Secondary Metabolites of Lichens as Both Anti-aggregative and Ant
Journal of Clinical and Cellular Immunology

Journal of Clinical and Cellular Immunology
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ISSN: 2155-9899

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Commentary - (2017) Volume 8, Issue 2

Secondary Metabolites of Lichens as Both Anti-aggregative and Antioxidant Agents in Tauopathies

Alberto Cornejo1* and Carlos Areche2
1Faculty of Medicine, School of Medical Technology, Andrés Bello University, Sazié 2315, Chile
2Department of Chemistry, Faculty of Sciences, University of Chile, Ñuñoa, Santiago 8320000, Chile
*Corresponding Author: Alberto Cornejo, Faculty of Medicine, School of Medical Technology, Andrés Bello University, Sazié 2315, First Floor, Santiago 8370092, Chile, Tel: +56227703610 Email:


This commentary described our findings of parietin, an anthraquinone, isolated from Ramalina terebrata as inhibitor of tau protein. Moreover, we considered important to link tauopathies with reactive oxygen species since oligomers and fibril-forming elements are responsible for activating reactive oxygen species, which cause inflammatory response and neurodegeneration. Together, we considered important to find naturally occurring compounds that might be able to stop aggregation and reduces ROS cells damage.

Keywords: Tauopathies; Secondary metabolites; Lichens; Reactive oxygen species; Inflammatory response; Neurodegeneration

Tauopathies and Neurotoxicity

Taoupathies are neurodegenerative disorders involving tau protein, such as progressive nuclear palsy (PSP), corticobasal degeneration (CBD), Pick´s disease among others. Tau is an unfolded protein which is found mainly in axons of mature and physiologically is involved in microtubule stability and axonal transport [1]. However, once tau becomes hyperphosphorylated it detaches from microtubule starting the aggregation process [2,3]. Pathological tau aggregates are able to activate glia cells that release cytotoxic factors, which cause pro inflammatory cytokines such as TNF-α, IL-1 and IL-6 and chemokines [4]. Tau phosphorylation is increased in both physiologically and pathological state [5], however phosphorylation is increased during development, suggesting that process is needed for neuronal plasticity [6]. Tau phosphorylation is an event highly regulated by kinases and phosphatases. Its balance is deregulated due to several stimuli such as oxidative stress [7]. Tau is able to form paired helical filaments closely related to neurofibrillary tangles [8,9]. Hyperphosphorylated tau protein is found in patients suffering with tauopathies in cerebrospinal fluid (CNS), which correlates well with hypocampal atrophy [10]. In addition, tauopathies have tau hyperphosphorylated as a hallmark; however, the degree of phosphorylation differs among them. In addition, it is important to notice that there is no single phosphorylation site associated to a particular tauopathy [5]. Moreover, tau has the propensity to form aggregates, since inside the full length protein (441 aminoacids) resides a region known as 4R (four microtubule binding domain) containing two hexapeptides 275VQIINK280 and 306VQIVYK311 both associated to β sheet formation [11]. Increased tau phosphorylation decreased its binding for microtubules. These species prone to form aggregates which are toxic in both cell and transgenic mouse model [12,13]. Despite that fact, there are evidences showing that soluble species and pre fibrils which are more related to toxicity [14]. An interesting UV raman spectroscopy study showed that at early stages, within the first hour, fibrillar aggregates possess a mixture of β-sheet and disordered content. Afterward, the UVRR spectra shows a consolidation in fibril structure, augmenting the content of β sheet [15], interesting is to remark that toxicity apparently relies on β sheet content [16].

Tauopathies and Reactive Oxygen Species

Reactive oxygen species (ROS) are reactive molecules such as hydroxyl (OH·), superoxide (O2·) and nitric monoxide (NO·). Besides, other molecules like hydrogen peroxide (H2O2) and peroxynitrite (ONOO) are not free radicals; however they are reported to generate free radicals [17,18].

In general, cells exposed to reactive oxygen species can overproduce free radicals that promotes oxidative damage on macromolecules, which can lead to pathological disorders such as stroke, chronic inflammation, also this species contribute to develop neurodegenerative disorders such as tauopathies. [18,19]. Once cells are in contact with toxic species, they are able to synthetize several enzymes in order to clear them, however residual superoxides and peroxides remain [18]. Moreover, there are evidences showing that ROS were first described in Pick´s disease and CBD [20]. It was also described that ROS associated to tauopathies, such as malondialdehyde (MDA) or 4-hydroxynonenal (HNE), a specie linked to polyunsaturated fatty acids. [21,22].

In contrast, antioxidants can prevent ROS that are able to induce injury. However, there are synthetic antioxidants that have shown either to induced cell toxicity or mutagenesis [23]. Thus it is timely to search for naturally occurring antioxidants. Hence, several antioxidant properties have been described associated to flavonoids, hydroxycinnamic derivatives, catechins, curcumin among others [24,25].

Importantly, the phenolic ring is the main moiety involved in scavenging ROS, metal chelator and modulates both the endogenous enzymatic-non enzymatic antioxidant system involved in neurodegenerative disorders including tauopathies [26].

Lichens as antioxidants and tau inhibitors source

Lichens are symbiotic association between a mycobiont (fungus) and either algae or cyanobacterium [27-29]. Besides lichens species are able to produce important secondary metabolites [30]. A remarkable feature of lichen species is their antioxidant capacity that resides in their phenolic moieties [31]. Interestingly, some depsides and depsidones isolated from lichens have shown antioxidant capacity [32-34]. Besides this, neuroprotective effect and cytotoxic potential have been described in Cetraria islandica and Vulpicida canadensis [35]. Two Xanthones isolated from Pyrenula japonica have a potent antioxidant capacity as compared with α-tocopherol and 2,6-di(tertbutyl)- 4-methylphenol (BHT) [36]. Moreover, ramalina isolated from Antartic Ramalina terebrata presented scavenging activity and it inhibits tyrosine enzyme activity. In addition, ramalina possess a very little toxicity in keratinocyte and fibroblast [37,38].

A β-orcinol depsidone, stictic acid and salazinic acid showed neuroprotective effect on U373MG cell line by diminishing ROS production. These compounds would be useful as antioxidant agents in Alzheimer´s disease [39], but it is important to notice that none of them have been tested as anti-tau inhibitor agent. Alternatively, a derivative plant polyphenol, curcumin, has been useful, since curcumin exerts a pleiotropic effect by combining both anti-aggregate and antioxidant activities.

Recently, we have characterized that parietin, an anthraquinone, isolated from Ramalina terebrata, lichen collected in the Antarctic region of “Península Fildes”, has effect on tau aggregation [40]. Docking studies of parietin and 306VQIVYK311 hexapeptide suggest that parietin bind steric zippers preventing β-sheet assembly [40]. According to the docking model, there are both types of interaction: hydrogen bond (HB) among phenolic groups, methoxy motif and lysine side chains. Besides this, hydrophobic interaction also occurs between methyl group of methoxy substituent and valine [40]. Interestingly, another anthraquinone, emodin, which inhibits tau aggregation has lower IC50 instead of parietin, we hypothesize that could be due to methoxy group at C-3 position in parietin (Figure 1). Moreover, another anthraquinone derived from plant, rhein, can reverse DNA methylation and de-suppression of Klotho, which has an essential role in anti-renal fibrosis in a mouse model [41,42]. Furthermore, in a senescence-accelerated mouse model, rhein reduces levels of Aβ [43], however both rhein and emodin are poorly active against Aβ in vitro aggregation assays [44]. Although, another anthraquinone, emodin, exerts profound effect over tau aggregation [45], and its scavenging capacity is lower as compared with alaternin [46], but there is no evidence that alaternin inhibits tau aggregation. Considering that oligomers or fibril-forming motif, exert their influence over inflammatory system, it would be interesting to find molecules isolated from natural sources that combine both anti-aggregative and scavenging properties, thus it would be a proper way to address drug design. In addition, it is interesting to mention that not only tauopathies exerts their damage on aggregation, since in neurodegenerative disorders such as Parkinson´s disease, α-synuclein is also prone to form aggregates and fibrils, and their toxicity is also linked to β sheet formation.


Figure 1: Anthraquinones compound tau inhibitors. A) Parietin IC50 72 μM over tau four microtubule binding domain (4R). B) Emodin IC50 0.3 μM over tau K-18 construct.


This work was supported by grants from the INACH RT 13-13 to Alberto Cornejo and Carlos Areche.


  1. Spillantini MG, Goedert M (2013) Tau pathology and neurodegeneration. Lancet Neurol 12: 609-622.
  2. Cho JH, Johnson GV (2003) Glycogen synthase kinase 3beta phosphorylates tau at both primed and unprimed sites. Differential impact on microtubule binding. J Biol Chem 278: 187-193.
  3. Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K (2001) Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U S A 98: 6923-6928.
  4. Olson JK, Miller SD (2004) Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 173: 3916-3924.
  5. Noble W, Hanger DP, Miller CC, Lovestone S (2013) The importance of tau phosphorylation for neurodegenerative diseases. Front Neurol 4: 83.
  6. Brion JP, Smith C, Couck AM, Gallo JM, Anderton BH (1993) Developmental changes in tau phosphorylation: fetal tau is transiently phosphorylated in a manner similar to paired helical filament-tau characteristic of Alzheimer's disease. J Neurochem 61: 2071-2080.
  7. Davis DR, Anderton BH, Brion JP, Reynolds CH, Hanger DP (1997) Oxidative stress induces dephosphorylation of tau in rat brain primary neuronal cultures. J Neurochem 68: 1590-1597.
  8. Götz J, Chen F, van Dorpe J, Nitsch RM (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293: 1491-1495.
  9. Goedert M, Spillantini MG, Cairns NJ, Crowther RA (1992) Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8: 159-168.
  10. Galvin JE, Fagan AM, Holtzman DM, Mintun MA, Morris JC (2010) Relationship of dementia screening tests with biomarkers of Alzheimer's disease. Brain 133: 3290-3300.
  11. von Bergen M, Friedhoff P, Biernat J, Heberle J, Mandelkow EM, et al. (2000) Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure. Proc Natl Acad Sci U S A 97: 5129-5134.
  12. Khlistunova I, Biernat J, Wang Y, Pickhardt M, von Bergen M, et al. (2006) Inducible expression of Tau repeat domain in cell models of tauopathy: aggregation is toxic to cells but can be reversed by inhibitor drugs. J Biol Chem 281: 1205-1214.
  13. Mocanu MM, Nissen A, Eckermann K, Khlistunova I, Biernat J, et al. (2008) The potential for beta-structure in the repeat domain of tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous Tau in inducible mouse models of tauopathy. J Neurosci 28: 737-748.
  14. Spires-Jones TL, Kopeikina KJ, Koffie RM, de Calignon A, Hyman BT (2011) Are tangles as toxic as they look? J Mol Neurosci 45: 438-444.
  15. Ramachandran G, Milán-Garcés EA, Udgaonkar JB, Puranik M (2014) Resonance Raman spectroscopic measurements delineate the structural changes that occur during tau fibril formation. Biochemistry 53: 6550-6565.
  16. Flach K, Hilbrich I, Schiffmann A, Gärtner U, Krüger M, et al. (2012) Tau oligomers impair artificial membrane integrity and cellular viability. J Biol Chem 287: 43223-43233.
  17. Gilgun-Sherki Y, Melamed E, Offen D (2001) Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier. Neuropharmacology 40: 959-975.
  18. Alavi Naini SM, Soussi-Yanicostas N (2015) Tau Hyperphosphorylation and Oxidative Stress, a Critical Vicious Circle in Neurodegenerative Tauopathies? Oxid Med Cell Longev 2015: 151979.
  19. Fang YZ, Yang S, Wu G (2002) Free radicals, antioxidants, and nutrition. Nutrition 18: 872-879.
  20. Castellani R, Smith MA, Richey PL, Kalaria R, Gambetti P, et al. (1995) Evidence for oxidative stress in Pick disease and corticobasal degeneration. Brain Res 696: 268-271.
  21. Martínez A, Carmona M, Portero-Otin M, Naudí A, Pamplona R, et al. (2008) Type-dependent oxidative damage in frontotemporal lobar degeneration: cortical astrocytes are targets of oxidative damage. J Neuropathol Exp Neurol 67: 1122-1136.
  22. Odetti P, Garibaldi S, Norese R, Angelini G, Marinelli L, et al. (2000) Lipoperoxidation is selectively involved in progressive supranuclear palsy. J Neuropathol Exp Neurol 59: 393-397.
  23. Grice HC, Clayson DB, Flamm WG, Ito N, Kroes R, et al. (1986) Panel discussion: Possible mechanisms of BHA carcinogenicity from a consideration of its chemical and biological properties. Food Chem Toxicol 24: 1235-1242.
  24. Gonzalez-Burgos E, Carretero ME, Gomez-Serranillos MP (2012) Diterpenoids isolated from Sideritis species protect astrocytes against oxidative stress via Nrf2. J Nat Prod 75: 1750-1758.
  25. Sundararajan R, Haja NA, Venkatesan K, Mukherjee K, Saha BP, et al. (2006) Cytisus scoparius link--a natural antioxidant. BMC Complement Altern Med 6: 8.
  26. Sayre LM, Perry G, Smith MA (2008) Oxidative stress and neurotoxicity. Chem Res Toxicol 21: 172-188.
  27. White PA, Oliveira RC, Oliveira AP, Serafini MR, Araújo AA, et al. (2014) Antioxidant Activity and Mechanisms of Action of Natural Compounds Isolated from Lichens: A Systematic Review. Molecules 19: 14496.
  28. Fernández-Moriano C, Gómez-Serranillos MP, Crespo A (2016) Antioxidant potential of lichen species and their secondary metabolites. A systematic review. Pharm Biol 54: 1-17.
  29. ShuklaV, Joshi GP, Rawat MSM (2010) Lichens as a potential natural source of bioactive compounds: a review. Phytochem Rev 9: 303-314.
  30. Molnar K, Farkas E (2010) Current results on biological activities of lichen secondary metabolites: a review. Z Naturforsch C 65: 157-173.
  31. Brewer MS (2011) Natural Antioxidants: Sources, Compounds, Mechanisms of Action, and Potential Applications. Compr Rev Food Sci Food Saf 10: 221-247.
  32. Kosanic M, Manojlovic N, Jankovic S, Stanojkovic T, Rankovic B (2013) Evernia prunastri and Pseudoevernia furfuraceae lichens and their major metabolites as antioxidant, antimicrobial and anticancer agents. Food Chem Toxicol 53: 112-118.
  33. Thadhani VM, Choudhary MI, Ali S, Omar I, Siddique H, et al. (2011) Antioxidant activity of some lichen metabolites. Nat Prod Res 25: 1827-1837.
  34. Lohézic-Le Dévéhat F, Tomasi S, Elix JA, Bernard A, Rouaud I, et al. (2007) Stictic acid derivatives from the lichen Usnea articulata and their antioxidant activities. J Nat Prod 70: 1218-1220.
  35. Fernández-Moriano C, Divakar PK, Crespo A, Gómez-Serranillos MP (2015) Neuroprotective activity and cytotoxic potential of two Parmeliaceae lichens: Identification of active compounds. Phytomedicine 22: 847-855.
  36. Takenaka Y, Tanahashi T, Nagakura N, Hamada N (2000) Production of xanthones with free radical scavenging properties, emodin and sclerotiorin by the cultured lichen mycobionts of Pyrenula japonica. Z Naturforsch C 55: 910-914.
  37. Pavlovic V, Stojanovic I, Jadranin M, Vajs V, Djordjevic I, et al. (2013) Effect of four lichen acids isolated from Hypogymnia physodes on viability of rat thymocytes. Food Chem Toxicol 51: 160-164.
  38. Paudel B, Bhattarai HD, Koh HY, Lee SG, Han SJ, et al. (2011) Ramalin, a novel nontoxic antioxidant compound from the Antarctic lichen Ramalina terebrata. Phytomedicine 184: 1285-1290.
  39. de Paz GA, Raggio J, Gómez-Serranillos MP, Palomino OM, González-Burgos E, et al. (2010) HPLC isolation of antioxidant constituents from Xanthoparmelia spp. J Pharm Biomed Anal 53: 165-171.
  40. Cornejo A, Salgado F, Caballero J, Vargas R, Simirgiotis M, et al. (2016) Secondary Metabolites in Ramalina terebrata Detected by UHPLC/ESI/MS/MS and Identification of Parietin as Tau Protein Inhibitor. Int J Mol Sci 17: E1303.
  41. Zhang Q, Yin S, Liu L, Liu Z, Cao W (2016) Rhein reversal of DNA hypermethylation-associated Klotho suppression ameliorates renal fibrosis in mice. Sci Rep 6: 34597.
  42. Zhang Q, Liu L, Lin W, Yin S, Duan A, et al. (2017) Rhein reverses Klotho repression via promoter demethylation and protects against kidney and bone injuries in mice with chronic kidney disease. Kidney Int 91: 144-156.
  43. Liu J, Hu G, Xu R, Qiao Y, Wu HP, et al. (2013) Rhein lysinate decreases the generation of beta-amyloid in the brain tissues of Alzheimer's disease model mice by inhibiting inflammatory response and oxidative stress. J Asian Nat Prod Res 15: 756-763.
  44. Guo JP, Yu S, McGeer PL (2010) Simple in vitro assays to identify amyloid-beta aggregation blockers for Alzheimer's disease therapy. J Alzheimers Dis 19: 1359-1370.
  45. Pickhardt M, Gazova Z, von Bergen M, Khlistunova I, Wang Y, et al. (2005) Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired helical filaments in vitro and in cells. J Biol Chem 280: 3628-3635.
  46. Choi JS, Chung HY, Jung HA, Park HJ, Yokozawa T (2000) Comparative evaluation of antioxidant potential of alaternin (2-hydroxyemodin) and emodin. J Agric Food Chem 48: 6347-6351.
Citation: Cornejo A, Areche C (2017) Secondary Metabolites of Lichens as Both Anti-aggregative and Antioxidant Agents in Tauopathies. J Clin Cell Immunol 8:496.

Copyright: © 2017 Cornejo A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.