Meroterpenes from marine invertebrates: structures, occurrence, and ecological implications

Meroterpenes are widely distributed among marine organisms; they are particularly abundant within brown algae, but other important sources include microorganisms and invertebrates. In the present review the structures and bioactivities of meroterpenes from marine invertebrates, mainly sponges and tunicates, are summarized. More than 300 molecules, often complex and with unique skeletons originating from intra- and inter-​mol. cyclizations, and(or) rearrangements, are illustrated. The reported syntheses are mentioned. The issue of a potential microbial link to their biosynthesis is also shortly outlined

Further Investigation of the Mediterranean Sponge Axinella polypoides: Isolation of a New Cyclonucleoside and a New Betaine

An exhaustive exploration into the metabolic content of the Mediterranean sponge Axinella-polypoides resulted in the isolation of the new betaine 5 and the new cyclonucleoside 8. The structures of the new metabolites were elucidated by spectroscopic methods assisted by computational methods. The analysis also provided evidence that the sponge does not elaborate pyrrole-imidazole alkaloids (PIAs) but, interestingly, it was shown to contain two already known cyclodipeptides, compounds 9 (verpacamide A) and 10

Role of DNA repair machinery and p53 in the testicular germ cell cancer: a review

Notwithstanding the peculiar sensitivity to cisplatin-based treatment, resulting in a very high percentage of cures even in advanced stages of the disease, still we do not know the biological mechanisms that make Testicular Germ Cell Tumor (TGCT) "unique" in the oncology scene. p53 and MDM2 seem to play a pivotal role, according to several in vitro observations, but no correlation has been found between their mutational or expression status in tissue samples and patients clinical outcome. Furthermore, other players seem to be on stage: DNA Damage Repair Machinery (DDR) , especially Homologous Recombination (HR) proteins, above all Ataxia Telangiectasia Mutated (ATM), cooperates with p53 in response to DNA damage, activating apoptotic cascade and contributing to cell "fate". Homologous Recombination deficiency has been assumed to be a Germ Cell Tumor characteristic underlying platinum-sensitivity, whereby Poly(ADP-ribose) polymerase (PARP), an enzyme involved in HR DNA repair, is an intriguing target: PARP inhibitors have already entered in clinical practice of other malignancies and trials are recruiting TGCT patients in order to validate their role in this disease. This paper aims to summarize evidence, trying to outline an overview of DDR implications not only in TGCT curability, but also in resistance to chemotherapy

Natural Variation of Model Mutant Phenotypes in Ciona intestinalis

BACKGROUND: The study of ascidians (Chordata, Tunicata) has made a considerable contribution to our understanding of the origin and evolution of basal chordates. To provide further information to support forward genetics in Ciona intestinalis, we used a combination of natural variation and neutral population genetics as an approach for the systematic identification of new mutations. In addition to the significance of developmental variation for phenotype-driven studies, this approach can encompass important implications in evolutionary and population biology. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report a preliminary survey for naturally occurring mutations in three geographically interconnected populations of C. intestinalis. The influence of historical, geographical and environmental factors on the distribution of abnormal phenotypes was assessed by means of 12 microsatellites. We identified 37 possible mutant loci with stereotyped defects in embryonic development that segregate in a way typical of recessive alleles. Local populations were found to differ in genetic organization and frequency distribution of phenotypic classes. CONCLUSIONS/SIGNIFICANCE: Natural genetic polymorphism of C. intestinalis constitutes a valuable source of phenotypes for studying embryonic development in ascidians. Correlating genetic structure and the occurrence of abnormal phenotypes is a crucial focus for understanding the selective forces that shape natural finite populations, and may provide insights of great importance into the evolutionary mechanisms that generate animal diversity

New Insights into the Evolution of Metazoan Tyrosinase Gene Family

Tyrosinases, widely distributed among animals, plants and fungi, are involved in the biosynthesis of melanin, a pigment that has been exploited, in the course of evolution, to serve different functions. We conducted a deep evolutionary analysis of tyrosinase family amongst metazoa, thanks to the availability of new sequenced genomes, assessing that tyrosinases (tyr) represent a distinctive feature of all the organisms included in our study and, interestingly, they show an independent expansion in most of the analyzed phyla. Tyrosinase-related proteins (tyrp), which derive from tyr but show distinct key residues in the catalytic domain, constitute an invention of chordate lineage. In addition we here reported a detailed study of the expression territories of the ascidian Ciona intestinalis tyr and tyrps. Furthermore, we put efforts in the identification of the regulatory sequences responsible for their expression in pigment cell lineage. Collectively, the results reported here enlarge our knowledge about the tyrosinase gene family as valuable resource for understanding the genetic components involved in pigment cells evolution and development

Characterization of new bioactive natural products from marine sources as pharmaceutical tools and lead compounds in drug discovery processes

Natural products have historically been a rich source of “lead compounds” in drug discovery. The investigation of terrestrial plants and marine organisms aimed at searching new biologically active compounds is a central issue of this kind of studies, trough structure elucidation combined with biological tests. My research activity has been mainly devoted to the discovery and to the chemical and pharmacological investigation of new bioactive natural products as “lead compounds” in the area of antitumor, anti inflammatory and antimalarial activities. My research work, described in this PhD thesis, was organized in two different topics, i) isolation and structural characterization of bioactive secondary metabolites from marine invertebrates; ii) synthesis of quinones derivatives endowed with cytotoxic and antimalarial activities from natural lead compounds. The fulfilment of my research project required the use of different procedures of isolation and extraction. The chemical characterization of the isolated compounds has been performed through an extensive spectroscopic analysis (UV, IR, ECD, 1D and 2D NMR) together with mass spectrometry and computational methods. I have also used synthetic methods both for the chemical derivatization of the isolated molecules and for the preparation of analogues on the simplified model of natural molecules. During the course of research conducted during the PhD course and whose results are reported in the following thesis, I have dealt with the extraction and chemical analysis of different species of sea squirts (Aplidium conicum, Ciona edwarsii, Aplidium elegans, Phallusia fumigata and Sidnyum elegans) and of the sponge Axinella polypoides. This analysis led to the isolation of new molecules, which are structurally different, with interesting bioactivity. Among these, two new meroterpenes, conithiaquinones A and B, and three alkyl sulphates with cytotoxic properties. Three sulfated sterols, phallusiasterols A-C, one of them with agonist activity on the pregnane X receptor (PXR) in HepG2 cells. The phosphoeleganin, a potent inhibitor of protein tyrosine phosphatase 1B (PTP1B). An analysis of the metabolic content of the sponge Axinella polypoides has provided important chemo-taxonomic information about the organism, in addition, led to the isolation of a new betaine and a new cyclonucleoside. Within the study of compounds with antimalarial activity, in collaboration with the University of Rome La Sapienza and the Department of Public Health, Microbiology and Virology, University of Milan, I have performed the synthesis and evaluation of in vitro on strains of Plasmodium falciparum D10 (chloroquine-sensitive) and W2 (chloroquine-resistant) of synthetic analogues of natural quinones, prepared on the pattern of two natural molecules previously isolated from an ascidian. The synthetic derivatives showed significant antimalarial activity and were also highlighted some structural requirements that are critical for the activity. Finally, during the period of research at the Institute of Materia Medica (SIMM ) in Shanghai, I started to study lipid-soluble extract of a fungal strain Penicillium sp, isolated from the Chinese mangrove Bruguiera gymnorrhiza. The analysis showed that the main component of the extract is a cytotoxic alkaloid, 2-(1-hydroxyethyl)-4 (3H) quinazolinone, which is currently subject to a broader drug screening

Bioactive Alkaloids of Marine Origin

The marine organisms, mainly invertebrates such as sponges and ascidians, are a rich source of varied natural alkaloids with unique chemical scaffolds and diverse bioactivities. From a medicinal chemistry perspective, the marine alkaloids' fascinating structures as well as their broad spectrum of pharmacological activity make them promising lead compounds for various druggable targets. The recent results in the field of marine alkaloids are thus here described. The structures and biological activities of selected typical classes of marine alkaloids are briefly illustrated, with the emphasis on the role of these natural products as leads for drug discovery

Molecular taxonomy confirms that the northeastern Atlantic and Mediterranean Sea harbor a single lancelet, Branchiostoma lanceolatum (Pallas, 1774) (Cephalochordata: Leptocardii: Branchiostomatidae).

Branchiostomatidae (lancelets or amphioxus) comprises about 30 species, several of which are well-established models in evolutionary development. Our zoological and ecological knowledge of the family is nonetheless limited. Despite evident differences can be found among known populations, the taxonomy of Branchiostoma lanceolatum (type species of the genus Branchiostoma) has never been investigated with modern methods through its range in the northeastern Atlantic and Mediterranean Sea. We address this via a multilocus molecular approach and comparing specimens collected from different European populations. Results obtained here confirm the presence of a single species inhabiting the range between the topotypical localities of B. lanceolatum (Atlantic Ocean) and of its junior synonym B. lubricum (Mediterranean Sea), without evincing geographical structure between populations. This suggests that environment most likely drives the characteristics observed in different geographic areas. The long larval phase and the slow mutation rate in lancelets may have played a key role in the evolutionary history of this iconic species

Ran GTPase, an eukaryotic gene novelty, is involved in amphioxus mitosis.

Ran (ras-related nuclear protein) is a small GTPase belonging to the RAS superfamily that is specialized in nuclear trafficking. Through different accessory proteins, Ran plays key roles in several processes including nuclear import-export, mitotic progression and spindle assembly. Consequently, Ran dysfunction has been linked to several human pathologies. This work illustrates the high degree of amino acid conservation of Ran orthologues across evolution, reflected in its conserved role in nuclear trafficking. Moreover, we studied the evolutionary scenario of the pre-metazoan genetic linkage between Ran and Stx, and we hypothesized that chromosomal proximity of these two genes across metazoans could be related to a regulatory logic or a functional linkage. We studied, for the first time, Ran expression during amphioxus development and reported its presence in the neural vesicle, mouth, gill slits and gut corresponding to body regions involved in active cell division

The evolutionary landscape of the Rab family in chordates

Intracellular traffic amongst organelles represents a key feature for eukaryotes and is orchestrated principally by members of Rab family, the largest within Ras superfamily. Given that variations in Rab repertoire have been fundamental in animal diversification, we provided the most exhaustive survey regarding the Rab toolkit of chordates. Our findings reveal the existence of 42 metazoan conserved subfamilies exhibiting a univocal intron/exon structure preserved from cnidarians to vertebrates. Since the current view does not capture the Rab complexity, we propose a new Rab family classification in three distinct monophyletic clades. The Rab complement of chordates shows a dramatic diversification due to genome duplications and independent gene duplications and losses with sharp differences amongst cephalochordates, tunicates and gnathostome vertebrates. Strikingly, the analysis of the domain architecture of this family highlighted the existence of chimeric calcium-binding Rabs, which are animal novelties characterized by a complex evolutionary history in gnathostomes and whose role in cellular metabolism is obscure. This work provides novel insights in the knowledge of Rab family: our hypothesis is that chordates represent a hotspot of Rab variability, with many events of gene gains and losses impacting intracellular traffic capabilities. Our results help to elucidate the role of Rab members in the transport amongst endomembranes and shed light on intracellular traffic routes in vertebrates. Then, since the predominant role of Rabs in the molecular communication between different cellular districts, this study paves to way to comprehend inherited or acquired human disorders provoked by dysfunctions in Rab genes