Beneficial Effects of Cyclic Ether 2-Butoxytetrahydrofuran from Sea Cucumber Holothuria scabra against Aβ Aggregate Toxicity in Transgenic Caenorhabditis elegans and Potential Chemical Interaction

Abstract

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.

Holothuria scabra extracts confer neuroprotective effect in C. elegans model of Alzheimer's disease by attenuating amyloid-β aggregation and toxicity

“… 19 , 20 Additionally, recent study from our group has shown that 2-butoxytetrahydrofuran (2-BTHF), a cyclic ether isolated from H. scabra , can interact with heat shock factor-1 (HSF-1) transcription factor to upregulate the expression of autophagic genes which mediate the clearance of Aβ aggregates through autophagy-lysosomal pathway. 46 Moreover, in addition to 2-BTHF there may be other bioactive substances in the extracts that exert this activity; for instance, diterpene glycosides or holothurins from H. scabra ethyl acetate extracts has been shown to reduce α-synuclein aggregation by activating the degradation process of autophagy-lysosomal pathway. 47 Therefore, it is likely that the bioactive substances included in the H. scabra extracts may exercise synergistic effects in either directly eliminating Aβ aggregates or indirectly reducing Aβ toxicity as demonstrated in other studies.…”

Tolcapone Derivative (Tol-D) Inhibits Aβ42 Fibrillogenesis and Ameliorates Aβ42-Induced Cytotoxicity and Cognitive Impairment

“…Transgenic C. elegans CL4176 expressed Aβ42 in muscle cells is often used in studies of AD as an in vivo model. − Therefore, in vivo experiments were performed with CL4176 to evaluate the feasibility of Tol-D inhibiting Aβ deposition in nematodes and the effect of Tol-D on the lifespan of nematodes.…”

Application of Caenorhabditis elegans in the evaluation of food nutrition: A review

“…The vicious changes of these signaling pathways and related signaling factors triggered neuroinflammatory reaction, Tau protein phosphorylation β‐ increased secretion of amyloid precursor, which led to the onset of AD (Figure 2). In general, the paralysis test, the fluorescent staining test of Aβ deposition, the ROS test and the chemotaxis test were used to study the AD resistance of the active substances from natural products in C. elegans (Tangrodchanapong et al, 2021). The cyclic ether 2‐butoxytetrahydrofuran extracted and purified from sea cucumbers could delay the paralysis progression in C. elegans and reduce the amount of Aβ‐forming precipitation, which meant that the cyclic ether 2‐butoxytetrahydrofuran had a great effect to resist AD (Tangrodchanapong et al, 2021).…”

“…In general, the paralysis test, the fluorescent staining test of Aβ deposition, the ROS test and the chemotaxis test were used to study the AD resistance of the active substances from natural products in C. elegans (Tangrodchanapong et al, 2021). The cyclic ether 2‐butoxytetrahydrofuran extracted and purified from sea cucumbers could delay the paralysis progression in C. elegans and reduce the amount of Aβ‐forming precipitation, which meant that the cyclic ether 2‐butoxytetrahydrofuran had a great effect to resist AD (Tangrodchanapong et al, 2021). Disulfide‐rich cyclic peptides from Clitoria ternatea could regulate AD through decreasing the neurotoxic aggregation of β‐amyloid peptides and the level of ROS in C. elegans (Kalmankar et al, 2021).…”

“…precipitation, which meant that the cyclic ether 2butoxytetrahydrofuran had a great effect to resist AD (Tangrodchanapong et al, 2021). Disulfide-rich cyclic peptides from Clitoria ternatea could regulate AD through decreasing the neurotoxic aggregation of βamyloid peptides and the level of ROS in C. elegans (Kalmankar et al, 2021).…”