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Beneficial Effects of Cyclic Ether 2-Butoxytetrahydrofuran from Sea Cucumber Holothuria scabra against Aβ Aggregate Toxicity in Transgenic Caenorhabditis elegans and Potential Chemical Interaction.
Tangrodchanapong T
,
Sornkaew N
,
Yurasakpong L
,
Niamnont N
,
Nantasenamat C
,
Sobhon P
,
Meemon K
.
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The pathological finding of amyloid-β (Aβ) aggregates is thought to be a leading cause of untreated Alzheimer's disease (AD). In this study, we isolated 2-butoxytetrahydrofuran (2-BTHF), a small cyclic ether, from Holothuria scabra and demonstrated its therapeutic potential against AD through the attenuation of Aβ aggregation in a transgenic Caenorhabditis elegans model. Our results revealed that amongst the five H. scabra isolated compounds, 2-BTHF was shown to be the most effective in suppressing worm paralysis caused by Aβ toxicity and in expressing strong neuroprotection in CL4176 and CL2355 strains, respectively. An immunoblot analysis showed that CL4176 and CL2006 treated with 2-BTHF showed no effect on the level of Aβ monomers but significantly reduced the toxic oligomeric form and the amount of 1,4-bis(3-carboxy-hydroxy-phenylethenyl)-benzene (X-34)-positive fibril deposits. This concurrently occurred with a reduction of reactive oxygen species (ROS) in the treated CL4176 worms. Mechanistically, heat shock factor 1 (HSF-1) (at residues histidine 63 (HIS63) and glutamine 72 (GLN72)) was shown to be 2-BTHF's potential target that might contribute to an increased expression of autophagy-related genes required for the breakdown of the Aβ aggregate, thus attenuating its toxicity. In conclusion, 2-BTHF from H. scabra could protect C. elegans from Aβ toxicity by suppressing its aggregation via an HSF-1-regulated autophagic pathway and has been implicated as a potential drug for AD.
Figure 1. Chemical structure and HMBC and COSY correlations of Compound 1: 6-hydroxylabda-7(8),12(13)-dien-17-hydroxy-18-O-β-d-glucopyranosyl-pyran-15-one (Holothuria A) (A); Compound 2: 3-hydroxylabda-7(8),12(13)-dien-17-hydroxy-18-O-β-d-glucopyranosyl-pyran-15-one (Holothuria B) (B); Compound 3: palmitic acid (C); Compound 4: bis (2-ethylhexyl) phthalate (D); and Compound 5: 2-butoxytetrahydrofuran (2-BTHF) (E).
Figure 2. Effect of Holothuria scabra isolated compounds on amyloid-β (Aβ)-induced paralysis in Caenorhabditis elegans strain CL4176. (A) Diagram illustrating the paralysis assays showing the time at which the temperature was increased from 16 to 25 °C in CL4176 and its control stain CL802, as well as the feeding duration of worms with different treatment regiments. (B–D,H–J) Time course of paralysis progression caused by Aβ expression in worms treated with either 1% DMSO (Ctrl); different doses of H. scabra Compounds 1, 2, 3, 4, and 5 (1, 10, 25, and 50 µg/mL); or positive control frondoside A at an effective dose 1 µM throughout experimental time. The paralyzed worms were counted at 2 h intervals. Results are represented as percentages ± SD of unparalyzed worms from three independent experiments with at least 100 worms in each experiment. (E–G,K–M) The PT50 values were quantified as a mean of time at which 50% worms treated with or without compounds were paralyzed. Error bars indicate SD. * p < 0.05 and ** p < 0.01 vs. untreated control CL4176 worms.
Figure 3. Effect of the bioactive 2-BTHF (5) compound on Aβ species in transgenic C. elegans strains. (A,B) Representative Western blot of Aβ species in CL4176 and CL2006 worms treated with or without 2-BTHF (5) at 1 µg/mL and detected by anti-Aβ antibody (6E10) or anti-actin. The levels of the Aβ monomer band at around 4 kDa (C) and the Aβ oligomer band at 20 kDa (D) obtained from untreated and treated worm tissues were quantified by Image J. The arrows indicate actin (43 kDa) or counted Aβ species (4 and 20 kDa). Data are shown as mean ± SD of the indicated band density from three independent experiments (exp) with 1000 worms in each group. *** p < 0.001 vs. untreated control.
Figure 4. Effect of 2-BTHF (5) on Aβ-forming deposits in the CL2006 transgenic C. elegans strain. Representative images of C. elegans with 1,4-bis(3-carboxy-hydroxy-phenylethenyl)-benzene (X-34) staining in wild-type N2 (A) and transgenic strain CL2006 treated with either vehicle (B), 2-BTHF (5) at 1 µg/mL (C), or frondoside A at 1 µM (D). White arrows indicate X-34-positive spots of Aβ deposits in the worm’s head, which was separated from the body by a pharyngeal bulb region that is shown in a bright-field image. Scale bars indicate 20 µm. (E) Aβ deposits in each group were quantified and expressed as mean number of positive spots ± SEM of Aβ deposits/area in individual worm’s head. Data were obtained in triplicate for each experiment with 23 worms for each analysis (n = 69). *** p < 0.001 vs. untreated control CL2006.
Figure 5. Effects of 2-BTHF (5) on the expression levels of genes involved with autophagy, transcriptional activities in IIS pathway in C. elegans strains, and its potential target on heat shock factor 1 (HSF-1) molecule. mRNA levels of autophagy-related genes in CL4176 (A) or CL802 (B) treated with vehicle or 2-BTHF (5) at 1 µg/mL. mRNA levels of HSF-1 and dauer formation 16 (DAF-16) target genes in CL4176 (C) or CL802 (D) treated with or without the compound. All mRNA expression levels in worms were quantified by quantitative RT-PCR at 36 h after temperature increase and normalized with the internal control act-1. Data are expressed as mean ± SD from three independent experiments. * p < 0.05, ** p < 0.01, and *** p < 0.001 vs. untreated control CL4176 worms. (E) Molecular docking model of 2-BTHF (5) binding to HSF-1. (F) 2-BTHF (5) molecule is bound to the DNA-binding domain (DBD) of HSF-1 at residues HIS63 and GLN72, shown in a magnified docking image.
Figure 6. Effect of 2-BTHF (5) on reactive oxygen species (ROS) in C. elegans strains. The transgenic CL4176 and CL802 C. elegans strains were cultured with or without the compounds starting from eggs at 16 °C for 36 h, followed by 25 °C for another 36 h. At the end of experiment, untreated and treated worms were subjected to a 2′,7′-dichlorodihydrofluorescein diacetate (DCF) assay for ROS detection. The ROS levels were expressed as percentage of fluorescence (%DCF) relative to untreated CL4176 control (Ctrl), which was set as 100%. Data were obtained in triplicate for each experiment with 60 worms for each analysis (n = 180). Error bars indicate SEM. * p < 0.05 vs. untreated CL4176.
Figure 7. Effect of 2-BTHF (5) on chemotaxis behavior in neuronal Aβ-expressing C. elegans CL2355 strain. (A) Schematic diagram of chemotaxis assay. CL2355 and its control strain CL2122 fed with vehicle or 2-BTHF (5) were placed on the center of the assay plate. After incubation for 1 h, migrated worms in each quadrant (A and D with chemical attractant; B and C for control without attractant) were scored and calculated for chemotactic index (CI). (B) Representative data are shown as CI ± SD and obtained in triplicate for each experiment with 60 worms for each analysis (n = 180) (n.s. p > 0.05, * p < 0.05, and *** p < 0.001).
Agrawal,
12-Crown-4 Ether Disrupts the Patient Brain-Derived Amyloid-β-Fibril Trimer: Insight from All-Atom Molecular Dynamics Simulations.
2016, Pubmed
Agrawal,
12-Crown-4 Ether Disrupts the Patient Brain-Derived Amyloid-β-Fibril Trimer: Insight from All-Atom Molecular Dynamics Simulations.
2016,
Pubmed
Benilova,
The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes.
2012,
Pubmed
Brothers,
The Physiological Roles of Amyloid-β Peptide Hint at New Ways to Treat Alzheimer's Disease.
2018,
Pubmed
Butterfield,
beta-Amyloid-associated free radical oxidative stress and neurotoxicity: implications for Alzheimer's disease.
1997,
Pubmed
Chalorak,
Holothuria scabra extracts exhibit anti-Parkinson potential in C. elegans: A model for anti-Parkinson testing.
2018,
Pubmed
,
Echinobase
Cheignon,
Oxidative stress and the amyloid beta peptide in Alzheimer's disease.
2018,
Pubmed
Chen,
Approaches for Studying Autophagy in Caenorhabditis elegans.
2017,
Pubmed
Chokchaisiri,
Labdane diterpenes from the aerial parts of Curcuma comosa enhance fetal hemoglobin production in an erythroid cell line.
2010,
Pubmed
Cohen,
Opposing activities protect against age-onset proteotoxicity.
2006,
Pubmed
Cohen,
The insulin paradox: aging, proteotoxicity and neurodegeneration.
2008,
Pubmed
Diomede,
Tetracycline and its analogues protect Caenorhabditis elegans from β amyloid-induced toxicity by targeting oligomers.
2010,
Pubmed
Diomede,
Oleuropein aglycone protects transgenic C. elegans strains expressing Aβ42 by reducing plaque load and motor deficit.
2013,
Pubmed
Drake,
Oxidative stress precedes fibrillar deposition of Alzheimer's disease amyloid beta-peptide (1-42) in a transgenic Caenorhabditis elegans model.
2003,
Pubmed
GBD 2016 Neurology Collaborators,
Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
2019,
Pubmed
Garcia-Osta,
Amyloid beta mediates memory formation.
2009,
Pubmed
Haass,
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.
2007,
Pubmed
Hobert,
Behavioral plasticity in C. elegans: paradigms, circuits, genes.
2003,
Pubmed
Irwin,
Parkinson's disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies.
2013,
Pubmed
Jattujan,
Holothuria scabra extracts possess anti-oxidant activity and promote stress resistance and lifespan extension in Caenorhabditis elegans.
2018,
Pubmed
,
Echinobase
Joyner,
Bringing natural products into the fold - exploring the therapeutic lead potential of secondary metabolites for the treatment of protein-misfolding-related neurodegenerative diseases.
2011,
Pubmed
Karamanos,
Mechanisms of amyloid formation revealed by solution NMR.
2015,
Pubmed
Kayed,
Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.
2003,
Pubmed
Kienlen-Campard,
Intracellular amyloid-beta 1-42, but not extracellular soluble amyloid-beta peptides, induces neuronal apoptosis.
2002,
Pubmed
Kiew,
Jewel of the seabed: sea cucumbers as nutritional and drug candidates.
2012,
Pubmed
,
Echinobase
Kumsta,
Hormetic heat stress and HSF-1 induce autophagy to improve survival and proteostasis in C. elegans.
2017,
Pubmed
LaFerla,
Intracellular amyloid-beta in Alzheimer's disease.
2007,
Pubmed
Larson,
Soluble Aβ oligomer production and toxicity.
2012,
Pubmed
Li,
rBTI reduced β-amyloid-induced toxicity by promoting autophagy-lysosomal degradation via DAF-16 in Caenorhabditis elegans.
2017,
Pubmed
Link,
Gene expression analysis in a transgenic Caenorhabditis elegans Alzheimer's disease model.
2003,
Pubmed
Link,
Visualization of fibrillar amyloid deposits in living, transgenic Caenorhabditis elegans animals using the sensitive amyloid dye, X-34.
2001,
Pubmed
Lublin,
Alzheimer's disease drug discovery: in vivo screening using Caenorhabditis elegans as a model for β-amyloid peptide-induced toxicity.
2013,
Pubmed
Margie,
C. elegans chemotaxis assay.
2013,
Pubmed
McColl,
The Caenorhabditis elegans A beta 1-42 model of Alzheimer disease predominantly expresses A beta 3-42.
2009,
Pubmed
Milton,
Anandamide and noladin ether prevent neurotoxicity of the human amyloid-beta peptide.
2002,
Pubmed
Neudegger,
Structure of human heat-shock transcription factor 1 in complex with DNA.
2016,
Pubmed
Nimmrich,
Is Alzheimer's disease a result of presynaptic failure? Synaptic dysfunctions induced by oligomeric beta-amyloid.
2009,
Pubmed
O'Mathúna,
New labdane diterpene glycosides from Amphiachyris amoena.
1995,
Pubmed
Pangestuti,
Medicinal and health benefit effects of functional sea cucumbers.
2018,
Pubmed
,
Echinobase
Pryor,
Unraveling the early events of amyloid-β protein (Aβ) aggregation: techniques for the determination of Aβ aggregate size.
2012,
Pubmed
Puzzo,
Amyloid-β peptide: Dr. Jekyll or Mr. Hyde?
2013,
Pubmed
Regitz,
Amyloid-beta (Aβ₁₋₄₂)-induced paralysis in Caenorhabditis elegans is inhibited by the polyphenol quercetin through activation of protein degradation pathways.
2014,
Pubmed
Regitz,
Resveratrol reduces amyloid-beta (Aβ₁₋₄₂)-induced paralysis through targeting proteostasis in an Alzheimer model of Caenorhabditis elegans.
2016,
Pubmed
Rohn,
Treatment of Caenorhabditis elegans with Small Selenium Species Enhances Antioxidant Defense Systems.
2019,
Pubmed
Salminen,
Amyloid-beta oligomers set fire to inflammasomes and induce Alzheimer's pathology.
2008,
Pubmed
Sangha,
Liuwei Dihuang (LWDH), a traditional Chinese medicinal formula, protects against β-amyloid toxicity in transgenic Caenorhabditis elegans.
2012,
Pubmed
Smith,
Elevation of oxidative free radicals in Alzheimer's disease models can be attenuated by Ginkgo biloba extract EGb 761.
2003,
Pubmed
Sultana,
Oxidatively modified proteins in Alzheimer's disease (AD), mild cognitive impairment and animal models of AD: role of Abeta in pathogenesis.
2009,
Pubmed
Tangrodchanapong,
Frondoside A Attenuates Amyloid-β Proteotoxicity in Transgenic Caenorhabditis elegans by Suppressing Its Formation.
2020,
Pubmed
,
Echinobase
Tarasoff-Conway,
Clearance systems in the brain-implications for Alzheimer disease.
2015,
Pubmed
Taylor,
Development of a proteolytically stable retro-inverso peptide inhibitor of beta-amyloid oligomerization as a potential novel treatment for Alzheimer's disease.
2010,
Pubmed
Tian,
Crown ethers attenuate aggregation of amyloid beta of Alzheimer's disease.
2014,
Pubmed
Umeda,
Intracellular amyloid β oligomers impair organelle transport and induce dendritic spine loss in primary neurons.
2015,
Pubmed
Urbanc,
In silico study of amyloid beta-protein folding and oligomerization.
2004,
Pubmed
Wolff,
Aβ42 pentamers/hexamers are the smallest detectable oligomers in solution.
2017,
Pubmed
Wu,
Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans.
2006,
Pubmed
Wu,
Heat shock treatment reduces beta amyloid toxicity in vivo by diminishing oligomers.
2010,
Pubmed
Yen,
Gene-diet interactions and aging in C. elegans.
2016,
Pubmed
Yi,
Compounds from the fruits of mangrove Sonneratia apetala: Isolation, molecular docking and antiaging effects using a Caenorhabditis elegans model.
2020,
Pubmed
Zhang,
Scorpion Venom Heat-Resistant Peptide Protects Transgenic Caenorhabditis elegans from β-Amyloid Toxicity.
2016,
Pubmed
