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  • 1.
    Aboye, Teshome L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Synthesis, Cyclization and Oxidative folding of backbone engineered Cyclotides2010Conference paper (Refereed)
  • 2.
    Aboye, Teshome L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bruhn, Jan G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Rosengren, K. Johan
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    A Cactus-Derived Toxin-Like Cystine Knot Peptide with Selective Antimicrobial Activity2015In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 16, no 7, p. 1068-1077Article in journal (Refereed)
    Abstract [en]

    Naturally occurring cystine knot peptides show a wide range of biological activity, and as they have inherent stability they represent potential scaffolds for peptide-based drug design and biomolecular engineering. Here we report the discovery, sequencing, chemical synthesis, three-dimensional solution structure determination and bioactivity of the first cystine knot peptide from Cactaceae (cactus) family: Ep-AMP1 from Echinopsis pachanoi. The structure of Ep-AMP1 (35 amino acids) conforms to that of the inhibitor cystine knot (or knottin) family but represents a novel diverse sequence; its activity was more than 500 times higher against bacterial than against eukaryotic cells. Rapid bactericidal action and liposome leakage implicate membrane permeabilisation as the mechanism of action. Sequence homology places Ec-AMP1 in the plant C6-type of antimicrobial peptides, but the three dimensional structure is highly similar to that of a spider neurotoxin.

  • 3.
    Aboye, Teshome Leta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Engineering of the Ultra-stable Cystine Knot Framework of Microproteins: Design, Chemical Synthesis and Structural Studies2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ultra-stable cystine knotted microproteins, in which two disulfides and their connecting backbones form a circle that is penetrated by the third disulfide bonds, have attracted high interest due to their resistance to degradation in vitro and potential for the development of peptide drugs. This thesis gives new insights into engineering of that framework of microproteins, including approaches to their chemical synthesis, backbone engineering, structural and biological evaluations.

    Synthetic and oxidative folding approaches for bracelet cyclotides, a family of cyclic cystine knotted microproteins, was developed using a model peptide, cycloviolacin O2. Following assembly of the peptide chain, protected peptide was generated by mild cleavage that was subsequently thioesterified and cyclized in solution. The cyclic peptide was oxidatively folded under optimized conditions containing co-solvent and non-ionic detergent affording native cycloviolacin O2 as a major product. To gain further insights into the heterogeneity, efficiency and kinetics of cyclotides’ oxidative folding, the intermediates that accumulate in oxidative refolding pathways of all cyclotide subfamilies: Möbius, bracelet and the hybrid cyclotides were quantitatively determined under four different folding conditions. The results were used for defining major folding pathways, which indicated that Möbius cyclotides might accumulate heterogeneous folding intermediates with one-, two- and three-disulfides, whereas bracelet tend to accumulate a homogenous intermediate with three-disulfides, depending on the buffer systems used.

    Furthermore, to probe the internal factors contributing to inefficiency of oxidative folding, as well as undesired bioactivities of bracelet cyclotides (e.g., cytotoxic activity), polymer-hybridized cyclotides were designed by replacing non-conserved residues with small isosteric polymers. The designed hybrid analogs in which hybridization involved replacement of loop 3 with isosteric polymers showed improved synthetic and oxidative folding properties. The cytoxicity of a model hybrid designed with replacement of loop 3 and 5 exhibited no cytotoxic activity at concentration of 128-fold relative to that of native peptide. Furthermore, 1D and 2D 1H NMR analysis of this hybrid showed that it had well structured fold.

    List of papers
    1. Discovery, synthesis, and structural determination of a toxine-like disulfide-rich peptide from the cactus Trichoserus pachanoi
    Open this publication in new window or tab >>Discovery, synthesis, and structural determination of a toxine-like disulfide-rich peptide from the cactus Trichoserus pachanoi
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-145716 (URN)
    Available from: 2011-02-10 Created: 2011-02-10 Last updated: 2011-05-04
    2. Ultra-stable peptide scaffolds for protein engineering-synthesis and folding of the circular cystine knotted cyclotide cycloviolacin O2
    Open this publication in new window or tab >>Ultra-stable peptide scaffolds for protein engineering-synthesis and folding of the circular cystine knotted cyclotide cycloviolacin O2
    2008 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 9, no 1, p. 103-113Article in journal (Refereed) Published
    Abstract [en]

    The cyclic cystine knot motif, as defined by the cyclotide peptide family, is an attractive scaffold for protein engineering. To date, however, the utilisation of this scaffold has been limited by the inability to synthesise members of the most diverse and biologically active subfamily, the bracelet cyclotides. This study describes the synthesis and first direct oxidative folding of a bracelet cyclotide-cycloviolacin O2-and thus provides an efficient method for exploring the most potent cyclic cystine knot peptides. The linear chain of cycloviolacin O2 was assembled by solid-phase Fmoc peptide synthesis and cyclised by thioester-mediated native chemical ligation, and the inherent difficulties of folding bracelet cyclotides were successfully overcome in a single-step reaction. The folding pathway was characterised and was found to include predominating fully oxidised intermediates that slowly converted to the native peptide structure.

    Keywords
    cyclotides, native chemical ligation, peptides, protein folding, synthesis, thioesters
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-98767 (URN)10.1002/cbic.200700357 (DOI)000252292200017 ()18058973 (PubMedID)
    Available from: 2009-03-03 Created: 2009-03-03 Last updated: 2018-01-13Bibliographically approved
    3. An Efficient Approach for the Total Synthesis of Cyclotides by Microwave Assisted Fmoc-SPPS
    Open this publication in new window or tab >>An Efficient Approach for the Total Synthesis of Cyclotides by Microwave Assisted Fmoc-SPPS
    2010 (English)In: International Journal of Peptide Research and Therapeutics, ISSN 1573-3149, Vol. 16, no 3, p. 167-176Article in journal (Refereed) Published
    Abstract [en]

    Cyclotides are mini-proteins of approximately 30 amino acid residues that have a unique structure consisting of a head-to-tail cyclized backbone and a knotted arrangement of three disulfide bonds. This unique cyclotide structure provides exceptional stability to chemical, enzymatic and thermal treatments and has been implicated as an ideal drug scaffold for the development into agricultural and biotechnological agents. In the current work, we present the first method for microwave assisted Fmoc-SPPS of cyclotides. This protocol adopts a strategy that combines optimized microwave assisted chemical reactions for Fmoc-SPPS of the peptide backbone, the cleavage of the protected peptide and the introduction of a thioester at the C-terminal carboxylic acid to obtain the head-to-tail cyclized cyclotide backbone by native chemical ligation. To exemplify the utility of this protocol in the synthesis of a wide array of different cyclotide sequences we synthesized representative members from the three cyclotide subfamilies-the Mobius kalata B1, the bracelet cycloviolacin O2 and the trypsin inhibitory MCoTI-II. In addition, a "one pot" reaction promoting both cyclization and oxidative folding of crude peptide thioester was adapted for kalata B1 and MCoTI-II.

    Keywords
    Cyclotides, Microwave chemistry, Fmoc-SPPS, Circular proteins, Cystine knot, Native chemical ligation
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-134899 (URN)10.1007/s10989-010-9221-0 (DOI)000281682600007 ()
    Available from: 2010-12-02 Created: 2010-12-02 Last updated: 2018-01-12Bibliographically approved
    4. Interlocking disulfides in circular proteins: toward efficient oxidative folding of cyclotides.
    Open this publication in new window or tab >>Interlocking disulfides in circular proteins: toward efficient oxidative folding of cyclotides.
    Show others...
    2011 (English)In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 14, no 1, p. 77-86Article in journal (Refereed) Published
    Abstract [en]

    Cyclotides are ultrastable plant proteins characterized by the presence of a cyclic amide backbone and three disulfide bonds that form a cystine knot. Because of their extreme stability, there has been significant interest in developing these molecules as a drug design scaffold. For this potential to be realized, efficient methods for the synthesis and oxidative folding of cyclotides need to be developed, yet we currently have only a basic understanding of the folding mechanism and the factors influencing this process. In this study, we determine the major factors influencing oxidative folding of the different subfamilies of cyclotides. The folding of all the cyclotides examined was heavily influenced by the concentration of redox reagents, with the folding rate and final yield of the native isomer greatly enhanced by high concentrations of oxidized glutathione. Addition of hydrophobic solvents to the buffer also enhanced the folding rates and appeared to alter the folding pathway. Significant deamidation and isoaspartate formation were seen when oxidation conditions were conducive to slow folding. The identification of factors that influence the folding and degradation pathways of cyclotides will facilitate the development of folding screens and optimized conditions for producing cyclotides and grafted analogs as stable peptide-based therapeutics.

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-139359 (URN)10.1089/ars.2010.3112 (DOI)000284572100009 ()20486762 (PubMedID)
    Available from: 2010-12-23 Created: 2010-12-23 Last updated: 2018-01-12Bibliographically approved
    5. Design, synthesis, structural and biological evaluation of backbone-engineered cyclotides
    Open this publication in new window or tab >>Design, synthesis, structural and biological evaluation of backbone-engineered cyclotides
    (English)Manuscript (preprint) (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-145719 (URN)
    Available from: 2011-02-10 Created: 2011-02-10 Last updated: 2011-05-04
  • 4.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Design, synthesis, structural and biological evaluation of backbone-engineered cyclotidesManuscript (preprint) (Other academic)
  • 5.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Clark, Richard J.
    University of Queensland, Institute for Molecular Bioscience.
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Craik, David J.
    University of Queensland, Institute for Molecular Bioscience.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Synthesis and Oxidative Folding of Cyclic Cystine Knot Peptides: Towards Backbone Engineering2010In: Peptides 2010: Tales of Peptides Proceedings of the Thirty-First European Peptide Symposium / [ed] Michal Lebl, Morten Meldal, Knud J. Jensen, Thomas Høeg-Jensen, European Peptide Society , 2010, p. 142-143Conference paper (Refereed)
  • 6.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Clark, Richard J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Roig, Marta Bajona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Craik, David J.
    University of Queensland, Institute for Molecular Bioscience.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Interlocking disulfides in circular proteins: toward efficient oxidative folding of cyclotides.2011In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 14, no 1, p. 77-86Article in journal (Refereed)
    Abstract [en]

    Cyclotides are ultrastable plant proteins characterized by the presence of a cyclic amide backbone and three disulfide bonds that form a cystine knot. Because of their extreme stability, there has been significant interest in developing these molecules as a drug design scaffold. For this potential to be realized, efficient methods for the synthesis and oxidative folding of cyclotides need to be developed, yet we currently have only a basic understanding of the folding mechanism and the factors influencing this process. In this study, we determine the major factors influencing oxidative folding of the different subfamilies of cyclotides. The folding of all the cyclotides examined was heavily influenced by the concentration of redox reagents, with the folding rate and final yield of the native isomer greatly enhanced by high concentrations of oxidized glutathione. Addition of hydrophobic solvents to the buffer also enhanced the folding rates and appeared to alter the folding pathway. Significant deamidation and isoaspartate formation were seen when oxidation conditions were conducive to slow folding. The identification of factors that influence the folding and degradation pathways of cyclotides will facilitate the development of folding screens and optimized conditions for producing cyclotides and grafted analogs as stable peptide-based therapeutics.

  • 7.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Clark, Richard. J.
    University of Queensland, Institute for Molecular Bioscience.
    Craik, David J.
    University of Queensland, Institute for Molecular Bioscience.
    Goransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Synthesis and folding of the circular cystine knotted cyclotide cycloviolacin O2.2008In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 74, no 9, p. 1158-1158Article in journal (Refereed)
  • 8.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Clark, Richard J.
    University of Queensland, Institute for Molecular Bioscience.
    Craik, David J.
    University of Queensland, Institute for Molecular Bioscience.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Synthesis and folding of the circular cystine knotted cyclotide cycloviolacin O22008In: Peptides 2008: Chemistry of Peptides in Life Science Technology and MedicineProceedings of The Thirtieth European Peptide Symposium / [ed] Hilkka Lankinen, The Finnish Peptide Society and The European Peptide Society , 2008, p. 280-281Conference paper (Refereed)
  • 9.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Rosengren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bruhn, G. Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Discovery, synthesis, and structural determination of a toxine-like disulfide-rich peptide from the cactus Trichoserus pachanoiManuscript (preprint) (Other academic)
  • 10. Ahmed, A. Ahmed
    et al.
    El-Seedi, Hesham R.
    Mahmoud, Ahmed A.
    El-Douski, Abd El-Aziz A.
    Zeid, Ibrahim F.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Eudesmane derivatives from Laggera crispata and Pluchea carolonesis1998In: Phytochemistry, ISSN 0031-9422, E-ISSN 1873-3700, Vol. 49, no 8, p. 2421-2424Article in journal (Refereed)
    Abstract [en]

    Investigation of the aerial parts of Laggera crispata and Pluchea carolonesis afforded in addition to several known compounds, three new eudesmane derivatives, 3β,4α-dihydroxy-7-epi-eudesm-11(13)-ene, 3α-(2′,3′-dihydroxy-2′-methylbutanoyl)-4,11-dihydroxy-6,7-dehydroeudesman-8-one and 3α-(3′-chloro-2′-hydroxy-2′-methylbutanoyl)cuauhtemone. The structures were elucidated by spectroscopic methods

  • 11.
    Ahnfelt, Nils-Otto
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of History of Science and Ideas, History of Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Fors, Hjalmar
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of History of Science and Ideas, History of Science. Hagströmer Library, Karolinska Institutet, Stockholm.
    Making Early Modern Medicine: Reproducing Swedish Bitters2016In: Ambix, ISSN 0002-6980, E-ISSN 1745-8234, Vol. 63, no 2, p. 162-183Article in journal (Refereed)
    Abstract [en]

    Historians of science and medicine have rarely applied themselves to reproducing the experiments and practices of medicine and pharmacy. This paper delineates our efforts to reproduce "Swedish Bitters," an early modern composite medicine in wide European use from the 1730s to the present. In its original formulation, it was made from seven medicinal simples: aloe, rhubarb, saffron, myrrh, gentian, zedoary and agarikon. These were mixed in alcohol together with some theriac, a composite medicine of classical origin. The paper delineates the compositional history of Swedish Bitters and the medical rationale underlying its composition. It also describes how we go about to reproduce the medicine in a laboratory using early modern pharmaceutical methods, and analyse it using contemporary methods of pharmaceutical chemistry. Our aim is twofold: first, to show how reproducing medicines may provide a path towards a deeper understanding of the role of sensual and practical knowledge in the wider context of early modern medical culture; and second, how it may yield interesting results from the point of view of contemporary pharmaceutical science.

  • 12. Al-Henhena, Nawal
    et al.
    Khalifa, Shaden A. M.
    Ying, Rozaida Poh Yuen
    Hassandarvish, Pouya
    Rouhollahi, Elham
    Al-Wajeeh, Nahla Saeed
    Ali, Habibah Mohd
    Abdulla, Mahmood Ameen
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Chemopreventive effects of Strobilanthes crispus leaf extract on azoxymethane-induced aberrant crypt foci in rat colon2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 13312Article in journal (Refereed)
    Abstract [en]

    In this work, microscopic and histological studies suggest that Strobilanthes crispus ethanol extract reduce azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in rats. S. crispus is considered a traditional medicine and used as an antioxidant. Its leaf contains a large amount of phenolic compounds to which its radical scavenging role is attributed and enhance its ability to eradicate oxidative stress reactions. The study was designed to determine the chemopreventive effect of S. crispus ethanol extract in vivo and in vitro by elucidating the effect of the extract on intermediate biomarkers which can be used as effective predictors of colon cancer. S. crispus was analyzed for DPPH free radical scavenging, nitric oxide (NO) and ferric acid reduction. The results indicated that S. crispus oral administration significantly inhibited colorectal carcinogenesis induced by AOM as revealed by the reduction in the number of ACF. S. crispus down-regulated the expression of PCNA, Bcl2 and beta-catenin. Additionally, it exerted a pronounced inhibitory effect on MDA and NO levels and stimulatory effect on CAT and GPx activities. These results demonstrate that S. crispus is a chemopreventive agent for colorectal cancer through the suppression of early and intermediate carcinogenic phases that may be related to its flavonoid content.

  • 13.
    Al-Henhena, Nawal
    et al.
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia.;Sanaa Univ, Fac Med, Dept Biochem, Sanaa, Yemen..
    Khalifa, Shaden A. M.
    Karolinska Univ Hosp, Dept Expt Hematol, SE-14186 Stockholm, Sweden..
    Ying, Rozaida Poh Yuen
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Ismail, Salmah
    Univ Malaya, Fac Sci, Inst Biol Sci, Kuala Lumpur 50603, Malaysia..
    Hamadi, Riad
    Sanaa Univ, Fac Med, Dept Biochem, Sanaa, Yemen..
    Shawter, Abdrabu N.
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Idris, Azila Mohd
    Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Azizan, Ainnul
    Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Al-Wajeeh, Nahla Saeed
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Abdulla, Mahmood Ameen
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Evaluation of chemopreventive potential of Strobilanthes crispus against colon cancer formation in vitro and in vivo2015In: BMC Complementary and Alternative Medicine, ISSN 1472-6882, E-ISSN 1472-6882, Vol. 15, article id 419Article in journal (Refereed)
    Abstract [en]

    Background: With cancer being one of the major causes of death around the world, studies are ongoing to find new chemotherapeutic leads. There are common mechanisms for colorectal cancer (CRC) formation. Several are connected with oxidative stress-induced cell apoptosis and others are related to imbalanced homeostasis or intake of drugs/toxins. Plants that have been used for decades in folk and traditional medicine have been accepted as one of the commonest sources of discovered natural agents of cancer chemotherapy and chemoprevention. The aim was to study the antioxidant and chemopreventive effects of Strobilanthes crispus on colorectal cancer formation. Methods: Five groups of rats were injected subcutaneously with AOM, 15 mg/kg body weight, each once weekly for 2 weeks. The cancer group was continued on 10 % Tween-20 feeding for 8 weeks. The standard drug group was continued on 35 mg/kg 5-fluorouracil intraperitoneal injection twice a week for 8 weeks, and the experimental groups were continued on 250 and 500 mg/kg S. crispus extract oral feeding for 8 weeks, respectively. The normal group was injected subcutaneously with normal saline once a week for 2 weeks, followed by oral administration of 10 % Tween-20 for 8 weeks. All the rats were sacrificed after 10 weeks. The colons were evaluated grossly and histopathologically for aberrant crypt foci (ACF). Gene expression was performed for Bax, Bcl2, Defa24, Slc24a3, and APC genes by real-time PCR. S. crispus and its fractions were evaluated for their chemopreventive effects against human colorectal adenocarcinoma cell line HT29 and cytotoxicity for normal human colon epithelial cell line CCD 841, and the active fraction was assessed for its components. Results: We observed significant decrease in total colonic ACF formation, malonaldehyde (MDA) and lactate dehydrogenase (LDH), increase in superoxide dismutase (SOD), up-regulation of APC, Bax and Slc24a3, and down-regulation of Defa24 and Bcl-2 in rats treated with Strobilanthes crispus. Conclusion: Our results support the in vivo protection of S. crispus against CRC formation (azoxymethane-induced aberrant crypt foci) and suggest that the mechanism is highly specific to protect from oxidative insults and the following apoptotic cascade.

  • 14. Al-Henhena, Nawal
    et al.
    Ying, Rozaida Poh Yuen
    Ismail, Salmah
    Najm, Wala
    Khalifa, Shaden A. M.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Abdulla, Mahmood Ameen
    Chemopreventive Efficacy of Andrographis paniculata on Azoxymethane-Induced Aberrant Colon Crypt Foci In Vivo2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, article id e111118Article in journal (Refereed)
    Abstract [en]

    Andrographis paniculata is a grass-shaped medicinal herb, traditionally used in Southeast Asia. The aim of this study was to evaluate the chemoprotective effects of A. paniculata on colorectal cancer. A. paniculata ethanol extract was tested on azoxymethane (AOM)-induced aberrant crypt foci (ACF) in vivo and in vitro. A. paniculata treated groups showed a significant reduction in the number of ACF of the treated rats. Microscopically, ACF showed remarkably elongated and stratified cells, and depletion of the submucosal glands of AOM group compared to the treated groups. Histologically, staining showed slightly elevated masses above the surrounding mucosa with oval or slit-like orifices. Immunohistochemically, expression of proliferating cell nuclear antigen (PCNA) and beta-catenin protein were down-regulated in the A. paniculata treated groups compared to the AOM group. When colon tissue was homogenized, malondialdehyde (MDA) and nitric oxide (NO) levels were significantly decreased, whereas superoxide dismutase (SOD) activity was increased in the treated groups compared to the AOM group. A. paniculata ethanol extract showed antioxidant and free radical scavenging activity, as elucidated by the measure of oxidative stress markers. Further, the active fractions were assessed against cell lines of CCD841 and HT29 colon cancer cells.

  • 15.
    Alsmark, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Foster, Peter G.
    Sicheritz-Ponten, Thomas
    Nakjang, Sirintra
    Embley, T. Martin
    Hirt, Robert P.
    Patterns of prokaryotic lateral gene transfers affecting parasitic microbial eukaryotes2013In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 14, no 2, p. R19-Article in journal (Refereed)
    Abstract [en]

    Background: The influence of lateral gene transfer on gene origins and biology in eukaryotes is poorly understood compared with those of prokaryotes. A number of independent investigations focusing on specific genes, individual genomes, or specific functional categories from various eukaryotes have indicated that lateral gene transfer does indeed affect eukaryotic genomes. However, the lack of common methodology and criteria in these studies makes it difficult to assess the general importance and influence of lateral gene transfer on eukaryotic genome evolution. Results: We used a phylogenomic approach to systematically investigate lateral gene transfer affecting the proteomes of thirteen, mainly parasitic, microbial eukaryotes, representing four of the six eukaryotic super-groups. All of the genomes investigated have been significantly affected by prokaryote-to-eukaryote lateral gene transfers, dramatically affecting the enzymes of core pathways, particularly amino acid and sugar metabolism, but also providing new genes of potential adaptive significance in the life of parasites. A broad range of prokaryotic donors is involved in such transfers, but there is clear and significant enrichment for bacterial groups that share the same habitats, including the human microbiota, as the parasites investigated. Conclusions: Our data show that ecology and lifestyle strongly influence gene origins and opportunities for gene transfer and reveal that, although the outlines of the core eukaryotic metabolism are conserved among lineages, the genes making up those pathways can have very different origins in different eukaryotes. Thus, from the perspective of the effects of lateral gene transfer on individual gene ancestries in different lineages, eukaryotic metabolism appears to be chimeric.

  • 16.
    Alsmark, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strese, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Wedén, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Microbial diversity of Alcyonium digitatum2013In: Phytochemistry Reviews, ISSN 1568-7767, E-ISSN 1572-980X, Vol. 12, no 3, p. 531-542Article, review/survey (Refereed)
    Abstract [en]

    Marine multi-cellular organisms are described as sources of many newly discovered bioactive compounds. Meanwhile, it has been demonstrated repeatedly for several natural products of reputed multicellular origin that they are, in fact, produced by endophytic unicellular organisms-such as microbial fungi or bacteria. Consequently, while studying compounds isolated from a living organism, it is essential to ensure that the sample integrity is not compromised. To test the diversity of the endobiome from Alcyonium digitatum, a cold water coral found along the Atlantic coasts of the northern hemisphere, we performed a culture dependent surveyed using a phylogenetic approach. A 1 cm(3) cube from the interior tissue of A. digitatum was excised under aseptic conditions, homogenized, spread onto agar-based growth medium plates and incubated in 22 A degrees C to promote microbial growth. Colonies were transferred to secondary medium plates, incubated, and after harvesting lysed using sterile water to release DNA. 16S and 23S rDNA regions were amplified using PCR, and sequenced for systematic evaluation using phylogenetic analysis. From this survey we identified a broad selection of bacteria, predominantly of the alpha-proteobacterial, bacteriodete, actinobacterial and firmicute lineages, demonstrating a significant biodiversity of the coral bacterial endobiome.

  • 17.
    Andersson Dunstan, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Liu, Boling
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Welch, Christopher J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Perera, Premila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Alphitol, a phenolic substance from Alphitonia zizyphoides which inhibits prostaglandin biosynthesis in vitro1998In: Phytochemistry, ISSN 0031-9422, E-ISSN 1873-3700, Vol. 48, no 3, p. 495-497Article in journal (Refereed)
    Abstract [en]

    The new phenolic compound, 3,5-dihydroxy-4-methoxy phenethyl alcohol, named alphitol, and betulinic acid were isolated from the bark of Alphitonia zizyphoides. The chemical structure of alphitol was determined by mass spectrometry in combination with one and two dimensional NMR, including HMBC. Both compounds inhibited prostaglandin biosynthesis in vitro, alphitol with an IC50 value of 0.66 mM, which is of the same magnitude as acetyl salicylic acid.

  • 18.
    Andersson Dunstan, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Noreen, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Serrano, Gudelia
    Cox, Paul A
    Perera, Premila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Evaluation of some Samoan and Peruvian medicinal plants by prostaglandin biosynthesis and rat ear oedema assays1997In: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 57, no 1, p. 35-56Article in journal (Refereed)
    Abstract [en]

    In our ongoing program to find new anti-inflammatory compounds, 58 extracts from 46 different medicinal plant species, used in treatment of inflammatory disorders - 38 plants from the traditional medicine of Western Samoa and eight originating from the indigenous medicine of the Shipibo-Conibo tribe of Peruvian Amazonia - were evaluated. The ability of all extracts to inhibit cyclooxygenase-1 catalysed prostaglandin biosynthesis in vitro was examined. Of the plant species tested 14 showed moderate to strong inhibition; including 11 Samoan and three Peruvian species. Further, 12 Samoan and all eight Peruvian species were investigated on their inhibitory activity of ethyl phenylpropiolate induced rat ear oedema in vivo Significant activity was shown by 10 of the Samoan and by all eight Peruvian species. An additional evaluation of the most active species was provided through a compilation of existing literature documenting traditional medicinal uses, pharmacological activity and chemical constituents. Several known cyclooxygenase-l inhibitors were reported to which the observed pharmacological activity can be attributed at least partly. The combination of chemical and pharmacological literature data and our experimental data may help to explain the anti-inflammatory use of these species in indigenous medicine.

  • 19.
    Andersson, Inger
    et al.
    Department of Molecular Biology, Swedish University of Agricultural Sciences.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Structure and function of Rubisco2008In: Plant physiology and biochemistry (Paris), ISSN 0981-9428, E-ISSN 1873-2690, Vol. 46, no 3, p. 275-291Article in journal (Refereed)
    Abstract [en]

    Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) is the major enzyme assimilating CO2 into the biosphere. At the same time Rubisco is an extremely inefficient catalyst and its carboxylase activity is compromised by an opposing oxygenase activity involving atmospheric O2. The shortcomings of Rubisco have implications for crop yield, nitrogen and water usage, and for the global carbon cycle. Numerous high-resolution crystal structures of different forms of Rubisco are now available, including structures of mutant enzymes. This review uses the information provided in these structures in a structure-based sequence alignment and discusses Rubisco function in the context of structural variations at all levels – amino acid sequence, fold, tertiary and quaternary structure – with an evolutionary perspective and an emphasis on the structural features of the enzyme that may determine its function as a carboxylase.

  • 20. Arnison, Paul G.
    et al.
    Bibb, Mervyn J.
    Bierbaum, Gabriele
    Bowers, Albert A.
    Bugni, Tim S.
    Bulaj, Grzegorz
    Camarero, Julio A.
    Campopiano, Dominic J.
    Challis, Gregory L.
    Clardy, Jon
    Cotter, Paul D.
    Craik, David J.
    Dawson, Michael
    Dittmann, Elke
    Donadio, Stefano
    Dorrestein, Pieter C.
    Entian, Karl-Dieter
    Fischbach, Michael A.
    Garavelli, John S.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gruber, Christian W.
    Haft, Daniel H.
    Hemscheidt, Thomas K.
    Hertweck, Christian
    Hill, Colin
    Horswill, Alexander R.
    Jaspars, Marcel
    Kelly, Wendy L.
    Klinman, Judith P.
    Kuipers, Oscar P.
    Link, A. James
    Liu, Wen
    Marahiel, Mohamed A.
    Mitchell, Douglas A.
    Moll, Gert N.
    Moore, Bradley S.
    Mueller, Rolf
    Nair, Satish K.
    Nes, Ingolf F.
    Norris, Gillian E.
    Olivera, Baldomero M.
    Onaka, Hiroyasu
    Patchett, Mark L.
    Piel, Joern
    Reaney, Martin J. T.
    Rebuffat, Sylvie
    Ross, R. Paul
    Sahl, Hans-Georg
    Schmidt, Eric W.
    Selsted, Michael E.
    Severinov, Konstantin
    Shen, Ben
    Sivonen, Kaarina
    Smith, Leif
    Stein, Torsten
    Suessmuth, Roderich D.
    Tagg, John R.
    Tang, Gong-Li
    Truman, Andrew W.
    Vederas, John C.
    Walsh, Christopher T.
    Walton, Jonathan D.
    Wenzel, Silke C.
    Willey, Joanne M.
    van der Donk, Wilfred A.
    Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature2013In: Natural product reports (Print), ISSN 0265-0568, E-ISSN 1460-4752, Vol. 30, no 1, p. 108-160Article, review/survey (Refereed)
    Abstract [en]

    This review presents recommended nomenclature for the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), a rapidly growing class of natural products. The current knowledge regarding the biosynthesis of the >20 distinct compound classes is also reviewed, and commonalities are discussed.

  • 21.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Dipsacales (Honeysuckle)2002In: Encyclopedia of Life Sciences, John Wiley & Sons , 2002Chapter in book (Other academic)
    Abstract [en]

    The plant order Dipsacales comprises about 2000 species belonging to the eight core families Adoxaceae, Caprifoliaceae, Collumelliaceae, Diervillaceae, Dipsacaceae, Linnaeceae, Morinaceae and Valerianaceae. It includes many ornamental plants such as honeysuckle and weigela.

  • 22.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Impulse Lecture: The odd fellow - Benefits of anomaly2014In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 80, no 16, p. 1373-1374Article in journal (Other academic)
  • 23.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Phylogeny and chemography2008In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 74, no 9, p. SL64-Article in journal (Refereed)
    Abstract [en]

    Natural compounds are evolutionary selected and pre-validated by Nature, displaying a unique diversity of chemical properties and corresponding biological activities. Of utmost importance for a rational discovery and exploration of new biologically active compounds are two aspects: one the identification and charting of the biologically relevant chemical space, the other a similar charting of the corresponding evolutionary space.

    he first key to this is the coverage of the natural products' chemical space. For this purpose we introduced ChemGPS-NP, with the aim to provide a tool for more efficient and stringent compound comparison, to identify parts of chemical space related to particular biological activities, and to track changes in chemical properties due to e.g. evolutionary traits and modifications in biosynthesis. Physical-chemical properties not directly discernible from structural data can be compared, making selection more rational when screening natural compounds and analogues.

    The second key would consequently be to explore evolutionary space by elucidating and utilising robust phylogenies for the organisms under study. From this basis reflecting the evolutionary history and hence biosynthesis development, further conclusions can be drawn.

    Based these initial attempts, the intersection of chemical and evolutionary space have been explored. With regard to e.g. compound classes such as iridoids, betalains, and sesquiterpene lactones, evolutionary patterns of changes in physical-chemical properties are observed and compared. For eight major classes of plant defence peptides analyses of structure base alignments provide arguments for rational classification. In addition, evolution of the enzyme Rubisco, have been explored with reference to major structural features.

  • 24.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Topical chemical space in relation to biological space2010In: Comprehensive Natural Products II: Chemistry and Biology / Volume 3 / [ed] L. Mander & H.-W. Lui, Oxford: Elsevier, 2010, p. 47-79Chapter in book (Refereed)
    Abstract [en]

    In this chapter, the mapping of physical–chemical descriptor space of natural products and its relation to the biological space, with emphasis on evolutionary and topical biological space, is discussed. A brief presentation of methods for phylogenetic analysis and their different advantages is followed by discussions of evolutionary implications. Examples from both unpublished and previously published studies are presented.

  • 25.
    Backlund, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Backlund, Maria
    Klum, Mattias
    Klum collection anteckningsbok2008Book (Other (popular science, discussion, etc.))
  • 26.
    Backlund, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Buonfiglio, R.
    AstraZeneca R&D, Discovery Sci, Computat Sci, Molndal, Sweden..
    Henz, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Vikeved, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Lai, Kuei-Hung
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Kogej, T.
    AstraZeneca R&D, Discovery Sci, Computat Sci, Molndal, Sweden..
    Charting biological activity in chemical property space using ChemGPS-NP2015In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 81, no 16, p. 1413-1413Article in journal (Other academic)
  • 27.
    Backlund, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gottfries, Johan
    AstraZeneca R&D, Mölndal.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Larsson, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Chemography and Phylogeny: navigating chemical and evolutionary space2006In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 72, no 11, p. 972-972Article in journal (Other academic)
  • 28.
    Backlund, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Rosén, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Larsson, Sonny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Teoribildning öppnar nya fält för naturproduktsforskning2008In: Läkemedelsvärlden, ISSN 1402-1927, no 6, p. 31-Article in journal (Other (popular science, discussion, etc.))
  • 29.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Växter i moderna läkemedel2002In: Ett växande vetande: Vetenskapsrådets temabok 2002, Stockholm: Vetenskapsrådet , 2002, Vol. Vetenskapsrådets temabok 2002 (Särtryck), p. 103-Chapter in book (Other (popular science, discussion, etc.))
  • 30.
    Bohlin, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Alsmark, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Klum, M.
    Weden, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strategies and methods for a sustainable search for bioactive compounds2012In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 78, no 11, p. 1031-1032Article in journal (Other academic)
  • 31.
    Bohlin, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bruhn, Jan G.Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bioassay methods in natural product research and drug development: proceedings of the international symposium on Bioassay Methods in Natural Product Research and Drug Development, held at the Biomedical Centre of Uppsala University, Sweden, from 24-27 August 19971999Conference proceedings (editor) (Other academic)
  • 32.
    Bohlin, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Felth, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bioassays in natural product research - Strategies and methods in the search for bioactive natural products2014In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 80, no 10, p. 753-753Article in journal (Other academic)
  • 33.
    Bohlin, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Alsmark, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Wedén, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Natural products in modern life science2010In: Phytochemistry Reviews, ISSN 1568-7767, E-ISSN 1572-980X, Vol. 9, no 2, p. 279-301Article in journal (Refereed)
    Abstract [en]

    With a realistic threat against biodiversity in rain forests and in the sea, a sustainable use of natural products is becoming more and more important. Basic research directed against different organisms in Nature could reveal unexpected insights into fundamental biological mechanisms but also new pharmaceutical or biotechnological possibilities of more immediate use. Many different strategies have been used prospecting the biodiversity of Earth in the search for novel structure-activity relationships, which has resulted in important discoveries in drug development. However, we believe that the development of multidisciplinary incentives will be necessary for a future successful exploration of Nature. With this aim, one way would be a modernization and renewal of a venerable proven interdisciplinary science, Pharmacognosy, which represents an integrated way of studying biological systems. This has been demonstrated based on an explanatory model where the different parts of the model are explained by our ongoing research. Anti-inflammatory natural products have been discovered based on ethnopharmacological observations, marine sponges in cold water have resulted in substances with ecological impact, combinatory strategy of ecology and chemistry has revealed new insights into the biodiversity of fungi, in depth studies of cyclic peptides (cyclotides) has created new possibilities for engineering of bioactive peptides, development of new strategies using phylogeny and chemography has resulted in new possibilities for navigating chemical and biological space, and using bioinformatic tools for understanding of lateral gene transfer could provide potential drug targets. A multidisciplinary subject like Pharmacognosy, one of several scientific disciplines bridging biology and chemistry with medicine, has a strategic position for studies of complex scientific questions based on observations in Nature. Furthermore, natural product research based on intriguing scientific questions in Nature can be of value to increase the attraction for young students in modern life science.

  • 34.
    Bohlin, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Modern pharmacognosy: Connecting biology and chemistry2007In: Pure and Applied Chemistry, ISSN 0033-4545, E-ISSN 1365-3075, Vol. 79, no 4, p. 763-774Article in journal (Refereed)
    Abstract [en]

    In many countries today, the number of students selecting chemistry for higher studies is decreasing. At the same time, interest in the environmental aspects of chemistry, green chemistry, and sustainable use of natural products is increasing among the young generation of students. By modernizing and renewing a venerable proven science, pharmacognosy would have a strategic position to connect biology and chemistry. This multidisciplinary subject is important for discovery of novel and unique molecules with drug potential, and for revealing unknown targets, by studying evolutionary structure-activity optimization in nature. In this paper, the overall aim and strategies of our research are presented and exemplified by three different research projects.

    Natural products are involved in scientific issues important for a sustainable society, and a multidisciplinary subject such as pharmacognosy can, therefore, be useful in increasing future interest in both chemistry and biology.

  • 35.
    Bohlin, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Rosén, Börje
    Podophyllotoxin derivatives: drug discovery and development1996In: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 1, no 8, p. 343-351Article, review/survey (Refereed)
    Abstract [en]

    The exploration and exploitation of podophyllin formulations provide an example of how a plant extract with established ethnomedical use, but also causing toxicity, can provide a basis for new drug discovery and development. Applications and potential applications include the treatment of venereal warts, psoriasis, rheumatoid arthritis, malaria and Alzheimer's disease. This review addresses the history and pharmacological action of these natural products and outlines the preclinical development and clinical trials of drugs in the pipeline and with marketing approval.

  • 36.
    Bohlin, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Vasänge, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Perera, P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bioassays using the phospholipid mediator PAF in the search for anti-inflammatory natural products1997In: Current organic chemistry, ISSN 1385-2728, E-ISSN 1875-5348, Vol. 1, no 4, p. 345-360Article in journal (Refereed)
  • 37.
    Boldbaatar, Delgerbat
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Findakly, Meriana
    Jabri, Safa
    Javzan, Batkhuu
    Choidash, Battsetseg
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Hellman, Bjorn
    Antigenotoxic and antioxidant effects of the Mongolian medicinal plant Leptopyrum fumarioides (L): An in vitro study2014In: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 155, no 1, p. 599-606Article in journal (Refereed)
    Abstract [en]

    Ethnopharmacological relevance: Leptopyrum fumarioides has been used in the traditional medicine of Mongolia for the treatment of various diseases, including drug intoxications. However, since there is only sparse information about its chemistry, active components, and pharmacological and toxicological effects, the major aim of the present study employing mouse lymphoma cells was to evaluate the genotoxic and antigenotoxic/antioxidative effects of extracts and components isolated from this plant. Material and methods: A crude methanol extract was separated into three different sub-extracts: dichloromethane, n-butanol, and water. The major constituent of the n-butanol extract, i.e., the flavone luteolin-7-O-glucoside and a mixture of the most abundant compounds in the dichloromethane sub-extract were then isolated. DNA damage was evaluated using the comet assay; the antioxidant activity was evaluated using the DPPH radical scavenging assay. Results: The crude methanol extract, the dichloromethane sub-extract and the mixture of compounds isolated from the latter fraction, increased the level of DNA damage after three hours of exposure. In contrast, no increase in DNA damage was observed in the cells that had been exposed to the n-butanol and water sub-extracts, or to the pure flavone. When non-DNA damaging concentrations of extracts and compounds were tested together with the DNA damaging agent catechol, all sub-extracts were found to reduce the catechol-induced DNA damage (the flavone was then found to be the most effective protective agent). The n-butanol sub-extract and the flavone were also found to have the most prominent antioxidative effects. Conclusion: Based on the results from the present study, components in Leptopyrum fumarioides were found to protect the DNA damage induced by catechol, probably by acting as potent antioxidants.

  • 38.
    Boldbaatar, Delgerbat
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Natl Univ Mongolia, Sch Engn & Appl Sci, Ulaanbaatar 46, Mongol Peo Rep..
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Synthesis, Structural Characterization, and Bioactivity of the Stable Peptide RCB-1 from Ricinus communis2015In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 78, no 11, p. 2545-2551Article in journal (Refereed)
    Abstract [en]

    The Ricinus communis biomarker peptides RCB-1 to -3 comprise homologous sequences of 19 (RCB-1) or 18 (RCB-2 and -3) amino acid residues. They all include four cysteine moieties, which form two disulfide bonds. However, neither the 3D structure nor the biological activity of any of these peptides is known. The synthesis of RCB-1, using microwave-assisted, Fmoc-based solid-phase peptide synthesis, and a method for its oxidative folding are reported. The tertiary structure of RCB-1, subsequently established using solution-state NMR, reveals a twisted loop fold with antiparallel ?-sheets reinforced by the two disulfide bonds. Moreover, RCB-1 was tested for antibacterial, antifungal, and cytotoxic activity, as well as in a serum stability assay, in which it proved to be remarkably stable.

  • 39. Botting, Joseph P.
    et al.
    Cardenas, Paco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Peel, John S.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Palaeobiology.
    A Crown-Group Demosponge from the Early Cambrian Sirius Passet Biota, North Greenland2015In: Palaeontology, ISSN 0031-0239, E-ISSN 1475-4983, Vol. 58, no 1, p. 35-43Article in journal (Refereed)
    Abstract [en]

    Calibration of the divergence times of sponge lineages and understanding of their phylogenetic history are hampered by the difficulty in recognizing crown versus stem groups in the fossil record. A new specimen from the lower Cambrian (Series 2, Stage 3; approximately 515Ma) Sirius Passet Biota of North Greenland has yielded a diagnostic spicule assemblage of the extant demosponge lineages Haploscleromorpha and/or Heteroscleromorpha. The specimen has disarticulated approximately in situ, but represents an individual sponge that possessed monaxon spicules combined with a range of slightly smaller sigma, toxa and unique spiral morphologies. The combination of spicule forms, together with their relatively large size, suggests that the sponge represents the stem lineage of Haploscleromorpha+Heteroscleromorpha. This is the first crown-group demosponge described from the early Cambrian and provides the most reliable calibration point currently available for phylogenetic studies.

  • 40. Broussalis, Adriana M.
    et al.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Coussio, Jorge D.
    Ferraro, Graciela
    Martino, Virginia
    Claeson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    First cyclotide from Hybanthus (Violaceae)2001In: Phytochemistry, ISSN 0031-9422, E-ISSN 1873-3700, Vol. 58, no 1, p. 47-51Article in journal (Refereed)
    Abstract [en]

    Hypa A, a novel macrocyclic polypeptide containing 30 amino acid residues, has been isolated from the n-butanol extract of the Argentine plant Hybanthus parviflorus. The sequence, cyclo-(SCVYIPCTITALLGCSCKNKVCYNGIPCAE), was determined by automated Edman degradation, quantitative amino acid analysis and nanospray MS/MS(2). Three intramolecular disulfide bridges stabilize the cyclic peptide backbone of hypa A. Using these structural features to classify the peptide as a cyclotide, we extended the distribution of that substance class to a new genus, and now propose a uniform nomenclature for cyclotides.

  • 41. Broussalis, Adriana M.
    et al.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Coussio, Jorge D.
    Ferraro, Graciela
    Martino, Virginia
    Claeson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    First cyclotide from Hybanthus (Violaceae)2001In: Phytochemistry, ISSN 0031-9422, E-ISSN 1873-3700, Vol. 58, no 1, p. 47-51Article in journal (Refereed)
    Abstract [en]

    Hypa A, a novel macrocyclic polypeptide containing 30 amino acid residues, has been isolated from the n-butanol extract of the Argentine plant Hybanthus parviflorus. The sequence, cyclo-(SCVYIPCTITALLGCSCKNKVCYNGIPCAE), was determined by automated Edman degradation, quantitative amino acid analysis and nanospray MS/MS2. Three intramolecular disulfide bridges stabilize the cyclic peptide backbone of hypa A. Using these structural features to classify the peptide as a cyclotide, we extended the distribution of that substance class to a new genus, and now propose a uniform nomenclature for cyclotides.

  • 42.
    Bruhn, Jan G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Ginkgo biloba: en översikt1996In: Svensk Farmacevtisk Tidskrift, ISSN 0039-6524, Vol. 100, no 2, p. 42-45Article in journal (Other academic)
  • 43.
    Bruhn, Jan G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Scientific reporting of unscientific data: a case of Ginkgo biloba being miscredited2003In: Phytomedicine, ISSN 0944-7113, E-ISSN 1618-095X, Vol. 10, no 4, p. 358-Article in journal (Refereed)
  • 44.
    Bruhn, Jan G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Molecular Pharmacognosy: an explanatory model1997In: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 2, no 6, p. 243-246Article, review/survey (Refereed)
    Abstract [en]

    Increased interest in the study of natural products as potential drugs and rapidly changing research strategies are driving us to reassess the role of pharmacognosy in the wider context of pharmaceutical research. The authors propose a new definition and an explanatory model of modern pharmacognosy that can be used as a theoretical foundation for future development of this classical branch of the life sciences.

  • 45.
    Bruhn, Jan G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    De Smet, Peter A. G. M.
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Beck, Olof
    Mescaline use for 5700 years2002In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 359, no 9320, p. 1866-Article in journal (Refereed)
    Abstract [en]

    Archaeological investigations in northeast Mexico and Trans-Pecos, Texas have shown that the use of psychotropic drugs in this region goes back to around 8500 BC. The aboriginal inhabitants of this region used the mescal bean, Sophora secundiflora, and buttons from the peyote cactus, Lophophora williamsii1.

    From an archaeological site in Coahuila, Mexico, several peyote buttons were retrieved and radiocarbon-dated to AD 810–1070. Alkaloid analysis revealed the presence of mescaline and four related tetrahydroisoquinoline alkaloids2. We have, however, analysed two much older samples of peyote buttons. These samples are thought to have been found in Shumla Cave number five on the Rio Grande, TX, USA, and are in the collection of the Witte Museum in San Antonio3. Radiocarbon dating showed a mean age of 5700 years.

    Standard alkaloid extraction procedures done on the samples gave residues that were analysed by thin-layer chromatography and gas chromatography-mass spectrometry. We were able to identify mescaline in both samples, based on identical retention times and Rf values, and similar mass-to-charge ratios and fragmentation pattern. The detection of mescaline in two different samples, both analysed by two methods based on different principles, is reliable evidence for the presence of this psychotropic drug.

    Freshly prepared peyote buttons can contain up to 8% of total alkaloids. The previously studied 1000-year-old sample had a lower content, around 2·25%. In our analysis, alkaloid content had fallen to 2%, and mescaline was the only peyote alkaloid we could identify. There was no trace of any of the other tetrahydroisoquinoline alkaloids typical for peyote.

    Earlier, nicotine and caffeine had been identified in plant remains from a medicine man's tomb in Bolivia, aged 1600 years4. Morphine has been found in a 3500 year old ceramic container from Cyprus5.

    From a scientific perspective, the studied peyote material seems to be the oldest plant drug that yielded a major bioactive compound on chemical analysis. From a cultural point of view, our identification of mescaline strengthens the evidence that Native Americans already recognised and valued the psychotropic properties of peyote as long as 5700 years ago.