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Bohlin, Lars
Publications (10 of 42) Show all publications
Bohlin, L., Cárdenas, P., Backlund, A. & Göransson, U. (2017). 35 Years of Marine Natural Product Research in Sweden: Cool Molecules and Models from Cold Waters.. Progress in molecular and subcellular biology, 55, 1-34
Open this publication in new window or tab >>35 Years of Marine Natural Product Research in Sweden: Cool Molecules and Models from Cold Waters.
2017 (English)In: Progress in molecular and subcellular biology, ISSN 0079-6484, Vol. 55, p. 1-34Article in journal (Refereed) Published
Abstract [en]

Currents efforts in marine biodiscovery have essentially focused on temperate to tropical shallow water organisms. With more than 6000 species of marine plants and animals, the Kosterfjord area has the richest marine biodiversity in Swedish waters, but it remains understudied. The overall objective of our marine pharmacognosy research is to explore and reveal the pharmacological potential of organisms from this poorly explored region. More generally, we wish to understand aspects of structure-activity relationships of chemical interactions in cold-water marine environment (shallow and deep). Our strategy is based on ecologically guided search for compounds through studies of physiology and organism interactions coupled to identification of bioactive molecules guided by especially in vivo assays. The research programme originated in the beginning of the 1980s with a broad screening of Swedish marine organisms using both in vitro and in vivo assays, resulting in isolation and identification of several different bioactive molecules. Two congenerous cyclopeptides, i.e. barettin and 8,9-dihydrobarettin, were isolated from the deep-sea sponge Geodia barretti, and structurally elucidated, guided by their antifouling activity and their affinity to a selection of human serotonin receptors. To optimize the activity a number of analogues of barettin were synthezised and tested for antifouling activity. Within the EU project BlueGenics, two larger homologous peptides, barrettides A and B, were isolated from G. baretti. Also, metabolic fingerprinting combined with sponge systematics was used to further study deep-sea natural product diversity in the genus Geodia. Finally, the chemical property space model 'ChemGPS-NP' has been developed and used in our research group, enabling a more efficient use of obtained compounds and exploration of possible biological activities and targets. Another approach is the broad application of phylogenetic frameworks, which can be used in prediction of where-in which organisms-to search for novel molecules or better sources of known molecules in marine organisms. In a further perspective, the deeper understanding of evolution and development of life on Earth can also provide answers to why marine organisms produce specific molecules.

National Category
Medical and Health Sciences Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-343348 (URN)10.1007/978-3-319-51284-6_1 (DOI)28238034 (PubMedID)
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-02-26
Carstens, B. B., Rosengren, K. J., Gunasekera, S., Schempp, S., Bohlin, L., Dahlstrom, M., . . . Göransson, U. (2015). Isolation, Characterization, and Synthesis of the Barrettides: Disulfide-Containing Peptides from the Marine Sponge Geodia barretti. Journal of natural products (Print), 78(8), 1886-1893
Open this publication in new window or tab >>Isolation, Characterization, and Synthesis of the Barrettides: Disulfide-Containing Peptides from the Marine Sponge Geodia barretti
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2015 (English)In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 78, no 8, p. 1886-1893Article in journal (Refereed) Published
Abstract [en]

Two disulfide-containing peptides, barrettides A (1) and B (2), from the cold-water marine sponge Geodia barretti are described. Those 31 amino acid residue long peptides were sequenced using mass spectrometry methods and structurally characterized using NMR spectroscopy. The structure of 1 was confirmed by total synthesis using the solid-phase peptide synthesis approach that was developed. The two peptides were found to differ only at a single position in their sequence. The three-dimensional structure of 1 revealed that these peptides possess a unique fold consisting of a long beta-hairpin structure that is cross-braced by two disulfide bonds in a ladder-like arrangement. The peptides are amphipathic in nature with the hydrophobic and charged residues clustered on separate faces of the molecule. The barrettides were found not to inhibit the growth of either Escherichia coli or Staphylococcus aureus but displayed antifouling activity against barnacle larvae (Balanus improvisus) without lethal effects in the concentrations tested.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-263532 (URN)10.1021/acs.jnatprod.5b00210 (DOI)000360773700011 ()26222779 (PubMedID)
Funder
Swedish Research Council, 2012-5063 2011-3403EU, FP7, Seventh Framework Programme, 311848
Available from: 2015-10-05 Created: 2015-10-02 Last updated: 2018-01-11
Svahn, S., Chryssanthou, E., Olsen, B., Bohlin, L. & Göransson, U. (2015). Penicillium nalgiovense Laxa isolated from Antarctica is a new source of the antifungal metabolite amphotericin B. Fungal biology and biothechnology, 2(1)
Open this publication in new window or tab >>Penicillium nalgiovense Laxa isolated from Antarctica is a new source of the antifungal metabolite amphotericin B
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2015 (English)In: Fungal biology and biothechnology, Vol. 2, no 1Article in journal (Refereed) Published
Abstract [en]

Background: The need for new antibiotic drugs increases as pathogenic microorganisms continue to develop resistance against current antibiotics. We obtained samples from Antarctica as part of a search for new antimicrobial metabolites derived from filamentous fungi. This terrestrial environment in the South Pole is hostile and extreme due to a sparsely populated food web, low temperatures, and insufficient liquid water availability. We hypothesize that this environment could cause the development of fungal defense or survival mechanisms not found elsewhere.

Results: We isolated a strain of Penicillium nalgiovense Laxa from a soil sample obtained from an abandoned penguin’s nest. Amphotericin B was the only metabolite secreted from P. nalgiovense Laxa with noticeable antimicrobial activity,with minimum inhibitory concentration of 0.125 µg/mL against Candida albicans. This is the first time that amphotericin B has been isolated from an organism other than the bacterium Streptomyces nodosus. In terms of amphotericin B production, cultures on solid medium proved to be a more reliable and favorable choice compared to a liquid.

Conclusions: These results encourage further investigation of the many unexplored sampling sites characterized by extreme conditions, and confirm filamentous fungi as potential sources of metabolites with antimicrobial activity.

Keywords
Amphotericin B, Penicillium nalgiovense Laxa, Antarctica
National Category
Medicinal Chemistry
Research subject
Pharmacognosy
Identifiers
urn:nbn:se:uu:diva-242609 (URN)10.1186/s40694-014-0011-x (DOI)
Available from: 2015-01-28 Created: 2015-01-28 Last updated: 2018-01-11Bibliographically approved
Wang, L., Gao, S., Jiang, W., Luo, C., Xu, M., Bohlin, L., . . . Huang, W. (2014). Antioxidative Dietary Compounds Modulate Gene Expression Associated with Apoptosis, DNA Repair, Inhibition of Cell Proliferation and Migration. International Journal of Molecular Sciences, 15(9), 16226-16245
Open this publication in new window or tab >>Antioxidative Dietary Compounds Modulate Gene Expression Associated with Apoptosis, DNA Repair, Inhibition of Cell Proliferation and Migration
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2014 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 15, no 9, p. 16226-16245Article, review/survey (Refereed) Published
Abstract [en]

Many dietary compounds are known to have health benefits owing to their antioxidative and anti-inflammatory properties. To determine the molecular mechanism of these food-derived compounds, we analyzed their effect on various genes related to cell apoptosis, DNA damage and repair, oxidation and inflammation using in vitro cell culture assays. This review further tests the hypothesis proposed previously that downstream products of COX-2 (cyclooxygenase-2) called electrophilic oxo-derivatives induce antioxidant responsive elements (ARE), which leads to cell proliferation under antioxidative conditions. Our findings support this hypothesis and show that cell proliferation was inhibited when COX-2 was down-regulated by polyphenols and polysaccharides. Flattened macrophage morphology was also observed following the induction of cytokine production by polysaccharides extracted from viili, a traditional Nordic fermented dairy product. Coix lacryma-jobi (coix) polysaccharides were found to reduce mitochondrial membrane potential and induce caspase-3- and 9-mediated apoptosis. In contrast, polyphenols from blueberries were involved in the ultraviolet-activated p53/Gadd45/MDM2 DNA repair system by restoring the cell membrane potential. Inhibition of hypoxia-inducible factor-1 by saponin extracts of ginsenoside (Ginsen) and Gynostemma and inhibition of S100A4 by coix polysaccharides inhibited cancer cell migration and invasion. These observations suggest that antioxidants and changes in cell membrane potential are the major driving forces that transfer signals through the cell membrane into the cytosol and nucleus, triggering gene expression, changes in cell proliferation and the induction of apoptosis or DNA repair.

Keywords
anti-inflammatory, antioxidants, apoptosis, cell migration and invasion, DNA repair
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-236788 (URN)10.3390/ijms150916226 (DOI)000343109700080 ()
Available from: 2014-12-03 Created: 2014-11-24 Last updated: 2018-01-11Bibliographically approved
Bohlin, L., Felth, J. & Strömstedt, A. A. (2014). Bioassays in natural product research - Strategies and methods in the search for bioactive natural products. Paper presented at 55th Annual Meeting of the American-Society-of-Pharmacognosy (ASP), AUG 02-06, 2014, Oxford, MS. Planta Medica, 80(10), 753-753
Open this publication in new window or tab >>Bioassays in natural product research - Strategies and methods in the search for bioactive natural products
2014 (English)In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 80, no 10, p. 753-753Article in journal, Meeting abstract (Other academic) Published
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-231492 (URN)000339781200021 ()
Conference
55th Annual Meeting of the American-Society-of-Pharmacognosy (ASP), AUG 02-06, 2014, Oxford, MS
Available from: 2014-09-08 Created: 2014-09-08 Last updated: 2018-01-11
Strömstedt, A. A., Felth, J. & Bohlin, L. (2014). Bioassays in Natural Product Research: Strategies and Methods in the Search for Anti-inflammatory and Antimicrobial Activity. Phytochemical Analysis, 25(1), 13-28
Open this publication in new window or tab >>Bioassays in Natural Product Research: Strategies and Methods in the Search for Anti-inflammatory and Antimicrobial Activity
2014 (English)In: Phytochemical Analysis, ISSN 0958-0344, E-ISSN 1099-1565, Vol. 25, no 1, p. 13-28Article, review/survey (Refereed) Published
Abstract [en]

Introduction: Identifying bioactive molecules from complex biomasses requires careful selection and execution of relevant bioassays in the various stages of the discovery process of potential leads and targets.

Objective: The aim of this review is to share our long-term experience in bioassay-guided isolation, and mechanistic studies, of bioactive compounds from different organisms in nature with emphasis on anti-inflammatory and antimicrobial activity.

Methods: In the search for anti-inflammatory activity, in vivo and in vitro model combinations with enzymes and cells involved in the inflammatory process have been used, such as cyclooxygenases, human neutrophils and human cancer cell lines. Methods concerning adsorption and perforation of bacteria, fungi, human cells and model membranes, have been developed and optimised, with emphasis on antimicrobial peptides and their interaction with the membrane target, in particular their ability to distinguish host from pathogen.

Results: A long-term research has provided experience of selection and combination of bioassay models, which has led to an increased understanding of ethnopharmacological and ecological observations, together with in-depth knowledge of mode of action of isolated compounds.

Conclusion: A more multidisciplinary approach and a higher degree of fundamental research in development of bioassays are often necessary to identify and to fully understand the mode of action of bioactive molecules with novel structure-activity relationships from natural sources. 

Selection and execution of relevant bioassays are critical in the various stages of the discovery process of potential drug leads and targets from natural sources. The aim of this review is to share our long-term experience in bioassay-guided isolation of bioactive compounds from different organisms in nature with emphasis on anti-inflammatory and antimicrobial activity. We conclude that an increased multidisciplinary approach and a higher degree of fundamental research in development of bioassays are essential to discover complex structure-activity relationships.

Keywords
bioassay, natural product, anti-inflammatory, antibacterial, antimicrobial, peptide, cytotoxicity, membrane, liposome
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-216247 (URN)10.1002/pca.2468 (DOI)000328554500002 ()
Available from: 2014-01-20 Created: 2014-01-20 Last updated: 2018-01-11Bibliographically approved
Koptina, A., Gunasekera, S., Muhammad, T., Bohlin, L., Alsmark, C. & Göransson, U. (2014). Microwave-assisted solid phase peptide synthesis of Asteropine A. In: Shabanov P.D. (Ed.), Phytopharm 2014, Saint-Petersburg, Russia 3-5 July 2014: . Paper presented at The 18th International Congress Phytopharm 2014, Saint-Petersburg, Russia 3-5 July 2014 (pp. 36). Saint-Petersburg, Russia, 12
Open this publication in new window or tab >>Microwave-assisted solid phase peptide synthesis of Asteropine A
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2014 (English)In: Phytopharm 2014, Saint-Petersburg, Russia 3-5 July 2014 / [ed] Shabanov P.D., Saint-Petersburg, Russia, 2014, Vol. 12, p. 36-Conference paper, Oral presentation with published abstract (Refereed)
Place, publisher, year, edition, pages
Saint-Petersburg, Russia: , 2014
Series
Onzory po kliniceskoj farmacologii i lekarstvennoj terapii, ISSN 1683-4100
National Category
Other Chemistry Topics
Research subject
Pharmacognosy
Identifiers
urn:nbn:se:uu:diva-245256 (URN)
Conference
The 18th International Congress Phytopharm 2014, Saint-Petersburg, Russia 3-5 July 2014
Funder
Carl Tryggers foundation EU, FP7, Seventh Framework Programme
Available from: 2015-02-26 Created: 2015-02-26 Last updated: 2015-03-04Bibliographically approved
Stenholm, A., Göransson, U. & Bohlin, L. (2013). Bioassay-guided Supercritical Fluid Extraction of Cyclooxygenase-2 Inhibiting Substances in Plantago major L.. Phytochemical Analysis, 24(2), 176-183
Open this publication in new window or tab >>Bioassay-guided Supercritical Fluid Extraction of Cyclooxygenase-2 Inhibiting Substances in Plantago major L.
2013 (English)In: Phytochemical Analysis, ISSN 0958-0344, E-ISSN 1099-1565, Vol. 24, no 2, p. 176-183Article in journal (Refereed) Published
Abstract [en]

Introduction - Selective extraction of plant materials is advantageous for obtaining extracts enriched with desired constituents, thereby reducing the need for subsequent chromatography purification. Such compounds include three cyclooxygenase-2 (COX-2) inhibitory substances in Plantago major L. targeted in this investigation: alpha-linolenic acid (alpha-LNA) (18:3 omega-3) and the triterpenic acids ursolic acid and oleanolic acid. Objective - To investigate the scope for tuning the selectivity of supercritical fluid extraction (SFE) using bioassay guidance, and Soxhlet extraction with dichloromethane as solvent as a reference technique, to optimise yields of these substances. Method - Extraction parameters were varied to optimise extracts' COX-2/COX-1 inhibitory effect ratios. The crude extracts were purified initially using a solid phase extraction (SPE) clean-up procedure and the target compounds were identified with GC-MS, LC-ESI-MS and LC-ESI-MS2 using GC-FID for quantification. Results - alpha-LNA was preferentially extracted in dynamic mode using unmodified carbon dioxide at 40 degrees C and 172 bar, at a 0.04% (w/w) yield with a COX-2/COX-1 inhibitory effect ratio of 1.5. Ursolic and oleanolic acids were dynamically extracted at 0.25% and 0.06% yields, respectively, with no traces of (alpha-LNA) and a COX-2/COX-1-inhibitory effect ratio of 1.1 using 10% (v/v) ethanol as polar modifier at 75 degrees C and 483 bar. The Soxhlet extracts had ursolic acid, oleanolic acid and alpha LNA yields up to 1.36%, 0.34% and 0.15%, respectively, with a COX-2/COX-1 inhibitory effect ratio of 1.2. Conclusion - The target substances can be extracted selectively by bioassay guided optimisation of SFE conditions.

Keywords
In vitro enzyme assay, Soxhlet, supercritical fluid extraction (SFE), cyclooxygenase-2, Plantago major L.
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-200457 (URN)10.1002/pca.2398 (DOI)000318002600012 ()
Available from: 2013-05-28 Created: 2013-05-28 Last updated: 2017-12-06Bibliographically approved
Felth, J., Lesiak-Mieczkowska, K., Haglund, C., Gullbo, J., Larsson, R., Linder, S., . . . Rickardson, L. (2013). Gambogic acid is cytotoxic to cancer cells through inhibition of the ubiquitin-proteasome system. Investigational new drugs, 31(3), 587-598
Open this publication in new window or tab >>Gambogic acid is cytotoxic to cancer cells through inhibition of the ubiquitin-proteasome system
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2013 (English)In: Investigational new drugs, ISSN 0167-6997, E-ISSN 1573-0646, Vol. 31, no 3, p. 587-598Article in journal (Other academic) Published
Abstract [en]

Gambogic acid (GA), displays cytotoxicity towards a wide variety of tumor cells and has been shown to affect many important cell-signaling pathways. In the present work, we investigated the mechanism of action of GA by analysis of drug-induced changes in gene expression profiles and identified GA and the derivative dihydro GA as possible inhibitors of the ubiquitin-proteasome system (UPS). Both GA and dihydro GA inhibited proteasome function in cells resulting in the accumulation of polyubiquitin complexes. In vitro experiments showed that both GA and dihydro GA inhibited 20S chymotrypsin activity and the inhibitory effects of GA and dihydro GA on proteasome function corresponded with apoptosis induction and cell death. In conclusion, our results show that GA and dihydro GA exert their cytotoxic activity through inhibition of the UPS, specifically by acting as inhibitors of the chymotrypsin activity of the 20S proteasome.

Keywords
gambogic acid, cancer, cytotoxic, proteasome inhibition
National Category
Pharmaceutical Sciences Pharmacology and Toxicology
Research subject
Pharmacognosy; Clinical Pharmacology
Identifiers
urn:nbn:se:uu:diva-147799 (URN)10.1007/s10637-012-9902-y (DOI)000318657000010 ()
Available from: 2011-03-02 Created: 2011-02-28 Last updated: 2018-01-12Bibliographically approved
Muigg, P., Rosen, J., Bohlin, L. & Backlund, A. (2013). In silico comparison of marine, terrestrial and synthetic compounds using ChemGPS-NP for navigating chemical space. Phytochemistry Reviews, 12(3), 449-457
Open this publication in new window or tab >>In silico comparison of marine, terrestrial and synthetic compounds using ChemGPS-NP for navigating chemical space
2013 (English)In: Phytochemistry Reviews, ISSN 1568-7767, E-ISSN 1572-980X, Vol. 12, no 3, p. 449-457Article, review/survey (Refereed) Published
Abstract [en]

Nature represents a vast source of chemical diversity, which is supposed to cover broader areas of chemical space than synthetically obtained substances typical of medicinal chemistry. With regard to drug discovery from nature, the terrestrial environment has been the most and longest studied source, while the investigation of compounds produced by marine organisms is still in its infancy. With the objective of demonstrating the enormous chemical diversity of nature, in particular that of the marine environment, we used the chemical space navigation tool ChemGPS-NP to compare sets of marine, terrestrial and synthetic compounds with respect to physico-chemical properties and their occupation of the biologically relevant chemical space. Despite considerable overlap, the three datasets clearly differ from each other by occupying and extending into different, specific, regions in chemical space. Synthetic compounds are e.g. comparably small, with some of them being highly flexible, while marine and terrestrial products are larger and characterised by higher and lower molecular flexibility, respectively, with increasing size. Moreover, the three datasets differ to some degree in polarity, aromaticity and heteroatom content. Taken together, ChemGPS-NP has been proven to be a useful tool for navigating large volumes of biologically relevant chemical space. In this study we demonstrated the chemical uniqueness and differences of large sets of natural products, with particular emphasis on marine substances. The hence de-veiled differences further underline the relevance of natural products, of both marine and terrester origin, for future drug discovery.

Keywords
ChemGPS-NP, Marine, Natural products, Chemical space
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-211141 (URN)10.1007/s11101-012-9256-2 (DOI)000324653400006 ()
Available from: 2013-11-20 Created: 2013-11-20 Last updated: 2018-02-26
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