A new invertebrate NPY-like polypeptide, ZoaNPY, from the Zoanthus sociatus, as a novel ligand of human NPY Y2 receptor rescues vascular insufficiency via PLC/PKC and Src- FAK-dependent signaling pathways.

Our recent multi-omics studies have revealed rich sources of novel bioactive proteins and polypeptides from marine organisms including cnidarians. In the present study, we initially conducted a transcriptomic analysis to review the composition profile of polypeptides from Zoanthus sociatus. Then, a newly discovered NPY-like polypeptide-ZoaNPY was selected for further in silico structural, binding and virtually pharmacological studies. To evaluate the pro-angiogenic effects of ZoaNPY, we employed an in vitro HUVECs model and an in vivo zebrafish model. Our results indicate that ZoaNPY, at 1-100 pmol, enhances cell survival, migration and tube formation in the endothelial cells. Besides, treatment with ZoaNPY could restore a chemically-induced vascular insufficiency in zebrafish embryos. Western blot results demonstrated the application of ZoaNPY could increase the phosphorylation of proteins related to angiogenesis signaling including PKC, PLC, FAK, Src, Akt, mTOR, MEK, and ERK1/2. Furthermore, through molecular docking and surface plasmon resonance (SPR) verification, ZoaNPY was shown to directly and physically interact with NPY Y2 receptor. In view of this, all evidence showed that the pro-angiogenic effects of ZoaNPY involve the activation of NPY Y2 receptor, thereby activating the Akt/mTOR, PLC/PKC, ERK/MEK and Src- FAK-dependent signaling pathways. Furthermore, in an excision wound model, the treatment with ZoaNPY was shown to accelerate the wound healing process in mice. Our findings provide new insights into the discovery and development of novel pro-angiogenic drugs derived from NPY-like polypeptides in the future.

Marine natural products.

Covering: January to the end of December 2022This review covers the literature published in 2022 for marine natural products (MNPs), with 645 citations (633 for the period January to December 2022) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, the submerged parts of mangroves and other intertidal plants. The emphasis is on new compounds (1417 in 384 papers for 2022), together with the relevant biological activities, source organisms and country of origin. Pertinent reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included. An analysis of NP structure class diversity in relation to biota source and biome is discussed.

Marine natural products.

Covering: January to December 2021This review covers the literature published in 2021 for marine natural products (MNPs), with 736 citations (724 for the period January to December 2021) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1425 in 416 papers for 2021), together with the relevant biological activities, source organisms and country of origin. Pertinent reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included. An analysis of the number of authors, their affiliations, domestic and international collection locations, focus of MNP studies, citation metrics and journal choices is discussed.

Therapeutic potential of marine macrolides: An overview from 1990 to 2022.

The sea is a vast ecosystem that has remained primarily unexploited and untapped, resulting in numerous organisms. Consequently, marine organisms have piqued the interest of scientists as an abundant source of natural resources with unique structural features and fascinating biological activities. Marine macrolide is a top-class natural product with a heavily oxygenated polyene backbone containing macrocyclic lactone. In the last few decades, significant efforts have been made to isolate and characterize macrolides' chemical and biological properties. Numerous macrolides are extracted from different marine organisms such as marine microorganisms, sponges, zooplankton, molluscs, cnidarians, red algae, tunicates, and bryozoans. Notably, the prominent macrolide sources are fungi, dinoflagellates, and sponges. Marine macrolides have several bioactive characteristics such as antimicrobial (antibacterial, antifungal, antimalarial, antiviral), anti-inflammatory, antidiabetic, cytotoxic, and neuroprotective activities. In brief, marine organisms are plentiful in naturally occurring macrolides, which can become the source of efficient and effective therapeutics for many diseases. This current review summarizes these exciting and promising novel marine macrolides in biological activities and possible therapeutic applications.

Marine natural products.

Covering: 2020This review covers the literature published in 2020 for marine natural products (MNPs), with 757 citations (747 for the period January to December 2020) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1407 in 420 papers for 2020), together with the relevant biological activities, source organisms and country of origin. Pertinent reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included. A meta analysis of bioactivity data relating to new MNPs reported over the last five years is also presented.

Jellyfish skin polysaccharides enhance intestinal barrier function and modulate the gut microbiota in mice with DSS-induced colitis.

Jellyfish skin polysaccharides (JSP) were isolated from Rhopilema esculentum Kishinouye and contained 55.11% polysaccharides and 2.26% uronic acid. To examine the anti-inflammatory, antioxidant and immunomodulatory activities of JSP in vivo, C57BL/6 mice were induced to develop ulcerative colitis by dextran sulfate sodium (DSS) and the roles of dietary JSP supplementation in modulating colitis were explored. JSP supplementation reduced the symptoms of colitis in mice, increased colon length, protected goblet cells, and improved intestinal epithelial integrity and permeability. JSP modulated oxidative stress and inflammatory responses, which was demonstrated by reduced MPO activity, NO level, and levels of pro-inflammatory cytokines including TNF-α, IL-1ß and IL-6 in mice. JSP suppressed NF-κB signaling pathways as evidenced by lower levels of phosphorylated p65 and IKB. Moreover, JSP supplementation enhanced the expression of tight junction proteins and mucins, and modulated the composition of the gut microbiota and the production of short-chain fatty acids. Taken together, these results reveal the anti-inflammatory effect of dietary JSP in vivo, suggesting the potential of JSP as a nutritional supplement or adjunct strategy in preventing or ameliorating colitis.

Thermostability of Ctenophore and Coelenterate Ca2+-Regulated Apo-photoproteins: A Comparative Study.

The stabilities of Ca2+-regulated ctenophore and coelenterate apo-photoproteins, apo-mnemiopsin (apo-Mne) and apo-aequorin (apo-Aeq), respectively, were compared biochemically, biophysically, and structurally. Despite high degrees of structural and functional conservation, drastic variations in stability and structural dynamics were found between the two proteins. Irreversible thermoinactivation experiments were performed upon incubation of apo-photoproteins at representative temperatures. The inactivation rate constants (kinact) at 50 °C were determined to be 0.001 and 0.004 min-1 for apo-Mne and apo-Aeq, respectively. Detailed analysis of the inactivation process suggests that the higher thermostability of apo-Mne is due to the higher activation energy (Ea) and subsequently higher values of ΔH* and ΔG* at a given temperature. According to molecular dynamics simulation studies, the higher hydrogen bond, electrostatic, and van der Waals energies in apo-Mne can validate the relationship between the thermal adaptation of apo-Mne and the energy barrier for the inactivation process. Our results show that favorable residues for protein thermostability such as hydrophobic, charged, and adopted α-helical structure residues are more frequent in the apo-Mne structure. Although the effect of acrylamide on fluorescence quenching suggests that the local flexibility in regions around Trp and Tyr residues of apo-Aeq is higher than that of apo-Mne, which results in it having a better ability to penetrate acrylamide molecules, the root-mean-square fluctuation of helix A in apo-Mne is higher than that in apo-Aeq. It seems that the greater flexibility of apo-Mne in these regions may be considered as a determining factor, affecting the thermal stability of apo-Mne through a balance between structural rigidity and flexibility.

Marine natural products.

This review covers the literature published in 2019 for marine natural products (MNPs), with 719 citations (701 for the period January to December 2019) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1490 in 440 papers for 2019), together with the relevant biological activities, source organisms and country of origin. Pertinent reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included. Methods used to study marine fungi and their chemical diversity have also been discussed.

Proteomic Analysis of the Venom of Jellyfishes Rhopilema esculentum and Sanderia malayensis.

Venomics, the study of biological venoms, could potentially provide a new source of therapeutic compounds, yet information on the venoms from marine organisms, including cnidarians (sea anemones, corals, and jellyfish), is limited. This study identified the putative toxins of two species of jellyfish-edible jellyfish Rhopilema esculentum Kishinouye, 1891, also known as flame jellyfish, and Amuska jellyfish Sanderia malayensis Goette, 1886. Utilizing nano-flow liquid chromatography tandem mass spectrometry (nLC-MS/MS), 3000 proteins were identified from the nematocysts in each of the above two jellyfish species. Forty and fifty-one putative toxins were identified in R. esculentum and S. malayensis, respectively, which were further classified into eight toxin families according to their predicted functions. Amongst the identified putative toxins, hemostasis-impairing toxins and proteases were found to be the most dominant members (>60%). The present study demonstrates the first proteomes of nematocysts from two jellyfish species with economic and environmental importance, and expands the foundation and understanding of cnidarian toxins.

Comparative Aspects of Structure and Function of Cnidarian Neuropeptides.

Cnidarians are early-branching animals in the eukaryotic tree of life. The phylum Cnidaria are divided into five classes: Scyphozoa (true jellyfish), Cubozoa (box jellyfish), Hydrozoa (species, Hydra and Hydractinia), Anthozoa (sea anemone, corals, and sea pen), and Staurozoa (stalked jellyfish). Peptides play important roles as signaling molecules in development and differentiation in cnidaria. For example, cnidaria use peptides for cell-to cell communication. Recent discoveries show that Hydra neuropeptides control several biological processes including muscle contraction, neuron differentiation, and metamorphosis. Here, I describe the structure and functions of neuropeptides in Hydra and other cnidarian species. I also discuss that so-called primitive nervous system of Hydra is in more complex than generally believed. I also discuss how cnidaria use peptides for communication among cells rather than in higher animals.

Microchemical identification of enantiomers in early-branching animals: Lineage-specific diversification in the usage of D-glutamate and D-aspartate.

D-amino acids are unique and essential signaling molecules in neural, hormonal, and immune systems. However, the presence of D-amino acids and their recruitment in early animals is mostly unknown due to limited information about prebilaterian metazoans. Here, we performed the comparative survey of L-/D-aspartate and L-/D-glutamate in representatives of four phyla of early-branching Metazoa: cnidarians (Aglantha); placozoans (Trichoplax), sponges (Sycon) and ctenophores (Pleurobrachia, Mnemiopsis, Bolinopsis, and Beroe), which are descendants of ancestral animal lineages distinct from Bilateria. Specifically, we used high-performance capillary electrophoresis for microchemical assays and quantification of the enantiomers. L-glutamate and L-aspartate were abundant analytes in all species studied. However, we showed that the placozoans, cnidarians, and sponges had high micromolar concentrations of D-aspartate, whereas D-glutamate was not detectable in our assays. In contrast, we found that in ctenophores, D-glutamate was the dominant enantiomer with no or trace amounts of D-aspartate. This situation illuminates prominent lineage-specific diversifications in the recruitment of D-amino acids and suggests distinct signaling functions of these molecules early in the animal evolution. We also hypothesize that a deep ancestry of such recruitment events might provide some constraints underlying the evolution of neural and other signaling systems in Metazoa.

Purified compounds from marine organism sea pen induce apoptosis in human breast cancer cell MDA-MB-231 and cervical cancer cell Hela.

Marine organisms are an important source of chemical compounds which are appropriate for use as therapeutic agents. Among them, Sea pens produce valuable chemical compounds being used as anti-cancer drugs. The aim of this study was to investigate anti-cancer property of extracted and purified compounds from marine organism Sea pen and evaluate their effects on inducing of apoptosis. The extracts were prepared from dried colony of Virgularia gustaviana. The compounds (3ß)-Cholest,5en,3ol (cholesterol) (15 mg), Hexadecanoic acid (2.5 mg) and 2-Hexadecanol (10.7 mg) were identified by GC-MS and NMR. The cytotoxic effects of the compounds were evaluated on Hela and MDA-Mb-231 human cancer cell lines with MTT assay. Immunocytochemistry and Western Blot analyses were used to evaluate the expression of apoptosis related markers Caspase 3, Caspase 8, Bax and BCL2 in cancer cells after treating with three compounds. The purified compounds reduced viability of human breast cancer cell line MDA-MB-231 and human cervical cancer cell line Hela concentration-dependently. 2-Hexadecanol reduced significantly the viability of both cancer cell lines in comparison to the other purified compounds. Treatment of cancer cells with the three purified compounds increased the expression of caspase-3, caspase-8 and Bax proteins and decreased the relative Bcl-2/Bax ratio, demonstrating induction of apoptosis as possible mechanism of action. According to the results, three purified compounds inhibit the growth of cancer cells by inducing of apoptosis pathway; an effect which needs to be further investigated in the future studies.

1H NMR Metabolic Profile of Scyphomedusa Rhizostoma pulmo (Scyphozoa, Cnidaria) in Female Gonads and Somatic Tissues: Preliminary Results.

The Mediterranean basin is one of the regions heavily affected by jellyfish bloom phenomena, mainly due to the presence of scyphozoans, such as Rhizostoma pulmo. The jellyfish have few natural predators, and their bodies represent an organic-rich substrate that can support rapid bacterial growth with great impact on the structure of marine food webs. In Asiatic countries, jellyfish are widely studied for their health benefits, but their nutritional and nutraceutical values still remain poorly characterized. In this study, the differences in the 1H NMR spectroscopy metabolic profiles of R. pulmo female gonads and body fractions (including umbrella and oral arms), in different sampling periods, were studied. For each body compartment both lipid and aqueous extracts were characterized and their 1H NMR metabolic profiles subjected to multivariate analysis. From a statistical analysis of the extracts, a higher contents of ω-3 polyunsaturated fatty acids (PUFAs), amino acid and osmolytes (homarine, betaine, taurine) with important roles in marine invertebrates were observed in female gonads, whereas umbrella and oral arms showed similar metabolic profiles. These results support a sustainable exploitation of the jellyfish for the extraction of bioactive compounds useful in nutraceutical, nutricosmetics, and functional food fields.

Marine natural products.

This review covers the literature published between January and December in 2018 for marine natural products (MNPs), with 717 citations (706 for the period January to December 2018) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1554 in 469 papers for 2018), together with the relevant biological activities, source organisms and country of origin. Reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included. The proportion of MNPs assigned absolute configuration over the last decade is also surveyed.

Biotechnological Applications of Scyphomedusae.

As people across the world live longer, chronic illness and diminished well-being are becoming major global public health challenges. Marine biotechnology may help overcome some of these challenges by developing new products and know-how derived from marine organisms. While some products from marine organisms such as microalgae, sponges, and fish have already found biotechnological applications, jellyfish have received little attention as a potential source of bioactive compounds. Nevertheless, recent studies have highlighted that scyphomedusae (Cnidaria, Scyphozoa) synthesise at least three main categories of compounds that may find biotechnological applications: collagen, fatty acids and components of crude venom. We review what is known about these compounds in scyphomedusae and their current biotechnological applications, which falls mainly into four categories of products: nutraceuticals, cosmeceuticals, biomedicals, and biomaterials. By defining the state of the art of biotechnological applications in scyphomedusae, we intend to promote the use of these bioactive compounds to increase the health and well-being of future societies.

Spatially conserved motifs in complement control protein domains determine functionality in regulators of complement activation-family proteins.

Regulation of complement activation in the host cells is mediated primarily by the regulators of complement activation (RCA) family proteins that are formed by tandemly repeating complement control protein (CCP) domains. Functional annotation of these proteins, however, is challenging as contiguous CCP domains are found in proteins with varied functions. Here, by employing an in silico approach, we identify five motifs which are conserved spatially in a specific order in the regulatory CCP domains of known RCA proteins. We report that the presence of these motifs in a specific pattern is sufficient to annotate regulatory domains in RCA proteins. We show that incorporation of the lost motif in the fourth long-homologous repeat (LHR-D) in complement receptor 1 regains its regulatory activity. Additionally, the motif pattern also helped annotate human polydom as a complement regulator. Thus, we propose that the motifs identified here are the determinants of functionality in RCA proteins.

The Sialic Acid-Dependent Nematocyst Discharge Process in Relation to Its Physical-Chemical Properties Is A Role Model for Nanomedical Diagnostic and Therapeutic Tools.

Formulas derived from theoretical physics provide important insights about the nematocyst discharge process of Cnidaria (Hydra, jellyfishes, box-jellyfishes and sea-anemones). Our model description of the fastest process in living nature raises and answers questions related to the material properties of the cell- and tubule-walls of nematocysts including their polysialic acid (polySia) dependent target function. Since a number of tumor-cells, especially brain-tumor cells such as neuroblastoma tissues carry the polysaccharide chain polySia in similar concentration as fish eggs or fish skin, it makes sense to use these findings for new diagnostic and therapeutic approaches in the field of nanomedicine. Therefore, the nematocyst discharge process can be considered as a bionic blue-print for future nanomedical devices in cancer diagnostics and therapies. This approach is promising because the physical background of this process can be described in a sufficient way with formulas presented here. Additionally, we discuss biophysical and biochemical experiments which will allow us to define proper boundary conditions in order to support our theoretical model approach. PolySia glycans occur in a similar density on malignant tumor cells than on the cell surfaces of Cnidarian predators and preys. The knowledge of the polySia-dependent initiation of the nematocyst discharge process in an intact nematocyte is an essential prerequisite regarding the further development of target-directed nanomedical devices for diagnostic and therapeutic purposes. The theoretical description as well as the computationally and experimentally derived results about the biophysical and biochemical parameters can contribute to a proper design of anti-tumor drug ejecting vessels which use a stylet-tubule system. Especially, the role of nematogalectins is of interest because these bridging proteins contribute as well as special collagen fibers to the elastic band properties. The basic concepts of the nematocyst discharge process inside the tubule cell walls of nematocysts were studied in jellyfishes and in Hydra which are ideal model organisms. Hydra has already been chosen by Alan Turing in order to figure out how the chemical basis of morphogenesis can be described in a fundamental way. This encouraged us to discuss the action of nematocysts in relation to morphological aspects and material requirements. Using these insights, it is now possible to discuss natural and artificial nematocyst-like vessels with optimized properties for a diagnostic and therapeutic use, e.g., in neurooncology. We show here that crucial physical parameters such as pressure thresholds and elasticity properties during the nematocyst discharge process can be described in a consistent and satisfactory way with an impact on the construction of new nanomedical devices.

"Beyond Primary Sequence"-Proteomic Data Reveal Complex Toxins in Cnidarian Venoms.

Venomous animals can deploy toxins for both predation and defense. These dual functions of toxins might be expected to promote the evolution of new venoms and alteration of their composition. Cnidarians are the most ancient venomous animals but our present understanding of their venom diversity is compromised by poor taxon sampling. New proteomic data were therefore generated to characterize toxins in venoms of a staurozoan, a hydrozoan, and an anthozoan. We then used a novel clustering approach to compare venom diversity in cnidarians to other venomous animals. Comparison of the presence or absence of 32 toxin protein families indicated venom composition did not vary widely among the 11 cnidarian species studied. Unsupervised clustering of toxin peptide sequences suggested that toxin composition of cnidarian venoms is just as complex as that in many venomous bilaterians, including marine snakes. The adaptive significance of maintaining a complex and relatively invariant venom remains unclear. Future study of cnidarian venom diversity, venom variation with nematocyst types and in different body regions are required to better understand venom evolution.

Antitrypanosomal activity of isololiolide isolated from the marine hydroid Macrorhynchia philippina (Cnidaria, Hydrozoa).

Marine invertebrates are a rich source of small antiparasitic compounds. Among them, Macrorhynchia philippina is a chemically underexplored marine cnidarian. In the search for candidates against the neglected protozoan Chagas disease, we performed a bio-guided fractionation to obtain active compounds. The structural characterization of the active compound was determined using NMR analysis and MS and resulted in the isololiolide, a compound described for the first time in this species. It showed in vitro activity against both trypomastigote and intracellular amastigotes of Trypanosoma cruzi, with IC50 values of 32 µM and 40 µM, respectively, with no mammalian cytotoxicity (>200 µM). The lethal action was investigated in T. cruzi using different fluorophores to study: (i) mitochondrial membrane potential; (ii) plasma membrane potential and (iii) plasma membrane permeability. Our results demonstrated that isololiolide caused disruption of the plasma membrane integrity and a strong depolarization of the mitochondrial membrane potential, rapidly leading the parasite to death. Despite being considered a possible covalent inhibitor, safety in silico studies of isololiolide also considered neither mutagenic nor genotoxic potential. Additionally, isololiolide showed no resemblance to interference compounds (PAINS), and it succeeded in most filters for drug-likeness. Isololiolide is a promising candidate for future optimization against Chagas disease.

Briarenones A‒C, New Briarellin Diterpenoids from the Gorgonian Briareum violaceum.

Three new eunicellin-derived diterpenoids of briarellin type, briarenones A‒C (1‒3), were isolated from a Formosan gorgonian Briareum violaceum. The chemical structures of the compounds were elucidated on the basis of extensive spectroscopic analyses, including two-dimensional (2D) NMR. The absolute configuration of 1 was further confirmed by a single crystal X-ray diffraction analysis. The in vitro cytotoxic and anti-inflammatory potentialities of the isolated metabolites were tested against the growth of a limited panel of cancer cell lines and against the production of superoxide anions and elastase release in N-formyl-methionyl-leucyl-phenyl-alanine and cytochalasin B (fMLF/CB)-stimulated human neutrophils, respectively.