Browsing by Subject "NATURAL-PRODUCTS"

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  • Zhao, Ke; Li, Jing; Zhang, Xiaoyue; Chen, Qiang; Liu, Maoke; Ao, Xiaolin; Gu, Yunfu; Liao, Decong; Xu, Kaiwei; Ma, Monggeng; Yu, Xiumei; Xiang, Quanju; Chen, Ji; Zhang, Xiaoping; Penttinen, Petri (2018)
    Many of the plant associated microbes may directly and indirectly contribute to plant growth and stress resistance. Our aim was to assess the plant growth-promoting and antimicrobial activities of actinobacteria isolated from Glycyrrhiza inflata Bat. plants to find strains that could be applied in agricultural industry, for example in reclaiming saline soils. We isolated 36 and 52 strains that showed morphological characteristics of actinobacteria from one year old and three year old G. inflata plants, respectively. Based on 16S rRNA gene sequence analysis, the strains represented ten actinobacterial genera. Most of the strains had plant growth promoting characteristics in vitro, tolerated 200 mM NaCl and inhibited the growth of at least one indicator organism. The eight selected Streptomyces strains increased the germination rate of G. inflata seeds under salt stress. In addition, the four best seed germination promoters promoted the growth of G. inflata in vivo. The best promoters of G. inflata growth, strains SCAU5283 and SCAU5215, inhibited a wide range of indicator organisms, and may thus be considered as promising candidates to be applied in inoculating G. inflata.
  • Nivala, Outi; Faccio, Greta; Arvas, Mikko; Permi, Perttu; Buchert, Johanna; Kruus, Kristiina; Mattinen, Maija-Liisa (2017)
    Background: Despite of the presence of sulfhydryl oxidases (SOXs) in the secretomes of industrially relevant organisms and their many potential applications, only few of these enzymes have been biochemically characterized. In addition, basic functions of most of the SOX enzymes reported so far are not fully understood. In particular, the physiological role of secreted fungal SOXs is unclear. Results: The recently identified SOX from Aspergillus tubingensis (AtSOX) was produced, purified and characterized in the present work. AtSOX had a pH optimum of 6.5, and showed a good pH stability retaining more than 80% of the initial activity in a pH range 4-8.5 within 20 h. More than 70% of the initial activity was retained after incubation at 50 degrees C for 20 h. AtSOX contains a non-covalently bound flavin cofactor. The enzyme oxidised a sulfhydryl group of glutathione to form a disulfide bond, as verified by nuclear magnetic resonance spectroscopy. AtSOX preferred glutathione as a substrate over cysteine and dithiothreitol. The activity of the enzyme was totally inhibited by 10 mM zinc sulphate. Peptide-and protein-bound sulfhydryl groups in bikunin, gliotoxin, holomycin, insulin B chain, and ribonuclease A, were not oxidised by the enzyme. Based on the analysis of 33 fungal genomes, SOX enzyme encoding genes were found close to nonribosomal peptide synthetases (NRPS) but not with polyketide synthases (PKS). In the phylogenetic tree, constructed from 25 SOX and thioredoxin reductase sequences from IPR000103 InterPro family, AtSOX was evolutionary closely related to other Aspergillus SOXs. Oxidoreductases involved in the maturation of nonribosomal peptides of fungal and bacterial origin, namely GliT, HlmI and DepH, were also evolutionary closely related to AtSOX whereas fungal thioreductases were more distant. Conclusions: AtSOX (55 kDa) is a fungal secreted flavin-dependent enzyme with good stability to both pH and temperature. A Michaelis-Menten behaviour was observed with reduced glutathione as a substrate. Based on the location of SOX enzyme encoding genes close to NRPSs, SOXs could be involved in the secondary metabolism and act as an accessory enzyme in the production of nonribosomal peptides.
  • Humisto, Anu; Jokela, Jouni; Teigen, Knut; Wahlsten, Matti; Permi, Perttu; Sivonen, Kaarina; Herfindal, Lars (2019)
    Hassallidins are cyclic glycolipopeptides produced by cyanobacteria and other prokaryotes. The hassallidin structure consists of a peptide ring of eight amino acids where a fatty acid chain, additional amino acids, and sugar moieties are attached. Hassallidins show antifungal activity against several opportunistic human pathogenic fungi, but does not harbor antibacterial effects. However, they have not been studied on mammalian cells, and the mechanism of action is unknown. We purified hassallidin D from cultured cyanobacterium Anabaena sp. UHCC 0258 and characterized its effect on mammalian and fungal cells. Ultrastructural analysis showed that hassallidin D disrupts cell membranes, causing a lytic/necrotic cell death with rapid presence of disintegrated outer membrane, accompanied by internalization of small molecules such as propidium iodide into the cells. Furthermore, artificial liposomal membrane assay showed that hassallidin D selectively targets sterol-containing membranes. Finally, in silico membrane modeling allowed us to study the interaction between hassallidin D and membranes in detail, and confirm the role of cholesterol for hassallidin-insertion into the membrane. This study demonstrates the mechanism of action of the natural compound hassallidin, and gives further insight into how bioactive lipopeptide metabolites selectively target eukaryotic cell membranes.
  • Humisto, Anu; Herfindal, Lars; Jokela, Jouni; Karkman, Antti; Bjørnstad, Ronja; Choudhury, Romi R.; Sivonen, Kaarina (2015)
    Cyanobacteria are an inspiring source of bioactive secondary metabolites. These bioactive agents are a diverse group of compounds which are varying in their bioactive targets, the mechanisms of action, and chemical structures. Cyanobacteria from various environments, especially marine benthic cyanobacteria, are found to be rich sources for the search for novel bioactive compounds. Several compounds with anticancer activities have been discovered from cyanobacteria and some of these have succeeded to enter the clinical trials. Varying anticancer agents are needed to overcome increasing challenges in cancer treatments. Different search methods are used to reveal anticancer compounds from natural products, but cell based methods are the most common. Cyanobacterial bioactive compounds as agents against acute myeloid leukemia are not well studied. Here we examined our new results combined with previous studies of anti-leukemic compounds from cyanobacteria with emphasis to reveal common features in strains producing such activity. We report that cyanobacteria harbor specific anti-leukemic compounds since several studied strains induced apoptosis against AML cells but were inactive against non-malignant cells like hepatocytes. We noted that particularly benthic strains from the Baltic Sea, such as Anabaena sp., were especially potential AML apoptosis inducers. Taken together, this review and re-analysis of data demonstrates the power of maintaining large culture collections for the search for novel bioactivities, and also how anti-AML activity in cyanobacteria can be revealed by relatively simple and low-cost assays.
  • Jones, Martin R.; Pinto, Ernani; Torres, Mariana A.; Dörr, Fabiane; Mazur-Marzec, Hanna; Szubert, Karolina; Tartaglione, Luciana; Dell'Aversano, Carmela; Miles, Christopher O.; Beach, Daniel G.; McCarron, Pearse; Sivonen, Kaarina; Fewer, David P.; Jokela, Jouni; Janssen, Elisabeth M.-L. (2021)
    Harmful cyanobacterial blooms, which frequently contain toxic secondary metabolites, are reported in aquatic environments around the world. More than two thousand cyanobacterial secondary metabolites have been reported from diverse sources over the past fifty years. A comprehensive, publically-accessible database detailing these secondary metabolites would facilitate research into their occurrence, functions and toxicological risks. To address this need we created CyanoMetDB, a highly curated, flat-file, openly-accessible database of cyanobacterial secondary metabolites collated from 850 peer-reviewed articles published between 1967 and 2020. CyanoMetDB contains 2010 cyanobacterial metabolites and 99 structurally related compounds. This has nearly doubled the number of entries with complete literature metadata and structural composition information compared to previously available open access databases. The dataset includes microcytsins, cyanopeptolins, other depsipeptides, anabaenopeptins, microginins, aeruginosins, cyclamides, cryptophycins, saxitoxins, spumigins, microviridins, and anatoxins among other metabolite classes. A comprehensive database dedicated to cyanobacterial secondary metabolites facilitates: (1) the detection and dereplication of known cyanobacterial toxins and secondary metabolites; (2) the identification of novel natural products from cyanobacteria; (3) research on biosynthesis of cyanobacterial secondary metabolites, including substructure searches; and (4) the investigation of their abundance, persistence, and toxicity in natural environments.
  • Kolsi, Laura E.; Leal, Ana S.; Yli-Kauhaluoma, Jari; Liby, Karen T.; Moreira, Vânia M. (2018)
    Low 5-year survival rates, increasing incidence, as well as the specific challenges of targeting pancreatic cancer, clearly support an urgent need for new multifunctional drugs for the prevention and treatment of this fatal disease. Natural products, such as abietane-type diterpenoids, are widely studied as promiscuous anticancer agents. In this study, dehydroabietic oximes were identified as potential compounds to target pancreatic cancer and cancer-related inflammation. The compounds inhibited the growth of human pancreatic cancer Aspc-1 cells with IC50 values in the low micromolar range and showed anti-inflammatory activity, measured as the inhibition of nitric oxide production, an important inflammatory mediator in the tumour microenvironment. Further studies revealed that the compounds were able to induce cancer cell differentiation and concomitantly downregulate cyclin D1 expression with upregulation of p27 levels, consistent with cell cycle arrest at the G1 phase. Moreover, a kinase profiling study showed that one of the compounds has isoform-selective, however modest, inhibitory activity on RSK2, an AGC kinase that has been implicated in cellular invasion and metastasis.
  • Zong, Guanghui; Hu, Zhijian; O'Keefe, Sarah; Tranter, Dale; Iannotti, Michael J.; Baron, Ludivine; Hall, Belinda; Corfield, Katherine; Paatero, Anja O.; Henderson, Mark J.; Roboti, Peristera; Zhou, Jianhong; Sun, Xianwei; Govindarajan, Mugunthan; Rohde, Jason M.; Blanchard, Nicolas; Simmonds, Rachel; Inglese, James; Du, Yuchun; Demangel, Caroline; High, Stephen; Paavilainen, Ville O.; Shi, Wei Q. (2019)
    Ipomoeassin F is a potent natural cytotoxin that inhibits growth of many tumor cell lines with single-digit nanomolar potency. However, its biological and pharmacological properties have remained largely unexplored. Building upon our earlier achievements in total synthesis and medicinal chemistry, we used chemical proteomics to identify Sec61 alpha (protein transport protein Sec61 subunit alpha isoform 1), the pore-forming subunit of the Sec61 protein translocon, as a direct binding partner of ipomoeassin F in living cells. The interaction is specific and strong enough to survive lysis conditions, enabling a biotin analogue of ipomoeassin F to pull down Sec61 alpha from live cells, yet it is also reversible, as judged by several experiments including fluorescent streptavidin staining, delayed competition in affinity pulldown, and inhibition of TNF biogenesis after washout. Sec61 alpha forms the central subunit of the ER protein translocation complex, and the binding of ipomoeassin F results in a substantial, yet selective, inhibition of protein translocation in vitro and a broad ranging inhibition of protein secretion in live cells. Lastly, the unique resistance profile demonstrated by specific amino acid single-point mutations in Sec61 alpha provides compelling evidence that Sec61 alpha is the primary molecular target of ipomoeassin F and strongly suggests that the binding of this natural product to Sec61 alpha is distinctive. Therefore, ipomoeassin F represents the first plant-derived, carbohydrate-based member of a novel structural class that offers new opportunities to explore Sec61 alpha function and to further investigate its potential as a therapeutic target for drug discovery.
  • de Vera, Caterina R.; Díaz Crespín, Guillermo; Hernández Daranas, Antonio; Montalvão Looga, Sofia; Lillsunde, Katja-Emilia; Tammela, Päivi; Perälä, Merja; Hongisto, Vesa; Virtanen, Johannes; Rischer, Heiko; Muller, Christian D.; Norte, Manuel; Fernández, José J.; Souto, María L. (2018)
    The study of marine natural products for their bioactive potential has gained strength in recent years. Oceans harbor a vast variety of organisms that offer a biological and chemical diversity with metabolic abilities unrivalled in terrestrial systems, which makes them an attractive target for bioprospecting as an almost untapped resource of biotechnological applications. Among them, there is no doubt that microalgae could become genuine cell factories for the biological synthesis of bioactive substances. Thus, in the course of inter-laboratory collaboration sponsored by the European Union (7th FP) into the MAREX Project focused on the discovery of novel bioactive compounds of marine origin for the European industry, a bioprospecting study on 33 microalgae strains was carried out. The strains were cultured at laboratory scale. Two extracts were prepared for each one (biomass and cell free culture medium) and, thus, screened to provide information on the antimicrobial, the anti-proliferative, and the apoptotic potential of the studied extracts. The outcome of this study provides additional scientific data for the selection of Alexandrium tamarensis WE, Gambierdiscus australes, Prorocentrum arenarium, Prorocentrum hoffmannianum, and Prorocentrum reticulatum (Pr-3) for further investigation and offers support for the continued research of new potential drugs for human therapeutics from cultured microalgae.
  • Tienaho, Jenni; Karonen, Maarit; Muilu-Mäkelä, Riina; Wähälä, Kristiina; Leon Denegri, Eduardo; Franzén, Robert; Karp, Matti; Santala, Ville; Sarjala, Tytti (2019)
    Endophytes are microorganisms living inside plant hosts and are known to be beneficial for the host plant vitality. In this study, we isolated three endophytic fungus species from the roots of Scots pine seedlings growing on Finnish drained peatland setting. The isolated fungi belonged to dark septate endophytes (DSE). The metabolic profiles of the hot water extracts of the fungi were investigated using Ultrahigh Performance Liquid Chromatography with Diode Array Detection and Electron Spray Ionization source Mass Spectrometry with Orbitrap analyzer (UPLC–DAD–ESI–MS–Orbitrap). Out of 318 metabolites, we were able to identify 220, of which a majority was amino acids and peptides. Additionally, opine amino acids, amino acid quinones, Amadori compounds, cholines, nucleobases, nucleosides, nucleotides, siderophores, sugars, sugar alcohols and disaccharides were found, as well as other previously reported metabolites from plants or endophytes. Some dierences of the metabolic profiles, regarding the amount and identity of the found metabolites, were observed even though the fungi were isolated from the same host. Many of the discovered metabolites have been described possessing biological activities and properties, which may make a favorable contribution to the host plant nutrient availability or abiotic and biotic stress tolerance.
  • Wang, Yinyin; Jafari, Mohieddin; Tang, Yun; Tang, Jing (2019)
    Plant-derived nature products, known as herb formulas, have been commonly used in Traditional Chinese Medicine (TCM) for disease prevention and treatment. The herbs have been traditionally classified into different categories according to the TCM Organ systems known as Meridians. Despite the increasing knowledge on the active components of the herbs, the rationale of Meridian classification remains poorly understood. In this study, we took a machine learning approach to explore the classification of Meridian. We determined the molecule features for 646 herbs and their active components including structure-based fingerprints and ADME properties (absorption, distribution, metabolism and excretion), and found that the Meridian can be predicted by machine learning approaches with a top accuracy of 0.83. We also identified the top compound features that were important for the Meridian prediction. To the best of our knowledge, this is the first time that molecular properties of the herb compounds are associated with the TCM Meridians. Taken together, the machine learning approach may provide novel insights for the understanding of molecular evidence of Meridians in TCM. Author summary In East Asia, plant-derived natural products, known as herb formulas, have been commonly used as Traditional Chinese Medicine (TCM) for disease prevention and treatment. According to the theory of TCM, herbs can be classified as different Meridians according to the balance of Yin and Yang, which are commonly understood as metaphysical concepts. Therefore, the scientific rational of Meridian classification remains poorly understood. The aim of our study was to provide a computational means to understand the classification of Meridians. We showed that the Meridians of herbs can be predicted by the molecular and chemical features of the ingredient compounds, suggesting that the Meridians indeed are associated with the properties of the compounds. Our work provided a novel chemoinformatics approach which may lead to a more systematic strategy to identify the mechanisms of action and active compounds for TCM herbs.
  • Jokinen, Janne J.; Sipponen, Arno (2016)
    Significance: The treatment of chronic wounds results in an enormous drain on healthcare resources in terms of workload, costs, frustration, and impaired quality of life, and it presents a clinical challenge for physicians worldwide. Effective local treatment of a chronic wound has an important role, particularly in patients who arebecause of their poor general condition, diminished life expectancy, or unacceptable operative riskoutside of surgical treatment. Recent Advances: Since 2002, our multidisciplinary research group has investigated the properties of Norway spruce (Picea abies) resin in wound healing and its therapeutic applications in wound care. Resin is a complex mixture of resin acids (e.g., abietic, neoabietic, dehydroabietic, pimaric, isopimaric, levopimaric, sandrakopimaric, and palustric acids) and lignans (e.g., pino-, larici-, matairesinol, and p-hydroxycinnamic acid) having substantial antimicrobial, wound-healing, and skin regeneration enhancing properties. Critical Issues: The cornerstone in successful wound care is an efficient causal treatment of the underlying co-morbidities, for example, diabetes, malnutrition, vascular- or certain systemic diseases. However, definitive diagnosis and specific therapy of a chronic wound is often difficult, because the etiology is practically always multi-factorial, and in the chronic phase, confounding factors such as infections invariably impede wound healing. Future Directions: To study the exact molecular mechanism of actions by which resin promotes cellular regeneration and epithelialization during the wound-healing process. To investigate potential antimicrobial properties of resin against the most ominous multidrug-resistant beta-lactamase (including carbapenemases and metallo--lactamases) producing bacteria, and to individualize those pharmacologically active compounds which are responsible for the antimicrobial activity of resin.
  • Heinilä, Lassi; Fewer, David; Jokela, Jouni; Wahlsten, Matti; Jortikka, Anna Elisabeth; Sivonen, Kaarina (2020)
    Cyanobacteria produce a wide range of lipopeptides that exhibit potent membrane-disrupting activities. Laxaphycins consist of two families of structurally distinct macrocyclic lipopeptides that act in a synergistic manner to produce antifungal and antiproliferative activities. Laxaphycins are produced by range of cyanobacteria but their biosynthetic origins remain unclear. Here, we identified the biosynthetic pathways responsible for the biosynthesis of the laxaphycins produced by Scytonema hofmannii PCC 7110. We show that these laxaphycins, called scytocyclamides, are produced by this cyanobacterium and are encoded in a single biosynthetic gene cluster with shared polyketide synthase enzymes initiating two distinct non-ribosomal peptide synthetase pathways. The unusual mechanism of shared enzymes synthesizing two distinct types of products may aid future research in identifying and expressing natural product biosynthetic pathways and in expanding the known biosynthetic logic of this important family of natural products.
  • Kibble, Milla; Khan, Suleiman A.; Saarinen, Niina; Iorio, Francesco; Saez-Rodriguez, Julio; Makela, Sari; Aittokallio, Tero (2016)
    Drug discovery is moving away from the single target-based approach towards harnessing the potential of polypharmacological agents that modulate the activity of multiple nodes in the complex networks of deregulations underlying disease phenotypes. Computational network pharmacology methods that use systems-level drug-response phenotypes, such as those originating from genome-wide transcriptomic profiles, have proved particularly effective for elucidating the mechanisms of action of multitargeted compounds. Here, we show, via the case study of the natural product pinosylvin, how the combination of two complementary network-based methods can provide novel, unexpected mechanistic insights. This case study also illustrates that elucidating the mechanism of action of multitargeted natural products through transcriptional response-based approaches is a challenging endeavor, often requiring multiple computational-experimental iterations.