt with chemotherapeutic agents improves drug efficacy and modulates redox dynamics in 4T1 spheroids. Furthermore, FuLt alone exhibits cytotoxic properties.

UVB radiation present in sunlight is the main pro-oxidative and pro-inflammatory factor that reaches human skin cells, including keratinocytes. Therefore, protective compounds eliminating the negative impact of UVB radiation are constantly being sought. This study aimed to estimate the effect of the lipid extract of microalgae Nannochloropsis oceanica (N.o.) on UVB-irradiated keratinocytes. A proteomic approach was used to estimate the proteomic profile of in vitro-treated keratinocytes. The results indicated 270 proteins had significantly altered expression in UVB-irradiated keratinocytes, while the treatment of cells with N.o. extract partially restored the levels of these proteins. Moreover, changes in protein structure resulting from the binding of glutathione (GSH) and thioredoxin (Trx) were also observed. Most of the GSH-modified proteins were involved in GSH or prostaglandin metabolism, while Trx-modified proteins were molecules related to Trx metabolism, as well as antioxidant and anti-inflammatory signaling. The treatment of cells with N.o. extract contributed to reversing the changes in the level of modification in individual proteins. It can be suggested that the lipid components of the microalgae N.o. extract protect keratinocytes against changes in metabolism induced by UVB radiation, modulating the antioxidant and pro-inflammatory responses of cells at the GSH and Trx-based signaling levels.

The co-culture technique, mimicking natural microbial interactions, has proven to be successful at activating silent biosynthetic gene clusters (BGCs) to produce novel metabolites or enhance the yield of specific metabolites. To effectively decode induction processes, it is critical to have a comprehensive understanding of intermicrobial interactions across both volatile and non-volatile metabolomes. As part of our attempt to uncover structurally unique and biologically active natural products from mangrove endophytic fungi, Phomopsis asparagi DHS-48 was co-cultured with another mangrove fungal strain, Pestalotiopsis sp. HHL-101. The competition interaction of the two strains was investigated using morphology and scanning electron microscopy (SEM), and it was discovered that the mycelia of the DHS-48 and HHL-101 compressed and tangled with each other in the co-culture system, forming an interwoven pattern. To profile volatile-mediated chemical interactions during fungal co-culture, headspace solid-phase microextraction gas chromatography mass spectrometry (HS-SPME-GC-MS) coupled with orthogonal partial least squares-discriminant analysis (OPLS-DA) was adopted. Meanwhile, non-volatile metabolites from both liquid and solid small-scale co-cultures were profiled via HPLC. Two new polyketides, named phaseolorin K (1) and pestaphthalide C (7), together with 11 known compounds (2-6, 8-13), were characterized from solid-state co-cultivation extracts of these two titled strains. Their planar structures were established by analysis of HRMS, MS/MS, and NMR spectroscopic data, while absolute configurations were assigned using ECD calculations. Co-culture feeding experiments demonstrated that DHS-48 exerts antagonistic activity against HHL-101 through altering its hyphal morphology, which mediated enhanced biosynthesis of non-volatile antimicrobial metabolites 5 and 6. Biological assays revealed that compounds 4-6 exhibited potent in vitro cytotoxicity against human cancer cell lines HeLa and HepG2, compared to the positive controls adriamycin and fluorouracil. Compound 2 moderately inhibited the proliferation of ConA-induced T and LPS-induced B murine spleen lymphocytes.

Microalgae, such as Euglena cantabrica, are rich in secondary metabolites, including polyphenols, which are valued for their antioxidant and therapeutic properties. Here a rapid, cost-effective and efficient protocol using a trichloroacetic acid (TCA) solution was developed for the production of an extract from E. cantabrica (EuPoly). The potential environmental and biomedical applications of this new extract were evaluated. The effects of EuPoly extract were tested on normal human dermal fibroblasts (NHDFs) and on breast cancer cells of the triple-negative MDA-MB-231 cell line. EuPoly was able to increase the NHDFs survival in oxidative -stress conditions and, on the contrary, to induce a decrease in cell viability of the breast cancer cells. EuPoly was also used to functionalize frustules (FEuPoly), mesoporous silica structures from diatoms. FEuPoly were investigated for the complexation of Cu²⁺ and Ni²⁺, as new potential tools for metal-ion decontamination. Finally, the scaffolding properties of FEuPoly were here assessed in the bone marrow mesenchymal stem cells (BM-MSCs) growth and their osteo-differentiation. This study provides new insights into the sustainable valorization of algae extracts, showing that TCA E. cantabrica extract and functionalized frustules may serve as multifunctional, eco-friendly resources for biomedical applications, as antioxidants and cancer cell inhibitor, metal ions-trapping and tissue osteo-repair.

Two previously undescribed highly oxygenated cembrane-type diterpenes, namely sarcocraol A (1) and sarcocraol B (2), along with five known compounds (3-7), have been isolated from the soft coral Sarcophyton crassocaule collected off Ximao Island in the South China Sea. Their structures were determined through comprehensive spectroscopic analysis, QM-NMR calculations, TDDFT-ECD computation, X-ray diffraction analysis, and by comparison with literature data. Plausible biosynthetic pathways for these compounds were also proposed. All compounds were evaluated for peroxisome proliferator-activated receptors (PPARs) transcriptional activity using luciferase assay. The bioassay results demonstrated that compound 1 exhibits selective PPAR-γ agonistic activity. Furthermore, it promoted glucose uptake in HepG2 cells by 1.18-, 1.45-, and 1.90-fold at concentrations of 2.5, 5, and 10 μM, respectively, whereas rosiglitazone (10 μM) produced a 2.47-fold increase over the induced control. Compound 1 at 10 μM induced mild lipid accumulation in 3T3-L1 cells, showing a 1.63-fold increase relative to the control, which was much lower than the 3.28-fold increase observed in rosiglitazone (10 μM) group indicating its potential antidiabetic properties. These findings suggested that compound 1 could be a promising lead for the development of antidiabetic agents.