Marine Compounds and Cancer 2020

The very first marine-derived anticancer drug, Cytarabine (aka Ara-C, Cytosar-U®), was approved by the FDA in 1969 for the treatment of leukemia. At the beginning of 2021, the list of approved marine-derived anticancer drugs consists of nine substances, five of which received approval within the last two years, demonstrating the rapid evolution of the field. The current book is a collection of scientific articles related to the exponentially growing field of anticancer marine compounds. These articles cover the whole field, from agents with cancer-preventive activity, to novel and previously characterized compounds with anticancer activity, both in vitro and in vivo, as well as the latest status of compounds under clinical development

Exploring the Multifaceted Roles of Glycosaminoglycans (GAGs) - New Advances and Further Challenges

Glycosaminoglycans are linear, anionic polysaccharides (GAGs) consisting of repeating disaccharides. GAGs are ubiquitously localized throughout the extracellular matrix (ECM) and to the cell membranes of cells in all tissues. They are either conjugated to protein cores in the form of proteoglycans, e.g., chondroitin/dermatan sulfate (CS/DS), heparin/heparan sulfate (Hep/HS) and keratan sulfate (KS), as well as non-sulfated hyaluronan (HA). By modulating biological signaling GAGs participate in the regulation of homeostasis and also participate in disease progression. The book, entitled “Exploring the multifaceted roles of glycosaminoglycans (GAGs)—new advances and further challenges”, features original research and review articles. These articles cover several GAG-related timely topics in structural biology and imaging; morphogenesis, cancer, and other disease therapy and drug developments; tissue engineering; and metabolic engineering. This book also includes an article illustrating how metabolic engineering can be used to create the novel chondroitin-like polysaccharide.A prerequisite for communicating in any discipline and across disciplines is familiarity with the appropriate terminology. Several nomenclature rules exist in the field of biochemistry. The historical description of GAGs follows IUPAC and IUB nomenclature. New structural depictions such as the structural nomenclature for glycan and their translation into machine-readable formats have opened the route for cross-references with popular bioinformatics resources and further connections with other exciting “omics” fields

Lysosome Biogenesis and Autophagy

Lysosomes degrade biological components acquired by endocytosis, the major cellular pathway for internalization of extracellular material, and macroautophagy. This chapter presents an overview of these two major degradative intracellular pathways, and highlights the emerging cross talks between them, in healthy and diseased conditions. The pathways to lysosomes include the biosynthetic transport routes, endocytic pathways, and the autophagy pathways. The central actors of the autophagy process are the ATG genes. Based on their organization in complexes and interactions, the ATG genes have been divided into many functional clusters that compose the core autophagy machinery. Cross talk between the endocytic and autophagic pathways occurs at many levels: transcriptional regulation, protein sharing, and compartmental connections. The chapter focuses on the fusion and fission events between compartments of the endolysosomal system and autophagic membranes, respectively. Lysosome-related disorders are caused by mutations in genes encoding for proteins that directly affect lysosomal functioning, including lysosomal hydrolases and lysosomal membrane proteins

A computational perspective of influenza a virus targets : neuraminidase and endonuclease.

Ph. D. University of KwaZulu-Natal, Durban 2016.Through the ages the viruses have plagued mankind claiming the lives of millions, pre-dating any advancements in the medicinal sciences. One such pathogenic virus is influenza A, which has been implicated in the 1918-Spanish flu, the 2006-avian flu outbreak and the 2009-swine flu pandemic. It is a highly sophisticated species, alluding efforts to thwart the spread of disease and infection. One of the main reasons influenza has survived this long is simple evolution. Natural mutation within the genome of virions expressed in proteins, enzymes or molecular structure render us unable to predict or take preventative measures against possible infection. Thus, research efforts toward the competitive inhibition of biological pathways that lead to the spread of disease, have become attractive targets. The influenza A virus has a number of chemotherapeutic targets, such as: 1) The surface antigens, hemagglutinin and neuraminidase, 2) RNA-dependent RNA polymerase, and 3) The M2 proton channel. Influenza RNA polymerase is composed of three large segments encoding polymerase acidic protein (PA), polymerase basic protein 1 (PB1) and polymerase basic protein 2 (PB2). The PA protein is an N-terminal domain subunit which contains the endonuclease activity. The influenza virus is incapable of synthesizing a 5’-mRNA cap, so it has adapted a cap-snatching mechanism whereby the PB2 subunit binds to the 5’-end of host mRNA, after which 10-14 nucleotides downstream the PA-subunit (aka PAN) cleaves the strand forming a primer for viral mRNA synthesis which is catalysed by the PB1 subunit. Influenza target identification is based primarily on evidence suggesting sequence conservation of each entity and its selective expression in the virus and not the host. In this thesis two enzymatic targets were investigated, the PA protein of RNA polymerase and neuraminidase. The studies focussed on using computational tools to: 1) provide insight into the mechanism of drug-resistance, 2) describe the conformational structure of the protein in the presence of point mutations and in complex with an inhibitor, 3) determine the essential binding pharmacophoric features to aid the design of new drug therapies. An array of computational techniques were employed in the studies, such as: molecular dynamics (MD) simulation, structure-based and ligand-based in silico screening, principal component analysis, radius of gyration analysis, binding free energy calculations and solventaccessible surface area analysis. The first study (Chapter 5) determined the mechanism of drug-resistance in influenza A neuraminidase as a consequence of antigenic variations. Two distinct mutations in the enzyme sequence that were investigated are H274Y and I222K. The active site residues of neuraminidase are conserved among the subtypes of influenza A. However, it was discovered that the occurrence of resistance to the drug oseltamivir, in the H1N1 species was different to the H5N1 virus. Although both systems shared a loss in hydrophobicity of the active site, the conformational distortion of the active site pocket distinguished the enzyme of the two viral entities, from one another. The discoveries made in the first study laid the foundation for the second study (Chapter 6), which was based on the in silico design and screen of potential neuraminidase inhibitors. As a result 10 characteristic molecular scaffolds were suggested as potential inhibitors. The pharmacophore design was constructed with consideration to the new conformational structure of the active site pocket. Chapter 7 is the third study of this thesis. The active site pocket enclosing the endonuclease activity of the PA subunit was investigated. Using molecular dynamics simulations and postdynamic analyses, a description of the protein conformation was offered. Subsequently, a pharmacophore was proposed as a potential scaffold to which endonuclease inhibitors may be modelled upon. It is my belief that the impact of the results derived from the above mentioned studies would greatly contribute to the development of new and effective anti-influenza drugs

Nutramara - Marine Functional Foods Research Initiative (MFFRI/07/01)

Final report of projectThe NutraMara – Marine Functional Foods Research Initiative was conceived by Sea Change - A Marine Knowledge, Research and Innovation Strategy for Ireland 2007-2013. The goal was to develop a collaborative funding mechanism that would create new research capacity and build the capabilities required to maximise the potential of Ireland’s extensive marine bioresources. By supporting a strong interdisciplinary research team, capable of exploring marine animals and plants as a sustainable source of materials for use as functional ingredients and foods, the vision for NutraMara was to position Ireland to the fore in use of marine bioresources as health beneficial ingredients. Commencing in 2008 and supported by funds of €5.2 million from the Marine Institute and the Department of Agriculture, Food and the Marine, the research programme was led by Teagasc as the head of a multi-institutional consortium. The NutraMara consortium comprises marine bioresources and bioscience expertise, with food science and technology expertise from University College Cork; University College Dublin; the National University of Ireland Galway; the University of Limerick and Ulster University. Research effort was directed towards exploring Ireland’s marine bioresources – including macro- and microalgae, finfish and shellfish from wild and cultured sources: and discards from processing fish as sources of novel ingredients with bioactive characteristics. This discovery activity involved the collection of over 600 samples from 39 species of algae and fish and the analysis of 5,800 extracts, which resulted in 3,000 positive “hits” for bioactivity. The NutraMara consortium has built a strong research capacity to identify, characterise and evaluate marine-origin bioactives for use as/in functional foods. It further built the capacity to develop model foods enhanced with these marine-origin functional ingredients; providing insights to the processing challenges associated with producing functional ingredients from marine organisms. The consortium was actively engaged in research activities designed to identify and assess bioactive compounds from available marine resources, including polyphenols, proteins/peptides, amino acids, polysaccharides, polyunsaturated fatty acids and materials with antioxidant, probiotic or prebiotic properties. A key component of NutraMara’s activities was the development of human capital. The recruitment of M.Sc. and PhD students and their integration within a dynamic research environment that has strong links to industry, provided lasting expertise and capabilities, which are relevant to the needs of Ireland’s food and marine sectors. NutraMara research led to the awarding of eighteen PhDs and recruitment of 21 post-doctoral researchers over the eight year research programme. In excess of 80 peer reviewed publications resulted from this research and more publications are planned. A further 100 posters and conference presentations were also delivered by NutraMara researchers and Principal Investigators. The development and implementation of training and exchange programmes aimed at providing early stage researchers with inter-disciplinary skills that are critical to their development as researchers, enhanced the research capacity of institutions, the industry sectors and the country as a whole. Principal Investigators involved in leading the NutraMara research programme have secured additional research grants of almost €6 million from national and international sources and are engaged in extensive research collaboration involving marine and food research expertise; an activity which did not exist prior to NutraMara. The dissemination of knowledge and transfer of research results to industry were key activities in the research programme. The research outputs and visibility of NutraMara activity nationally resulted in 10 companies engaging in research and development activity with the consortium. Regular workshops and conferences organised by NutraMara attracted close to five hundred participants from Ireland and overseas. Members of the NutraMara core PI group have contributed to the formulation of new national foods and marine research policy and national research agenda, both during the national prioritisation exercise and in sectoral research strategies. This final project report describes the process by which research targets were identified, and the results of extensive screening and evaluation of compounds extracted from marine bioresources. It also highlights the development of new protocols designed to extract compounds in ways that are food friendly. Evaluating the functional properties, bioactivity and bioavailability of high potential marine compounds involved in vitro and in vivo testing. Pilot animal and human intervention studies yielded further insight to the potential and challenges in developing marine functional ingredients. As a result of work completed within the NutraMara consortium, Ireland is well positioned to continue to contribute to the development of ingredients derived from marine organisms and in doing so support the on-going development of Ireland’s food sector.Marine Institut

Non-covalent interactions in organotin(IV) derivatives of 5,7-ditertbutyl- and 5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine as recognition motifs in crystalline self- assembly and their in vitro antistaphylococcal activity

Non-covalent interactions are known to play a key role in biological compounds due to their stabilization of the tertiary and quaternary structure of proteins [1]. Ligands similar to purine rings, such as triazolo pyrimidine ones, are very versatile in their interactions with metals and can act as model systems for natural bio-inorganic compounds [2]. A considerable series (twelve novel compounds are reported) of 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp) and 5,7-diphenyl- 1,2,4-triazolo[1,5-a]pyrimidine (dptp) were synthesized and investigated by FT-IR and 119Sn M\uf6ssbauer in the solid state and by 1H and 13C NMR spectroscopy, in solution [3]. The X-ray crystal and molecular structures of Et2SnCl2(dbtp)2 and Ph2SnCl2(EtOH)2(dptp)2 were described, in this latter pyrimidine molecules are not directly bound to the metal center but strictly H-bonded, through N(3), to the -OH group of the ethanol moieties. The network of hydrogen bonding and aromatic interactions involving pyrimidine and phenyl rings in both complexes drives their self-assembly. Noncovalent interactions involving aromatic rings are key processes in both chemical and biological recognition, contributing to overall complex stability and forming recognition motifs. It is noteworthy that in Ph2SnCl2(EtOH)2(dptp)2 \u3c0\u2013\u3c0 stacking interactions between pairs of antiparallel triazolopyrimidine rings mimick basepair interactions physiologically occurring in DNA (Fig.1). M\uf6ssbauer spectra suggest for Et2SnCl2(dbtp)2 a distorted octahedral structure, with C-Sn-C bond angles lower than 180\ub0. The estimated angle for Et2SnCl2(dbtp)2 is virtually identical to that determined by X-ray diffraction. Ph2SnCl2(EtOH)2(dptp)2 is characterized by an essentially linear C-Sn-C fragment according to the X-ray all-trans structure. The compounds were screened for their in vitro antibacterial activity on a group of reference staphylococcal strains susceptible or resistant to methicillin and against two reference Gramnegative pathogens [4] . We tested the biological activity of all the specimen against a group of staphylococcal reference strains (S. aureus ATCC 25923, S. aureus ATCC 29213, methicillin resistant S. aureus 43866 and S. epidermidis RP62A) along with Gram-negative pathogens (P. aeruginosa ATCC9027 and E. coli ATCC25922). Ph2SnCl2(EtOH)2(dptp)2 showed good antibacterial activity with a MIC value of 5 \u3bcg mL-1 against S. aureus ATCC29213 and also resulted active against methicillin resistant S. epidermidis RP62A

Marine Functional Foods Research Initiative (NutraMara)

Sea Change—A Marine Knowledge, Research & Innovation Strategy for Ireland 2007-2013—was launched in early 2007 and was the outcome of extensive analysis and consultation with government departments, state agencies, industry and the third-level sector. It outlines a vision for the development of Ireland’s marine sector and sets clear objectives aimed at achieving this vision, namely to: 1. Assist existing, and largely indigenous, marine sub-sectors to improve their overall competitiveness and engage in activity that adds value to their outputs by utilising knowledge and technology arising from research. 2. Build new research capacity and capability and utilise fundamental knowledge and technology to create new marine-related commercial opportunities and companies. 3. Inform public policy, governance and regulation by applying the knowledge derived from marine research and monitoring. 4. Increase the marine sector’s competitiveness and stimulate the commercialisation of the marine resource in a manner that ensures its sustainability and protects marine biodiversity and ecosystems. 5. Strengthen the economic, social and cultural base of marine dependant regional/rural communities. The Sea Change strategy was developed as an integral part of the government’s Strategy for Science, Technology and Innovation (SSTI) and the Marine Institute as the lead implementation agency is working within SSTI policy and with government departments and agencies to deliver on the Strategy. The Marine Institute managed Marine Research Sub-Programme, one of eight sub-programmes within the Science, Technology and Innovation (STI) Programme of the National Development Plan 2007—2013, targets funding to meet the objectives of the Sea Change strategy. Over the lifetime of Sea Change, funding will be provided for: • Project-Based Awards o Strategic Research Projects o Applied Research Projects o Demonstration Projects o Desk/Feasibility Studies • Researcher Awards o Strategic Research Appointments o Research Capacity/Competency Building o Post-Doctoral Fellowships o PhD Scholarships • Industry-Led Research Awards o Company Awards o Collaborative Awards • Infrastructure Awards o Infrastructure Acquisition o Access to InfrastructurNutraMara – Marine Functional Foods Research Initiative: The goal was to create new research capacity and build the capabilities required to maximise the potential of Ireland’s extensive marine bioresources. By supporting a strong interdisciplinary research team, capable of exploring marine animals and plants as a sustainable source of materials for use as functional ingredients and foods, the vision for NutraMara was to position Ireland to the fore in use of marine bioresources as health beneficial ingredients.Lead Partner: Teagasc – The Irish Food and Agriculture Authority Project Partners: National University of Ireland Galway University College Dublin University of Limerick Ulster University University College Cor

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

This work was supported by the National Institute of General Medical Sciences [GM131919].In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.PostprintPeer reviewe